Robert M. McCarron, DO

Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are each rare psychiatric emergencies that can lead to fatal outcomes. Their clinical presentations can overlap, which can make it difficult to differentiate between the 2 syndromes; however, their treatments are distinct, and it is imperative to know how to identify symptoms and accurately diagnose each of them to provide appropriate intervention. This article summarizes the 2 syndromes and their treatments, with a focus on how clinicians can distinguish them, provide prompt intervention, and prevent occurrence.

Serotonin syndrome

Mechanism. The decarboxylation and hydroxylation of tryptophan forms serotonin, also known as 5-hydroxytryptamine (5-HT), which can then be metabolized by monoamine oxidase-A (MAO-A) into 5-hydroxyindoleacetic acid (5-HIAA).¹Medications can disrupt this pathway of serotonin production or its metabolism, and result in excessive levels of serotonin, which subsequently leads to an overactivation of central and peripheral serotonin receptors.¹ Increased receptor activation leads to further upregulation, and ultimately more serotonin transmission. This can be caused by monotherapy or use of multiple serotonergic agents, polypharmacy with a combination of medication classes, drug interactions, or overdose. The wide variety of medications often prescribed by different clinicians can make identification of excessive serotonergic activity difficult, especially because mood stabilizers such as lithium,² and non-psychiatric medications such as ciprofloxacin and fluconazole, can also contribute. Table 1³ lists medications that can cause SS. The pathways that increase serotonin transmission, potentially causing SS, include:

• inhibition of serotonin uptake (seen with selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], and tricyclic antidepressants [TCAs])
• inhibition of serotonin metabolism (seen with monoamine oxidase inhibitors [MAOIs])
• increased serotonin synthesis (seen with stimulants)
• increased serotonin release (seen with stimulants and opiates)
• activation of serotonin receptors (seen with lithium)
• inhibition of certain cytochrome P450 (CYP450) enzymes (seen with ciprofloxacin, fluconazole, etc.).

It is important to recognize that various serotonergic agents are involved in the CYP450 system. Inhibition of the CYP450 pathway by common antibiotics such as ciprofloxacin, or antifungals such as fluconazole, may result in an accumulation of serotonergic agents and place patients at increased risk for developing SS.

Clinical presentation. The clinical presentation of SS can range from mild to fatal. There is no specific laboratory test for diagnosis, although an elevation of the total creatine kinase (CK) and leukocyte count, as well as increased transaminase levels or lower bicarbonate levels, have been reported in the literature.⁴

Symptoms of SS generally present within 24 hours of starting/changing therapy and include a triad of mental status changes (altered mental status [AMS]), autonomic instability, and abnormalities of neuromuscular tone. Examples of AMS include agitation, anxiety, disorientation, and restlessness. Symptoms of autonomic instability include hypertension, tachycardia, tachypnea, hyperthermia, diaphoresis, flushed skin, vomiting, diarrhea, and arrhythmias. Symptoms stemming from changes in neuro­muscular tone include tremors, clonus, hyperreflexia, and muscle rigidity.¹ The multiple possible clinical presentations, as well as symptoms that overlap with those of other syndromes, can make SS difficult to recognize quickly in a clinical setting.

Diagnostic criteria. Sternbach’s diagnostic criteria for SS are defined as the presence of 3 or more of the 10 most common clinical features (Table 2⁵). Due to concerns that Sternbach’s diagnostic criteria overemphasized an abnormal mental state (leading to possible confusion of SS with other AMS syndromes), the Hunter serotonin toxicity criteria⁶ (Figure⁶) were developed in 2003, and were found to be more sensitive and specific than Sternbach’s criteria. Both tools are often used in clinical practice.

Treatment. Treatment of SS begins with prompt discontinuation of all sero­tonergic agents. The intensity of treatment depends on the severity of the symptoms. Mild symptoms can be managed with supportive care,³ and in such cases, the syndrome generally resolves within 24 hours.⁷ Clinicians may use supportive care to normalize vital signs (oxygenation to maintain SpO2 >94%, IV fluids for volume depletion, cooling agents, antihypertensives, benzodiazepines for sedation or control of agitation, etc.). Patients who are more ill may require more aggressive treatment, such as the use of a serotonergic antagonist (ie, cyproheptadine) and those who are severely hyperthermic (temperature >41.1ºC) may require neuromuscular sedation, paralysis, and possibly endotracheal intubation.³

Continue to: Management pitfalls include...

Management pitfalls include misdiagnosis of SS, failure to recognize its rapid rate of progression, and adverse effects of pharmacologic therapy.³ The most effective treatment for SS is prevention. SS can be prevented by astute pharmacologic understanding, avoidance of polypharmacy, and physician education.³

Neuroleptic malignant syndrome

Possible mechanisms. Neuromuscular malignant syndrome is thought to result from dopamine receptor antagonism leading to a hypodopaminergic state in the striatum and hypothalamus.⁸ The pathophysiology behind NMS has not fully been elucidated; however, several hypotheses attempt to explain this life-threatening reaction. The first focuses on dopamine D2 receptor antagonism, because many of the neuroleptic (antipsychotic) medications that can precipitate NMS are involved in dopamine blockade. In this theory, blocking dopamine D2 receptors in the anterior hypothalamus explains the hyperthermia seen in NMS, while blockade in the corpus striatum is believed to lead to muscle rigidity.⁹

The second hypothesis suggests that neuroleptics may have a direct toxic effect to muscle cells. Neuroleptics influence calcium transport across the sarcoplasmic reticulum and can lead to increased calcium release, which may contribute to the muscle rigidity and hyperthermia seen in NMS.⁹

The third hypothesis involves hyperactivity of the sympathetic nervous system; it is thought that psychologic stressors alter frontal lobe function, with neuroleptics disrupting the inhibitory pathways of the sympathetic nervous system. The autonomic nervous system innervates multiple organ systems, so this excessively dysregulated sympathetic nervous system may be responsible for multiple NMS symptoms (hyperthermia, muscle rigidity, hypertension, diaphoresis, tachycardia, elevated CK.¹⁰

NMS can be caused by neuroleptic agents (both first- and second-generation anti­psychotics) as well as antiemetics (Table 3¹). The time between use of these medications and onset of symptoms is highly variable. NMS can occur after a single dose, after a dose adjustment, or possibly after years of treatment with the same medication. It is not dose-dependent.¹¹ In certain individuals, NMS may occur at therapeutic doses.

Continue to: Clinical presentation

Clinical presentation. Patients with NMS typically present with a tetrad of symptoms: mental status changes, muscular rigidity, hyperthermia, and autonomic instability.¹² Mental status changes can include confusion and agitation, as well as catatonic signs and mutism. The muscular rigidity of NMS is characterized by “lead pipe rigidity” and may be accompanied by tremor, dystonia, or dyskinesias. Laboratory findings include elevated serum CK (from severe rigidity), often >1,000 U/L, although normal levels can be observed if rigidity has not yet developed.¹³

Treatment. The first step for treatment is to discontinue the causative medication.¹⁴ Initiate supportive therapy immediately to restrict the progression of symptoms. Interventions include cooling blankets, fluid resuscitation, and antihypertensives to maintain autonomic stability¹⁵ or benzodiazepines to control agitation. In severe cases, muscular rigidity may extend to the airways and intubation may be required. The severity of these symptoms may warrant admission to the ICU for close monitoring. Pharmacologic treatment with dantrolene (a muscle relaxant that blocks calcium efflux from the sarcoplasmic reticulum) and bromocriptine (a dopamine agonist) have been utilized.¹⁴ In case reports, electroconvulsive therapy (ECT) has been used to treat NMS^15,16; however, prospective research comparing ECT with traditional treatment has not been conducted. It is also worth mentioning that if a clinician wishes to restart the neuroleptic medication, a 2-week washout period will minimize the risk of NMS recurrence.¹⁷

Differentiating between SS and NMS

Differentiating between these 2 syndromes (Table 4¹⁷) is critical to direct appropriate intervention. Table 5¹⁷ outlines the treatment overview for SS and NMS.

Detailed history. A detailed history is imperative in making accurate diagnoses. Useful components of the history include a patient’s duration of symptoms and medication history (prescription medications as well as over-the-counter medications, supplements, and illicit drugs). Also assess for medical comorbidities, because certain medical diagnoses may alert the clinician that it is likely the patient had been prescribed serotonergic agents or neuroleptics, and renal or liver impairment may alert the clinician of decreased metabolism rates. Medication history is arguably the most useful piece of the interview, because serotonergic agents can cause SS, whereas dopamine blockers cause NMS. It should be noted that excess serotonin acts as a true toxidrome and is concentration-dependent in causing SS, whereas NMS is an idiosyncratic reaction to a drug.

Physical exam. Although there are many overlapping clinical manifestations, SS produces neuromuscular hyperactivity (ie, clonus, hyperreflexia), whereas NMS is characterized by more sluggish responses (ie, rigidity, bradyreflexia).¹⁸

Continue to: Laboratory findings

Laboratory findings. Overlap between NMS and SS also occurs with lab findings; both syndromes can result in leukocytosis, elevated CK from muscle damage, and low serum iron levels. However, these findings are more commonly associated with NMS and are seen in 75% of cases.^17,19

Course of illness. Duration of symptoms can also help differentiate the 2 syndromes. SS typically develops within 24 hours of starting/changing therapy, whereas NMS symptoms can be present for days to weeks. Resolution of symptoms may also be helpful in differentiation because SS typically resolves within a few days of initiating treatment, whereas NMS resolves within 9 to 14 days of starting treatment.¹⁹

Bottom Line

The clinical presentations of serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) overlap, which can make them difficult to differentiate; however, they each have distinct approaches to treatment. Features in SS that are distinct from NMS include a history of serotonergic agents, rapid onset of symptoms, hyperreflexia, and clonus. NMS is slower in onset and can be found in patients who are prescribed dopamine antagonists, with distinct symptoms of rigidity and hyporeflexia.

