Reviews

Life expectancy for both males and females has been increasing over the past several decades to an average of 76 years. However, the life expectancy among individuals with schizophrenia in the United States is 61 years—a 20% reduction.¹ Patients with schizophrenia are known to be at increased risk of several comorbid medical conditions, such as type 2 diabetes mellitus (T2DM), coronary artery disease, and digestive and liver disorders, compared with healthy people (Figure, page 32).^2-5 This risk may be heightened by several factors, including sedentary lifestyle, a high rate of cigarette use, poor self-management skills, homelessness, and poor diet. 

Although substantial attention is paid to the psychiatric and behavioral management of schizophrenia, many barriers impede the detection and treatment of patients’ medical conditions, which have been implicated in excess unforeseen deaths. Patients with schizophrenia might experience delays in diagnosis, leading to more acute comorbidity at time of diagnosis and premature mortality

Cardiovascular disease is the leading cause of death among psychiatric patients.⁶ Key risk factors for cardiovascular disease include smoking, obesity, hypertension, dyslipidemia, diabetes, and lack of physical activity, all of which are more prevalent among patients with schizophrenia.⁷ In addition, antipsychotics are associated with adverse metabolic effects.⁸ In general, smoking and obesity are the most modifiable and preventable risk factors for many medical conditions, such as cardiovascular disease, hyperlipidemia, diabetes, and many forms of cancer (Table 1).

In this article, we discuss how to manage common medical comorbidities in patients with schizophrenia. Comprehensive management for all these medical conditions in this population is beyond the scope of this article; we limit ourselves to discussing (1) how common these conditions are in patients with schizophrenia compared with the general population and (2) what can be done in psychiatric practice to manage these medical comorbidities (Box).

Obesity
Obesity—defined as body mass index (BMI) of >30—is common among patients with schizophrenia. The condition leads to poor self-image, decreased treatment adherence, and an increased risk of many chronic medical conditions (Table 1). Being overweight or obese can increase stigma and social discrimination, which will undermine self-esteem and, in turn, affect adherence with medications, leading to relapse.

The prevalence of obesity among patients with schizophrenia is almost double that of the general population⁹ (Figure^2-5). Several factors predispose these patients to overweight or obese, including sedentary lifestyle, lack of exercise, a high-fat diet, medications side effects, and genetic factors. Recent studies report the incidence of weight gain among patients treated with antipsychotics is as high as 80%¹⁰ (Table 2).

Mechanisms involved in antipsychotic-induced weight gain are not completely understood, but antagonism of serotonergic (5-HT2C, 5-HT1A), histamine (H1), dopamine (D2), muscarinic, and other receptors are involved in modulation of food intake. Decreased energy expenditure also has been blamed for antipsychotic-induced weight gain.¹⁰

Pharmacotherapy and bariatric surgery can be as effective among patients with schizophrenia as they are among the general population. Maintaining a BMI of <25 kg/m² lowers the risk of cardiovascular disease by 35% to 55%.⁶ Metformin has modest potential for offsetting weight gain and providing some metabolic control in overweight outpatients with schizophrenia,¹¹ and should be considered early when treating at-risk patients.

Managing obesity. Clinicians can apply several measures to manage obesity in a patient with schizophrenia:

• Educate the patient, and the family, about the risks of being overweight or obese.
• Monitor weight and BMI at each visit.
• Advise smoking cessation.
• When clinically appropriate, switch to an antipsychotic with a lower risk of weight gain—eg, from olanzapine or high-dose quetiapine to a high- or medium-potency typical antipsychotic (eg, haloperidol, perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2, page 36).
• Consider prophylactic use of metformin with an antipsychotic; the drug has modest potential for offsetting weight gain and providing better metabolic control in an overweight patient with schizophrenia.¹¹
• Encourage the patient to engage in modest physical activity; for example, a 20-minute walk, every day, reduces the risk of cardiovascular disease by 35% to 55%.⁶
• Recommend a formal lifestyle modification program, such as behavioral group-based treatment for weight reduction.¹²
• Refer the patient and family to a dietitian.

Type 2 diabetes mellitus
There is strong association between T2DM and schizophrenia that is related to abnormal glucose regulation independent of any adverse medication effect.¹³ Ryan et al¹⁴ reported that first-episode, drug-naïve patients with schizophrenia had a higher level of intra-abdominal fat than age- and BMI-matched healthy controls, suggesting that schizophrenia could be associated with changes in adiposity that might increase the risk of insulin resistance, hyperlipidemia, and dyslipidemia. Mechanisms that increase the risk of T2DM in schizophrenia include genetic and environmental factors, such as family history, lack of physical activity, and poor diet.

Diagnosis. All patients with schizophrenia should be evaluated for undiagnosed diabetes. The diagnosis of T2DM is made by documenting:

• a fasting plasma glucose reading of ≥126 mg/dL
• symptoms of T2DM, along with a random plasma glucose reading of ≥200 mg/dL
• 2-hour reading of a plasma glucose level >200 mg/dL on an oral glucose tolerance test.

Recent guidelines also suggest using a hemoglobin A_1c value cutoff of ≥6.5% to diagnose T2DM.

In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, 38% of patients with schizophrenia and diabetes were not receiving any treatment for T2DM.¹⁵

Risk factors for T2DM are:

• BMI >25
• a first-degree relative with diabetes
• lack of physical activity
• being a member of a high-risk ethnic group (African American, Hispanic American, Native American, Asian American, or Pacific Islander)
• having delivered a baby >9 lb or having had gestational diabetes
• hypertension
• high-density lipoprotein (HDL) cholesterol level of ≤35 mg/dL
• triglyceride level of ≥250 mg/dL
• history of an abnormal glucose tolerance test
• history of abnormal findings on a fasting plasma glucose test
• history of vascular disease.

Early detection and management.

• Educate the patient and family about signs and symptoms of T2DM, such as polyuria, nocturia, polydipsia, fatigue, visual disturbances, and (in women) vulvitis. Also, psychiatrists should be aware of, and inquire about, symptoms of diabetic ketoacidosis.
• At the start of therapy with any antipsychotic, particularly a second-generation antipsychotic (SGA), ask patients about a family history of diabetes and measure the hemoglobin A_1c value.
• Monitor the hemoglobin A_1c level 4 months after starting an antipsychotic, then annually, in a patient with significant risk factors for diabetes.
• Monitor blood glucose every 6 months in patients with no change from initial results and more frequently in those with significant risk factors for diabetes and those who gain weight.
• Order a lipid panel and measure the serum glucose level to rule out dyslipidemia and diabetes, because a patient with high lipid levels and diabetes is at higher risk of developing cardiovascular conditions.
• Advocate for smoking cessation.
• Switch to an antipsychotic with a lower risk of diabetes when clinically appropriate, such as switching a patient from olanzapine or high-dose quetiapine to a high- or medium-potency typical antipsychotic (such as haloperidol or perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2).
• Consider prophylactic use of metformin along with antipsychotics. Metformin has been used to improve insulin sensitivity and can lead to weight loss in diabetic and non-diabetic patients. The drug has modest potential for offsetting weight gain and providing better metabolic control in overweight outpatients with schizophrenia.¹¹ Metformin is simple to use, does not lead to hypoglycemia, does not require serum glucose monitoring, and has a favorable safety profile.¹¹
• Educate the patient about modest physical activity. For example, a 20-minute walk every day reduces the risk of cardiovascular disease by 35% to 55%.⁶
• Refer the patient to a dietitian to develop an appropriate diet plan.
• When diabetes is diagnosed, ensure appropriate follow-up and initiation or continuation of therapy with a general practitioner or an endocrinologist.
• Reinforce the need for ongoing follow-up and compliance with therapy for diabetes.

Hyperlipidemia and dyslipidemia
Elevated cholesterol and triglyceride levels are associated with cardiovascular diseases, such as ischemic heart disease and myocardial infarction. A 10% increase in cholesterol levels is associated with a 20% to 30% increase in the risk of coronary artery disease; lowering cholesterol by 10% decreases the risk by 20% to 30%.¹⁶ Triglyceride levels ≥250 mg/dL are associated with 2-fold higher risk of cardiovascular disease.¹⁶

The incidence of dyslipidemia is not as well studied as diabetes in patients with schizophrenia. There is increased prevalence of dyslipidemia in patients with schizophrenia compared with the general population because of obesity, lack of physical activity, and poor dietary habits.¹⁶

Data regarding the effects of first-generation antipsychotics (FGAs) on lipid levels are limited, but high-potency drugs, such as haloperidol, seem to carry a lower risk of hyperlipidemia than low-potency drugs, such as chlorpromazine and thioridazine.¹⁷ A comprehensive review on the effects of SGAs on plasma lipid levels suggested that clozapine, olanzapine, and quetiapine are associated with a higher risk of dyslipidemia¹⁷ (Table 2).

In the CATIE study, olanzapine and clozapine were associated with a greater increase in the serum level of cholesterol and triglycerides compared with other antipsychotics, even after adjusting for treatment duration. Furthermore, a retrospective chart review of patients who switched to aripiprazole from other SGAs showed a decrease in levels of total cholesterol and low-density lipoprotein cholesterol¹⁵ (Table 2).

Patients with schizophrenia are more likely to have dyslipidemia go undiagnosed, and therefore are less likely to be treated for the disorder. In the CATIE study, 88% of patients with dyslipidemia were not receiving any treatment.¹⁵

Management for dyslipidemia.

• Educate the patient and family about risks involved with dyslipidemia.
• Monitor weight and BMI at each visit.
• Monitor lipids to rule out dyslipidemia. Obtain a pretreatment fasting or random lipid profile for any patient receiving an antipsychotic; repeat at least every 6 months after starting the antipsychotic.
• Counsel the patient to quit smoking.
• Switch to an antipsychotic with lower risk of weight gain and dyslipidemia, such as switching from olanzapine or high-dose quetiapine to high- or medium-potency typical antipsychotics (such as, haloperidol or perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2).
• Educate and encourage the patient about modest physical activity. For example, a 20-minute walk everyday will reduce cardiovascular disease risk by 35% to 55%.⁶
• Refer to a dietitian if indicated.
• Ensure follow-up and initiation of treatment with a general practitioner.
• Educate and encourage the patient about modest physical activity. For example, a 20-minute walk everyday will reduce cardiovascular disease risk by 35% to 55%.

Metabolic syndrome
Metabolic syndrome is cluster of cardiovascular risk factors, including central adiposity, hyperglycemia, dyslipidemia, and hypertension. The National Cholesterol Education Program’s Adult Treatment Panel III report defines metabolic syndrome as the presence of 3 of 5 of the following factors:

• abdominal obesity (waist circumference of >40 inches in men, or >35 inches in women)
• triglyceride level, >150 mg/dL
• HDL cholesterol, <40 mg/dL in men and <50 mg/dL in women
• blood pressure, >130/85 mm Hg
• fasting plasma glucose level, >110 mg/dL.

The presence of metabolic syndrome in the general population is a strong predictor of cardiovascular diseases and diabetes.¹⁸ The adverse effects of metabolic syndrome are thought to relate to atherogenic dyslipidemia, higher blood pressure, insulin resistance with or without glucose intolerance, a proinflammatory state, and a prothrombotic state.

The prevalence of metabolic syndrome in patients with schizophrenia is 2- to 3-fold higher than the general population.¹⁹ In the CATIE study, approximately one-third of patients met criteria for metabolic syndrome at baseline.¹⁵ In a prospective study, De Hert et al²⁰ reported that patients who were started on a SGA had more than twice the rate of developing metabolic syndrome compared with those treated with a FGA (Table 2). Other possible causes of metabolic syndrome are visceral adiposity and insulin resistance.¹⁶Management of the metabolic syndrome involves addressing the individual components that have been described in the preceding sections on T2DM and dyslipidemia.

Hepatitis C
Hepatitis C virus (HCV) infection is thought to be the most common blood-borne illness, with an estimated prevalence of 1% of the U.S. population. Some studies suggest that as many as 16% of people with schizophrenia have HCV infection.⁴ Risk factors for HCV infection include unsafe sexual practices, prostitution, homosexuality, homelessness, and IV drug use.

