Med/Psych Update

Dr. Xiong is assistant clinical professor, departments of internal medicine and psychiatry and behavioral sciences, University of California, Davis. Dr. Kenedi is an adjunct professor of psychiatry at Duke University Medical Center in Durham, NC, and a consultant (attending physician) in internal medicine and liaison psychiatry, Auckland City Hospital, Auckland, New Zealand.

Principal Source: U.S. Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150:396-404.

Cardiovascular disease (CVD) is the leading cause of death in the United States, accounting for >50% of all deaths. In persons age >40, the lifetime risk of death from CVD is 2 in 3 for men and more than 1 in 2 for women.¹ Persons with severe mental illness have nearly twice the risk of death from CVD compared with the general population, which may be attributed to:

• lifestyle factors, including poor diet, lack of exercise, and tobacco dependence²
• antipsychotic medications, which have been shown to increase the risk of CVD³
• lower likelihood of undergoing cardiovascular procedures—including percutaneous transluminal coronary angioplasty and coronary artery bypass graft surgery—after myocardial infarction (MI).⁴

Psychiatrists are often the primary contact for patients with mental illness, giving us an opportunity to collaborate with primary care physicians and apply preventative measures that can reduce illness and improve patients’ morbidity and mortality. In addition to evaluating patients for possible hypercholesterolemia and diabetes, adding daily aspirin for primary prevention of heart attacks and strokes is an easily implementable option that could make a real difference in their health and quality of life.

New aspirin recommendations

The U.S. Preventive Services Task Force (USPSTF) found evidence that daily aspirin decreases the incidence of MI in men and ischemic strokes in women.¹ However, total mortality for either gender was not significantly reduced.⁵ The USPSTF’s updated recommendations reflect results of the Women’s Health Study⁶ with different guidelines for men and women.

The USPSTF recommends daily aspirin for men age 45 to 79 and for women age 55 to 79 when the benefits of decreased MI for men and ischemic strokes for women outweigh the risks of increased GI bleeding ( Table 1 ).¹ This grade A recommendation means there is high certainty of substantial net benefit.

Aspirin is not recommended for patients age ≥80 because of insufficient evidence of harm or benefit. The risks of MI in men age <45 and stroke in women age <55 are low, and daily aspirin generally is not indicated.

Optimal aspirin dose is unclear. The USPSTF recommends approximately 75 mg/d (effectively 81 mg/d or 1 “baby aspirin” in most U.S. settings). Higher aspirin doses might not be more effective for primary prevention and could increase the risk of GI bleeding. Note that some patients with a history of cardiovascular or cerebrovascular events might receive higher aspirin doses for secondary prevention of additional injury.

Risk assessment. In addition to age, other risk factors for CVD include:

• diabetes
• high total cholesterol (>240 mg/dL)
• low high-density lipoprotein cholesterol or so-called “good cholesterol” (<40 mg/dL for men, <50 mg/dL for women)
• hypertension
• smoking
• family history.

Several online tools—based on data from the Framingham Heart Study and other cohorts—can help estimate a patient’s CVD risk ( see Related Resources ), or consult with your patient’s primary care physician.

Potential harm of aspirin. USPSTF considers age and gender the most important risk factors for GI bleeding. GI bleeding is defined as serious hemorrhage, perforation, or other complications that could lead to hospitalization or death. Other risk factors include:

• upper GI pain
• history of gastric or duodenal ulcers
• NSAID use
• heavy, regular alcohol consumption.

In general, men have twice the risk of GI bleeding compared with women.¹ The baseline number of GI bleeding events for individuals without a history of GI pain or bleeds taking daily aspirin is 4 per 10,000 person-years for women and 8 per 10,000 for men.¹ Patients with preexisting GI ulcers who receive daily aspirin have more than 2 to 3 times the baseline risk of serious GI bleeding.⁷ NSAIDs taken with daily aspirin can quadruple the risk of GI bleeding compared with aspirin use alone, although antacid therapy can reduce this risk.⁸ Co-administered anticoagulants (eg, warfarin) also significantly increase the risk—especially when compliance with medication and monitoring is poor. Aspirin also increases the risk of hematuria, easy bruising, and epistaxis.