Related Resources

• Kimmel R. Serotonin syndrome or NMS? Clues to diagnosis. Current Psychiatry. 2010;9(2):92.
• Strawn JR, Keck Jr PE, Caroff SN. Neuroleptic malignant syndrome: Answers to 6 tough questions. Current Psychiatry. 2008;7(1):95-101.

Drug Brand Names

Amantadine • Symmetrel
Amitriptyline • Elavil, Endep
Aripiprazole • Abilify
Bromocriptine • Cycloset, Parlodel
Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Ciprofloxacin • Cipro
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Cyclobenzaprine • Amrix, Flexeril
Cyproheptadine • Periactin
Dantrolene • Dantrium
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dextromethorphan • Benylin, Dexalone
Dolasetron • Anzemet
Doxepin • Silenor
Droperidol • Inapsine
Duloxetine • Cymbalt
Escitalopram • Lexapro
Fentanyl • Actiq, Duragesic
Fluconazole • Diflucan
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Granisetron • Kytril
Haloperidol • Haldol
Isocarboxazid • Marplan
Levomilnacipran • Fetzima
Linezolid • Zyvox
Lithium • Eskalith, Lithobid
Meperidone • Demerol
Metoclopramide • Reglan
Milnacipran • Savella
Nefazodone • Serzone
Olanzapine • Zyprexa
Ondansetron • Zofran
Paliperidone • Invega
Palonosetron • Aloxi
Paroxetine • Paxil
Pentazocine • Talwin, Talacen
Perphenazine • Trilafon
Phenelzine • Nardil
Procarbazine • Matulane
Prochlorperazine • Compazine
Promethazine • Phenergan
Quetiapine • Seroquel
Rasagiline • Azilect
Risperidone • Risperdal
Safinamide • Xadago
Selegiline • Eldepryl, Zelapar
Sertraline • Zoloft
Sibutramine • Meridia
Tedizolid • Sivextro
Thioridazine • Mellaril
Tranylcypromine • Parnate
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Vilazodone • Viibryd
Vortioxetine • Trintellix
Valproate • Depacon
Ziprasidone • Geodon

Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are each rare psychiatric emergencies that can lead to fatal outcomes. Their clinical presentations can overlap, which can make it difficult to differentiate between the 2 syndromes; however, their treatments are distinct, and it is imperative to know how to identify symptoms and accurately diagnose each of them to provide appropriate intervention. This article summarizes the 2 syndromes and their treatments, with a focus on how clinicians can distinguish them, provide prompt intervention, and prevent occurrence.

Serotonin syndrome

Mechanism. The decarboxylation and hydroxylation of tryptophan forms serotonin, also known as 5-hydroxytryptamine (5-HT), which can then be metabolized by monoamine oxidase-A (MAO-A) into 5-hydroxyindoleacetic acid (5-HIAA).¹Medications can disrupt this pathway of serotonin production or its metabolism, and result in excessive levels of serotonin, which subsequently leads to an overactivation of central and peripheral serotonin receptors.¹ Increased receptor activation leads to further upregulation, and ultimately more serotonin transmission. This can be caused by monotherapy or use of multiple serotonergic agents, polypharmacy with a combination of medication classes, drug interactions, or overdose. The wide variety of medications often prescribed by different clinicians can make identification of excessive serotonergic activity difficult, especially because mood stabilizers such as lithium,² and non-psychiatric medications such as ciprofloxacin and fluconazole, can also contribute. Table 1³ lists medications that can cause SS. The pathways that increase serotonin transmission, potentially causing SS, include:

• inhibition of serotonin uptake (seen with selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], and tricyclic antidepressants [TCAs])
• inhibition of serotonin metabolism (seen with monoamine oxidase inhibitors [MAOIs])
• increased serotonin synthesis (seen with stimulants)
• increased serotonin release (seen with stimulants and opiates)
• activation of serotonin receptors (seen with lithium)
• inhibition of certain cytochrome P450 (CYP450) enzymes (seen with ciprofloxacin, fluconazole, etc.).

It is important to recognize that various serotonergic agents are involved in the CYP450 system. Inhibition of the CYP450 pathway by common antibiotics such as ciprofloxacin, or antifungals such as fluconazole, may result in an accumulation of serotonergic agents and place patients at increased risk for developing SS.

Clinical presentation. The clinical presentation of SS can range from mild to fatal. There is no specific laboratory test for diagnosis, although an elevation of the total creatine kinase (CK) and leukocyte count, as well as increased transaminase levels or lower bicarbonate levels, have been reported in the literature.⁴

Symptoms of SS generally present within 24 hours of starting/changing therapy and include a triad of mental status changes (altered mental status [AMS]), autonomic instability, and abnormalities of neuromuscular tone. Examples of AMS include agitation, anxiety, disorientation, and restlessness. Symptoms of autonomic instability include hypertension, tachycardia, tachypnea, hyperthermia, diaphoresis, flushed skin, vomiting, diarrhea, and arrhythmias. Symptoms stemming from changes in neuro­muscular tone include tremors, clonus, hyperreflexia, and muscle rigidity.¹ The multiple possible clinical presentations, as well as symptoms that overlap with those of other syndromes, can make SS difficult to recognize quickly in a clinical setting.

Diagnostic criteria. Sternbach’s diagnostic criteria for SS are defined as the presence of 3 or more of the 10 most common clinical features (Table 2⁵). Due to concerns that Sternbach’s diagnostic criteria overemphasized an abnormal mental state (leading to possible confusion of SS with other AMS syndromes), the Hunter serotonin toxicity criteria⁶ (Figure⁶) were developed in 2003, and were found to be more sensitive and specific than Sternbach’s criteria. Both tools are often used in clinical practice.

Treatment. Treatment of SS begins with prompt discontinuation of all sero­tonergic agents. The intensity of treatment depends on the severity of the symptoms. Mild symptoms can be managed with supportive care,³ and in such cases, the syndrome generally resolves within 24 hours.⁷ Clinicians may use supportive care to normalize vital signs (oxygenation to maintain SpO2 >94%, IV fluids for volume depletion, cooling agents, antihypertensives, benzodiazepines for sedation or control of agitation, etc.). Patients who are more ill may require more aggressive treatment, such as the use of a serotonergic antagonist (ie, cyproheptadine) and those who are severely hyperthermic (temperature >41.1ºC) may require neuromuscular sedation, paralysis, and possibly endotracheal intubation.³

Continue to: Management pitfalls include...

Management pitfalls include misdiagnosis of SS, failure to recognize its rapid rate of progression, and adverse effects of pharmacologic therapy.³ The most effective treatment for SS is prevention. SS can be prevented by astute pharmacologic understanding, avoidance of polypharmacy, and physician education.³

Neuroleptic malignant syndrome

Possible mechanisms. Neuromuscular malignant syndrome is thought to result from dopamine receptor antagonism leading to a hypodopaminergic state in the striatum and hypothalamus.⁸ The pathophysiology behind NMS has not fully been elucidated; however, several hypotheses attempt to explain this life-threatening reaction. The first focuses on dopamine D2 receptor antagonism, because many of the neuroleptic (antipsychotic) medications that can precipitate NMS are involved in dopamine blockade. In this theory, blocking dopamine D2 receptors in the anterior hypothalamus explains the hyperthermia seen in NMS, while blockade in the corpus striatum is believed to lead to muscle rigidity.⁹

The second hypothesis suggests that neuroleptics may have a direct toxic effect to muscle cells. Neuroleptics influence calcium transport across the sarcoplasmic reticulum and can lead to increased calcium release, which may contribute to the muscle rigidity and hyperthermia seen in NMS.⁹

The third hypothesis involves hyperactivity of the sympathetic nervous system; it is thought that psychologic stressors alter frontal lobe function, with neuroleptics disrupting the inhibitory pathways of the sympathetic nervous system. The autonomic nervous system innervates multiple organ systems, so this excessively dysregulated sympathetic nervous system may be responsible for multiple NMS symptoms (hyperthermia, muscle rigidity, hypertension, diaphoresis, tachycardia, elevated CK.¹⁰

NMS can be caused by neuroleptic agents (both first- and second-generation anti­psychotics) as well as antiemetics (Table 3¹). The time between use of these medications and onset of symptoms is highly variable. NMS can occur after a single dose, after a dose adjustment, or possibly after years of treatment with the same medication. It is not dose-dependent.¹¹ In certain individuals, NMS may occur at therapeutic doses.

Continue to: Clinical presentation

Clinical presentation. Patients with NMS typically present with a tetrad of symptoms: mental status changes, muscular rigidity, hyperthermia, and autonomic instability.¹² Mental status changes can include confusion and agitation, as well as catatonic signs and mutism. The muscular rigidity of NMS is characterized by “lead pipe rigidity” and may be accompanied by tremor, dystonia, or dyskinesias. Laboratory findings include elevated serum CK (from severe rigidity), often >1,000 U/L, although normal levels can be observed if rigidity has not yet developed.¹³

Treatment. The first step for treatment is to discontinue the causative medication.¹⁴ Initiate supportive therapy immediately to restrict the progression of symptoms. Interventions include cooling blankets, fluid resuscitation, and antihypertensives to maintain autonomic stability¹⁵ or benzodiazepines to control agitation. In severe cases, muscular rigidity may extend to the airways and intubation may be required. The severity of these symptoms may warrant admission to the ICU for close monitoring. Pharmacologic treatment with dantrolene (a muscle relaxant that blocks calcium efflux from the sarcoplasmic reticulum) and bromocriptine (a dopamine agonist) have been utilized.¹⁴ In case reports, electroconvulsive therapy (ECT) has been used to treat NMS^15,16; however, prospective research comparing ECT with traditional treatment has not been conducted. It is also worth mentioning that if a clinician wishes to restart the neuroleptic medication, a 2-week washout period will minimize the risk of NMS recurrence.¹⁷

Differentiating between SS and NMS

Differentiating between these 2 syndromes (Table 4¹⁷) is critical to direct appropriate intervention. Table 5¹⁷ outlines the treatment overview for SS and NMS.