HCV treatments typically have involved regimens with interferon alfa, which is associated with significant neuropsychiatric side effects, including depression and suicide. There is a dearth of research on treatment of HCV in patients with schizophrenia; however, at least 1 study suggests that there was no increase in psychiatric symptoms in patients treated with interferon-containing regimens.²¹ There is even less evidence to guide the use of newer, non-interferon–based HCV treatment regimens that are better tolerated and have a higher response rate in the general population; there is reason, however, to be hopeful about their potential in patients with schizophrenia and HCV infection.

Managing HCV infection.

• Educate the patients and family about risk factors associated with contracting HCV.
• Screen for HCV infection in patients with schizophrenia because there is higher prevalence of HCV in these patients compared with the general population.
• When HCV infection is diagnosed, educate the patients and family about available treatments.
• Facilitate referral to an HCV specialist for appropriate treatment.

HIV/AIDS
HIV infection is highly prevalent among people suffering from severe mental illness such as schizophrenia. The incidence of HIV/AIDS in patients with schizophrenia is estimated to be 4% to 23%, compared with 0.6% in the general population.²² Risk factors associated with a higher incidence of HIV/AIDS in patients with schizophrenia are lack of knowledge about contracting HIV, unsafe sexual practices, prostitution, homosexuality, homelessness, and IV drug use.²²

Managing HIV/AIDS.

• Educate the patient and family about risk factors associated with contracting HIV/AIDS.
• Educate patients about safe sex practices.
• All patients with schizophrenia should be screened for HIV because there is 10-fold higher HIV prevalence in schizophrenia compared with the general population.
• When HIV infection is diagnosed, facilitate referral to a HIV or infectious disease specialist for treatment.
• Educate the patient in whom HIV/AIDS has been diagnosed about the importance of (1) adherence to his (her) HIV medication regimen and (2) follow-up visits with an infectious disease practitioner and appropriate laboratory tests.
• Educate the patient’s family and significant other about the illness.
• Screen for and treat substance use.
• At each visit, inquire about the patient’s adherence to HIV medical therapy, viral load, and CD4 cell count.

Chronic obstructive pulmonary disease
Patients with schizophrenia are more likely to suffer from respiratory disease, such as chronic obstructive pulmonary disease (COPD) and asthma, compared with the general population.²³ Smoking is a major risk factor for COPD. In a study by Dickerson et al,²⁴ 64% of people with schizophrenia were current smokers, compared with 19% of those without mental illness.

A high rate of smoking rate among people with schizophrenia suggests a “self-medication” hypothesis: That is, stimulation of CNS nicotinic cholinergic receptors treats the negative symptoms of schizophrenia and overcomes the dopamine blocking effects of antipsychotics.²⁵ Among SGAs, only clozapine has a substantial body of evidence to support its association with decreased smoking behavior.

Managing COPD.

• Educate the patient and family about risk factors associated with COPD and smoking.
• Screen for tobacco use at each visit; try to increase motivation to quit smoking.
• Educate the patients and family about the value and availability of smoking cessation programs.
• Prescribe medication to help with smoking cessation when needed. Bupropion and varenicline have been shown to be effective in patients with schizophrenia; nicotine replacement therapies are safe and can be helpful.
• When treating a patient who is in the process of quitting, encourage and help him to maintain his commitment and enlist support from his family.
• Refer to an appropriate medical provider (primary care provider or pulmonologist) for a patient with an established or suspected diagnosis of COPD.

Cancer
Since 1909, when the Board of Control of the Commissioners in Lunacy for England and Wales noted the possibility of a decreased incidence in cancer among psychiatric patients, this connection has been a matter of controversy.²⁶ Subsequent research has been equivocal; the prevalence of cancer has been reported to be either increased, similar, or decreased compared with the general population.^26-28 Risk factors for cancer, including smoking, obesity, poor diet, sedentary lifestyle, and hyperprolactinemia, are more common among patients with schizophrenia.

Genetic factors and a possible protective effect from antipsychotics have been cited as potential causes of decreased prevalence. Clozapine is associated with an increased risk of leukemia. No conclusion can be drawn about the overall prevalence of cancer in schizophrenia.

Managing cancer in a patient with schizophrenia, however, poses a significant challenge²⁹; he might lack capacity to make decisions about cancer treatment. The patient—or his surrogate decision-makers—need to carefully weigh current quality of life against potential benefits of treatment and risks of side effects. Adherence to complex, often toxic, therapies can be challenging for the patient with psychosis. Successful cancer treatment often requires close collaboration between the cancer treatment team and the patient’s support system, including the treating psychiatrist and case management teams.

Bottom Line
Patients with schizophrenia are at higher risk of developing comorbid medical
conditions because of the illness itself, lifestyle behaviors, genetics, and adverse
effects of medications. Because mental health clinicians focus attention on the
psychiatric and behavioral aspect of treatment, often there is delay in screening,
detecting, and treating medical comorbidities. This screening can be done in any
psychiatric practice, which can lead to timely management for those conditions
and preventing premature mortality in patients with schizophrenia.

Life expectancy for both males and females has been increasing over the past several decades to an average of 76 years. However, the life expectancy among individuals with schizophrenia in the United States is 61 years—a 20% reduction.¹ Patients with schizophrenia are known to be at increased risk of several comorbid medical conditions, such as type 2 diabetes mellitus (T2DM), coronary artery disease, and digestive and liver disorders, compared with healthy people (Figure, page 32).^2-5 This risk may be heightened by several factors, including sedentary lifestyle, a high rate of cigarette use, poor self-management skills, homelessness, and poor diet. 

Although substantial attention is paid to the psychiatric and behavioral management of schizophrenia, many barriers impede the detection and treatment of patients’ medical conditions, which have been implicated in excess unforeseen deaths. Patients with schizophrenia might experience delays in diagnosis, leading to more acute comorbidity at time of diagnosis and premature mortality

Cardiovascular disease is the leading cause of death among psychiatric patients.⁶ Key risk factors for cardiovascular disease include smoking, obesity, hypertension, dyslipidemia, diabetes, and lack of physical activity, all of which are more prevalent among patients with schizophrenia.⁷ In addition, antipsychotics are associated with adverse metabolic effects.⁸ In general, smoking and obesity are the most modifiable and preventable risk factors for many medical conditions, such as cardiovascular disease, hyperlipidemia, diabetes, and many forms of cancer (Table 1).

In this article, we discuss how to manage common medical comorbidities in patients with schizophrenia. Comprehensive management for all these medical conditions in this population is beyond the scope of this article; we limit ourselves to discussing (1) how common these conditions are in patients with schizophrenia compared with the general population and (2) what can be done in psychiatric practice to manage these medical comorbidities (Box).

Obesity
Obesity—defined as body mass index (BMI) of >30—is common among patients with schizophrenia. The condition leads to poor self-image, decreased treatment adherence, and an increased risk of many chronic medical conditions (Table 1). Being overweight or obese can increase stigma and social discrimination, which will undermine self-esteem and, in turn, affect adherence with medications, leading to relapse.

The prevalence of obesity among patients with schizophrenia is almost double that of the general population⁹ (Figure^2-5). Several factors predispose these patients to overweight or obese, including sedentary lifestyle, lack of exercise, a high-fat diet, medications side effects, and genetic factors. Recent studies report the incidence of weight gain among patients treated with antipsychotics is as high as 80%¹⁰ (Table 2).

Mechanisms involved in antipsychotic-induced weight gain are not completely understood, but antagonism of serotonergic (5-HT2C, 5-HT1A), histamine (H1), dopamine (D2), muscarinic, and other receptors are involved in modulation of food intake. Decreased energy expenditure also has been blamed for antipsychotic-induced weight gain.¹⁰

Pharmacotherapy and bariatric surgery can be as effective among patients with schizophrenia as they are among the general population. Maintaining a BMI of <25 kg/m² lowers the risk of cardiovascular disease by 35% to 55%.⁶ Metformin has modest potential for offsetting weight gain and providing some metabolic control in overweight outpatients with schizophrenia,¹¹ and should be considered early when treating at-risk patients.

Managing obesity. Clinicians can apply several measures to manage obesity in a patient with schizophrenia:

• Educate the patient, and the family, about the risks of being overweight or obese.
• Monitor weight and BMI at each visit.
• Advise smoking cessation.
• When clinically appropriate, switch to an antipsychotic with a lower risk of weight gain—eg, from olanzapine or high-dose quetiapine to a high- or medium-potency typical antipsychotic (eg, haloperidol, perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2, page 36).
• Consider prophylactic use of metformin with an antipsychotic; the drug has modest potential for offsetting weight gain and providing better metabolic control in an overweight patient with schizophrenia.¹¹
• Encourage the patient to engage in modest physical activity; for example, a 20-minute walk, every day, reduces the risk of cardiovascular disease by 35% to 55%.⁶
• Recommend a formal lifestyle modification program, such as behavioral group-based treatment for weight reduction.¹²
• Refer the patient and family to a dietitian.

Type 2 diabetes mellitus
There is strong association between T2DM and schizophrenia that is related to abnormal glucose regulation independent of any adverse medication effect.¹³ Ryan et al¹⁴ reported that first-episode, drug-naïve patients with schizophrenia had a higher level of intra-abdominal fat than age- and BMI-matched healthy controls, suggesting that schizophrenia could be associated with changes in adiposity that might increase the risk of insulin resistance, hyperlipidemia, and dyslipidemia. Mechanisms that increase the risk of T2DM in schizophrenia include genetic and environmental factors, such as family history, lack of physical activity, and poor diet.

Diagnosis. All patients with schizophrenia should be evaluated for undiagnosed diabetes. The diagnosis of T2DM is made by documenting:

• a fasting plasma glucose reading of ≥126 mg/dL
• symptoms of T2DM, along with a random plasma glucose reading of ≥200 mg/dL
• 2-hour reading of a plasma glucose level >200 mg/dL on an oral glucose tolerance test.

Recent guidelines also suggest using a hemoglobin A_1c value cutoff of ≥6.5% to diagnose T2DM.

In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, 38% of patients with schizophrenia and diabetes were not receiving any treatment for T2DM.¹⁵

Risk factors for T2DM are:

• BMI >25
• a first-degree relative with diabetes
• lack of physical activity
• being a member of a high-risk ethnic group (African American, Hispanic American, Native American, Asian American, or Pacific Islander)
• having delivered a baby >9 lb or having had gestational diabetes
• hypertension
• high-density lipoprotein (HDL) cholesterol level of ≤35 mg/dL
• triglyceride level of ≥250 mg/dL
• history of an abnormal glucose tolerance test
• history of abnormal findings on a fasting plasma glucose test
• history of vascular disease.

Early detection and management.

• Educate the patient and family about signs and symptoms of T2DM, such as polyuria, nocturia, polydipsia, fatigue, visual disturbances, and (in women) vulvitis. Also, psychiatrists should be aware of, and inquire about, symptoms of diabetic ketoacidosis.
• At the start of therapy with any antipsychotic, particularly a second-generation antipsychotic (SGA), ask patients about a family history of diabetes and measure the hemoglobin A_1c value.
• Monitor the hemoglobin A_1c level 4 months after starting an antipsychotic, then annually, in a patient with significant risk factors for diabetes.
• Monitor blood glucose every 6 months in patients with no change from initial results and more frequently in those with significant risk factors for diabetes and those who gain weight.
• Order a lipid panel and measure the serum glucose level to rule out dyslipidemia and diabetes, because a patient with high lipid levels and diabetes is at higher risk of developing cardiovascular conditions.
• Advocate for smoking cessation.
• Switch to an antipsychotic with a lower risk of diabetes when clinically appropriate, such as switching a patient from olanzapine or high-dose quetiapine to a high- or medium-potency typical antipsychotic (such as haloperidol or perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2).
• Consider prophylactic use of metformin along with antipsychotics. Metformin has been used to improve insulin sensitivity and can lead to weight loss in diabetic and non-diabetic patients. The drug has modest potential for offsetting weight gain and providing better metabolic control in overweight outpatients with schizophrenia.¹¹ Metformin is simple to use, does not lead to hypoglycemia, does not require serum glucose monitoring, and has a favorable safety profile.¹¹
• Educate the patient about modest physical activity. For example, a 20-minute walk every day reduces the risk of cardiovascular disease by 35% to 55%.⁶
• Refer the patient to a dietitian to develop an appropriate diet plan.
• When diabetes is diagnosed, ensure appropriate follow-up and initiation or continuation of therapy with a general practitioner or an endocrinologist.
• Reinforce the need for ongoing follow-up and compliance with therapy for diabetes.

