Rajesh Rajesh, MD

Prostate cancer is the most frequently diagnosed cancer in men and the third leading cause of cancer death in men worldwide.¹ An estimated 174,650 new cases are diagnosed each year in the United States; 31,620 American men die annually from the disease.² Although prostate cancer can be a serious disease, many men do not die from it. In fact, 2.9 million men who were diagnosed with prostate cancer at some point are alive today.³

Risk factors. Prostate cancer develops mainly in men ages ≥ 65 years and rarely occurs before age 40. In addition to age, family history and African American ethnicity are the major nonmodifiable risk factors for prostate cancer.⁴ From the 1970s to the most recent statistical analysis of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, African American men have continued to have significantly higher incidence of, and mortality rates from, prostate cancer than their European American counterparts. African American men are also more likely than men of European ancestry to have aggressive prostate cancers.⁵ Other risk factors include geographic location (higher risk in Northern Europe, North America, and Australia; lower risk in Asia, Africa, and South and Central America), mutations in the BRCA2 gene, and hereditary non-polyposis colon cancer syndrome.⁴

Prostate-specific antigen (PSA) was first used as a screening tool for prostate cancer in 1991.⁶ Prostate cancer incidence, especially organ-confined disease, has dramatically increased since then.⁷ PSA testing has a low sensitivity and specificity for the detection of prostate cancer, and there is no clear threshold at which biopsy can or should be offered. The most commonly used cutoff value of 4 ng/mL has a false-positive rate of about 70%.⁸

Benign prostatic conditions such as hypertrophy and infection can elevate PSA levels. In addition, the PSA test does not distinguish between aggressive and slow-growing cancers, and about 15% of patients with prostate cancer have a normal PSA level.⁹

A word about the digital rectal exam. While PSA testing has been the mainstay of prostate cancer screening, a few studies have included digital rectal exam (DRE) in their protocols. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial showed that DRE captured an additional 2% of men with prostate cancer in the setting of a normal PSA test result.¹⁰ In the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, the overall detection rate for prostate cancer was found to be better when DRE was combined with PSA and prostate biopsy than when DRE was used alone (4.5% vs 2.5%).¹¹ Nevertheless, generally speaking, DRE can be omitted in the era of PSA screening.

Screening guidelines vary

Recommendations for prostate cancer screening vary by organization and are summarized in TABLE 1.^9,12-14 In 2012, the US Preventive Services Task Force (USPSTF) recommended against PSA-based screening for prostate cancer (Category D).¹⁵ In 2018, ­USPSTF provided an update with a new recommendation that clinicians inform men ages 55 to 69 years about the potential benefits and harms of PSA-based screening (Category C).¹⁴ The USPSTF continues to recommend against PSA-based screening for men ages ≥ 70 years (Category D).¹⁴

Does PSA-based screening improve patient-centered outcomes?

Several randomized controlled trials (RCTs) such as the Quebec Prospective Randomized Controlled Trial,¹⁶ the Norrköping Sweden Study,¹⁷ ERSPC,¹¹ and PLCO¹⁰ have been conducted to assess the benefits of PSA testing. PLCO and ERSPC have contributed significantly to our understanding of prostate cancer screening even though their 13-year follow-up results are conflicting (TABLE 2).^10,11,18

Continue to: In the ERSPC 13-year follow-up publication...

In the ERSPC 13-year follow-up publication, the authors concluded that a substantial reduction in prostate cancer mortality is attributable to testing with PSA.¹⁸ Despite limitations in the study design (eg, France entered after 2 years, screening intervals varied between 2 and 4 years, biopsy indications varied, and screening was discontinued at different times), PSA screening detected more prostate cancer than was detected in the control arm (10.2% vs 6.8%).

In the initial 11 years of follow-up, the study group experienced a 21% reduction in prostate cancer mortality, even though the absolute decrease ranged from only 0.6% (545 per 89,352) to 0.5% (355 per 72,891). The updated absolute risk reduction of death from prostate cancer at 13 years of follow-up showed a larger benefit: 0.11 per 1000 person-years or 1.28 per 1000 men randomized, which is equivalent to 1 prostate cancer death averted per 781 (95% confidence interval [CI], 490-1929) men invited for screening, or 1 per 27 (17-66) additional prostate cancers detected.

The PLCO trial did not show any significant difference in prostate cancer detection (11.1% screened vs 9.9% control), and there was no improvement in prostate cancer mortality (3.7 vs 3.4 death per 10,000 person-years).¹⁰ However, the PLCO trial suffered from issues of contamination, which may have influenced the overall results. About 52% of men in the control (usual care) group received a PSA test at some point during the study. And more than two-thirds of the men who had a prostate biopsy because of a positive PSA test did not have prostate cancer.

Community standards for the PSA threshold for biopsy were applied in various centers (> 4 ng/ml in general) in PLCO, whereas in ­ERSPC, a cut-off PSA value ≥ 3 ng/mL was used for biopsy. Because of the lower PSA threshold, ERSPC may have identified cancers that would have had good outcomes without any intervention.

The harms of PSA screening

While it is unclear whether PSA screening results in any improvement in patient-centered outcomes, it does lead to downstream intervention due to overdiagnosis, which precipitates unnecessary anxiety, biopsies, and overtreatment (eg, excess radiation, overuse of androgen deprivation therapy).¹⁹ Biopsies carry the risk of hematuria (22.6%), hematospermia (50.4%), and urinary tract infection.²⁰ Data from SEER-Medicare showed that prostate biopsy was associated with a 2.65-fold increased risk of hospitalization within 30 days of the procedure compared to a control population.²¹

Continue to: Overdiagnosis leads to overtreatment...

Overdiagnosis leads to overtreatment of low-risk prostate cancer. Both traditional treatment options for prostate cancer—radical prostatectomy and radiotherapy—are associated with urinary incontinence, erectile dysfunction, and issues with bowel function.^22,23

The Prostate Cancer Intervention vs Observation Trial (PIVOT),²⁴ the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4),²⁵ and the Prostate Testing for Cancer and Treatment (ProtecT) trial,^22,23 are the major RCTs that looked at the outcomes of treatment modalities for localized prostate cancer in the modern era of PSA testing.

PIVOT compared passive observation with radical prostatectomy.²⁴ After 20 years of follow-up on 731 patients, the researchers concluded that radical prostatectomy did not reduce all-cause or prostate cancer–related mortality (TABLE 3).²⁴

SPCG-4 showed survival benefits for men who underwent radical prostatectomy compared with men in a watchful waiting group, but only 5% of the study cohort had cancer detected by PSA screening (TABLE 4).²⁵ The rest had either palpable tumors or symptoms of a tumor.

ProtecT, which followed patients with localized prostate cancer for more than 10 years,compared the outcomes and adverse effects of active surveillance, radical prostatectomy, and radiotherapy.²³ Prostate cancer–specific mortality was low irrespective of the treatment,²³ and there was no significant difference in all-cause mortality or prostate cancer–specific mortality between the 3 treatment groups.²³ The active surveillance group had considerably fewer adverse events.^22,23 The incidence rates of erectile dysfunction and urinary incontinence at the 1- and 6-year follow-up marks are outlined in TABLE 5.²²

Continue to: The purpose of active monitoring...

The purpose of active monitoring is to minimize overtreatment by avoiding immediate radical intervention. Radical treatments with curative intent can be undertaken at any point while patients are being actively monitored. It is important to note that the active monitoring that took place in ProtecT²³ was very different from the passive surveillance of PIVOT²⁴ and SPCG-4.²⁵ In ProtecT, once an elevated serum PSA level was noted, PSA levels were monitored every 3 months in the first year and every 6 to 12 months thereafter.²³ Triggers to reassess patients and consider a change in clinical management were based largely on changes in PSA levels. Participants with an increase of at least 50% in PSA level during the previous 12 months were offered either continued monitoring or treatment after further testing.

Making individualized decisions about prostate cancer screening

Traditionally, the goal of cancer screening has been to maximize the number of people screened. Generally, the information provided to patients about cancer screening emphasizes the benefits and minimizes the harms. Recently, however, there has been a shift in communication about cancer screening with the emphasis now being placed on informed decision-making and encouraging patients to make individual decisions about screening participation.²⁶

Although current guidelines regarding PSA screening differ by organization, generally speaking, PSA screening should be offered only to men with a life expectancy > 10 years.

The treatment option of active surveillance, with its lower incidence of adverse outcomes, is an important reason for patients to make individualized decisions about prostate cancer screening.

Another reason relates to 5-alpha-­reductase inhibitors. Although their role in the management of prostate cancer is currently not well defined, a reduction of almost 25% in the risk of prostate cancer and improvement in the performance of PSA has been reported.²⁷

The PSA test has low sensitivity and specificity and lacks a clear cut-off value that warrants prostate biopsy.

And yet another reason is that there are alternate strategies to manage the majority of patients who have been diagnosed with low-risk disease through transrectal ultrasound biopsy. The ERSPC study mentions multiparametric magnetic resonance imaging combined with targeted biopsy to identify high-grade disease.^28,29 Genetic and epigenetic assays of the biopsied tissue can help grade disease based on aggressiveness.³⁰ Transperineal mapping biopsy using a mapping software program can identify specific disease sites within the prostate gland, so that patients can be offered the option of targeted therapy.³⁰

Continue to: Applying shared decision-making to prostate cancer screening

Balancing errors of omission with errors of commission is challenging. Shared decision-making (SDM) is an approach whereby clinicians and patients share the best available evidence when faced with the task of medical decision-making and in which patients are supported while they consider their options and achieve their preferences.³¹ SDM is well supported by evidence from a number of RCTs and results in increased knowledge, involvement, and confidence on the part of patients.³² An individualized approach using the schematic diagram (FIGURE 1^3,18) may be helpful.

Barriers to SDM success. Many factors can interfere with the success of SDM including limited or poor communication; lack of time during busy office visits; and patients’ cultural, informational, and/or emotional needs. To improve patient-centered communication, we can: (1) make information understandable and available to patients and families; (2) prioritize training in communication; (3) use decision aid tools to facilitate communication; and (4) work to improve the payment model to incentivize patient-centered communication. Tools that facilitate SDM include videotapes, patient group discussions, brief scripts read to patients, and informational pamphlets. One such tool is the American Society for Clinical Oncology’s decision aid tool for PSA testing.³³

Limited knowledge among patients. Decisions regarding treatment among men diagnosed with localized prostate cancer can be difficult because there are several treatment options with similar prognoses, but there are differences in adverse effects. One population-based cohort study of men with newly diagnosed localized prostate cancer found that most men had significant knowledge deficits regarding the survival benefits of the 2 major treatment options—surgery and radiation.³⁴ In a large population-based study, 38% of men with localized prostate cancer reported receiving help from their primary care providers in the decision-making process for treatment.³⁵

Learning to employ SDM. Elwyn et al proposed a 3-step model to incorporate SDM into clinical practice.³¹ They described key steps that include: choice talk (making sure patients are informed about the reasonable options), option talk (providing more detailed information about the options), and decision talk (supporting the work of patients considering their preferences and deciding what is best). Properly employing these methods requires training using simulations.³¹

The bottom line

Although current guidelines regarding PSA screening differ by organization, generally speaking PSA screening should be offered only to men with a life expectancy > 10 years. The PSA test has low sensitivity and specificity and lacks a clear cut-off value that warrants prostate biopsy. Men who choose to have PSA testing increase their chances of detecting prostate cancer, but most prostate cancers are slow growing and do not cause death. The decision to undergo PSA screening should be made by both the provider and the patient, after a discussion of the limited benefits and associated harms. The interval of follow-up screening may vary from 2 to 4 years depending on patient age, level of PSA, and whether a patient is taking medications such as 5-alpha-reductase inhibitors.

CORRESPONDENCE
Jaividhya Dasarathy, MD, FAAFP, 2500 Metro Health Medical Drive, Cleveland, Ohio 44109; jxd114@case.edu.

Prostate cancer is the most frequently diagnosed cancer in men and the third leading cause of cancer death in men worldwide.¹ An estimated 174,650 new cases are diagnosed each year in the United States; 31,620 American men die annually from the disease.² Although prostate cancer can be a serious disease, many men do not die from it. In fact, 2.9 million men who were diagnosed with prostate cancer at some point are alive today.³

Risk factors. Prostate cancer develops mainly in men ages ≥ 65 years and rarely occurs before age 40. In addition to age, family history and African American ethnicity are the major nonmodifiable risk factors for prostate cancer.⁴ From the 1970s to the most recent statistical analysis of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, African American men have continued to have significantly higher incidence of, and mortality rates from, prostate cancer than their European American counterparts. African American men are also more likely than men of European ancestry to have aggressive prostate cancers.⁵ Other risk factors include geographic location (higher risk in Northern Europe, North America, and Australia; lower risk in Asia, Africa, and South and Central America), mutations in the BRCA2 gene, and hereditary non-polyposis colon cancer syndrome.⁴

Prostate-specific antigen (PSA) was first used as a screening tool for prostate cancer in 1991.⁶ Prostate cancer incidence, especially organ-confined disease, has dramatically increased since then.⁷ PSA testing has a low sensitivity and specificity for the detection of prostate cancer, and there is no clear threshold at which biopsy can or should be offered. The most commonly used cutoff value of 4 ng/mL has a false-positive rate of about 70%.⁸

Benign prostatic conditions such as hypertrophy and infection can elevate PSA levels. In addition, the PSA test does not distinguish between aggressive and slow-growing cancers, and about 15% of patients with prostate cancer have a normal PSA level.⁹

A word about the digital rectal exam. While PSA testing has been the mainstay of prostate cancer screening, a few studies have included digital rectal exam (DRE) in their protocols. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial showed that DRE captured an additional 2% of men with prostate cancer in the setting of a normal PSA test result.¹⁰ In the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, the overall detection rate for prostate cancer was found to be better when DRE was combined with PSA and prostate biopsy than when DRE was used alone (4.5% vs 2.5%).¹¹ Nevertheless, generally speaking, DRE can be omitted in the era of PSA screening.

Screening guidelines vary

Recommendations for prostate cancer screening vary by organization and are summarized in TABLE 1.^9,12-14 In 2012, the US Preventive Services Task Force (USPSTF) recommended against PSA-based screening for prostate cancer (Category D).¹⁵ In 2018, ­USPSTF provided an update with a new recommendation that clinicians inform men ages 55 to 69 years about the potential benefits and harms of PSA-based screening (Category C).¹⁴ The USPSTF continues to recommend against PSA-based screening for men ages ≥ 70 years (Category D).¹⁴

Does PSA-based screening improve patient-centered outcomes?

Several randomized controlled trials (RCTs) such as the Quebec Prospective Randomized Controlled Trial,¹⁶ the Norrköping Sweden Study,¹⁷ ERSPC,¹¹ and PLCO¹⁰ have been conducted to assess the benefits of PSA testing. PLCO and ERSPC have contributed significantly to our understanding of prostate cancer screening even though their 13-year follow-up results are conflicting (TABLE 2).^10,11,18

Continue to: In the ERSPC 13-year follow-up publication...

In the ERSPC 13-year follow-up publication, the authors concluded that a substantial reduction in prostate cancer mortality is attributable to testing with PSA.¹⁸ Despite limitations in the study design (eg, France entered after 2 years, screening intervals varied between 2 and 4 years, biopsy indications varied, and screening was discontinued at different times), PSA screening detected more prostate cancer than was detected in the control arm (10.2% vs 6.8%).

In the initial 11 years of follow-up, the study group experienced a 21% reduction in prostate cancer mortality, even though the absolute decrease ranged from only 0.6% (545 per 89,352) to 0.5% (355 per 72,891). The updated absolute risk reduction of death from prostate cancer at 13 years of follow-up showed a larger benefit: 0.11 per 1000 person-years or 1.28 per 1000 men randomized, which is equivalent to 1 prostate cancer death averted per 781 (95% confidence interval [CI], 490-1929) men invited for screening, or 1 per 27 (17-66) additional prostate cancers detected.