Detailed history. A detailed history is imperative in making accurate diagnoses. Useful components of the history include a patient’s duration of symptoms and medication history (prescription medications as well as over-the-counter medications, supplements, and illicit drugs). Also assess for medical comorbidities, because certain medical diagnoses may alert the clinician that it is likely the patient had been prescribed serotonergic agents or neuroleptics, and renal or liver impairment may alert the clinician of decreased metabolism rates. Medication history is arguably the most useful piece of the interview, because serotonergic agents can cause SS, whereas dopamine blockers cause NMS. It should be noted that excess serotonin acts as a true toxidrome and is concentration-dependent in causing SS, whereas NMS is an idiosyncratic reaction to a drug.

Physical exam. Although there are many overlapping clinical manifestations, SS produces neuromuscular hyperactivity (ie, clonus, hyperreflexia), whereas NMS is characterized by more sluggish responses (ie, rigidity, bradyreflexia).¹⁸

Continue to: Laboratory findings

Laboratory findings. Overlap between NMS and SS also occurs with lab findings; both syndromes can result in leukocytosis, elevated CK from muscle damage, and low serum iron levels. However, these findings are more commonly associated with NMS and are seen in 75% of cases.^17,19

Course of illness. Duration of symptoms can also help differentiate the 2 syndromes. SS typically develops within 24 hours of starting/changing therapy, whereas NMS symptoms can be present for days to weeks. Resolution of symptoms may also be helpful in differentiation because SS typically resolves within a few days of initiating treatment, whereas NMS resolves within 9 to 14 days of starting treatment.¹⁹

Bottom Line

The clinical presentations of serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) overlap, which can make them difficult to differentiate; however, they each have distinct approaches to treatment. Features in SS that are distinct from NMS include a history of serotonergic agents, rapid onset of symptoms, hyperreflexia, and clonus. NMS is slower in onset and can be found in patients who are prescribed dopamine antagonists, with distinct symptoms of rigidity and hyporeflexia.

Related Resources

• Kimmel R. Serotonin syndrome or NMS? Clues to diagnosis. Current Psychiatry. 2010;9(2):92.
• Strawn JR, Keck Jr PE, Caroff SN. Neuroleptic malignant syndrome: Answers to 6 tough questions. Current Psychiatry. 2008;7(1):95-101.

Drug Brand Names

Amantadine • Symmetrel
Amitriptyline • Elavil, Endep
Aripiprazole • Abilify
Bromocriptine • Cycloset, Parlodel
Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Ciprofloxacin • Cipro
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Cyclobenzaprine • Amrix, Flexeril
Cyproheptadine • Periactin
Dantrolene • Dantrium
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dextromethorphan • Benylin, Dexalone
Dolasetron • Anzemet
Doxepin • Silenor
Droperidol • Inapsine
Duloxetine • Cymbalt
Escitalopram • Lexapro
Fentanyl • Actiq, Duragesic
Fluconazole • Diflucan
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Granisetron • Kytril
Haloperidol • Haldol
Isocarboxazid • Marplan
Levomilnacipran • Fetzima
Linezolid • Zyvox
Lithium • Eskalith, Lithobid
Meperidone • Demerol
Metoclopramide • Reglan
Milnacipran • Savella
Nefazodone • Serzone
Olanzapine • Zyprexa
Ondansetron • Zofran
Paliperidone • Invega
Palonosetron • Aloxi
Paroxetine • Paxil
Pentazocine • Talwin, Talacen
Perphenazine • Trilafon
Phenelzine • Nardil
Procarbazine • Matulane
Prochlorperazine • Compazine
Promethazine • Phenergan
Quetiapine • Seroquel
Rasagiline • Azilect
Risperidone • Risperdal
Safinamide • Xadago
Selegiline • Eldepryl, Zelapar
Sertraline • Zoloft
Sibutramine • Meridia
Tedizolid • Sivextro
Thioridazine • Mellaril
Tranylcypromine • Parnate
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Vilazodone • Viibryd
Vortioxetine • Trintellix
Valproate • Depacon
Ziprasidone • Geodon

Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are each rare psychiatric emergencies that can lead to fatal outcomes. Their clinical presentations can overlap, which can make it difficult to differentiate between the 2 syndromes; however, their treatments are distinct, and it is imperative to know how to identify symptoms and accurately diagnose each of them to provide appropriate intervention. This article summarizes the 2 syndromes and their treatments, with a focus on how clinicians can distinguish them, provide prompt intervention, and prevent occurrence.

Serotonin syndrome

Mechanism. The decarboxylation and hydroxylation of tryptophan forms serotonin, also known as 5-hydroxytryptamine (5-HT), which can then be metabolized by monoamine oxidase-A (MAO-A) into 5-hydroxyindoleacetic acid (5-HIAA).¹Medications can disrupt this pathway of serotonin production or its metabolism, and result in excessive levels of serotonin, which subsequently leads to an overactivation of central and peripheral serotonin receptors.¹ Increased receptor activation leads to further upregulation, and ultimately more serotonin transmission. This can be caused by monotherapy or use of multiple serotonergic agents, polypharmacy with a combination of medication classes, drug interactions, or overdose. The wide variety of medications often prescribed by different clinicians can make identification of excessive serotonergic activity difficult, especially because mood stabilizers such as lithium,² and non-psychiatric medications such as ciprofloxacin and fluconazole, can also contribute. Table 1³ lists medications that can cause SS. The pathways that increase serotonin transmission, potentially causing SS, include:

• inhibition of serotonin uptake (seen with selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], and tricyclic antidepressants [TCAs])
• inhibition of serotonin metabolism (seen with monoamine oxidase inhibitors [MAOIs])
• increased serotonin synthesis (seen with stimulants)
• increased serotonin release (seen with stimulants and opiates)
• activation of serotonin receptors (seen with lithium)
• inhibition of certain cytochrome P450 (CYP450) enzymes (seen with ciprofloxacin, fluconazole, etc.).

It is important to recognize that various serotonergic agents are involved in the CYP450 system. Inhibition of the CYP450 pathway by common antibiotics such as ciprofloxacin, or antifungals such as fluconazole, may result in an accumulation of serotonergic agents and place patients at increased risk for developing SS.

Clinical presentation. The clinical presentation of SS can range from mild to fatal. There is no specific laboratory test for diagnosis, although an elevation of the total creatine kinase (CK) and leukocyte count, as well as increased transaminase levels or lower bicarbonate levels, have been reported in the literature.⁴

Symptoms of SS generally present within 24 hours of starting/changing therapy and include a triad of mental status changes (altered mental status [AMS]), autonomic instability, and abnormalities of neuromuscular tone. Examples of AMS include agitation, anxiety, disorientation, and restlessness. Symptoms of autonomic instability include hypertension, tachycardia, tachypnea, hyperthermia, diaphoresis, flushed skin, vomiting, diarrhea, and arrhythmias. Symptoms stemming from changes in neuro­muscular tone include tremors, clonus, hyperreflexia, and muscle rigidity.¹ The multiple possible clinical presentations, as well as symptoms that overlap with those of other syndromes, can make SS difficult to recognize quickly in a clinical setting.

Diagnostic criteria. Sternbach’s diagnostic criteria for SS are defined as the presence of 3 or more of the 10 most common clinical features (Table 2⁵). Due to concerns that Sternbach’s diagnostic criteria overemphasized an abnormal mental state (leading to possible confusion of SS with other AMS syndromes), the Hunter serotonin toxicity criteria⁶ (Figure⁶) were developed in 2003, and were found to be more sensitive and specific than Sternbach’s criteria. Both tools are often used in clinical practice.

Treatment. Treatment of SS begins with prompt discontinuation of all sero­tonergic agents. The intensity of treatment depends on the severity of the symptoms. Mild symptoms can be managed with supportive care,³ and in such cases, the syndrome generally resolves within 24 hours.⁷ Clinicians may use supportive care to normalize vital signs (oxygenation to maintain SpO2 >94%, IV fluids for volume depletion, cooling agents, antihypertensives, benzodiazepines for sedation or control of agitation, etc.). Patients who are more ill may require more aggressive treatment, such as the use of a serotonergic antagonist (ie, cyproheptadine) and those who are severely hyperthermic (temperature >41.1ºC) may require neuromuscular sedation, paralysis, and possibly endotracheal intubation.³

Continue to: Management pitfalls include...

Management pitfalls include misdiagnosis of SS, failure to recognize its rapid rate of progression, and adverse effects of pharmacologic therapy.³ The most effective treatment for SS is prevention. SS can be prevented by astute pharmacologic understanding, avoidance of polypharmacy, and physician education.³

Neuroleptic malignant syndrome

Possible mechanisms. Neuromuscular malignant syndrome is thought to result from dopamine receptor antagonism leading to a hypodopaminergic state in the striatum and hypothalamus.⁸ The pathophysiology behind NMS has not fully been elucidated; however, several hypotheses attempt to explain this life-threatening reaction. The first focuses on dopamine D2 receptor antagonism, because many of the neuroleptic (antipsychotic) medications that can precipitate NMS are involved in dopamine blockade. In this theory, blocking dopamine D2 receptors in the anterior hypothalamus explains the hyperthermia seen in NMS, while blockade in the corpus striatum is believed to lead to muscle rigidity.⁹

The second hypothesis suggests that neuroleptics may have a direct toxic effect to muscle cells. Neuroleptics influence calcium transport across the sarcoplasmic reticulum and can lead to increased calcium release, which may contribute to the muscle rigidity and hyperthermia seen in NMS.⁹

The third hypothesis involves hyperactivity of the sympathetic nervous system; it is thought that psychologic stressors alter frontal lobe function, with neuroleptics disrupting the inhibitory pathways of the sympathetic nervous system. The autonomic nervous system innervates multiple organ systems, so this excessively dysregulated sympathetic nervous system may be responsible for multiple NMS symptoms (hyperthermia, muscle rigidity, hypertension, diaphoresis, tachycardia, elevated CK.¹⁰

NMS can be caused by neuroleptic agents (both first- and second-generation anti­psychotics) as well as antiemetics (Table 3¹). The time between use of these medications and onset of symptoms is highly variable. NMS can occur after a single dose, after a dose adjustment, or possibly after years of treatment with the same medication. It is not dose-dependent.¹¹ In certain individuals, NMS may occur at therapeutic doses.