Hyperlipidemia and dyslipidemia
Elevated cholesterol and triglyceride levels are associated with cardiovascular diseases, such as ischemic heart disease and myocardial infarction. A 10% increase in cholesterol levels is associated with a 20% to 30% increase in the risk of coronary artery disease; lowering cholesterol by 10% decreases the risk by 20% to 30%.¹⁶ Triglyceride levels ≥250 mg/dL are associated with 2-fold higher risk of cardiovascular disease.¹⁶

The incidence of dyslipidemia is not as well studied as diabetes in patients with schizophrenia. There is increased prevalence of dyslipidemia in patients with schizophrenia compared with the general population because of obesity, lack of physical activity, and poor dietary habits.¹⁶

Data regarding the effects of first-generation antipsychotics (FGAs) on lipid levels are limited, but high-potency drugs, such as haloperidol, seem to carry a lower risk of hyperlipidemia than low-potency drugs, such as chlorpromazine and thioridazine.¹⁷ A comprehensive review on the effects of SGAs on plasma lipid levels suggested that clozapine, olanzapine, and quetiapine are associated with a higher risk of dyslipidemia¹⁷ (Table 2).

In the CATIE study, olanzapine and clozapine were associated with a greater increase in the serum level of cholesterol and triglycerides compared with other antipsychotics, even after adjusting for treatment duration. Furthermore, a retrospective chart review of patients who switched to aripiprazole from other SGAs showed a decrease in levels of total cholesterol and low-density lipoprotein cholesterol¹⁵ (Table 2).

Patients with schizophrenia are more likely to have dyslipidemia go undiagnosed, and therefore are less likely to be treated for the disorder. In the CATIE study, 88% of patients with dyslipidemia were not receiving any treatment.¹⁵

Management for dyslipidemia.

• Educate the patient and family about risks involved with dyslipidemia.
• Monitor weight and BMI at each visit.
• Monitor lipids to rule out dyslipidemia. Obtain a pretreatment fasting or random lipid profile for any patient receiving an antipsychotic; repeat at least every 6 months after starting the antipsychotic.
• Counsel the patient to quit smoking.
• Switch to an antipsychotic with lower risk of weight gain and dyslipidemia, such as switching from olanzapine or high-dose quetiapine to high- or medium-potency typical antipsychotics (such as, haloperidol or perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2).
• Educate and encourage the patient about modest physical activity. For example, a 20-minute walk everyday will reduce cardiovascular disease risk by 35% to 55%.⁶
• Refer to a dietitian if indicated.
• Ensure follow-up and initiation of treatment with a general practitioner.
• Educate and encourage the patient about modest physical activity. For example, a 20-minute walk everyday will reduce cardiovascular disease risk by 35% to 55%.

Metabolic syndrome
Metabolic syndrome is cluster of cardiovascular risk factors, including central adiposity, hyperglycemia, dyslipidemia, and hypertension. The National Cholesterol Education Program’s Adult Treatment Panel III report defines metabolic syndrome as the presence of 3 of 5 of the following factors:

• abdominal obesity (waist circumference of >40 inches in men, or >35 inches in women)
• triglyceride level, >150 mg/dL
• HDL cholesterol, <40 mg/dL in men and <50 mg/dL in women
• blood pressure, >130/85 mm Hg
• fasting plasma glucose level, >110 mg/dL.

The presence of metabolic syndrome in the general population is a strong predictor of cardiovascular diseases and diabetes.¹⁸ The adverse effects of metabolic syndrome are thought to relate to atherogenic dyslipidemia, higher blood pressure, insulin resistance with or without glucose intolerance, a proinflammatory state, and a prothrombotic state.

The prevalence of metabolic syndrome in patients with schizophrenia is 2- to 3-fold higher than the general population.¹⁹ In the CATIE study, approximately one-third of patients met criteria for metabolic syndrome at baseline.¹⁵ In a prospective study, De Hert et al²⁰ reported that patients who were started on a SGA had more than twice the rate of developing metabolic syndrome compared with those treated with a FGA (Table 2). Other possible causes of metabolic syndrome are visceral adiposity and insulin resistance.¹⁶Management of the metabolic syndrome involves addressing the individual components that have been described in the preceding sections on T2DM and dyslipidemia.

Hepatitis C
Hepatitis C virus (HCV) infection is thought to be the most common blood-borne illness, with an estimated prevalence of 1% of the U.S. population. Some studies suggest that as many as 16% of people with schizophrenia have HCV infection.⁴ Risk factors for HCV infection include unsafe sexual practices, prostitution, homosexuality, homelessness, and IV drug use.

HCV treatments typically have involved regimens with interferon alfa, which is associated with significant neuropsychiatric side effects, including depression and suicide. There is a dearth of research on treatment of HCV in patients with schizophrenia; however, at least 1 study suggests that there was no increase in psychiatric symptoms in patients treated with interferon-containing regimens.²¹ There is even less evidence to guide the use of newer, non-interferon–based HCV treatment regimens that are better tolerated and have a higher response rate in the general population; there is reason, however, to be hopeful about their potential in patients with schizophrenia and HCV infection.

Managing HCV infection.

• Educate the patients and family about risk factors associated with contracting HCV.
• Screen for HCV infection in patients with schizophrenia because there is higher prevalence of HCV in these patients compared with the general population.
• When HCV infection is diagnosed, educate the patients and family about available treatments.
• Facilitate referral to an HCV specialist for appropriate treatment.

HIV/AIDS
HIV infection is highly prevalent among people suffering from severe mental illness such as schizophrenia. The incidence of HIV/AIDS in patients with schizophrenia is estimated to be 4% to 23%, compared with 0.6% in the general population.²² Risk factors associated with a higher incidence of HIV/AIDS in patients with schizophrenia are lack of knowledge about contracting HIV, unsafe sexual practices, prostitution, homosexuality, homelessness, and IV drug use.²²

Managing HIV/AIDS.

• Educate the patient and family about risk factors associated with contracting HIV/AIDS.
• Educate patients about safe sex practices.
• All patients with schizophrenia should be screened for HIV because there is 10-fold higher HIV prevalence in schizophrenia compared with the general population.
• When HIV infection is diagnosed, facilitate referral to a HIV or infectious disease specialist for treatment.
• Educate the patient in whom HIV/AIDS has been diagnosed about the importance of (1) adherence to his (her) HIV medication regimen and (2) follow-up visits with an infectious disease practitioner and appropriate laboratory tests.
• Educate the patient’s family and significant other about the illness.
• Screen for and treat substance use.
• At each visit, inquire about the patient’s adherence to HIV medical therapy, viral load, and CD4 cell count.

Chronic obstructive pulmonary disease
Patients with schizophrenia are more likely to suffer from respiratory disease, such as chronic obstructive pulmonary disease (COPD) and asthma, compared with the general population.²³ Smoking is a major risk factor for COPD. In a study by Dickerson et al,²⁴ 64% of people with schizophrenia were current smokers, compared with 19% of those without mental illness.

A high rate of smoking rate among people with schizophrenia suggests a “self-medication” hypothesis: That is, stimulation of CNS nicotinic cholinergic receptors treats the negative symptoms of schizophrenia and overcomes the dopamine blocking effects of antipsychotics.²⁵ Among SGAs, only clozapine has a substantial body of evidence to support its association with decreased smoking behavior.

Managing COPD.

• Educate the patient and family about risk factors associated with COPD and smoking.
• Screen for tobacco use at each visit; try to increase motivation to quit smoking.
• Educate the patients and family about the value and availability of smoking cessation programs.
• Prescribe medication to help with smoking cessation when needed. Bupropion and varenicline have been shown to be effective in patients with schizophrenia; nicotine replacement therapies are safe and can be helpful.
• When treating a patient who is in the process of quitting, encourage and help him to maintain his commitment and enlist support from his family.
• Refer to an appropriate medical provider (primary care provider or pulmonologist) for a patient with an established or suspected diagnosis of COPD.

Cancer
Since 1909, when the Board of Control of the Commissioners in Lunacy for England and Wales noted the possibility of a decreased incidence in cancer among psychiatric patients, this connection has been a matter of controversy.²⁶ Subsequent research has been equivocal; the prevalence of cancer has been reported to be either increased, similar, or decreased compared with the general population.^26-28 Risk factors for cancer, including smoking, obesity, poor diet, sedentary lifestyle, and hyperprolactinemia, are more common among patients with schizophrenia.

Genetic factors and a possible protective effect from antipsychotics have been cited as potential causes of decreased prevalence. Clozapine is associated with an increased risk of leukemia. No conclusion can be drawn about the overall prevalence of cancer in schizophrenia.

Managing cancer in a patient with schizophrenia, however, poses a significant challenge²⁹; he might lack capacity to make decisions about cancer treatment. The patient—or his surrogate decision-makers—need to carefully weigh current quality of life against potential benefits of treatment and risks of side effects. Adherence to complex, often toxic, therapies can be challenging for the patient with psychosis. Successful cancer treatment often requires close collaboration between the cancer treatment team and the patient’s support system, including the treating psychiatrist and case management teams.

Bottom Line
Patients with schizophrenia are at higher risk of developing comorbid medical
conditions because of the illness itself, lifestyle behaviors, genetics, and adverse
effects of medications. Because mental health clinicians focus attention on the
psychiatric and behavioral aspect of treatment, often there is delay in screening,
detecting, and treating medical comorbidities. This screening can be done in any
psychiatric practice, which can lead to timely management for those conditions
and preventing premature mortality in patients with schizophrenia.

Life expectancy for both males and females has been increasing over the past several decades to an average of 76 years. However, the life expectancy among individuals with schizophrenia in the United States is 61 years—a 20% reduction.¹ Patients with schizophrenia are known to be at increased risk of several comorbid medical conditions, such as type 2 diabetes mellitus (T2DM), coronary artery disease, and digestive and liver disorders, compared with healthy people (Figure, page 32).^2-5 This risk may be heightened by several factors, including sedentary lifestyle, a high rate of cigarette use, poor self-management skills, homelessness, and poor diet. 

Although substantial attention is paid to the psychiatric and behavioral management of schizophrenia, many barriers impede the detection and treatment of patients’ medical conditions, which have been implicated in excess unforeseen deaths. Patients with schizophrenia might experience delays in diagnosis, leading to more acute comorbidity at time of diagnosis and premature mortality

Cardiovascular disease is the leading cause of death among psychiatric patients.⁶ Key risk factors for cardiovascular disease include smoking, obesity, hypertension, dyslipidemia, diabetes, and lack of physical activity, all of which are more prevalent among patients with schizophrenia.⁷ In addition, antipsychotics are associated with adverse metabolic effects.⁸ In general, smoking and obesity are the most modifiable and preventable risk factors for many medical conditions, such as cardiovascular disease, hyperlipidemia, diabetes, and many forms of cancer (Table 1).

In this article, we discuss how to manage common medical comorbidities in patients with schizophrenia. Comprehensive management for all these medical conditions in this population is beyond the scope of this article; we limit ourselves to discussing (1) how common these conditions are in patients with schizophrenia compared with the general population and (2) what can be done in psychiatric practice to manage these medical comorbidities (Box).

