Med/Psych Update

At approximately 3 to 4 million patients, hepatitis C virus (HCV) is the most common viral hepatitis in the United States. Patients with mental illness are disproportionately affected by HCV and the management of their disease poses particular challenges.

HCV is commonly transmitted via IV drug use and blood transfusions; transmission through sexual contact is rare. Most patients with HCV are asymptomatic, although some do develop symptoms of acute hepatitis. Most HCV infections become chronic, with a high incidence of liver failure requiring liver transplantation.

Hepatitis refers to inflammation of the liver, which could have various etiologies, including viral infections, alcohol abuse, or autoimmune disease. Viral hepatitis refers to infection from 5 distinct groups of virus, coined A through E.¹ This article will focus on chronic HCV (Table 1).

CASE Bipolar disorder, stress, history of IV drug use

Ms. S, age 48, has bipolar I disorder and has been hospitalized 4 times in the past, including once for a suicide attempt. She has 3 children and works as a cashier. Her psychiatric symptoms have been stable on lurasidone, 80 mg/d, and escitalopram, 10 mg/d. Recently, Ms. S has been under more stress at her job. Sometimes she misses doses of her medication, and then becomes more irritable and impulsive. Her husband, noting that she has used IV heroin in the past, comes with her today and is concerned that she is “not acting right.” What is Ms. S’s risk for HCV?

HCV in mental illness

Compared with the general population, HCV is more prevalent among chronically mentally ill persons. In one study, HCV occurred twice as often in men vs women with chronic mental illness.² Up to 50% of patients with HCV have a history of mental illness and nearly 90% have a history of substance use disorders.³ Among 668 chronically mentally ill patients at 4 public sector clinics, risk factors for HCV were common and included use of injection drugs (>20%), sharing needles (14%), and crack cocaine use (>20%).⁴ Higher rates of HCV were reported in hospitalized patients with schizophrenia and comorbid psychoactive substance abuse in Japan.⁵ Because of the high prevalence in this population, it is essential to assess for substance use disorders. Employing a non-judgmental approach with motivational interviewing techniques can be effective.⁶

Individuals with mental illness should be screened for HCV risk factors, such as unprotected intercourse with high-risk partners and sharing needles used for illicit drug use. Patients frequently underreport these activities. At-risk individuals should undergo laboratory testing for the HIV-1 antibody, hepatitis C antibodies, and hepatitis B antibodies. Mental health providers should counsel patients about risk reduction (eg, avoiding unprotected sexual intercourse and sharing of drug paraphernalia). Educating patients about complications of viral hepatitis, such as liver failure, could be motivation to change risky behaviors.

CASE continued

During your interview with Ms. S, she becomes irritable and tells you that you are asking too many questions. It is clear that she is not taking her medications consistently, but she agrees to do so because she does not want to lose custody of her children. She denies current use of heroin but her husband says, “I don’t know what she is doing.” In addition to advising her on reducing risk factors, you order appropriate screening tests, including hepatitis and HIV antibody tests.

Screening guidelines

The U.S. Preventive Services Task Force and the CDC both recommend a 1-time screening for HCV in asymptomatic or low-risk patients born between 1945 and 1965.^1,7 Furthermore, both organizations recommend screening for HCV in persons at high risk, including:

• those with a history of injection drug use
• persons with recognizable exposure, such as needlesticks
• persons who received blood transfusions before 1992
• medical conditions, such as long-term dialysis.

There is no vaccine for HCV; however, patients with HCV should receive vaccination against hepatitis B.

Diagnosis

Acute symptoms include fever, fatigue, headache, cough, nausea, and vomiting. Jaundice could develop, often accompanied by pain in the right upper quadrant. If there is suspicion of viral hepatitis, psychiatrists can initiate the laboratory evaluation. Chronic hepatitis, on the other hand, often is asymptomatic, although stigmata of chronic liver disease (eg, jaundice, ascites, peripheral edema) might be detected on physical exam.⁸ Elevated serum transaminases are seen with acute viral hepatitis, although levels could vary in chronic cases. Serologic detection of anti-HCV antibodies establishes a HCV diagnosis.

Treatment recommendations

All patients who test positive for HCV should be evaluated and treated by a hepatologist. Goals of therapy are to reduce complications from chronic viral hepatitis, including cirrhosis and hepatic failure. Duration and optimal regimen depends on the HCV genotype.⁸ Treatment outcomes are measured by virological parameters, including serum aminotransferases, HCV RNA levels, and histology. The most important parameter in treating chronic HCV is the sustained virological response (SVR), which is the absence of HCV RNA 12 weeks after completing therapy.⁹

Treatment is recommended for all persons with chronic HCV infection, according to current treatment guidelines, which are updated regularly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.¹⁰ Until recently, treatment consisted of IV pegylated interferon (PEG-IFN) in combination with oral ribavirin. Success rates with this regimen are approximately 40% to 50%. The advent of direct-acting antivirals (DAAs) has revolutionized treatment of chronic HCV. These agents include simeprevir, sofosbuvir, ledipasvir, and the combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (brand name, Viekira Pak). Advantages of these agents are oral administration, high treatment success rates (>90%), shorter treatment duration (12 weeks vs up to 48 weeks with older regimens), and few serious adverse effects^9-11; drawbacks include the pricing of these regimens, which could cost upward of ≥$100,000 for a 12-week course, and a lack of coverage under some health insurance plans.¹² The manufacturers of 2 agents, telaprevir and boceprevir, removed them from the market because of decreased demand related to their unfavorable side-effect profile and the availability of better tolerated agents.

Treatment considerations for interferon in psychiatric patients

Various neuropsychiatric symptoms have been reported with the use of PEG-IFN. The range of reported symptoms include:

• depressed mood
• anxiety
• hostility
• slowness
• fatigue
• sleep disturbance
• lethargy
• irritability
• emotional lability
• social withdrawal
• poor concentration.^13,14

Depressive symptoms can present as early as 1 month after starting treatment, but typically occur at 8 to 12 weeks. A systematic review and meta-analysis of 26 observational studies found a cumulative 25% risk of interferon (IFN)-induced depression in the general HCV population.¹⁵ Risk factors for IFN-induced depression include:

• female sex
• history of major depression or other psychiatric disorder
• low educational level
• the presence of baseline subthreshold depressive symptoms.

Because of the risk of inducing depression, there was initial hesitation with providing IFN treatment to patients with psychiatric disorders. However, there is evidence that individuals with chronic psychiatric illness can be treated safely with IFN-based regimens and achieve results similar to non-psychiatric populations.^16,17 For example, patients with schizophrenia in a small Veterans Affairs database who received IFN for HCV did not experience higher rates of symptoms of schizophrenia, depression, or mania over 8 years of follow-up.¹⁸ Furthermore, those with schizophrenia were just as likely to reach SVR as patients without psychiatric illness.¹⁹ Other encouraging results have been reported in depressed patients. One study found similar rates of treatment completion and SVR in patients with a history of major depressive disorder compared with those without depression.²⁰ No difference in frequency of neuropsychiatric side effects was found between the groups.

Presence of a psychiatric disorder is no longer an absolute contraindication to IFN treatment for HCV. Optimal control of psychiatric symptoms should be attained in all patients before starting HCV treatment, and close clinical monitoring is warranted. A review of 9 studies showed benefit of antidepressants for HCV patients with elevated baseline depression or a history of IFN-induced depression.²¹ The largest body of evidence supports the safety and efficacy of selective serotonin reuptake inhibitors for treating IFN-induced depression. Although no antidepressants are FDA-approved for this indication, the best-studied agents include citalopram, escitalopram, sertraline, and paroxetine.

A review of 6 studies on using antidepressants to prevent IFN-induced depression concluded there was inadequate evidence to support this approach in all patients.²² Pretreatment primarily is indicated for those with elevated depressive symptoms at baseline or those with a history of IFN-induced depression. The prevailing approach to IFN-induced depression assessment, prevention, and treatment is summarized in Table 2.

CASE continued

Ms. S tests positive for the HCV antibody but negative for HIV and hepatitis B. She immediately receives the hepatitis B vaccine series. Her sister discourages her from receiving treatment for HCV, warning her, “it will make you crazy depressed.” As a result, Ms. S avoids following up with the hepatologist. Her psychiatrist, aware that she now was taking her psychotropic medication and seeing that her mood is stable, educates her about new treatment options for HCV that do not cause depression. Ms. S finally agrees to see a hepatologist to discuss her treatment options.

IFN-free regimens

With the arrival of the DAAs, the potential now exists to use IFN-free treatment regimens,¹⁰ which could eliminate concerns about IFN-induced depression.

Clinical trials of the DAAs and real-world use so far do not indicate an elevated risk for neuropsychiatric symptoms, including depression.¹¹ As a result, more patients with severe psychiatric illness likely will be eligible to receive treatment for HCV. However, as clinical experience builds with these new agents, it is important to monitor the experience of patients with psychiatric comorbidity. Current treatment guidelines for HCV genotype 1, which is most common in the United States, do not include IFN-based regimens.¹⁰ Treatment of genotype 3, which affects 6% of the U.S. population, still includes IFN. Therefore, the risk of IFN-induced depression still exists for some patients with HCV. Table 3¹⁰ describes current treatment regimens in use for HCV without cirrhosis (see Related Resources for treating HCV with cirrhosis).

Evolving role of the psychiatrist

The availability of shorter, better-tolerated regimens means that the psychiatric contraindications to HCV treatment will be eased. With the emergence of non-IFN treatment regimens, the role of mental health providers could shift toward assisting with treatment adherence, monitoring drug–drug interactions, and managing comorbid substance use disorders.¹⁰

The psychiatrist’s role might shift away from the psychosocial assessment of factors affecting treatment eligibility, such as IFN-associated depressive symptoms. Clinical focus will likely shift to supporting adherence to HCV treatment regimens.²³ Because depression and substance use disorders are risk factors for non-adherence, mental health providers may be called upon to optimize treatment of these conditions before beginning DAA regimens. A multi-dose regimen might be complicated for those with severe mental illness, and increased psychiatric and community support could be needed in these patients.²³ Furthermore, models of care that integrate an HCV specialist with psychiatric care have demonstrated benefits.^6,23 Long-term follow-up with a mental health provider will be key to provide ongoing psychiatric support, especially for those who do not achieve SVR.

Psychotropic drug–drug interactions with DAAs

Both sofosbuvir and ledipasvir are substrates of P-glycoprotein and not metabolized by cytochrome P450 (CYP) enzymes.²⁴ Therefore, there are no known contraindications with psychotropic medications. However, co-administration of P-glycoprotein inducers, such as St. John’s wort, could reduce sofosbuvir and ledipasvir levels leading to reduced therapeutic efficacy.

Because it has been used for many years as an HIV treatment, drug interactions with ritonavir have been well-described. This agent is a “pan-inhibitor” and inhibits the CYP3A4, 2D6, 2C9, and 2C19 enzymes and could increase levels of any psychotropic metabolized by these enzymes.²⁵ After several weeks of treatment, it also could induce CYP3A4, which could lead to reduced efficacy of oral contraceptives because ethinylestradiol is metabolized by CYP3A4. Ritonavir is primarily metabolized by CYP3A4 (and CYP2D6 to a smaller degree). Carbamazepine induces CYP3A4, which may lead to decreased levels of ritonavir.²³ This, in turn, could reduce the likelihood of attaining SVR and successful treatment of HCV.

Boceprevir, telaprevir, and simeprevir inhibit CYP3A4 to varying degrees and therefore could affect psychotropic medications metabolized by this enzyme.^23,26,27 These DAAs are metabolized by CYP3A4; therefore CYP3A4 inducers, such as carbamazepine, could lower DAA blood levels, increasing risk of HCV treatment failure and viral resistance.

Daclatasvir is a substrate of CYP3A4 and an inhibitor of P-glycoprotein.²⁸ Concomitant buprenorphine or buprenorphine/naloxone levels may be increased, although the manufacturer does not recommend dosage adjustment. Elbasvir and grazoprevir are metabolized by CYP3A4.²⁹ Drug–drug interactions therefore may result when administered with either CYP3A4 inducers or inhibitors.

CASE Conclusion

Ms. S sees her new hepatologist, Dr. Smith. She decides to try a 12-week course of ledipasvir/sofosbuvir. Dr. Smith collaborates frequently with Ms. S’s psychiatrist to discuss her case and to help monitor her psychiatric symptoms. She follows up closely with her psychiatrist for symptom monitoring and to help ensure treatment compliance. Ms. S does well with the IFN-free treatment regimen and experiences no worsening of her psychiatric symptoms during treatment.

At approximately 3 to 4 million patients, hepatitis C virus (HCV) is the most common viral hepatitis in the United States. Patients with mental illness are disproportionately affected by HCV and the management of their disease poses particular challenges.

HCV is commonly transmitted via IV drug use and blood transfusions; transmission through sexual contact is rare. Most patients with HCV are asymptomatic, although some do develop symptoms of acute hepatitis. Most HCV infections become chronic, with a high incidence of liver failure requiring liver transplantation.

Hepatitis refers to inflammation of the liver, which could have various etiologies, including viral infections, alcohol abuse, or autoimmune disease. Viral hepatitis refers to infection from 5 distinct groups of virus, coined A through E.¹ This article will focus on chronic HCV (Table 1).

CASE Bipolar disorder, stress, history of IV drug use

Ms. S, age 48, has bipolar I disorder and has been hospitalized 4 times in the past, including once for a suicide attempt. She has 3 children and works as a cashier. Her psychiatric symptoms have been stable on lurasidone, 80 mg/d, and escitalopram, 10 mg/d. Recently, Ms. S has been under more stress at her job. Sometimes she misses doses of her medication, and then becomes more irritable and impulsive. Her husband, noting that she has used IV heroin in the past, comes with her today and is concerned that she is “not acting right.” What is Ms. S’s risk for HCV?

HCV in mental illness

Compared with the general population, HCV is more prevalent among chronically mentally ill persons. In one study, HCV occurred twice as often in men vs women with chronic mental illness.² Up to 50% of patients with HCV have a history of mental illness and nearly 90% have a history of substance use disorders.³ Among 668 chronically mentally ill patients at 4 public sector clinics, risk factors for HCV were common and included use of injection drugs (>20%), sharing needles (14%), and crack cocaine use (>20%).⁴ Higher rates of HCV were reported in hospitalized patients with schizophrenia and comorbid psychoactive substance abuse in Japan.⁵ Because of the high prevalence in this population, it is essential to assess for substance use disorders. Employing a non-judgmental approach with motivational interviewing techniques can be effective.⁶

Individuals with mental illness should be screened for HCV risk factors, such as unprotected intercourse with high-risk partners and sharing needles used for illicit drug use. Patients frequently underreport these activities. At-risk individuals should undergo laboratory testing for the HIV-1 antibody, hepatitis C antibodies, and hepatitis B antibodies. Mental health providers should counsel patients about risk reduction (eg, avoiding unprotected sexual intercourse and sharing of drug paraphernalia). Educating patients about complications of viral hepatitis, such as liver failure, could be motivation to change risky behaviors.

CASE continued

During your interview with Ms. S, she becomes irritable and tells you that you are asking too many questions. It is clear that she is not taking her medications consistently, but she agrees to do so because she does not want to lose custody of her children. She denies current use of heroin but her husband says, “I don’t know what she is doing.” In addition to advising her on reducing risk factors, you order appropriate screening tests, including hepatitis and HIV antibody tests.

Screening guidelines

The U.S. Preventive Services Task Force and the CDC both recommend a 1-time screening for HCV in asymptomatic or low-risk patients born between 1945 and 1965.^1,7 Furthermore, both organizations recommend screening for HCV in persons at high risk, including:

• those with a history of injection drug use
• persons with recognizable exposure, such as needlesticks
• persons who received blood transfusions before 1992
• medical conditions, such as long-term dialysis.

There is no vaccine for HCV; however, patients with HCV should receive vaccination against hepatitis B.

Diagnosis

Acute symptoms include fever, fatigue, headache, cough, nausea, and vomiting. Jaundice could develop, often accompanied by pain in the right upper quadrant. If there is suspicion of viral hepatitis, psychiatrists can initiate the laboratory evaluation. Chronic hepatitis, on the other hand, often is asymptomatic, although stigmata of chronic liver disease (eg, jaundice, ascites, peripheral edema) might be detected on physical exam.⁸ Elevated serum transaminases are seen with acute viral hepatitis, although levels could vary in chronic cases. Serologic detection of anti-HCV antibodies establishes a HCV diagnosis.

Treatment recommendations

All patients who test positive for HCV should be evaluated and treated by a hepatologist. Goals of therapy are to reduce complications from chronic viral hepatitis, including cirrhosis and hepatic failure. Duration and optimal regimen depends on the HCV genotype.⁸ Treatment outcomes are measured by virological parameters, including serum aminotransferases, HCV RNA levels, and histology. The most important parameter in treating chronic HCV is the sustained virological response (SVR), which is the absence of HCV RNA 12 weeks after completing therapy.⁹

Treatment is recommended for all persons with chronic HCV infection, according to current treatment guidelines, which are updated regularly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.¹⁰ Until recently, treatment consisted of IV pegylated interferon (PEG-IFN) in combination with oral ribavirin. Success rates with this regimen are approximately 40% to 50%. The advent of direct-acting antivirals (DAAs) has revolutionized treatment of chronic HCV. These agents include simeprevir, sofosbuvir, ledipasvir, and the combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (brand name, Viekira Pak). Advantages of these agents are oral administration, high treatment success rates (>90%), shorter treatment duration (12 weeks vs up to 48 weeks with older regimens), and few serious adverse effects^9-11; drawbacks include the pricing of these regimens, which could cost upward of ≥$100,000 for a 12-week course, and a lack of coverage under some health insurance plans.¹² The manufacturers of 2 agents, telaprevir and boceprevir, removed them from the market because of decreased demand related to their unfavorable side-effect profile and the availability of better tolerated agents.

Treatment considerations for interferon in psychiatric patients

Various neuropsychiatric symptoms have been reported with the use of PEG-IFN. The range of reported symptoms include:

• depressed mood
• anxiety
• hostility
• slowness
• fatigue
• sleep disturbance
• lethargy
• irritability
• emotional lability
• social withdrawal
• poor concentration.^13,14

Depressive symptoms can present as early as 1 month after starting treatment, but typically occur at 8 to 12 weeks. A systematic review and meta-analysis of 26 observational studies found a cumulative 25% risk of interferon (IFN)-induced depression in the general HCV population.¹⁵ Risk factors for IFN-induced depression include:

• female sex
• history of major depression or other psychiatric disorder
• low educational level
• the presence of baseline subthreshold depressive symptoms.

Because of the risk of inducing depression, there was initial hesitation with providing IFN treatment to patients with psychiatric disorders. However, there is evidence that individuals with chronic psychiatric illness can be treated safely with IFN-based regimens and achieve results similar to non-psychiatric populations.^16,17 For example, patients with schizophrenia in a small Veterans Affairs database who received IFN for HCV did not experience higher rates of symptoms of schizophrenia, depression, or mania over 8 years of follow-up.¹⁸ Furthermore, those with schizophrenia were just as likely to reach SVR as patients without psychiatric illness.¹⁹ Other encouraging results have been reported in depressed patients. One study found similar rates of treatment completion and SVR in patients with a history of major depressive disorder compared with those without depression.²⁰ No difference in frequency of neuropsychiatric side effects was found between the groups.

Presence of a psychiatric disorder is no longer an absolute contraindication to IFN treatment for HCV. Optimal control of psychiatric symptoms should be attained in all patients before starting HCV treatment, and close clinical monitoring is warranted. A review of 9 studies showed benefit of antidepressants for HCV patients with elevated baseline depression or a history of IFN-induced depression.²¹ The largest body of evidence supports the safety and efficacy of selective serotonin reuptake inhibitors for treating IFN-induced depression. Although no antidepressants are FDA-approved for this indication, the best-studied agents include citalopram, escitalopram, sertraline, and paroxetine.

A review of 6 studies on using antidepressants to prevent IFN-induced depression concluded there was inadequate evidence to support this approach in all patients.²² Pretreatment primarily is indicated for those with elevated depressive symptoms at baseline or those with a history of IFN-induced depression. The prevailing approach to IFN-induced depression assessment, prevention, and treatment is summarized in Table 2.

CASE continued

Ms. S tests positive for the HCV antibody but negative for HIV and hepatitis B. She immediately receives the hepatitis B vaccine series. Her sister discourages her from receiving treatment for HCV, warning her, “it will make you crazy depressed.” As a result, Ms. S avoids following up with the hepatologist. Her psychiatrist, aware that she now was taking her psychotropic medication and seeing that her mood is stable, educates her about new treatment options for HCV that do not cause depression. Ms. S finally agrees to see a hepatologist to discuss her treatment options.

IFN-free regimens

With the arrival of the DAAs, the potential now exists to use IFN-free treatment regimens,¹⁰ which could eliminate concerns about IFN-induced depression.

Clinical trials of the DAAs and real-world use so far do not indicate an elevated risk for neuropsychiatric symptoms, including depression.¹¹ As a result, more patients with severe psychiatric illness likely will be eligible to receive treatment for HCV. However, as clinical experience builds with these new agents, it is important to monitor the experience of patients with psychiatric comorbidity. Current treatment guidelines for HCV genotype 1, which is most common in the United States, do not include IFN-based regimens.¹⁰ Treatment of genotype 3, which affects 6% of the U.S. population, still includes IFN. Therefore, the risk of IFN-induced depression still exists for some patients with HCV. Table 3¹⁰ describes current treatment regimens in use for HCV without cirrhosis (see Related Resources for treating HCV with cirrhosis).

Evolving role of the psychiatrist

The availability of shorter, better-tolerated regimens means that the psychiatric contraindications to HCV treatment will be eased. With the emergence of non-IFN treatment regimens, the role of mental health providers could shift toward assisting with treatment adherence, monitoring drug–drug interactions, and managing comorbid substance use disorders.¹⁰

The psychiatrist’s role might shift away from the psychosocial assessment of factors affecting treatment eligibility, such as IFN-associated depressive symptoms. Clinical focus will likely shift to supporting adherence to HCV treatment regimens.²³ Because depression and substance use disorders are risk factors for non-adherence, mental health providers may be called upon to optimize treatment of these conditions before beginning DAA regimens. A multi-dose regimen might be complicated for those with severe mental illness, and increased psychiatric and community support could be needed in these patients.²³ Furthermore, models of care that integrate an HCV specialist with psychiatric care have demonstrated benefits.^6,23 Long-term follow-up with a mental health provider will be key to provide ongoing psychiatric support, especially for those who do not achieve SVR.

Psychotropic drug–drug interactions with DAAs

Both sofosbuvir and ledipasvir are substrates of P-glycoprotein and not metabolized by cytochrome P450 (CYP) enzymes.²⁴ Therefore, there are no known contraindications with psychotropic medications. However, co-administration of P-glycoprotein inducers, such as St. John’s wort, could reduce sofosbuvir and ledipasvir levels leading to reduced therapeutic efficacy.

Because it has been used for many years as an HIV treatment, drug interactions with ritonavir have been well-described. This agent is a “pan-inhibitor” and inhibits the CYP3A4, 2D6, 2C9, and 2C19 enzymes and could increase levels of any psychotropic metabolized by these enzymes.²⁵ After several weeks of treatment, it also could induce CYP3A4, which could lead to reduced efficacy of oral contraceptives because ethinylestradiol is metabolized by CYP3A4. Ritonavir is primarily metabolized by CYP3A4 (and CYP2D6 to a smaller degree). Carbamazepine induces CYP3A4, which may lead to decreased levels of ritonavir.²³ This, in turn, could reduce the likelihood of attaining SVR and successful treatment of HCV.

Boceprevir, telaprevir, and simeprevir inhibit CYP3A4 to varying degrees and therefore could affect psychotropic medications metabolized by this enzyme.^23,26,27 These DAAs are metabolized by CYP3A4; therefore CYP3A4 inducers, such as carbamazepine, could lower DAA blood levels, increasing risk of HCV treatment failure and viral resistance.

Daclatasvir is a substrate of CYP3A4 and an inhibitor of P-glycoprotein.²⁸ Concomitant buprenorphine or buprenorphine/naloxone levels may be increased, although the manufacturer does not recommend dosage adjustment. Elbasvir and grazoprevir are metabolized by CYP3A4.²⁹ Drug–drug interactions therefore may result when administered with either CYP3A4 inducers or inhibitors.

CASE Conclusion

Ms. S sees her new hepatologist, Dr. Smith. She decides to try a 12-week course of ledipasvir/sofosbuvir. Dr. Smith collaborates frequently with Ms. S’s psychiatrist to discuss her case and to help monitor her psychiatric symptoms. She follows up closely with her psychiatrist for symptom monitoring and to help ensure treatment compliance. Ms. S does well with the IFN-free treatment regimen and experiences no worsening of her psychiatric symptoms during treatment.

At approximately 3 to 4 million patients, hepatitis C virus (HCV) is the most common viral hepatitis in the United States. Patients with mental illness are disproportionately affected by HCV and the management of their disease poses particular challenges.

HCV is commonly transmitted via IV drug use and blood transfusions; transmission through sexual contact is rare. Most patients with HCV are asymptomatic, although some do develop symptoms of acute hepatitis. Most HCV infections become chronic, with a high incidence of liver failure requiring liver transplantation.

Hepatitis refers to inflammation of the liver, which could have various etiologies, including viral infections, alcohol abuse, or autoimmune disease. Viral hepatitis refers to infection from 5 distinct groups of virus, coined A through E.¹ This article will focus on chronic HCV (Table 1).

CASE Bipolar disorder, stress, history of IV drug use

Ms. S, age 48, has bipolar I disorder and has been hospitalized 4 times in the past, including once for a suicide attempt. She has 3 children and works as a cashier. Her psychiatric symptoms have been stable on lurasidone, 80 mg/d, and escitalopram, 10 mg/d. Recently, Ms. S has been under more stress at her job. Sometimes she misses doses of her medication, and then becomes more irritable and impulsive. Her husband, noting that she has used IV heroin in the past, comes with her today and is concerned that she is “not acting right.” What is Ms. S’s risk for HCV?

HCV in mental illness

Compared with the general population, HCV is more prevalent among chronically mentally ill persons. In one study, HCV occurred twice as often in men vs women with chronic mental illness.² Up to 50% of patients with HCV have a history of mental illness and nearly 90% have a history of substance use disorders.³ Among 668 chronically mentally ill patients at 4 public sector clinics, risk factors for HCV were common and included use of injection drugs (>20%), sharing needles (14%), and crack cocaine use (>20%).⁴ Higher rates of HCV were reported in hospitalized patients with schizophrenia and comorbid psychoactive substance abuse in Japan.⁵ Because of the high prevalence in this population, it is essential to assess for substance use disorders. Employing a non-judgmental approach with motivational interviewing techniques can be effective.⁶

Individuals with mental illness should be screened for HCV risk factors, such as unprotected intercourse with high-risk partners and sharing needles used for illicit drug use. Patients frequently underreport these activities. At-risk individuals should undergo laboratory testing for the HIV-1 antibody, hepatitis C antibodies, and hepatitis B antibodies. Mental health providers should counsel patients about risk reduction (eg, avoiding unprotected sexual intercourse and sharing of drug paraphernalia). Educating patients about complications of viral hepatitis, such as liver failure, could be motivation to change risky behaviors.