Continue to: Clinical presentation

Clinical presentation. Patients with NMS typically present with a tetrad of symptoms: mental status changes, muscular rigidity, hyperthermia, and autonomic instability.¹² Mental status changes can include confusion and agitation, as well as catatonic signs and mutism. The muscular rigidity of NMS is characterized by “lead pipe rigidity” and may be accompanied by tremor, dystonia, or dyskinesias. Laboratory findings include elevated serum CK (from severe rigidity), often >1,000 U/L, although normal levels can be observed if rigidity has not yet developed.¹³

Treatment. The first step for treatment is to discontinue the causative medication.¹⁴ Initiate supportive therapy immediately to restrict the progression of symptoms. Interventions include cooling blankets, fluid resuscitation, and antihypertensives to maintain autonomic stability¹⁵ or benzodiazepines to control agitation. In severe cases, muscular rigidity may extend to the airways and intubation may be required. The severity of these symptoms may warrant admission to the ICU for close monitoring. Pharmacologic treatment with dantrolene (a muscle relaxant that blocks calcium efflux from the sarcoplasmic reticulum) and bromocriptine (a dopamine agonist) have been utilized.¹⁴ In case reports, electroconvulsive therapy (ECT) has been used to treat NMS^15,16; however, prospective research comparing ECT with traditional treatment has not been conducted. It is also worth mentioning that if a clinician wishes to restart the neuroleptic medication, a 2-week washout period will minimize the risk of NMS recurrence.¹⁷

Differentiating between SS and NMS

Differentiating between these 2 syndromes (Table 4¹⁷) is critical to direct appropriate intervention. Table 5¹⁷ outlines the treatment overview for SS and NMS.

Detailed history. A detailed history is imperative in making accurate diagnoses. Useful components of the history include a patient’s duration of symptoms and medication history (prescription medications as well as over-the-counter medications, supplements, and illicit drugs). Also assess for medical comorbidities, because certain medical diagnoses may alert the clinician that it is likely the patient had been prescribed serotonergic agents or neuroleptics, and renal or liver impairment may alert the clinician of decreased metabolism rates. Medication history is arguably the most useful piece of the interview, because serotonergic agents can cause SS, whereas dopamine blockers cause NMS. It should be noted that excess serotonin acts as a true toxidrome and is concentration-dependent in causing SS, whereas NMS is an idiosyncratic reaction to a drug.

Physical exam. Although there are many overlapping clinical manifestations, SS produces neuromuscular hyperactivity (ie, clonus, hyperreflexia), whereas NMS is characterized by more sluggish responses (ie, rigidity, bradyreflexia).¹⁸

Continue to: Laboratory findings

Laboratory findings. Overlap between NMS and SS also occurs with lab findings; both syndromes can result in leukocytosis, elevated CK from muscle damage, and low serum iron levels. However, these findings are more commonly associated with NMS and are seen in 75% of cases.^17,19

Course of illness. Duration of symptoms can also help differentiate the 2 syndromes. SS typically develops within 24 hours of starting/changing therapy, whereas NMS symptoms can be present for days to weeks. Resolution of symptoms may also be helpful in differentiation because SS typically resolves within a few days of initiating treatment, whereas NMS resolves within 9 to 14 days of starting treatment.¹⁹

Bottom Line

The clinical presentations of serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) overlap, which can make them difficult to differentiate; however, they each have distinct approaches to treatment. Features in SS that are distinct from NMS include a history of serotonergic agents, rapid onset of symptoms, hyperreflexia, and clonus. NMS is slower in onset and can be found in patients who are prescribed dopamine antagonists, with distinct symptoms of rigidity and hyporeflexia.

Related Resources

• Kimmel R. Serotonin syndrome or NMS? Clues to diagnosis. Current Psychiatry. 2010;9(2):92.
• Strawn JR, Keck Jr PE, Caroff SN. Neuroleptic malignant syndrome: Answers to 6 tough questions. Current Psychiatry. 2008;7(1):95-101.

Drug Brand Names

Amantadine • Symmetrel
Amitriptyline • Elavil, Endep
Aripiprazole • Abilify
Bromocriptine • Cycloset, Parlodel
Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Ciprofloxacin • Cipro
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Cyclobenzaprine • Amrix, Flexeril
Cyproheptadine • Periactin
Dantrolene • Dantrium
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dextromethorphan • Benylin, Dexalone
Dolasetron • Anzemet
Doxepin • Silenor
Droperidol • Inapsine
Duloxetine • Cymbalt
Escitalopram • Lexapro
Fentanyl • Actiq, Duragesic
Fluconazole • Diflucan
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Granisetron • Kytril
Haloperidol • Haldol
Isocarboxazid • Marplan
Levomilnacipran • Fetzima
Linezolid • Zyvox
Lithium • Eskalith, Lithobid
Meperidone • Demerol
Metoclopramide • Reglan
Milnacipran • Savella
Nefazodone • Serzone
Olanzapine • Zyprexa
Ondansetron • Zofran
Paliperidone • Invega
Palonosetron • Aloxi
Paroxetine • Paxil
Pentazocine • Talwin, Talacen
Perphenazine • Trilafon
Phenelzine • Nardil
Procarbazine • Matulane
Prochlorperazine • Compazine
Promethazine • Phenergan
Quetiapine • Seroquel
Rasagiline • Azilect
Risperidone • Risperdal
Safinamide • Xadago
Selegiline • Eldepryl, Zelapar
Sertraline • Zoloft
Sibutramine • Meridia
Tedizolid • Sivextro
Thioridazine • Mellaril
Tranylcypromine • Parnate
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Vilazodone • Viibryd
Vortioxetine • Trintellix
Valproate • Depacon
Ziprasidone • Geodon

Hypertension is a widespread, under-recognized, and undertreated cause of morbidity and mortality in the United States and is associated with several psychiatric illnesses. Left untreated, hypertension can have significant consequences, including increased risk of stroke, coronary heart disease, heart failure, chronic kidney failure, and death. Approximately 70 million adults in the United States have hypertension, but only 60% of them have been diagnosed, and of those only 50% have their blood pressure under control.¹ In 2013, 360,000 deaths in the United States were attributed to hypertension.²

Hypertension is associated with major depressive disorder, generalized anxiety disorder, bipolar disorder, and schizophrenia.^3-5 Additionally, impulsive eating disorders, substance abuse, anxiety, and depression are associated with a hypertension diagnosis, although patients with panic disorder develop hypertension at a younger age.⁶ A 2007 study found a 61% prevalence of hypertension in those with bipolar disorder compared with 41% among the general population.⁷ The strong link between bipolar disorder and hypertension might be because of a common disease mechanism; both are associated with hyperactive cellular calcium signaling and increased platelet intracellular calcium ion concentrations.⁸

Hypertension not only is common among patients with psychiatric illness, it likely contributes to worse clinical outcomes. Studies across different cultures have found higher mortality rates in individuals with mental illness.^9-11 Persons with schizophrenia and other severe mental illnesses may lose ≥25 years of life expectancy, with the primary cause of death being cardiovascular disease, not suicide.¹² Patients with depression have a 50% greater risk of cardiovascular disease, which is equivalent to the risk of smoking.¹³ 

Schizophrenia is strongly associated with numerous comorbidities and has been linked significantly to an elevated 10-year cardiac risk after controlling for body mass index.⁵ The high rate of non-treatment of hypertension for patients with schizophrenia (62.4%) is especially concerning.¹⁴

Because of the well-documented morbidity and mortality of hypertension and its increased prevalence and undertreatment in the psychiatric population, mental health providers are in an important position to recognize hypertension and evaluate its inherent risks to direct their patients toward proper treatment. This article reviews:

• the signs and symptoms of hypertension
• the mental health provider’s role in the evaluation and diagnosis
• how psychotropic drugs influence blood pressure and drug–drug interactions
• the management of hypertension in psychiatric patients, including strategies for counseling and lifestyle management.

Diagnosing hypertension

Hypertension is defined as a blood pressure >140/90 mm Hg, the average of ≥2 properly measured readings at ≥2 visits in a medical setting.¹⁵ The proper equipment, including a well-fitting blood pressure cuff, and technique to measure blood pressure are essential to avoid misdiagnosis. The patient should be at rest for ≥5 minutes, without active pain or emotional distress.

Most cases of hypertension (90% to 95%) are primary, commonly called essential hypertension. However, the differential diagnosis also should consider secondary causes, which may include:

• obesity
• medications
• chronic alcohol use
• methamphetamine or cocaine use
• primary kidney disease
• atherosclerotic renal artery stenosis
• obstructive sleep apnea
• hypothyroidism
• primary hyperaldosteronism
• narrowing of the aorta
• Cushing syndrome
• primary hyperparathyroidism
• polycythemia
• pheochromocytoma.

Medical evaluation. Once the diagnosis of hypertension is made, a medical evaluation is indicated to determine if the patient has end-organ damage from the elevated pressures, such as renal disease or heart disease, to identify other modifiable cardiovascular risk factors, such as hyperlipidemia, and to screen for secondary causes of hypertension. This evaluation includes¹⁵:

• a physical exam
• review of medications
• lipid profile
• urinalysis to screen for proteinuria
• serum electrolytes and creatinine
• electrocardiogram to screen for left ventricular hypertrophy or prior infarction
• fasting glucose or hemoglobin A1_c to screen for type 2 diabetes mellitus.