Obesity
Obesity—defined as body mass index (BMI) of >30—is common among patients with schizophrenia. The condition leads to poor self-image, decreased treatment adherence, and an increased risk of many chronic medical conditions (Table 1). Being overweight or obese can increase stigma and social discrimination, which will undermine self-esteem and, in turn, affect adherence with medications, leading to relapse.

The prevalence of obesity among patients with schizophrenia is almost double that of the general population⁹ (Figure^2-5). Several factors predispose these patients to overweight or obese, including sedentary lifestyle, lack of exercise, a high-fat diet, medications side effects, and genetic factors. Recent studies report the incidence of weight gain among patients treated with antipsychotics is as high as 80%¹⁰ (Table 2).

Mechanisms involved in antipsychotic-induced weight gain are not completely understood, but antagonism of serotonergic (5-HT2C, 5-HT1A), histamine (H1), dopamine (D2), muscarinic, and other receptors are involved in modulation of food intake. Decreased energy expenditure also has been blamed for antipsychotic-induced weight gain.¹⁰

Pharmacotherapy and bariatric surgery can be as effective among patients with schizophrenia as they are among the general population. Maintaining a BMI of <25 kg/m² lowers the risk of cardiovascular disease by 35% to 55%.⁶ Metformin has modest potential for offsetting weight gain and providing some metabolic control in overweight outpatients with schizophrenia,¹¹ and should be considered early when treating at-risk patients.

Managing obesity. Clinicians can apply several measures to manage obesity in a patient with schizophrenia:

• Educate the patient, and the family, about the risks of being overweight or obese.
• Monitor weight and BMI at each visit.
• Advise smoking cessation.
• When clinically appropriate, switch to an antipsychotic with a lower risk of weight gain—eg, from olanzapine or high-dose quetiapine to a high- or medium-potency typical antipsychotic (eg, haloperidol, perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2, page 36).
• Consider prophylactic use of metformin with an antipsychotic; the drug has modest potential for offsetting weight gain and providing better metabolic control in an overweight patient with schizophrenia.¹¹
• Encourage the patient to engage in modest physical activity; for example, a 20-minute walk, every day, reduces the risk of cardiovascular disease by 35% to 55%.⁶
• Recommend a formal lifestyle modification program, such as behavioral group-based treatment for weight reduction.¹²
• Refer the patient and family to a dietitian.

Type 2 diabetes mellitus
There is strong association between T2DM and schizophrenia that is related to abnormal glucose regulation independent of any adverse medication effect.¹³ Ryan et al¹⁴ reported that first-episode, drug-naïve patients with schizophrenia had a higher level of intra-abdominal fat than age- and BMI-matched healthy controls, suggesting that schizophrenia could be associated with changes in adiposity that might increase the risk of insulin resistance, hyperlipidemia, and dyslipidemia. Mechanisms that increase the risk of T2DM in schizophrenia include genetic and environmental factors, such as family history, lack of physical activity, and poor diet.

Diagnosis. All patients with schizophrenia should be evaluated for undiagnosed diabetes. The diagnosis of T2DM is made by documenting:

• a fasting plasma glucose reading of ≥126 mg/dL
• symptoms of T2DM, along with a random plasma glucose reading of ≥200 mg/dL
• 2-hour reading of a plasma glucose level >200 mg/dL on an oral glucose tolerance test.

Recent guidelines also suggest using a hemoglobin A_1c value cutoff of ≥6.5% to diagnose T2DM.

In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, 38% of patients with schizophrenia and diabetes were not receiving any treatment for T2DM.¹⁵

Risk factors for T2DM are:

• BMI >25
• a first-degree relative with diabetes
• lack of physical activity
• being a member of a high-risk ethnic group (African American, Hispanic American, Native American, Asian American, or Pacific Islander)
• having delivered a baby >9 lb or having had gestational diabetes
• hypertension
• high-density lipoprotein (HDL) cholesterol level of ≤35 mg/dL
• triglyceride level of ≥250 mg/dL
• history of an abnormal glucose tolerance test
• history of abnormal findings on a fasting plasma glucose test
• history of vascular disease.

Early detection and management.

• Educate the patient and family about signs and symptoms of T2DM, such as polyuria, nocturia, polydipsia, fatigue, visual disturbances, and (in women) vulvitis. Also, psychiatrists should be aware of, and inquire about, symptoms of diabetic ketoacidosis.
• At the start of therapy with any antipsychotic, particularly a second-generation antipsychotic (SGA), ask patients about a family history of diabetes and measure the hemoglobin A_1c value.
• Monitor the hemoglobin A_1c level 4 months after starting an antipsychotic, then annually, in a patient with significant risk factors for diabetes.
• Monitor blood glucose every 6 months in patients with no change from initial results and more frequently in those with significant risk factors for diabetes and those who gain weight.
• Order a lipid panel and measure the serum glucose level to rule out dyslipidemia and diabetes, because a patient with high lipid levels and diabetes is at higher risk of developing cardiovascular conditions.
• Advocate for smoking cessation.
• Switch to an antipsychotic with a lower risk of diabetes when clinically appropriate, such as switching a patient from olanzapine or high-dose quetiapine to a high- or medium-potency typical antipsychotic (such as haloperidol or perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2).
• Consider prophylactic use of metformin along with antipsychotics. Metformin has been used to improve insulin sensitivity and can lead to weight loss in diabetic and non-diabetic patients. The drug has modest potential for offsetting weight gain and providing better metabolic control in overweight outpatients with schizophrenia.¹¹ Metformin is simple to use, does not lead to hypoglycemia, does not require serum glucose monitoring, and has a favorable safety profile.¹¹
• Educate the patient about modest physical activity. For example, a 20-minute walk every day reduces the risk of cardiovascular disease by 35% to 55%.⁶
• Refer the patient to a dietitian to develop an appropriate diet plan.
• When diabetes is diagnosed, ensure appropriate follow-up and initiation or continuation of therapy with a general practitioner or an endocrinologist.
• Reinforce the need for ongoing follow-up and compliance with therapy for diabetes.

Hyperlipidemia and dyslipidemia
Elevated cholesterol and triglyceride levels are associated with cardiovascular diseases, such as ischemic heart disease and myocardial infarction. A 10% increase in cholesterol levels is associated with a 20% to 30% increase in the risk of coronary artery disease; lowering cholesterol by 10% decreases the risk by 20% to 30%.¹⁶ Triglyceride levels ≥250 mg/dL are associated with 2-fold higher risk of cardiovascular disease.¹⁶

The incidence of dyslipidemia is not as well studied as diabetes in patients with schizophrenia. There is increased prevalence of dyslipidemia in patients with schizophrenia compared with the general population because of obesity, lack of physical activity, and poor dietary habits.¹⁶

Data regarding the effects of first-generation antipsychotics (FGAs) on lipid levels are limited, but high-potency drugs, such as haloperidol, seem to carry a lower risk of hyperlipidemia than low-potency drugs, such as chlorpromazine and thioridazine.¹⁷ A comprehensive review on the effects of SGAs on plasma lipid levels suggested that clozapine, olanzapine, and quetiapine are associated with a higher risk of dyslipidemia¹⁷ (Table 2).

In the CATIE study, olanzapine and clozapine were associated with a greater increase in the serum level of cholesterol and triglycerides compared with other antipsychotics, even after adjusting for treatment duration. Furthermore, a retrospective chart review of patients who switched to aripiprazole from other SGAs showed a decrease in levels of total cholesterol and low-density lipoprotein cholesterol¹⁵ (Table 2).

Patients with schizophrenia are more likely to have dyslipidemia go undiagnosed, and therefore are less likely to be treated for the disorder. In the CATIE study, 88% of patients with dyslipidemia were not receiving any treatment.¹⁵

Management for dyslipidemia.

• Educate the patient and family about risks involved with dyslipidemia.
• Monitor weight and BMI at each visit.
• Monitor lipids to rule out dyslipidemia. Obtain a pretreatment fasting or random lipid profile for any patient receiving an antipsychotic; repeat at least every 6 months after starting the antipsychotic.
• Counsel the patient to quit smoking.
• Switch to an antipsychotic with lower risk of weight gain and dyslipidemia, such as switching from olanzapine or high-dose quetiapine to high- or medium-potency typical antipsychotics (such as, haloperidol or perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2).
• Educate and encourage the patient about modest physical activity. For example, a 20-minute walk everyday will reduce cardiovascular disease risk by 35% to 55%.⁶
• Refer to a dietitian if indicated.
• Ensure follow-up and initiation of treatment with a general practitioner.
• Educate and encourage the patient about modest physical activity. For example, a 20-minute walk everyday will reduce cardiovascular disease risk by 35% to 55%.

Metabolic syndrome
Metabolic syndrome is cluster of cardiovascular risk factors, including central adiposity, hyperglycemia, dyslipidemia, and hypertension. The National Cholesterol Education Program’s Adult Treatment Panel III report defines metabolic syndrome as the presence of 3 of 5 of the following factors:

• abdominal obesity (waist circumference of >40 inches in men, or >35 inches in women)
• triglyceride level, >150 mg/dL
• HDL cholesterol, <40 mg/dL in men and <50 mg/dL in women
• blood pressure, >130/85 mm Hg
• fasting plasma glucose level, >110 mg/dL.

The presence of metabolic syndrome in the general population is a strong predictor of cardiovascular diseases and diabetes.¹⁸ The adverse effects of metabolic syndrome are thought to relate to atherogenic dyslipidemia, higher blood pressure, insulin resistance with or without glucose intolerance, a proinflammatory state, and a prothrombotic state.

The prevalence of metabolic syndrome in patients with schizophrenia is 2- to 3-fold higher than the general population.¹⁹ In the CATIE study, approximately one-third of patients met criteria for metabolic syndrome at baseline.¹⁵ In a prospective study, De Hert et al²⁰ reported that patients who were started on a SGA had more than twice the rate of developing metabolic syndrome compared with those treated with a FGA (Table 2). Other possible causes of metabolic syndrome are visceral adiposity and insulin resistance.¹⁶Management of the metabolic syndrome involves addressing the individual components that have been described in the preceding sections on T2DM and dyslipidemia.

Hepatitis C
Hepatitis C virus (HCV) infection is thought to be the most common blood-borne illness, with an estimated prevalence of 1% of the U.S. population. Some studies suggest that as many as 16% of people with schizophrenia have HCV infection.⁴ Risk factors for HCV infection include unsafe sexual practices, prostitution, homosexuality, homelessness, and IV drug use.

HCV treatments typically have involved regimens with interferon alfa, which is associated with significant neuropsychiatric side effects, including depression and suicide. There is a dearth of research on treatment of HCV in patients with schizophrenia; however, at least 1 study suggests that there was no increase in psychiatric symptoms in patients treated with interferon-containing regimens.²¹ There is even less evidence to guide the use of newer, non-interferon–based HCV treatment regimens that are better tolerated and have a higher response rate in the general population; there is reason, however, to be hopeful about their potential in patients with schizophrenia and HCV infection.

Managing HCV infection.

• Educate the patients and family about risk factors associated with contracting HCV.
• Screen for HCV infection in patients with schizophrenia because there is higher prevalence of HCV in these patients compared with the general population.
• When HCV infection is diagnosed, educate the patients and family about available treatments.
• Facilitate referral to an HCV specialist for appropriate treatment.

HIV/AIDS
HIV infection is highly prevalent among people suffering from severe mental illness such as schizophrenia. The incidence of HIV/AIDS in patients with schizophrenia is estimated to be 4% to 23%, compared with 0.6% in the general population.²² Risk factors associated with a higher incidence of HIV/AIDS in patients with schizophrenia are lack of knowledge about contracting HIV, unsafe sexual practices, prostitution, homosexuality, homelessness, and IV drug use.²²

Managing HIV/AIDS.