The PLCO trial did not show any significant difference in prostate cancer detection (11.1% screened vs 9.9% control), and there was no improvement in prostate cancer mortality (3.7 vs 3.4 death per 10,000 person-years).¹⁰ However, the PLCO trial suffered from issues of contamination, which may have influenced the overall results. About 52% of men in the control (usual care) group received a PSA test at some point during the study. And more than two-thirds of the men who had a prostate biopsy because of a positive PSA test did not have prostate cancer.

Community standards for the PSA threshold for biopsy were applied in various centers (> 4 ng/ml in general) in PLCO, whereas in ­ERSPC, a cut-off PSA value ≥ 3 ng/mL was used for biopsy. Because of the lower PSA threshold, ERSPC may have identified cancers that would have had good outcomes without any intervention.

The harms of PSA screening

While it is unclear whether PSA screening results in any improvement in patient-centered outcomes, it does lead to downstream intervention due to overdiagnosis, which precipitates unnecessary anxiety, biopsies, and overtreatment (eg, excess radiation, overuse of androgen deprivation therapy).¹⁹ Biopsies carry the risk of hematuria (22.6%), hematospermia (50.4%), and urinary tract infection.²⁰ Data from SEER-Medicare showed that prostate biopsy was associated with a 2.65-fold increased risk of hospitalization within 30 days of the procedure compared to a control population.²¹

Continue to: Overdiagnosis leads to overtreatment...

Overdiagnosis leads to overtreatment of low-risk prostate cancer. Both traditional treatment options for prostate cancer—radical prostatectomy and radiotherapy—are associated with urinary incontinence, erectile dysfunction, and issues with bowel function.^22,23

The Prostate Cancer Intervention vs Observation Trial (PIVOT),²⁴ the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4),²⁵ and the Prostate Testing for Cancer and Treatment (ProtecT) trial,^22,23 are the major RCTs that looked at the outcomes of treatment modalities for localized prostate cancer in the modern era of PSA testing.

PIVOT compared passive observation with radical prostatectomy.²⁴ After 20 years of follow-up on 731 patients, the researchers concluded that radical prostatectomy did not reduce all-cause or prostate cancer–related mortality (TABLE 3).²⁴

SPCG-4 showed survival benefits for men who underwent radical prostatectomy compared with men in a watchful waiting group, but only 5% of the study cohort had cancer detected by PSA screening (TABLE 4).²⁵ The rest had either palpable tumors or symptoms of a tumor.

ProtecT, which followed patients with localized prostate cancer for more than 10 years,compared the outcomes and adverse effects of active surveillance, radical prostatectomy, and radiotherapy.²³ Prostate cancer–specific mortality was low irrespective of the treatment,²³ and there was no significant difference in all-cause mortality or prostate cancer–specific mortality between the 3 treatment groups.²³ The active surveillance group had considerably fewer adverse events.^22,23 The incidence rates of erectile dysfunction and urinary incontinence at the 1- and 6-year follow-up marks are outlined in TABLE 5.²²

Continue to: The purpose of active monitoring...

The purpose of active monitoring is to minimize overtreatment by avoiding immediate radical intervention. Radical treatments with curative intent can be undertaken at any point while patients are being actively monitored. It is important to note that the active monitoring that took place in ProtecT²³ was very different from the passive surveillance of PIVOT²⁴ and SPCG-4.²⁵ In ProtecT, once an elevated serum PSA level was noted, PSA levels were monitored every 3 months in the first year and every 6 to 12 months thereafter.²³ Triggers to reassess patients and consider a change in clinical management were based largely on changes in PSA levels. Participants with an increase of at least 50% in PSA level during the previous 12 months were offered either continued monitoring or treatment after further testing.

Making individualized decisions about prostate cancer screening

Traditionally, the goal of cancer screening has been to maximize the number of people screened. Generally, the information provided to patients about cancer screening emphasizes the benefits and minimizes the harms. Recently, however, there has been a shift in communication about cancer screening with the emphasis now being placed on informed decision-making and encouraging patients to make individual decisions about screening participation.²⁶

Although current guidelines regarding PSA screening differ by organization, generally speaking, PSA screening should be offered only to men with a life expectancy > 10 years.

The treatment option of active surveillance, with its lower incidence of adverse outcomes, is an important reason for patients to make individualized decisions about prostate cancer screening.

Another reason relates to 5-alpha-­reductase inhibitors. Although their role in the management of prostate cancer is currently not well defined, a reduction of almost 25% in the risk of prostate cancer and improvement in the performance of PSA has been reported.²⁷

The PSA test has low sensitivity and specificity and lacks a clear cut-off value that warrants prostate biopsy.

And yet another reason is that there are alternate strategies to manage the majority of patients who have been diagnosed with low-risk disease through transrectal ultrasound biopsy. The ERSPC study mentions multiparametric magnetic resonance imaging combined with targeted biopsy to identify high-grade disease.^28,29 Genetic and epigenetic assays of the biopsied tissue can help grade disease based on aggressiveness.³⁰ Transperineal mapping biopsy using a mapping software program can identify specific disease sites within the prostate gland, so that patients can be offered the option of targeted therapy.³⁰

Continue to: Applying shared decision-making to prostate cancer screening

Balancing errors of omission with errors of commission is challenging. Shared decision-making (SDM) is an approach whereby clinicians and patients share the best available evidence when faced with the task of medical decision-making and in which patients are supported while they consider their options and achieve their preferences.³¹ SDM is well supported by evidence from a number of RCTs and results in increased knowledge, involvement, and confidence on the part of patients.³² An individualized approach using the schematic diagram (FIGURE 1^3,18) may be helpful.

Barriers to SDM success. Many factors can interfere with the success of SDM including limited or poor communication; lack of time during busy office visits; and patients’ cultural, informational, and/or emotional needs. To improve patient-centered communication, we can: (1) make information understandable and available to patients and families; (2) prioritize training in communication; (3) use decision aid tools to facilitate communication; and (4) work to improve the payment model to incentivize patient-centered communication. Tools that facilitate SDM include videotapes, patient group discussions, brief scripts read to patients, and informational pamphlets. One such tool is the American Society for Clinical Oncology’s decision aid tool for PSA testing.³³

Limited knowledge among patients. Decisions regarding treatment among men diagnosed with localized prostate cancer can be difficult because there are several treatment options with similar prognoses, but there are differences in adverse effects. One population-based cohort study of men with newly diagnosed localized prostate cancer found that most men had significant knowledge deficits regarding the survival benefits of the 2 major treatment options—surgery and radiation.³⁴ In a large population-based study, 38% of men with localized prostate cancer reported receiving help from their primary care providers in the decision-making process for treatment.³⁵

Learning to employ SDM. Elwyn et al proposed a 3-step model to incorporate SDM into clinical practice.³¹ They described key steps that include: choice talk (making sure patients are informed about the reasonable options), option talk (providing more detailed information about the options), and decision talk (supporting the work of patients considering their preferences and deciding what is best). Properly employing these methods requires training using simulations.³¹

The bottom line

Although current guidelines regarding PSA screening differ by organization, generally speaking PSA screening should be offered only to men with a life expectancy > 10 years. The PSA test has low sensitivity and specificity and lacks a clear cut-off value that warrants prostate biopsy. Men who choose to have PSA testing increase their chances of detecting prostate cancer, but most prostate cancers are slow growing and do not cause death. The decision to undergo PSA screening should be made by both the provider and the patient, after a discussion of the limited benefits and associated harms. The interval of follow-up screening may vary from 2 to 4 years depending on patient age, level of PSA, and whether a patient is taking medications such as 5-alpha-reductase inhibitors.

CORRESPONDENCE
Jaividhya Dasarathy, MD, FAAFP, 2500 Metro Health Medical Drive, Cleveland, Ohio 44109; jxd114@case.edu.

Prostate cancer is the most frequently diagnosed cancer in men and the third leading cause of cancer death in men worldwide.¹ An estimated 174,650 new cases are diagnosed each year in the United States; 31,620 American men die annually from the disease.² Although prostate cancer can be a serious disease, many men do not die from it. In fact, 2.9 million men who were diagnosed with prostate cancer at some point are alive today.³

Risk factors. Prostate cancer develops mainly in men ages ≥ 65 years and rarely occurs before age 40. In addition to age, family history and African American ethnicity are the major nonmodifiable risk factors for prostate cancer.⁴ From the 1970s to the most recent statistical analysis of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, African American men have continued to have significantly higher incidence of, and mortality rates from, prostate cancer than their European American counterparts. African American men are also more likely than men of European ancestry to have aggressive prostate cancers.⁵ Other risk factors include geographic location (higher risk in Northern Europe, North America, and Australia; lower risk in Asia, Africa, and South and Central America), mutations in the BRCA2 gene, and hereditary non-polyposis colon cancer syndrome.⁴

Prostate-specific antigen (PSA) was first used as a screening tool for prostate cancer in 1991.⁶ Prostate cancer incidence, especially organ-confined disease, has dramatically increased since then.⁷ PSA testing has a low sensitivity and specificity for the detection of prostate cancer, and there is no clear threshold at which biopsy can or should be offered. The most commonly used cutoff value of 4 ng/mL has a false-positive rate of about 70%.⁸

Benign prostatic conditions such as hypertrophy and infection can elevate PSA levels. In addition, the PSA test does not distinguish between aggressive and slow-growing cancers, and about 15% of patients with prostate cancer have a normal PSA level.⁹

A word about the digital rectal exam. While PSA testing has been the mainstay of prostate cancer screening, a few studies have included digital rectal exam (DRE) in their protocols. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial showed that DRE captured an additional 2% of men with prostate cancer in the setting of a normal PSA test result.¹⁰ In the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, the overall detection rate for prostate cancer was found to be better when DRE was combined with PSA and prostate biopsy than when DRE was used alone (4.5% vs 2.5%).¹¹ Nevertheless, generally speaking, DRE can be omitted in the era of PSA screening.

Screening guidelines vary

Recommendations for prostate cancer screening vary by organization and are summarized in TABLE 1.^9,12-14 In 2012, the US Preventive Services Task Force (USPSTF) recommended against PSA-based screening for prostate cancer (Category D).¹⁵ In 2018, ­USPSTF provided an update with a new recommendation that clinicians inform men ages 55 to 69 years about the potential benefits and harms of PSA-based screening (Category C).¹⁴ The USPSTF continues to recommend against PSA-based screening for men ages ≥ 70 years (Category D).¹⁴

Does PSA-based screening improve patient-centered outcomes?

Several randomized controlled trials (RCTs) such as the Quebec Prospective Randomized Controlled Trial,¹⁶ the Norrköping Sweden Study,¹⁷ ERSPC,¹¹ and PLCO¹⁰ have been conducted to assess the benefits of PSA testing. PLCO and ERSPC have contributed significantly to our understanding of prostate cancer screening even though their 13-year follow-up results are conflicting (TABLE 2).^10,11,18

Continue to: In the ERSPC 13-year follow-up publication...

In the ERSPC 13-year follow-up publication, the authors concluded that a substantial reduction in prostate cancer mortality is attributable to testing with PSA.¹⁸ Despite limitations in the study design (eg, France entered after 2 years, screening intervals varied between 2 and 4 years, biopsy indications varied, and screening was discontinued at different times), PSA screening detected more prostate cancer than was detected in the control arm (10.2% vs 6.8%).

In the initial 11 years of follow-up, the study group experienced a 21% reduction in prostate cancer mortality, even though the absolute decrease ranged from only 0.6% (545 per 89,352) to 0.5% (355 per 72,891). The updated absolute risk reduction of death from prostate cancer at 13 years of follow-up showed a larger benefit: 0.11 per 1000 person-years or 1.28 per 1000 men randomized, which is equivalent to 1 prostate cancer death averted per 781 (95% confidence interval [CI], 490-1929) men invited for screening, or 1 per 27 (17-66) additional prostate cancers detected.

The PLCO trial did not show any significant difference in prostate cancer detection (11.1% screened vs 9.9% control), and there was no improvement in prostate cancer mortality (3.7 vs 3.4 death per 10,000 person-years).¹⁰ However, the PLCO trial suffered from issues of contamination, which may have influenced the overall results. About 52% of men in the control (usual care) group received a PSA test at some point during the study. And more than two-thirds of the men who had a prostate biopsy because of a positive PSA test did not have prostate cancer.

Community standards for the PSA threshold for biopsy were applied in various centers (> 4 ng/ml in general) in PLCO, whereas in ­ERSPC, a cut-off PSA value ≥ 3 ng/mL was used for biopsy. Because of the lower PSA threshold, ERSPC may have identified cancers that would have had good outcomes without any intervention.

The harms of PSA screening

While it is unclear whether PSA screening results in any improvement in patient-centered outcomes, it does lead to downstream intervention due to overdiagnosis, which precipitates unnecessary anxiety, biopsies, and overtreatment (eg, excess radiation, overuse of androgen deprivation therapy).¹⁹ Biopsies carry the risk of hematuria (22.6%), hematospermia (50.4%), and urinary tract infection.²⁰ Data from SEER-Medicare showed that prostate biopsy was associated with a 2.65-fold increased risk of hospitalization within 30 days of the procedure compared to a control population.²¹

Continue to: Overdiagnosis leads to overtreatment...

Overdiagnosis leads to overtreatment of low-risk prostate cancer. Both traditional treatment options for prostate cancer—radical prostatectomy and radiotherapy—are associated with urinary incontinence, erectile dysfunction, and issues with bowel function.^22,23

The Prostate Cancer Intervention vs Observation Trial (PIVOT),²⁴ the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4),²⁵ and the Prostate Testing for Cancer and Treatment (ProtecT) trial,^22,23 are the major RCTs that looked at the outcomes of treatment modalities for localized prostate cancer in the modern era of PSA testing.

PIVOT compared passive observation with radical prostatectomy.²⁴ After 20 years of follow-up on 731 patients, the researchers concluded that radical prostatectomy did not reduce all-cause or prostate cancer–related mortality (TABLE 3).²⁴

SPCG-4 showed survival benefits for men who underwent radical prostatectomy compared with men in a watchful waiting group, but only 5% of the study cohort had cancer detected by PSA screening (TABLE 4).²⁵ The rest had either palpable tumors or symptoms of a tumor.

ProtecT, which followed patients with localized prostate cancer for more than 10 years,compared the outcomes and adverse effects of active surveillance, radical prostatectomy, and radiotherapy.²³ Prostate cancer–specific mortality was low irrespective of the treatment,²³ and there was no significant difference in all-cause mortality or prostate cancer–specific mortality between the 3 treatment groups.²³ The active surveillance group had considerably fewer adverse events.^22,23 The incidence rates of erectile dysfunction and urinary incontinence at the 1- and 6-year follow-up marks are outlined in TABLE 5.²²

Continue to: The purpose of active monitoring...

The purpose of active monitoring is to minimize overtreatment by avoiding immediate radical intervention. Radical treatments with curative intent can be undertaken at any point while patients are being actively monitored. It is important to note that the active monitoring that took place in ProtecT²³ was very different from the passive surveillance of PIVOT²⁴ and SPCG-4.²⁵ In ProtecT, once an elevated serum PSA level was noted, PSA levels were monitored every 3 months in the first year and every 6 to 12 months thereafter.²³ Triggers to reassess patients and consider a change in clinical management were based largely on changes in PSA levels. Participants with an increase of at least 50% in PSA level during the previous 12 months were offered either continued monitoring or treatment after further testing.

Making individualized decisions about prostate cancer screening

Traditionally, the goal of cancer screening has been to maximize the number of people screened. Generally, the information provided to patients about cancer screening emphasizes the benefits and minimizes the harms. Recently, however, there has been a shift in communication about cancer screening with the emphasis now being placed on informed decision-making and encouraging patients to make individual decisions about screening participation.²⁶

Although current guidelines regarding PSA screening differ by organization, generally speaking, PSA screening should be offered only to men with a life expectancy > 10 years.

The treatment option of active surveillance, with its lower incidence of adverse outcomes, is an important reason for patients to make individualized decisions about prostate cancer screening.

Another reason relates to 5-alpha-­reductase inhibitors. Although their role in the management of prostate cancer is currently not well defined, a reduction of almost 25% in the risk of prostate cancer and improvement in the performance of PSA has been reported.²⁷

The PSA test has low sensitivity and specificity and lacks a clear cut-off value that warrants prostate biopsy.