Psychotropic drugs. In psychiatric patients, the evaluation must consider the potential impact psychotropic drug effects and drug–drug interactions can have on blood pressure (Table 2). For example, patients taking both diuretics and lithium are at increased risk for dehydration and increased serum lithium levels, which could cause severe neurologic symptoms and renal insufficiency.¹⁶ Several antihypertensives when taken with venlafaxine can increase blood pressure, but antihypertensives with α-1 blocking psychotropics can decrease blood pressure. Monoamine oxidase inhibitors can cause hypotension or hypertension with various classes of antihypertensives. Stimulants, such as methylphenidate, atomoxetine, dextroamphetamine, armodafinil, or modafinil, alone or combined with antihypertensives, can cause hypertension.¹⁷

Substance abuse, particularly alcohol, methamphetamine, and cocaine, can cause difficulty controlling blood pressure. Patients with refractory hypertension should have a reassessment of substance abuse as a potential cause.

Screening guidelines for mental health providers

For many patients with severe mental illness, visits to their mental health providers might be their only contact with the medical system. Therefore, screening in the mental health settings could detect cases that otherwise would be missed.

Screening recommendations. The U.S. Preventive Services Task Force recommends screening for hypertension in the general population beginning at age 18.¹⁸ Adults age 18 to 39 with normal blood pressure (<130/85 mm Hg) and no other risk factors (eg, overweight, obese, or African American) can be screened every 3 years. Those with risk factors or a blood pressure of 130/85 to 139/89 mm Hg and adults age ≥40 should have annual screenings.

Ideally, psychiatrists and other mental health providers should monitor blood pressure at each visit, especially in patients taking psychotropics because of their higher risk for hypertension.

Optimizing treatment. Once the diagnosis of essential hypertension is established, identifying psychiatric comorbidities and the severity of psychiatric symptoms are important to optimize treatment adherence. Patients with increased depressive symptoms are less likely to comply with antihypertensive medication,¹⁹ and patients with confirmed depression are 3 times more likely to not adhere to medical treatment recommendations than non-depressed patients.²⁰

Physicians’ attitudes toward hypertension also can affect patients’ compliance and blood pressure control.²¹ Psychiatrists should be empathetic and motivational toward patients attempting to control their blood pressure. The Seventh Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure states, “Motivation improves when patients have positive experiences with, and trust in, the clinician. Empathy builds trust and is a potent motivator.”²²

Treatment and management

Treatment of hypertension significantly reduces the risk of stroke, myocardial infarction, renal injury, heart failure, and premature death. Studies show that treatment that reduces systolic blood pressure by 12 mm Hg over 10 years will prevent 1 death for every 11 patients with essential hypertension. In those with concomitant cardiovascular disease or target organ damage, such a reduction would prevent death in 1 of every 9 patients treated.¹⁵Blood pressure goals. The 2014 Eighth Joint National Committee Guideline for Management of High Blood Pressure in Adults provides guidance on blood pressure goals depending on patients’ underlying medical history (Figure).²³ Based on expert opinion and randomized controlled studies, blood pressure goals for patients without diabetes or chronic kidney disease (CKD)—an estimated or measured glomerular filtration rate (GFR) of ≤60 mL/min/1.73 m²—depend on age: <140/90 mm Hg for age 18 to 59 and <150/90 mm Hg for age ≥60. For patients with diabetes or CKD, the blood pressure goal is <140/90 mm Hg, regardless of age.

However, not all experts agree on these specific blood pressure goals. A major trial (SPRINT) published in 2015 found that intensive blood pressure goals do benefit higher-risk, non-diabetic patients.²⁴ Specifically, the study randomized patients age ≥50 with systolic blood pressure of 130 to 180 mm Hg and increased cardiovascular risk to systolic blood pressure targets of <140 mm Hg (standard) or <120 mm Hg (intensive). Characteristics of increased cardiovascular risk were clinical or subclinical cardiovascular disease other than stroke, CKD with GFR of 20 to 60 mL/min/1.73 m², age ≥75, or Framingham 10-year coronary heart disease risk score ≥15%. Intensive treatment significantly reduced overall mortality and the rate of acute coronary syndrome, myocardial infarction, heart failure, stroke, or cardiovascular death. However, the results of this study have not been assimilated into any recent guidelines. Therefore, consider a goal of <120 mm Hg for non-diabetic patients age ≥50 with any of these factors.

Lifestyle modifications. Psychiatrists are well equipped to motivate and encourage behavioral modification in patients with hypertension. Counseling and structured training courses could help to effectively lower blood pressure.²⁵ Patients should receive education on lifestyle modifications including:

• weight reduction
• physical activity
• moderate alcohol consumption
• decreased sodium consumption
• implementation of the Dietary Approaches to Stop Hypertension (DASH) or Mediterranean diets.¹⁵

Maintaining a normal body weight is ideal, but weight reduction of 10 lb can reduce blood pressure in overweight patients. The DASH diet, consisting of fruits, vegetables, low-fat dairy products, high calcium and potassium intake, and reduced saturated and total fat intake can decrease systolic blood pressure from 8 to 14 mm Hg. Reduction of sodium intake to ≤2,400 mg/d can reduce systolic blood pressure from 2 to 8 mm Hg. Regular aerobic exercise of 30 minutes a day most days of the week can reduce systolic blood pressure up to 9 mm Hg. Patients also should be encouraged to quit smoking. Patients who implement ≥2 these modifications get better results.

Antihypertensive medications. Patients who do not reach their goals with lifestyle measures alone should receive antihypertensive medications. Most patients will require ≥2 agents to control their blood pressure. Clinical trials show that some patient subgroups have better outcomes with different first-line agents.

For example, in non-African American patients, thiazide diuretics, calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors are first-line treatments (Table 3). For African American patients without CKD, first-line treatments should be thiazide diuretics and calcium channel blockers, because angiotensin-converting enzyme inhibitors and angiotensin receptor blockers do not reduce cardiovascular events as effectively. African American patients with CKD and proteinuria, however, benefit from angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and are preferred first-line agents. However, blood pressure control is a more important factor in improving outcomes than the choice of medication.

Psychiatrists’ role. Psychiatrists should aim to collaborate with the primary care provider when treating hypertension. However, when integrative care is not possible, they should start a first-line medication with follow-up in 1 month or sooner for patients with severe hypertension (>160/100 mm Hg) or significant comorbidities (eg, CKD, congestive heart failure, coronary disease). Patients with blood pressure >160/100 mm Hg often are started on a thiazide diuretic with one other medication because a single agent usually does not achieve goal blood pressure. Patients with CKD need close monitoring of potassium and creatinine when starting angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, usually within 1 to 2 days of starting or adjusting their medication. Adjust or add medication dosages monthly until blood pressure goals are reached.

A general internist, cardiologist, or nephrologist who has expertise in managing complex cases should oversee care of a psychiatric patient in any of the following scenarios:

• suspected secondary cause of hypertension
• adverse reaction to antihypertensive medications
• complicated comorbid conditions (ie, creatinine >1.8 mg/dL, worsening renal failure, hyperkalemia, heart failure, coronary disease)
• blood pressure >180/120 mm Hg
• requires ≥3 antihypertensive medications.

Summing up

Hypertension is a significant comorbidity in many psychiatric patients, but usually is asymptomatic. Often the psychiatrist or other mental health provider will diagnose hypertension because of their frequent contact with these patients. Once the diagnosis is made, an initial evaluation can direct lifestyle modifications. Patients who continue to have significant elevation of blood pressure should start pharmacotherapy, either by the psychiatrist or by ensuring follow-up with a primary care physician. The psychiatrist may be able to manage cases of essential hypertension, but always must be vigilant for potential drug–disease or drug–drug interactions during treatment. A team-based approach may improve health outcomes in psychiatric patients.

Hypertension is a widespread, under-recognized, and undertreated cause of morbidity and mortality in the United States and is associated with several psychiatric illnesses. Left untreated, hypertension can have significant consequences, including increased risk of stroke, coronary heart disease, heart failure, chronic kidney failure, and death. Approximately 70 million adults in the United States have hypertension, but only 60% of them have been diagnosed, and of those only 50% have their blood pressure under control.¹ In 2013, 360,000 deaths in the United States were attributed to hypertension.²

Hypertension is associated with major depressive disorder, generalized anxiety disorder, bipolar disorder, and schizophrenia.^3-5 Additionally, impulsive eating disorders, substance abuse, anxiety, and depression are associated with a hypertension diagnosis, although patients with panic disorder develop hypertension at a younger age.⁶ A 2007 study found a 61% prevalence of hypertension in those with bipolar disorder compared with 41% among the general population.⁷ The strong link between bipolar disorder and hypertension might be because of a common disease mechanism; both are associated with hyperactive cellular calcium signaling and increased platelet intracellular calcium ion concentrations.⁸

Hypertension not only is common among patients with psychiatric illness, it likely contributes to worse clinical outcomes. Studies across different cultures have found higher mortality rates in individuals with mental illness.^9-11 Persons with schizophrenia and other severe mental illnesses may lose ≥25 years of life expectancy, with the primary cause of death being cardiovascular disease, not suicide.¹² Patients with depression have a 50% greater risk of cardiovascular disease, which is equivalent to the risk of smoking.¹³ 

Schizophrenia is strongly associated with numerous comorbidities and has been linked significantly to an elevated 10-year cardiac risk after controlling for body mass index.⁵ The high rate of non-treatment of hypertension for patients with schizophrenia (62.4%) is especially concerning.¹⁴

Because of the well-documented morbidity and mortality of hypertension and its increased prevalence and undertreatment in the psychiatric population, mental health providers are in an important position to recognize hypertension and evaluate its inherent risks to direct their patients toward proper treatment. This article reviews:

• the signs and symptoms of hypertension
• the mental health provider’s role in the evaluation and diagnosis
• how psychotropic drugs influence blood pressure and drug–drug interactions
• the management of hypertension in psychiatric patients, including strategies for counseling and lifestyle management.

Diagnosing hypertension

Hypertension is defined as a blood pressure >140/90 mm Hg, the average of ≥2 properly measured readings at ≥2 visits in a medical setting.¹⁵ The proper equipment, including a well-fitting blood pressure cuff, and technique to measure blood pressure are essential to avoid misdiagnosis. The patient should be at rest for ≥5 minutes, without active pain or emotional distress.