CASE continued

During your interview with Ms. S, she becomes irritable and tells you that you are asking too many questions. It is clear that she is not taking her medications consistently, but she agrees to do so because she does not want to lose custody of her children. She denies current use of heroin but her husband says, “I don’t know what she is doing.” In addition to advising her on reducing risk factors, you order appropriate screening tests, including hepatitis and HIV antibody tests.

Screening guidelines

The U.S. Preventive Services Task Force and the CDC both recommend a 1-time screening for HCV in asymptomatic or low-risk patients born between 1945 and 1965.^1,7 Furthermore, both organizations recommend screening for HCV in persons at high risk, including:

• those with a history of injection drug use
• persons with recognizable exposure, such as needlesticks
• persons who received blood transfusions before 1992
• medical conditions, such as long-term dialysis.

There is no vaccine for HCV; however, patients with HCV should receive vaccination against hepatitis B.

Diagnosis

Acute symptoms include fever, fatigue, headache, cough, nausea, and vomiting. Jaundice could develop, often accompanied by pain in the right upper quadrant. If there is suspicion of viral hepatitis, psychiatrists can initiate the laboratory evaluation. Chronic hepatitis, on the other hand, often is asymptomatic, although stigmata of chronic liver disease (eg, jaundice, ascites, peripheral edema) might be detected on physical exam.⁸ Elevated serum transaminases are seen with acute viral hepatitis, although levels could vary in chronic cases. Serologic detection of anti-HCV antibodies establishes a HCV diagnosis.

Treatment recommendations

All patients who test positive for HCV should be evaluated and treated by a hepatologist. Goals of therapy are to reduce complications from chronic viral hepatitis, including cirrhosis and hepatic failure. Duration and optimal regimen depends on the HCV genotype.⁸ Treatment outcomes are measured by virological parameters, including serum aminotransferases, HCV RNA levels, and histology. The most important parameter in treating chronic HCV is the sustained virological response (SVR), which is the absence of HCV RNA 12 weeks after completing therapy.⁹

Treatment is recommended for all persons with chronic HCV infection, according to current treatment guidelines, which are updated regularly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.¹⁰ Until recently, treatment consisted of IV pegylated interferon (PEG-IFN) in combination with oral ribavirin. Success rates with this regimen are approximately 40% to 50%. The advent of direct-acting antivirals (DAAs) has revolutionized treatment of chronic HCV. These agents include simeprevir, sofosbuvir, ledipasvir, and the combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (brand name, Viekira Pak). Advantages of these agents are oral administration, high treatment success rates (>90%), shorter treatment duration (12 weeks vs up to 48 weeks with older regimens), and few serious adverse effects^9-11; drawbacks include the pricing of these regimens, which could cost upward of ≥$100,000 for a 12-week course, and a lack of coverage under some health insurance plans.¹² The manufacturers of 2 agents, telaprevir and boceprevir, removed them from the market because of decreased demand related to their unfavorable side-effect profile and the availability of better tolerated agents.

Treatment considerations for interferon in psychiatric patients

Various neuropsychiatric symptoms have been reported with the use of PEG-IFN. The range of reported symptoms include:

• depressed mood
• anxiety
• hostility
• slowness
• fatigue
• sleep disturbance
• lethargy
• irritability
• emotional lability
• social withdrawal
• poor concentration.^13,14

Depressive symptoms can present as early as 1 month after starting treatment, but typically occur at 8 to 12 weeks. A systematic review and meta-analysis of 26 observational studies found a cumulative 25% risk of interferon (IFN)-induced depression in the general HCV population.¹⁵ Risk factors for IFN-induced depression include:

• female sex
• history of major depression or other psychiatric disorder
• low educational level
• the presence of baseline subthreshold depressive symptoms.

Because of the risk of inducing depression, there was initial hesitation with providing IFN treatment to patients with psychiatric disorders. However, there is evidence that individuals with chronic psychiatric illness can be treated safely with IFN-based regimens and achieve results similar to non-psychiatric populations.^16,17 For example, patients with schizophrenia in a small Veterans Affairs database who received IFN for HCV did not experience higher rates of symptoms of schizophrenia, depression, or mania over 8 years of follow-up.¹⁸ Furthermore, those with schizophrenia were just as likely to reach SVR as patients without psychiatric illness.¹⁹ Other encouraging results have been reported in depressed patients. One study found similar rates of treatment completion and SVR in patients with a history of major depressive disorder compared with those without depression.²⁰ No difference in frequency of neuropsychiatric side effects was found between the groups.

Presence of a psychiatric disorder is no longer an absolute contraindication to IFN treatment for HCV. Optimal control of psychiatric symptoms should be attained in all patients before starting HCV treatment, and close clinical monitoring is warranted. A review of 9 studies showed benefit of antidepressants for HCV patients with elevated baseline depression or a history of IFN-induced depression.²¹ The largest body of evidence supports the safety and efficacy of selective serotonin reuptake inhibitors for treating IFN-induced depression. Although no antidepressants are FDA-approved for this indication, the best-studied agents include citalopram, escitalopram, sertraline, and paroxetine.

A review of 6 studies on using antidepressants to prevent IFN-induced depression concluded there was inadequate evidence to support this approach in all patients.²² Pretreatment primarily is indicated for those with elevated depressive symptoms at baseline or those with a history of IFN-induced depression. The prevailing approach to IFN-induced depression assessment, prevention, and treatment is summarized in Table 2.

CASE continued

Ms. S tests positive for the HCV antibody but negative for HIV and hepatitis B. She immediately receives the hepatitis B vaccine series. Her sister discourages her from receiving treatment for HCV, warning her, “it will make you crazy depressed.” As a result, Ms. S avoids following up with the hepatologist. Her psychiatrist, aware that she now was taking her psychotropic medication and seeing that her mood is stable, educates her about new treatment options for HCV that do not cause depression. Ms. S finally agrees to see a hepatologist to discuss her treatment options.

IFN-free regimens

With the arrival of the DAAs, the potential now exists to use IFN-free treatment regimens,¹⁰ which could eliminate concerns about IFN-induced depression.

Clinical trials of the DAAs and real-world use so far do not indicate an elevated risk for neuropsychiatric symptoms, including depression.¹¹ As a result, more patients with severe psychiatric illness likely will be eligible to receive treatment for HCV. However, as clinical experience builds with these new agents, it is important to monitor the experience of patients with psychiatric comorbidity. Current treatment guidelines for HCV genotype 1, which is most common in the United States, do not include IFN-based regimens.¹⁰ Treatment of genotype 3, which affects 6% of the U.S. population, still includes IFN. Therefore, the risk of IFN-induced depression still exists for some patients with HCV. Table 3¹⁰ describes current treatment regimens in use for HCV without cirrhosis (see Related Resources for treating HCV with cirrhosis).

Evolving role of the psychiatrist

The availability of shorter, better-tolerated regimens means that the psychiatric contraindications to HCV treatment will be eased. With the emergence of non-IFN treatment regimens, the role of mental health providers could shift toward assisting with treatment adherence, monitoring drug–drug interactions, and managing comorbid substance use disorders.¹⁰

The psychiatrist’s role might shift away from the psychosocial assessment of factors affecting treatment eligibility, such as IFN-associated depressive symptoms. Clinical focus will likely shift to supporting adherence to HCV treatment regimens.²³ Because depression and substance use disorders are risk factors for non-adherence, mental health providers may be called upon to optimize treatment of these conditions before beginning DAA regimens. A multi-dose regimen might be complicated for those with severe mental illness, and increased psychiatric and community support could be needed in these patients.²³ Furthermore, models of care that integrate an HCV specialist with psychiatric care have demonstrated benefits.^6,23 Long-term follow-up with a mental health provider will be key to provide ongoing psychiatric support, especially for those who do not achieve SVR.

Psychotropic drug–drug interactions with DAAs

Both sofosbuvir and ledipasvir are substrates of P-glycoprotein and not metabolized by cytochrome P450 (CYP) enzymes.²⁴ Therefore, there are no known contraindications with psychotropic medications. However, co-administration of P-glycoprotein inducers, such as St. John’s wort, could reduce sofosbuvir and ledipasvir levels leading to reduced therapeutic efficacy.

Because it has been used for many years as an HIV treatment, drug interactions with ritonavir have been well-described. This agent is a “pan-inhibitor” and inhibits the CYP3A4, 2D6, 2C9, and 2C19 enzymes and could increase levels of any psychotropic metabolized by these enzymes.²⁵ After several weeks of treatment, it also could induce CYP3A4, which could lead to reduced efficacy of oral contraceptives because ethinylestradiol is metabolized by CYP3A4. Ritonavir is primarily metabolized by CYP3A4 (and CYP2D6 to a smaller degree). Carbamazepine induces CYP3A4, which may lead to decreased levels of ritonavir.²³ This, in turn, could reduce the likelihood of attaining SVR and successful treatment of HCV.

Boceprevir, telaprevir, and simeprevir inhibit CYP3A4 to varying degrees and therefore could affect psychotropic medications metabolized by this enzyme.^23,26,27 These DAAs are metabolized by CYP3A4; therefore CYP3A4 inducers, such as carbamazepine, could lower DAA blood levels, increasing risk of HCV treatment failure and viral resistance.

Daclatasvir is a substrate of CYP3A4 and an inhibitor of P-glycoprotein.²⁸ Concomitant buprenorphine or buprenorphine/naloxone levels may be increased, although the manufacturer does not recommend dosage adjustment. Elbasvir and grazoprevir are metabolized by CYP3A4.²⁹ Drug–drug interactions therefore may result when administered with either CYP3A4 inducers or inhibitors.

CASE Conclusion

Ms. S sees her new hepatologist, Dr. Smith. She decides to try a 12-week course of ledipasvir/sofosbuvir. Dr. Smith collaborates frequently with Ms. S’s psychiatrist to discuss her case and to help monitor her psychiatric symptoms. She follows up closely with her psychiatrist for symptom monitoring and to help ensure treatment compliance. Ms. S does well with the IFN-free treatment regimen and experiences no worsening of her psychiatric symptoms during treatment.

Sexually transmitted infections (STIs) continue to be a significant public health problem with potentially serious complications.¹ The incidence of new STIs, including viral STIs, in the United States is estimated at 19 million cases per year.²Chlamydia trachomatis remains the most common bacterial STI with an estimated annual incidence of 2.8 million cases in the United States and 50 million worldwide. Second in prevalence is gonococcal infection. Herpes simplex virus is one of the most common viral STIs, but the incidence of human papillomavirus virus (HPV), which is associated with cervical cancer, has steadily increased worldwide.³ Young persons age 15 to 24 are at the highest risk of acquiring new STIs with almost 50% of new cases reported among this age group.⁴

STIs can have serious complications and sequelae. For example, 20% to 40% of women who have chlamydia infections and 10% to 20% of women who have gonococcal infections develop pelvic inflammatory disease (PID),² which increases the risk for ectopic pregnancy, infertility, and chronic pelvic pain.

Patients with mental illness are at high risk of acquiring STIs. In the United States, the prevalence of HIV among patients with psychiatric illness is 10 to 20 times higher than in the general population.^4,5 Factors contributing to increased vulnerability to STIs among psychiatric patients include:

• impaired autonomy
• increased impulsivity
• increased susceptibility to coerced sex.⁶
  

Furthermore, a higher incidence of poverty, placement in risky environments, and overall poor health and medical care also contribute to the high prevalence of STIs and their complications in this population (Table 1). Because of risk factors specific to psychiatric illness, standard STI prevention interventions are not always successful and novel and innovative behavioral approaches are necessary.⁷

Case Abdominal pain and fever

Ms. K, age 25, has a history of bipolar disorder treated with lithium and presents to the community psychiatrist with lower abdominal pain. She recently recovered from a manic episode and has started to reintegrate with the community mental health team. She refuses to see her primary care physician and is adamant that she wishes to see her psychiatrist, who is the only doctor she has rapport with.

Ms. K reports lower abdominal pain for 3 or 4 days and fever for 1 day. The pain is dull in character. She denies diarrhea, vomiting, or urinary symptoms, but on further questioning describes new-onset, foul-smelling vaginal discharge without vaginal bleeding. Her menstrual cycle usually is regular, but her last menstrual period occurred 2 months ago. Her medical history includes an appendectomy at age 10 and she is a current cigarette smoker. Chart notes taken during her manic episode describe high-risk behavior, including having unprotected sexual intercourse with several partners. On examination, she is febrile and tachycardic with a tender lower abdomen.

Diagnosing STIs

To diagnose an STI, first a clinician must consider its likelihood. Taking a thorough sexual history allows assessment of the need for further investigation and provides an opportunity to discuss risk reduction. In accordance with recent guidelines,⁸ all health care providers are encouraged to consider the sexual history a routine aspect of the clinical encounter. The Centers for Disease Control and Prevention’s (CDC’s) “Five Ps” approach (Table 2) is an excellent tool for guiding investigation and counseling.⁹

The Figure provides health care providers with an algorithm to guide testing for STIs among psychiatric patients. Note that chlamydia, gonorrhea, syphilis, chancroid, viral hepatitis, and HIV must be reported to state public health agencies and the CDC.

Modern laboratory techniques make diagnosing STIs easier. Analysis of urine or serum reduces the need for invasive sampling. If swabs are required for diagnosis, patient self-collection of urethral, vulvovaginal, rectal, or pharyngeal specimens is as accurate as clinician collected samples and is better tolerated.⁸ Because of variation in diagnostic assays, we recommend contacting the laboratory before sending non-standard samples to ensure accurate collection and analysis.

Guidelines for preventing and screening for STIs

There are no prevention guidelines for STIs specific to the psychiatric population, although there is a clear need for focused intervention in this vulnerable patient group.¹⁰ Rates of STI screening generally are low in the psychiatric setting,¹¹ which results in a considerable burden of disease. All psychiatric patients should be encouraged to engage with STI screening programs that are in line with national guidelines. In the inpatient psychiatric or medical environment, clinicians have a responsibility to ensure that STI screening is considered for each patient.

Patients with mental illness should be assumed to be sexually active, even if they do not volunteer this information to clinicians. Employ a low threshold for recommending safer sex practices including condom use. Encourage women to develop a relationship with a family practitioner, internist, or gynecologist. Advise men who have sex with men (MSM) to visit a doctor regularly for screening of HIV and rectal, anal, and oral STIs as behavior and symptoms dictate.

HPV. Routine HPV screening is not recommended; however, 2 vaccines are available to prevent oncogenic HPV (types 16 and 18). All females age 13 to 26 should receive 3 doses of HPV vaccine over a 6-month period. The quadrivalent vaccine (Gardasil) also protects against HPV types 6 and 11, which cause 90% of genital warts and is preferred when available. Males age 9 to 26 also can receive the vaccine, although ideally it should be administered before sexual activity begins.¹⁵ Women still should attend routine cervical cancer screening even if they have the vaccine because 30% of cervical cancers are not caused by HPV 16/18. However, this means that 70% of cervical cancers are associated with HPV 16/18, making screening and the vaccine an important public health initiative. There also is a link between HPV and oral cancers.

Treating STIs among mentally ill individuals

Treatment of STIs among mentally ill individuals is important to prevent medical complications and to reduce transmission. Here are a few additional questions to keep in mind when treating a patient with psychiatric illness:

Does the patient have a primary psychiatric disorder, or is the patient’s current psychiatric presentation a result of the infection?
Some STIs can manifest with psychiatric symptoms—for example, neurosyphilis and HIV-associated neurocognitive disorders—and pose a diagnostic challenge. Obtaining a longitudinal history of the patient’s mental health, age of onset, and family history can help clarify the cause.

Are there any psychiatric adverse effects of STI treatment?

Most drugs used for treating common STIs are not known to cause psychiatric adverse effects (See the American Psychiatric Association¹⁶ and Sockalingham et al¹⁷ for a thorough discussion of HIV and hepatitis C treatment). The exception is fluoroquinolones, which could be prescribed for PID if cephalosporin therapy is not feasible. CNS effects of fluoroquinolones include insomnia, restlessness, confusion, and, in rare cases, mania and psychosis.

What are possible medication interactions to keep in mind when treating a psychiatric patient?
Nonsteroidal anti-inflammatory drugs (NSAIDs), other than sulindac, could increase serum lithium levels. Although NSAIDs are not contraindicated in patients taking lithium, other pain relievers, such as acetaminophen, may be preferred as a first-line choice.

Carbamazepine could lower serum levels of doxycycline.¹⁸
Azithromycin and other macrolides, as well as fluoroquinolones, could have QTc prolonging effects and has been associated with torsades de pointes.¹⁹ Several psychiatric medications, in particular, atypical antipsychotics, also could prolong the QTc interval. This could be a consideration in patients with underlying long QT intervals at baseline or a family history of sudden cardiac death.

Psychiatric patients might refuse or not adhere to their medication. Refusals could be the result of grandiose delusions (“I don’t need treatment”) or paranoia (“The doctor is trying to poison me”). Consider 1-time doses of antibiotics that can be given in the clinic for uncomplicated infections when adherence is an issue. Because psychiatric patients are at higher risk for acquiring STIs, education and counseling—especially substance abuse counseling—are vital as both primary and secondary prevention strategies. Treatment of STIs should be accompanied by referrals to the social work team or a therapist when appropriate.

Finally, as with any proposed treatment, it is important to consider whether the patient has capacity to consent to or refuse treatment. To assess for capacity, a patient must be able to:

• communicate a choice
• understand the relevant information
• appreciate the medical consequences of the decision
• demonstrate the ability to reason about treatment choices.²⁰

Case continued

In the emergency department, Ms. K’s vital signs are: temperature 39.5°C; pulse 110 beats per minute; blood pressure 96/67 mm Hg; and breathing 20 respirations per minute. She complains of nausea and has 2 episodes of emesis. She allows clinicians to perform a complete physical examination, including pelvic exam. Her cervix is inflamed, and she is noted to have adnexal and cervical motion tenderness.

Labs and imaging confirm a diagnosis of PID due to gonorrhea and she is admitted to the hospital for IV antibiotics. She continues to experience nausea and vomiting, but also complains of dizziness and diarrhea. Her speech is slurred and a coarse tremor is noticed in her hands. Renal function tests show slight impairment, probably due to dehydration. A pregnancy test is negative.

Lithium is held. Her nausea, vomiting, and diarrhea resolve quickly, and Ms. K asks to leave. When she is told that she is not ready for discharge, Ms. K becomes upset and rips out her IV yelling, “I don’t need treatment from you guys!” A psychiatry consult is called to assess for her capacity to refuse treatment. The team determines that she has capacity, but she becomes agreeable to remaining in the hospital after a phone conversation with her community mental health team.

Ms. K improves with antibiotic treatment. HIV and syphilis serology tests are negative. Before discharge, both the community psychiatrist and her primary care physicians are informed her lithium was held during hospitalization and restarted before discharge. Ms. K also is educated about the signs and symptoms of lithium toxicity, as well as common STIs.

Clinical considerations

• Physicians should have a low threshold of suspicion for PID in a sexually active young woman who presents with abdominal pain and shuffling gait, which is a natural attempt to reduce cervical irritation and is associated with PID.
• Ask about sexual history and symptoms of STIs.
• Rule out STIs in men presenting with urinary tract infections.
• If chlamydia is diagnosed, treatment for gonorrhea also is essential, and vice versa.
• Always think about HIV and hepatatis B and C in a patient with a STI.
• Treatment with single-dose medications can be effective.
• Risk of STIs is higher during episodes of mania or psychosis.
• Consider hospitalization if medically indicated or if you suspect non-adherence to therapy. It is important to remember that all kinds of systemic infections—including PID—can result in dehydration and alter renal metabolism leading to lithium accumulation.
• Mentally ill patients might require placement under involuntary commitment if they are found to be a danger to themselves or others. It is important to liaise with both the community psychiatry team and primary care physician both during hospitalization and before discharge to ensure a smooth transition.

Sexually transmitted infections (STIs) continue to be a significant public health problem with potentially serious complications.¹ The incidence of new STIs, including viral STIs, in the United States is estimated at 19 million cases per year.²Chlamydia trachomatis remains the most common bacterial STI with an estimated annual incidence of 2.8 million cases in the United States and 50 million worldwide. Second in prevalence is gonococcal infection. Herpes simplex virus is one of the most common viral STIs, but the incidence of human papillomavirus virus (HPV), which is associated with cervical cancer, has steadily increased worldwide.³ Young persons age 15 to 24 are at the highest risk of acquiring new STIs with almost 50% of new cases reported among this age group.⁴

STIs can have serious complications and sequelae. For example, 20% to 40% of women who have chlamydia infections and 10% to 20% of women who have gonococcal infections develop pelvic inflammatory disease (PID),² which increases the risk for ectopic pregnancy, infertility, and chronic pelvic pain.

Patients with mental illness are at high risk of acquiring STIs. In the United States, the prevalence of HIV among patients with psychiatric illness is 10 to 20 times higher than in the general population.^4,5 Factors contributing to increased vulnerability to STIs among psychiatric patients include:

• impaired autonomy
• increased impulsivity
• increased susceptibility to coerced sex.⁶
  

Furthermore, a higher incidence of poverty, placement in risky environments, and overall poor health and medical care also contribute to the high prevalence of STIs and their complications in this population (Table 1). Because of risk factors specific to psychiatric illness, standard STI prevention interventions are not always successful and novel and innovative behavioral approaches are necessary.⁷

Case Abdominal pain and fever

Ms. K, age 25, has a history of bipolar disorder treated with lithium and presents to the community psychiatrist with lower abdominal pain. She recently recovered from a manic episode and has started to reintegrate with the community mental health team. She refuses to see her primary care physician and is adamant that she wishes to see her psychiatrist, who is the only doctor she has rapport with.

Ms. K reports lower abdominal pain for 3 or 4 days and fever for 1 day. The pain is dull in character. She denies diarrhea, vomiting, or urinary symptoms, but on further questioning describes new-onset, foul-smelling vaginal discharge without vaginal bleeding. Her menstrual cycle usually is regular, but her last menstrual period occurred 2 months ago. Her medical history includes an appendectomy at age 10 and she is a current cigarette smoker. Chart notes taken during her manic episode describe high-risk behavior, including having unprotected sexual intercourse with several partners. On examination, she is febrile and tachycardic with a tender lower abdomen.

Diagnosing STIs

To diagnose an STI, first a clinician must consider its likelihood. Taking a thorough sexual history allows assessment of the need for further investigation and provides an opportunity to discuss risk reduction. In accordance with recent guidelines,⁸ all health care providers are encouraged to consider the sexual history a routine aspect of the clinical encounter. The Centers for Disease Control and Prevention’s (CDC’s) “Five Ps” approach (Table 2) is an excellent tool for guiding investigation and counseling.⁹

The Figure provides health care providers with an algorithm to guide testing for STIs among psychiatric patients. Note that chlamydia, gonorrhea, syphilis, chancroid, viral hepatitis, and HIV must be reported to state public health agencies and the CDC.

Modern laboratory techniques make diagnosing STIs easier. Analysis of urine or serum reduces the need for invasive sampling. If swabs are required for diagnosis, patient self-collection of urethral, vulvovaginal, rectal, or pharyngeal specimens is as accurate as clinician collected samples and is better tolerated.⁸ Because of variation in diagnostic assays, we recommend contacting the laboratory before sending non-standard samples to ensure accurate collection and analysis.

Guidelines for preventing and screening for STIs

There are no prevention guidelines for STIs specific to the psychiatric population, although there is a clear need for focused intervention in this vulnerable patient group.¹⁰ Rates of STI screening generally are low in the psychiatric setting,¹¹ which results in a considerable burden of disease. All psychiatric patients should be encouraged to engage with STI screening programs that are in line with national guidelines. In the inpatient psychiatric or medical environment, clinicians have a responsibility to ensure that STI screening is considered for each patient.

Patients with mental illness should be assumed to be sexually active, even if they do not volunteer this information to clinicians. Employ a low threshold for recommending safer sex practices including condom use. Encourage women to develop a relationship with a family practitioner, internist, or gynecologist. Advise men who have sex with men (MSM) to visit a doctor regularly for screening of HIV and rectal, anal, and oral STIs as behavior and symptoms dictate.

HPV. Routine HPV screening is not recommended; however, 2 vaccines are available to prevent oncogenic HPV (types 16 and 18). All females age 13 to 26 should receive 3 doses of HPV vaccine over a 6-month period. The quadrivalent vaccine (Gardasil) also protects against HPV types 6 and 11, which cause 90% of genital warts and is preferred when available. Males age 9 to 26 also can receive the vaccine, although ideally it should be administered before sexual activity begins.¹⁵ Women still should attend routine cervical cancer screening even if they have the vaccine because 30% of cervical cancers are not caused by HPV 16/18. However, this means that 70% of cervical cancers are associated with HPV 16/18, making screening and the vaccine an important public health initiative. There also is a link between HPV and oral cancers.

Treating STIs among mentally ill individuals

Treatment of STIs among mentally ill individuals is important to prevent medical complications and to reduce transmission. Here are a few additional questions to keep in mind when treating a patient with psychiatric illness:

Does the patient have a primary psychiatric disorder, or is the patient’s current psychiatric presentation a result of the infection?
Some STIs can manifest with psychiatric symptoms—for example, neurosyphilis and HIV-associated neurocognitive disorders—and pose a diagnostic challenge. Obtaining a longitudinal history of the patient’s mental health, age of onset, and family history can help clarify the cause.

Are there any psychiatric adverse effects of STI treatment?

Most drugs used for treating common STIs are not known to cause psychiatric adverse effects (See the American Psychiatric Association¹⁶ and Sockalingham et al¹⁷ for a thorough discussion of HIV and hepatitis C treatment). The exception is fluoroquinolones, which could be prescribed for PID if cephalosporin therapy is not feasible. CNS effects of fluoroquinolones include insomnia, restlessness, confusion, and, in rare cases, mania and psychosis.

What are possible medication interactions to keep in mind when treating a psychiatric patient?
Nonsteroidal anti-inflammatory drugs (NSAIDs), other than sulindac, could increase serum lithium levels. Although NSAIDs are not contraindicated in patients taking lithium, other pain relievers, such as acetaminophen, may be preferred as a first-line choice.

Carbamazepine could lower serum levels of doxycycline.¹⁸
Azithromycin and other macrolides, as well as fluoroquinolones, could have QTc prolonging effects and has been associated with torsades de pointes.¹⁹ Several psychiatric medications, in particular, atypical antipsychotics, also could prolong the QTc interval. This could be a consideration in patients with underlying long QT intervals at baseline or a family history of sudden cardiac death.

Psychiatric patients might refuse or not adhere to their medication. Refusals could be the result of grandiose delusions (“I don’t need treatment”) or paranoia (“The doctor is trying to poison me”). Consider 1-time doses of antibiotics that can be given in the clinic for uncomplicated infections when adherence is an issue. Because psychiatric patients are at higher risk for acquiring STIs, education and counseling—especially substance abuse counseling—are vital as both primary and secondary prevention strategies. Treatment of STIs should be accompanied by referrals to the social work team or a therapist when appropriate.