Because consuming >3 standard drinks a day also increases the risk of GI bleeding by up to 6 fold, patients with untreated chronic alcohol abuse or dependence might not be good candidates for daily aspirin therapy.⁹ Contrary to popular belief and pharmaceutical marketing, enteric-coated tablets do not seem to reduce the risk of bleeding because aspirin impacts platelet function, not the lining of the stomach.

Table 1

USPSTF recommendations for daily aspirin use
in primary prevention of cardiovascular disease

Aspirin for psychiatric patients

Patients who have serious mental illness are at increased risk for CVD and often experience systemic barriers to receiving appropriate medical care.¹⁰ Psychiatrists can provide and advocate for primary care services for our patients, including daily aspirin use to prevent CVD when appropriate, and encourage a closer relationship with a primary care physician before an adverse event occurs. Aspirin use in psychiatric patients is associated with:

• potential drug-drug interaction with valproate¹¹
• mildly increased risk of bleeding as a result of reduced platelet function with the use of selective serotonin reuptake inhibitors.¹²

Balancing benefits vs risks. The USPSTF recommendation assumes that the value of preventing 1 MI or stroke is roughly equivalent to (or slightly less than) the cost of 1 GI bleeding event caused by aspirin. For example, among 1,000 men age 45 to 79 who have a ≥4% risk of MI over 10 years, 12.8 MIs would be prevented for every 8 GI bleeds caused by aspirin by following the current recommendations.¹

The USPSTF guidelines are based on average levels of risk for age and gender. Some men age <45 may decide that it is more important to avoid a cardiovascular event rather than an episode of GI bleeding and might choose to begin daily aspirin. Aspirin use should be discouraged in most patients at high risk for GI bleeding. The point where the potential benefits outweigh the risks must be determined on an individual basis ( Table 2 ).

Table 2

Aspirin to prevent cardiovascular disease and stroke:
When benefits outweigh risks

Related resources

• National Cholesterol Education Program. Online heart attack risk assessment tool. http://hp2010.nhlbihin.net/atpiii/calculator.asp.
• Framingham Heart study calculator. www.framinghamheartstudy.org/risk/coronary.html.
• National Cholesterol Education Program. www.nhlbi.nih.gov/health/public/heart/chol/wyntk.htm#risk.
• Colorado Neurological Institute. Online stroke risk assessment tool. www.thecni.org/Public/CNICenters/StrokeCenter/StrokeRiskCalculator/index.cfm.
• Agency for Healthcare Research and Quality. Fact sheet on aspirin to prevent cardiovascular disease. www.ahrq.gov/clinic/cvd/aspprovider.htm.

Drug brand names

• Valproate • Depacon
• Warfarin • Coumadin

Disclosures

Dr. Xiong reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Kenedi receives grant/research support from Duke University Medical Center and Auckland University.

Dr. Xiong is assistant clinical professor, departments of internal medicine and psychiatry and behavioral sciences, University of California, Davis. Dr. Kenedi is an adjunct professor of psychiatry at Duke University Medical Center in Durham, NC, and a consultant (attending physician) in internal medicine and liaison psychiatry, Auckland City Hospital, Auckland, New Zealand.

Principal Source: U.S. Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150:396-404.

Cardiovascular disease (CVD) is the leading cause of death in the United States, accounting for >50% of all deaths. In persons age >40, the lifetime risk of death from CVD is 2 in 3 for men and more than 1 in 2 for women.¹ Persons with severe mental illness have nearly twice the risk of death from CVD compared with the general population, which may be attributed to:

• lifestyle factors, including poor diet, lack of exercise, and tobacco dependence²
• antipsychotic medications, which have been shown to increase the risk of CVD³
• lower likelihood of undergoing cardiovascular procedures—including percutaneous transluminal coronary angioplasty and coronary artery bypass graft surgery—after myocardial infarction (MI).⁴

Psychiatrists are often the primary contact for patients with mental illness, giving us an opportunity to collaborate with primary care physicians and apply preventative measures that can reduce illness and improve patients’ morbidity and mortality. In addition to evaluating patients for possible hypercholesterolemia and diabetes, adding daily aspirin for primary prevention of heart attacks and strokes is an easily implementable option that could make a real difference in their health and quality of life.