Most cases of hypertension (90% to 95%) are primary, commonly called essential hypertension. However, the differential diagnosis also should consider secondary causes, which may include:

• obesity
• medications
• chronic alcohol use
• methamphetamine or cocaine use
• primary kidney disease
• atherosclerotic renal artery stenosis
• obstructive sleep apnea
• hypothyroidism
• primary hyperaldosteronism
• narrowing of the aorta
• Cushing syndrome
• primary hyperparathyroidism
• polycythemia
• pheochromocytoma.

Medical evaluation. Once the diagnosis of hypertension is made, a medical evaluation is indicated to determine if the patient has end-organ damage from the elevated pressures, such as renal disease or heart disease, to identify other modifiable cardiovascular risk factors, such as hyperlipidemia, and to screen for secondary causes of hypertension. This evaluation includes¹⁵:

• a physical exam
• review of medications
• lipid profile
• urinalysis to screen for proteinuria
• serum electrolytes and creatinine
• electrocardiogram to screen for left ventricular hypertrophy or prior infarction
• fasting glucose or hemoglobin A1_c to screen for type 2 diabetes mellitus.

Psychotropic drugs. In psychiatric patients, the evaluation must consider the potential impact psychotropic drug effects and drug–drug interactions can have on blood pressure (Table 2). For example, patients taking both diuretics and lithium are at increased risk for dehydration and increased serum lithium levels, which could cause severe neurologic symptoms and renal insufficiency.¹⁶ Several antihypertensives when taken with venlafaxine can increase blood pressure, but antihypertensives with α-1 blocking psychotropics can decrease blood pressure. Monoamine oxidase inhibitors can cause hypotension or hypertension with various classes of antihypertensives. Stimulants, such as methylphenidate, atomoxetine, dextroamphetamine, armodafinil, or modafinil, alone or combined with antihypertensives, can cause hypertension.¹⁷

Substance abuse, particularly alcohol, methamphetamine, and cocaine, can cause difficulty controlling blood pressure. Patients with refractory hypertension should have a reassessment of substance abuse as a potential cause.

Screening guidelines for mental health providers

For many patients with severe mental illness, visits to their mental health providers might be their only contact with the medical system. Therefore, screening in the mental health settings could detect cases that otherwise would be missed.

Screening recommendations. The U.S. Preventive Services Task Force recommends screening for hypertension in the general population beginning at age 18.¹⁸ Adults age 18 to 39 with normal blood pressure (<130/85 mm Hg) and no other risk factors (eg, overweight, obese, or African American) can be screened every 3 years. Those with risk factors or a blood pressure of 130/85 to 139/89 mm Hg and adults age ≥40 should have annual screenings.

Ideally, psychiatrists and other mental health providers should monitor blood pressure at each visit, especially in patients taking psychotropics because of their higher risk for hypertension.

Optimizing treatment. Once the diagnosis of essential hypertension is established, identifying psychiatric comorbidities and the severity of psychiatric symptoms are important to optimize treatment adherence. Patients with increased depressive symptoms are less likely to comply with antihypertensive medication,¹⁹ and patients with confirmed depression are 3 times more likely to not adhere to medical treatment recommendations than non-depressed patients.²⁰

Physicians’ attitudes toward hypertension also can affect patients’ compliance and blood pressure control.²¹ Psychiatrists should be empathetic and motivational toward patients attempting to control their blood pressure. The Seventh Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure states, “Motivation improves when patients have positive experiences with, and trust in, the clinician. Empathy builds trust and is a potent motivator.”²²

Treatment and management

Treatment of hypertension significantly reduces the risk of stroke, myocardial infarction, renal injury, heart failure, and premature death. Studies show that treatment that reduces systolic blood pressure by 12 mm Hg over 10 years will prevent 1 death for every 11 patients with essential hypertension. In those with concomitant cardiovascular disease or target organ damage, such a reduction would prevent death in 1 of every 9 patients treated.¹⁵Blood pressure goals. The 2014 Eighth Joint National Committee Guideline for Management of High Blood Pressure in Adults provides guidance on blood pressure goals depending on patients’ underlying medical history (Figure).²³ Based on expert opinion and randomized controlled studies, blood pressure goals for patients without diabetes or chronic kidney disease (CKD)—an estimated or measured glomerular filtration rate (GFR) of ≤60 mL/min/1.73 m²—depend on age: <140/90 mm Hg for age 18 to 59 and <150/90 mm Hg for age ≥60. For patients with diabetes or CKD, the blood pressure goal is <140/90 mm Hg, regardless of age.

However, not all experts agree on these specific blood pressure goals. A major trial (SPRINT) published in 2015 found that intensive blood pressure goals do benefit higher-risk, non-diabetic patients.²⁴ Specifically, the study randomized patients age ≥50 with systolic blood pressure of 130 to 180 mm Hg and increased cardiovascular risk to systolic blood pressure targets of <140 mm Hg (standard) or <120 mm Hg (intensive). Characteristics of increased cardiovascular risk were clinical or subclinical cardiovascular disease other than stroke, CKD with GFR of 20 to 60 mL/min/1.73 m², age ≥75, or Framingham 10-year coronary heart disease risk score ≥15%. Intensive treatment significantly reduced overall mortality and the rate of acute coronary syndrome, myocardial infarction, heart failure, stroke, or cardiovascular death. However, the results of this study have not been assimilated into any recent guidelines. Therefore, consider a goal of <120 mm Hg for non-diabetic patients age ≥50 with any of these factors.

Lifestyle modifications. Psychiatrists are well equipped to motivate and encourage behavioral modification in patients with hypertension. Counseling and structured training courses could help to effectively lower blood pressure.²⁵ Patients should receive education on lifestyle modifications including:

• weight reduction
• physical activity
• moderate alcohol consumption
• decreased sodium consumption
• implementation of the Dietary Approaches to Stop Hypertension (DASH) or Mediterranean diets.¹⁵

Maintaining a normal body weight is ideal, but weight reduction of 10 lb can reduce blood pressure in overweight patients. The DASH diet, consisting of fruits, vegetables, low-fat dairy products, high calcium and potassium intake, and reduced saturated and total fat intake can decrease systolic blood pressure from 8 to 14 mm Hg. Reduction of sodium intake to ≤2,400 mg/d can reduce systolic blood pressure from 2 to 8 mm Hg. Regular aerobic exercise of 30 minutes a day most days of the week can reduce systolic blood pressure up to 9 mm Hg. Patients also should be encouraged to quit smoking. Patients who implement ≥2 these modifications get better results.

Antihypertensive medications. Patients who do not reach their goals with lifestyle measures alone should receive antihypertensive medications. Most patients will require ≥2 agents to control their blood pressure. Clinical trials show that some patient subgroups have better outcomes with different first-line agents.

For example, in non-African American patients, thiazide diuretics, calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors are first-line treatments (Table 3). For African American patients without CKD, first-line treatments should be thiazide diuretics and calcium channel blockers, because angiotensin-converting enzyme inhibitors and angiotensin receptor blockers do not reduce cardiovascular events as effectively. African American patients with CKD and proteinuria, however, benefit from angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and are preferred first-line agents. However, blood pressure control is a more important factor in improving outcomes than the choice of medication.

Psychiatrists’ role. Psychiatrists should aim to collaborate with the primary care provider when treating hypertension. However, when integrative care is not possible, they should start a first-line medication with follow-up in 1 month or sooner for patients with severe hypertension (>160/100 mm Hg) or significant comorbidities (eg, CKD, congestive heart failure, coronary disease). Patients with blood pressure >160/100 mm Hg often are started on a thiazide diuretic with one other medication because a single agent usually does not achieve goal blood pressure. Patients with CKD need close monitoring of potassium and creatinine when starting angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, usually within 1 to 2 days of starting or adjusting their medication. Adjust or add medication dosages monthly until blood pressure goals are reached.

A general internist, cardiologist, or nephrologist who has expertise in managing complex cases should oversee care of a psychiatric patient in any of the following scenarios:

• suspected secondary cause of hypertension
• adverse reaction to antihypertensive medications
• complicated comorbid conditions (ie, creatinine >1.8 mg/dL, worsening renal failure, hyperkalemia, heart failure, coronary disease)
• blood pressure >180/120 mm Hg
• requires ≥3 antihypertensive medications.

Summing up

Hypertension is a significant comorbidity in many psychiatric patients, but usually is asymptomatic. Often the psychiatrist or other mental health provider will diagnose hypertension because of their frequent contact with these patients. Once the diagnosis is made, an initial evaluation can direct lifestyle modifications. Patients who continue to have significant elevation of blood pressure should start pharmacotherapy, either by the psychiatrist or by ensuring follow-up with a primary care physician. The psychiatrist may be able to manage cases of essential hypertension, but always must be vigilant for potential drug–disease or drug–drug interactions during treatment. A team-based approach may improve health outcomes in psychiatric patients.

Hypertension is a widespread, under-recognized, and undertreated cause of morbidity and mortality in the United States and is associated with several psychiatric illnesses. Left untreated, hypertension can have significant consequences, including increased risk of stroke, coronary heart disease, heart failure, chronic kidney failure, and death. Approximately 70 million adults in the United States have hypertension, but only 60% of them have been diagnosed, and of those only 50% have their blood pressure under control.¹ In 2013, 360,000 deaths in the United States were attributed to hypertension.²

Hypertension is associated with major depressive disorder, generalized anxiety disorder, bipolar disorder, and schizophrenia.^3-5 Additionally, impulsive eating disorders, substance abuse, anxiety, and depression are associated with a hypertension diagnosis, although patients with panic disorder develop hypertension at a younger age.⁶ A 2007 study found a 61% prevalence of hypertension in those with bipolar disorder compared with 41% among the general population.⁷ The strong link between bipolar disorder and hypertension might be because of a common disease mechanism; both are associated with hyperactive cellular calcium signaling and increased platelet intracellular calcium ion concentrations.⁸

Hypertension not only is common among patients with psychiatric illness, it likely contributes to worse clinical outcomes. Studies across different cultures have found higher mortality rates in individuals with mental illness.^9-11 Persons with schizophrenia and other severe mental illnesses may lose ≥25 years of life expectancy, with the primary cause of death being cardiovascular disease, not suicide.¹² Patients with depression have a 50% greater risk of cardiovascular disease, which is equivalent to the risk of smoking.¹³ 

Schizophrenia is strongly associated with numerous comorbidities and has been linked significantly to an elevated 10-year cardiac risk after controlling for body mass index.⁵ The high rate of non-treatment of hypertension for patients with schizophrenia (62.4%) is especially concerning.¹⁴

Because of the well-documented morbidity and mortality of hypertension and its increased prevalence and undertreatment in the psychiatric population, mental health providers are in an important position to recognize hypertension and evaluate its inherent risks to direct their patients toward proper treatment. This article reviews:

• the signs and symptoms of hypertension
• the mental health provider’s role in the evaluation and diagnosis
• how psychotropic drugs influence blood pressure and drug–drug interactions
• the management of hypertension in psychiatric patients, including strategies for counseling and lifestyle management.