And yet another reason is that there are alternate strategies to manage the majority of patients who have been diagnosed with low-risk disease through transrectal ultrasound biopsy. The ERSPC study mentions multiparametric magnetic resonance imaging combined with targeted biopsy to identify high-grade disease.^28,29 Genetic and epigenetic assays of the biopsied tissue can help grade disease based on aggressiveness.³⁰ Transperineal mapping biopsy using a mapping software program can identify specific disease sites within the prostate gland, so that patients can be offered the option of targeted therapy.³⁰

Continue to: Applying shared decision-making to prostate cancer screening

Balancing errors of omission with errors of commission is challenging. Shared decision-making (SDM) is an approach whereby clinicians and patients share the best available evidence when faced with the task of medical decision-making and in which patients are supported while they consider their options and achieve their preferences.³¹ SDM is well supported by evidence from a number of RCTs and results in increased knowledge, involvement, and confidence on the part of patients.³² An individualized approach using the schematic diagram (FIGURE 1^3,18) may be helpful.

Barriers to SDM success. Many factors can interfere with the success of SDM including limited or poor communication; lack of time during busy office visits; and patients’ cultural, informational, and/or emotional needs. To improve patient-centered communication, we can: (1) make information understandable and available to patients and families; (2) prioritize training in communication; (3) use decision aid tools to facilitate communication; and (4) work to improve the payment model to incentivize patient-centered communication. Tools that facilitate SDM include videotapes, patient group discussions, brief scripts read to patients, and informational pamphlets. One such tool is the American Society for Clinical Oncology’s decision aid tool for PSA testing.³³

Limited knowledge among patients. Decisions regarding treatment among men diagnosed with localized prostate cancer can be difficult because there are several treatment options with similar prognoses, but there are differences in adverse effects. One population-based cohort study of men with newly diagnosed localized prostate cancer found that most men had significant knowledge deficits regarding the survival benefits of the 2 major treatment options—surgery and radiation.³⁴ In a large population-based study, 38% of men with localized prostate cancer reported receiving help from their primary care providers in the decision-making process for treatment.³⁵

Learning to employ SDM. Elwyn et al proposed a 3-step model to incorporate SDM into clinical practice.³¹ They described key steps that include: choice talk (making sure patients are informed about the reasonable options), option talk (providing more detailed information about the options), and decision talk (supporting the work of patients considering their preferences and deciding what is best). Properly employing these methods requires training using simulations.³¹

The bottom line

Although current guidelines regarding PSA screening differ by organization, generally speaking PSA screening should be offered only to men with a life expectancy > 10 years. The PSA test has low sensitivity and specificity and lacks a clear cut-off value that warrants prostate biopsy. Men who choose to have PSA testing increase their chances of detecting prostate cancer, but most prostate cancers are slow growing and do not cause death. The decision to undergo PSA screening should be made by both the provider and the patient, after a discussion of the limited benefits and associated harms. The interval of follow-up screening may vary from 2 to 4 years depending on patient age, level of PSA, and whether a patient is taking medications such as 5-alpha-reductase inhibitors.

CORRESPONDENCE
Jaividhya Dasarathy, MD, FAAFP, 2500 Metro Health Medical Drive, Cleveland, Ohio 44109; jxd114@case.edu.

CASE 1

Two days after reviving her boyfriend with naloxone, a woman and her 30-year-old boyfriend presented to our family medicine clinic. They explained that he had injected heroin and shortly thereafter he stopped breathing and his lips turned blue. The patient’s girlfriend did not call emergency medical services (EMS) at the time because she was afraid of getting arrested due to past incarceration for possession of illegal drugs. Instead, she revived him with naloxone that she found in his bag.

Both the patient and his girlfriend were scared and surprised by his “terrible reaction,” as he had previously purchased heroin from the same dealer and used the same dose without similar effects. However, the patient did note that the drug he purchased this time had a bright white tinge, when normally the drug was light yellow.

On physical examination, the patient’s heart rate and blood pressure were normal. There were needle track marks on both forearms, elbows, and upper arms. A laboratory workup obtained during this visit revealed anemia and a normal basic metabolic panel. A hepatitis C virus antibody test was positive, and a hepatic function panel revealed elevated transaminase levels. Urine toxicology was positive for opioids and negative for other substances.

CASE 2

A 58-year-old man with a history of chronic hepatitis C, polysubstance abuse, and schizophrenia was transported to the emergency department by EMS after his family found him unresponsive in his bedroom. The patient had agonal breathing when EMS arrived, so they administered naloxone (4 mg intranasal and 4 mg intravenous). His breathing improved, but his mental status did not. He was still obtunded upon arrival in the emergency department and vomited 4 tan-colored patches. The patient was tachycardic (heart rate, 108 beats/min), hypertensive (blood pressure, 189/95 mm Hg), and had rapid shallow breathing (respiratory rate, 38 breaths/min). He was intubated for airway protection, at which time 2 more tan-colored patches were removed from his pharynx.

Laboratory evaluation revealed an acute kidney injury with a high anion metabolic acidosis. A hepatic function panel showed elevated transaminase levels. Plasma acetaminophen and salicylate levels were normal. A computed tomography head scan was normal. Urine toxicology was negative for opioids but was positive for cocaine and benzodiazepines.

THE DIAGNOSIS

Opioid overdose caused the acute respiratory depression in both cases. In Case 1, the patient unknowingly overdosed on heroin laced with fentanyl, known as China White, which likely caused the drug’s bright white tinge. In Case 2, the patient’s overdose was the result of oral ingestion of fentanyl patches. (Limited urine toxicology was negative for opiates because fentanyl is a fully synthetic opioid that shows up only with a specific or extended assay. More on this in a bit.)

DISCUSSION

The fatal drug overdose epidemic in the United States is growing. From 2000 to 2014, the mortality rate from drug overdose increased by 137%, including a 200% increase in the rate of overdose deaths related to opioids (ie, pain medications, heroin).¹ Between 2013 and 2014, the age-adjusted mortality rate related to methadone, a synthetic opioid, remained unchanged; however, age-adjusted mortality rates related to natural and semisynthetic opioid pain medications, heroin, and synthetic opioids other than methadone (eg, fentanyl) increased by 9%, 26%, and 80%, respectively. In 2014, a sharp increase in overdose deaths related to synthetic opioids other than methadone coincided with law enforcement reports of increased availability of illegal fentanyl; however, the toxicology panel used by coroners and medical examiners at that time could not distinguish between illegal and prescription fentanyl.¹

Continue to: Among 70,237 drug overdose deaths...

Among 70,237 drug overdose deaths in the United States in 2017, 47,600 (67.8%) involved an opioid. From 2013 to 2017, drug overdose death rates increased in 35 of 50 states and the District of Columbia, and significant increases in death rates involving synthetic opioids occurred in 15 out of 20 states, likely driven by illicitly manufactured fentanyl.²

Fentanyl-laced heroin: More common, but not new

In October 1991, 3-methylfentanyl was identified in 16 fatal drug overdoses in Allegheny County, Pennsylvania, contributing to a 4-fold increase in overdose deaths compared to the previous year. Fentanyl mixed with heroin and other drugs is commonly found in the Midwest, Northeast, and Southern regions of the United States; in 2014, more than 80% of fentanyl confiscations occurred in 10 states within these regions, with the highest incidence occurring in Ohio.³

When combined with fentanyl, heroin becomes 50 to 100 times more potent, resulting in a subjective high with exaggerated central nervous system depression manifesting as lethargy, miosis, and respiratory depression.⁴ Most drug users are unaware and unable to identify when heroin is laced with fentanyl, which may contribute to the rise in deaths from unintentional drug overdose.^1,5,6

Oral abuse of fentanyl patches can be fatal

Heroin is 50 to 100 times more potent when combined with fentanyl.

Outcomes from oral abuse of fentanyl patches have ranged from transient overdose symptoms, such as lethargy and respiratory depression, to death.^7-9 When administered in a medical setting, transbuccal fentanyl has a bioavailability of 50% to 65% across the buccal membrane. Nearly 20% of the drug escapes hepatic first pass metabolism when fentanyl patches are ingested orally and enters the systemic circulation, resulting in severe overdose and potentially death. Prolonged chewing and sucking on fentanyl patches increases the contact time with the buccal membrane, resulting in increased systemic absorption compared to oral ingestion without chewing/sucking.^7-9

Urine toxicology screening detects compounds based on a chemical assay for drugs—generally codeine, morphine, and their metabolites. Because fentanyl is a fully synthetic opioid, its structure is not like morphine or codeine. Therefore, fentanyl could not be detected on traditional urine toxicology screens for opiates. To detect the fentanyl, a urine drug screen would need an assay exclusively for fentanyl or its metabolite, norfentanyl.¹⁰ The fentanyl specific assay is increasingly available as part of commercially available, extended-panel urine toxicology testing.¹¹

Continue to: Survival of fentanyl overdose depends on naloxone availability

Naloxone is a safe and effective antidote to an opioid overdose. It comes in 3 preparations, including intramuscular and subcutaneous injections and an intranasal spray.¹² Concerns that naloxone will harm patients with opioid dependence are unfounded. Naloxone can induce symptoms of opioid withdrawal, such as yawning, lacrimation, piloerection, diaphoresis, myalgia, vomiting, and diarrhea. While these withdrawal symptoms are unpleasant, they are not life threatening.¹² Due to its high potency, large doses of naloxone (ie, 4–16 mg) are required to reverse the effects of a fentanyl overdose.¹³ Intranasal naloxone hydrochloride 4 mg delivered in a single spray is preferred due to the ease of administration. Repeat doses may be necessary if respiratory depression continues or recurs prior to the arrival of emergency medical services. Increasing the availability of naloxone to first responders has the potential to save many lives.⁶

THE TAKEAWAY

Fentanyl is a major contributor to the growing drug overdose crisis in the United States. When laced with heroin or consumed orally in the form of transdermal patches, fentanyl becomes more potent and is increasingly fatal. It’s crucial that primary care physicians be able to identify and educate at-risk patients about the fatal consequences of fentanyl overdose and coordinate care to help get them into an appropriate rehabilitation program.

In order to quickly recognize the signs of fentanyl-related overdose, it’s important to be alert for this possibility. At the bedside, the most easily recognized abnormality associated with fentanyl or other opioid overdose is a decline in respiratory rate culminating in apnea.¹⁰ A respiratory rate of 12 breaths/min or less in a patient who is not in physiologic sleep strongly suggests acute opioid intoxication, particularly when accompanied by miosis or stupor. Other signs include bradycardia, hypotension, and seizures from anoxia.¹⁰

Naloxone is a safe and effective antidote that is critical to the prevention of fatal opioid overdoses.

Apart from the severity of symptoms, it is hard to clinically distinguish fentanyl overdose from other opiate overdose incidents. Given the degree to which illegal opiates are contaminated with fentanyl in the United States,³ it is appropriate to screen for fentanyl with extended panel urine toxicology testing in patients with suspected opioid overdose.

CORRESPONDENCE
Jaividhya Dasarathy, MD, 2500 MetroHealth Medical Center, Cleveland, OH 44109; Jdasarathy@metrohealth.org

CASE 1

Two days after reviving her boyfriend with naloxone, a woman and her 30-year-old boyfriend presented to our family medicine clinic. They explained that he had injected heroin and shortly thereafter he stopped breathing and his lips turned blue. The patient’s girlfriend did not call emergency medical services (EMS) at the time because she was afraid of getting arrested due to past incarceration for possession of illegal drugs. Instead, she revived him with naloxone that she found in his bag.

Both the patient and his girlfriend were scared and surprised by his “terrible reaction,” as he had previously purchased heroin from the same dealer and used the same dose without similar effects. However, the patient did note that the drug he purchased this time had a bright white tinge, when normally the drug was light yellow.

On physical examination, the patient’s heart rate and blood pressure were normal. There were needle track marks on both forearms, elbows, and upper arms. A laboratory workup obtained during this visit revealed anemia and a normal basic metabolic panel. A hepatitis C virus antibody test was positive, and a hepatic function panel revealed elevated transaminase levels. Urine toxicology was positive for opioids and negative for other substances.

CASE 2

A 58-year-old man with a history of chronic hepatitis C, polysubstance abuse, and schizophrenia was transported to the emergency department by EMS after his family found him unresponsive in his bedroom. The patient had agonal breathing when EMS arrived, so they administered naloxone (4 mg intranasal and 4 mg intravenous). His breathing improved, but his mental status did not. He was still obtunded upon arrival in the emergency department and vomited 4 tan-colored patches. The patient was tachycardic (heart rate, 108 beats/min), hypertensive (blood pressure, 189/95 mm Hg), and had rapid shallow breathing (respiratory rate, 38 breaths/min). He was intubated for airway protection, at which time 2 more tan-colored patches were removed from his pharynx.

Laboratory evaluation revealed an acute kidney injury with a high anion metabolic acidosis. A hepatic function panel showed elevated transaminase levels. Plasma acetaminophen and salicylate levels were normal. A computed tomography head scan was normal. Urine toxicology was negative for opioids but was positive for cocaine and benzodiazepines.

THE DIAGNOSIS

Opioid overdose caused the acute respiratory depression in both cases. In Case 1, the patient unknowingly overdosed on heroin laced with fentanyl, known as China White, which likely caused the drug’s bright white tinge. In Case 2, the patient’s overdose was the result of oral ingestion of fentanyl patches. (Limited urine toxicology was negative for opiates because fentanyl is a fully synthetic opioid that shows up only with a specific or extended assay. More on this in a bit.)

DISCUSSION

The fatal drug overdose epidemic in the United States is growing. From 2000 to 2014, the mortality rate from drug overdose increased by 137%, including a 200% increase in the rate of overdose deaths related to opioids (ie, pain medications, heroin).¹ Between 2013 and 2014, the age-adjusted mortality rate related to methadone, a synthetic opioid, remained unchanged; however, age-adjusted mortality rates related to natural and semisynthetic opioid pain medications, heroin, and synthetic opioids other than methadone (eg, fentanyl) increased by 9%, 26%, and 80%, respectively. In 2014, a sharp increase in overdose deaths related to synthetic opioids other than methadone coincided with law enforcement reports of increased availability of illegal fentanyl; however, the toxicology panel used by coroners and medical examiners at that time could not distinguish between illegal and prescription fentanyl.¹

Continue to: Among 70,237 drug overdose deaths...

Among 70,237 drug overdose deaths in the United States in 2017, 47,600 (67.8%) involved an opioid. From 2013 to 2017, drug overdose death rates increased in 35 of 50 states and the District of Columbia, and significant increases in death rates involving synthetic opioids occurred in 15 out of 20 states, likely driven by illicitly manufactured fentanyl.²

Fentanyl-laced heroin: More common, but not new

In October 1991, 3-methylfentanyl was identified in 16 fatal drug overdoses in Allegheny County, Pennsylvania, contributing to a 4-fold increase in overdose deaths compared to the previous year. Fentanyl mixed with heroin and other drugs is commonly found in the Midwest, Northeast, and Southern regions of the United States; in 2014, more than 80% of fentanyl confiscations occurred in 10 states within these regions, with the highest incidence occurring in Ohio.³

When combined with fentanyl, heroin becomes 50 to 100 times more potent, resulting in a subjective high with exaggerated central nervous system depression manifesting as lethargy, miosis, and respiratory depression.⁴ Most drug users are unaware and unable to identify when heroin is laced with fentanyl, which may contribute to the rise in deaths from unintentional drug overdose.^1,5,6

Oral abuse of fentanyl patches can be fatal

Heroin is 50 to 100 times more potent when combined with fentanyl.