Finally, as with any proposed treatment, it is important to consider whether the patient has capacity to consent to or refuse treatment. To assess for capacity, a patient must be able to:

• communicate a choice
• understand the relevant information
• appreciate the medical consequences of the decision
• demonstrate the ability to reason about treatment choices.²⁰

Case continued

In the emergency department, Ms. K’s vital signs are: temperature 39.5°C; pulse 110 beats per minute; blood pressure 96/67 mm Hg; and breathing 20 respirations per minute. She complains of nausea and has 2 episodes of emesis. She allows clinicians to perform a complete physical examination, including pelvic exam. Her cervix is inflamed, and she is noted to have adnexal and cervical motion tenderness.

Labs and imaging confirm a diagnosis of PID due to gonorrhea and she is admitted to the hospital for IV antibiotics. She continues to experience nausea and vomiting, but also complains of dizziness and diarrhea. Her speech is slurred and a coarse tremor is noticed in her hands. Renal function tests show slight impairment, probably due to dehydration. A pregnancy test is negative.

Lithium is held. Her nausea, vomiting, and diarrhea resolve quickly, and Ms. K asks to leave. When she is told that she is not ready for discharge, Ms. K becomes upset and rips out her IV yelling, “I don’t need treatment from you guys!” A psychiatry consult is called to assess for her capacity to refuse treatment. The team determines that she has capacity, but she becomes agreeable to remaining in the hospital after a phone conversation with her community mental health team.

Ms. K improves with antibiotic treatment. HIV and syphilis serology tests are negative. Before discharge, both the community psychiatrist and her primary care physicians are informed her lithium was held during hospitalization and restarted before discharge. Ms. K also is educated about the signs and symptoms of lithium toxicity, as well as common STIs.

Clinical considerations

• Physicians should have a low threshold of suspicion for PID in a sexually active young woman who presents with abdominal pain and shuffling gait, which is a natural attempt to reduce cervical irritation and is associated with PID.
• Ask about sexual history and symptoms of STIs.
• Rule out STIs in men presenting with urinary tract infections.
• If chlamydia is diagnosed, treatment for gonorrhea also is essential, and vice versa.
• Always think about HIV and hepatatis B and C in a patient with a STI.
• Treatment with single-dose medications can be effective.
• Risk of STIs is higher during episodes of mania or psychosis.
• Consider hospitalization if medically indicated or if you suspect non-adherence to therapy. It is important to remember that all kinds of systemic infections—including PID—can result in dehydration and alter renal metabolism leading to lithium accumulation.
• Mentally ill patients might require placement under involuntary commitment if they are found to be a danger to themselves or others. It is important to liaise with both the community psychiatry team and primary care physician both during hospitalization and before discharge to ensure a smooth transition.

Sexually transmitted infections (STIs) continue to be a significant public health problem with potentially serious complications.¹ The incidence of new STIs, including viral STIs, in the United States is estimated at 19 million cases per year.²Chlamydia trachomatis remains the most common bacterial STI with an estimated annual incidence of 2.8 million cases in the United States and 50 million worldwide. Second in prevalence is gonococcal infection. Herpes simplex virus is one of the most common viral STIs, but the incidence of human papillomavirus virus (HPV), which is associated with cervical cancer, has steadily increased worldwide.³ Young persons age 15 to 24 are at the highest risk of acquiring new STIs with almost 50% of new cases reported among this age group.⁴

STIs can have serious complications and sequelae. For example, 20% to 40% of women who have chlamydia infections and 10% to 20% of women who have gonococcal infections develop pelvic inflammatory disease (PID),² which increases the risk for ectopic pregnancy, infertility, and chronic pelvic pain.

Patients with mental illness are at high risk of acquiring STIs. In the United States, the prevalence of HIV among patients with psychiatric illness is 10 to 20 times higher than in the general population.^4,5 Factors contributing to increased vulnerability to STIs among psychiatric patients include:

• impaired autonomy
• increased impulsivity
• increased susceptibility to coerced sex.⁶
  

Furthermore, a higher incidence of poverty, placement in risky environments, and overall poor health and medical care also contribute to the high prevalence of STIs and their complications in this population (Table 1). Because of risk factors specific to psychiatric illness, standard STI prevention interventions are not always successful and novel and innovative behavioral approaches are necessary.⁷

Case Abdominal pain and fever

Ms. K, age 25, has a history of bipolar disorder treated with lithium and presents to the community psychiatrist with lower abdominal pain. She recently recovered from a manic episode and has started to reintegrate with the community mental health team. She refuses to see her primary care physician and is adamant that she wishes to see her psychiatrist, who is the only doctor she has rapport with.

Ms. K reports lower abdominal pain for 3 or 4 days and fever for 1 day. The pain is dull in character. She denies diarrhea, vomiting, or urinary symptoms, but on further questioning describes new-onset, foul-smelling vaginal discharge without vaginal bleeding. Her menstrual cycle usually is regular, but her last menstrual period occurred 2 months ago. Her medical history includes an appendectomy at age 10 and she is a current cigarette smoker. Chart notes taken during her manic episode describe high-risk behavior, including having unprotected sexual intercourse with several partners. On examination, she is febrile and tachycardic with a tender lower abdomen.

Diagnosing STIs

To diagnose an STI, first a clinician must consider its likelihood. Taking a thorough sexual history allows assessment of the need for further investigation and provides an opportunity to discuss risk reduction. In accordance with recent guidelines,⁸ all health care providers are encouraged to consider the sexual history a routine aspect of the clinical encounter. The Centers for Disease Control and Prevention’s (CDC’s) “Five Ps” approach (Table 2) is an excellent tool for guiding investigation and counseling.⁹

The Figure provides health care providers with an algorithm to guide testing for STIs among psychiatric patients. Note that chlamydia, gonorrhea, syphilis, chancroid, viral hepatitis, and HIV must be reported to state public health agencies and the CDC.

Modern laboratory techniques make diagnosing STIs easier. Analysis of urine or serum reduces the need for invasive sampling. If swabs are required for diagnosis, patient self-collection of urethral, vulvovaginal, rectal, or pharyngeal specimens is as accurate as clinician collected samples and is better tolerated.⁸ Because of variation in diagnostic assays, we recommend contacting the laboratory before sending non-standard samples to ensure accurate collection and analysis.

Guidelines for preventing and screening for STIs

There are no prevention guidelines for STIs specific to the psychiatric population, although there is a clear need for focused intervention in this vulnerable patient group.¹⁰ Rates of STI screening generally are low in the psychiatric setting,¹¹ which results in a considerable burden of disease. All psychiatric patients should be encouraged to engage with STI screening programs that are in line with national guidelines. In the inpatient psychiatric or medical environment, clinicians have a responsibility to ensure that STI screening is considered for each patient.

Patients with mental illness should be assumed to be sexually active, even if they do not volunteer this information to clinicians. Employ a low threshold for recommending safer sex practices including condom use. Encourage women to develop a relationship with a family practitioner, internist, or gynecologist. Advise men who have sex with men (MSM) to visit a doctor regularly for screening of HIV and rectal, anal, and oral STIs as behavior and symptoms dictate.

HPV. Routine HPV screening is not recommended; however, 2 vaccines are available to prevent oncogenic HPV (types 16 and 18). All females age 13 to 26 should receive 3 doses of HPV vaccine over a 6-month period. The quadrivalent vaccine (Gardasil) also protects against HPV types 6 and 11, which cause 90% of genital warts and is preferred when available. Males age 9 to 26 also can receive the vaccine, although ideally it should be administered before sexual activity begins.¹⁵ Women still should attend routine cervical cancer screening even if they have the vaccine because 30% of cervical cancers are not caused by HPV 16/18. However, this means that 70% of cervical cancers are associated with HPV 16/18, making screening and the vaccine an important public health initiative. There also is a link between HPV and oral cancers.

Treating STIs among mentally ill individuals

Treatment of STIs among mentally ill individuals is important to prevent medical complications and to reduce transmission. Here are a few additional questions to keep in mind when treating a patient with psychiatric illness:

Does the patient have a primary psychiatric disorder, or is the patient’s current psychiatric presentation a result of the infection?
Some STIs can manifest with psychiatric symptoms—for example, neurosyphilis and HIV-associated neurocognitive disorders—and pose a diagnostic challenge. Obtaining a longitudinal history of the patient’s mental health, age of onset, and family history can help clarify the cause.

Are there any psychiatric adverse effects of STI treatment?

Most drugs used for treating common STIs are not known to cause psychiatric adverse effects (See the American Psychiatric Association¹⁶ and Sockalingham et al¹⁷ for a thorough discussion of HIV and hepatitis C treatment). The exception is fluoroquinolones, which could be prescribed for PID if cephalosporin therapy is not feasible. CNS effects of fluoroquinolones include insomnia, restlessness, confusion, and, in rare cases, mania and psychosis.

What are possible medication interactions to keep in mind when treating a psychiatric patient?
Nonsteroidal anti-inflammatory drugs (NSAIDs), other than sulindac, could increase serum lithium levels. Although NSAIDs are not contraindicated in patients taking lithium, other pain relievers, such as acetaminophen, may be preferred as a first-line choice.

Carbamazepine could lower serum levels of doxycycline.¹⁸
Azithromycin and other macrolides, as well as fluoroquinolones, could have QTc prolonging effects and has been associated with torsades de pointes.¹⁹ Several psychiatric medications, in particular, atypical antipsychotics, also could prolong the QTc interval. This could be a consideration in patients with underlying long QT intervals at baseline or a family history of sudden cardiac death.

Psychiatric patients might refuse or not adhere to their medication. Refusals could be the result of grandiose delusions (“I don’t need treatment”) or paranoia (“The doctor is trying to poison me”). Consider 1-time doses of antibiotics that can be given in the clinic for uncomplicated infections when adherence is an issue. Because psychiatric patients are at higher risk for acquiring STIs, education and counseling—especially substance abuse counseling—are vital as both primary and secondary prevention strategies. Treatment of STIs should be accompanied by referrals to the social work team or a therapist when appropriate.

Finally, as with any proposed treatment, it is important to consider whether the patient has capacity to consent to or refuse treatment. To assess for capacity, a patient must be able to:

• communicate a choice
• understand the relevant information
• appreciate the medical consequences of the decision
• demonstrate the ability to reason about treatment choices.²⁰

Case continued

In the emergency department, Ms. K’s vital signs are: temperature 39.5°C; pulse 110 beats per minute; blood pressure 96/67 mm Hg; and breathing 20 respirations per minute. She complains of nausea and has 2 episodes of emesis. She allows clinicians to perform a complete physical examination, including pelvic exam. Her cervix is inflamed, and she is noted to have adnexal and cervical motion tenderness.

Labs and imaging confirm a diagnosis of PID due to gonorrhea and she is admitted to the hospital for IV antibiotics. She continues to experience nausea and vomiting, but also complains of dizziness and diarrhea. Her speech is slurred and a coarse tremor is noticed in her hands. Renal function tests show slight impairment, probably due to dehydration. A pregnancy test is negative.

Lithium is held. Her nausea, vomiting, and diarrhea resolve quickly, and Ms. K asks to leave. When she is told that she is not ready for discharge, Ms. K becomes upset and rips out her IV yelling, “I don’t need treatment from you guys!” A psychiatry consult is called to assess for her capacity to refuse treatment. The team determines that she has capacity, but she becomes agreeable to remaining in the hospital after a phone conversation with her community mental health team.

Ms. K improves with antibiotic treatment. HIV and syphilis serology tests are negative. Before discharge, both the community psychiatrist and her primary care physicians are informed her lithium was held during hospitalization and restarted before discharge. Ms. K also is educated about the signs and symptoms of lithium toxicity, as well as common STIs.

Clinical considerations

• Physicians should have a low threshold of suspicion for PID in a sexually active young woman who presents with abdominal pain and shuffling gait, which is a natural attempt to reduce cervical irritation and is associated with PID.
• Ask about sexual history and symptoms of STIs.
• Rule out STIs in men presenting with urinary tract infections.
• If chlamydia is diagnosed, treatment for gonorrhea also is essential, and vice versa.
• Always think about HIV and hepatatis B and C in a patient with a STI.
• Treatment with single-dose medications can be effective.
• Risk of STIs is higher during episodes of mania or psychosis.
• Consider hospitalization if medically indicated or if you suspect non-adherence to therapy. It is important to remember that all kinds of systemic infections—including PID—can result in dehydration and alter renal metabolism leading to lithium accumulation.
• Mentally ill patients might require placement under involuntary commitment if they are found to be a danger to themselves or others. It is important to liaise with both the community psychiatry team and primary care physician both during hospitalization and before discharge to ensure a smooth transition.

High serum cholesterol is a leading cause of heart attack and stroke,^1,2 yet remains one of the most under-screened and undertreated modifiable risk factors in persons with mental illness. Well tolerated and effective treatments can considerably lower the risk of cardiovascular events, and should be offered to psychiatric patients who are at high risk, while considering possible adverse effects and potential interactions between psychotropics and medications used to lower cholesterol.

Systematic lowering of total cholesterol and, particularly, atherogenic low-density lipoprotein (LDL) and non-high density lipoprotein (HDL) cholesterol, results in consistent and significant reduction in risk of cardiovascular events in persons at risk for developing cardiovascular disease (CVD) and in preventing reoccurrence of these events.^1,3,4 Even individuals who have relatively lower levels of total cholesterol but are at high risk (such as if a cardiovascular event has occurred) could reduce their CVD risk (known as secondary prevention) through lipid lowering therapies.^5,6

Adults with psychiatric illness shoulder a disproportionate burden of CVD morbidity and mortality, especially those with severe mental illness (SMI, schizophrenia, schizoaffective disorder, bipolar disorder, treatment-resistant depression).^7-9 Among modifiable CVD risk factors, dyslipidemia has the highest rates of missed screenings and treatment within psychiatric populations. In one analysis, up to 90% of adults with SMI and identified lipid disorders did not receive treatment.¹⁰ Persons with SMI generally do not receive guideline-concordant, systematic quality preventive care, which contributes to a widening mortality gap for this population.^11,12

This review aims to provide clinicians with practical guidance on the assessment and management of high cholesterol to improve recognition and treatment, lower CVD risk, and reduce this observed mortality gap.

Screening and diagnosis

In 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) released updated guidelines on diagnosing and managing high cholesterol to reduce CVD risk.¹ These guidelines focus on updated 10-year CVD risk assessment models with treatment goals reliant on adherence to statin therapy rather than pre-specified cholesterol targets listed in previous guidelines.¹³

Updates to assessment and treatment guidelines have removed some barriers to screening and diagnosing high cholesterol—namely, fasting lipid panels are no longer required to determine 10-year CVD risk and initiate treatment.¹⁴ For adults taking a second-generation antipsychotic that is associated with weight gain and metabolic syndrome, experts generally recommend yearly non-fasting lipid panels.^6,14

The United States Preventive Services Task Force recommends screening:

• men age ≥35 at average risk for CVD every 5 years
• women age ≥45 every 5 years¹⁵
• adults as young as age 20 who have accelerated risk factors, such as cigarette smoking and hypertension
• adults with a family history of heart attack or stroke in male first-degree relative age ≥50 and female first-degree relatives age ≥60.

Many adults receiving care in behavioral health settings, regardless of their medication regimen, qualify for screening at least every 5 years, if not more frequently. Although statin treatment before age 40 is less beneficial and likely not necessary for primary prevention, monitoring could help identify alternative therapies and prioritize more intensive diet and lifestyle modifications.

Treatment and management

Dietary modification and lifestyle changes (exercise, quitting smoking), lowering high cholesterol with medications, and switching from highly metabolically active drugs to less metabolically active ones can help lower total cholesterol in patients at risk of CVD.

Statins

HMG-CoA reductase inhibitors (statins) consistently reduce total cholesterol and non-HDL cholesterol by 30% to 50%, depending on drug and dosage (potency, listed as low, medium, and high). Not all statins are equally effective at lowering cholesterol; some are more potent than others (Table 2).¹⁶

Individuals are eligible for statin therapy based on their level of CVD risk. Persons at higher risk generally benefit from greater intensity statin treatment and cholesterol reduction; highest intensity statin regimens can lower total cholesterol by approximately 50%.

There are 4 statin eligibility classes (Table 3). Most adults fall into category 4: 10-year risk of >7.5% and needing primary prevention. In addition to removing specific LDL targets as therapy goals, calculation of this risk percentage and the specific cut-off values have been the most controversial aspects of the new cholesterol guidelines. Most experts agree that, in adults age 40 to 75, 10-year risk >10% indicates daily statin use as tolerated for primary prevention, and 10-year risk <5% does not warrant statin use. Recent large studies have validated these new techniques for calculating risk, and found them to be beneficial in potential for cost savings and risk classification.^17,18

Considerations in psychiatric patients. Statins have been associated with depression in case series, but larger analyses have not confirmed this association.¹⁹ Emerging evidence has identified a potential correlation between statin use and accelerated onset of T2DM, but the absolute risk is relatively low and most experts continue to recommend statin therapy despite this potential risk.¹³ Many statins, including atorvastatin, are available as a generic and can be taken once daily. Some, such as simvastatin, have notable interactions with commonly prescribed psychotropics including risperidone and quetiapine. Pravastatin is dually excreted by the liver and kidneys and may have fewer drug-drug interactions in patients with psychiatric illness taking common psychotropic therapies, but is not considered a high-potency statin and might not confer adequate benefits in CVD risk reduction.

Contraindications. Statins are pregnancy category X, and generally should not be prescribed for women of childbearing age without intensive counseling. The most notable adverse effects for statins include muscle aches and cramps (myalgia), but generally are not severe. If encountered, consider checking a serum creatinine kinase (CK) level, and if significantly elevated above 10 times the upper limit, stopping statin therapy would be advised. If the CK is only mildly elevated, consider lowering the dosage or switching to a lower potency agent. Lovastatin and pravastatin generally are better tolerated than atorvastatin and are considered lower potency (Table 2).

Statins can be safely used in the presence of liver conditions, such as hepatitis C and alcohol use, although periodic monitoring of transaminase levels is recommended. For adults in the general population without liver disease, regular monitoring of transaminase levels is not necessary.

Alternate lipid-lowering pharmacotherapies unfortunately have fallen out of favor. Fibrates, niacin, ezetimibe, and omega-3 fatty acids once were recommended to lower triglycerides or raise HDL cholesterol levels, but since have been shown to have little effect on cardiovascular morbidity or mortality. Adding further medications, other than statins, to lower cholesterol values to pre-defined targets is not the current standard of care.

High triglyceride concentrations traditionally have been addressed directly, but failure to improve CVD mortality or morbidity by treating triglycerides alone has resulted in refocusing clinical efforts in dyslipidemia management on atherogenic cholesterol, including LDL and non-HDL fractions.²⁰ Non-fasting triglycerides >500 mg/dL should be retested when fasting, and levels that remain >500 mg/dL could place the patient at risk for pancreatitis and might warrant intervention with fibrates at that time. This scenario is not common, and referral to a primary care physician or endocrinologist may be warranted.

Lifestyle changes

With or without statin therapies, diet and lifestyle changes are the cornerstone of healthy living and should be encouraged in all patients. Most overweight or obese patients will benefit from exercise and dietary modifications. Such interventions have shown potential for reducing total cholesterol and non-HDL and HDL cholesterol, but rarely are these interventions sustained long enough to produce meaningful reduction in CVD risk through lipid lowering. Diets rich in isocaloric tree nuts and red-yeast rice extract—a form of a statin—have shown promise in reducing cholesterol, but typically take excessive personal resources and are not sustained to the degree necessary to reduce CVD risk over time.²¹ Similarly, regular exercise routines can help lower overall cholesterol numbers, but rarely reduce total cholesterol by >10%.

Because individuals with SMI smoke at a higher rate than the general population, it should be noted that smoking cessation is associated with a reduction in total cholesterol and a trial of smoking cessation therapy is warranted before initiating a statin medication for primary prevention of CVD. Many patients would discover that their 10-year ASCVD risk would fall under the level needed for statin therapy if they could successfully stop smoking.

Switching pharmacotherapies

Switching antipsychotic agents from highly metabolically risky compounds, such as risperidone and olanzapine, to less metabolically active compounds, such as aripiprazole, ziprasidone, or haloperidol, have been associated with improvements in lipid profiles.^22-24 Clinicians must weigh the potential benefits of switching therapies against the risk of psychiatric destabilization and long-term adherence, keeping in mind that changes in lipids seen with switching could be mild (approximately 10% reduction in total cholesterol).

Summing up

Cholesterol management is considered part of a program to systematically lower CVD risk. Statin therapy usually is indicated for life, or until the age of 75, at which point treatment risks and benefits change because of life expectancy. Other components of CVD risk reduction include a focus on blood pressure control, smoking cessation, T2DM management, and weight loss. Tracking lipid profiles over time to ensure broad targets of 30% to 50% reduction in total cholesterol, approximately 3 months after initiation and yearly thereafter, can help ensure adherence to therapy. With systematic lowering of modifiable CVD risk factors, we can hope to gradually improve the quality of life for our patients with mental illnesses (see the Box for a case example illustrating successful use of these strategies).

High serum cholesterol is a leading cause of heart attack and stroke,^1,2 yet remains one of the most under-screened and undertreated modifiable risk factors in persons with mental illness. Well tolerated and effective treatments can considerably lower the risk of cardiovascular events, and should be offered to psychiatric patients who are at high risk, while considering possible adverse effects and potential interactions between psychotropics and medications used to lower cholesterol.

Systematic lowering of total cholesterol and, particularly, atherogenic low-density lipoprotein (LDL) and non-high density lipoprotein (HDL) cholesterol, results in consistent and significant reduction in risk of cardiovascular events in persons at risk for developing cardiovascular disease (CVD) and in preventing reoccurrence of these events.^1,3,4 Even individuals who have relatively lower levels of total cholesterol but are at high risk (such as if a cardiovascular event has occurred) could reduce their CVD risk (known as secondary prevention) through lipid lowering therapies.^5,6

Adults with psychiatric illness shoulder a disproportionate burden of CVD morbidity and mortality, especially those with severe mental illness (SMI, schizophrenia, schizoaffective disorder, bipolar disorder, treatment-resistant depression).^7-9 Among modifiable CVD risk factors, dyslipidemia has the highest rates of missed screenings and treatment within psychiatric populations. In one analysis, up to 90% of adults with SMI and identified lipid disorders did not receive treatment.¹⁰ Persons with SMI generally do not receive guideline-concordant, systematic quality preventive care, which contributes to a widening mortality gap for this population.^11,12

This review aims to provide clinicians with practical guidance on the assessment and management of high cholesterol to improve recognition and treatment, lower CVD risk, and reduce this observed mortality gap.

Screening and diagnosis

In 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) released updated guidelines on diagnosing and managing high cholesterol to reduce CVD risk.¹ These guidelines focus on updated 10-year CVD risk assessment models with treatment goals reliant on adherence to statin therapy rather than pre-specified cholesterol targets listed in previous guidelines.¹³

Updates to assessment and treatment guidelines have removed some barriers to screening and diagnosing high cholesterol—namely, fasting lipid panels are no longer required to determine 10-year CVD risk and initiate treatment.¹⁴ For adults taking a second-generation antipsychotic that is associated with weight gain and metabolic syndrome, experts generally recommend yearly non-fasting lipid panels.^6,14

The United States Preventive Services Task Force recommends screening:

• men age ≥35 at average risk for CVD every 5 years
• women age ≥45 every 5 years¹⁵
• adults as young as age 20 who have accelerated risk factors, such as cigarette smoking and hypertension
• adults with a family history of heart attack or stroke in male first-degree relative age ≥50 and female first-degree relatives age ≥60.

Many adults receiving care in behavioral health settings, regardless of their medication regimen, qualify for screening at least every 5 years, if not more frequently. Although statin treatment before age 40 is less beneficial and likely not necessary for primary prevention, monitoring could help identify alternative therapies and prioritize more intensive diet and lifestyle modifications.

Treatment and management

Dietary modification and lifestyle changes (exercise, quitting smoking), lowering high cholesterol with medications, and switching from highly metabolically active drugs to less metabolically active ones can help lower total cholesterol in patients at risk of CVD.

Statins

HMG-CoA reductase inhibitors (statins) consistently reduce total cholesterol and non-HDL cholesterol by 30% to 50%, depending on drug and dosage (potency, listed as low, medium, and high). Not all statins are equally effective at lowering cholesterol; some are more potent than others (Table 2).¹⁶

Individuals are eligible for statin therapy based on their level of CVD risk. Persons at higher risk generally benefit from greater intensity statin treatment and cholesterol reduction; highest intensity statin regimens can lower total cholesterol by approximately 50%.

There are 4 statin eligibility classes (Table 3). Most adults fall into category 4: 10-year risk of >7.5% and needing primary prevention. In addition to removing specific LDL targets as therapy goals, calculation of this risk percentage and the specific cut-off values have been the most controversial aspects of the new cholesterol guidelines. Most experts agree that, in adults age 40 to 75, 10-year risk >10% indicates daily statin use as tolerated for primary prevention, and 10-year risk <5% does not warrant statin use. Recent large studies have validated these new techniques for calculating risk, and found them to be beneficial in potential for cost savings and risk classification.^17,18

Considerations in psychiatric patients. Statins have been associated with depression in case series, but larger analyses have not confirmed this association.¹⁹ Emerging evidence has identified a potential correlation between statin use and accelerated onset of T2DM, but the absolute risk is relatively low and most experts continue to recommend statin therapy despite this potential risk.¹³ Many statins, including atorvastatin, are available as a generic and can be taken once daily. Some, such as simvastatin, have notable interactions with commonly prescribed psychotropics including risperidone and quetiapine. Pravastatin is dually excreted by the liver and kidneys and may have fewer drug-drug interactions in patients with psychiatric illness taking common psychotropic therapies, but is not considered a high-potency statin and might not confer adequate benefits in CVD risk reduction.

Contraindications. Statins are pregnancy category X, and generally should not be prescribed for women of childbearing age without intensive counseling. The most notable adverse effects for statins include muscle aches and cramps (myalgia), but generally are not severe. If encountered, consider checking a serum creatinine kinase (CK) level, and if significantly elevated above 10 times the upper limit, stopping statin therapy would be advised. If the CK is only mildly elevated, consider lowering the dosage or switching to a lower potency agent. Lovastatin and pravastatin generally are better tolerated than atorvastatin and are considered lower potency (Table 2).

Statins can be safely used in the presence of liver conditions, such as hepatitis C and alcohol use, although periodic monitoring of transaminase levels is recommended. For adults in the general population without liver disease, regular monitoring of transaminase levels is not necessary.

Alternate lipid-lowering pharmacotherapies unfortunately have fallen out of favor. Fibrates, niacin, ezetimibe, and omega-3 fatty acids once were recommended to lower triglycerides or raise HDL cholesterol levels, but since have been shown to have little effect on cardiovascular morbidity or mortality. Adding further medications, other than statins, to lower cholesterol values to pre-defined targets is not the current standard of care.