Diagnosing hypertension

Hypertension is defined as a blood pressure >140/90 mm Hg, the average of ≥2 properly measured readings at ≥2 visits in a medical setting.¹⁵ The proper equipment, including a well-fitting blood pressure cuff, and technique to measure blood pressure are essential to avoid misdiagnosis. The patient should be at rest for ≥5 minutes, without active pain or emotional distress.

Most cases of hypertension (90% to 95%) are primary, commonly called essential hypertension. However, the differential diagnosis also should consider secondary causes, which may include:

• obesity
• medications
• chronic alcohol use
• methamphetamine or cocaine use
• primary kidney disease
• atherosclerotic renal artery stenosis
• obstructive sleep apnea
• hypothyroidism
• primary hyperaldosteronism
• narrowing of the aorta
• Cushing syndrome
• primary hyperparathyroidism
• polycythemia
• pheochromocytoma.

Medical evaluation. Once the diagnosis of hypertension is made, a medical evaluation is indicated to determine if the patient has end-organ damage from the elevated pressures, such as renal disease or heart disease, to identify other modifiable cardiovascular risk factors, such as hyperlipidemia, and to screen for secondary causes of hypertension. This evaluation includes¹⁵:

• a physical exam
• review of medications
• lipid profile
• urinalysis to screen for proteinuria
• serum electrolytes and creatinine
• electrocardiogram to screen for left ventricular hypertrophy or prior infarction
• fasting glucose or hemoglobin A1_c to screen for type 2 diabetes mellitus.

Psychotropic drugs. In psychiatric patients, the evaluation must consider the potential impact psychotropic drug effects and drug–drug interactions can have on blood pressure (Table 2). For example, patients taking both diuretics and lithium are at increased risk for dehydration and increased serum lithium levels, which could cause severe neurologic symptoms and renal insufficiency.¹⁶ Several antihypertensives when taken with venlafaxine can increase blood pressure, but antihypertensives with α-1 blocking psychotropics can decrease blood pressure. Monoamine oxidase inhibitors can cause hypotension or hypertension with various classes of antihypertensives. Stimulants, such as methylphenidate, atomoxetine, dextroamphetamine, armodafinil, or modafinil, alone or combined with antihypertensives, can cause hypertension.¹⁷

Substance abuse, particularly alcohol, methamphetamine, and cocaine, can cause difficulty controlling blood pressure. Patients with refractory hypertension should have a reassessment of substance abuse as a potential cause.

Screening guidelines for mental health providers

For many patients with severe mental illness, visits to their mental health providers might be their only contact with the medical system. Therefore, screening in the mental health settings could detect cases that otherwise would be missed.

Screening recommendations. The U.S. Preventive Services Task Force recommends screening for hypertension in the general population beginning at age 18.¹⁸ Adults age 18 to 39 with normal blood pressure (<130/85 mm Hg) and no other risk factors (eg, overweight, obese, or African American) can be screened every 3 years. Those with risk factors or a blood pressure of 130/85 to 139/89 mm Hg and adults age ≥40 should have annual screenings.

Ideally, psychiatrists and other mental health providers should monitor blood pressure at each visit, especially in patients taking psychotropics because of their higher risk for hypertension.

Optimizing treatment. Once the diagnosis of essential hypertension is established, identifying psychiatric comorbidities and the severity of psychiatric symptoms are important to optimize treatment adherence. Patients with increased depressive symptoms are less likely to comply with antihypertensive medication,¹⁹ and patients with confirmed depression are 3 times more likely to not adhere to medical treatment recommendations than non-depressed patients.²⁰

Physicians’ attitudes toward hypertension also can affect patients’ compliance and blood pressure control.²¹ Psychiatrists should be empathetic and motivational toward patients attempting to control their blood pressure. The Seventh Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure states, “Motivation improves when patients have positive experiences with, and trust in, the clinician. Empathy builds trust and is a potent motivator.”²²

Treatment and management

Treatment of hypertension significantly reduces the risk of stroke, myocardial infarction, renal injury, heart failure, and premature death. Studies show that treatment that reduces systolic blood pressure by 12 mm Hg over 10 years will prevent 1 death for every 11 patients with essential hypertension. In those with concomitant cardiovascular disease or target organ damage, such a reduction would prevent death in 1 of every 9 patients treated.¹⁵Blood pressure goals. The 2014 Eighth Joint National Committee Guideline for Management of High Blood Pressure in Adults provides guidance on blood pressure goals depending on patients’ underlying medical history (Figure).²³ Based on expert opinion and randomized controlled studies, blood pressure goals for patients without diabetes or chronic kidney disease (CKD)—an estimated or measured glomerular filtration rate (GFR) of ≤60 mL/min/1.73 m²—depend on age: <140/90 mm Hg for age 18 to 59 and <150/90 mm Hg for age ≥60. For patients with diabetes or CKD, the blood pressure goal is <140/90 mm Hg, regardless of age.

However, not all experts agree on these specific blood pressure goals. A major trial (SPRINT) published in 2015 found that intensive blood pressure goals do benefit higher-risk, non-diabetic patients.²⁴ Specifically, the study randomized patients age ≥50 with systolic blood pressure of 130 to 180 mm Hg and increased cardiovascular risk to systolic blood pressure targets of <140 mm Hg (standard) or <120 mm Hg (intensive). Characteristics of increased cardiovascular risk were clinical or subclinical cardiovascular disease other than stroke, CKD with GFR of 20 to 60 mL/min/1.73 m², age ≥75, or Framingham 10-year coronary heart disease risk score ≥15%. Intensive treatment significantly reduced overall mortality and the rate of acute coronary syndrome, myocardial infarction, heart failure, stroke, or cardiovascular death. However, the results of this study have not been assimilated into any recent guidelines. Therefore, consider a goal of <120 mm Hg for non-diabetic patients age ≥50 with any of these factors.

Lifestyle modifications. Psychiatrists are well equipped to motivate and encourage behavioral modification in patients with hypertension. Counseling and structured training courses could help to effectively lower blood pressure.²⁵ Patients should receive education on lifestyle modifications including:

• weight reduction
• physical activity
• moderate alcohol consumption
• decreased sodium consumption
• implementation of the Dietary Approaches to Stop Hypertension (DASH) or Mediterranean diets.¹⁵

Maintaining a normal body weight is ideal, but weight reduction of 10 lb can reduce blood pressure in overweight patients. The DASH diet, consisting of fruits, vegetables, low-fat dairy products, high calcium and potassium intake, and reduced saturated and total fat intake can decrease systolic blood pressure from 8 to 14 mm Hg. Reduction of sodium intake to ≤2,400 mg/d can reduce systolic blood pressure from 2 to 8 mm Hg. Regular aerobic exercise of 30 minutes a day most days of the week can reduce systolic blood pressure up to 9 mm Hg. Patients also should be encouraged to quit smoking. Patients who implement ≥2 these modifications get better results.

Antihypertensive medications. Patients who do not reach their goals with lifestyle measures alone should receive antihypertensive medications. Most patients will require ≥2 agents to control their blood pressure. Clinical trials show that some patient subgroups have better outcomes with different first-line agents.

For example, in non-African American patients, thiazide diuretics, calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors are first-line treatments (Table 3). For African American patients without CKD, first-line treatments should be thiazide diuretics and calcium channel blockers, because angiotensin-converting enzyme inhibitors and angiotensin receptor blockers do not reduce cardiovascular events as effectively. African American patients with CKD and proteinuria, however, benefit from angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and are preferred first-line agents. However, blood pressure control is a more important factor in improving outcomes than the choice of medication.

Psychiatrists’ role. Psychiatrists should aim to collaborate with the primary care provider when treating hypertension. However, when integrative care is not possible, they should start a first-line medication with follow-up in 1 month or sooner for patients with severe hypertension (>160/100 mm Hg) or significant comorbidities (eg, CKD, congestive heart failure, coronary disease). Patients with blood pressure >160/100 mm Hg often are started on a thiazide diuretic with one other medication because a single agent usually does not achieve goal blood pressure. Patients with CKD need close monitoring of potassium and creatinine when starting angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, usually within 1 to 2 days of starting or adjusting their medication. Adjust or add medication dosages monthly until blood pressure goals are reached.

A general internist, cardiologist, or nephrologist who has expertise in managing complex cases should oversee care of a psychiatric patient in any of the following scenarios:

• suspected secondary cause of hypertension
• adverse reaction to antihypertensive medications
• complicated comorbid conditions (ie, creatinine >1.8 mg/dL, worsening renal failure, hyperkalemia, heart failure, coronary disease)
• blood pressure >180/120 mm Hg
• requires ≥3 antihypertensive medications.