New aspirin recommendations

The U.S. Preventive Services Task Force (USPSTF) found evidence that daily aspirin decreases the incidence of MI in men and ischemic strokes in women.¹ However, total mortality for either gender was not significantly reduced.⁵ The USPSTF’s updated recommendations reflect results of the Women’s Health Study⁶ with different guidelines for men and women.

The USPSTF recommends daily aspirin for men age 45 to 79 and for women age 55 to 79 when the benefits of decreased MI for men and ischemic strokes for women outweigh the risks of increased GI bleeding ( Table 1 ).¹ This grade A recommendation means there is high certainty of substantial net benefit.

Aspirin is not recommended for patients age ≥80 because of insufficient evidence of harm or benefit. The risks of MI in men age <45 and stroke in women age <55 are low, and daily aspirin generally is not indicated.

Optimal aspirin dose is unclear. The USPSTF recommends approximately 75 mg/d (effectively 81 mg/d or 1 “baby aspirin” in most U.S. settings). Higher aspirin doses might not be more effective for primary prevention and could increase the risk of GI bleeding. Note that some patients with a history of cardiovascular or cerebrovascular events might receive higher aspirin doses for secondary prevention of additional injury.

Risk assessment. In addition to age, other risk factors for CVD include:

• diabetes
• high total cholesterol (>240 mg/dL)
• low high-density lipoprotein cholesterol or so-called “good cholesterol” (<40 mg/dL for men, <50 mg/dL for women)
• hypertension
• smoking
• family history.

Several online tools—based on data from the Framingham Heart Study and other cohorts—can help estimate a patient’s CVD risk ( see Related Resources ), or consult with your patient’s primary care physician.

Potential harm of aspirin. USPSTF considers age and gender the most important risk factors for GI bleeding. GI bleeding is defined as serious hemorrhage, perforation, or other complications that could lead to hospitalization or death. Other risk factors include:

• upper GI pain
• history of gastric or duodenal ulcers
• NSAID use
• heavy, regular alcohol consumption.

In general, men have twice the risk of GI bleeding compared with women.¹ The baseline number of GI bleeding events for individuals without a history of GI pain or bleeds taking daily aspirin is 4 per 10,000 person-years for women and 8 per 10,000 for men.¹ Patients with preexisting GI ulcers who receive daily aspirin have more than 2 to 3 times the baseline risk of serious GI bleeding.⁷ NSAIDs taken with daily aspirin can quadruple the risk of GI bleeding compared with aspirin use alone, although antacid therapy can reduce this risk.⁸ Co-administered anticoagulants (eg, warfarin) also significantly increase the risk—especially when compliance with medication and monitoring is poor. Aspirin also increases the risk of hematuria, easy bruising, and epistaxis.

Because consuming >3 standard drinks a day also increases the risk of GI bleeding by up to 6 fold, patients with untreated chronic alcohol abuse or dependence might not be good candidates for daily aspirin therapy.⁹ Contrary to popular belief and pharmaceutical marketing, enteric-coated tablets do not seem to reduce the risk of bleeding because aspirin impacts platelet function, not the lining of the stomach.

Table 1

USPSTF recommendations for daily aspirin use
in primary prevention of cardiovascular disease

Aspirin for psychiatric patients

Patients who have serious mental illness are at increased risk for CVD and often experience systemic barriers to receiving appropriate medical care.¹⁰ Psychiatrists can provide and advocate for primary care services for our patients, including daily aspirin use to prevent CVD when appropriate, and encourage a closer relationship with a primary care physician before an adverse event occurs. Aspirin use in psychiatric patients is associated with:

• potential drug-drug interaction with valproate¹¹
• mildly increased risk of bleeding as a result of reduced platelet function with the use of selective serotonin reuptake inhibitors.¹²