High triglyceride concentrations traditionally have been addressed directly, but failure to improve CVD mortality or morbidity by treating triglycerides alone has resulted in refocusing clinical efforts in dyslipidemia management on atherogenic cholesterol, including LDL and non-HDL fractions.²⁰ Non-fasting triglycerides >500 mg/dL should be retested when fasting, and levels that remain >500 mg/dL could place the patient at risk for pancreatitis and might warrant intervention with fibrates at that time. This scenario is not common, and referral to a primary care physician or endocrinologist may be warranted.

Lifestyle changes

With or without statin therapies, diet and lifestyle changes are the cornerstone of healthy living and should be encouraged in all patients. Most overweight or obese patients will benefit from exercise and dietary modifications. Such interventions have shown potential for reducing total cholesterol and non-HDL and HDL cholesterol, but rarely are these interventions sustained long enough to produce meaningful reduction in CVD risk through lipid lowering. Diets rich in isocaloric tree nuts and red-yeast rice extract—a form of a statin—have shown promise in reducing cholesterol, but typically take excessive personal resources and are not sustained to the degree necessary to reduce CVD risk over time.²¹ Similarly, regular exercise routines can help lower overall cholesterol numbers, but rarely reduce total cholesterol by >10%.

Because individuals with SMI smoke at a higher rate than the general population, it should be noted that smoking cessation is associated with a reduction in total cholesterol and a trial of smoking cessation therapy is warranted before initiating a statin medication for primary prevention of CVD. Many patients would discover that their 10-year ASCVD risk would fall under the level needed for statin therapy if they could successfully stop smoking.

Switching pharmacotherapies

Switching antipsychotic agents from highly metabolically risky compounds, such as risperidone and olanzapine, to less metabolically active compounds, such as aripiprazole, ziprasidone, or haloperidol, have been associated with improvements in lipid profiles.^22-24 Clinicians must weigh the potential benefits of switching therapies against the risk of psychiatric destabilization and long-term adherence, keeping in mind that changes in lipids seen with switching could be mild (approximately 10% reduction in total cholesterol).

Summing up

Cholesterol management is considered part of a program to systematically lower CVD risk. Statin therapy usually is indicated for life, or until the age of 75, at which point treatment risks and benefits change because of life expectancy. Other components of CVD risk reduction include a focus on blood pressure control, smoking cessation, T2DM management, and weight loss. Tracking lipid profiles over time to ensure broad targets of 30% to 50% reduction in total cholesterol, approximately 3 months after initiation and yearly thereafter, can help ensure adherence to therapy. With systematic lowering of modifiable CVD risk factors, we can hope to gradually improve the quality of life for our patients with mental illnesses (see the Box for a case example illustrating successful use of these strategies).

High serum cholesterol is a leading cause of heart attack and stroke,^1,2 yet remains one of the most under-screened and undertreated modifiable risk factors in persons with mental illness. Well tolerated and effective treatments can considerably lower the risk of cardiovascular events, and should be offered to psychiatric patients who are at high risk, while considering possible adverse effects and potential interactions between psychotropics and medications used to lower cholesterol.

Systematic lowering of total cholesterol and, particularly, atherogenic low-density lipoprotein (LDL) and non-high density lipoprotein (HDL) cholesterol, results in consistent and significant reduction in risk of cardiovascular events in persons at risk for developing cardiovascular disease (CVD) and in preventing reoccurrence of these events.^1,3,4 Even individuals who have relatively lower levels of total cholesterol but are at high risk (such as if a cardiovascular event has occurred) could reduce their CVD risk (known as secondary prevention) through lipid lowering therapies.^5,6

Adults with psychiatric illness shoulder a disproportionate burden of CVD morbidity and mortality, especially those with severe mental illness (SMI, schizophrenia, schizoaffective disorder, bipolar disorder, treatment-resistant depression).^7-9 Among modifiable CVD risk factors, dyslipidemia has the highest rates of missed screenings and treatment within psychiatric populations. In one analysis, up to 90% of adults with SMI and identified lipid disorders did not receive treatment.¹⁰ Persons with SMI generally do not receive guideline-concordant, systematic quality preventive care, which contributes to a widening mortality gap for this population.^11,12

This review aims to provide clinicians with practical guidance on the assessment and management of high cholesterol to improve recognition and treatment, lower CVD risk, and reduce this observed mortality gap.

Screening and diagnosis

In 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) released updated guidelines on diagnosing and managing high cholesterol to reduce CVD risk.¹ These guidelines focus on updated 10-year CVD risk assessment models with treatment goals reliant on adherence to statin therapy rather than pre-specified cholesterol targets listed in previous guidelines.¹³

Updates to assessment and treatment guidelines have removed some barriers to screening and diagnosing high cholesterol—namely, fasting lipid panels are no longer required to determine 10-year CVD risk and initiate treatment.¹⁴ For adults taking a second-generation antipsychotic that is associated with weight gain and metabolic syndrome, experts generally recommend yearly non-fasting lipid panels.^6,14

The United States Preventive Services Task Force recommends screening:

• men age ≥35 at average risk for CVD every 5 years
• women age ≥45 every 5 years¹⁵
• adults as young as age 20 who have accelerated risk factors, such as cigarette smoking and hypertension
• adults with a family history of heart attack or stroke in male first-degree relative age ≥50 and female first-degree relatives age ≥60.

Many adults receiving care in behavioral health settings, regardless of their medication regimen, qualify for screening at least every 5 years, if not more frequently. Although statin treatment before age 40 is less beneficial and likely not necessary for primary prevention, monitoring could help identify alternative therapies and prioritize more intensive diet and lifestyle modifications.

Treatment and management

Dietary modification and lifestyle changes (exercise, quitting smoking), lowering high cholesterol with medications, and switching from highly metabolically active drugs to less metabolically active ones can help lower total cholesterol in patients at risk of CVD.

Statins

HMG-CoA reductase inhibitors (statins) consistently reduce total cholesterol and non-HDL cholesterol by 30% to 50%, depending on drug and dosage (potency, listed as low, medium, and high). Not all statins are equally effective at lowering cholesterol; some are more potent than others (Table 2).¹⁶

Individuals are eligible for statin therapy based on their level of CVD risk. Persons at higher risk generally benefit from greater intensity statin treatment and cholesterol reduction; highest intensity statin regimens can lower total cholesterol by approximately 50%.

There are 4 statin eligibility classes (Table 3). Most adults fall into category 4: 10-year risk of >7.5% and needing primary prevention. In addition to removing specific LDL targets as therapy goals, calculation of this risk percentage and the specific cut-off values have been the most controversial aspects of the new cholesterol guidelines. Most experts agree that, in adults age 40 to 75, 10-year risk >10% indicates daily statin use as tolerated for primary prevention, and 10-year risk <5% does not warrant statin use. Recent large studies have validated these new techniques for calculating risk, and found them to be beneficial in potential for cost savings and risk classification.^17,18

Considerations in psychiatric patients. Statins have been associated with depression in case series, but larger analyses have not confirmed this association.¹⁹ Emerging evidence has identified a potential correlation between statin use and accelerated onset of T2DM, but the absolute risk is relatively low and most experts continue to recommend statin therapy despite this potential risk.¹³ Many statins, including atorvastatin, are available as a generic and can be taken once daily. Some, such as simvastatin, have notable interactions with commonly prescribed psychotropics including risperidone and quetiapine. Pravastatin is dually excreted by the liver and kidneys and may have fewer drug-drug interactions in patients with psychiatric illness taking common psychotropic therapies, but is not considered a high-potency statin and might not confer adequate benefits in CVD risk reduction.

Contraindications. Statins are pregnancy category X, and generally should not be prescribed for women of childbearing age without intensive counseling. The most notable adverse effects for statins include muscle aches and cramps (myalgia), but generally are not severe. If encountered, consider checking a serum creatinine kinase (CK) level, and if significantly elevated above 10 times the upper limit, stopping statin therapy would be advised. If the CK is only mildly elevated, consider lowering the dosage or switching to a lower potency agent. Lovastatin and pravastatin generally are better tolerated than atorvastatin and are considered lower potency (Table 2).

Statins can be safely used in the presence of liver conditions, such as hepatitis C and alcohol use, although periodic monitoring of transaminase levels is recommended. For adults in the general population without liver disease, regular monitoring of transaminase levels is not necessary.

Alternate lipid-lowering pharmacotherapies unfortunately have fallen out of favor. Fibrates, niacin, ezetimibe, and omega-3 fatty acids once were recommended to lower triglycerides or raise HDL cholesterol levels, but since have been shown to have little effect on cardiovascular morbidity or mortality. Adding further medications, other than statins, to lower cholesterol values to pre-defined targets is not the current standard of care.

High triglyceride concentrations traditionally have been addressed directly, but failure to improve CVD mortality or morbidity by treating triglycerides alone has resulted in refocusing clinical efforts in dyslipidemia management on atherogenic cholesterol, including LDL and non-HDL fractions.²⁰ Non-fasting triglycerides >500 mg/dL should be retested when fasting, and levels that remain >500 mg/dL could place the patient at risk for pancreatitis and might warrant intervention with fibrates at that time. This scenario is not common, and referral to a primary care physician or endocrinologist may be warranted.

Lifestyle changes

With or without statin therapies, diet and lifestyle changes are the cornerstone of healthy living and should be encouraged in all patients. Most overweight or obese patients will benefit from exercise and dietary modifications. Such interventions have shown potential for reducing total cholesterol and non-HDL and HDL cholesterol, but rarely are these interventions sustained long enough to produce meaningful reduction in CVD risk through lipid lowering. Diets rich in isocaloric tree nuts and red-yeast rice extract—a form of a statin—have shown promise in reducing cholesterol, but typically take excessive personal resources and are not sustained to the degree necessary to reduce CVD risk over time.²¹ Similarly, regular exercise routines can help lower overall cholesterol numbers, but rarely reduce total cholesterol by >10%.

Because individuals with SMI smoke at a higher rate than the general population, it should be noted that smoking cessation is associated with a reduction in total cholesterol and a trial of smoking cessation therapy is warranted before initiating a statin medication for primary prevention of CVD. Many patients would discover that their 10-year ASCVD risk would fall under the level needed for statin therapy if they could successfully stop smoking.

Switching pharmacotherapies

Switching antipsychotic agents from highly metabolically risky compounds, such as risperidone and olanzapine, to less metabolically active compounds, such as aripiprazole, ziprasidone, or haloperidol, have been associated with improvements in lipid profiles.^22-24 Clinicians must weigh the potential benefits of switching therapies against the risk of psychiatric destabilization and long-term adherence, keeping in mind that changes in lipids seen with switching could be mild (approximately 10% reduction in total cholesterol).

Summing up

Cholesterol management is considered part of a program to systematically lower CVD risk. Statin therapy usually is indicated for life, or until the age of 75, at which point treatment risks and benefits change because of life expectancy. Other components of CVD risk reduction include a focus on blood pressure control, smoking cessation, T2DM management, and weight loss. Tracking lipid profiles over time to ensure broad targets of 30% to 50% reduction in total cholesterol, approximately 3 months after initiation and yearly thereafter, can help ensure adherence to therapy. With systematic lowering of modifiable CVD risk factors, we can hope to gradually improve the quality of life for our patients with mental illnesses (see the Box for a case example illustrating successful use of these strategies).

Cancer screening is an important example of secondary prevention—the aim being to detect disease at an early stage, when treatment can prevent symptomatic disease. Over the years, screening tests for breast cancer, colorectal cancer (CRC), cervical cancer, and, most recently, lung cancer have been developed and recommended by the U.S. Preventive Services Task Force (USPSTF). Among breast cancer, cervical cancer, and CRC, the screening rate for CRC remains lowest, at 58.6%.¹

The importance of screening for CRC is highlighted by the facts that:

• CRC is the third most commonly diagnosed form of cancer in the United States among both men and women
• CRC is the second leading cause of cancer-related death.²

The overall decrease in the incidence of CRC in the United States has been credited to improvements in screening and removal of potentially precancerous lesions.³

Harmful disparity puts the mentally ill at exceptional risk

Screening patterns for CRC among patients with mental illness are poorly characterized, but it is known that the overall cancer screening rate among patients with severe psychiatric illness lags significantly behind the rate in the general population.^4,5 In addition, studies have shown that mortality among patients with CRC who have a mental disorder is elevated, compared with CRC patients who do not have a psychiatric diagnosis.⁶

Why this disparity? It might be that CRC is more likely to be diagnosed at an advanced stage among these patients, or that they are less likely to receive cancer treatment after diagnosis, or are more likely to have a longer delay between diagnosis and initial treatment than patients who do not have a psychiatric diagnosis.⁷

Regardless, psychiatric practitioners can make a significant impact on reducing this health disparity by leveraging their unique therapeutic relationship to educate patients about screening options and dispel myths about cancer screening. In this article, we outline practical strategies for CRC screening and weigh the advantages and disadvantages for the use of several tools and guidelines in psychiatric patients.

What is the pathogenesis of colorectal cancer?

Most cases of CRC evolve from polyps, abnormal growths on the lining of the colon or rectum. Constituting an estimated 96% of all polyps, adenomas are by far the most common form in the colon and rectum.

Adenomas also are most likely to transform over time to dysplasia, and then to progress to cancer.⁸ Although all adenomas have malignant potential, <10% evolve to adenocarcinoma. This proposed adenoma➝carcinoma sequence is not well understood; however, it is known that CRC usually develops slowly—over 10 to 15 years.⁹ Detection and removal of adenomas and treatable, localized carcinomas form the basis of screening for CRC.

Risk factors for colorectal cancer

A number of risk factors for CRC have been identified.

Specific heritable conditions, such as Lynch syndrome and familial adenomatous polyposis, pose the greatest risk of CRC, particularly at younger ages and compared with people without such a history.¹⁰

Family history. One of the strongest risk factors for CRC remains a family history of the disease. People who have a first-degree relative with a diagnosis of CRC are at 2 to 3 times the risk of CRC, compared with people without a family history of the disease. This risk increases further if multiple family members are affected or if the diagnosis was made in a relative at a young age.^11,12

Other non-modifiable risk factors include a personal history of inflammatory bowel disease, type 2 diabetes mellitus, male sex, African American heritage, and increasing age.^13-15

Common modifiable risk factors include obesity, smoking, and alcohol consumption.^16-18

What is the role of screening?

CRC screening is only appropriate for patients who are asymptomatic. CRC generally is asymptomatic in early stages. Prognosis also is most favorable when CRC is detected in the asymptomatic stage.

As lesions of CRC grow, the presentation might include hematochezia, melena, abdominal pain, weight loss, occult anemia, constipation or diarrhea, and changes in stool caliber.¹⁹ These signs and symptoms are not highly specific for CRC, however, and might be indicative of other gastrointestinal pathology, including inflammatory bowel disease, diverticulitis, irritable bowel syndrome, infectious colitis, hemorrhoids, and mesenteric ischemia.

Symptomatic patients should be referred directly for diagnostic evaluation. Colonoscopy with biopsy is the standard for diagnosing CRC. Once a diagnosis of CRC is made, patients should be referred to a specialist to discuss treatment; options largely depend on the stage of the cancer at diagnosis.

What screening tests are available?

Unlike screening for other cancers, there are a number of reasonable options for CRC screening; Table 1¹⁵ compares their relative pros and cons. Each test has its benefits and drawbacks, allowing the screening strategy to be customized based on patient preference and characteristics, but this variability also can lead to confusion by patient and provider about those options.

Stool-based tests detect trace amounts of blood from early-stage treatable cancers. Highly sensitive fecal occult blood testing (FOBT) has been shown specifically to decrease mortality from CRC.²⁰ Stool-based tests are inexpensive and noninvasive, but require:

• more frequent testing
• that the patient collect the stool specimen
• follow-up colonoscopy when test results are positive.

Endoscopic and imaging tests detect polyps and early-stage treatable cancers; all require some degree of bowel preparation, and some require sedation. Testing intervals vary but, as a group, are longer than the interval between stool-based tests because polyps grow slowly. Because colonoscopy with biopsy is the preferred screening method for diagnosing CRC, it is the only screening option that also is a diagnostic procedure.

Where can screening guidelines be found?

Several professional organizations have developed guidelines for CRC screening. The 2 major

An update to both guidelines was released in 2008. Table 2^21,22 summarizes their recommendations.

Both guidelines recommend that screening begin at age 50 (Box). The primary differences between the 2 guidelines lie in the scope of recommended options for screening and the time frame for discontinuing screening:

• USPSTF requires a higher level of evidence for screening options and limits recommended options to FOBT, sigmoidoscopy combined with FOBT, and colonoscopy.
• ACS-MSTF-ACR emphasizes options that detect premalignant polyps, and generally is more inclusive of testing options; it also delineates tests as useful for either (1) early detection of cancer (stool-based studies) or (2) cancer prevention (endoscopic and imaging tests).

On the question of when to stop screening, ACS-MSTF-ACR bases its recommendations on life expectancy; USPSTF sets a specific age for ending screening.^21,22

Recommendations of a third entity, the American College of Gastroenterology (ACG), are similar to those of ACS-MSTF-ACR; however, ACG (1) recommends beginning screening African American patients at age 45 because of their increased risk of CRC and (2) gives preference to colonoscopy as the preferred screening modality.²³

Guidelines vary for high-risk patients (those with a history of familial adenomatous polyposis or another inherited syndrome associated with CRC; those with a family history of CRC in the young; those with a history of radiation exposure, history of CRC, or inflammatory bowel disease; and those with several first-degree relatives with CRC). Patients who fall into any of these categories should be referred for specialty care to establish the time of initial screening and the interval of subsequent screening.

CRC screening in the presence of psychiatric illness

Psychiatrists have an opportunity to support their patients when considering potentially confusing CRC screening recommendations. This opportunity might occur during a discussion about general preventive care, or a patient might come to an appointment after visiting a primary care provider, and ask for advice about screening options.

The potential benefits of CRC screening are negated if a patient is unable or unwilling to complete the test or undergo timely follow-up of positive results. It is important, therefore, to individualize screening recommendations—keeping in mind the degree of impairment from mental illness and the patient’s preferences and reliability to engage in follow-up. To date, there are no agreed-on screening guidelines specifically for patients with comorbid mental illness.

Adapting USPSTF guidelines for CRC screening of average-risk patients with mental illness, we offer the following recommendations:

Recommend screening. Begin routine screening at age 50. Patients with well-controlled or mild symptoms should be screened with a stool study with or without flexible sigmoidoscopy. Stool studies are safe, noninvasive, and require no bowel preparation; when used alone, however, they need to be performed yearly.

Screening accuracy is increased when a stool-based test is combined with flexible sigmoidoscopy; screening then can be performed less often. Unlike colonoscopy, flexible sigmoidoscopy does not involve sedation; a high-functioning patient might find this appealing and tolerate the greater frequency of screening. On the other hand, some patients might not accept the inconvenience of collecting the stool sample with the kit provided and returning it to the lab for processing.

Manage psychiatric illness optimally. For a patient with moderate or severe psychiatric symptoms, first attempt to optimize treatment of the underlying psychiatric condition before establishing a CRC screening program. If control of symptoms is likely to improve over the next 1 or 2 visits, it might be reasonable to defer screening until symptoms are better controlled and then reassess the patient before making specific screening recommendations. Screening should not be delayed, however, if significant improvement in symptoms is not expected in the near future. Lengthy delay might lead to failure in initiating screening at all.

We recommend that patients with persistent moderate or severe symptoms be screened with traditional colonoscopy. The sedation associated with colonoscopy (1) may be preferable to some patients with more severe illness and (2) allows for screening and diagnostic biopsy if needed during the same procedure. Screening with colonoscopy also:

• avoids the yearly adherence to a screening program that is needed with stool cards alone
• does not rely on patients collecting and returning stool kits for processing.

A potential challenge for patients with limited social support is the requirement to have someone accompany the patient on the day of colonoscopy.

Take steps to improve the screening rate. In addition to specific recommendations based on symptom severity, there are systems-level interventions that should be considered to improve the screening rate. These include:

• addressing transportation issues that are a barrier to screening
• considering the use of health navigators or peer advocates to help guide patients through the sometimes complex systems of care.

A more comprehensive systems-level intervention for mental health clinics that work primarily with persistent and severe mentally ill populations might include employing a care coordinator to organize referrals to primary care or even exploring reverse integration. In reverse integration, primary care providers co-locate within the mental health clinic, (1) allowing for “one-stop shopping” of mental health and primary care needs and (2) facilitating collaboration and shared treatment planning between primary care and mental health for complex patients.

Cancer screening is an important example of secondary prevention—the aim being to detect disease at an early stage, when treatment can prevent symptomatic disease. Over the years, screening tests for breast cancer, colorectal cancer (CRC), cervical cancer, and, most recently, lung cancer have been developed and recommended by the U.S. Preventive Services Task Force (USPSTF). Among breast cancer, cervical cancer, and CRC, the screening rate for CRC remains lowest, at 58.6%.¹

The importance of screening for CRC is highlighted by the facts that:

• CRC is the third most commonly diagnosed form of cancer in the United States among both men and women
• CRC is the second leading cause of cancer-related death.²

The overall decrease in the incidence of CRC in the United States has been credited to improvements in screening and removal of potentially precancerous lesions.³

Harmful disparity puts the mentally ill at exceptional risk

Screening patterns for CRC among patients with mental illness are poorly characterized, but it is known that the overall cancer screening rate among patients with severe psychiatric illness lags significantly behind the rate in the general population.^4,5 In addition, studies have shown that mortality among patients with CRC who have a mental disorder is elevated, compared with CRC patients who do not have a psychiatric diagnosis.⁶

Why this disparity? It might be that CRC is more likely to be diagnosed at an advanced stage among these patients, or that they are less likely to receive cancer treatment after diagnosis, or are more likely to have a longer delay between diagnosis and initial treatment than patients who do not have a psychiatric diagnosis.⁷

Regardless, psychiatric practitioners can make a significant impact on reducing this health disparity by leveraging their unique therapeutic relationship to educate patients about screening options and dispel myths about cancer screening. In this article, we outline practical strategies for CRC screening and weigh the advantages and disadvantages for the use of several tools and guidelines in psychiatric patients.

What is the pathogenesis of colorectal cancer?

Most cases of CRC evolve from polyps, abnormal growths on the lining of the colon or rectum. Constituting an estimated 96% of all polyps, adenomas are by far the most common form in the colon and rectum.

Adenomas also are most likely to transform over time to dysplasia, and then to progress to cancer.⁸ Although all adenomas have malignant potential, <10% evolve to adenocarcinoma. This proposed adenoma➝carcinoma sequence is not well understood; however, it is known that CRC usually develops slowly—over 10 to 15 years.⁹ Detection and removal of adenomas and treatable, localized carcinomas form the basis of screening for CRC.

Risk factors for colorectal cancer

A number of risk factors for CRC have been identified.

Specific heritable conditions, such as Lynch syndrome and familial adenomatous polyposis, pose the greatest risk of CRC, particularly at younger ages and compared with people without such a history.¹⁰

Family history. One of the strongest risk factors for CRC remains a family history of the disease. People who have a first-degree relative with a diagnosis of CRC are at 2 to 3 times the risk of CRC, compared with people without a family history of the disease. This risk increases further if multiple family members are affected or if the diagnosis was made in a relative at a young age.^11,12

Other non-modifiable risk factors include a personal history of inflammatory bowel disease, type 2 diabetes mellitus, male sex, African American heritage, and increasing age.^13-15

Common modifiable risk factors include obesity, smoking, and alcohol consumption.^16-18

What is the role of screening?

CRC screening is only appropriate for patients who are asymptomatic. CRC generally is asymptomatic in early stages. Prognosis also is most favorable when CRC is detected in the asymptomatic stage.

As lesions of CRC grow, the presentation might include hematochezia, melena, abdominal pain, weight loss, occult anemia, constipation or diarrhea, and changes in stool caliber.¹⁹ These signs and symptoms are not highly specific for CRC, however, and might be indicative of other gastrointestinal pathology, including inflammatory bowel disease, diverticulitis, irritable bowel syndrome, infectious colitis, hemorrhoids, and mesenteric ischemia.

Symptomatic patients should be referred directly for diagnostic evaluation. Colonoscopy with biopsy is the standard for diagnosing CRC. Once a diagnosis of CRC is made, patients should be referred to a specialist to discuss treatment; options largely depend on the stage of the cancer at diagnosis.

What screening tests are available?

Unlike screening for other cancers, there are a number of reasonable options for CRC screening; Table 1¹⁵ compares their relative pros and cons. Each test has its benefits and drawbacks, allowing the screening strategy to be customized based on patient preference and characteristics, but this variability also can lead to confusion by patient and provider about those options.

Stool-based tests detect trace amounts of blood from early-stage treatable cancers. Highly sensitive fecal occult blood testing (FOBT) has been shown specifically to decrease mortality from CRC.²⁰ Stool-based tests are inexpensive and noninvasive, but require:

• more frequent testing
• that the patient collect the stool specimen
• follow-up colonoscopy when test results are positive.

Endoscopic and imaging tests detect polyps and early-stage treatable cancers; all require some degree of bowel preparation, and some require sedation. Testing intervals vary but, as a group, are longer than the interval between stool-based tests because polyps grow slowly. Because colonoscopy with biopsy is the preferred screening method for diagnosing CRC, it is the only screening option that also is a diagnostic procedure.

Where can screening guidelines be found?

Several professional organizations have developed guidelines for CRC screening. The 2 major

An update to both guidelines was released in 2008. Table 2^21,22 summarizes their recommendations.

Both guidelines recommend that screening begin at age 50 (Box). The primary differences between the 2 guidelines lie in the scope of recommended options for screening and the time frame for discontinuing screening:

• USPSTF requires a higher level of evidence for screening options and limits recommended options to FOBT, sigmoidoscopy combined with FOBT, and colonoscopy.
• ACS-MSTF-ACR emphasizes options that detect premalignant polyps, and generally is more inclusive of testing options; it also delineates tests as useful for either (1) early detection of cancer (stool-based studies) or (2) cancer prevention (endoscopic and imaging tests).

On the question of when to stop screening, ACS-MSTF-ACR bases its recommendations on life expectancy; USPSTF sets a specific age for ending screening.^21,22

Recommendations of a third entity, the American College of Gastroenterology (ACG), are similar to those of ACS-MSTF-ACR; however, ACG (1) recommends beginning screening African American patients at age 45 because of their increased risk of CRC and (2) gives preference to colonoscopy as the preferred screening modality.²³

Guidelines vary for high-risk patients (those with a history of familial adenomatous polyposis or another inherited syndrome associated with CRC; those with a family history of CRC in the young; those with a history of radiation exposure, history of CRC, or inflammatory bowel disease; and those with several first-degree relatives with CRC). Patients who fall into any of these categories should be referred for specialty care to establish the time of initial screening and the interval of subsequent screening.

CRC screening in the presence of psychiatric illness

Psychiatrists have an opportunity to support their patients when considering potentially confusing CRC screening recommendations. This opportunity might occur during a discussion about general preventive care, or a patient might come to an appointment after visiting a primary care provider, and ask for advice about screening options.

The potential benefits of CRC screening are negated if a patient is unable or unwilling to complete the test or undergo timely follow-up of positive results. It is important, therefore, to individualize screening recommendations—keeping in mind the degree of impairment from mental illness and the patient’s preferences and reliability to engage in follow-up. To date, there are no agreed-on screening guidelines specifically for patients with comorbid mental illness.