• Educate the patient and family about risk factors associated with contracting HIV/AIDS.
• Educate patients about safe sex practices.
• All patients with schizophrenia should be screened for HIV because there is 10-fold higher HIV prevalence in schizophrenia compared with the general population.
• When HIV infection is diagnosed, facilitate referral to a HIV or infectious disease specialist for treatment.
• Educate the patient in whom HIV/AIDS has been diagnosed about the importance of (1) adherence to his (her) HIV medication regimen and (2) follow-up visits with an infectious disease practitioner and appropriate laboratory tests.
• Educate the patient’s family and significant other about the illness.
• Screen for and treat substance use.
• At each visit, inquire about the patient’s adherence to HIV medical therapy, viral load, and CD4 cell count.

Chronic obstructive pulmonary disease
Patients with schizophrenia are more likely to suffer from respiratory disease, such as chronic obstructive pulmonary disease (COPD) and asthma, compared with the general population.²³ Smoking is a major risk factor for COPD. In a study by Dickerson et al,²⁴ 64% of people with schizophrenia were current smokers, compared with 19% of those without mental illness.

A high rate of smoking rate among people with schizophrenia suggests a “self-medication” hypothesis: That is, stimulation of CNS nicotinic cholinergic receptors treats the negative symptoms of schizophrenia and overcomes the dopamine blocking effects of antipsychotics.²⁵ Among SGAs, only clozapine has a substantial body of evidence to support its association with decreased smoking behavior.

Managing COPD.

• Educate the patient and family about risk factors associated with COPD and smoking.
• Screen for tobacco use at each visit; try to increase motivation to quit smoking.
• Educate the patients and family about the value and availability of smoking cessation programs.
• Prescribe medication to help with smoking cessation when needed. Bupropion and varenicline have been shown to be effective in patients with schizophrenia; nicotine replacement therapies are safe and can be helpful.
• When treating a patient who is in the process of quitting, encourage and help him to maintain his commitment and enlist support from his family.
• Refer to an appropriate medical provider (primary care provider or pulmonologist) for a patient with an established or suspected diagnosis of COPD.

Cancer
Since 1909, when the Board of Control of the Commissioners in Lunacy for England and Wales noted the possibility of a decreased incidence in cancer among psychiatric patients, this connection has been a matter of controversy.²⁶ Subsequent research has been equivocal; the prevalence of cancer has been reported to be either increased, similar, or decreased compared with the general population.^26-28 Risk factors for cancer, including smoking, obesity, poor diet, sedentary lifestyle, and hyperprolactinemia, are more common among patients with schizophrenia.

Genetic factors and a possible protective effect from antipsychotics have been cited as potential causes of decreased prevalence. Clozapine is associated with an increased risk of leukemia. No conclusion can be drawn about the overall prevalence of cancer in schizophrenia.

Managing cancer in a patient with schizophrenia, however, poses a significant challenge²⁹; he might lack capacity to make decisions about cancer treatment. The patient—or his surrogate decision-makers—need to carefully weigh current quality of life against potential benefits of treatment and risks of side effects. Adherence to complex, often toxic, therapies can be challenging for the patient with psychosis. Successful cancer treatment often requires close collaboration between the cancer treatment team and the patient’s support system, including the treating psychiatrist and case management teams.

Bottom Line
Patients with schizophrenia are at higher risk of developing comorbid medical
conditions because of the illness itself, lifestyle behaviors, genetics, and adverse
effects of medications. Because mental health clinicians focus attention on the
psychiatric and behavioral aspect of treatment, often there is delay in screening,
detecting, and treating medical comorbidities. This screening can be done in any
psychiatric practice, which can lead to timely management for those conditions
and preventing premature mortality in patients with schizophrenia.

Patients who have chronic pain and those with a major depressive disorder (MDD) share clinical features, including fatigue, cognitive complaints, and functional limitation. Sleep disturbance and anxiety are common with both disorders. Because pain and depression share common neurobiological pathways (see Part 1 of this article in the February 2016 issue and at CurrentPsychiatry.com) and clinical manifestations, you can use similar strategies and, often, the same agents to treat both conditions when they occur together (Table 1).

What are the medical options?
Antidepressants. Using an antidepressant to treat chronic pain is a common practice in primary care and specialty practice. Antidepressants that modulate multiple neurotransmitters appear to be more efficacious than those with a single mechanism of action.¹ Convergent evidence from preclinical and clinical studies supports the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) as more effective analgesic agents, compared with the mostly noradrenergic antidepressants, which, in turn, are more effective than selective serotonin reuptake inhibitors (SSRIs).² The mechanism of the analgesic action of antidepressants appears to rely on their inhibitory effects of norepinephrine and serotonin reuptake, thereby elevating the performance of endogenous descending pain regulatory pathways.³

Tricyclic antidepressants (TCAs), primarily amitriptyline, nortriptyline, and desipramine, have the advantage of years of clinical experience and low cost. Their side effect burden, however, is higher, especially in geriatric patients. Dose-dependent side effects include sedation, constipation, dry mouth, urinary retention, and orthostatic hypotension.

TCAs must be used with caution in patients with suicidal ideation because of the risk of a potentially lethal intentional overdose.

The key to using a TCA is to start with a low dosage, followed by slow titration. Typically, the dosages of TCAs used in clinical trials that focused on pain have been lower (25 to 100 mg/d of amitriptyline or equivalent) than the dosage typically necessary for treating depression; however, some experts have found that titrating TCAs to higher dosages with an option of monitoring serum levels may benefit some patients.⁴

SNRIs are considered first-line agents for both neuropathic pain and fibromyalgia. Duloxetine has been shown to be effective in both conditions⁵; venlafaxine also has shown efficacy in neuropathic pain.⁶ Milnacipran, another SNRI that blocks 5-HT, and norepinephrine equally and exerts a mild N-methyl-D-aspartate inhibition, has proven efficacy in fibromyalgia.^7,8

SSRIs for alleviating central pain or neuropathic pain are supported by minimal evidence only.⁹ A review of the effectiveness of various antidepressants on pain in diabetic neuropathy concluded that fluoxetine was no more effective than placebo.^10,11 Schreiber and Pick¹¹ evaluated the antinociceptive properties of several SSRIs and offered the opinion that fluoxetine, fluvoxamine, and citalopram were, at best, weak antinociceptors.

Opioids. Data on the long-term benefits of opioids are limited, except for use in carefully selected patients; in any case, risk of abuse, diversion, and even death with these agents is quite high.¹² Also, there is evidence that opioid-induced hyperalgesia might limit the usefulness of opioids for controlling chronic pain.¹³

Gabapentin and pregabalin, both anticonvulsants, act by binding to the α-2-σ subunit of voltage-gated calcium channels within the CNS.¹⁴ By reducing calcium influx at nerve terminals, the drugs diminish the release of several neurotransmitters, including glutamate, noradrenaline, and substance P. This mechanism is thought to be the basis for the analgesic, anticonvulsant, and anxiolytic effects of these drugs.¹⁵

Gabapentin and pregabalin have been shown to decrease pain intensity and improve quality of life and function in patients with neuropathic pain conditions. Pregabalin also has shown efficacy in treating central neuropathic pain and fibromyalgia.¹⁶

Added benefits of these drugs is that they have (1) a better side effect profile than TCAs and (2) fewer drug interactions when they are used as a component of combination therapy. Pregabalin has the additional advantage of less-frequent dosing, linear pharmacokinetics, and a predictable dose-response relationship.¹⁷

Addressing other comorbid psychiatric conditions
Sleep disturbance is common among patients with chronic pain. Sleep deprivation causes a hyperexcitable state that amplifies the pain response.¹⁸

When a patient presents with chronic pain, depression, and disturbed sleep, consider using a sedating antidepressant, such as a TCA. Alternatively, gabapentin or pregabalin can be added to an SNRI; anticonvulsants have been shown to improve quality of sleep.¹⁹ Cognitive-behavioral interventions targeting sleep disturbance may be a helpful adjunct in these patients.²⁰

When anxiety is comorbid with chronic pain, antidepressants with proven efficacy in treating anxiety disorders, such as duloxetine or venlafaxine, can be used. When chronic pain coexists with a specific anxiety disorder (social anxiety disorder, obsessive-compulsive disorder, panic disorder), an SSRI might be more advantageous than an SNRI,²¹ especially if it is combined with a more efficacious analgesic.

Benzodiazepines should be avoided as a routine treatment for comorbid anxiety and pain, because these agents can produce sedation and cognitive interference, and carry the potential for dependence.

Fatigue. In patients who, in addition to pain and depression, complain of fatigue, an activating agent such as milnacipran or adjunct bupropion might be preferable to other agents. Modafinil has been shown to be a well-tolerated and potentially effective augmenting agent for antidepressants when fatigue and sleepiness are present as residual symptoms²²; consider them as adjuncts when managing patients who have chronic pain and depression that manifests as excessive sleepiness and/or fatigue.

Cognitive complaints. We have noted that disturbances of cognition are common in patients with depression and chronic pain, and that cognitive dysfunction might improve after antidepressant treatment.

Studies suggest that SSRIs, duloxetine, and other antidepressants, such as bupropion, might exert a positive effect on learning, memory, and executive function in depressed patients.²³ Beneficial effects of antidepressants may be “pseudo-specific,” however—that is, predominantly a reflection of overall improvement in mood, not on specific amelioration of the cognitive disturbance.

Vortioxetine has shown promise in improving cognitive function in adults with MDD; its cognitive benefits are largely independent of its antidepressant effect.²⁴ The utility of vortioxetine in chronic pain patients has not been studied, but its positive impact on mood, anxiety, sleep, and cognition might make it a consideration for patients with comorbid depression—although it is uncertain at this time whether putative noradrenergic activity makes it suitable for use in chronic pain disorders.

Last, avoid TCAs in patients who have cognitive complaints. These agents have anticholinergic effects that can have an adverse impact on cognitive function.

Cautions: Drug−drug interactions, suicide risk, disrupted sleep
Avoiding drug−drug interactions is an important consideration when treating comorbid disorders. Many chronic pain patients take over-the-counter or prescribed nonsteroidal anti-inflammatory drugs for analgesia; these agents can increase the risk of gastrointestinal bleeding when they are combined with an SSRI or an SNRI.

The use of the opioid tramadol with an SNRI or a TCA is discouraged because of the risk of serotonin syndrome.

Combining a sedating antidepressant, such as a TCA, with gabapentin or pregabalin can increase the risk of CNS depression and psychomotor impairment, especially in geriatric patients. An opioid analgesic is likely to amplify these effects.

Suicidal ideation is not uncommon in patients with chronic pain and depression. To minimize the risk of suicide in patients with a chronic pain disorder, you should ensure optimal pain control by combining the most efficacious analgesic agent with psychotherapeutic interventions and optimal antidepressant treatment. Furthermore, cognitive-behavioral therapy (CBT) (see the discussion below) might not only improve pain coping skills, but also ameliorate catastrophizing, anxiety, and concomitant sleep disturbance.

Complaints of sleep disturbance and anxiety can compound the risk of suicide in a chronic pain patient. When possible, these complex patients should be treated by a multidisciplinary team that includes a pain management specialist, psychotherapist, and primary care clinician. It is important to strengthen the clinician−patient relationship to facilitate close monitoring of symptoms and to provide a trusting environment in which patients feel free to discuss thoughts of suicide or self-harm. For such patients, prescribing opiates and TCAs in small quantities is a prudent action.

When a patient struggles with suicidal thoughts, his (her) family might need to dispense these medications. Most important, if a patient is actively suicidal, consider referral to an inpatient facility or intensive outpatient program, where aggressive treatment of depressive symptoms and intensive monitoring and support can be provided.²⁵

Usefulness of non-drug interventions
There is, of course, a diversity of non-drug treatments for MDD and for chronic pain; discussion here focuses primarily on modalities with established efficacy in both disease states (Table 2). On rare occasions, non-drug treatments can constitute a stand-alone approach; most often, they are incorporated into a multimodal treatment plan or applied as an adjunct intervention.²⁶

Psychotherapy. The most robust evidence supports the use of CBT in addressing MDD and chronic pain—occurring individually and comorbidly.^26-28 Efficacy is well established in MDD, as monotherapy and adjunct treatment, spanning acute and maintenance phases.