Outcomes from oral abuse of fentanyl patches have ranged from transient overdose symptoms, such as lethargy and respiratory depression, to death.^7-9 When administered in a medical setting, transbuccal fentanyl has a bioavailability of 50% to 65% across the buccal membrane. Nearly 20% of the drug escapes hepatic first pass metabolism when fentanyl patches are ingested orally and enters the systemic circulation, resulting in severe overdose and potentially death. Prolonged chewing and sucking on fentanyl patches increases the contact time with the buccal membrane, resulting in increased systemic absorption compared to oral ingestion without chewing/sucking.^7-9

Urine toxicology screening detects compounds based on a chemical assay for drugs—generally codeine, morphine, and their metabolites. Because fentanyl is a fully synthetic opioid, its structure is not like morphine or codeine. Therefore, fentanyl could not be detected on traditional urine toxicology screens for opiates. To detect the fentanyl, a urine drug screen would need an assay exclusively for fentanyl or its metabolite, norfentanyl.¹⁰ The fentanyl specific assay is increasingly available as part of commercially available, extended-panel urine toxicology testing.¹¹

Continue to: Survival of fentanyl overdose depends on naloxone availability

Naloxone is a safe and effective antidote to an opioid overdose. It comes in 3 preparations, including intramuscular and subcutaneous injections and an intranasal spray.¹² Concerns that naloxone will harm patients with opioid dependence are unfounded. Naloxone can induce symptoms of opioid withdrawal, such as yawning, lacrimation, piloerection, diaphoresis, myalgia, vomiting, and diarrhea. While these withdrawal symptoms are unpleasant, they are not life threatening.¹² Due to its high potency, large doses of naloxone (ie, 4–16 mg) are required to reverse the effects of a fentanyl overdose.¹³ Intranasal naloxone hydrochloride 4 mg delivered in a single spray is preferred due to the ease of administration. Repeat doses may be necessary if respiratory depression continues or recurs prior to the arrival of emergency medical services. Increasing the availability of naloxone to first responders has the potential to save many lives.⁶

THE TAKEAWAY

Fentanyl is a major contributor to the growing drug overdose crisis in the United States. When laced with heroin or consumed orally in the form of transdermal patches, fentanyl becomes more potent and is increasingly fatal. It’s crucial that primary care physicians be able to identify and educate at-risk patients about the fatal consequences of fentanyl overdose and coordinate care to help get them into an appropriate rehabilitation program.

In order to quickly recognize the signs of fentanyl-related overdose, it’s important to be alert for this possibility. At the bedside, the most easily recognized abnormality associated with fentanyl or other opioid overdose is a decline in respiratory rate culminating in apnea.¹⁰ A respiratory rate of 12 breaths/min or less in a patient who is not in physiologic sleep strongly suggests acute opioid intoxication, particularly when accompanied by miosis or stupor. Other signs include bradycardia, hypotension, and seizures from anoxia.¹⁰

Naloxone is a safe and effective antidote that is critical to the prevention of fatal opioid overdoses.

Apart from the severity of symptoms, it is hard to clinically distinguish fentanyl overdose from other opiate overdose incidents. Given the degree to which illegal opiates are contaminated with fentanyl in the United States,³ it is appropriate to screen for fentanyl with extended panel urine toxicology testing in patients with suspected opioid overdose.

CORRESPONDENCE
Jaividhya Dasarathy, MD, 2500 MetroHealth Medical Center, Cleveland, OH 44109; Jdasarathy@metrohealth.org

CASE 1

Two days after reviving her boyfriend with naloxone, a woman and her 30-year-old boyfriend presented to our family medicine clinic. They explained that he had injected heroin and shortly thereafter he stopped breathing and his lips turned blue. The patient’s girlfriend did not call emergency medical services (EMS) at the time because she was afraid of getting arrested due to past incarceration for possession of illegal drugs. Instead, she revived him with naloxone that she found in his bag.

Both the patient and his girlfriend were scared and surprised by his “terrible reaction,” as he had previously purchased heroin from the same dealer and used the same dose without similar effects. However, the patient did note that the drug he purchased this time had a bright white tinge, when normally the drug was light yellow.

On physical examination, the patient’s heart rate and blood pressure were normal. There were needle track marks on both forearms, elbows, and upper arms. A laboratory workup obtained during this visit revealed anemia and a normal basic metabolic panel. A hepatitis C virus antibody test was positive, and a hepatic function panel revealed elevated transaminase levels. Urine toxicology was positive for opioids and negative for other substances.

CASE 2

A 58-year-old man with a history of chronic hepatitis C, polysubstance abuse, and schizophrenia was transported to the emergency department by EMS after his family found him unresponsive in his bedroom. The patient had agonal breathing when EMS arrived, so they administered naloxone (4 mg intranasal and 4 mg intravenous). His breathing improved, but his mental status did not. He was still obtunded upon arrival in the emergency department and vomited 4 tan-colored patches. The patient was tachycardic (heart rate, 108 beats/min), hypertensive (blood pressure, 189/95 mm Hg), and had rapid shallow breathing (respiratory rate, 38 breaths/min). He was intubated for airway protection, at which time 2 more tan-colored patches were removed from his pharynx.

Laboratory evaluation revealed an acute kidney injury with a high anion metabolic acidosis. A hepatic function panel showed elevated transaminase levels. Plasma acetaminophen and salicylate levels were normal. A computed tomography head scan was normal. Urine toxicology was negative for opioids but was positive for cocaine and benzodiazepines.

THE DIAGNOSIS

Opioid overdose caused the acute respiratory depression in both cases. In Case 1, the patient unknowingly overdosed on heroin laced with fentanyl, known as China White, which likely caused the drug’s bright white tinge. In Case 2, the patient’s overdose was the result of oral ingestion of fentanyl patches. (Limited urine toxicology was negative for opiates because fentanyl is a fully synthetic opioid that shows up only with a specific or extended assay. More on this in a bit.)

DISCUSSION

The fatal drug overdose epidemic in the United States is growing. From 2000 to 2014, the mortality rate from drug overdose increased by 137%, including a 200% increase in the rate of overdose deaths related to opioids (ie, pain medications, heroin).¹ Between 2013 and 2014, the age-adjusted mortality rate related to methadone, a synthetic opioid, remained unchanged; however, age-adjusted mortality rates related to natural and semisynthetic opioid pain medications, heroin, and synthetic opioids other than methadone (eg, fentanyl) increased by 9%, 26%, and 80%, respectively. In 2014, a sharp increase in overdose deaths related to synthetic opioids other than methadone coincided with law enforcement reports of increased availability of illegal fentanyl; however, the toxicology panel used by coroners and medical examiners at that time could not distinguish between illegal and prescription fentanyl.¹

Continue to: Among 70,237 drug overdose deaths...

Among 70,237 drug overdose deaths in the United States in 2017, 47,600 (67.8%) involved an opioid. From 2013 to 2017, drug overdose death rates increased in 35 of 50 states and the District of Columbia, and significant increases in death rates involving synthetic opioids occurred in 15 out of 20 states, likely driven by illicitly manufactured fentanyl.²

Fentanyl-laced heroin: More common, but not new

In October 1991, 3-methylfentanyl was identified in 16 fatal drug overdoses in Allegheny County, Pennsylvania, contributing to a 4-fold increase in overdose deaths compared to the previous year. Fentanyl mixed with heroin and other drugs is commonly found in the Midwest, Northeast, and Southern regions of the United States; in 2014, more than 80% of fentanyl confiscations occurred in 10 states within these regions, with the highest incidence occurring in Ohio.³

When combined with fentanyl, heroin becomes 50 to 100 times more potent, resulting in a subjective high with exaggerated central nervous system depression manifesting as lethargy, miosis, and respiratory depression.⁴ Most drug users are unaware and unable to identify when heroin is laced with fentanyl, which may contribute to the rise in deaths from unintentional drug overdose.^1,5,6

Oral abuse of fentanyl patches can be fatal

Heroin is 50 to 100 times more potent when combined with fentanyl.

Outcomes from oral abuse of fentanyl patches have ranged from transient overdose symptoms, such as lethargy and respiratory depression, to death.^7-9 When administered in a medical setting, transbuccal fentanyl has a bioavailability of 50% to 65% across the buccal membrane. Nearly 20% of the drug escapes hepatic first pass metabolism when fentanyl patches are ingested orally and enters the systemic circulation, resulting in severe overdose and potentially death. Prolonged chewing and sucking on fentanyl patches increases the contact time with the buccal membrane, resulting in increased systemic absorption compared to oral ingestion without chewing/sucking.^7-9

Urine toxicology screening detects compounds based on a chemical assay for drugs—generally codeine, morphine, and their metabolites. Because fentanyl is a fully synthetic opioid, its structure is not like morphine or codeine. Therefore, fentanyl could not be detected on traditional urine toxicology screens for opiates. To detect the fentanyl, a urine drug screen would need an assay exclusively for fentanyl or its metabolite, norfentanyl.¹⁰ The fentanyl specific assay is increasingly available as part of commercially available, extended-panel urine toxicology testing.¹¹

Continue to: Survival of fentanyl overdose depends on naloxone availability

Naloxone is a safe and effective antidote to an opioid overdose. It comes in 3 preparations, including intramuscular and subcutaneous injections and an intranasal spray.¹² Concerns that naloxone will harm patients with opioid dependence are unfounded. Naloxone can induce symptoms of opioid withdrawal, such as yawning, lacrimation, piloerection, diaphoresis, myalgia, vomiting, and diarrhea. While these withdrawal symptoms are unpleasant, they are not life threatening.¹² Due to its high potency, large doses of naloxone (ie, 4–16 mg) are required to reverse the effects of a fentanyl overdose.¹³ Intranasal naloxone hydrochloride 4 mg delivered in a single spray is preferred due to the ease of administration. Repeat doses may be necessary if respiratory depression continues or recurs prior to the arrival of emergency medical services. Increasing the availability of naloxone to first responders has the potential to save many lives.⁶

THE TAKEAWAY

Fentanyl is a major contributor to the growing drug overdose crisis in the United States. When laced with heroin or consumed orally in the form of transdermal patches, fentanyl becomes more potent and is increasingly fatal. It’s crucial that primary care physicians be able to identify and educate at-risk patients about the fatal consequences of fentanyl overdose and coordinate care to help get them into an appropriate rehabilitation program.

In order to quickly recognize the signs of fentanyl-related overdose, it’s important to be alert for this possibility. At the bedside, the most easily recognized abnormality associated with fentanyl or other opioid overdose is a decline in respiratory rate culminating in apnea.¹⁰ A respiratory rate of 12 breaths/min or less in a patient who is not in physiologic sleep strongly suggests acute opioid intoxication, particularly when accompanied by miosis or stupor. Other signs include bradycardia, hypotension, and seizures from anoxia.¹⁰

Naloxone is a safe and effective antidote that is critical to the prevention of fatal opioid overdoses.

Apart from the severity of symptoms, it is hard to clinically distinguish fentanyl overdose from other opiate overdose incidents. Given the degree to which illegal opiates are contaminated with fentanyl in the United States,³ it is appropriate to screen for fentanyl with extended panel urine toxicology testing in patients with suspected opioid overdose.

CORRESPONDENCE
Jaividhya Dasarathy, MD, 2500 MetroHealth Medical Center, Cleveland, OH 44109; Jdasarathy@metrohealth.org

In a typical primary care practice, detecting and managing mental health problems competes with other priorities such as treating acute physical illness, monitoring chronic disease, providing preventive health services, and assessing compliance with standards of care.¹ These competing demands for a primary care provider’s time, paired with limited mental health resources in the community, may result in suboptimal behavioral health care.^1-3 Even when referrals are made to mental health care providers, depression is adequately treated only 20% of the time.^2,3 Additionally, individuals with serious mental illness and substance use disorders often do not receive adequate general medical care.^4,5

Approximately 30% of adults with physical disorders also have one or more behavioral health conditions, such as anxiety, panic, mood, or substance use disorders.⁶ Although physical and behavioral health conditions are inextricably linked, their assessment and treatment get separated into different silos.⁷ Given that fewer than 20% of depressed patients are seen by a psychiatrist or psychologist,⁸ the responsibility of providing mental health care often falls on the primary care physician.^8,9

Efforts to improve the treatment of common mental disorders in primary care have traditionally focused on screening for these disorders, educating primary care providers, developing treatment guidelines, and referring patients to mental health specialty care.¹⁰ However, behavioral health integration offers another way forward.

WHAT IS BEHAVIORAL HEALTH INTEGRATION?

Behavioral health integration (BHI) in primary care refers to primary care physicians and behavioral health clinicians working in concert with patients to address their primary care and behavioral health needs.¹¹

Numerous overlapping terms have been used to describe BHI, and this has caused some confusion. In 2013, the Agency for Healthcare Research and Quality (AHRQ) issued a lexicon standardizing the terminology used in BHI.¹¹ The commonly used terms are coordinated care, co-located care, and integrated care (TABLE 1),^11,12 and they may be best understood as part of a BHI continuum. A combined expert panel of the Substance Abuse and Mental Health Services Administration (SAMHSA) and the Health Resources and Services Administration (HRSA) has developed a conceptual framework defining 6 levels of integrated care spanning the 3 practice structures of coordinated care, co-located care, and integrated care (FIGURE 1).^12,13Reverse co-location is another frequently used term; it refers to primary care providers who work in settings devoted to mental health or chemical dependency treatment.¹¹

COORDINATED CARE AND THE COLLABORATIVE CARE MODEL

BHI at the level of coordinated care has almost exclusively been studied and practiced along the lines of the collaborative care model (CCM).^14-16 This model represents an advanced level of coordinated care in the BHI continuum. The most substantial evidence for CCM lies in the management of depression and anxiety.^14-16

Usual care involves the primary care physician and the patient. CCM adds 2 vital roles—a behavioral health care manager and a psychiatric consultant. A behavioral health care manager is typically a counselor, clinical social worker, psychologist, or psychiatric nurse who performs all care-management tasks including offering psychotherapy when that is part of the treatment plan.

Continue to: The care manager's functions include...

The care manager’s functions include systematic follow-up with structured monitoring of symptoms and treatment adherence, coordination and communication among care providers, patient education, and self-management support, including the use of motivational interviewing. The behavioral health care manager performs this systematic follow up by maintaining a patient “registry”—case-management software used in conjunction with, or embedded in, the practice electronic health record to track patients’ data and clinical outcomes, as well as to facilitate decision-making.

The care manager communicates with the psychiatrist, who offers suggestions for drug therapy, which is prescribed by the primary care physician. The care manager also regularly evaluates the patient’s status using a standardized scale, communicates these scores to the psychiatrist, and transmits any recommendations to the primary care physician (FIGURE 2).¹⁷

EVIDENCE FOR CCM

Collaborative and routine care were compared in a 2012 Cochrane review that included 79 randomized controlled trials (RCTs) involving 24,308 patients worldwide.¹⁶ Seventy-two of the 79 RCTs focused on patients with depression or depression with anxiety, while 6 studies included participants with only anxiety disorders.¹⁶ One additional study focused on mental health quality of life. (To learn about CCM and severe mental illness and substance use disorder, see “Less well studied: CCM and severe mental illness, alcohol dependence.”^18-20)

For adults with depression treated with the CCM, significantly greater improvement in depression outcome measures was seen in the short-term (standardized mean difference [SMD] = -0.34; 95% confidence interval [CI], -0.41 to -0.27; risk ratio [RR] = 1.32; 95% CI, 1.22-1.43), in the medium term (SMD = -0.28; 95% CI, -0.41 to -0.15; RR = 1.31; 95% CI, 1.17–1.48), and in the long term (SMD = -0.35; 95% CI, -0.46 to -0.24; RR = 1.29; 95% CI, 1.18–1.41).¹⁶

Comparisons of mental health quality of life over the short term (0-6 months), medium term (7-12 months), and long term (13-24 months) did not show any significant difference between CCM and routine care.¹⁶ Comparisons of physical health quality of life over the short term and medium term did not show any significant difference between CCM and routine care.¹⁶

Continue to: Significantly greater improvement...