Balancing benefits vs risks. The USPSTF recommendation assumes that the value of preventing 1 MI or stroke is roughly equivalent to (or slightly less than) the cost of 1 GI bleeding event caused by aspirin. For example, among 1,000 men age 45 to 79 who have a ≥4% risk of MI over 10 years, 12.8 MIs would be prevented for every 8 GI bleeds caused by aspirin by following the current recommendations.¹

The USPSTF guidelines are based on average levels of risk for age and gender. Some men age <45 may decide that it is more important to avoid a cardiovascular event rather than an episode of GI bleeding and might choose to begin daily aspirin. Aspirin use should be discouraged in most patients at high risk for GI bleeding. The point where the potential benefits outweigh the risks must be determined on an individual basis ( Table 2 ).

Table 2

Aspirin to prevent cardiovascular disease and stroke:
When benefits outweigh risks

Related resources

• National Cholesterol Education Program. Online heart attack risk assessment tool. http://hp2010.nhlbihin.net/atpiii/calculator.asp.
• Framingham Heart study calculator. www.framinghamheartstudy.org/risk/coronary.html.
• National Cholesterol Education Program. www.nhlbi.nih.gov/health/public/heart/chol/wyntk.htm#risk.
• Colorado Neurological Institute. Online stroke risk assessment tool. www.thecni.org/Public/CNICenters/StrokeCenter/StrokeRiskCalculator/index.cfm.
• Agency for Healthcare Research and Quality. Fact sheet on aspirin to prevent cardiovascular disease. www.ahrq.gov/clinic/cvd/aspprovider.htm.

Drug brand names

• Valproate • Depacon
• Warfarin • Coumadin

Disclosures

Dr. Xiong reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Kenedi receives grant/research support from Duke University Medical Center and Auckland University.

Dr. Xiong is assistant clinical professor, departments of internal medicine and psychiatry and behavioral sciences, University of California, Davis. Dr. Kenedi is an adjunct professor of psychiatry at Duke University Medical Center in Durham, NC, and a consultant (attending physician) in internal medicine and liaison psychiatry, Auckland City Hospital, Auckland, New Zealand.

Principal Source: U.S. Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150:396-404.

Cardiovascular disease (CVD) is the leading cause of death in the United States, accounting for >50% of all deaths. In persons age >40, the lifetime risk of death from CVD is 2 in 3 for men and more than 1 in 2 for women.¹ Persons with severe mental illness have nearly twice the risk of death from CVD compared with the general population, which may be attributed to:

• lifestyle factors, including poor diet, lack of exercise, and tobacco dependence²
• antipsychotic medications, which have been shown to increase the risk of CVD³
• lower likelihood of undergoing cardiovascular procedures—including percutaneous transluminal coronary angioplasty and coronary artery bypass graft surgery—after myocardial infarction (MI).⁴

Psychiatrists are often the primary contact for patients with mental illness, giving us an opportunity to collaborate with primary care physicians and apply preventative measures that can reduce illness and improve patients’ morbidity and mortality. In addition to evaluating patients for possible hypercholesterolemia and diabetes, adding daily aspirin for primary prevention of heart attacks and strokes is an easily implementable option that could make a real difference in their health and quality of life.

New aspirin recommendations

The U.S. Preventive Services Task Force (USPSTF) found evidence that daily aspirin decreases the incidence of MI in men and ischemic strokes in women.¹ However, total mortality for either gender was not significantly reduced.⁵ The USPSTF’s updated recommendations reflect results of the Women’s Health Study⁶ with different guidelines for men and women.

The USPSTF recommends daily aspirin for men age 45 to 79 and for women age 55 to 79 when the benefits of decreased MI for men and ischemic strokes for women outweigh the risks of increased GI bleeding ( Table 1 ).¹ This grade A recommendation means there is high certainty of substantial net benefit.

Aspirin is not recommended for patients age ≥80 because of insufficient evidence of harm or benefit. The risks of MI in men age <45 and stroke in women age <55 are low, and daily aspirin generally is not indicated.