Furthermore, CBT also has support from randomized trials, meta-analyses, and treatment guidelines, either as monotherapy or co-therapy for both short-term relief and long-term pain reduction. Additionally, CBT has demonstrated value for relieving pain-related disability.^26,28

Combination of a special form of CBT, rumination-focused CBT with ongoing pharmacological therapy over a 26-week period in a group of medication-refractory MDD patients produced a remission rate of 62%, compared with 21% in a treatment-as-usual group.²⁹ This is of particular interest in chronic pain patients, because rumination-related phenomena of pain catastrophizing and avoidance facilitate a transition from acute to chronic pain, while augmenting pain severity and associated disability.³⁰

Catastrophizing also has been implicated in mediating the relationship between pain and sleep disturbance. Not surprisingly, a randomized controlled study demonstrated the benefit of 8-week, Internet-delivered CBT in patients suffering from comorbid chronic pain, depression, and anxiety. Treatment significantly diminished pain catastrophizing, depression, and anxiety; maintenance of improvement was demonstrated after 1 year of follow-up.³¹

Other behavioral and psychological approaches. Biofeedback, mindfulness-based stress reduction, relaxation training and diaphragmatic breathing, guided imagery, hypnosis, and supportive groups might play an important role as components of an integrated mind−body approach to chronic pain,^28,32,33 while also providing mood benefits.

Exercise. The role of exercise as a primary treatment of MDD continues to be controversial, but its benefits as an add-on intervention are indisputable. Exercise not only complements pharmacotherapy to produce greater reduction in depressive scores and improvement in quality of life, it might aid in reestablishing social contacts when conducted in a group setting—an effect that can be of great value in both MDD and chronic pain.³⁴

Exercise and restorative therapies provide several benefits for chronic pain patients, including:

• improved pain control, cognition, and mood
• greater strength and endurance
• cardiovascular and metabolic benefits
• improved bone health and functionality.^{26,28,32,33,35}

To achieve optimal benefit, an exercise program must be customized to fit the patient’s physical condition, level of fitness, and specific type of pain.³⁵ Preliminary evidence suggests that, beyond improvement in pain and functionality, exercise might reduce depressive symptoms in chronic pain patients.³⁶

Patients who have chronic pain and those with a major depressive disorder (MDD) share clinical features, including fatigue, cognitive complaints, and functional limitation. Sleep disturbance and anxiety are common with both disorders. Because pain and depression share common neurobiological pathways (see Part 1 of this article in the February 2016 issue and at CurrentPsychiatry.com) and clinical manifestations, you can use similar strategies and, often, the same agents to treat both conditions when they occur together (Table 1).

What are the medical options?
Antidepressants. Using an antidepressant to treat chronic pain is a common practice in primary care and specialty practice. Antidepressants that modulate multiple neurotransmitters appear to be more efficacious than those with a single mechanism of action.¹ Convergent evidence from preclinical and clinical studies supports the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) as more effective analgesic agents, compared with the mostly noradrenergic antidepressants, which, in turn, are more effective than selective serotonin reuptake inhibitors (SSRIs).² The mechanism of the analgesic action of antidepressants appears to rely on their inhibitory effects of norepinephrine and serotonin reuptake, thereby elevating the performance of endogenous descending pain regulatory pathways.³

Tricyclic antidepressants (TCAs), primarily amitriptyline, nortriptyline, and desipramine, have the advantage of years of clinical experience and low cost. Their side effect burden, however, is higher, especially in geriatric patients. Dose-dependent side effects include sedation, constipation, dry mouth, urinary retention, and orthostatic hypotension.

TCAs must be used with caution in patients with suicidal ideation because of the risk of a potentially lethal intentional overdose.

The key to using a TCA is to start with a low dosage, followed by slow titration. Typically, the dosages of TCAs used in clinical trials that focused on pain have been lower (25 to 100 mg/d of amitriptyline or equivalent) than the dosage typically necessary for treating depression; however, some experts have found that titrating TCAs to higher dosages with an option of monitoring serum levels may benefit some patients.⁴

SNRIs are considered first-line agents for both neuropathic pain and fibromyalgia. Duloxetine has been shown to be effective in both conditions⁵; venlafaxine also has shown efficacy in neuropathic pain.⁶ Milnacipran, another SNRI that blocks 5-HT, and norepinephrine equally and exerts a mild N-methyl-D-aspartate inhibition, has proven efficacy in fibromyalgia.^7,8

SSRIs for alleviating central pain or neuropathic pain are supported by minimal evidence only.⁹ A review of the effectiveness of various antidepressants on pain in diabetic neuropathy concluded that fluoxetine was no more effective than placebo.^10,11 Schreiber and Pick¹¹ evaluated the antinociceptive properties of several SSRIs and offered the opinion that fluoxetine, fluvoxamine, and citalopram were, at best, weak antinociceptors.

Opioids. Data on the long-term benefits of opioids are limited, except for use in carefully selected patients; in any case, risk of abuse, diversion, and even death with these agents is quite high.¹² Also, there is evidence that opioid-induced hyperalgesia might limit the usefulness of opioids for controlling chronic pain.¹³

Gabapentin and pregabalin, both anticonvulsants, act by binding to the α-2-σ subunit of voltage-gated calcium channels within the CNS.¹⁴ By reducing calcium influx at nerve terminals, the drugs diminish the release of several neurotransmitters, including glutamate, noradrenaline, and substance P. This mechanism is thought to be the basis for the analgesic, anticonvulsant, and anxiolytic effects of these drugs.¹⁵

Gabapentin and pregabalin have been shown to decrease pain intensity and improve quality of life and function in patients with neuropathic pain conditions. Pregabalin also has shown efficacy in treating central neuropathic pain and fibromyalgia.¹⁶

Added benefits of these drugs is that they have (1) a better side effect profile than TCAs and (2) fewer drug interactions when they are used as a component of combination therapy. Pregabalin has the additional advantage of less-frequent dosing, linear pharmacokinetics, and a predictable dose-response relationship.¹⁷

Addressing other comorbid psychiatric conditions
Sleep disturbance is common among patients with chronic pain. Sleep deprivation causes a hyperexcitable state that amplifies the pain response.¹⁸

When a patient presents with chronic pain, depression, and disturbed sleep, consider using a sedating antidepressant, such as a TCA. Alternatively, gabapentin or pregabalin can be added to an SNRI; anticonvulsants have been shown to improve quality of sleep.¹⁹ Cognitive-behavioral interventions targeting sleep disturbance may be a helpful adjunct in these patients.²⁰

When anxiety is comorbid with chronic pain, antidepressants with proven efficacy in treating anxiety disorders, such as duloxetine or venlafaxine, can be used. When chronic pain coexists with a specific anxiety disorder (social anxiety disorder, obsessive-compulsive disorder, panic disorder), an SSRI might be more advantageous than an SNRI,²¹ especially if it is combined with a more efficacious analgesic.

Benzodiazepines should be avoided as a routine treatment for comorbid anxiety and pain, because these agents can produce sedation and cognitive interference, and carry the potential for dependence.

Fatigue. In patients who, in addition to pain and depression, complain of fatigue, an activating agent such as milnacipran or adjunct bupropion might be preferable to other agents. Modafinil has been shown to be a well-tolerated and potentially effective augmenting agent for antidepressants when fatigue and sleepiness are present as residual symptoms²²; consider them as adjuncts when managing patients who have chronic pain and depression that manifests as excessive sleepiness and/or fatigue.

Cognitive complaints. We have noted that disturbances of cognition are common in patients with depression and chronic pain, and that cognitive dysfunction might improve after antidepressant treatment.

Studies suggest that SSRIs, duloxetine, and other antidepressants, such as bupropion, might exert a positive effect on learning, memory, and executive function in depressed patients.²³ Beneficial effects of antidepressants may be “pseudo-specific,” however—that is, predominantly a reflection of overall improvement in mood, not on specific amelioration of the cognitive disturbance.

Vortioxetine has shown promise in improving cognitive function in adults with MDD; its cognitive benefits are largely independent of its antidepressant effect.²⁴ The utility of vortioxetine in chronic pain patients has not been studied, but its positive impact on mood, anxiety, sleep, and cognition might make it a consideration for patients with comorbid depression—although it is uncertain at this time whether putative noradrenergic activity makes it suitable for use in chronic pain disorders.

Last, avoid TCAs in patients who have cognitive complaints. These agents have anticholinergic effects that can have an adverse impact on cognitive function.

Cautions: Drug−drug interactions, suicide risk, disrupted sleep
Avoiding drug−drug interactions is an important consideration when treating comorbid disorders. Many chronic pain patients take over-the-counter or prescribed nonsteroidal anti-inflammatory drugs for analgesia; these agents can increase the risk of gastrointestinal bleeding when they are combined with an SSRI or an SNRI.

The use of the opioid tramadol with an SNRI or a TCA is discouraged because of the risk of serotonin syndrome.

Combining a sedating antidepressant, such as a TCA, with gabapentin or pregabalin can increase the risk of CNS depression and psychomotor impairment, especially in geriatric patients. An opioid analgesic is likely to amplify these effects.

Suicidal ideation is not uncommon in patients with chronic pain and depression. To minimize the risk of suicide in patients with a chronic pain disorder, you should ensure optimal pain control by combining the most efficacious analgesic agent with psychotherapeutic interventions and optimal antidepressant treatment. Furthermore, cognitive-behavioral therapy (CBT) (see the discussion below) might not only improve pain coping skills, but also ameliorate catastrophizing, anxiety, and concomitant sleep disturbance.

Complaints of sleep disturbance and anxiety can compound the risk of suicide in a chronic pain patient. When possible, these complex patients should be treated by a multidisciplinary team that includes a pain management specialist, psychotherapist, and primary care clinician. It is important to strengthen the clinician−patient relationship to facilitate close monitoring of symptoms and to provide a trusting environment in which patients feel free to discuss thoughts of suicide or self-harm. For such patients, prescribing opiates and TCAs in small quantities is a prudent action.

When a patient struggles with suicidal thoughts, his (her) family might need to dispense these medications. Most important, if a patient is actively suicidal, consider referral to an inpatient facility or intensive outpatient program, where aggressive treatment of depressive symptoms and intensive monitoring and support can be provided.²⁵

Usefulness of non-drug interventions
There is, of course, a diversity of non-drug treatments for MDD and for chronic pain; discussion here focuses primarily on modalities with established efficacy in both disease states (Table 2). On rare occasions, non-drug treatments can constitute a stand-alone approach; most often, they are incorporated into a multimodal treatment plan or applied as an adjunct intervention.²⁶

Psychotherapy. The most robust evidence supports the use of CBT in addressing MDD and chronic pain—occurring individually and comorbidly.^26-28 Efficacy is well established in MDD, as monotherapy and adjunct treatment, spanning acute and maintenance phases.

Furthermore, CBT also has support from randomized trials, meta-analyses, and treatment guidelines, either as monotherapy or co-therapy for both short-term relief and long-term pain reduction. Additionally, CBT has demonstrated value for relieving pain-related disability.^26,28

Combination of a special form of CBT, rumination-focused CBT with ongoing pharmacological therapy over a 26-week period in a group of medication-refractory MDD patients produced a remission rate of 62%, compared with 21% in a treatment-as-usual group.²⁹ This is of particular interest in chronic pain patients, because rumination-related phenomena of pain catastrophizing and avoidance facilitate a transition from acute to chronic pain, while augmenting pain severity and associated disability.³⁰

Catastrophizing also has been implicated in mediating the relationship between pain and sleep disturbance. Not surprisingly, a randomized controlled study demonstrated the benefit of 8-week, Internet-delivered CBT in patients suffering from comorbid chronic pain, depression, and anxiety. Treatment significantly diminished pain catastrophizing, depression, and anxiety; maintenance of improvement was demonstrated after 1 year of follow-up.³¹

Other behavioral and psychological approaches. Biofeedback, mindfulness-based stress reduction, relaxation training and diaphragmatic breathing, guided imagery, hypnosis, and supportive groups might play an important role as components of an integrated mind−body approach to chronic pain,^28,32,33 while also providing mood benefits.