Significantly greater improvement in anxiety outcomes was seen for adults treated with CCM in the short term (SMD = -0.30; 95% CI, -0.44 to -0.17; RR = 1.50; 95% CI, 1.21–1.87), in the medium term (SMD = -0.33; 95% CI, -0.47 to -0.19; RR = 1.41; 95% CI, 1.18-1.69), and in the long term (SMD = -0.20; 95% CI, -0.34 to -0.06; RR = 1.26; 95% CI, 1.11–1.42).¹⁶

A 2016 systematic review of 94 RCTs involving more than 25,000 patients also provided high-quality evidence that collaborative care yields small-to-moderate improvements in symptoms from mood disorders and mental health-related quality of life.¹⁵ A 2006 meta-analysis of 37 RCTs comprising 12,355 patients showed that collaborative care involving a case manager is more effective than standard care in improving depression outcomes at 6 months (SMD = 0.25; 95% CI, 0.18-0.32) and up to 5 years (SMD = 0.15; 95% CI, 0.001-0.31).²¹

Better care of mental health disorders also improves medical outcomes

Several trials have focused on jointly managing depression and a chronic physical condition such as chronic pain, diabetes, and coronary heart disease,²² demonstrating improved outcomes for both depression and the comanaged conditions.

• Chronic pain. When compared with usual care, collaborative care resulted in moderate reductions in both pain severity and associated disability (41.5% vs 17.3%; RR = 2.4; 95% CI, 1.6-3.2).²³
• Diabetes. Patients managed collaboratively were more likely to have a decrease of ≥ 1% in the glycated hemoglobin level from baseline (36% vs 19%; P = .006).²⁴
• Cardiovascular disease. Significant real-world risk reduction was achieved by improving blood pressure control (58% achieved blood pressure control compared with a projected target of 20%).²²

IS THERE A COMMON THREAD AMONG SUCCESSFUL CCMs?

Attempts to identify commonalities between the many iterations of successful CCMs have produced varying results due to differing selections of relevant RCTs.^25-29 However, a few common features have been identified:

• care managers assess symptoms at baseline and at follow-up using a standardized measure such as the Patient Health Questionnaire (PHQ-9);
• care managers monitor treatment adherence;
• follow-up is active for at least 16 weeks;
• primary care and mental health providers actively engage in patient management; and
• mental health specialists regularly supervise care managers.

The one feature that is consistent with improved outcomes is the presence of the care manager.^25-29

Continue to: The improvement associated...

The improvement associated with collaborative care is clinically meaningful to patients and physicians. In one RCT, collaborative care doubled response rates of depression treatment compared with usual care.³ Quality improvement data from real-world implementation of collaborative care programs suggests that similar outcomes can be achieved in a variety of settings.³⁰

COST BENEFITS OF CCM

Collaborative care for depression is associated with lower health care costs.^29,31

Patients with diabetes managed collaboratively have shown HbA_1c decreases of ≥ 1% from baseline more frequently than usual-care patients.

A meta-analysis of 57 RCTs in 2012 showed that CCM improves depression outcomes across populations, settings, and outcome domains, and that these results are achieved at little to no increase in treatment costs compared with usual care (Cohen’s d = 0.05; 95% CI, –0.02–0.12).²⁶

When collaborative care was compared with routine care in an RCT involving 1801 primary care patients ≥ 60 years who were suffering from depression, a cost saving of $3363 per patient over 4 years was demonstrated in the intervention arm.³¹

A technical analysis of 94 RCTs in 2015 concluded that CCM is cost effective compared with usual care, with a range of $15,000 to $80,000 per quality-adjusted life year gained. These studies also indicated that organizations’ costs to implement CCM increase in the short term. Based on this analysis, organizations would need to invest between $3 to $22 per patient per month to implement and sustain CCMs, depending on the prevalence of depression in the population.²⁹

Continue to: OTHER MODELS OF BHI

Higher levels of BHI such as co-location and integration do not have the same quality of evidence as CCM.

A 2009 Cochrane review of 42 studies involving 3880 patients found that mental health workers delivering psychological therapy and psychosocial interventions in primary care settings brought about significant reductions in primary care physician consultations (SMD = ‐0.17; 95% CI, ‐0.30 to ‐0.05); a relative risk reduction of 23% in psychotropic prescribing (RR = 0.67; 95% CI, 0.56–0.79); a decrease in prescribing costs (SMD = ‐0.22; 95% CI, ‐0.38 to ‐0.07); and a relative risk reduction in mental health referral of 87% (RR = 0.13; 95% CI, 0.09–0.20) for the patients they were seeing.³² The authors concluded the changes were modest in magnitude and inconsistent across different studies.³²

Collaborative care has improved depression outcomes at little to no increase in treatment costs compared with usual care.

Embedding medical providers in behavior health centers—ie, the reverse co-location model—also has very limited evidence. An RCT involving 120 veterans found that patients enrolled in a reverse co-location clinic did significantly better than controls seen in a general care clinic in terms of continuity of care and preventive care such as screening for hypertension (84.7% vs 65.6%; X ² = 5.9, P = .01), diabetes (71.2% vs 45.9%; X ² = 7.9, P < .005), hepatitis (39% vs 14.8%; X ² = 9, P = .003), and cholesterol (79.7% vs 57.4%; X ² = 6.9, P = .009).³³

HOW TO IMPLEMENT A SUCCESSFUL BHI PROGRAM

A demonstration and evaluation project involving 11 diverse practices in Colorado explored ways to integrate behavioral health in primary care. Five main themes emerged^34,35:

• Frame integrated care as a necessary paradigm shift to patient-centered, whole-person health care.
• Define relationships and protocols up front, understanding that they will evolve.
• Build inclusive, empowered teams to provide the foundation for integration.
• Develop a change management strategy of continuous evaluation and course correction.
• Use targeted data collection pertinent to integrated care to drive improvement and impart accountability.

The one feature that is consistent with improved outcomes is the presence of a care manager.

The Institute for Clinical and Economic Review has organized an extensive list of resources³⁶ for implementing BHI models, a sampling of which is shown in TABLE 2.

Continue to: TAKE-AWAY POINTS

There is high quality evidence that collaborative care works for the management of depression and anxiety disorder in primary care, and this is associated with significant cost savings. The one feature consistent in most successful BHI models is the care manager. More research is needed to identify which model of BHI works best for patients with SMI and substance use disorders. BHI cannot be accomplished by a few small changes to traditional care but requires a fundamental rethinking of care practices.

CORRESPONDENCE
Rajesh (FNU) Rajesh, MD, Main Campus Family Medicine Clinic, MetroHealth, 2500 MetroHealth Drive, Cleveland, OH 44109; frajesh@metrohealth.org

In a typical primary care practice, detecting and managing mental health problems competes with other priorities such as treating acute physical illness, monitoring chronic disease, providing preventive health services, and assessing compliance with standards of care.¹ These competing demands for a primary care provider’s time, paired with limited mental health resources in the community, may result in suboptimal behavioral health care.^1-3 Even when referrals are made to mental health care providers, depression is adequately treated only 20% of the time.^2,3 Additionally, individuals with serious mental illness and substance use disorders often do not receive adequate general medical care.^4,5

Approximately 30% of adults with physical disorders also have one or more behavioral health conditions, such as anxiety, panic, mood, or substance use disorders.⁶ Although physical and behavioral health conditions are inextricably linked, their assessment and treatment get separated into different silos.⁷ Given that fewer than 20% of depressed patients are seen by a psychiatrist or psychologist,⁸ the responsibility of providing mental health care often falls on the primary care physician.^8,9

Efforts to improve the treatment of common mental disorders in primary care have traditionally focused on screening for these disorders, educating primary care providers, developing treatment guidelines, and referring patients to mental health specialty care.¹⁰ However, behavioral health integration offers another way forward.

WHAT IS BEHAVIORAL HEALTH INTEGRATION?

Behavioral health integration (BHI) in primary care refers to primary care physicians and behavioral health clinicians working in concert with patients to address their primary care and behavioral health needs.¹¹

Numerous overlapping terms have been used to describe BHI, and this has caused some confusion. In 2013, the Agency for Healthcare Research and Quality (AHRQ) issued a lexicon standardizing the terminology used in BHI.¹¹ The commonly used terms are coordinated care, co-located care, and integrated care (TABLE 1),^11,12 and they may be best understood as part of a BHI continuum. A combined expert panel of the Substance Abuse and Mental Health Services Administration (SAMHSA) and the Health Resources and Services Administration (HRSA) has developed a conceptual framework defining 6 levels of integrated care spanning the 3 practice structures of coordinated care, co-located care, and integrated care (FIGURE 1).^12,13Reverse co-location is another frequently used term; it refers to primary care providers who work in settings devoted to mental health or chemical dependency treatment.¹¹

COORDINATED CARE AND THE COLLABORATIVE CARE MODEL

BHI at the level of coordinated care has almost exclusively been studied and practiced along the lines of the collaborative care model (CCM).^14-16 This model represents an advanced level of coordinated care in the BHI continuum. The most substantial evidence for CCM lies in the management of depression and anxiety.^14-16

Usual care involves the primary care physician and the patient. CCM adds 2 vital roles—a behavioral health care manager and a psychiatric consultant. A behavioral health care manager is typically a counselor, clinical social worker, psychologist, or psychiatric nurse who performs all care-management tasks including offering psychotherapy when that is part of the treatment plan.

Continue to: The care manager's functions include...

The care manager’s functions include systematic follow-up with structured monitoring of symptoms and treatment adherence, coordination and communication among care providers, patient education, and self-management support, including the use of motivational interviewing. The behavioral health care manager performs this systematic follow up by maintaining a patient “registry”—case-management software used in conjunction with, or embedded in, the practice electronic health record to track patients’ data and clinical outcomes, as well as to facilitate decision-making.

The care manager communicates with the psychiatrist, who offers suggestions for drug therapy, which is prescribed by the primary care physician. The care manager also regularly evaluates the patient’s status using a standardized scale, communicates these scores to the psychiatrist, and transmits any recommendations to the primary care physician (FIGURE 2).¹⁷

EVIDENCE FOR CCM

Collaborative and routine care were compared in a 2012 Cochrane review that included 79 randomized controlled trials (RCTs) involving 24,308 patients worldwide.¹⁶ Seventy-two of the 79 RCTs focused on patients with depression or depression with anxiety, while 6 studies included participants with only anxiety disorders.¹⁶ One additional study focused on mental health quality of life. (To learn about CCM and severe mental illness and substance use disorder, see “Less well studied: CCM and severe mental illness, alcohol dependence.”^18-20)

For adults with depression treated with the CCM, significantly greater improvement in depression outcome measures was seen in the short-term (standardized mean difference [SMD] = -0.34; 95% confidence interval [CI], -0.41 to -0.27; risk ratio [RR] = 1.32; 95% CI, 1.22-1.43), in the medium term (SMD = -0.28; 95% CI, -0.41 to -0.15; RR = 1.31; 95% CI, 1.17–1.48), and in the long term (SMD = -0.35; 95% CI, -0.46 to -0.24; RR = 1.29; 95% CI, 1.18–1.41).¹⁶

Comparisons of mental health quality of life over the short term (0-6 months), medium term (7-12 months), and long term (13-24 months) did not show any significant difference between CCM and routine care.¹⁶ Comparisons of physical health quality of life over the short term and medium term did not show any significant difference between CCM and routine care.¹⁶

Continue to: Significantly greater improvement...

Significantly greater improvement in anxiety outcomes was seen for adults treated with CCM in the short term (SMD = -0.30; 95% CI, -0.44 to -0.17; RR = 1.50; 95% CI, 1.21–1.87), in the medium term (SMD = -0.33; 95% CI, -0.47 to -0.19; RR = 1.41; 95% CI, 1.18-1.69), and in the long term (SMD = -0.20; 95% CI, -0.34 to -0.06; RR = 1.26; 95% CI, 1.11–1.42).¹⁶

A 2016 systematic review of 94 RCTs involving more than 25,000 patients also provided high-quality evidence that collaborative care yields small-to-moderate improvements in symptoms from mood disorders and mental health-related quality of life.¹⁵ A 2006 meta-analysis of 37 RCTs comprising 12,355 patients showed that collaborative care involving a case manager is more effective than standard care in improving depression outcomes at 6 months (SMD = 0.25; 95% CI, 0.18-0.32) and up to 5 years (SMD = 0.15; 95% CI, 0.001-0.31).²¹

Better care of mental health disorders also improves medical outcomes

Several trials have focused on jointly managing depression and a chronic physical condition such as chronic pain, diabetes, and coronary heart disease,²² demonstrating improved outcomes for both depression and the comanaged conditions.

• Chronic pain. When compared with usual care, collaborative care resulted in moderate reductions in both pain severity and associated disability (41.5% vs 17.3%; RR = 2.4; 95% CI, 1.6-3.2).²³
• Diabetes. Patients managed collaboratively were more likely to have a decrease of ≥ 1% in the glycated hemoglobin level from baseline (36% vs 19%; P = .006).²⁴
• Cardiovascular disease. Significant real-world risk reduction was achieved by improving blood pressure control (58% achieved blood pressure control compared with a projected target of 20%).²²

IS THERE A COMMON THREAD AMONG SUCCESSFUL CCMs?

Attempts to identify commonalities between the many iterations of successful CCMs have produced varying results due to differing selections of relevant RCTs.^25-29 However, a few common features have been identified:

• care managers assess symptoms at baseline and at follow-up using a standardized measure such as the Patient Health Questionnaire (PHQ-9);
• care managers monitor treatment adherence;
• follow-up is active for at least 16 weeks;
• primary care and mental health providers actively engage in patient management; and
• mental health specialists regularly supervise care managers.

The one feature that is consistent with improved outcomes is the presence of the care manager.^25-29

Continue to: The improvement associated...

The improvement associated with collaborative care is clinically meaningful to patients and physicians. In one RCT, collaborative care doubled response rates of depression treatment compared with usual care.³ Quality improvement data from real-world implementation of collaborative care programs suggests that similar outcomes can be achieved in a variety of settings.³⁰

COST BENEFITS OF CCM

Collaborative care for depression is associated with lower health care costs.^29,31

Patients with diabetes managed collaboratively have shown HbA_1c decreases of ≥ 1% from baseline more frequently than usual-care patients.

A meta-analysis of 57 RCTs in 2012 showed that CCM improves depression outcomes across populations, settings, and outcome domains, and that these results are achieved at little to no increase in treatment costs compared with usual care (Cohen’s d = 0.05; 95% CI, –0.02–0.12).²⁶

When collaborative care was compared with routine care in an RCT involving 1801 primary care patients ≥ 60 years who were suffering from depression, a cost saving of $3363 per patient over 4 years was demonstrated in the intervention arm.³¹

A technical analysis of 94 RCTs in 2015 concluded that CCM is cost effective compared with usual care, with a range of $15,000 to $80,000 per quality-adjusted life year gained. These studies also indicated that organizations’ costs to implement CCM increase in the short term. Based on this analysis, organizations would need to invest between $3 to $22 per patient per month to implement and sustain CCMs, depending on the prevalence of depression in the population.²⁹

Continue to: OTHER MODELS OF BHI

Higher levels of BHI such as co-location and integration do not have the same quality of evidence as CCM.

A 2009 Cochrane review of 42 studies involving 3880 patients found that mental health workers delivering psychological therapy and psychosocial interventions in primary care settings brought about significant reductions in primary care physician consultations (SMD = ‐0.17; 95% CI, ‐0.30 to ‐0.05); a relative risk reduction of 23% in psychotropic prescribing (RR = 0.67; 95% CI, 0.56–0.79); a decrease in prescribing costs (SMD = ‐0.22; 95% CI, ‐0.38 to ‐0.07); and a relative risk reduction in mental health referral of 87% (RR = 0.13; 95% CI, 0.09–0.20) for the patients they were seeing.³² The authors concluded the changes were modest in magnitude and inconsistent across different studies.³²

Collaborative care has improved depression outcomes at little to no increase in treatment costs compared with usual care.

Embedding medical providers in behavior health centers—ie, the reverse co-location model—also has very limited evidence. An RCT involving 120 veterans found that patients enrolled in a reverse co-location clinic did significantly better than controls seen in a general care clinic in terms of continuity of care and preventive care such as screening for hypertension (84.7% vs 65.6%; X ² = 5.9, P = .01), diabetes (71.2% vs 45.9%; X ² = 7.9, P < .005), hepatitis (39% vs 14.8%; X ² = 9, P = .003), and cholesterol (79.7% vs 57.4%; X ² = 6.9, P = .009).³³

HOW TO IMPLEMENT A SUCCESSFUL BHI PROGRAM

A demonstration and evaluation project involving 11 diverse practices in Colorado explored ways to integrate behavioral health in primary care. Five main themes emerged^34,35:

• Frame integrated care as a necessary paradigm shift to patient-centered, whole-person health care.
• Define relationships and protocols up front, understanding that they will evolve.
• Build inclusive, empowered teams to provide the foundation for integration.
• Develop a change management strategy of continuous evaluation and course correction.
• Use targeted data collection pertinent to integrated care to drive improvement and impart accountability.