Adapting USPSTF guidelines for CRC screening of average-risk patients with mental illness, we offer the following recommendations:

Recommend screening. Begin routine screening at age 50. Patients with well-controlled or mild symptoms should be screened with a stool study with or without flexible sigmoidoscopy. Stool studies are safe, noninvasive, and require no bowel preparation; when used alone, however, they need to be performed yearly.

Screening accuracy is increased when a stool-based test is combined with flexible sigmoidoscopy; screening then can be performed less often. Unlike colonoscopy, flexible sigmoidoscopy does not involve sedation; a high-functioning patient might find this appealing and tolerate the greater frequency of screening. On the other hand, some patients might not accept the inconvenience of collecting the stool sample with the kit provided and returning it to the lab for processing.

Manage psychiatric illness optimally. For a patient with moderate or severe psychiatric symptoms, first attempt to optimize treatment of the underlying psychiatric condition before establishing a CRC screening program. If control of symptoms is likely to improve over the next 1 or 2 visits, it might be reasonable to defer screening until symptoms are better controlled and then reassess the patient before making specific screening recommendations. Screening should not be delayed, however, if significant improvement in symptoms is not expected in the near future. Lengthy delay might lead to failure in initiating screening at all.

We recommend that patients with persistent moderate or severe symptoms be screened with traditional colonoscopy. The sedation associated with colonoscopy (1) may be preferable to some patients with more severe illness and (2) allows for screening and diagnostic biopsy if needed during the same procedure. Screening with colonoscopy also:

• avoids the yearly adherence to a screening program that is needed with stool cards alone
• does not rely on patients collecting and returning stool kits for processing.

A potential challenge for patients with limited social support is the requirement to have someone accompany the patient on the day of colonoscopy.

Take steps to improve the screening rate. In addition to specific recommendations based on symptom severity, there are systems-level interventions that should be considered to improve the screening rate. These include:

• addressing transportation issues that are a barrier to screening
• considering the use of health navigators or peer advocates to help guide patients through the sometimes complex systems of care.

A more comprehensive systems-level intervention for mental health clinics that work primarily with persistent and severe mentally ill populations might include employing a care coordinator to organize referrals to primary care or even exploring reverse integration. In reverse integration, primary care providers co-locate within the mental health clinic, (1) allowing for “one-stop shopping” of mental health and primary care needs and (2) facilitating collaboration and shared treatment planning between primary care and mental health for complex patients.

Cancer screening is an important example of secondary prevention—the aim being to detect disease at an early stage, when treatment can prevent symptomatic disease. Over the years, screening tests for breast cancer, colorectal cancer (CRC), cervical cancer, and, most recently, lung cancer have been developed and recommended by the U.S. Preventive Services Task Force (USPSTF). Among breast cancer, cervical cancer, and CRC, the screening rate for CRC remains lowest, at 58.6%.¹

The importance of screening for CRC is highlighted by the facts that:

• CRC is the third most commonly diagnosed form of cancer in the United States among both men and women
• CRC is the second leading cause of cancer-related death.²

The overall decrease in the incidence of CRC in the United States has been credited to improvements in screening and removal of potentially precancerous lesions.³

Harmful disparity puts the mentally ill at exceptional risk

Screening patterns for CRC among patients with mental illness are poorly characterized, but it is known that the overall cancer screening rate among patients with severe psychiatric illness lags significantly behind the rate in the general population.^4,5 In addition, studies have shown that mortality among patients with CRC who have a mental disorder is elevated, compared with CRC patients who do not have a psychiatric diagnosis.⁶

Why this disparity? It might be that CRC is more likely to be diagnosed at an advanced stage among these patients, or that they are less likely to receive cancer treatment after diagnosis, or are more likely to have a longer delay between diagnosis and initial treatment than patients who do not have a psychiatric diagnosis.⁷

Regardless, psychiatric practitioners can make a significant impact on reducing this health disparity by leveraging their unique therapeutic relationship to educate patients about screening options and dispel myths about cancer screening. In this article, we outline practical strategies for CRC screening and weigh the advantages and disadvantages for the use of several tools and guidelines in psychiatric patients.

What is the pathogenesis of colorectal cancer?

Most cases of CRC evolve from polyps, abnormal growths on the lining of the colon or rectum. Constituting an estimated 96% of all polyps, adenomas are by far the most common form in the colon and rectum.

Adenomas also are most likely to transform over time to dysplasia, and then to progress to cancer.⁸ Although all adenomas have malignant potential, <10% evolve to adenocarcinoma. This proposed adenoma➝carcinoma sequence is not well understood; however, it is known that CRC usually develops slowly—over 10 to 15 years.⁹ Detection and removal of adenomas and treatable, localized carcinomas form the basis of screening for CRC.

Risk factors for colorectal cancer

A number of risk factors for CRC have been identified.

Specific heritable conditions, such as Lynch syndrome and familial adenomatous polyposis, pose the greatest risk of CRC, particularly at younger ages and compared with people without such a history.¹⁰

Family history. One of the strongest risk factors for CRC remains a family history of the disease. People who have a first-degree relative with a diagnosis of CRC are at 2 to 3 times the risk of CRC, compared with people without a family history of the disease. This risk increases further if multiple family members are affected or if the diagnosis was made in a relative at a young age.^11,12

Other non-modifiable risk factors include a personal history of inflammatory bowel disease, type 2 diabetes mellitus, male sex, African American heritage, and increasing age.^13-15

Common modifiable risk factors include obesity, smoking, and alcohol consumption.^16-18

What is the role of screening?

CRC screening is only appropriate for patients who are asymptomatic. CRC generally is asymptomatic in early stages. Prognosis also is most favorable when CRC is detected in the asymptomatic stage.

As lesions of CRC grow, the presentation might include hematochezia, melena, abdominal pain, weight loss, occult anemia, constipation or diarrhea, and changes in stool caliber.¹⁹ These signs and symptoms are not highly specific for CRC, however, and might be indicative of other gastrointestinal pathology, including inflammatory bowel disease, diverticulitis, irritable bowel syndrome, infectious colitis, hemorrhoids, and mesenteric ischemia.

Symptomatic patients should be referred directly for diagnostic evaluation. Colonoscopy with biopsy is the standard for diagnosing CRC. Once a diagnosis of CRC is made, patients should be referred to a specialist to discuss treatment; options largely depend on the stage of the cancer at diagnosis.

What screening tests are available?

Unlike screening for other cancers, there are a number of reasonable options for CRC screening; Table 1¹⁵ compares their relative pros and cons. Each test has its benefits and drawbacks, allowing the screening strategy to be customized based on patient preference and characteristics, but this variability also can lead to confusion by patient and provider about those options.

Stool-based tests detect trace amounts of blood from early-stage treatable cancers. Highly sensitive fecal occult blood testing (FOBT) has been shown specifically to decrease mortality from CRC.²⁰ Stool-based tests are inexpensive and noninvasive, but require:

• more frequent testing
• that the patient collect the stool specimen
• follow-up colonoscopy when test results are positive.

Endoscopic and imaging tests detect polyps and early-stage treatable cancers; all require some degree of bowel preparation, and some require sedation. Testing intervals vary but, as a group, are longer than the interval between stool-based tests because polyps grow slowly. Because colonoscopy with biopsy is the preferred screening method for diagnosing CRC, it is the only screening option that also is a diagnostic procedure.

Where can screening guidelines be found?

Several professional organizations have developed guidelines for CRC screening. The 2 major

An update to both guidelines was released in 2008. Table 2^21,22 summarizes their recommendations.

Both guidelines recommend that screening begin at age 50 (Box). The primary differences between the 2 guidelines lie in the scope of recommended options for screening and the time frame for discontinuing screening:

• USPSTF requires a higher level of evidence for screening options and limits recommended options to FOBT, sigmoidoscopy combined with FOBT, and colonoscopy.
• ACS-MSTF-ACR emphasizes options that detect premalignant polyps, and generally is more inclusive of testing options; it also delineates tests as useful for either (1) early detection of cancer (stool-based studies) or (2) cancer prevention (endoscopic and imaging tests).

On the question of when to stop screening, ACS-MSTF-ACR bases its recommendations on life expectancy; USPSTF sets a specific age for ending screening.^21,22

Recommendations of a third entity, the American College of Gastroenterology (ACG), are similar to those of ACS-MSTF-ACR; however, ACG (1) recommends beginning screening African American patients at age 45 because of their increased risk of CRC and (2) gives preference to colonoscopy as the preferred screening modality.²³

Guidelines vary for high-risk patients (those with a history of familial adenomatous polyposis or another inherited syndrome associated with CRC; those with a family history of CRC in the young; those with a history of radiation exposure, history of CRC, or inflammatory bowel disease; and those with several first-degree relatives with CRC). Patients who fall into any of these categories should be referred for specialty care to establish the time of initial screening and the interval of subsequent screening.

CRC screening in the presence of psychiatric illness

Psychiatrists have an opportunity to support their patients when considering potentially confusing CRC screening recommendations. This opportunity might occur during a discussion about general preventive care, or a patient might come to an appointment after visiting a primary care provider, and ask for advice about screening options.

The potential benefits of CRC screening are negated if a patient is unable or unwilling to complete the test or undergo timely follow-up of positive results. It is important, therefore, to individualize screening recommendations—keeping in mind the degree of impairment from mental illness and the patient’s preferences and reliability to engage in follow-up. To date, there are no agreed-on screening guidelines specifically for patients with comorbid mental illness.

Adapting USPSTF guidelines for CRC screening of average-risk patients with mental illness, we offer the following recommendations:

Recommend screening. Begin routine screening at age 50. Patients with well-controlled or mild symptoms should be screened with a stool study with or without flexible sigmoidoscopy. Stool studies are safe, noninvasive, and require no bowel preparation; when used alone, however, they need to be performed yearly.

Screening accuracy is increased when a stool-based test is combined with flexible sigmoidoscopy; screening then can be performed less often. Unlike colonoscopy, flexible sigmoidoscopy does not involve sedation; a high-functioning patient might find this appealing and tolerate the greater frequency of screening. On the other hand, some patients might not accept the inconvenience of collecting the stool sample with the kit provided and returning it to the lab for processing.

Manage psychiatric illness optimally. For a patient with moderate or severe psychiatric symptoms, first attempt to optimize treatment of the underlying psychiatric condition before establishing a CRC screening program. If control of symptoms is likely to improve over the next 1 or 2 visits, it might be reasonable to defer screening until symptoms are better controlled and then reassess the patient before making specific screening recommendations. Screening should not be delayed, however, if significant improvement in symptoms is not expected in the near future. Lengthy delay might lead to failure in initiating screening at all.

We recommend that patients with persistent moderate or severe symptoms be screened with traditional colonoscopy. The sedation associated with colonoscopy (1) may be preferable to some patients with more severe illness and (2) allows for screening and diagnostic biopsy if needed during the same procedure. Screening with colonoscopy also:

• avoids the yearly adherence to a screening program that is needed with stool cards alone
• does not rely on patients collecting and returning stool kits for processing.

A potential challenge for patients with limited social support is the requirement to have someone accompany the patient on the day of colonoscopy.

Take steps to improve the screening rate. In addition to specific recommendations based on symptom severity, there are systems-level interventions that should be considered to improve the screening rate. These include:

• addressing transportation issues that are a barrier to screening
• considering the use of health navigators or peer advocates to help guide patients through the sometimes complex systems of care.

A more comprehensive systems-level intervention for mental health clinics that work primarily with persistent and severe mentally ill populations might include employing a care coordinator to organize referrals to primary care or even exploring reverse integration. In reverse integration, primary care providers co-locate within the mental health clinic, (1) allowing for “one-stop shopping” of mental health and primary care needs and (2) facilitating collaboration and shared treatment planning between primary care and mental health for complex patients.

Chronic obstructive pulmonary disease (COPD) usually is not diagnosed until clinically apparent and moderately advanced. Patients might not notice chronic dyspnea and smoker’s cough, or might consider their symptoms “normal” and not seek medical care. Delayed diagnosis is particularly prevalent in the psychiatric population, in which co-existing medical problems tend to remain unrecognized and untreated.¹

Life expectancy of people with serious mental illness (SMI) is 13 to 30 years less than that of the general population—a gap that has widened over time.² Pulmonary disease is a leading cause of elevated mortality risk in SMI, along with cardiovascular and infectious disease, diabetes, and barriers to care. Having a comorbid mental illness triples the mortality risk of chronic lower respiratory disease (Table 1).³

This article describes how you can intervene and improve quality of life for your patients with COPD by:

• asking all patients, especially smokers, if they are experiencing classic symptoms of COPD
• advocating for and supporting smoking cessation efforts
• avoiding drug interactions and off-target dosing related to COPD and nicotine replacement therapy
• considering, if feasible, a switch from typical to atypical antipsychotic therapy, which could reduce smoking behavior.

What is COPD?
COPD is preventable and treatable. It is characterized by “persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lungs to inhaled noxious particles or gases.”⁴

Smoking tobacco is the greatest risk factor for developing COPD.⁵ An estimated 50% to 80% of people with schizophrenia are smokers, as are 55% of people with bipolar disorder.⁶ COPD is a leading cause of morbidity and mortality worldwide,^7,8 and its prevalence is projected to increase as the global population and smoking rates grow.⁹

A simplified schema of the pathophysiology of COPD implicates 4 lung areas: parenchyma, pulmonary vasculature, central airways, and peripheral airways.¹⁰ Variation in the areas affected and severity of change contributes to the disease’s heterogeneous presentation, which can include pulmonary hypertension, hypersecretion of mucus, ciliary dysfunction, airway hyperinflation, and impaired gas exchange.^11,12 Many of these features lead to systemic effects as well, particularly on cardiac function.

When to test a patient for COPD
Early diagnosis and treatment can substantially improve quality-of-life outcomes for patients with COPD. The clinical approach (Figure 1) begins with recognizing classic symptoms. Consider COPD in any patient with:

• dyspnea (particularly if becoming worse, persistent, or associated with exercise)
• chronic cough
• chronic sputum production
• history of risk-factor exposure (particularly tobacco smoke)
• family history of COPD.⁴

If the history and physical exam suggest COPD (Table 2), spirometry is the most reliable test to quantify and characterize lung dysfunction. It is not indicated as a screening tool for healthy adults or appropriate when a patient is acutely ill. Forced expiratory volume in the first second of expiration divided by the measured forced vital capacity (FEV1/FVC) < 0.7 defines clinical COPD and determines the need for pharmacologic intervention. Laboratory studies could be useful in certain clinical scenarios, such as serum testing for alpha₁-antitrypsin deficiency in patients age <45 with emphysema. Plain film imaging might be useful to support a COPD diagnosis or rule out alternate diagnoses.

Psychopharmacology issues with comorbid COPD
Pharmacotherapy for psychiatric disorders can exacerbate comorbid COPD. For example, long-term use of phenothiazine-related typical antipsychotics for schizophrenia has been linked to an increased incidence of COPD.¹³ Antipsychotic side effects such as acute laryngeal dystonia and tardive dyskinesia, most commonly seen with first-generation antipsychotic use, can aggravate dyspnea caused by COPD. Opioids and most hypnotics, sedatives, and anxiolytics suppress the respiratory drive, and therefore should be used with caution in patients with COPD.

Carefully monitor serum levels of medications before and during attempts at smoking cessation. Nicotine’s induction of the cytochrome P450 1A2 system increases the metabolism of antipsychotics such as clozapine, fluvoxamine, olanzapine, and haloperidol. As a result, potentially toxic drug levels can occur when a smoker tries to quit.¹⁴

Screen patients with COPD for co­morbid psychiatric conditions. New psychiatric symptoms can emerge after COPD has been diagnosed, even in patients without pre-existing psychopathology.

Anxiety is a particularly common COPD comorbidity that can be difficult to manage. Selective serotonin reuptake inhibitors, buspirone, cognitive-behavioral therapy, and pulmonary rehabilitation can be helpful, although the effect of antidepressants on respiration is controversial. Nortriptyline has been shown to be effective in treating both anxiety and depressive symptoms in patients with COPD.¹⁵ Avoid using hypnotics to manage sleep problems related to COPD; instead, focus on minimizing sleep disturbance by limiting cough and dyspnea.

Antipsychotics and nicotine metabolism
Multiple studies have focused on the interplay among nicotine, dopamine, and antipsychotic agents. Nicotine receptors are present in the ventral tegmental dopaminergic cell bodies, which induce the release of dopamine and other neurotransmitters when stimulated. Smoking has been noted to increase in patients administered haloperidol (a dopamine antagonist) and to decrease with administration of bromocriptine (a dopamine agonist).¹⁶ This suggests that psychiatric patients might smoke to overcome the dopamine blockade caused by most typical antipsychotics, therefore alleviating their negative and extrapyramidal side effects.¹⁷

Alternatively, some studies suggest that a difference in dopamine receptor occupancy between typical and atypical antipsychotics leads to different effects on smoking behavior.¹⁸ When used long term, typical antipsychotics might increase dopamine receptors or dopamine sensitivity, and thus reinforce the positive effect of nicotine by increasing the number of receptors that can be stimulated, whereas atypical antipsychotics help stimulate the release of dopamine directly through partial agonist of serotonin 5-HT1A receptors.^19,20 Atypical antipsychotics also appear to decrease cue-elicited cravings in people who are not mentally ill, whereas haloperidol does not.²¹

Based on these findings, switching patients with COPD from a typical to an atypical antipsychotic, if feasible, might make smoking cessation more manageable.²² Multiple studies have shown that clozapine is the preferred atypical antipsychotic because it is associated with the most significant decrease in smoking behaviors.²³

First-line therapy: Nicotine replacement
Smoking cessation slows the progression of COPD and leads to marked improvements in cough, expectoration, breathlessness, and wheezing.^24,25 Nicotine replacement therapy (NRT)—gum, inhaler, lozenges, nasal spray, and skin patch—is considered first-line pharmacotherapy. These nicotine substitutes can decrease withdrawal symptoms, although they do not appear to be as effective for light smokers (eg, <10 cigarettes/d), compared with heavy smokers (eg, ≥20 cigarettes/d).²⁶

Long-term smoking abstinence can be improved with combination therapies. A nicotine patch, kept in place for as long as 24 hours, often is used with a nicotine gum or nasal spray. Another option combines the patch with a first-line, non-NRT intervention, such as sustained-release bupropion. Use bupropion with caution in psychiatric patients, however. Do not combine it with a monoamine oxidase inhibitor, and do not prescribe it to patients with an eating disorder or history of seizures.²⁶ Bupropion could induce mania in patients with bipolar disorder.

Varenicline, a nicotinic receptor partial agonist indicated to aid in smoking cessation, has been shown to reduce pleasure gained from tobacco as well as cravings. It can increase the likelihood of abstinence from smoking for as long as 1 year, but it also can provoke behavioral changes, depressed mood, and suicidal ideation. These risks—described in an FDA black-box warning of serious neuropsychiatric events—warrant due caution when prescribing varenicline to patients with depression. The FDA also has warned that varenicline could lead to decreased alcohol tolerance and atypically aggressive behavior during intoxication, which is of particular concern because of the high rate of alcohol use among people with SMI.

Motivating and supporting change
When counseling patients with mental illness about smoking cessation, consider unique motivations that, if disregarded, could undermine your efforts. As described above, smoking can ameliorate negative and extrapyramidal symptoms associated with typical antipsychotics. This could explain the significantly higher rates of smoking associated with typical antipsychotics, compared with atypical antipsychotics.²⁷ Patients also could use smoking as self-medication for depression and anxiety. Therefore, take care to offer alternate methods for coping, along with smoking cessation recommendations.²²

Screen all adult patients for tobacco use, and offer prompt cessation counseling and pharmacologic interventions._²⁸As a motivational intervention, the “5 As” framework—ask, advise, assess, assist, arrange—can help gauge patients’ smoking status and willingness to quit, as well as emphasize the importance of establishing a concrete, manageable plan.²⁹

Keep in mind the barriers all patients face in their fight to quit smoking, such as nicotine withdrawal, weight gain, and loss of a coping mechanism for stress.²⁹ Patients with schizophrenia can be motivated to quit smoking and participate in treatment for nicotine dependence.³⁰

Besides encouraging smoking cessation, you can educate patients in behaviors that will improve COPD symptoms and management. These include:

• reducing the risk of lung infections through vaccinations (influenza yearly, pneumonia once in adulthood) and avoiding crowds during peak cold and influenza season
• participating in physical activity, which could slow lung function decline
• adhering to prescribed medication
• eating a balanced diet
• seeking medical care early during an exacerbation.

Coaching patients in symptom control
Smoking cessation may have the greatest long-term benefit for patients with COPD, but symptom management is important as well (Figure 2). Pharmacotherapy for COPD usually is advanced in steps, but a more aggressive approach may be necessary for patients presenting with severe symptoms.

Mainstays of COPD therapy are inhaled bronchodilators, consisting of β2 agonists and anticholinergics, alone or in combination. Short-acting formulations are used for mild and intermittent symptoms; long-acting bronchodilators are added if symptoms persist.⁴ When dyspnea, wheezing, and activity intolerance are not well-controlled with bronchodilators, an inhaled corticosteroid can be tried, either alone or in combination with a long-acting bronchodilator.⁴

Adherence to medical recommendations is critical for successful COPD management, but inhaled therapy can be difficult for psychiatric patients—especially patients with cognitive or functional impairment. Asking them to demonstrate their inhaler technique can help assess treatment effectiveness.³¹

Referral to a pulmonologist is strongly advised in cases of:

• advanced, end-stage COPD (FEV1 <50% predicted value despite adherence to recommended treatment, or rapid decline of FEV1)
• COPD in patients age <50
• frequent exacerbations
• possible complications related to chronic heart failure
• indications for oxygen treatment (eg, resting or ambulatory oxygen saturation ≤88% or PaO₂ ≤55 mm Hg).³²

Chronic obstructive pulmonary disease (COPD) usually is not diagnosed until clinically apparent and moderately advanced. Patients might not notice chronic dyspnea and smoker’s cough, or might consider their symptoms “normal” and not seek medical care. Delayed diagnosis is particularly prevalent in the psychiatric population, in which co-existing medical problems tend to remain unrecognized and untreated.¹

Life expectancy of people with serious mental illness (SMI) is 13 to 30 years less than that of the general population—a gap that has widened over time.² Pulmonary disease is a leading cause of elevated mortality risk in SMI, along with cardiovascular and infectious disease, diabetes, and barriers to care. Having a comorbid mental illness triples the mortality risk of chronic lower respiratory disease (Table 1).³

This article describes how you can intervene and improve quality of life for your patients with COPD by:

• asking all patients, especially smokers, if they are experiencing classic symptoms of COPD
• advocating for and supporting smoking cessation efforts
• avoiding drug interactions and off-target dosing related to COPD and nicotine replacement therapy
• considering, if feasible, a switch from typical to atypical antipsychotic therapy, which could reduce smoking behavior.

What is COPD?
COPD is preventable and treatable. It is characterized by “persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lungs to inhaled noxious particles or gases.”⁴

Smoking tobacco is the greatest risk factor for developing COPD.⁵ An estimated 50% to 80% of people with schizophrenia are smokers, as are 55% of people with bipolar disorder.⁶ COPD is a leading cause of morbidity and mortality worldwide,^7,8 and its prevalence is projected to increase as the global population and smoking rates grow.⁹

A simplified schema of the pathophysiology of COPD implicates 4 lung areas: parenchyma, pulmonary vasculature, central airways, and peripheral airways.¹⁰ Variation in the areas affected and severity of change contributes to the disease’s heterogeneous presentation, which can include pulmonary hypertension, hypersecretion of mucus, ciliary dysfunction, airway hyperinflation, and impaired gas exchange.^11,12 Many of these features lead to systemic effects as well, particularly on cardiac function.

When to test a patient for COPD
Early diagnosis and treatment can substantially improve quality-of-life outcomes for patients with COPD. The clinical approach (Figure 1) begins with recognizing classic symptoms. Consider COPD in any patient with:

• dyspnea (particularly if becoming worse, persistent, or associated with exercise)
• chronic cough
• chronic sputum production
• history of risk-factor exposure (particularly tobacco smoke)
• family history of COPD.⁴

If the history and physical exam suggest COPD (Table 2), spirometry is the most reliable test to quantify and characterize lung dysfunction. It is not indicated as a screening tool for healthy adults or appropriate when a patient is acutely ill. Forced expiratory volume in the first second of expiration divided by the measured forced vital capacity (FEV1/FVC) < 0.7 defines clinical COPD and determines the need for pharmacologic intervention. Laboratory studies could be useful in certain clinical scenarios, such as serum testing for alpha₁-antitrypsin deficiency in patients age <45 with emphysema. Plain film imaging might be useful to support a COPD diagnosis or rule out alternate diagnoses.

Psychopharmacology issues with comorbid COPD
Pharmacotherapy for psychiatric disorders can exacerbate comorbid COPD. For example, long-term use of phenothiazine-related typical antipsychotics for schizophrenia has been linked to an increased incidence of COPD.¹³ Antipsychotic side effects such as acute laryngeal dystonia and tardive dyskinesia, most commonly seen with first-generation antipsychotic use, can aggravate dyspnea caused by COPD. Opioids and most hypnotics, sedatives, and anxiolytics suppress the respiratory drive, and therefore should be used with caution in patients with COPD.

Carefully monitor serum levels of medications before and during attempts at smoking cessation. Nicotine’s induction of the cytochrome P450 1A2 system increases the metabolism of antipsychotics such as clozapine, fluvoxamine, olanzapine, and haloperidol. As a result, potentially toxic drug levels can occur when a smoker tries to quit.¹⁴

Screen patients with COPD for co­morbid psychiatric conditions. New psychiatric symptoms can emerge after COPD has been diagnosed, even in patients without pre-existing psychopathology.

Anxiety is a particularly common COPD comorbidity that can be difficult to manage. Selective serotonin reuptake inhibitors, buspirone, cognitive-behavioral therapy, and pulmonary rehabilitation can be helpful, although the effect of antidepressants on respiration is controversial. Nortriptyline has been shown to be effective in treating both anxiety and depressive symptoms in patients with COPD.¹⁵ Avoid using hypnotics to manage sleep problems related to COPD; instead, focus on minimizing sleep disturbance by limiting cough and dyspnea.