Exercise. The role of exercise as a primary treatment of MDD continues to be controversial, but its benefits as an add-on intervention are indisputable. Exercise not only complements pharmacotherapy to produce greater reduction in depressive scores and improvement in quality of life, it might aid in reestablishing social contacts when conducted in a group setting—an effect that can be of great value in both MDD and chronic pain.³⁴

Exercise and restorative therapies provide several benefits for chronic pain patients, including:

• improved pain control, cognition, and mood
• greater strength and endurance
• cardiovascular and metabolic benefits
• improved bone health and functionality.^{26,28,32,33,35}

To achieve optimal benefit, an exercise program must be customized to fit the patient’s physical condition, level of fitness, and specific type of pain.³⁵ Preliminary evidence suggests that, beyond improvement in pain and functionality, exercise might reduce depressive symptoms in chronic pain patients.³⁶

Patients who have chronic pain and those with a major depressive disorder (MDD) share clinical features, including fatigue, cognitive complaints, and functional limitation. Sleep disturbance and anxiety are common with both disorders. Because pain and depression share common neurobiological pathways (see Part 1 of this article in the February 2016 issue and at CurrentPsychiatry.com) and clinical manifestations, you can use similar strategies and, often, the same agents to treat both conditions when they occur together (Table 1).

What are the medical options?
Antidepressants. Using an antidepressant to treat chronic pain is a common practice in primary care and specialty practice. Antidepressants that modulate multiple neurotransmitters appear to be more efficacious than those with a single mechanism of action.¹ Convergent evidence from preclinical and clinical studies supports the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) as more effective analgesic agents, compared with the mostly noradrenergic antidepressants, which, in turn, are more effective than selective serotonin reuptake inhibitors (SSRIs).² The mechanism of the analgesic action of antidepressants appears to rely on their inhibitory effects of norepinephrine and serotonin reuptake, thereby elevating the performance of endogenous descending pain regulatory pathways.³

Tricyclic antidepressants (TCAs), primarily amitriptyline, nortriptyline, and desipramine, have the advantage of years of clinical experience and low cost. Their side effect burden, however, is higher, especially in geriatric patients. Dose-dependent side effects include sedation, constipation, dry mouth, urinary retention, and orthostatic hypotension.

TCAs must be used with caution in patients with suicidal ideation because of the risk of a potentially lethal intentional overdose.

The key to using a TCA is to start with a low dosage, followed by slow titration. Typically, the dosages of TCAs used in clinical trials that focused on pain have been lower (25 to 100 mg/d of amitriptyline or equivalent) than the dosage typically necessary for treating depression; however, some experts have found that titrating TCAs to higher dosages with an option of monitoring serum levels may benefit some patients.⁴

SNRIs are considered first-line agents for both neuropathic pain and fibromyalgia. Duloxetine has been shown to be effective in both conditions⁵; venlafaxine also has shown efficacy in neuropathic pain.⁶ Milnacipran, another SNRI that blocks 5-HT, and norepinephrine equally and exerts a mild N-methyl-D-aspartate inhibition, has proven efficacy in fibromyalgia.^7,8

SSRIs for alleviating central pain or neuropathic pain are supported by minimal evidence only.⁹ A review of the effectiveness of various antidepressants on pain in diabetic neuropathy concluded that fluoxetine was no more effective than placebo.^10,11 Schreiber and Pick¹¹ evaluated the antinociceptive properties of several SSRIs and offered the opinion that fluoxetine, fluvoxamine, and citalopram were, at best, weak antinociceptors.

Opioids. Data on the long-term benefits of opioids are limited, except for use in carefully selected patients; in any case, risk of abuse, diversion, and even death with these agents is quite high.¹² Also, there is evidence that opioid-induced hyperalgesia might limit the usefulness of opioids for controlling chronic pain.¹³

Gabapentin and pregabalin, both anticonvulsants, act by binding to the α-2-σ subunit of voltage-gated calcium channels within the CNS.¹⁴ By reducing calcium influx at nerve terminals, the drugs diminish the release of several neurotransmitters, including glutamate, noradrenaline, and substance P. This mechanism is thought to be the basis for the analgesic, anticonvulsant, and anxiolytic effects of these drugs.¹⁵

Gabapentin and pregabalin have been shown to decrease pain intensity and improve quality of life and function in patients with neuropathic pain conditions. Pregabalin also has shown efficacy in treating central neuropathic pain and fibromyalgia.¹⁶

Added benefits of these drugs is that they have (1) a better side effect profile than TCAs and (2) fewer drug interactions when they are used as a component of combination therapy. Pregabalin has the additional advantage of less-frequent dosing, linear pharmacokinetics, and a predictable dose-response relationship.¹⁷

Addressing other comorbid psychiatric conditions
Sleep disturbance is common among patients with chronic pain. Sleep deprivation causes a hyperexcitable state that amplifies the pain response.¹⁸

When a patient presents with chronic pain, depression, and disturbed sleep, consider using a sedating antidepressant, such as a TCA. Alternatively, gabapentin or pregabalin can be added to an SNRI; anticonvulsants have been shown to improve quality of sleep.¹⁹ Cognitive-behavioral interventions targeting sleep disturbance may be a helpful adjunct in these patients.²⁰

When anxiety is comorbid with chronic pain, antidepressants with proven efficacy in treating anxiety disorders, such as duloxetine or venlafaxine, can be used. When chronic pain coexists with a specific anxiety disorder (social anxiety disorder, obsessive-compulsive disorder, panic disorder), an SSRI might be more advantageous than an SNRI,²¹ especially if it is combined with a more efficacious analgesic.

Benzodiazepines should be avoided as a routine treatment for comorbid anxiety and pain, because these agents can produce sedation and cognitive interference, and carry the potential for dependence.

Fatigue. In patients who, in addition to pain and depression, complain of fatigue, an activating agent such as milnacipran or adjunct bupropion might be preferable to other agents. Modafinil has been shown to be a well-tolerated and potentially effective augmenting agent for antidepressants when fatigue and sleepiness are present as residual symptoms²²; consider them as adjuncts when managing patients who have chronic pain and depression that manifests as excessive sleepiness and/or fatigue.

Cognitive complaints. We have noted that disturbances of cognition are common in patients with depression and chronic pain, and that cognitive dysfunction might improve after antidepressant treatment.

Studies suggest that SSRIs, duloxetine, and other antidepressants, such as bupropion, might exert a positive effect on learning, memory, and executive function in depressed patients.²³ Beneficial effects of antidepressants may be “pseudo-specific,” however—that is, predominantly a reflection of overall improvement in mood, not on specific amelioration of the cognitive disturbance.

Vortioxetine has shown promise in improving cognitive function in adults with MDD; its cognitive benefits are largely independent of its antidepressant effect.²⁴ The utility of vortioxetine in chronic pain patients has not been studied, but its positive impact on mood, anxiety, sleep, and cognition might make it a consideration for patients with comorbid depression—although it is uncertain at this time whether putative noradrenergic activity makes it suitable for use in chronic pain disorders.

Last, avoid TCAs in patients who have cognitive complaints. These agents have anticholinergic effects that can have an adverse impact on cognitive function.

Cautions: Drug−drug interactions, suicide risk, disrupted sleep
Avoiding drug−drug interactions is an important consideration when treating comorbid disorders. Many chronic pain patients take over-the-counter or prescribed nonsteroidal anti-inflammatory drugs for analgesia; these agents can increase the risk of gastrointestinal bleeding when they are combined with an SSRI or an SNRI.

The use of the opioid tramadol with an SNRI or a TCA is discouraged because of the risk of serotonin syndrome.

Combining a sedating antidepressant, such as a TCA, with gabapentin or pregabalin can increase the risk of CNS depression and psychomotor impairment, especially in geriatric patients. An opioid analgesic is likely to amplify these effects.

Suicidal ideation is not uncommon in patients with chronic pain and depression. To minimize the risk of suicide in patients with a chronic pain disorder, you should ensure optimal pain control by combining the most efficacious analgesic agent with psychotherapeutic interventions and optimal antidepressant treatment. Furthermore, cognitive-behavioral therapy (CBT) (see the discussion below) might not only improve pain coping skills, but also ameliorate catastrophizing, anxiety, and concomitant sleep disturbance.

Complaints of sleep disturbance and anxiety can compound the risk of suicide in a chronic pain patient. When possible, these complex patients should be treated by a multidisciplinary team that includes a pain management specialist, psychotherapist, and primary care clinician. It is important to strengthen the clinician−patient relationship to facilitate close monitoring of symptoms and to provide a trusting environment in which patients feel free to discuss thoughts of suicide or self-harm. For such patients, prescribing opiates and TCAs in small quantities is a prudent action.

When a patient struggles with suicidal thoughts, his (her) family might need to dispense these medications. Most important, if a patient is actively suicidal, consider referral to an inpatient facility or intensive outpatient program, where aggressive treatment of depressive symptoms and intensive monitoring and support can be provided.²⁵

Usefulness of non-drug interventions
There is, of course, a diversity of non-drug treatments for MDD and for chronic pain; discussion here focuses primarily on modalities with established efficacy in both disease states (Table 2). On rare occasions, non-drug treatments can constitute a stand-alone approach; most often, they are incorporated into a multimodal treatment plan or applied as an adjunct intervention.²⁶

Psychotherapy. The most robust evidence supports the use of CBT in addressing MDD and chronic pain—occurring individually and comorbidly.^26-28 Efficacy is well established in MDD, as monotherapy and adjunct treatment, spanning acute and maintenance phases.

Furthermore, CBT also has support from randomized trials, meta-analyses, and treatment guidelines, either as monotherapy or co-therapy for both short-term relief and long-term pain reduction. Additionally, CBT has demonstrated value for relieving pain-related disability.^26,28

Combination of a special form of CBT, rumination-focused CBT with ongoing pharmacological therapy over a 26-week period in a group of medication-refractory MDD patients produced a remission rate of 62%, compared with 21% in a treatment-as-usual group.²⁹ This is of particular interest in chronic pain patients, because rumination-related phenomena of pain catastrophizing and avoidance facilitate a transition from acute to chronic pain, while augmenting pain severity and associated disability.³⁰

Catastrophizing also has been implicated in mediating the relationship between pain and sleep disturbance. Not surprisingly, a randomized controlled study demonstrated the benefit of 8-week, Internet-delivered CBT in patients suffering from comorbid chronic pain, depression, and anxiety. Treatment significantly diminished pain catastrophizing, depression, and anxiety; maintenance of improvement was demonstrated after 1 year of follow-up.³¹

Other behavioral and psychological approaches. Biofeedback, mindfulness-based stress reduction, relaxation training and diaphragmatic breathing, guided imagery, hypnosis, and supportive groups might play an important role as components of an integrated mind−body approach to chronic pain,^28,32,33 while also providing mood benefits.

Exercise. The role of exercise as a primary treatment of MDD continues to be controversial, but its benefits as an add-on intervention are indisputable. Exercise not only complements pharmacotherapy to produce greater reduction in depressive scores and improvement in quality of life, it might aid in reestablishing social contacts when conducted in a group setting—an effect that can be of great value in both MDD and chronic pain.³⁴

Exercise and restorative therapies provide several benefits for chronic pain patients, including:

• improved pain control, cognition, and mood
• greater strength and endurance
• cardiovascular and metabolic benefits
• improved bone health and functionality.^{26,28,32,33,35}

To achieve optimal benefit, an exercise program must be customized to fit the patient’s physical condition, level of fitness, and specific type of pain.³⁵ Preliminary evidence suggests that, beyond improvement in pain and functionality, exercise might reduce depressive symptoms in chronic pain patients.³⁶

Non-drug treatment options, such as behavioral techniques and environment adjustment, should be considered before initiating pharmacotherapy in older patients with behavioral deregulation caused by a neurocognitive disorder. Before considering any interventions, including medical therapy, an evaluation and development of a profile of behavioral symptoms is warranted.