The one feature that is consistent with improved outcomes is the presence of a care manager.

The Institute for Clinical and Economic Review has organized an extensive list of resources³⁶ for implementing BHI models, a sampling of which is shown in TABLE 2.

Continue to: TAKE-AWAY POINTS

There is high quality evidence that collaborative care works for the management of depression and anxiety disorder in primary care, and this is associated with significant cost savings. The one feature consistent in most successful BHI models is the care manager. More research is needed to identify which model of BHI works best for patients with SMI and substance use disorders. BHI cannot be accomplished by a few small changes to traditional care but requires a fundamental rethinking of care practices.

CORRESPONDENCE
Rajesh (FNU) Rajesh, MD, Main Campus Family Medicine Clinic, MetroHealth, 2500 MetroHealth Drive, Cleveland, OH 44109; frajesh@metrohealth.org

In a typical primary care practice, detecting and managing mental health problems competes with other priorities such as treating acute physical illness, monitoring chronic disease, providing preventive health services, and assessing compliance with standards of care.¹ These competing demands for a primary care provider’s time, paired with limited mental health resources in the community, may result in suboptimal behavioral health care.^1-3 Even when referrals are made to mental health care providers, depression is adequately treated only 20% of the time.^2,3 Additionally, individuals with serious mental illness and substance use disorders often do not receive adequate general medical care.^4,5

Approximately 30% of adults with physical disorders also have one or more behavioral health conditions, such as anxiety, panic, mood, or substance use disorders.⁶ Although physical and behavioral health conditions are inextricably linked, their assessment and treatment get separated into different silos.⁷ Given that fewer than 20% of depressed patients are seen by a psychiatrist or psychologist,⁸ the responsibility of providing mental health care often falls on the primary care physician.^8,9

Efforts to improve the treatment of common mental disorders in primary care have traditionally focused on screening for these disorders, educating primary care providers, developing treatment guidelines, and referring patients to mental health specialty care.¹⁰ However, behavioral health integration offers another way forward.

WHAT IS BEHAVIORAL HEALTH INTEGRATION?

Behavioral health integration (BHI) in primary care refers to primary care physicians and behavioral health clinicians working in concert with patients to address their primary care and behavioral health needs.¹¹

Numerous overlapping terms have been used to describe BHI, and this has caused some confusion. In 2013, the Agency for Healthcare Research and Quality (AHRQ) issued a lexicon standardizing the terminology used in BHI.¹¹ The commonly used terms are coordinated care, co-located care, and integrated care (TABLE 1),^11,12 and they may be best understood as part of a BHI continuum. A combined expert panel of the Substance Abuse and Mental Health Services Administration (SAMHSA) and the Health Resources and Services Administration (HRSA) has developed a conceptual framework defining 6 levels of integrated care spanning the 3 practice structures of coordinated care, co-located care, and integrated care (FIGURE 1).^12,13Reverse co-location is another frequently used term; it refers to primary care providers who work in settings devoted to mental health or chemical dependency treatment.¹¹

COORDINATED CARE AND THE COLLABORATIVE CARE MODEL

BHI at the level of coordinated care has almost exclusively been studied and practiced along the lines of the collaborative care model (CCM).^14-16 This model represents an advanced level of coordinated care in the BHI continuum. The most substantial evidence for CCM lies in the management of depression and anxiety.^14-16

Usual care involves the primary care physician and the patient. CCM adds 2 vital roles—a behavioral health care manager and a psychiatric consultant. A behavioral health care manager is typically a counselor, clinical social worker, psychologist, or psychiatric nurse who performs all care-management tasks including offering psychotherapy when that is part of the treatment plan.

Continue to: The care manager's functions include...

The care manager’s functions include systematic follow-up with structured monitoring of symptoms and treatment adherence, coordination and communication among care providers, patient education, and self-management support, including the use of motivational interviewing. The behavioral health care manager performs this systematic follow up by maintaining a patient “registry”—case-management software used in conjunction with, or embedded in, the practice electronic health record to track patients’ data and clinical outcomes, as well as to facilitate decision-making.

The care manager communicates with the psychiatrist, who offers suggestions for drug therapy, which is prescribed by the primary care physician. The care manager also regularly evaluates the patient’s status using a standardized scale, communicates these scores to the psychiatrist, and transmits any recommendations to the primary care physician (FIGURE 2).¹⁷

EVIDENCE FOR CCM

Collaborative and routine care were compared in a 2012 Cochrane review that included 79 randomized controlled trials (RCTs) involving 24,308 patients worldwide.¹⁶ Seventy-two of the 79 RCTs focused on patients with depression or depression with anxiety, while 6 studies included participants with only anxiety disorders.¹⁶ One additional study focused on mental health quality of life. (To learn about CCM and severe mental illness and substance use disorder, see “Less well studied: CCM and severe mental illness, alcohol dependence.”^18-20)

For adults with depression treated with the CCM, significantly greater improvement in depression outcome measures was seen in the short-term (standardized mean difference [SMD] = -0.34; 95% confidence interval [CI], -0.41 to -0.27; risk ratio [RR] = 1.32; 95% CI, 1.22-1.43), in the medium term (SMD = -0.28; 95% CI, -0.41 to -0.15; RR = 1.31; 95% CI, 1.17–1.48), and in the long term (SMD = -0.35; 95% CI, -0.46 to -0.24; RR = 1.29; 95% CI, 1.18–1.41).¹⁶

Comparisons of mental health quality of life over the short term (0-6 months), medium term (7-12 months), and long term (13-24 months) did not show any significant difference between CCM and routine care.¹⁶ Comparisons of physical health quality of life over the short term and medium term did not show any significant difference between CCM and routine care.¹⁶

Continue to: Significantly greater improvement...

Significantly greater improvement in anxiety outcomes was seen for adults treated with CCM in the short term (SMD = -0.30; 95% CI, -0.44 to -0.17; RR = 1.50; 95% CI, 1.21–1.87), in the medium term (SMD = -0.33; 95% CI, -0.47 to -0.19; RR = 1.41; 95% CI, 1.18-1.69), and in the long term (SMD = -0.20; 95% CI, -0.34 to -0.06; RR = 1.26; 95% CI, 1.11–1.42).¹⁶

A 2016 systematic review of 94 RCTs involving more than 25,000 patients also provided high-quality evidence that collaborative care yields small-to-moderate improvements in symptoms from mood disorders and mental health-related quality of life.¹⁵ A 2006 meta-analysis of 37 RCTs comprising 12,355 patients showed that collaborative care involving a case manager is more effective than standard care in improving depression outcomes at 6 months (SMD = 0.25; 95% CI, 0.18-0.32) and up to 5 years (SMD = 0.15; 95% CI, 0.001-0.31).²¹

Better care of mental health disorders also improves medical outcomes

Several trials have focused on jointly managing depression and a chronic physical condition such as chronic pain, diabetes, and coronary heart disease,²² demonstrating improved outcomes for both depression and the comanaged conditions.

• Chronic pain. When compared with usual care, collaborative care resulted in moderate reductions in both pain severity and associated disability (41.5% vs 17.3%; RR = 2.4; 95% CI, 1.6-3.2).²³
• Diabetes. Patients managed collaboratively were more likely to have a decrease of ≥ 1% in the glycated hemoglobin level from baseline (36% vs 19%; P = .006).²⁴
• Cardiovascular disease. Significant real-world risk reduction was achieved by improving blood pressure control (58% achieved blood pressure control compared with a projected target of 20%).²²

IS THERE A COMMON THREAD AMONG SUCCESSFUL CCMs?

Attempts to identify commonalities between the many iterations of successful CCMs have produced varying results due to differing selections of relevant RCTs.^25-29 However, a few common features have been identified:

• care managers assess symptoms at baseline and at follow-up using a standardized measure such as the Patient Health Questionnaire (PHQ-9);
• care managers monitor treatment adherence;
• follow-up is active for at least 16 weeks;
• primary care and mental health providers actively engage in patient management; and
• mental health specialists regularly supervise care managers.

The one feature that is consistent with improved outcomes is the presence of the care manager.^25-29

Continue to: The improvement associated...

The improvement associated with collaborative care is clinically meaningful to patients and physicians. In one RCT, collaborative care doubled response rates of depression treatment compared with usual care.³ Quality improvement data from real-world implementation of collaborative care programs suggests that similar outcomes can be achieved in a variety of settings.³⁰

COST BENEFITS OF CCM

Collaborative care for depression is associated with lower health care costs.^29,31

Patients with diabetes managed collaboratively have shown HbA_1c decreases of ≥ 1% from baseline more frequently than usual-care patients.

A meta-analysis of 57 RCTs in 2012 showed that CCM improves depression outcomes across populations, settings, and outcome domains, and that these results are achieved at little to no increase in treatment costs compared with usual care (Cohen’s d = 0.05; 95% CI, –0.02–0.12).²⁶

When collaborative care was compared with routine care in an RCT involving 1801 primary care patients ≥ 60 years who were suffering from depression, a cost saving of $3363 per patient over 4 years was demonstrated in the intervention arm.³¹

A technical analysis of 94 RCTs in 2015 concluded that CCM is cost effective compared with usual care, with a range of $15,000 to $80,000 per quality-adjusted life year gained. These studies also indicated that organizations’ costs to implement CCM increase in the short term. Based on this analysis, organizations would need to invest between $3 to $22 per patient per month to implement and sustain CCMs, depending on the prevalence of depression in the population.²⁹

Continue to: OTHER MODELS OF BHI

Higher levels of BHI such as co-location and integration do not have the same quality of evidence as CCM.

A 2009 Cochrane review of 42 studies involving 3880 patients found that mental health workers delivering psychological therapy and psychosocial interventions in primary care settings brought about significant reductions in primary care physician consultations (SMD = ‐0.17; 95% CI, ‐0.30 to ‐0.05); a relative risk reduction of 23% in psychotropic prescribing (RR = 0.67; 95% CI, 0.56–0.79); a decrease in prescribing costs (SMD = ‐0.22; 95% CI, ‐0.38 to ‐0.07); and a relative risk reduction in mental health referral of 87% (RR = 0.13; 95% CI, 0.09–0.20) for the patients they were seeing.³² The authors concluded the changes were modest in magnitude and inconsistent across different studies.³²

Collaborative care has improved depression outcomes at little to no increase in treatment costs compared with usual care.

Embedding medical providers in behavior health centers—ie, the reverse co-location model—also has very limited evidence. An RCT involving 120 veterans found that patients enrolled in a reverse co-location clinic did significantly better than controls seen in a general care clinic in terms of continuity of care and preventive care such as screening for hypertension (84.7% vs 65.6%; X ² = 5.9, P = .01), diabetes (71.2% vs 45.9%; X ² = 7.9, P < .005), hepatitis (39% vs 14.8%; X ² = 9, P = .003), and cholesterol (79.7% vs 57.4%; X ² = 6.9, P = .009).³³

HOW TO IMPLEMENT A SUCCESSFUL BHI PROGRAM

A demonstration and evaluation project involving 11 diverse practices in Colorado explored ways to integrate behavioral health in primary care. Five main themes emerged^34,35:

• Frame integrated care as a necessary paradigm shift to patient-centered, whole-person health care.
• Define relationships and protocols up front, understanding that they will evolve.
• Build inclusive, empowered teams to provide the foundation for integration.
• Develop a change management strategy of continuous evaluation and course correction.
• Use targeted data collection pertinent to integrated care to drive improvement and impart accountability.

The one feature that is consistent with improved outcomes is the presence of a care manager.

The Institute for Clinical and Economic Review has organized an extensive list of resources³⁶ for implementing BHI models, a sampling of which is shown in TABLE 2.

Continue to: TAKE-AWAY POINTS

There is high quality evidence that collaborative care works for the management of depression and anxiety disorder in primary care, and this is associated with significant cost savings. The one feature consistent in most successful BHI models is the care manager. More research is needed to identify which model of BHI works best for patients with SMI and substance use disorders. BHI cannot be accomplished by a few small changes to traditional care but requires a fundamental rethinking of care practices.

CORRESPONDENCE
Rajesh (FNU) Rajesh, MD, Main Campus Family Medicine Clinic, MetroHealth, 2500 MetroHealth Drive, Cleveland, OH 44109; frajesh@metrohealth.org

THE CASE

Steven R,* a 21-year-old man, visited the clinic accompanied by his mother. He did not speak much, and his mother provided his history. Over the previous 2 months, she had overheard him whispering in an agitated voice, even though no one else was nearby. And, lately, he refused to answer or make calls on his cell phone, claiming that if he did it would activate a deadly chip that had been implanted in his brain by evil aliens. He also stopped attending classes at the community college. He occasionally had a few beers with his friends, but he had never been known to abuse alcohol or use other recreational drugs.

How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

Schizophrenia is a psychotic illness in which the individual loses contact with reality and often experiences hallucinations, delusions, or thought disorders. Criteria for schizophrenia described in the Diagnostic and Statistical Manual of Mental Disorders 5^th edition (DSM-5) include signs and symptoms of at least 6 months’ duration, as well as at least one month of active-phase positive and negative symptoms.¹

Delusions, hallucinations, disorganized speech, and disorganized behavior are examples of positive symptoms. Negative symptoms include a decrease in the range and intensity of expressed emotions (ie, affective flattening) and a diminished initiation of goal-directed activities (ie, avolition).

Approximately 7 in 1000 people will develop the disorder in their lifetime.² Schizophrenia is considered a “serious mental illness” because of its chronic course and often poor long-term social and vocational outcomes.^3,4 Symptom onset is generally between late adolescence and the mid-30s.⁵

Getting closer to understanding its origin

Both genetic susceptibility and environmental factors influence the incidence of schizophrenia.⁴ Newer models of the disease have identified genes (ZDHHC8 and DTNBP1) whose mutations may increase the risk of schizophrenia.⁶ Physiologic insults during fetal life—hypoxia, maternal infection, maternal stress, and maternal malnutrition—account for a small portion of schizophrenia cases.⁶

Abnormalities in neurotransmission are the basis for theories on the pathophysiology of schizophrenia. Most of these theories center on either an excess or a deficiency of neurotransmitters, including dopamine, serotonin, and glutamate. Other theories implicate aspartate, glycine, and gamma-aminobutyric acid as part of the neurochemical imbalance of schizophrenia.⁷

ESTABLISHING A DIAGNOSIS

Although psychotic symptoms may be a prominent part of schizophrenia, not all psychoses indicate a primary psychiatric disorder such as schizophrenia. Broadly, psychoses can be categorized as primary or secondary.

Primary psychoses include schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, and mood disorders (major depressive disorder and borderline personality disorder) with psychotic features.¹ Difficulty in distinguishing between these entities can necessitate referral to a psychiatrist.

Secondary psychoses arise from a precursor such as delirium, dementia, medical illness, or adverse effects of medications or illicit substances. Medical illnesses that cause psychotic symptoms include: ^5,8

• seizures (especially temporal lobe epilepsy),
• cerebrovascular accidents,
• intracranial space-occupying lesions,
• neuropsychiatric disorders (eg, Wilson’s or Parkinson’s disease),
• endocrine disorders (eg, thyroid or adrenal disease),
• autoimmune disease (eg, systemic lupus erythematosus, Hashimoto encephalopathy),
• deficiencies of vitamins A, B₁, B₁₂, or niacin,
• infections (eg, human immunodeficiency virus [HIV], encephalitis, parasites, and prion disease),
• narcolepsy, and
• metabolic disease (eg, acute intermittent porphyria, Tay-Sach’s disease, Niemann-Pick disease).