Optimal aspirin dose is unclear. The USPSTF recommends approximately 75 mg/d (effectively 81 mg/d or 1 “baby aspirin” in most U.S. settings). Higher aspirin doses might not be more effective for primary prevention and could increase the risk of GI bleeding. Note that some patients with a history of cardiovascular or cerebrovascular events might receive higher aspirin doses for secondary prevention of additional injury.

Risk assessment. In addition to age, other risk factors for CVD include:

• diabetes
• high total cholesterol (>240 mg/dL)
• low high-density lipoprotein cholesterol or so-called “good cholesterol” (<40 mg/dL for men, <50 mg/dL for women)
• hypertension
• smoking
• family history.

Several online tools—based on data from the Framingham Heart Study and other cohorts—can help estimate a patient’s CVD risk ( see Related Resources ), or consult with your patient’s primary care physician.

Potential harm of aspirin. USPSTF considers age and gender the most important risk factors for GI bleeding. GI bleeding is defined as serious hemorrhage, perforation, or other complications that could lead to hospitalization or death. Other risk factors include:

• upper GI pain
• history of gastric or duodenal ulcers
• NSAID use
• heavy, regular alcohol consumption.

In general, men have twice the risk of GI bleeding compared with women.¹ The baseline number of GI bleeding events for individuals without a history of GI pain or bleeds taking daily aspirin is 4 per 10,000 person-years for women and 8 per 10,000 for men.¹ Patients with preexisting GI ulcers who receive daily aspirin have more than 2 to 3 times the baseline risk of serious GI bleeding.⁷ NSAIDs taken with daily aspirin can quadruple the risk of GI bleeding compared with aspirin use alone, although antacid therapy can reduce this risk.⁸ Co-administered anticoagulants (eg, warfarin) also significantly increase the risk—especially when compliance with medication and monitoring is poor. Aspirin also increases the risk of hematuria, easy bruising, and epistaxis.

Because consuming >3 standard drinks a day also increases the risk of GI bleeding by up to 6 fold, patients with untreated chronic alcohol abuse or dependence might not be good candidates for daily aspirin therapy.⁹ Contrary to popular belief and pharmaceutical marketing, enteric-coated tablets do not seem to reduce the risk of bleeding because aspirin impacts platelet function, not the lining of the stomach.

Table 1

USPSTF recommendations for daily aspirin use
in primary prevention of cardiovascular disease

Aspirin for psychiatric patients

Patients who have serious mental illness are at increased risk for CVD and often experience systemic barriers to receiving appropriate medical care.¹⁰ Psychiatrists can provide and advocate for primary care services for our patients, including daily aspirin use to prevent CVD when appropriate, and encourage a closer relationship with a primary care physician before an adverse event occurs. Aspirin use in psychiatric patients is associated with:

• potential drug-drug interaction with valproate¹¹
• mildly increased risk of bleeding as a result of reduced platelet function with the use of selective serotonin reuptake inhibitors.¹²

Balancing benefits vs risks. The USPSTF recommendation assumes that the value of preventing 1 MI or stroke is roughly equivalent to (or slightly less than) the cost of 1 GI bleeding event caused by aspirin. For example, among 1,000 men age 45 to 79 who have a ≥4% risk of MI over 10 years, 12.8 MIs would be prevented for every 8 GI bleeds caused by aspirin by following the current recommendations.¹

The USPSTF guidelines are based on average levels of risk for age and gender. Some men age <45 may decide that it is more important to avoid a cardiovascular event rather than an episode of GI bleeding and might choose to begin daily aspirin. Aspirin use should be discouraged in most patients at high risk for GI bleeding. The point where the potential benefits outweigh the risks must be determined on an individual basis ( Table 2 ).