Antipsychotics and nicotine metabolism
Multiple studies have focused on the interplay among nicotine, dopamine, and antipsychotic agents. Nicotine receptors are present in the ventral tegmental dopaminergic cell bodies, which induce the release of dopamine and other neurotransmitters when stimulated. Smoking has been noted to increase in patients administered haloperidol (a dopamine antagonist) and to decrease with administration of bromocriptine (a dopamine agonist).¹⁶ This suggests that psychiatric patients might smoke to overcome the dopamine blockade caused by most typical antipsychotics, therefore alleviating their negative and extrapyramidal side effects.¹⁷

Alternatively, some studies suggest that a difference in dopamine receptor occupancy between typical and atypical antipsychotics leads to different effects on smoking behavior.¹⁸ When used long term, typical antipsychotics might increase dopamine receptors or dopamine sensitivity, and thus reinforce the positive effect of nicotine by increasing the number of receptors that can be stimulated, whereas atypical antipsychotics help stimulate the release of dopamine directly through partial agonist of serotonin 5-HT1A receptors.^19,20 Atypical antipsychotics also appear to decrease cue-elicited cravings in people who are not mentally ill, whereas haloperidol does not.²¹

Based on these findings, switching patients with COPD from a typical to an atypical antipsychotic, if feasible, might make smoking cessation more manageable.²² Multiple studies have shown that clozapine is the preferred atypical antipsychotic because it is associated with the most significant decrease in smoking behaviors.²³

First-line therapy: Nicotine replacement
Smoking cessation slows the progression of COPD and leads to marked improvements in cough, expectoration, breathlessness, and wheezing.^24,25 Nicotine replacement therapy (NRT)—gum, inhaler, lozenges, nasal spray, and skin patch—is considered first-line pharmacotherapy. These nicotine substitutes can decrease withdrawal symptoms, although they do not appear to be as effective for light smokers (eg, <10 cigarettes/d), compared with heavy smokers (eg, ≥20 cigarettes/d).²⁶

Long-term smoking abstinence can be improved with combination therapies. A nicotine patch, kept in place for as long as 24 hours, often is used with a nicotine gum or nasal spray. Another option combines the patch with a first-line, non-NRT intervention, such as sustained-release bupropion. Use bupropion with caution in psychiatric patients, however. Do not combine it with a monoamine oxidase inhibitor, and do not prescribe it to patients with an eating disorder or history of seizures.²⁶ Bupropion could induce mania in patients with bipolar disorder.

Varenicline, a nicotinic receptor partial agonist indicated to aid in smoking cessation, has been shown to reduce pleasure gained from tobacco as well as cravings. It can increase the likelihood of abstinence from smoking for as long as 1 year, but it also can provoke behavioral changes, depressed mood, and suicidal ideation. These risks—described in an FDA black-box warning of serious neuropsychiatric events—warrant due caution when prescribing varenicline to patients with depression. The FDA also has warned that varenicline could lead to decreased alcohol tolerance and atypically aggressive behavior during intoxication, which is of particular concern because of the high rate of alcohol use among people with SMI.

Motivating and supporting change
When counseling patients with mental illness about smoking cessation, consider unique motivations that, if disregarded, could undermine your efforts. As described above, smoking can ameliorate negative and extrapyramidal symptoms associated with typical antipsychotics. This could explain the significantly higher rates of smoking associated with typical antipsychotics, compared with atypical antipsychotics.²⁷ Patients also could use smoking as self-medication for depression and anxiety. Therefore, take care to offer alternate methods for coping, along with smoking cessation recommendations.²²

Screen all adult patients for tobacco use, and offer prompt cessation counseling and pharmacologic interventions._²⁸As a motivational intervention, the “5 As” framework—ask, advise, assess, assist, arrange—can help gauge patients’ smoking status and willingness to quit, as well as emphasize the importance of establishing a concrete, manageable plan.²⁹

Keep in mind the barriers all patients face in their fight to quit smoking, such as nicotine withdrawal, weight gain, and loss of a coping mechanism for stress.²⁹ Patients with schizophrenia can be motivated to quit smoking and participate in treatment for nicotine dependence.³⁰

Besides encouraging smoking cessation, you can educate patients in behaviors that will improve COPD symptoms and management. These include:

• reducing the risk of lung infections through vaccinations (influenza yearly, pneumonia once in adulthood) and avoiding crowds during peak cold and influenza season
• participating in physical activity, which could slow lung function decline
• adhering to prescribed medication
• eating a balanced diet
• seeking medical care early during an exacerbation.

Coaching patients in symptom control
Smoking cessation may have the greatest long-term benefit for patients with COPD, but symptom management is important as well (Figure 2). Pharmacotherapy for COPD usually is advanced in steps, but a more aggressive approach may be necessary for patients presenting with severe symptoms.

Mainstays of COPD therapy are inhaled bronchodilators, consisting of β2 agonists and anticholinergics, alone or in combination. Short-acting formulations are used for mild and intermittent symptoms; long-acting bronchodilators are added if symptoms persist.⁴ When dyspnea, wheezing, and activity intolerance are not well-controlled with bronchodilators, an inhaled corticosteroid can be tried, either alone or in combination with a long-acting bronchodilator.⁴

Adherence to medical recommendations is critical for successful COPD management, but inhaled therapy can be difficult for psychiatric patients—especially patients with cognitive or functional impairment. Asking them to demonstrate their inhaler technique can help assess treatment effectiveness.³¹

Referral to a pulmonologist is strongly advised in cases of:

• advanced, end-stage COPD (FEV1 <50% predicted value despite adherence to recommended treatment, or rapid decline of FEV1)
• COPD in patients age <50
• frequent exacerbations
• possible complications related to chronic heart failure
• indications for oxygen treatment (eg, resting or ambulatory oxygen saturation ≤88% or PaO₂ ≤55 mm Hg).³²

Chronic obstructive pulmonary disease (COPD) usually is not diagnosed until clinically apparent and moderately advanced. Patients might not notice chronic dyspnea and smoker’s cough, or might consider their symptoms “normal” and not seek medical care. Delayed diagnosis is particularly prevalent in the psychiatric population, in which co-existing medical problems tend to remain unrecognized and untreated.¹

Life expectancy of people with serious mental illness (SMI) is 13 to 30 years less than that of the general population—a gap that has widened over time.² Pulmonary disease is a leading cause of elevated mortality risk in SMI, along with cardiovascular and infectious disease, diabetes, and barriers to care. Having a comorbid mental illness triples the mortality risk of chronic lower respiratory disease (Table 1).³

This article describes how you can intervene and improve quality of life for your patients with COPD by:

• asking all patients, especially smokers, if they are experiencing classic symptoms of COPD
• advocating for and supporting smoking cessation efforts
• avoiding drug interactions and off-target dosing related to COPD and nicotine replacement therapy
• considering, if feasible, a switch from typical to atypical antipsychotic therapy, which could reduce smoking behavior.

What is COPD?
COPD is preventable and treatable. It is characterized by “persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lungs to inhaled noxious particles or gases.”⁴

Smoking tobacco is the greatest risk factor for developing COPD.⁵ An estimated 50% to 80% of people with schizophrenia are smokers, as are 55% of people with bipolar disorder.⁶ COPD is a leading cause of morbidity and mortality worldwide,^7,8 and its prevalence is projected to increase as the global population and smoking rates grow.⁹

A simplified schema of the pathophysiology of COPD implicates 4 lung areas: parenchyma, pulmonary vasculature, central airways, and peripheral airways.¹⁰ Variation in the areas affected and severity of change contributes to the disease’s heterogeneous presentation, which can include pulmonary hypertension, hypersecretion of mucus, ciliary dysfunction, airway hyperinflation, and impaired gas exchange.^11,12 Many of these features lead to systemic effects as well, particularly on cardiac function.

When to test a patient for COPD
Early diagnosis and treatment can substantially improve quality-of-life outcomes for patients with COPD. The clinical approach (Figure 1) begins with recognizing classic symptoms. Consider COPD in any patient with:

• dyspnea (particularly if becoming worse, persistent, or associated with exercise)
• chronic cough
• chronic sputum production
• history of risk-factor exposure (particularly tobacco smoke)
• family history of COPD.⁴

If the history and physical exam suggest COPD (Table 2), spirometry is the most reliable test to quantify and characterize lung dysfunction. It is not indicated as a screening tool for healthy adults or appropriate when a patient is acutely ill. Forced expiratory volume in the first second of expiration divided by the measured forced vital capacity (FEV1/FVC) < 0.7 defines clinical COPD and determines the need for pharmacologic intervention. Laboratory studies could be useful in certain clinical scenarios, such as serum testing for alpha₁-antitrypsin deficiency in patients age <45 with emphysema. Plain film imaging might be useful to support a COPD diagnosis or rule out alternate diagnoses.

Psychopharmacology issues with comorbid COPD
Pharmacotherapy for psychiatric disorders can exacerbate comorbid COPD. For example, long-term use of phenothiazine-related typical antipsychotics for schizophrenia has been linked to an increased incidence of COPD.¹³ Antipsychotic side effects such as acute laryngeal dystonia and tardive dyskinesia, most commonly seen with first-generation antipsychotic use, can aggravate dyspnea caused by COPD. Opioids and most hypnotics, sedatives, and anxiolytics suppress the respiratory drive, and therefore should be used with caution in patients with COPD.

Carefully monitor serum levels of medications before and during attempts at smoking cessation. Nicotine’s induction of the cytochrome P450 1A2 system increases the metabolism of antipsychotics such as clozapine, fluvoxamine, olanzapine, and haloperidol. As a result, potentially toxic drug levels can occur when a smoker tries to quit.¹⁴

Screen patients with COPD for co­morbid psychiatric conditions. New psychiatric symptoms can emerge after COPD has been diagnosed, even in patients without pre-existing psychopathology.

Anxiety is a particularly common COPD comorbidity that can be difficult to manage. Selective serotonin reuptake inhibitors, buspirone, cognitive-behavioral therapy, and pulmonary rehabilitation can be helpful, although the effect of antidepressants on respiration is controversial. Nortriptyline has been shown to be effective in treating both anxiety and depressive symptoms in patients with COPD.¹⁵ Avoid using hypnotics to manage sleep problems related to COPD; instead, focus on minimizing sleep disturbance by limiting cough and dyspnea.

Antipsychotics and nicotine metabolism
Multiple studies have focused on the interplay among nicotine, dopamine, and antipsychotic agents. Nicotine receptors are present in the ventral tegmental dopaminergic cell bodies, which induce the release of dopamine and other neurotransmitters when stimulated. Smoking has been noted to increase in patients administered haloperidol (a dopamine antagonist) and to decrease with administration of bromocriptine (a dopamine agonist).¹⁶ This suggests that psychiatric patients might smoke to overcome the dopamine blockade caused by most typical antipsychotics, therefore alleviating their negative and extrapyramidal side effects.¹⁷

Alternatively, some studies suggest that a difference in dopamine receptor occupancy between typical and atypical antipsychotics leads to different effects on smoking behavior.¹⁸ When used long term, typical antipsychotics might increase dopamine receptors or dopamine sensitivity, and thus reinforce the positive effect of nicotine by increasing the number of receptors that can be stimulated, whereas atypical antipsychotics help stimulate the release of dopamine directly through partial agonist of serotonin 5-HT1A receptors.^19,20 Atypical antipsychotics also appear to decrease cue-elicited cravings in people who are not mentally ill, whereas haloperidol does not.²¹

Based on these findings, switching patients with COPD from a typical to an atypical antipsychotic, if feasible, might make smoking cessation more manageable.²² Multiple studies have shown that clozapine is the preferred atypical antipsychotic because it is associated with the most significant decrease in smoking behaviors.²³

First-line therapy: Nicotine replacement
Smoking cessation slows the progression of COPD and leads to marked improvements in cough, expectoration, breathlessness, and wheezing.^24,25 Nicotine replacement therapy (NRT)—gum, inhaler, lozenges, nasal spray, and skin patch—is considered first-line pharmacotherapy. These nicotine substitutes can decrease withdrawal symptoms, although they do not appear to be as effective for light smokers (eg, <10 cigarettes/d), compared with heavy smokers (eg, ≥20 cigarettes/d).²⁶

Long-term smoking abstinence can be improved with combination therapies. A nicotine patch, kept in place for as long as 24 hours, often is used with a nicotine gum or nasal spray. Another option combines the patch with a first-line, non-NRT intervention, such as sustained-release bupropion. Use bupropion with caution in psychiatric patients, however. Do not combine it with a monoamine oxidase inhibitor, and do not prescribe it to patients with an eating disorder or history of seizures.²⁶ Bupropion could induce mania in patients with bipolar disorder.

Varenicline, a nicotinic receptor partial agonist indicated to aid in smoking cessation, has been shown to reduce pleasure gained from tobacco as well as cravings. It can increase the likelihood of abstinence from smoking for as long as 1 year, but it also can provoke behavioral changes, depressed mood, and suicidal ideation. These risks—described in an FDA black-box warning of serious neuropsychiatric events—warrant due caution when prescribing varenicline to patients with depression. The FDA also has warned that varenicline could lead to decreased alcohol tolerance and atypically aggressive behavior during intoxication, which is of particular concern because of the high rate of alcohol use among people with SMI.

Motivating and supporting change
When counseling patients with mental illness about smoking cessation, consider unique motivations that, if disregarded, could undermine your efforts. As described above, smoking can ameliorate negative and extrapyramidal symptoms associated with typical antipsychotics. This could explain the significantly higher rates of smoking associated with typical antipsychotics, compared with atypical antipsychotics.²⁷ Patients also could use smoking as self-medication for depression and anxiety. Therefore, take care to offer alternate methods for coping, along with smoking cessation recommendations.²²

Screen all adult patients for tobacco use, and offer prompt cessation counseling and pharmacologic interventions._²⁸As a motivational intervention, the “5 As” framework—ask, advise, assess, assist, arrange—can help gauge patients’ smoking status and willingness to quit, as well as emphasize the importance of establishing a concrete, manageable plan.²⁹

Keep in mind the barriers all patients face in their fight to quit smoking, such as nicotine withdrawal, weight gain, and loss of a coping mechanism for stress.²⁹ Patients with schizophrenia can be motivated to quit smoking and participate in treatment for nicotine dependence.³⁰

Besides encouraging smoking cessation, you can educate patients in behaviors that will improve COPD symptoms and management. These include:

• reducing the risk of lung infections through vaccinations (influenza yearly, pneumonia once in adulthood) and avoiding crowds during peak cold and influenza season
• participating in physical activity, which could slow lung function decline
• adhering to prescribed medication
• eating a balanced diet
• seeking medical care early during an exacerbation.

Coaching patients in symptom control
Smoking cessation may have the greatest long-term benefit for patients with COPD, but symptom management is important as well (Figure 2). Pharmacotherapy for COPD usually is advanced in steps, but a more aggressive approach may be necessary for patients presenting with severe symptoms.

Mainstays of COPD therapy are inhaled bronchodilators, consisting of β2 agonists and anticholinergics, alone or in combination. Short-acting formulations are used for mild and intermittent symptoms; long-acting bronchodilators are added if symptoms persist.⁴ When dyspnea, wheezing, and activity intolerance are not well-controlled with bronchodilators, an inhaled corticosteroid can be tried, either alone or in combination with a long-acting bronchodilator.⁴

Adherence to medical recommendations is critical for successful COPD management, but inhaled therapy can be difficult for psychiatric patients—especially patients with cognitive or functional impairment. Asking them to demonstrate their inhaler technique can help assess treatment effectiveness.³¹

Referral to a pulmonologist is strongly advised in cases of:

• advanced, end-stage COPD (FEV1 <50% predicted value despite adherence to recommended treatment, or rapid decline of FEV1)
• COPD in patients age <50
• frequent exacerbations
• possible complications related to chronic heart failure
• indications for oxygen treatment (eg, resting or ambulatory oxygen saturation ≤88% or PaO₂ ≤55 mm Hg).³²

Pain is one of the most common symptoms for which patients seek medical care, with an associated estimated annual cost of $600 billion.¹ Using a multimodal approach to care—thorough evaluation, cognitive-behavioral and psychophysiological therapy, physical therapy, medications, and other interventions—can help patients effectively manage their condition and achieve healthier outcomes.

Evaluating a patient with pain
When developing a safe, comprehensive, and effective treatment plan for patients with chronic pain, first perform a thorough history and physical exam using the following elements:

Pain history. The PQRST mnemonic (Table 1) can help you obtain critical information and assist in determining the appropriate diagnosis and cause of the patient’s pain complaints.

Psychiatric history. Document the mental health history of the patient and first-degree relatives.

Medical history. Knowing the medical history could reveal comorbidities contributing to a patient’s pain complaint.

Treatment history. Listing past and current treatments for pain, including effectiveness, helps the clinician understand if an existing treatment plan should be modified.

Functional status. Document current level of daily activity, how life activities are affected by pain; strategies used to help cope with pain; level of physical and emotional support provided in home, work, and school environments; and active stressors (eg, financial, interpersonal).

Psychosocial history. Document historical information related to coping skills, trauma history, family of origin, abuse, interpersonal relationships, social support, and academic and vocational functioning.

Substance use or abuse. Assess for use of controlled substances (ie, early refills; lost medications; obtaining medications from multiple prescribers, friends, families, or strangers; use of prescribed and non-prescribed medications for non-medical and medical purposes), nicotine, alcohol, illicit substances, and caffeine. A thorough inventory can help to identify substances a patient is using that could affect daily functioning and pain level.

Behavioral observations. Assessing mental status (eg, insight, pain behavior, co­operation) can be useful. Paying attention to pain behaviors, such as complaints of pain, decreased activity, increased medication intake, or altered facial expressions or body posture, can help the clinician gain insight to the extent that pain affects the patient’s quality of life.

The information gathered in the patient evaluation can be used to design a multimodal treatment plan to achieve maximum effectiveness.

Assessing psychiatric illness
Current approaches to pain evaluation and treatment recommend use of a biopsychosocial orientation because psychological, behavioral, and social factors can influence the experience and impact of pain, regardless of the primary cause.² A comprehensive psychiatric evaluation, diagnosis, and treatment plan should consider the broader context in which a patient’s pain occurs.

Regarding psychiatric illness, past and current symptoms, treatment history, and risk assessment should all be included. Using the “AMPS approach” (Figure)³—assessing Anxiety, Mood (depression and mania), Psychotic symptoms (paranoid ideation and hallucinations), and Substance use—helps screen for comorbid psychiatric conditions in patients with chronic pain.

Sleep assessment
Chronic pain patients often experience significant sleep disturbance that could be caused by physiological aspects of the pain condition, environmental factors (eg, uncomfortable bedding), a comorbid sleep disorder (eg, sleep apnea), a psychiatric disorder, or a combination of the above.

Obstructive and central sleep apnea are characterized by nighttime hypoxia, which leads to frequent disruption of the sleep-wake cycle and often manifests as daytime fatigue, irritability, depression, drowsiness, headaches, and increased pain sensitivity. Changes in sleep arousal can lead to neuro­psychological changes during the day, such as decreased attention, memory problems, impaired executive functioning, and reduced impulse control.

Screen patients for central and obstructive sleep apnea before prescribing opioids or benzodiazepines for pain because these medications can cause or exacerbate underlying sleep apnea. Although many screening tools, such as the Epworth Sleepiness Scale, assess daytime somnolence,⁴ the STOP-BANG questionnaire is a quick, validated, and efficient screening tool that often is used to assess sleep apnea risk^5,6 (Table 2). The presence of ≥3 risk factors identifies patients at increased risk and warrants consideration for further workup by a sleep specialist.^7,8

Pharmacotherapy for chronic pain
Non-opioid medications. Pain can be broadly categorized as neuropathic or nociceptive. Neuropathic pain can be described by patients as numbness, burning, electric-like, and tingling, and is associated with nerve damage. Nociceptive pain commonly is described as similar to a toothache with descriptors such as stabbing, sharp, or a dull aching sensation; it is often, but not always, associated with acute injury or ongoing trauma to tissue. Drug treatment is most successful when the appropriate class of medication is matched to the specific type of pain.

Nociceptive pain often is successfully treated with non-steroidal anti-inflammatory drugs and acetaminophen. Non-selective COX inhibitors (eg, ibuprofen, indomethacin, ketorolac) and COX-2 selective inhibitors (eg, celecoxib) have been associated with cardiovascular, gastrointestinal, and renal disease; acetaminophen is associated with liver dysfunction.^9-11 However, the absolute risk for complications in healthy patients is low.¹² To minimize risk, use these agents for the shortest duration and at the lowest effective dosage possible.

Neuropathic pain can be addressed with certain antidepressants¹³—specifically, those that increase serotonin and norepinephrine (eg, tricyclic antidepressants [TCAs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]), or medications that block ion channels (eg, anticonvulsants). TCAs (eg, desipramine, nortriptyline, amitriptyline) are among the best studied and most cost effective medications for treating neuropathic pain,^14,15 but they can have sedating and anticholinergic effects, as well as cardiac adverse effects (ie, prolongation of the QTc interval). SNRIs (eg, venlafaxine, desvenlafaxine, duloxetine, and milnacipran) can be effective and often are better tolerated than TCAs.¹⁴

Some newer anticonvulsants (eg, gabapentin and pregabalin) have been found to be more effective than placebo for a variety of neuropathic pain conditions.^16,17 Although they have few drug-drug interactions, anticonvulsants can cause dizziness, forgetfulness, and sedation. These adverse effects can be minimized by starting at a low dosage and titrating carefully. Because hepatic or renal impairment can affect metabolism or excretion of these drugs, review the prescribing information to determine safe dosing.

Targeted injection of medications to major pain generators (eg, an epidural steroid for radicular neck and back pain; facet injections for facet-related neck and back pain; trigger point injections for myofascial pain; occipital nerve blocks for occipital neuralgia; and botulinum toxin A injections for chronic migraine headache) can be effective in reducing discomfort and increasing function in patients with chronic pain. A detailed discussion of such therapies is beyond the scope of this article, but have been reviewed extensively elsewhere.^18,19

Opioids. Although there is little evidence of long-term efficacy with chronic opioid therapy for most patients, a trial of opioids might be warranted for select patients who do not respond to other medications. Because the risk–benefit ratio for chronic opioid therapy is high,^20-22 a decision to initiate a trial of a low-dosage opioid should be made only after careful consideration of those risks. It is generally agreed that treatment of chronic pain with low-dosage opioid therapy is more likely to be successful when it is used as an adjuvant to non-opioid modalities (eg, physical reconditioning, injection therapies, spinal cord stimulation, neurobehavioral interventions, non-opioid medications).

The Federation of State Medical Boards has stated that excessive reliance on opioid medications for treating chronic pain is a deviation from best practices.²³ To maximize benefit and minimize risk, clinicians should carefully select appropriate patients, establish functional goals, and regularly monitor for efficacy and compliance. Thoroughly document these steps in the patient’s record for later reference.²³

After establishing a clinical diagnosis for the cause of the pain, you should determine the risk of opioid abuse or misuse by using any one of the available risk assessment tools (Box). Understand, however, that no single tool has been shown to be more effective than others.

Although patients and some clinicians tend to overvalue the benefits of chronic opioid therapy, many do not fully appreciate the risks (eg, respiratory depression and death), which can be exacerbated if the patient is using other substance that suppress respiration (eg, benzodiazepines, alcohol, and illicit substances). Written informed consent and treatment agreement is highly recommended; components of such a document are listed in Table 3.²³

Develop a treatment plan that emphasizes functional goals based on the patient’s physical limitations and that incorporates some type of daily, atraumatic physical activity. This plan should be documented and reviewed regularly to help monitor treatment effectiveness.

After an initial trial of a few weeks, the patient and clinician should meet to review the 5 “A”s (Table 4)²⁴ to determine the success of the opioid regimen. Consulting your state’s prescription drug monitoring program (if one is available), obtaining a random urine drug test, and doing a pill count can provide useful, objective data. If the patient has not made progress but has experienced no adverse effects, then a small dosage increase might be warranted. If any of the 5 “A”s indicates lack of improvement or increased risk, consider stopping opioid therapy and exploring non-opioid options to manage chronic pain.

Referrals to a pain specialist or an addiction specialist, or both, might be needed, depending on the patient’s condition at any given follow-up visit. Such referral decisions, as well as all treatment plans, should be documented clearly in the medical record to prevent any misunderstanding, false accusations, or medicolegal repercussions regarding the rationale for continuing or terminating opioid-based treatment.

Non-pharmaceutical therapy for treating pain
The pain management field has successfully integrated the biopsychosocial model into regular practice. This model advocates the use of multimodal non-drug interventions in conjunction with opioid and non-opioid medications. Such interventions address behavioral, cognitive, sociocultural (psychosocial), lifestyle, and physiological dimensions of pain. A partial list of non-drug interventions is provided in Table 5.

Integration of these interventions within a biopsychosocial framework can assist you in making a comprehensive treatment plan. For example, patients with focal myofascial shoulder and back pain might derive only transient benefit from trigger point injection. However, concurrent referral to a pain psychologist and physical therapist could substantially improve functional outcomes by addressing factors that directly and indirectly influence myofascial pain. Inclusion of cognitive-behavioral therapy (addressing psychosocial and lifestyle dimensions), surface electromyography, psychophysiological interventions/biofeedback (addressing psychosocial, lifestyle, and physiological dimensions), and physical therapy (addressing lifestyle and physiological dimensions) allows the patient to learn coping skills, decrease physiological arousal that can lead to unnecessary tensing of muscles, and strengthen core muscle groups.

Pain is one of the most common symptoms for which patients seek medical care, with an associated estimated annual cost of $600 billion.¹ Using a multimodal approach to care—thorough evaluation, cognitive-behavioral and psychophysiological therapy, physical therapy, medications, and other interventions—can help patients effectively manage their condition and achieve healthier outcomes.

Evaluating a patient with pain
When developing a safe, comprehensive, and effective treatment plan for patients with chronic pain, first perform a thorough history and physical exam using the following elements:

Pain history. The PQRST mnemonic (Table 1) can help you obtain critical information and assist in determining the appropriate diagnosis and cause of the patient’s pain complaints.

Psychiatric history. Document the mental health history of the patient and first-degree relatives.

Medical history. Knowing the medical history could reveal comorbidities contributing to a patient’s pain complaint.

Treatment history. Listing past and current treatments for pain, including effectiveness, helps the clinician understand if an existing treatment plan should be modified.

Functional status. Document current level of daily activity, how life activities are affected by pain; strategies used to help cope with pain; level of physical and emotional support provided in home, work, and school environments; and active stressors (eg, financial, interpersonal).

Psychosocial history. Document historical information related to coping skills, trauma history, family of origin, abuse, interpersonal relationships, social support, and academic and vocational functioning.

Substance use or abuse. Assess for use of controlled substances (ie, early refills; lost medications; obtaining medications from multiple prescribers, friends, families, or strangers; use of prescribed and non-prescribed medications for non-medical and medical purposes), nicotine, alcohol, illicit substances, and caffeine. A thorough inventory can help to identify substances a patient is using that could affect daily functioning and pain level.

Behavioral observations. Assessing mental status (eg, insight, pain behavior, co­operation) can be useful. Paying attention to pain behaviors, such as complaints of pain, decreased activity, increased medication intake, or altered facial expressions or body posture, can help the clinician gain insight to the extent that pain affects the patient’s quality of life.

The information gathered in the patient evaluation can be used to design a multimodal treatment plan to achieve maximum effectiveness.

Assessing psychiatric illness
Current approaches to pain evaluation and treatment recommend use of a biopsychosocial orientation because psychological, behavioral, and social factors can influence the experience and impact of pain, regardless of the primary cause.² A comprehensive psychiatric evaluation, diagnosis, and treatment plan should consider the broader context in which a patient’s pain occurs.

Regarding psychiatric illness, past and current symptoms, treatment history, and risk assessment should all be included. Using the “AMPS approach” (Figure)³—assessing Anxiety, Mood (depression and mania), Psychotic symptoms (paranoid ideation and hallucinations), and Substance use—helps screen for comorbid psychiatric conditions in patients with chronic pain.