Several recreational drugs can cause psychotic symptoms: cocaine, amphetamines, cannabis, synthetic cannabinoids, inhalants, opioids, and hallucinogens. Psychotic symptoms can also appear during withdrawal from alcohol (delirium tremens) and from sedative hypnotics such as benzodiazepines. Prescribed medications such as anticholinergics, corticosteroids, dopaminergic agents (L-dopa), stimulants (amphetamines), and interferons can also induce psychotic symptoms.

First rule out causes of secondary psychosis

Rule out causes of secondary psychosis by conducting a detailed history and physical examination and ordering appropriate lab tests and imaging studies. If the patient’s psychosis is of recent onset, make sure the laboratory work-up includes a complete blood count (CBC), renal function testing, urine culture and sensitivity and urine toxicology, and measures of electrolytes, blood glucose, thyroid-stimulating hormone (TSH), vitamin B₁₂, folic acid, erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), HIV antibody, and serum fluorescent treponemal antibody absorption (FTA-ABS).⁹

All antipsychotic agents are comparably effective, but adverse effects differ.

Consider cranial computed tomography or magnetic resonance imaging if there are focal neurologic deficits or if the patient’s presentation is atypical (eg, new onset psychosis in old age).⁹ Clinical presentation may also indicate a need for electroencephalography, ceruloplasmin measurement, a dexamethasone suppression test, a corticotropin stimulation test, 24-hour urine porphyrin and copper assays, chest radiography, or cerebrospinal fluid analysis.⁹

FACTORS TO CONSIDER IN TREATMENT DECISIONS

Although primary care physicians may encounter individuals experiencing their first episode of psychosis, it’s more likely that patients presenting with signs and symptoms of the disorder have been experiencing them for some time and have received no psychiatric care. In both instances, schizophrenia is best managed in conjunction with a psychiatrist until symptoms are stabilized.⁵ Psychosis does not always require hospitalization. But urgent psychiatry referral is recommended, if possible. Consider admission to a psychiatric inpatient unit for anyone who poses a danger to self or others.^8,10

Patients with schizophrenia have a higher incidence of medical illness—particularly cardiovascular disease—than the general population.

Treatment for schizophrenia is most effective with an interprofessional and collaborative approach that includes medication, psychological treatment, social supports, and primary care clinical management.^11,12 The last aspect takes on particular importance given that people with schizophrenia, compared with the general population, have a higher incidence of medical illness, particularly cardiovascular disease.¹³

Medications (TABLE 1^5,8) are grouped into first-generation antipsychotics (FGAs) and second-generation, or atypical, antipsychotics (SGAs), with the 2 classes being equally effective.^14-16 Quality of life is also similar at one year for patients treated with either drug class.¹⁴

Adverse effects can differ. The main difference between these medications is their adverse effect profiles. FGAs cause extrapyramidal symptoms (dystonia, akathisia, and tardive dyskinesia) more often than SGAs. Among the SGAs, olanzapine, asenapine, paliperidone, clozapine, and quetiapine cause significant weight gain, glucose dysregulation, and lipid abnormalities.^5,8,12,17 Clozapine is associated with agranulocytosis, as well. Risperidone causes mild to moderate weight gain.^5,8,12,17 Aripiprazole, lurasidone, and ziprasidone are considered weight neutral and cause no significant glucose dysregulation or lipid abnormalities.^5,8,12,17 All antipsychotics can cause QT prolongation and neuroleptic malignant syndrome.^5,8,12,17

Keys to successful treatment. Antipsychotics are most effective in treating positive symptoms of schizophrenia and show limited, if any, effect on negative or cognitive symptoms.^18,19 Give patients an adequate trial of therapy (at least 4 weeks at a therapeutic dose) before discontinuing the drug or offering a different medication.²⁰ All patients who report symptom relief while receiving antipsychotics should receive maintenance therapy.¹²

As with all chronic illnesses, success in managing schizophrenia requires patient adherence to the medication regimen. Discontinuation of antipsychotics is a common problem in schizophrenia, resulting in relapse. Long-acting injectable agents (LAIs) were developed to address this problem (TABLE 2).²¹ Although LAIs are typically used to ensure adherence during maintenance treatment, recent research has suggested they may also be effective for patients with early-phase or first-episode disease.²²

What to watch for. Patients on SGAs may develop metabolic abnormalities, and ongoing monitoring of relevant parameters is key (TABLE 3^23-27). More frequent monitoring may be necessary in patients with cardiovascular risk factors. Continue antipsychotics for at least 6 months to prevent relapse.¹² Also keep in mind the “Choosing Wisely” recommendation from the American Psychiatric Association of not prescribing 2 or more antipsychotics concurrently.²⁸

Adjunctive treatment should also be offered

In addition to receiving medication, patients with schizophrenia should be offered adjunctive therapies such as cognitive behavioral therapy, family intervention, and social skills training.^10-12 Among patients with schizophrenia, the incidences of anxiety disorder, panic symptoms, posttraumatic stress disorder, and obsessive compulsive disorder are higher than in the general population.²⁹ To address these conditions, medications such as selective serotonin reuptake inhibitors and anxiolytics can be used simultaneously with antipsychotic agents.

CLINICAL COURSE AND PROGNOSIS CAN VARY

Schizophrenia can have a variable clinical course that includes remissions and exacerbations, or it can follow a more persistently chronic course.

Mortality for patients with schizophrenia is 2 to 3 times higher than that of the general population.³⁰ Most deaths are due to an increased incidence of cardiovascular disease, respiratory illness, cancer, stroke, and other thromboembolic events.³⁰

The lifetime prevalence of suicide attempts among individuals with schizophrenia is 20% to 40%,³¹ and approximately 5% complete suicide.³² Risk factors include command hallucinations, a history of suicide attempts, intoxication with substances, anxiety, and physical pain.³² Clozapine has been shown to reduce suicide risk and may be considered for patients who are at high risk for suicide.³²

Therapeutic response varies among patients with schizophrenia, with one-third remaining symptomatic despite adequate treatment regimens.⁴

CARE MANAGERS CAN HELP ADDRESS BARRIERS TO CARE

Certain patient, provider, and health care system factors can hamper the provision of primary care to people with schizophrenia. Symptoms of the illness may disrupt the patient’s ability to engage with a provider or clinic. Access to mental health services may be limited based on geography. Even when primary care and mental health services are available, a patient with schizophrenia can find it challenging to schedule appointments. Reducing such barriers by using care managers may be an effective way to improve the overall quality and effectiveness of primary care for patients with schizophrenia.³³

A review of the literature suggests that up to one-third of individuals with serious mental illnesses who have had some contact with the mental health system disengage from care.¹² Poor engagement may lead to worse clinical outcomes, with symptom relapse and re-hospitalizations. Disengagement from treatment may indicate a patient’s belief that treatment is not necessary, is not meeting his or her needs, or is not being provided in a collaborative manner.

Consider a long-acting agent if patient adherence to treatment is uncertain.

Although shared decision-making is difficult with patients who have schizophrenia, emerging evidence suggests that this approach coupled with patient-centered care will improve engagement with mental health treatment.¹² Models of integrated care are being developed and have shown promise in ensuring access to behavioral health for these patients.³⁴

CASE

The primary care physician talked with Mr. R and his mother about the diagnosis of schizophrenia. He screened for suicide risk, and the patient denied having suicidal thoughts. Both the patient and his mother agreed to his starting medication.

Blood and urine samples were collected for a CBC and ESR, as well as to evaluate renal function, electrolytes, glucose, TSH, vitamin B₁₂, folic acid, ANAs, and HIV antibodies. A serum FTA-ABS test was done, as was a urine culture and sensitivity test and a toxicology screen. Because of the patient’s obesity, the physician decided to prescribe a weight-neutral SGA, aripiprazole 10 mg/d. The physician spoke with the clinic’s care coordinator to schedule an appointment with the psychiatry intake department and to follow up on the phone with the patient and his mother. He also scheduled a follow-up appointment for 2 weeks later.

At the follow-up visit, the patient showed no improvement. His blood and urine test results revealed no metabolic abnormalities or infectious or inflammatory illnesses. His urine toxicology result showed no illicit substances. The physician increased the dosage of aripiprazole to 15 mg/d and asked the patient to return in 2 weeks.

At the next follow-up visit, the patient was more verbal and said he was not hearing voices. His mother also acknowledged an improvement. He had already been scheduled for a psychiatry intake appointment, and he and his mother were reminded about this. Mr. R was also asked to make a follow-up primary care appointment for one month from the current visit.

CORRESPONDENCE
Rajesh (Fnu) Rajesh, MD, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109; frajesh@metrohealth.org.

THE CASE

Steven R,* a 21-year-old man, visited the clinic accompanied by his mother. He did not speak much, and his mother provided his history. Over the previous 2 months, she had overheard him whispering in an agitated voice, even though no one else was nearby. And, lately, he refused to answer or make calls on his cell phone, claiming that if he did it would activate a deadly chip that had been implanted in his brain by evil aliens. He also stopped attending classes at the community college. He occasionally had a few beers with his friends, but he had never been known to abuse alcohol or use other recreational drugs.

How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

Schizophrenia is a psychotic illness in which the individual loses contact with reality and often experiences hallucinations, delusions, or thought disorders. Criteria for schizophrenia described in the Diagnostic and Statistical Manual of Mental Disorders 5^th edition (DSM-5) include signs and symptoms of at least 6 months’ duration, as well as at least one month of active-phase positive and negative symptoms.¹

Delusions, hallucinations, disorganized speech, and disorganized behavior are examples of positive symptoms. Negative symptoms include a decrease in the range and intensity of expressed emotions (ie, affective flattening) and a diminished initiation of goal-directed activities (ie, avolition).

Approximately 7 in 1000 people will develop the disorder in their lifetime.² Schizophrenia is considered a “serious mental illness” because of its chronic course and often poor long-term social and vocational outcomes.^3,4 Symptom onset is generally between late adolescence and the mid-30s.⁵

Getting closer to understanding its origin

Both genetic susceptibility and environmental factors influence the incidence of schizophrenia.⁴ Newer models of the disease have identified genes (ZDHHC8 and DTNBP1) whose mutations may increase the risk of schizophrenia.⁶ Physiologic insults during fetal life—hypoxia, maternal infection, maternal stress, and maternal malnutrition—account for a small portion of schizophrenia cases.⁶

Abnormalities in neurotransmission are the basis for theories on the pathophysiology of schizophrenia. Most of these theories center on either an excess or a deficiency of neurotransmitters, including dopamine, serotonin, and glutamate. Other theories implicate aspartate, glycine, and gamma-aminobutyric acid as part of the neurochemical imbalance of schizophrenia.⁷

ESTABLISHING A DIAGNOSIS

Although psychotic symptoms may be a prominent part of schizophrenia, not all psychoses indicate a primary psychiatric disorder such as schizophrenia. Broadly, psychoses can be categorized as primary or secondary.

Primary psychoses include schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, and mood disorders (major depressive disorder and borderline personality disorder) with psychotic features.¹ Difficulty in distinguishing between these entities can necessitate referral to a psychiatrist.

Secondary psychoses arise from a precursor such as delirium, dementia, medical illness, or adverse effects of medications or illicit substances. Medical illnesses that cause psychotic symptoms include: ^5,8

• seizures (especially temporal lobe epilepsy),
• cerebrovascular accidents,
• intracranial space-occupying lesions,
• neuropsychiatric disorders (eg, Wilson’s or Parkinson’s disease),
• endocrine disorders (eg, thyroid or adrenal disease),
• autoimmune disease (eg, systemic lupus erythematosus, Hashimoto encephalopathy),
• deficiencies of vitamins A, B₁, B₁₂, or niacin,
• infections (eg, human immunodeficiency virus [HIV], encephalitis, parasites, and prion disease),
• narcolepsy, and
• metabolic disease (eg, acute intermittent porphyria, Tay-Sach’s disease, Niemann-Pick disease).

Several recreational drugs can cause psychotic symptoms: cocaine, amphetamines, cannabis, synthetic cannabinoids, inhalants, opioids, and hallucinogens. Psychotic symptoms can also appear during withdrawal from alcohol (delirium tremens) and from sedative hypnotics such as benzodiazepines. Prescribed medications such as anticholinergics, corticosteroids, dopaminergic agents (L-dopa), stimulants (amphetamines), and interferons can also induce psychotic symptoms.

First rule out causes of secondary psychosis

Rule out causes of secondary psychosis by conducting a detailed history and physical examination and ordering appropriate lab tests and imaging studies. If the patient’s psychosis is of recent onset, make sure the laboratory work-up includes a complete blood count (CBC), renal function testing, urine culture and sensitivity and urine toxicology, and measures of electrolytes, blood glucose, thyroid-stimulating hormone (TSH), vitamin B₁₂, folic acid, erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), HIV antibody, and serum fluorescent treponemal antibody absorption (FTA-ABS).⁹

All antipsychotic agents are comparably effective, but adverse effects differ.

Consider cranial computed tomography or magnetic resonance imaging if there are focal neurologic deficits or if the patient’s presentation is atypical (eg, new onset psychosis in old age).⁹ Clinical presentation may also indicate a need for electroencephalography, ceruloplasmin measurement, a dexamethasone suppression test, a corticotropin stimulation test, 24-hour urine porphyrin and copper assays, chest radiography, or cerebrospinal fluid analysis.⁹

FACTORS TO CONSIDER IN TREATMENT DECISIONS

Although primary care physicians may encounter individuals experiencing their first episode of psychosis, it’s more likely that patients presenting with signs and symptoms of the disorder have been experiencing them for some time and have received no psychiatric care. In both instances, schizophrenia is best managed in conjunction with a psychiatrist until symptoms are stabilized.⁵ Psychosis does not always require hospitalization. But urgent psychiatry referral is recommended, if possible. Consider admission to a psychiatric inpatient unit for anyone who poses a danger to self or others.^8,10

Patients with schizophrenia have a higher incidence of medical illness—particularly cardiovascular disease—than the general population.

Treatment for schizophrenia is most effective with an interprofessional and collaborative approach that includes medication, psychological treatment, social supports, and primary care clinical management.^11,12 The last aspect takes on particular importance given that people with schizophrenia, compared with the general population, have a higher incidence of medical illness, particularly cardiovascular disease.¹³

Medications (TABLE 1^5,8) are grouped into first-generation antipsychotics (FGAs) and second-generation, or atypical, antipsychotics (SGAs), with the 2 classes being equally effective.^14-16 Quality of life is also similar at one year for patients treated with either drug class.¹⁴

Adverse effects can differ. The main difference between these medications is their adverse effect profiles. FGAs cause extrapyramidal symptoms (dystonia, akathisia, and tardive dyskinesia) more often than SGAs. Among the SGAs, olanzapine, asenapine, paliperidone, clozapine, and quetiapine cause significant weight gain, glucose dysregulation, and lipid abnormalities.^5,8,12,17 Clozapine is associated with agranulocytosis, as well. Risperidone causes mild to moderate weight gain.^5,8,12,17 Aripiprazole, lurasidone, and ziprasidone are considered weight neutral and cause no significant glucose dysregulation or lipid abnormalities.^5,8,12,17 All antipsychotics can cause QT prolongation and neuroleptic malignant syndrome.^5,8,12,17

Keys to successful treatment. Antipsychotics are most effective in treating positive symptoms of schizophrenia and show limited, if any, effect on negative or cognitive symptoms.^18,19 Give patients an adequate trial of therapy (at least 4 weeks at a therapeutic dose) before discontinuing the drug or offering a different medication.²⁰ All patients who report symptom relief while receiving antipsychotics should receive maintenance therapy.¹²

As with all chronic illnesses, success in managing schizophrenia requires patient adherence to the medication regimen. Discontinuation of antipsychotics is a common problem in schizophrenia, resulting in relapse. Long-acting injectable agents (LAIs) were developed to address this problem (TABLE 2).²¹ Although LAIs are typically used to ensure adherence during maintenance treatment, recent research has suggested they may also be effective for patients with early-phase or first-episode disease.²²

What to watch for. Patients on SGAs may develop metabolic abnormalities, and ongoing monitoring of relevant parameters is key (TABLE 3^23-27). More frequent monitoring may be necessary in patients with cardiovascular risk factors. Continue antipsychotics for at least 6 months to prevent relapse.¹² Also keep in mind the “Choosing Wisely” recommendation from the American Psychiatric Association of not prescribing 2 or more antipsychotics concurrently.²⁸

Adjunctive treatment should also be offered

In addition to receiving medication, patients with schizophrenia should be offered adjunctive therapies such as cognitive behavioral therapy, family intervention, and social skills training.^10-12 Among patients with schizophrenia, the incidences of anxiety disorder, panic symptoms, posttraumatic stress disorder, and obsessive compulsive disorder are higher than in the general population.²⁹ To address these conditions, medications such as selective serotonin reuptake inhibitors and anxiolytics can be used simultaneously with antipsychotic agents.