Table 2

Aspirin to prevent cardiovascular disease and stroke:
When benefits outweigh risks

Related resources

• National Cholesterol Education Program. Online heart attack risk assessment tool. http://hp2010.nhlbihin.net/atpiii/calculator.asp.
• Framingham Heart study calculator. www.framinghamheartstudy.org/risk/coronary.html.
• National Cholesterol Education Program. www.nhlbi.nih.gov/health/public/heart/chol/wyntk.htm#risk.
• Colorado Neurological Institute. Online stroke risk assessment tool. www.thecni.org/Public/CNICenters/StrokeCenter/StrokeRiskCalculator/index.cfm.
• Agency for Healthcare Research and Quality. Fact sheet on aspirin to prevent cardiovascular disease. www.ahrq.gov/clinic/cvd/aspprovider.htm.

Drug brand names

• Valproate • Depacon
• Warfarin • Coumadin

Disclosures

Dr. Xiong reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Kenedi receives grant/research support from Duke University Medical Center and Auckland University.

Mrs. E, age 31, develops rapid, pressured speech and insomnia for 4 consecutive nights, but reports a normal energy level after receiving high-dose methylprednisolone for an acute flare of systemic lupus erythematosus (SLE).

Her medical history indicates an overlap syndrome between SLE and systemic sclerosis for the last 5 years, migraine headaches, and 4 spontaneous miscarriages, but she has no psychiatric history. Her family history is negative for psychiatric illness and positive for diabetes mellitus, hypertension, and coronary artery disease.

Mrs. E lives with her husband and 10-year-old son. She admits to multiple stressors, including her health problems and financial dificulties, which recently led to the family’s decision to move to her mother-in-law’s house. Mrs. E denies using illicit drugs, cigarettes, or alcohol.

Mrs. E is admitted to the hospital, and her corticosteroid dosage is reduced with a switch to prednisone, 60 mg/d. She is started on risperidone, 1 mg at bedtime, which is titrated without adverse effect. Her psychotic symptoms improve over 4 days, and she is discharged on prednisone, 60 mg/d, and risperidone, 0.5 mg in the morning and 2 mg at night.

After completing her corticosteroid course, Mrs. E experiences complete resolution of psychiatric symptoms and is tapered off risperidone after 6 months.

Corticosteroid use can cause a variety of psychiatric syndromes, including mania, psychosis, depression, and delirium. A meta-analysis reports severe psychotic reactions in 5.7% of patients taking corticosteroids and mild-to-moderate reactions in 28% of patients.¹ Hypomania, mania, and psychosis are the most common psychiatric reactions to acute corticosteroid therapy.² This article reviews case reports and open-label trials of antipsychotics, mood stabilizers, and anticonvulsants to treat corticosteroid-induced mania and psychosis and outlines treatment options.

Symptoms

Corticosteroid-induced psychosis represents a spectrum of psychological changes that can occur at any time during treatment. Mild-to-moderate symptoms include agitation, anxiety, insomnia, irritability, and restlessness, whereas severe symptoms include mania, depression, and psychosis.³ Case reports reveal:

• mania and hypomania in 35% of patients with corticosteroid-induced psychosis
• acute psychotic disorder in 24% of patients, with hallucinations reported in one-half of these cases
• depression, which is more common with chronic corticosteroid therapy, in 28% of patients.⁴

Delirium and cognitive deficits also have been reported, although these symptoms generally subside with corticosteroid reduction or withdrawal.^4,5

Psychiatric symptoms often develop after 4 days of corticosteroid therapy, although they can occur late in therapy or after treatment ends.⁶ Delirium often resolves within a few days, psychosis within 7 days, and mania within 2 to 3 weeks, whereas depression can last for more than 3 weeks.⁴ A 3-level grading system can gauge severity of corticosteroid-induced psychosis; grade 2 or 3 warrants treatment (Table 1).⁴

Table 1

Grading scale for corticosteroid-induced psychiatric symptoms

Risk factors

High corticosteroid dose is the primary risk factor for psychosis. The Boston Collaborative Drug Surveillance Program reported that among individuals taking prednisone, psychiatric disturbances are seen in:

• 1.3% of patients taking <40 mg/d
• 4.6% of patients taking 40 to 80 mg/d
• 18.4% of patients taking >80 mg/d.⁷