Sleep assessment
Chronic pain patients often experience significant sleep disturbance that could be caused by physiological aspects of the pain condition, environmental factors (eg, uncomfortable bedding), a comorbid sleep disorder (eg, sleep apnea), a psychiatric disorder, or a combination of the above.

Obstructive and central sleep apnea are characterized by nighttime hypoxia, which leads to frequent disruption of the sleep-wake cycle and often manifests as daytime fatigue, irritability, depression, drowsiness, headaches, and increased pain sensitivity. Changes in sleep arousal can lead to neuro­psychological changes during the day, such as decreased attention, memory problems, impaired executive functioning, and reduced impulse control.

Screen patients for central and obstructive sleep apnea before prescribing opioids or benzodiazepines for pain because these medications can cause or exacerbate underlying sleep apnea. Although many screening tools, such as the Epworth Sleepiness Scale, assess daytime somnolence,⁴ the STOP-BANG questionnaire is a quick, validated, and efficient screening tool that often is used to assess sleep apnea risk^5,6 (Table 2). The presence of ≥3 risk factors identifies patients at increased risk and warrants consideration for further workup by a sleep specialist.^7,8

Pharmacotherapy for chronic pain
Non-opioid medications. Pain can be broadly categorized as neuropathic or nociceptive. Neuropathic pain can be described by patients as numbness, burning, electric-like, and tingling, and is associated with nerve damage. Nociceptive pain commonly is described as similar to a toothache with descriptors such as stabbing, sharp, or a dull aching sensation; it is often, but not always, associated with acute injury or ongoing trauma to tissue. Drug treatment is most successful when the appropriate class of medication is matched to the specific type of pain.

Nociceptive pain often is successfully treated with non-steroidal anti-inflammatory drugs and acetaminophen. Non-selective COX inhibitors (eg, ibuprofen, indomethacin, ketorolac) and COX-2 selective inhibitors (eg, celecoxib) have been associated with cardiovascular, gastrointestinal, and renal disease; acetaminophen is associated with liver dysfunction.^9-11 However, the absolute risk for complications in healthy patients is low.¹² To minimize risk, use these agents for the shortest duration and at the lowest effective dosage possible.

Neuropathic pain can be addressed with certain antidepressants¹³—specifically, those that increase serotonin and norepinephrine (eg, tricyclic antidepressants [TCAs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]), or medications that block ion channels (eg, anticonvulsants). TCAs (eg, desipramine, nortriptyline, amitriptyline) are among the best studied and most cost effective medications for treating neuropathic pain,^14,15 but they can have sedating and anticholinergic effects, as well as cardiac adverse effects (ie, prolongation of the QTc interval). SNRIs (eg, venlafaxine, desvenlafaxine, duloxetine, and milnacipran) can be effective and often are better tolerated than TCAs.¹⁴

Some newer anticonvulsants (eg, gabapentin and pregabalin) have been found to be more effective than placebo for a variety of neuropathic pain conditions.^16,17 Although they have few drug-drug interactions, anticonvulsants can cause dizziness, forgetfulness, and sedation. These adverse effects can be minimized by starting at a low dosage and titrating carefully. Because hepatic or renal impairment can affect metabolism or excretion of these drugs, review the prescribing information to determine safe dosing.

Targeted injection of medications to major pain generators (eg, an epidural steroid for radicular neck and back pain; facet injections for facet-related neck and back pain; trigger point injections for myofascial pain; occipital nerve blocks for occipital neuralgia; and botulinum toxin A injections for chronic migraine headache) can be effective in reducing discomfort and increasing function in patients with chronic pain. A detailed discussion of such therapies is beyond the scope of this article, but have been reviewed extensively elsewhere.^18,19

Opioids. Although there is little evidence of long-term efficacy with chronic opioid therapy for most patients, a trial of opioids might be warranted for select patients who do not respond to other medications. Because the risk–benefit ratio for chronic opioid therapy is high,^20-22 a decision to initiate a trial of a low-dosage opioid should be made only after careful consideration of those risks. It is generally agreed that treatment of chronic pain with low-dosage opioid therapy is more likely to be successful when it is used as an adjuvant to non-opioid modalities (eg, physical reconditioning, injection therapies, spinal cord stimulation, neurobehavioral interventions, non-opioid medications).

The Federation of State Medical Boards has stated that excessive reliance on opioid medications for treating chronic pain is a deviation from best practices.²³ To maximize benefit and minimize risk, clinicians should carefully select appropriate patients, establish functional goals, and regularly monitor for efficacy and compliance. Thoroughly document these steps in the patient’s record for later reference.²³

After establishing a clinical diagnosis for the cause of the pain, you should determine the risk of opioid abuse or misuse by using any one of the available risk assessment tools (Box). Understand, however, that no single tool has been shown to be more effective than others.

Although patients and some clinicians tend to overvalue the benefits of chronic opioid therapy, many do not fully appreciate the risks (eg, respiratory depression and death), which can be exacerbated if the patient is using other substance that suppress respiration (eg, benzodiazepines, alcohol, and illicit substances). Written informed consent and treatment agreement is highly recommended; components of such a document are listed in Table 3.²³

Develop a treatment plan that emphasizes functional goals based on the patient’s physical limitations and that incorporates some type of daily, atraumatic physical activity. This plan should be documented and reviewed regularly to help monitor treatment effectiveness.

After an initial trial of a few weeks, the patient and clinician should meet to review the 5 “A”s (Table 4)²⁴ to determine the success of the opioid regimen. Consulting your state’s prescription drug monitoring program (if one is available), obtaining a random urine drug test, and doing a pill count can provide useful, objective data. If the patient has not made progress but has experienced no adverse effects, then a small dosage increase might be warranted. If any of the 5 “A”s indicates lack of improvement or increased risk, consider stopping opioid therapy and exploring non-opioid options to manage chronic pain.

Referrals to a pain specialist or an addiction specialist, or both, might be needed, depending on the patient’s condition at any given follow-up visit. Such referral decisions, as well as all treatment plans, should be documented clearly in the medical record to prevent any misunderstanding, false accusations, or medicolegal repercussions regarding the rationale for continuing or terminating opioid-based treatment.

Non-pharmaceutical therapy for treating pain
The pain management field has successfully integrated the biopsychosocial model into regular practice. This model advocates the use of multimodal non-drug interventions in conjunction with opioid and non-opioid medications. Such interventions address behavioral, cognitive, sociocultural (psychosocial), lifestyle, and physiological dimensions of pain. A partial list of non-drug interventions is provided in Table 5.

Integration of these interventions within a biopsychosocial framework can assist you in making a comprehensive treatment plan. For example, patients with focal myofascial shoulder and back pain might derive only transient benefit from trigger point injection. However, concurrent referral to a pain psychologist and physical therapist could substantially improve functional outcomes by addressing factors that directly and indirectly influence myofascial pain. Inclusion of cognitive-behavioral therapy (addressing psychosocial and lifestyle dimensions), surface electromyography, psychophysiological interventions/biofeedback (addressing psychosocial, lifestyle, and physiological dimensions), and physical therapy (addressing lifestyle and physiological dimensions) allows the patient to learn coping skills, decrease physiological arousal that can lead to unnecessary tensing of muscles, and strengthen core muscle groups.

Pain is one of the most common symptoms for which patients seek medical care, with an associated estimated annual cost of $600 billion.¹ Using a multimodal approach to care—thorough evaluation, cognitive-behavioral and psychophysiological therapy, physical therapy, medications, and other interventions—can help patients effectively manage their condition and achieve healthier outcomes.

Evaluating a patient with pain
When developing a safe, comprehensive, and effective treatment plan for patients with chronic pain, first perform a thorough history and physical exam using the following elements:

Pain history. The PQRST mnemonic (Table 1) can help you obtain critical information and assist in determining the appropriate diagnosis and cause of the patient’s pain complaints.

Psychiatric history. Document the mental health history of the patient and first-degree relatives.

Medical history. Knowing the medical history could reveal comorbidities contributing to a patient’s pain complaint.

Treatment history. Listing past and current treatments for pain, including effectiveness, helps the clinician understand if an existing treatment plan should be modified.

Functional status. Document current level of daily activity, how life activities are affected by pain; strategies used to help cope with pain; level of physical and emotional support provided in home, work, and school environments; and active stressors (eg, financial, interpersonal).

Psychosocial history. Document historical information related to coping skills, trauma history, family of origin, abuse, interpersonal relationships, social support, and academic and vocational functioning.

Substance use or abuse. Assess for use of controlled substances (ie, early refills; lost medications; obtaining medications from multiple prescribers, friends, families, or strangers; use of prescribed and non-prescribed medications for non-medical and medical purposes), nicotine, alcohol, illicit substances, and caffeine. A thorough inventory can help to identify substances a patient is using that could affect daily functioning and pain level.

Behavioral observations. Assessing mental status (eg, insight, pain behavior, co­operation) can be useful. Paying attention to pain behaviors, such as complaints of pain, decreased activity, increased medication intake, or altered facial expressions or body posture, can help the clinician gain insight to the extent that pain affects the patient’s quality of life.

The information gathered in the patient evaluation can be used to design a multimodal treatment plan to achieve maximum effectiveness.

Assessing psychiatric illness
Current approaches to pain evaluation and treatment recommend use of a biopsychosocial orientation because psychological, behavioral, and social factors can influence the experience and impact of pain, regardless of the primary cause.² A comprehensive psychiatric evaluation, diagnosis, and treatment plan should consider the broader context in which a patient’s pain occurs.

Regarding psychiatric illness, past and current symptoms, treatment history, and risk assessment should all be included. Using the “AMPS approach” (Figure)³—assessing Anxiety, Mood (depression and mania), Psychotic symptoms (paranoid ideation and hallucinations), and Substance use—helps screen for comorbid psychiatric conditions in patients with chronic pain.

Sleep assessment
Chronic pain patients often experience significant sleep disturbance that could be caused by physiological aspects of the pain condition, environmental factors (eg, uncomfortable bedding), a comorbid sleep disorder (eg, sleep apnea), a psychiatric disorder, or a combination of the above.

Obstructive and central sleep apnea are characterized by nighttime hypoxia, which leads to frequent disruption of the sleep-wake cycle and often manifests as daytime fatigue, irritability, depression, drowsiness, headaches, and increased pain sensitivity. Changes in sleep arousal can lead to neuro­psychological changes during the day, such as decreased attention, memory problems, impaired executive functioning, and reduced impulse control.

Screen patients for central and obstructive sleep apnea before prescribing opioids or benzodiazepines for pain because these medications can cause or exacerbate underlying sleep apnea. Although many screening tools, such as the Epworth Sleepiness Scale, assess daytime somnolence,⁴ the STOP-BANG questionnaire is a quick, validated, and efficient screening tool that often is used to assess sleep apnea risk^5,6 (Table 2). The presence of ≥3 risk factors identifies patients at increased risk and warrants consideration for further workup by a sleep specialist.^7,8

Pharmacotherapy for chronic pain
Non-opioid medications. Pain can be broadly categorized as neuropathic or nociceptive. Neuropathic pain can be described by patients as numbness, burning, electric-like, and tingling, and is associated with nerve damage. Nociceptive pain commonly is described as similar to a toothache with descriptors such as stabbing, sharp, or a dull aching sensation; it is often, but not always, associated with acute injury or ongoing trauma to tissue. Drug treatment is most successful when the appropriate class of medication is matched to the specific type of pain.

Nociceptive pain often is successfully treated with non-steroidal anti-inflammatory drugs and acetaminophen. Non-selective COX inhibitors (eg, ibuprofen, indomethacin, ketorolac) and COX-2 selective inhibitors (eg, celecoxib) have been associated with cardiovascular, gastrointestinal, and renal disease; acetaminophen is associated with liver dysfunction.^9-11 However, the absolute risk for complications in healthy patients is low.¹² To minimize risk, use these agents for the shortest duration and at the lowest effective dosage possible.

Neuropathic pain can be addressed with certain antidepressants¹³—specifically, those that increase serotonin and norepinephrine (eg, tricyclic antidepressants [TCAs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]), or medications that block ion channels (eg, anticonvulsants). TCAs (eg, desipramine, nortriptyline, amitriptyline) are among the best studied and most cost effective medications for treating neuropathic pain,^14,15 but they can have sedating and anticholinergic effects, as well as cardiac adverse effects (ie, prolongation of the QTc interval). SNRIs (eg, venlafaxine, desvenlafaxine, duloxetine, and milnacipran) can be effective and often are better tolerated than TCAs.¹⁴

Some newer anticonvulsants (eg, gabapentin and pregabalin) have been found to be more effective than placebo for a variety of neuropathic pain conditions.^16,17 Although they have few drug-drug interactions, anticonvulsants can cause dizziness, forgetfulness, and sedation. These adverse effects can be minimized by starting at a low dosage and titrating carefully. Because hepatic or renal impairment can affect metabolism or excretion of these drugs, review the prescribing information to determine safe dosing.

Targeted injection of medications to major pain generators (eg, an epidural steroid for radicular neck and back pain; facet injections for facet-related neck and back pain; trigger point injections for myofascial pain; occipital nerve blocks for occipital neuralgia; and botulinum toxin A injections for chronic migraine headache) can be effective in reducing discomfort and increasing function in patients with chronic pain. A detailed discussion of such therapies is beyond the scope of this article, but have been reviewed extensively elsewhere.^18,19

Opioids. Although there is little evidence of long-term efficacy with chronic opioid therapy for most patients, a trial of opioids might be warranted for select patients who do not respond to other medications. Because the risk–benefit ratio for chronic opioid therapy is high,^20-22 a decision to initiate a trial of a low-dosage opioid should be made only after careful consideration of those risks. It is generally agreed that treatment of chronic pain with low-dosage opioid therapy is more likely to be successful when it is used as an adjuvant to non-opioid modalities (eg, physical reconditioning, injection therapies, spinal cord stimulation, neurobehavioral interventions, non-opioid medications).

The Federation of State Medical Boards has stated that excessive reliance on opioid medications for treating chronic pain is a deviation from best practices.²³ To maximize benefit and minimize risk, clinicians should carefully select appropriate patients, establish functional goals, and regularly monitor for efficacy and compliance. Thoroughly document these steps in the patient’s record for later reference.²³

After establishing a clinical diagnosis for the cause of the pain, you should determine the risk of opioid abuse or misuse by using any one of the available risk assessment tools (Box). Understand, however, that no single tool has been shown to be more effective than others.

Although patients and some clinicians tend to overvalue the benefits of chronic opioid therapy, many do not fully appreciate the risks (eg, respiratory depression and death), which can be exacerbated if the patient is using other substance that suppress respiration (eg, benzodiazepines, alcohol, and illicit substances). Written informed consent and treatment agreement is highly recommended; components of such a document are listed in Table 3.²³

Develop a treatment plan that emphasizes functional goals based on the patient’s physical limitations and that incorporates some type of daily, atraumatic physical activity. This plan should be documented and reviewed regularly to help monitor treatment effectiveness.

After an initial trial of a few weeks, the patient and clinician should meet to review the 5 “A”s (Table 4)²⁴ to determine the success of the opioid regimen. Consulting your state’s prescription drug monitoring program (if one is available), obtaining a random urine drug test, and doing a pill count can provide useful, objective data. If the patient has not made progress but has experienced no adverse effects, then a small dosage increase might be warranted. If any of the 5 “A”s indicates lack of improvement or increased risk, consider stopping opioid therapy and exploring non-opioid options to manage chronic pain.

Referrals to a pain specialist or an addiction specialist, or both, might be needed, depending on the patient’s condition at any given follow-up visit. Such referral decisions, as well as all treatment plans, should be documented clearly in the medical record to prevent any misunderstanding, false accusations, or medicolegal repercussions regarding the rationale for continuing or terminating opioid-based treatment.

Non-pharmaceutical therapy for treating pain
The pain management field has successfully integrated the biopsychosocial model into regular practice. This model advocates the use of multimodal non-drug interventions in conjunction with opioid and non-opioid medications. Such interventions address behavioral, cognitive, sociocultural (psychosocial), lifestyle, and physiological dimensions of pain. A partial list of non-drug interventions is provided in Table 5.

Integration of these interventions within a biopsychosocial framework can assist you in making a comprehensive treatment plan. For example, patients with focal myofascial shoulder and back pain might derive only transient benefit from trigger point injection. However, concurrent referral to a pain psychologist and physical therapist could substantially improve functional outcomes by addressing factors that directly and indirectly influence myofascial pain. Inclusion of cognitive-behavioral therapy (addressing psychosocial and lifestyle dimensions), surface electromyography, psychophysiological interventions/biofeedback (addressing psychosocial, lifestyle, and physiological dimensions), and physical therapy (addressing lifestyle and physiological dimensions) allows the patient to learn coping skills, decrease physiological arousal that can lead to unnecessary tensing of muscles, and strengthen core muscle groups.

More than 45% of people worldwide suffer from headache at some point in their life.¹ Head pain can lead to disabil­ity and functional decline, yet headache disorders often are underdiagnosed and poorly assessed. For example, 60% of migraine and tension-type headaches go undiagnosed and 50% of persons suffering from migraine have severe functional dis­ability or require bed rest.^2-4

Because head pain can be associated with secondary medical and psy­chiatric conditions, diagnosis can be challenging. This article reviews the medical and psychological aspects of major headaches and assists with clinical assessment. We present clinical interviewing tools and a diagram to enhance focused, efficient assessment and inform treatment plans.

Classification of headache
Headache is a common complaint, yet it is often underdiagnosed and ineffectively treated. The World Health Organization estimates that, globally, 50% of people with headache self-treat their pain.⁵ The International Headache Society classifies headache as primary or sec­ondary; approximately 90% of complaints are from primary headache.⁶

Assessment and diagnosis of headache can be complex because of overlapping, subjective symptoms. It is important to have a general understanding of primary and secondary causes of headache so that interrelated symptoms do not obscure the most accurate diagnosis and effective treatment course. Although most headache complaints are benign, ruling out secondary causes helps gauge the likelihood of developing severe sequelae from underlying pathology.

By definition, primary headaches are idiopathic and commonly include migraine, tension-type, cluster, and hemicrania conti­nua headache. Secondary headaches have an underlying pathology, which could improve by targeting the disorder. Common secondary causes of headache include:
   • trauma
   • vascular abnormalities
   • structural abnormalities
   • chemical (including medications)
   • inflammation or infection
   • metabolic conditions
   • diseases of the neck and pericranial and intracranial structures
   • psychiatric conditions.

Table 1 illustrates common causes of head pain. More definitive criteria for symptoms and diagnosis can be found in the International Classification of Headache Disorders.⁷

Migraine typically causes pulsating pain in a localized area of the head that lasts as long as 72 hours and can be associated with nausea, vomiting, photophobia, phono-phobia, and aura. Patients report varying precipitating factors but commonly cite cer­tain foods, menstruation, and sleep depri­vation. Although rare, migraine with aura has been linked to ischemic stroke; most cases have been reported in female smokers and oral contraceptive users age <45.⁹

Because migraines can be debilitat­ing, some patients—typically those with ≥4 attacks a month—opt for prophylactic medication. Effective prophylactics include amitriptyline, propranolol, divalproex sodium, and topiramate, which should be monitored closely and given a trial for sev­eral months before switching to another drug. Commonly used abortive treatments include triptans and anti-emetics such as metoclopramide.

Meperidine and ketorolac are popular second-line agents for migraine. Botulinum toxin A also has been used in severe cases to reduce the number of headache days in chronic migraine patients.⁶ 

Cluster headache is rare, but typically exhibits repeated burning and intense unilateral periorbital or retro-orbital pain that lasts 15 minutes to 3 hours over several weeks. Men are predominantly affected. Cluster headaches typically improve with oxygen treatment.
 

Biopsychosocial model of head pain
The biomedical model has helped iden­ tify pathophysiological pain mechanisms and pharmacotherapeutic agents for headache. However, during assessment, limiting one’s attention to the linear rela­tionship between pathology, mechanism of action, and pain oversimplifies common questions clinicians face when assessing chronic head pain.

Advancements in the last 3 decades have expanded the conceptualization of head pain to integrate sociocultural, envi­ronmental, behavioral, affective, cogni­tive, and biological variables—otherwise known as the biopsychosocial model.^10,11 The biopsychosocial model is a multidi­mensional theory that helps answer dif­ficult clinical assessment questions and complex patient presentations (Table 2).^10-13 Many unusual responses to pain treatment, questionable validity of pain behavior, and disproportionate pain perception and functional decline are explained by non-pathophysiological and non-biomechani­cal models.

Psychiatric comorbidity and head pain
Psychiatric conditions are highly prevalent among persons with primary headache. Verri et al¹⁴ found that 90% of chronic daily headache patients had ≥1 psychiatric con­dition; depression and anxiety were most common. Of concern, 1 study found that headache is associated with increased frequency of suicidal ideation among patients with chronic pain.¹⁵ It is critical for clinicians to screen for psychiatric comor­bidities in patients with chronic head­ache. Conversely, clinicians might want to screen for headache in their patients with psychiatric illness.

Migraine. Mood disorders are com­mon among patients who suffer from migraine. The rate of depression is 2 to 4 times higher in those with migraine compared with healthy controls.^16,17 In a large-scale study, patients with migraine had a 1.9-fold higher risk (compared with controls) of having a comorbid depres­sive episode; a 2-fold higher risk of manic episodes; and a 3-fold higher risk of both mania and depression.¹⁸ In a study of 62 inpatients, Fasmer¹⁹ reported that 46% of patients with unipolar depression and 44% of patients with bipolar disorder experienced migraine (77% of the bipolar disorder patients with migraine had bipo­lar II disorder). Patients with migraine are at increased risk of suicide attempts (odds ratio 4.3; 95% CI, 1.2-15.7).²⁰ 

Tension-type headache. The relationship between psychiatric comorbidity in tension-type headache is well established. In con­trast to what is seen with migraines, Puca et al²¹ found a higher prevalence of anxiety disorders (52.5%) than depressive disorders (36.4%) in patients with tension-type head­ache. Generalized anxiety disorder was one of the most prevalent anxiety conditions (83.3%), and dysthymia was the most prev­alent mood disorder (45.6%). In the same study, 21.7% of patients were found to have a comorbid somatoform disorder.²¹

Emotional and cognitive factors can co-occur in patients with tension-type head­ache and a comorbid psychiatric condition. For example, difficulty identifying or rec­ognizing emotions—commonly referred to as alexithymia—has been linked to tension-type headache.²² Additionally, maladap­tive cognitive appraisal of stress is more common among patients with tension-type headache when compared with those without headaches.²³ Being mindful of and recognizing these co-occurring emotional and cognitive factors will help clinicians construct a more accurate assessment and effective behavioral treatment plan.

Clinical assessment with a useful mnemonic
Clinical assessment of psychiatric illness is essential when evaluating chronic pain patients. Using the acronym AMPS (Anxiety, Mood, Psychosis, and Substance use disor­ders) (Table 3) is an efficient way for the cli­nician to ask pertinent questions regarding common psychiatric conditions that could have a direct effect on chronic pain.²⁴ Head pain can be more intense when combined with untreated anxiety, depression, psycho­sis, or a substance use disorder. Untreated anxiety, for example, can amplify sympathetic response to pain and complicate treatment.

Investigating head pain patients for an underlying mood disorder is essential to providing successful treatment. Consider:
   • starting psychotherapy modalities that address both pain and psychiatric illness, such as cognitive-behavioral therapy (CBT)
   • reframing unhelpful pain beliefs
   • managing activity-rest levels
   • biofeedback
   • supportive group therapy
   • reducing family members’ reinforce­ment of the patient’s pain behavior or sick role.²⁵

Assessing for somatic symptom disorders
In addition to using the AMPS approach for psychiatric assessment, clinicians should evaluate for somatization, which can pres­ent as head pain. Somatic symptom dis­orders (SSD) are a class of conditions that are impacted by affective, cognitive, and reinforcing factors that might or might not be consciously or intentionally produced. Patients with an SSD have somatic symp­toms that are distressing or cause significant disruption of daily life because of excessive thoughts, feelings, or behaviors related to the somatic symptoms, for ≥6 months. The Figure outlines SSD, related conditions, and their respective prominent symptoms to assist in the differential diagnosis.²⁶

Note that some headache conditions present with severe distress because of their abrupt onset and severity of symptoms (eg, cluster headaches). Therefore, the expectation and likelihood of psychological disturbance should be factored into a diag­nosis of SSD and related conditions as seen in the Figure.

Secondary factors of unusual pain behavior or treatment response. The role of thoughts, affect, and behaviors is clinically meaningful in understand­ing SSD and similar conditions. Specific questions about cultural beliefs and ritu­als as they relate to exacerbations of head pain are of value. Table 4^13,27 lists behavioral, cognitive, and affective dimen­sions of head pain using the biopsychoso­cial model, and further clarifies common questions that arise with unusual pain response and complex patient presenta­tions, which were outlined in the begin­ning of the article.

Functional assessment to rule out the disproportional impact of pain on daily activities is helpful in understanding the somatization process. Neurocognitive functioning should be assessed, particu­larly because frontal and subcortical dys­regulation has been observed in head pain sufferers.^29,30 Patients with cognitive changes as a result of a medical illness (eg, stroke, head concussion, brain tumor, or seizures) are especially at risk for neuro­cognitive dysfunction.

Neuropsychological assessment can be useful, not only to assess neurocogni­tive functioning (eg, Repeated Battery for the Assessment of Neuropsychological Status) but to identify objective test pro­files associated with altered motivation (eg, Rey 15-Item Test, Minnesota Multiphasic Personality Inventory-2-Restructured Form F Scale, Personality Assessment Inventory [PAI] Negative Impression Management) and somatization processes (eg, PAI Somatization Scale). These instruments help to identify the severity of psychiatric and neurocognitive symptoms by com­paring scores to normative (eg, healthy control group), clinical (eg, somatization, traumatic brain injury, mild cognitive impairment), and altered motivation (eg, persons instructed to exaggerate symp­toms) databases.

If the clinician pursues neurocognitive assessment, direct referral to a neuropsy­chologist, referral to neurologist, or admin­istration of a cognitive screening tool such as the Montreal Cognitive Assessment, Saint Louis University Mental Status, or Cognitive Log is recommended. If the cognitive screening is positive, next steps include: referring for full neuropsycholog­ical assessment, which includes complete cognitive and motor testing, personality testing, and integration of neuroimaging data (eg, MRI, CT scans, and/or EEG).

Assessing the patients’ self-talk or thought patterns as they describe their head pain will help clinicians understand belief systems that may be distorting the reality of the medical condition. For exam­ple, a patient might report that “my pain feels like someone is hitting me with an axe”; this is a catastrophic thought that can distort the clarity and perceptibility of pain. Encouraging patients to monitor and analyze their anxiety and associated negative thoughts is an important strat­egy for improving mood and decreasing somatization. Recording daily thoughts and CBT can help the patient identify and appropriately address his (her) cognitive distortions and futile thinking.