CLINICAL COURSE AND PROGNOSIS CAN VARY

Schizophrenia can have a variable clinical course that includes remissions and exacerbations, or it can follow a more persistently chronic course.

Mortality for patients with schizophrenia is 2 to 3 times higher than that of the general population.³⁰ Most deaths are due to an increased incidence of cardiovascular disease, respiratory illness, cancer, stroke, and other thromboembolic events.³⁰

The lifetime prevalence of suicide attempts among individuals with schizophrenia is 20% to 40%,³¹ and approximately 5% complete suicide.³² Risk factors include command hallucinations, a history of suicide attempts, intoxication with substances, anxiety, and physical pain.³² Clozapine has been shown to reduce suicide risk and may be considered for patients who are at high risk for suicide.³²

Therapeutic response varies among patients with schizophrenia, with one-third remaining symptomatic despite adequate treatment regimens.⁴

CARE MANAGERS CAN HELP ADDRESS BARRIERS TO CARE

Certain patient, provider, and health care system factors can hamper the provision of primary care to people with schizophrenia. Symptoms of the illness may disrupt the patient’s ability to engage with a provider or clinic. Access to mental health services may be limited based on geography. Even when primary care and mental health services are available, a patient with schizophrenia can find it challenging to schedule appointments. Reducing such barriers by using care managers may be an effective way to improve the overall quality and effectiveness of primary care for patients with schizophrenia.³³

A review of the literature suggests that up to one-third of individuals with serious mental illnesses who have had some contact with the mental health system disengage from care.¹² Poor engagement may lead to worse clinical outcomes, with symptom relapse and re-hospitalizations. Disengagement from treatment may indicate a patient’s belief that treatment is not necessary, is not meeting his or her needs, or is not being provided in a collaborative manner.

Consider a long-acting agent if patient adherence to treatment is uncertain.

Although shared decision-making is difficult with patients who have schizophrenia, emerging evidence suggests that this approach coupled with patient-centered care will improve engagement with mental health treatment.¹² Models of integrated care are being developed and have shown promise in ensuring access to behavioral health for these patients.³⁴

CASE

The primary care physician talked with Mr. R and his mother about the diagnosis of schizophrenia. He screened for suicide risk, and the patient denied having suicidal thoughts. Both the patient and his mother agreed to his starting medication.

Blood and urine samples were collected for a CBC and ESR, as well as to evaluate renal function, electrolytes, glucose, TSH, vitamin B₁₂, folic acid, ANAs, and HIV antibodies. A serum FTA-ABS test was done, as was a urine culture and sensitivity test and a toxicology screen. Because of the patient’s obesity, the physician decided to prescribe a weight-neutral SGA, aripiprazole 10 mg/d. The physician spoke with the clinic’s care coordinator to schedule an appointment with the psychiatry intake department and to follow up on the phone with the patient and his mother. He also scheduled a follow-up appointment for 2 weeks later.

At the follow-up visit, the patient showed no improvement. His blood and urine test results revealed no metabolic abnormalities or infectious or inflammatory illnesses. His urine toxicology result showed no illicit substances. The physician increased the dosage of aripiprazole to 15 mg/d and asked the patient to return in 2 weeks.

At the next follow-up visit, the patient was more verbal and said he was not hearing voices. His mother also acknowledged an improvement. He had already been scheduled for a psychiatry intake appointment, and he and his mother were reminded about this. Mr. R was also asked to make a follow-up primary care appointment for one month from the current visit.

CORRESPONDENCE
Rajesh (Fnu) Rajesh, MD, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109; frajesh@metrohealth.org.

THE CASE

Steven R,* a 21-year-old man, visited the clinic accompanied by his mother. He did not speak much, and his mother provided his history. Over the previous 2 months, she had overheard him whispering in an agitated voice, even though no one else was nearby. And, lately, he refused to answer or make calls on his cell phone, claiming that if he did it would activate a deadly chip that had been implanted in his brain by evil aliens. He also stopped attending classes at the community college. He occasionally had a few beers with his friends, but he had never been known to abuse alcohol or use other recreational drugs.

How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

Schizophrenia is a psychotic illness in which the individual loses contact with reality and often experiences hallucinations, delusions, or thought disorders. Criteria for schizophrenia described in the Diagnostic and Statistical Manual of Mental Disorders 5^th edition (DSM-5) include signs and symptoms of at least 6 months’ duration, as well as at least one month of active-phase positive and negative symptoms.¹

Delusions, hallucinations, disorganized speech, and disorganized behavior are examples of positive symptoms. Negative symptoms include a decrease in the range and intensity of expressed emotions (ie, affective flattening) and a diminished initiation of goal-directed activities (ie, avolition).

Approximately 7 in 1000 people will develop the disorder in their lifetime.² Schizophrenia is considered a “serious mental illness” because of its chronic course and often poor long-term social and vocational outcomes.^3,4 Symptom onset is generally between late adolescence and the mid-30s.⁵

Getting closer to understanding its origin

Both genetic susceptibility and environmental factors influence the incidence of schizophrenia.⁴ Newer models of the disease have identified genes (ZDHHC8 and DTNBP1) whose mutations may increase the risk of schizophrenia.⁶ Physiologic insults during fetal life—hypoxia, maternal infection, maternal stress, and maternal malnutrition—account for a small portion of schizophrenia cases.⁶

Abnormalities in neurotransmission are the basis for theories on the pathophysiology of schizophrenia. Most of these theories center on either an excess or a deficiency of neurotransmitters, including dopamine, serotonin, and glutamate. Other theories implicate aspartate, glycine, and gamma-aminobutyric acid as part of the neurochemical imbalance of schizophrenia.⁷

ESTABLISHING A DIAGNOSIS

Although psychotic symptoms may be a prominent part of schizophrenia, not all psychoses indicate a primary psychiatric disorder such as schizophrenia. Broadly, psychoses can be categorized as primary or secondary.

Primary psychoses include schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, and mood disorders (major depressive disorder and borderline personality disorder) with psychotic features.¹ Difficulty in distinguishing between these entities can necessitate referral to a psychiatrist.

Secondary psychoses arise from a precursor such as delirium, dementia, medical illness, or adverse effects of medications or illicit substances. Medical illnesses that cause psychotic symptoms include: ^5,8

• seizures (especially temporal lobe epilepsy),
• cerebrovascular accidents,
• intracranial space-occupying lesions,
• neuropsychiatric disorders (eg, Wilson’s or Parkinson’s disease),
• endocrine disorders (eg, thyroid or adrenal disease),
• autoimmune disease (eg, systemic lupus erythematosus, Hashimoto encephalopathy),
• deficiencies of vitamins A, B₁, B₁₂, or niacin,
• infections (eg, human immunodeficiency virus [HIV], encephalitis, parasites, and prion disease),
• narcolepsy, and
• metabolic disease (eg, acute intermittent porphyria, Tay-Sach’s disease, Niemann-Pick disease).

Several recreational drugs can cause psychotic symptoms: cocaine, amphetamines, cannabis, synthetic cannabinoids, inhalants, opioids, and hallucinogens. Psychotic symptoms can also appear during withdrawal from alcohol (delirium tremens) and from sedative hypnotics such as benzodiazepines. Prescribed medications such as anticholinergics, corticosteroids, dopaminergic agents (L-dopa), stimulants (amphetamines), and interferons can also induce psychotic symptoms.

First rule out causes of secondary psychosis

Rule out causes of secondary psychosis by conducting a detailed history and physical examination and ordering appropriate lab tests and imaging studies. If the patient’s psychosis is of recent onset, make sure the laboratory work-up includes a complete blood count (CBC), renal function testing, urine culture and sensitivity and urine toxicology, and measures of electrolytes, blood glucose, thyroid-stimulating hormone (TSH), vitamin B₁₂, folic acid, erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), HIV antibody, and serum fluorescent treponemal antibody absorption (FTA-ABS).⁹

All antipsychotic agents are comparably effective, but adverse effects differ.

Consider cranial computed tomography or magnetic resonance imaging if there are focal neurologic deficits or if the patient’s presentation is atypical (eg, new onset psychosis in old age).⁹ Clinical presentation may also indicate a need for electroencephalography, ceruloplasmin measurement, a dexamethasone suppression test, a corticotropin stimulation test, 24-hour urine porphyrin and copper assays, chest radiography, or cerebrospinal fluid analysis.⁹

FACTORS TO CONSIDER IN TREATMENT DECISIONS

Although primary care physicians may encounter individuals experiencing their first episode of psychosis, it’s more likely that patients presenting with signs and symptoms of the disorder have been experiencing them for some time and have received no psychiatric care. In both instances, schizophrenia is best managed in conjunction with a psychiatrist until symptoms are stabilized.⁵ Psychosis does not always require hospitalization. But urgent psychiatry referral is recommended, if possible. Consider admission to a psychiatric inpatient unit for anyone who poses a danger to self or others.^8,10

Patients with schizophrenia have a higher incidence of medical illness—particularly cardiovascular disease—than the general population.

Treatment for schizophrenia is most effective with an interprofessional and collaborative approach that includes medication, psychological treatment, social supports, and primary care clinical management.^11,12 The last aspect takes on particular importance given that people with schizophrenia, compared with the general population, have a higher incidence of medical illness, particularly cardiovascular disease.¹³

Medications (TABLE 1^5,8) are grouped into first-generation antipsychotics (FGAs) and second-generation, or atypical, antipsychotics (SGAs), with the 2 classes being equally effective.^14-16 Quality of life is also similar at one year for patients treated with either drug class.¹⁴

Adverse effects can differ. The main difference between these medications is their adverse effect profiles. FGAs cause extrapyramidal symptoms (dystonia, akathisia, and tardive dyskinesia) more often than SGAs. Among the SGAs, olanzapine, asenapine, paliperidone, clozapine, and quetiapine cause significant weight gain, glucose dysregulation, and lipid abnormalities.^5,8,12,17 Clozapine is associated with agranulocytosis, as well. Risperidone causes mild to moderate weight gain.^5,8,12,17 Aripiprazole, lurasidone, and ziprasidone are considered weight neutral and cause no significant glucose dysregulation or lipid abnormalities.^5,8,12,17 All antipsychotics can cause QT prolongation and neuroleptic malignant syndrome.^5,8,12,17

Keys to successful treatment. Antipsychotics are most effective in treating positive symptoms of schizophrenia and show limited, if any, effect on negative or cognitive symptoms.^18,19 Give patients an adequate trial of therapy (at least 4 weeks at a therapeutic dose) before discontinuing the drug or offering a different medication.²⁰ All patients who report symptom relief while receiving antipsychotics should receive maintenance therapy.¹²

As with all chronic illnesses, success in managing schizophrenia requires patient adherence to the medication regimen. Discontinuation of antipsychotics is a common problem in schizophrenia, resulting in relapse. Long-acting injectable agents (LAIs) were developed to address this problem (TABLE 2).²¹ Although LAIs are typically used to ensure adherence during maintenance treatment, recent research has suggested they may also be effective for patients with early-phase or first-episode disease.²²

What to watch for. Patients on SGAs may develop metabolic abnormalities, and ongoing monitoring of relevant parameters is key (TABLE 3^23-27). More frequent monitoring may be necessary in patients with cardiovascular risk factors. Continue antipsychotics for at least 6 months to prevent relapse.¹² Also keep in mind the “Choosing Wisely” recommendation from the American Psychiatric Association of not prescribing 2 or more antipsychotics concurrently.²⁸

Adjunctive treatment should also be offered

In addition to receiving medication, patients with schizophrenia should be offered adjunctive therapies such as cognitive behavioral therapy, family intervention, and social skills training.^10-12 Among patients with schizophrenia, the incidences of anxiety disorder, panic symptoms, posttraumatic stress disorder, and obsessive compulsive disorder are higher than in the general population.²⁹ To address these conditions, medications such as selective serotonin reuptake inhibitors and anxiolytics can be used simultaneously with antipsychotic agents.

CLINICAL COURSE AND PROGNOSIS CAN VARY

Schizophrenia can have a variable clinical course that includes remissions and exacerbations, or it can follow a more persistently chronic course.

Mortality for patients with schizophrenia is 2 to 3 times higher than that of the general population.³⁰ Most deaths are due to an increased incidence of cardiovascular disease, respiratory illness, cancer, stroke, and other thromboembolic events.³⁰

The lifetime prevalence of suicide attempts among individuals with schizophrenia is 20% to 40%,³¹ and approximately 5% complete suicide.³² Risk factors include command hallucinations, a history of suicide attempts, intoxication with substances, anxiety, and physical pain.³² Clozapine has been shown to reduce suicide risk and may be considered for patients who are at high risk for suicide.³²

Therapeutic response varies among patients with schizophrenia, with one-third remaining symptomatic despite adequate treatment regimens.⁴

CARE MANAGERS CAN HELP ADDRESS BARRIERS TO CARE

Certain patient, provider, and health care system factors can hamper the provision of primary care to people with schizophrenia. Symptoms of the illness may disrupt the patient’s ability to engage with a provider or clinic. Access to mental health services may be limited based on geography. Even when primary care and mental health services are available, a patient with schizophrenia can find it challenging to schedule appointments. Reducing such barriers by using care managers may be an effective way to improve the overall quality and effectiveness of primary care for patients with schizophrenia.³³

A review of the literature suggests that up to one-third of individuals with serious mental illnesses who have had some contact with the mental health system disengage from care.¹² Poor engagement may lead to worse clinical outcomes, with symptom relapse and re-hospitalizations. Disengagement from treatment may indicate a patient’s belief that treatment is not necessary, is not meeting his or her needs, or is not being provided in a collaborative manner.

Consider a long-acting agent if patient adherence to treatment is uncertain.

Although shared decision-making is difficult with patients who have schizophrenia, emerging evidence suggests that this approach coupled with patient-centered care will improve engagement with mental health treatment.¹² Models of integrated care are being developed and have shown promise in ensuring access to behavioral health for these patients.³⁴

CASE

The primary care physician talked with Mr. R and his mother about the diagnosis of schizophrenia. He screened for suicide risk, and the patient denied having suicidal thoughts. Both the patient and his mother agreed to his starting medication.

Blood and urine samples were collected for a CBC and ESR, as well as to evaluate renal function, electrolytes, glucose, TSH, vitamin B₁₂, folic acid, ANAs, and HIV antibodies. A serum FTA-ABS test was done, as was a urine culture and sensitivity test and a toxicology screen. Because of the patient’s obesity, the physician decided to prescribe a weight-neutral SGA, aripiprazole 10 mg/d. The physician spoke with the clinic’s care coordinator to schedule an appointment with the psychiatry intake department and to follow up on the phone with the patient and his mother. He also scheduled a follow-up appointment for 2 weeks later.

At the follow-up visit, the patient showed no improvement. His blood and urine test results revealed no metabolic abnormalities or infectious or inflammatory illnesses. His urine toxicology result showed no illicit substances. The physician increased the dosage of aripiprazole to 15 mg/d and asked the patient to return in 2 weeks.

At the next follow-up visit, the patient was more verbal and said he was not hearing voices. His mother also acknowledged an improvement. He had already been scheduled for a psychiatry intake appointment, and he and his mother were reminded about this. Mr. R was also asked to make a follow-up primary care appointment for one month from the current visit.

CORRESPONDENCE
Rajesh (Fnu) Rajesh, MD, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109; frajesh@metrohealth.org.