Summing up

Hypertension is a significant comorbidity in many psychiatric patients, but usually is asymptomatic. Often the psychiatrist or other mental health provider will diagnose hypertension because of their frequent contact with these patients. Once the diagnosis is made, an initial evaluation can direct lifestyle modifications. Patients who continue to have significant elevation of blood pressure should start pharmacotherapy, either by the psychiatrist or by ensuring follow-up with a primary care physician. The psychiatrist may be able to manage cases of essential hypertension, but always must be vigilant for potential drug–disease or drug–drug interactions during treatment. A team-based approach may improve health outcomes in psychiatric patients.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

With few exceptions, I have found that patients who have chronic moder­ate or severe mental illness tend to be relatively more vulnerable in terms of (1) receiving suboptimal primary medical care and (2) suffering a result­ing increase in morbidity, mortality, and disability.

Across the board, I’ve found, psychiatrists are more likely to treat patients who are chronically vulnerable.

Why are they so vulnerable?
The unique vulnerability of patients with severe mental illness stems from several causative factors:
   • the stigma attached to mental illness
   • poor implementation of parity in reimbursement for mental health services
   • a suboptimal-sized mental health workforce
   • related poor patient-centered support
   • most important, these patients’ lack of primary and preventive medical care.

Here are a few examples that dem­onstrate how dire the situation is:

Smoking cigarettes is one of the most dangerous modifiable risk factors for vascular disease and early death. People with mental illness smoke almost half (44%) of the cigarettes sold in the United States and are twice as likely to smoke than those who do not have a mental illness.^1,2

HIV infection is at least 2 or 3 times more prevalent among people with severe mental illness as it is in the gen­eral population.³

Hepatitis C infection is at least twice as prevalent in people with a diagno­sis of schizophrenia as it is in the gen­eral population.⁴

Schizophrenia. As many as 60% of premature deaths among people with schizophrenia are attributable to a medical illness.⁵ For example, those with schizophrenia have an increased 10-year cardiac mortality; compara­tively higher rates of hypertension, diabetes, and smoking; and, on aver­age, a lower level of high-density lipoprotein cholesterol. Nasrallah et al reported that the rate of untreated hypertension among patients with schizophrenia is 62.4%.⁶

Premature death. People who have a diagnosis of severe mental illness are at risk of dying prematurely by as much as 25 years.^5,7-10

Who should take the lead?
How can psychiatrists address this ongoing vulnerability within the men­tally ill patient population, and advo­cate for their patients? A comprehensive answer to this question is beyond the scope of this article, but I can offer this prescription for your consideration.

Be an advocate. You, as a psychiatrist, are well positioned to counter the men­tal health-related stigma and advocate for implementation of mental health parity nationwide. In addition to par­ticipating in community education and outreach, become a member of, and get involved in, established organiza­tions, such as the American Psychiatric Association, that advocates for psychi­atric patients at all levels.

Keep patients connected. Make sure your patients are connected with a pri­mary care provider, and use your psy­chotherapeutic skills to help patients understand the importance of receiv­ing primary and secondary preventive medical care.

Monitor health and disease. As a phy­sician first and a psychiatrist second, closely monitor your patients for general medical conditions that are related to the presence and treatment of psychiatric disorders. Consider routinely reviewing pertinent lab work with patients—even results of tests ordered by a primary care provider (eg, the metabolic panel and a thyroid-stimulating hormone level in patients taking lithium).

Collaborate with your primary care col­leagues; they need your help as much as you can use their help! Make sure your patients witness this collaboration, because it mirrors how you would like them to interact with their primary care provider.

Educate yourself. Education in the essentials of psychiatry-based preven­tive medical care is key, as we work to more effectively address the increased disability, morbidity, mortality, and overall vulnerability in our patients. Stay “current” on general medical top­ics by reading the “Med/Psych Update” section of Current Psychiatry and relevant articles in other clinical guides to both integrated and preventive medicine.¹¹

With few exceptions, I have found that patients who have chronic moder­ate or severe mental illness tend to be relatively more vulnerable in terms of (1) receiving suboptimal primary medical care and (2) suffering a result­ing increase in morbidity, mortality, and disability.

Across the board, I’ve found, psychiatrists are more likely to treat patients who are chronically vulnerable.

Why are they so vulnerable?
The unique vulnerability of patients with severe mental illness stems from several causative factors:
   • the stigma attached to mental illness
   • poor implementation of parity in reimbursement for mental health services
   • a suboptimal-sized mental health workforce
   • related poor patient-centered support
   • most important, these patients’ lack of primary and preventive medical care.

Here are a few examples that dem­onstrate how dire the situation is:

Smoking cigarettes is one of the most dangerous modifiable risk factors for vascular disease and early death. People with mental illness smoke almost half (44%) of the cigarettes sold in the United States and are twice as likely to smoke than those who do not have a mental illness.^1,2

HIV infection is at least 2 or 3 times more prevalent among people with severe mental illness as it is in the gen­eral population.³

Hepatitis C infection is at least twice as prevalent in people with a diagno­sis of schizophrenia as it is in the gen­eral population.⁴

Schizophrenia. As many as 60% of premature deaths among people with schizophrenia are attributable to a medical illness.⁵ For example, those with schizophrenia have an increased 10-year cardiac mortality; compara­tively higher rates of hypertension, diabetes, and smoking; and, on aver­age, a lower level of high-density lipoprotein cholesterol. Nasrallah et al reported that the rate of untreated hypertension among patients with schizophrenia is 62.4%.⁶

Premature death. People who have a diagnosis of severe mental illness are at risk of dying prematurely by as much as 25 years.^5,7-10

Who should take the lead?
How can psychiatrists address this ongoing vulnerability within the men­tally ill patient population, and advo­cate for their patients? A comprehensive answer to this question is beyond the scope of this article, but I can offer this prescription for your consideration.

Be an advocate. You, as a psychiatrist, are well positioned to counter the men­tal health-related stigma and advocate for implementation of mental health parity nationwide. In addition to par­ticipating in community education and outreach, become a member of, and get involved in, established organiza­tions, such as the American Psychiatric Association, that advocates for psychi­atric patients at all levels.

Keep patients connected. Make sure your patients are connected with a pri­mary care provider, and use your psy­chotherapeutic skills to help patients understand the importance of receiv­ing primary and secondary preventive medical care.

Monitor health and disease. As a phy­sician first and a psychiatrist second, closely monitor your patients for general medical conditions that are related to the presence and treatment of psychiatric disorders. Consider routinely reviewing pertinent lab work with patients—even results of tests ordered by a primary care provider (eg, the metabolic panel and a thyroid-stimulating hormone level in patients taking lithium).

Collaborate with your primary care col­leagues; they need your help as much as you can use their help! Make sure your patients witness this collaboration, because it mirrors how you would like them to interact with their primary care provider.

Educate yourself. Education in the essentials of psychiatry-based preven­tive medical care is key, as we work to more effectively address the increased disability, morbidity, mortality, and overall vulnerability in our patients. Stay “current” on general medical top­ics by reading the “Med/Psych Update” section of Current Psychiatry and relevant articles in other clinical guides to both integrated and preventive medicine.¹¹

With few exceptions, I have found that patients who have chronic moder­ate or severe mental illness tend to be relatively more vulnerable in terms of (1) receiving suboptimal primary medical care and (2) suffering a result­ing increase in morbidity, mortality, and disability.

Across the board, I’ve found, psychiatrists are more likely to treat patients who are chronically vulnerable.

Why are they so vulnerable?
The unique vulnerability of patients with severe mental illness stems from several causative factors:
   • the stigma attached to mental illness
   • poor implementation of parity in reimbursement for mental health services
   • a suboptimal-sized mental health workforce
   • related poor patient-centered support
   • most important, these patients’ lack of primary and preventive medical care.

Here are a few examples that dem­onstrate how dire the situation is:

Smoking cigarettes is one of the most dangerous modifiable risk factors for vascular disease and early death. People with mental illness smoke almost half (44%) of the cigarettes sold in the United States and are twice as likely to smoke than those who do not have a mental illness.^1,2

HIV infection is at least 2 or 3 times more prevalent among people with severe mental illness as it is in the gen­eral population.³

Hepatitis C infection is at least twice as prevalent in people with a diagno­sis of schizophrenia as it is in the gen­eral population.⁴

Schizophrenia. As many as 60% of premature deaths among people with schizophrenia are attributable to a medical illness.⁵ For example, those with schizophrenia have an increased 10-year cardiac mortality; compara­tively higher rates of hypertension, diabetes, and smoking; and, on aver­age, a lower level of high-density lipoprotein cholesterol. Nasrallah et al reported that the rate of untreated hypertension among patients with schizophrenia is 62.4%.⁶

Premature death. People who have a diagnosis of severe mental illness are at risk of dying prematurely by as much as 25 years.^5,7-10

Who should take the lead?
How can psychiatrists address this ongoing vulnerability within the men­tally ill patient population, and advo­cate for their patients? A comprehensive answer to this question is beyond the scope of this article, but I can offer this prescription for your consideration.

Be an advocate. You, as a psychiatrist, are well positioned to counter the men­tal health-related stigma and advocate for implementation of mental health parity nationwide. In addition to par­ticipating in community education and outreach, become a member of, and get involved in, established organiza­tions, such as the American Psychiatric Association, that advocates for psychi­atric patients at all levels.

Keep patients connected. Make sure your patients are connected with a pri­mary care provider, and use your psy­chotherapeutic skills to help patients understand the importance of receiv­ing primary and secondary preventive medical care.

Monitor health and disease. As a phy­sician first and a psychiatrist second, closely monitor your patients for general medical conditions that are related to the presence and treatment of psychiatric disorders. Consider routinely reviewing pertinent lab work with patients—even results of tests ordered by a primary care provider (eg, the metabolic panel and a thyroid-stimulating hormone level in patients taking lithium).

Collaborate with your primary care col­leagues; they need your help as much as you can use their help! Make sure your patients witness this collaboration, because it mirrors how you would like them to interact with their primary care provider.

Educate yourself. Education in the essentials of psychiatry-based preven­tive medical care is key, as we work to more effectively address the increased disability, morbidity, mortality, and overall vulnerability in our patients. Stay “current” on general medical top­ics by reading the “Med/Psych Update” section of Current Psychiatry and relevant articles in other clinical guides to both integrated and preventive medicine.¹¹