The purpose of such a profile is to:

• guide a patient-specific treatment plan
• measure treatment response (whether medication-related or otherwise).

Developing a profile for a patient can lead to a more tailored treatment plan. Such a plan includes identification of mitigating factors for the patient’s behavior and use of specific interventions, with a preference for non-medication interventions.

Profile assessment can guide treatment
The disruptive-behavior profile that I created (Table) can be used as an initial screening device; the score (1 through 4) in each domain indicates the intensity of intervention required. The profile also can be used to evaluate treatment response.

For example, when caring for a person with a neurocognitive disorder with agitation and disruptive behavior, this profile can be used by the caregiver as a reporting tool for the behavioral heath professional providing consultation. Based on this report, the behavioral health professional can evaluate the predisposing, precipitating, and perpetuating factors of the behavioral disturbance, and a treatment plan can be implemented. After interventions are applied, follow-up assessment with the tool can assess the response to the intervention.

The scale can aid in averting overuse of non-specific medication therapy and, if required, can guide pharmacotherapy. This assessment tool can be useful for clinicians providing care for patients with a neurocognitive disorder, not only in choosing treatment, but also to justify clinical rationale.

How does this scale compare with others?
The Neuropsychiatric Inventory (NPI), Behavioral Pathology in Alzheimer’s Disease (Behave-AD), Cohen-Mansfield Agitation Inventory, and Brief Agitation Rating Scale provide valuable information for clinical care. However:

• Use of the NPI in everyday practice is limited; time spent completing the NPI scale remains a significant impediment for the busy clinician.
• Behave-AD requires a higher level of skill for some caregivers to estimate behavioral symptoms and answer questions about severity.
• Cohen-Mansfeld and Brief Agitation Rating Scale provide a limited description of the intensity of behavioral disturbance.

Developing a treatment plan and justifying pharmacotherapy in patients with a neurocognitive disorder is a challenge for clinicians. The scale that I developed aims to (1) assist the busy clinician who must construct a targeted treatment plan and (2) avoid pharmacotherapy when it is unnecessary. If pharmacotherapy is warranted on the basis of any of the domain scores in the profile, it should be documented with a judicious rationale.

Non-drug treatment options, such as behavioral techniques and environment adjustment, should be considered before initiating pharmacotherapy in older patients with behavioral deregulation caused by a neurocognitive disorder. Before considering any interventions, including medical therapy, an evaluation and development of a profile of behavioral symptoms is warranted.

The purpose of such a profile is to:

• guide a patient-specific treatment plan
• measure treatment response (whether medication-related or otherwise).

Developing a profile for a patient can lead to a more tailored treatment plan. Such a plan includes identification of mitigating factors for the patient’s behavior and use of specific interventions, with a preference for non-medication interventions.

Profile assessment can guide treatment
The disruptive-behavior profile that I created (Table) can be used as an initial screening device; the score (1 through 4) in each domain indicates the intensity of intervention required. The profile also can be used to evaluate treatment response.

For example, when caring for a person with a neurocognitive disorder with agitation and disruptive behavior, this profile can be used by the caregiver as a reporting tool for the behavioral heath professional providing consultation. Based on this report, the behavioral health professional can evaluate the predisposing, precipitating, and perpetuating factors of the behavioral disturbance, and a treatment plan can be implemented. After interventions are applied, follow-up assessment with the tool can assess the response to the intervention.

The scale can aid in averting overuse of non-specific medication therapy and, if required, can guide pharmacotherapy. This assessment tool can be useful for clinicians providing care for patients with a neurocognitive disorder, not only in choosing treatment, but also to justify clinical rationale.

How does this scale compare with others?
The Neuropsychiatric Inventory (NPI), Behavioral Pathology in Alzheimer’s Disease (Behave-AD), Cohen-Mansfield Agitation Inventory, and Brief Agitation Rating Scale provide valuable information for clinical care. However:

• Use of the NPI in everyday practice is limited; time spent completing the NPI scale remains a significant impediment for the busy clinician.
• Behave-AD requires a higher level of skill for some caregivers to estimate behavioral symptoms and answer questions about severity.
• Cohen-Mansfeld and Brief Agitation Rating Scale provide a limited description of the intensity of behavioral disturbance.

Developing a treatment plan and justifying pharmacotherapy in patients with a neurocognitive disorder is a challenge for clinicians. The scale that I developed aims to (1) assist the busy clinician who must construct a targeted treatment plan and (2) avoid pharmacotherapy when it is unnecessary. If pharmacotherapy is warranted on the basis of any of the domain scores in the profile, it should be documented with a judicious rationale.

Non-drug treatment options, such as behavioral techniques and environment adjustment, should be considered before initiating pharmacotherapy in older patients with behavioral deregulation caused by a neurocognitive disorder. Before considering any interventions, including medical therapy, an evaluation and development of a profile of behavioral symptoms is warranted.

The purpose of such a profile is to:

• guide a patient-specific treatment plan
• measure treatment response (whether medication-related or otherwise).

Developing a profile for a patient can lead to a more tailored treatment plan. Such a plan includes identification of mitigating factors for the patient’s behavior and use of specific interventions, with a preference for non-medication interventions.

Profile assessment can guide treatment
The disruptive-behavior profile that I created (Table) can be used as an initial screening device; the score (1 through 4) in each domain indicates the intensity of intervention required. The profile also can be used to evaluate treatment response.

For example, when caring for a person with a neurocognitive disorder with agitation and disruptive behavior, this profile can be used by the caregiver as a reporting tool for the behavioral heath professional providing consultation. Based on this report, the behavioral health professional can evaluate the predisposing, precipitating, and perpetuating factors of the behavioral disturbance, and a treatment plan can be implemented. After interventions are applied, follow-up assessment with the tool can assess the response to the intervention.

The scale can aid in averting overuse of non-specific medication therapy and, if required, can guide pharmacotherapy. This assessment tool can be useful for clinicians providing care for patients with a neurocognitive disorder, not only in choosing treatment, but also to justify clinical rationale.

How does this scale compare with others?
The Neuropsychiatric Inventory (NPI), Behavioral Pathology in Alzheimer’s Disease (Behave-AD), Cohen-Mansfield Agitation Inventory, and Brief Agitation Rating Scale provide valuable information for clinical care. However:

• Use of the NPI in everyday practice is limited; time spent completing the NPI scale remains a significant impediment for the busy clinician.
• Behave-AD requires a higher level of skill for some caregivers to estimate behavioral symptoms and answer questions about severity.
• Cohen-Mansfeld and Brief Agitation Rating Scale provide a limited description of the intensity of behavioral disturbance.

Developing a treatment plan and justifying pharmacotherapy in patients with a neurocognitive disorder is a challenge for clinicians. The scale that I developed aims to (1) assist the busy clinician who must construct a targeted treatment plan and (2) avoid pharmacotherapy when it is unnecessary. If pharmacotherapy is warranted on the basis of any of the domain scores in the profile, it should be documented with a judicious rationale.

An amphetamine-based, extended-release, orally disintegrating tablet for patients age ≥6 diagnosed with attention-deficit/hyperactivity disorder (ADHD) won FDA approval on January 28, 2016 (Table).¹

Adzenys XR-ODT is the first extended-release, orally disintegrating tablet for ADHD, Neos Therapeutics, Inc. the drug’s manufacturer, said in a statement.² The newly approved agent is bioequivalent to Adderall XR (the capsule form of extended-release mixed amphetamine salts), and patients taking Adderall XR can be switched to the new drug. Equivalent dosages of the 2 drugs are outlined on the prescribing information.¹

“The novel features of an extended-release orally disintegrating tablet ... make Adzenys XR-ODT attractive for use in both children (6 and older) and adults,” Alice R. Mao, MD, Medical Director, Memorial Park Psychiatry, Houston, Texas, said in the statement.²

As a condition of the approval, Neos must annually report the status of 3 post-marketing studies of children diagnosed with ADHD taking Adzenys XR-ODT, according to the approval letter.² One is a single-dose, open-label study of children ages 4 and 5; the second is a randomized, double-blind, placebo-controlled titration study of children ages 4 and 5; and the third is a 1-year, open-label safety study of patients ages 4 and 5.

For patients age 6 to 17, the starting dosage is 6.3 mg once daily in the morning; for adults, it is 12.5 mg once daily in the morning, according to the label.¹ The medication will be available in 4 other dose strengths: 3.1 mg, 9.4 mg, 15.7 mg, and 18.8 mg.

The most common adverse reactions to the drug among pediatric patients include loss of appetite, insomnia, and abdominal pain. Among adult patients, adverse reactions include dry mouth, loss of appetite, and insomnia.

An amphetamine-based, extended-release, orally disintegrating tablet for patients age ≥6 diagnosed with attention-deficit/hyperactivity disorder (ADHD) won FDA approval on January 28, 2016 (Table).¹

Adzenys XR-ODT is the first extended-release, orally disintegrating tablet for ADHD, Neos Therapeutics, Inc. the drug’s manufacturer, said in a statement.² The newly approved agent is bioequivalent to Adderall XR (the capsule form of extended-release mixed amphetamine salts), and patients taking Adderall XR can be switched to the new drug. Equivalent dosages of the 2 drugs are outlined on the prescribing information.¹

“The novel features of an extended-release orally disintegrating tablet ... make Adzenys XR-ODT attractive for use in both children (6 and older) and adults,” Alice R. Mao, MD, Medical Director, Memorial Park Psychiatry, Houston, Texas, said in the statement.²

As a condition of the approval, Neos must annually report the status of 3 post-marketing studies of children diagnosed with ADHD taking Adzenys XR-ODT, according to the approval letter.² One is a single-dose, open-label study of children ages 4 and 5; the second is a randomized, double-blind, placebo-controlled titration study of children ages 4 and 5; and the third is a 1-year, open-label safety study of patients ages 4 and 5.

For patients age 6 to 17, the starting dosage is 6.3 mg once daily in the morning; for adults, it is 12.5 mg once daily in the morning, according to the label.¹ The medication will be available in 4 other dose strengths: 3.1 mg, 9.4 mg, 15.7 mg, and 18.8 mg.

The most common adverse reactions to the drug among pediatric patients include loss of appetite, insomnia, and abdominal pain. Among adult patients, adverse reactions include dry mouth, loss of appetite, and insomnia.

An amphetamine-based, extended-release, orally disintegrating tablet for patients age ≥6 diagnosed with attention-deficit/hyperactivity disorder (ADHD) won FDA approval on January 28, 2016 (Table).¹

Adzenys XR-ODT is the first extended-release, orally disintegrating tablet for ADHD, Neos Therapeutics, Inc. the drug’s manufacturer, said in a statement.² The newly approved agent is bioequivalent to Adderall XR (the capsule form of extended-release mixed amphetamine salts), and patients taking Adderall XR can be switched to the new drug. Equivalent dosages of the 2 drugs are outlined on the prescribing information.¹

“The novel features of an extended-release orally disintegrating tablet ... make Adzenys XR-ODT attractive for use in both children (6 and older) and adults,” Alice R. Mao, MD, Medical Director, Memorial Park Psychiatry, Houston, Texas, said in the statement.²

As a condition of the approval, Neos must annually report the status of 3 post-marketing studies of children diagnosed with ADHD taking Adzenys XR-ODT, according to the approval letter.² One is a single-dose, open-label study of children ages 4 and 5; the second is a randomized, double-blind, placebo-controlled titration study of children ages 4 and 5; and the third is a 1-year, open-label safety study of patients ages 4 and 5.

For patients age 6 to 17, the starting dosage is 6.3 mg once daily in the morning; for adults, it is 12.5 mg once daily in the morning, according to the label.¹ The medication will be available in 4 other dose strengths: 3.1 mg, 9.4 mg, 15.7 mg, and 18.8 mg.

The most common adverse reactions to the drug among pediatric patients include loss of appetite, insomnia, and abdominal pain. Among adult patients, adverse reactions include dry mouth, loss of appetite, and insomnia.