When implementing a treatment plan for somatization disorder, we propose the mnemonic device CARE MD:
   • CBT
   • Assess (by ruling out a medical cause for somatic complaints)
   • Regular visits
   • Empathy
   • Med-psych interface (help the patient connect physical complaints and emotional stressors)
   • Do no harm.

Clinical recommendations
Chronic head pain can be debilitating; psy­chodiagnostic assessment should therefore be considered an important part of the diagnosis and treatment plan. After rul­ing out common and emergent primary or secondary causes of head pain, consider psychiatric comorbidities. Depression and anxiety have a strong bidirectional rela­tionship with chronic headache; therefore, we suggest evaluating patients with the intention of alleviating both psychiatric symptoms and head pain.

It is important to diligently assess for common psychiatric comorbidities; using the AMPS and CARE MD mnemonics, along with screening for somatization disorders, is an easy and effective way to evaluate for relevant psychiatric conditions associated with chronic head pain. Because many patients have unusual and compli­cated responses to head pain that can be explained by non-pathophysiological and non-biomechanical models, using the bio­psychosocial model is essential for effec­tive diagnosis, assessment, and treatment. Abortive and prophylactic medical inter­ventions, as well as behavioral, sociocul­tural, and cognitive assessment, are vital to a comprehensive treatment approach.

Bottom Line
The psychodiagnostic assessment can help the astute clinician identify comorbid psychiatric conditions, psychological factors, and somatic symptoms to develop a comprehensive biopsychosocial treatment plan for patients with chronic head pain. Rule out primary and secondary causes of pain and screen for somatization disorders. Consider medication and psychotherapeutic treatment options.

Related Resources
• Pompili M, Di Cosimo D, Innamorati M, et al. Psychiatric co­morbidity in patients with chronic daily headache and mi­graine: a selective overview including personality traits and suicide risk. J Headache Pain. 2009;10(4):283-290.
• Sinclair AJ, Sturrock A, Davies B, et al. Headache manage­ment: pharmacological approaches [published online July 3, 2015]. Pract Neurol. doi: 10.1136/practneurol-2015-001167.

Drug Brand Names
Amitriptyline • Elavil                            Meperidine • Demerol
Botulinum toxin A • Botox                   Metoclopramide • Reglan
Divalproex sodium • Depakote             Propranolol • Inderide
Ketorolac • Toradol                              Topiramate • Topamax

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

More than 45% of people worldwide suffer from headache at some point in their life.¹ Head pain can lead to disabil­ity and functional decline, yet headache disorders often are underdiagnosed and poorly assessed. For example, 60% of migraine and tension-type headaches go undiagnosed and 50% of persons suffering from migraine have severe functional dis­ability or require bed rest.^2-4

Because head pain can be associated with secondary medical and psy­chiatric conditions, diagnosis can be challenging. This article reviews the medical and psychological aspects of major headaches and assists with clinical assessment. We present clinical interviewing tools and a diagram to enhance focused, efficient assessment and inform treatment plans.

Classification of headache
Headache is a common complaint, yet it is often underdiagnosed and ineffectively treated. The World Health Organization estimates that, globally, 50% of people with headache self-treat their pain.⁵ The International Headache Society classifies headache as primary or sec­ondary; approximately 90% of complaints are from primary headache.⁶

Assessment and diagnosis of headache can be complex because of overlapping, subjective symptoms. It is important to have a general understanding of primary and secondary causes of headache so that interrelated symptoms do not obscure the most accurate diagnosis and effective treatment course. Although most headache complaints are benign, ruling out secondary causes helps gauge the likelihood of developing severe sequelae from underlying pathology.

By definition, primary headaches are idiopathic and commonly include migraine, tension-type, cluster, and hemicrania conti­nua headache. Secondary headaches have an underlying pathology, which could improve by targeting the disorder. Common secondary causes of headache include:
   • trauma
   • vascular abnormalities
   • structural abnormalities
   • chemical (including medications)
   • inflammation or infection
   • metabolic conditions
   • diseases of the neck and pericranial and intracranial structures
   • psychiatric conditions.

Table 1 illustrates common causes of head pain. More definitive criteria for symptoms and diagnosis can be found in the International Classification of Headache Disorders.⁷

Migraine typically causes pulsating pain in a localized area of the head that lasts as long as 72 hours and can be associated with nausea, vomiting, photophobia, phono-phobia, and aura. Patients report varying precipitating factors but commonly cite cer­tain foods, menstruation, and sleep depri­vation. Although rare, migraine with aura has been linked to ischemic stroke; most cases have been reported in female smokers and oral contraceptive users age <45.⁹

Because migraines can be debilitat­ing, some patients—typically those with ≥4 attacks a month—opt for prophylactic medication. Effective prophylactics include amitriptyline, propranolol, divalproex sodium, and topiramate, which should be monitored closely and given a trial for sev­eral months before switching to another drug. Commonly used abortive treatments include triptans and anti-emetics such as metoclopramide.

Meperidine and ketorolac are popular second-line agents for migraine. Botulinum toxin A also has been used in severe cases to reduce the number of headache days in chronic migraine patients.⁶ 

Cluster headache is rare, but typically exhibits repeated burning and intense unilateral periorbital or retro-orbital pain that lasts 15 minutes to 3 hours over several weeks. Men are predominantly affected. Cluster headaches typically improve with oxygen treatment.
 

Biopsychosocial model of head pain
The biomedical model has helped iden­ tify pathophysiological pain mechanisms and pharmacotherapeutic agents for headache. However, during assessment, limiting one’s attention to the linear rela­tionship between pathology, mechanism of action, and pain oversimplifies common questions clinicians face when assessing chronic head pain.

Advancements in the last 3 decades have expanded the conceptualization of head pain to integrate sociocultural, envi­ronmental, behavioral, affective, cogni­tive, and biological variables—otherwise known as the biopsychosocial model.^10,11 The biopsychosocial model is a multidi­mensional theory that helps answer dif­ficult clinical assessment questions and complex patient presentations (Table 2).^10-13 Many unusual responses to pain treatment, questionable validity of pain behavior, and disproportionate pain perception and functional decline are explained by non-pathophysiological and non-biomechani­cal models.

Psychiatric comorbidity and head pain
Psychiatric conditions are highly prevalent among persons with primary headache. Verri et al¹⁴ found that 90% of chronic daily headache patients had ≥1 psychiatric con­dition; depression and anxiety were most common. Of concern, 1 study found that headache is associated with increased frequency of suicidal ideation among patients with chronic pain.¹⁵ It is critical for clinicians to screen for psychiatric comor­bidities in patients with chronic head­ache. Conversely, clinicians might want to screen for headache in their patients with psychiatric illness.

Migraine. Mood disorders are com­mon among patients who suffer from migraine. The rate of depression is 2 to 4 times higher in those with migraine compared with healthy controls.^16,17 In a large-scale study, patients with migraine had a 1.9-fold higher risk (compared with controls) of having a comorbid depres­sive episode; a 2-fold higher risk of manic episodes; and a 3-fold higher risk of both mania and depression.¹⁸ In a study of 62 inpatients, Fasmer¹⁹ reported that 46% of patients with unipolar depression and 44% of patients with bipolar disorder experienced migraine (77% of the bipolar disorder patients with migraine had bipo­lar II disorder). Patients with migraine are at increased risk of suicide attempts (odds ratio 4.3; 95% CI, 1.2-15.7).²⁰ 

Tension-type headache. The relationship between psychiatric comorbidity in tension-type headache is well established. In con­trast to what is seen with migraines, Puca et al²¹ found a higher prevalence of anxiety disorders (52.5%) than depressive disorders (36.4%) in patients with tension-type head­ache. Generalized anxiety disorder was one of the most prevalent anxiety conditions (83.3%), and dysthymia was the most prev­alent mood disorder (45.6%). In the same study, 21.7% of patients were found to have a comorbid somatoform disorder.²¹

Emotional and cognitive factors can co-occur in patients with tension-type head­ache and a comorbid psychiatric condition. For example, difficulty identifying or rec­ognizing emotions—commonly referred to as alexithymia—has been linked to tension-type headache.²² Additionally, maladap­tive cognitive appraisal of stress is more common among patients with tension-type headache when compared with those without headaches.²³ Being mindful of and recognizing these co-occurring emotional and cognitive factors will help clinicians construct a more accurate assessment and effective behavioral treatment plan.

Clinical assessment with a useful mnemonic
Clinical assessment of psychiatric illness is essential when evaluating chronic pain patients. Using the acronym AMPS (Anxiety, Mood, Psychosis, and Substance use disor­ders) (Table 3) is an efficient way for the cli­nician to ask pertinent questions regarding common psychiatric conditions that could have a direct effect on chronic pain.²⁴ Head pain can be more intense when combined with untreated anxiety, depression, psycho­sis, or a substance use disorder. Untreated anxiety, for example, can amplify sympathetic response to pain and complicate treatment.

Investigating head pain patients for an underlying mood disorder is essential to providing successful treatment. Consider:
   • starting psychotherapy modalities that address both pain and psychiatric illness, such as cognitive-behavioral therapy (CBT)
   • reframing unhelpful pain beliefs
   • managing activity-rest levels
   • biofeedback
   • supportive group therapy
   • reducing family members’ reinforce­ment of the patient’s pain behavior or sick role.²⁵

Assessing for somatic symptom disorders
In addition to using the AMPS approach for psychiatric assessment, clinicians should evaluate for somatization, which can pres­ent as head pain. Somatic symptom dis­orders (SSD) are a class of conditions that are impacted by affective, cognitive, and reinforcing factors that might or might not be consciously or intentionally produced. Patients with an SSD have somatic symp­toms that are distressing or cause significant disruption of daily life because of excessive thoughts, feelings, or behaviors related to the somatic symptoms, for ≥6 months. The Figure outlines SSD, related conditions, and their respective prominent symptoms to assist in the differential diagnosis.²⁶

Note that some headache conditions present with severe distress because of their abrupt onset and severity of symptoms (eg, cluster headaches). Therefore, the expectation and likelihood of psychological disturbance should be factored into a diag­nosis of SSD and related conditions as seen in the Figure.

Secondary factors of unusual pain behavior or treatment response. The role of thoughts, affect, and behaviors is clinically meaningful in understand­ing SSD and similar conditions. Specific questions about cultural beliefs and ritu­als as they relate to exacerbations of head pain are of value. Table 4^13,27 lists behavioral, cognitive, and affective dimen­sions of head pain using the biopsychoso­cial model, and further clarifies common questions that arise with unusual pain response and complex patient presenta­tions, which were outlined in the begin­ning of the article.

Functional assessment to rule out the disproportional impact of pain on daily activities is helpful in understanding the somatization process. Neurocognitive functioning should be assessed, particu­larly because frontal and subcortical dys­regulation has been observed in head pain sufferers.^29,30 Patients with cognitive changes as a result of a medical illness (eg, stroke, head concussion, brain tumor, or seizures) are especially at risk for neuro­cognitive dysfunction.

Neuropsychological assessment can be useful, not only to assess neurocogni­tive functioning (eg, Repeated Battery for the Assessment of Neuropsychological Status) but to identify objective test pro­files associated with altered motivation (eg, Rey 15-Item Test, Minnesota Multiphasic Personality Inventory-2-Restructured Form F Scale, Personality Assessment Inventory [PAI] Negative Impression Management) and somatization processes (eg, PAI Somatization Scale). These instruments help to identify the severity of psychiatric and neurocognitive symptoms by com­paring scores to normative (eg, healthy control group), clinical (eg, somatization, traumatic brain injury, mild cognitive impairment), and altered motivation (eg, persons instructed to exaggerate symp­toms) databases.

If the clinician pursues neurocognitive assessment, direct referral to a neuropsy­chologist, referral to neurologist, or admin­istration of a cognitive screening tool such as the Montreal Cognitive Assessment, Saint Louis University Mental Status, or Cognitive Log is recommended. If the cognitive screening is positive, next steps include: referring for full neuropsycholog­ical assessment, which includes complete cognitive and motor testing, personality testing, and integration of neuroimaging data (eg, MRI, CT scans, and/or EEG).

Assessing the patients’ self-talk or thought patterns as they describe their head pain will help clinicians understand belief systems that may be distorting the reality of the medical condition. For exam­ple, a patient might report that “my pain feels like someone is hitting me with an axe”; this is a catastrophic thought that can distort the clarity and perceptibility of pain. Encouraging patients to monitor and analyze their anxiety and associated negative thoughts is an important strat­egy for improving mood and decreasing somatization. Recording daily thoughts and CBT can help the patient identify and appropriately address his (her) cognitive distortions and futile thinking.

When implementing a treatment plan for somatization disorder, we propose the mnemonic device CARE MD:
   • CBT
   • Assess (by ruling out a medical cause for somatic complaints)
   • Regular visits
   • Empathy
   • Med-psych interface (help the patient connect physical complaints and emotional stressors)
   • Do no harm.

Clinical recommendations
Chronic head pain can be debilitating; psy­chodiagnostic assessment should therefore be considered an important part of the diagnosis and treatment plan. After rul­ing out common and emergent primary or secondary causes of head pain, consider psychiatric comorbidities. Depression and anxiety have a strong bidirectional rela­tionship with chronic headache; therefore, we suggest evaluating patients with the intention of alleviating both psychiatric symptoms and head pain.

It is important to diligently assess for common psychiatric comorbidities; using the AMPS and CARE MD mnemonics, along with screening for somatization disorders, is an easy and effective way to evaluate for relevant psychiatric conditions associated with chronic head pain. Because many patients have unusual and compli­cated responses to head pain that can be explained by non-pathophysiological and non-biomechanical models, using the bio­psychosocial model is essential for effec­tive diagnosis, assessment, and treatment. Abortive and prophylactic medical inter­ventions, as well as behavioral, sociocul­tural, and cognitive assessment, are vital to a comprehensive treatment approach.

Bottom Line
The psychodiagnostic assessment can help the astute clinician identify comorbid psychiatric conditions, psychological factors, and somatic symptoms to develop a comprehensive biopsychosocial treatment plan for patients with chronic head pain. Rule out primary and secondary causes of pain and screen for somatization disorders. Consider medication and psychotherapeutic treatment options.

Related Resources
• Pompili M, Di Cosimo D, Innamorati M, et al. Psychiatric co­morbidity in patients with chronic daily headache and mi­graine: a selective overview including personality traits and suicide risk. J Headache Pain. 2009;10(4):283-290.
• Sinclair AJ, Sturrock A, Davies B, et al. Headache manage­ment: pharmacological approaches [published online July 3, 2015]. Pract Neurol. doi: 10.1136/practneurol-2015-001167.

Drug Brand Names
Amitriptyline • Elavil                            Meperidine • Demerol
Botulinum toxin A • Botox                   Metoclopramide • Reglan
Divalproex sodium • Depakote             Propranolol • Inderide
Ketorolac • Toradol                              Topiramate • Topamax

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

More than 45% of people worldwide suffer from headache at some point in their life.¹ Head pain can lead to disabil­ity and functional decline, yet headache disorders often are underdiagnosed and poorly assessed. For example, 60% of migraine and tension-type headaches go undiagnosed and 50% of persons suffering from migraine have severe functional dis­ability or require bed rest.^2-4

Because head pain can be associated with secondary medical and psy­chiatric conditions, diagnosis can be challenging. This article reviews the medical and psychological aspects of major headaches and assists with clinical assessment. We present clinical interviewing tools and a diagram to enhance focused, efficient assessment and inform treatment plans.

Classification of headache
Headache is a common complaint, yet it is often underdiagnosed and ineffectively treated. The World Health Organization estimates that, globally, 50% of people with headache self-treat their pain.⁵ The International Headache Society classifies headache as primary or sec­ondary; approximately 90% of complaints are from primary headache.⁶

Assessment and diagnosis of headache can be complex because of overlapping, subjective symptoms. It is important to have a general understanding of primary and secondary causes of headache so that interrelated symptoms do not obscure the most accurate diagnosis and effective treatment course. Although most headache complaints are benign, ruling out secondary causes helps gauge the likelihood of developing severe sequelae from underlying pathology.

By definition, primary headaches are idiopathic and commonly include migraine, tension-type, cluster, and hemicrania conti­nua headache. Secondary headaches have an underlying pathology, which could improve by targeting the disorder. Common secondary causes of headache include:
   • trauma
   • vascular abnormalities
   • structural abnormalities
   • chemical (including medications)
   • inflammation or infection
   • metabolic conditions
   • diseases of the neck and pericranial and intracranial structures
   • psychiatric conditions.

Table 1 illustrates common causes of head pain. More definitive criteria for symptoms and diagnosis can be found in the International Classification of Headache Disorders.⁷

Migraine typically causes pulsating pain in a localized area of the head that lasts as long as 72 hours and can be associated with nausea, vomiting, photophobia, phono-phobia, and aura. Patients report varying precipitating factors but commonly cite cer­tain foods, menstruation, and sleep depri­vation. Although rare, migraine with aura has been linked to ischemic stroke; most cases have been reported in female smokers and oral contraceptive users age <45.⁹

Because migraines can be debilitat­ing, some patients—typically those with ≥4 attacks a month—opt for prophylactic medication. Effective prophylactics include amitriptyline, propranolol, divalproex sodium, and topiramate, which should be monitored closely and given a trial for sev­eral months before switching to another drug. Commonly used abortive treatments include triptans and anti-emetics such as metoclopramide.

Meperidine and ketorolac are popular second-line agents for migraine. Botulinum toxin A also has been used in severe cases to reduce the number of headache days in chronic migraine patients.⁶ 

Cluster headache is rare, but typically exhibits repeated burning and intense unilateral periorbital or retro-orbital pain that lasts 15 minutes to 3 hours over several weeks. Men are predominantly affected. Cluster headaches typically improve with oxygen treatment.
 

Biopsychosocial model of head pain
The biomedical model has helped iden­ tify pathophysiological pain mechanisms and pharmacotherapeutic agents for headache. However, during assessment, limiting one’s attention to the linear rela­tionship between pathology, mechanism of action, and pain oversimplifies common questions clinicians face when assessing chronic head pain.

Advancements in the last 3 decades have expanded the conceptualization of head pain to integrate sociocultural, envi­ronmental, behavioral, affective, cogni­tive, and biological variables—otherwise known as the biopsychosocial model.^10,11 The biopsychosocial model is a multidi­mensional theory that helps answer dif­ficult clinical assessment questions and complex patient presentations (Table 2).^10-13 Many unusual responses to pain treatment, questionable validity of pain behavior, and disproportionate pain perception and functional decline are explained by non-pathophysiological and non-biomechani­cal models.

Psychiatric comorbidity and head pain
Psychiatric conditions are highly prevalent among persons with primary headache. Verri et al¹⁴ found that 90% of chronic daily headache patients had ≥1 psychiatric con­dition; depression and anxiety were most common. Of concern, 1 study found that headache is associated with increased frequency of suicidal ideation among patients with chronic pain.¹⁵ It is critical for clinicians to screen for psychiatric comor­bidities in patients with chronic head­ache. Conversely, clinicians might want to screen for headache in their patients with psychiatric illness.

Migraine. Mood disorders are com­mon among patients who suffer from migraine. The rate of depression is 2 to 4 times higher in those with migraine compared with healthy controls.^16,17 In a large-scale study, patients with migraine had a 1.9-fold higher risk (compared with controls) of having a comorbid depres­sive episode; a 2-fold higher risk of manic episodes; and a 3-fold higher risk of both mania and depression.¹⁸ In a study of 62 inpatients, Fasmer¹⁹ reported that 46% of patients with unipolar depression and 44% of patients with bipolar disorder experienced migraine (77% of the bipolar disorder patients with migraine had bipo­lar II disorder). Patients with migraine are at increased risk of suicide attempts (odds ratio 4.3; 95% CI, 1.2-15.7).²⁰ 

Tension-type headache. The relationship between psychiatric comorbidity in tension-type headache is well established. In con­trast to what is seen with migraines, Puca et al²¹ found a higher prevalence of anxiety disorders (52.5%) than depressive disorders (36.4%) in patients with tension-type head­ache. Generalized anxiety disorder was one of the most prevalent anxiety conditions (83.3%), and dysthymia was the most prev­alent mood disorder (45.6%). In the same study, 21.7% of patients were found to have a comorbid somatoform disorder.²¹

Emotional and cognitive factors can co-occur in patients with tension-type head­ache and a comorbid psychiatric condition. For example, difficulty identifying or rec­ognizing emotions—commonly referred to as alexithymia—has been linked to tension-type headache.²² Additionally, maladap­tive cognitive appraisal of stress is more common among patients with tension-type headache when compared with those without headaches.²³ Being mindful of and recognizing these co-occurring emotional and cognitive factors will help clinicians construct a more accurate assessment and effective behavioral treatment plan.

Clinical assessment with a useful mnemonic
Clinical assessment of psychiatric illness is essential when evaluating chronic pain patients. Using the acronym AMPS (Anxiety, Mood, Psychosis, and Substance use disor­ders) (Table 3) is an efficient way for the cli­nician to ask pertinent questions regarding common psychiatric conditions that could have a direct effect on chronic pain.²⁴ Head pain can be more intense when combined with untreated anxiety, depression, psycho­sis, or a substance use disorder. Untreated anxiety, for example, can amplify sympathetic response to pain and complicate treatment.

Investigating head pain patients for an underlying mood disorder is essential to providing successful treatment. Consider:
   • starting psychotherapy modalities that address both pain and psychiatric illness, such as cognitive-behavioral therapy (CBT)
   • reframing unhelpful pain beliefs
   • managing activity-rest levels
   • biofeedback
   • supportive group therapy
   • reducing family members’ reinforce­ment of the patient’s pain behavior or sick role.²⁵

Assessing for somatic symptom disorders
In addition to using the AMPS approach for psychiatric assessment, clinicians should evaluate for somatization, which can pres­ent as head pain. Somatic symptom dis­orders (SSD) are a class of conditions that are impacted by affective, cognitive, and reinforcing factors that might or might not be consciously or intentionally produced. Patients with an SSD have somatic symp­toms that are distressing or cause significant disruption of daily life because of excessive thoughts, feelings, or behaviors related to the somatic symptoms, for ≥6 months. The Figure outlines SSD, related conditions, and their respective prominent symptoms to assist in the differential diagnosis.²⁶

Note that some headache conditions present with severe distress because of their abrupt onset and severity of symptoms (eg, cluster headaches). Therefore, the expectation and likelihood of psychological disturbance should be factored into a diag­nosis of SSD and related conditions as seen in the Figure.

Secondary factors of unusual pain behavior or treatment response. The role of thoughts, affect, and behaviors is clinically meaningful in understand­ing SSD and similar conditions. Specific questions about cultural beliefs and ritu­als as they relate to exacerbations of head pain are of value. Table 4^13,27 lists behavioral, cognitive, and affective dimen­sions of head pain using the biopsychoso­cial model, and further clarifies common questions that arise with unusual pain response and complex patient presenta­tions, which were outlined in the begin­ning of the article.

Functional assessment to rule out the disproportional impact of pain on daily activities is helpful in understanding the somatization process. Neurocognitive functioning should be assessed, particu­larly because frontal and subcortical dys­regulation has been observed in head pain sufferers.^29,30 Patients with cognitive changes as a result of a medical illness (eg, stroke, head concussion, brain tumor, or seizures) are especially at risk for neuro­cognitive dysfunction.

Neuropsychological assessment can be useful, not only to assess neurocogni­tive functioning (eg, Repeated Battery for the Assessment of Neuropsychological Status) but to identify objective test pro­files associated with altered motivation (eg, Rey 15-Item Test, Minnesota Multiphasic Personality Inventory-2-Restructured Form F Scale, Personality Assessment Inventory [PAI] Negative Impression Management) and somatization processes (eg, PAI Somatization Scale). These instruments help to identify the severity of psychiatric and neurocognitive symptoms by com­paring scores to normative (eg, healthy control group), clinical (eg, somatization, traumatic brain injury, mild cognitive impairment), and altered motivation (eg, persons instructed to exaggerate symp­toms) databases.

If the clinician pursues neurocognitive assessment, direct referral to a neuropsy­chologist, referral to neurologist, or admin­istration of a cognitive screening tool such as the Montreal Cognitive Assessment, Saint Louis University Mental Status, or Cognitive Log is recommended. If the cognitive screening is positive, next steps include: referring for full neuropsycholog­ical assessment, which includes complete cognitive and motor testing, personality testing, and integration of neuroimaging data (eg, MRI, CT scans, and/or EEG).

Assessing the patients’ self-talk or thought patterns as they describe their head pain will help clinicians understand belief systems that may be distorting the reality of the medical condition. For exam­ple, a patient might report that “my pain feels like someone is hitting me with an axe”; this is a catastrophic thought that can distort the clarity and perceptibility of pain. Encouraging patients to monitor and analyze their anxiety and associated negative thoughts is an important strat­egy for improving mood and decreasing somatization. Recording daily thoughts and CBT can help the patient identify and appropriately address his (her) cognitive distortions and futile thinking.

When implementing a treatment plan for somatization disorder, we propose the mnemonic device CARE MD:
   • CBT
   • Assess (by ruling out a medical cause for somatic complaints)
   • Regular visits
   • Empathy
   • Med-psych interface (help the patient connect physical complaints and emotional stressors)
   • Do no harm.

Clinical recommendations
Chronic head pain can be debilitating; psy­chodiagnostic assessment should therefore be considered an important part of the diagnosis and treatment plan. After rul­ing out common and emergent primary or secondary causes of head pain, consider psychiatric comorbidities. Depression and anxiety have a strong bidirectional rela­tionship with chronic headache; therefore, we suggest evaluating patients with the intention of alleviating both psychiatric symptoms and head pain.

It is important to diligently assess for common psychiatric comorbidities; using the AMPS and CARE MD mnemonics, along with screening for somatization disorders, is an easy and effective way to evaluate for relevant psychiatric conditions associated with chronic head pain. Because many patients have unusual and compli­cated responses to head pain that can be explained by non-pathophysiological and non-biomechanical models, using the bio­psychosocial model is essential for effec­tive diagnosis, assessment, and treatment. Abortive and prophylactic medical inter­ventions, as well as behavioral, sociocul­tural, and cognitive assessment, are vital to a comprehensive treatment approach.

Bottom Line
The psychodiagnostic assessment can help the astute clinician identify comorbid psychiatric conditions, psychological factors, and somatic symptoms to develop a comprehensive biopsychosocial treatment plan for patients with chronic head pain. Rule out primary and secondary causes of pain and screen for somatization disorders. Consider medication and psychotherapeutic treatment options.

Related Resources
• Pompili M, Di Cosimo D, Innamorati M, et al. Psychiatric co­morbidity in patients with chronic daily headache and mi­graine: a selective overview including personality traits and suicide risk. J Headache Pain. 2009;10(4):283-290.
• Sinclair AJ, Sturrock A, Davies B, et al. Headache manage­ment: pharmacological approaches [published online July 3, 2015]. Pract Neurol. doi: 10.1136/practneurol-2015-001167.

Drug Brand Names
Amitriptyline • Elavil                            Meperidine • Demerol
Botulinum toxin A • Botox                   Metoclopramide • Reglan
Divalproex sodium • Depakote             Propranolol • Inderide
Ketorolac • Toradol                              Topiramate • Topamax

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.