However, the corticosteroid dosage does not predict onset, severity, type of reaction, or duration.^3,7 Female patients are at higher risk of corticosteroid-induced psychosis, even after one controls for medical conditions diagnosed more often in women, such as SLE and rheumatoid arthritis.³ Previous episodes of corticosteroid-induced psychosis, history of psychiatric illness, and age are not associated with corticosteroid-induced psychosis.³

Treatment

Management includes tapering corticosteroids, with or without adding medications to treat the acute state. Decreasing corticosteroids to the lowest dose possible—<40 mg/d—or gradually discontinuing therapy to prevent triggering adrenal insufficiency may improve psychotic symptoms and avoids the risk of adverse effects from adjunctive medications.

Psychopharmacologic treatment may be necessary, depending on the severity of psychosis or the underlying disease, particularly if corticosteroids cannot be tapered or discontinued. Evidence from open-label trials (Table 2)^8-12 and case reports indicates that psychotic symptoms could be prevented and treated with off-label antipsychotics, mood stabilizers, and anticonvulsants.

Consider your patient’s underlying medical condition when selecting psychotropics. For example, try to avoid prescribing:

• antipsychotics to patients with cardiac conduction abnormalities
• lithium to patients who need diuretic or angiotensin-converting enzyme inhibitor therapy or those with underlying renal insufficiency.

When appropriate, collaborate with the provider who prescribed the corticosteroids because tapering or discontinuation might not be possible.

Table 2

Corticosteroid-induced psychosis: Adjunctive treatment studies

Antipsychotics

Open-label trial. Olanzapine reduced psychiatric symptoms in a 5-week, open-label trial of 12 outpatients experiencing manic or mixed symptoms secondary to corticosteroids.⁸ At baseline, patients had a mean score of 15.25 on the Young Mania Rating Scale (YMRS) on a mean prednisone dose of 14.4 mg/d. After receiving olanzapine, 2.5 mg/d titrated to a maximum 20 mg/d (mean 8.5 mg/d), subjects demonstrated a significant decrease on the YMRS (P=.002), Hamilton Rating Scale for Depression (HRSD) (P=.005), and Brief Psychiatric Rating Scale (BPRS) (P=.006) with no change in extrapyramidal side-effect scales, weight, or glucose measurements.

Case reports. Among antipsychotics, olanzapine has the greatest number of case reports for treating corticosteroid-induced psychosis, mainly for mania.^13-15 Benefit with olanzapine was demonstrated at dosages from 2.5 to 15 mg/d and improvement occurred within days to weeks. Several patients remained symptom-free with olanzapine and continued corticosteroid therapy.

Other reports describe benefit with risperidone for a variety of psychiatric symptoms—including hypomania, hallucinations, and delusions—associated with corticosteroid therapy.^16-19 Risperidone dosing ranged from 1 to 4 mg/d, and symptoms improved within days to weeks.

One case report describes quetiapine for the treatment of corticosteroid-induced mania.²⁰ The patient’s symptoms improved within 10 hours of initiating quetiapine, 25 mg/d, and YMRS score decreased from 31 before therapy to 5 at discharge. No case reports exist for ziprasidone or aripiprazole.

Mood stabilizers

Cohort study. One study suggests that lithium may be effective for preventing and treating corticosteroid-induced psychosis. A retrospective cohort study examined records of patients diagnosed with multiple sclerosis or retrobulbar neuritis who were treated with corticotropin.⁹ Corticotropin has been reported to cause psychotic reactions in up to 11% of patients through a mechanism thought to mirror corticosteroid-induced psychosis (Box).^21-23 Psychiatric symptoms developed in 38% of patients treated with lithium compared with 62% of controls. No patients pretreated with lithium maintained at 0.8 to 1.2 mEq/L reported mood disturbances or psychotic reactions.

Case reports. Among mood stabilizers, lithium has the greatest number of case reports on its use for prevention and treatment of corticosteroid-induced psychosis. In these reports, patients pretreated with lithium did not experience a relapse of psychosis related to chronic corticosteroid therapy.^24-27 Case reports also describe benefit with valproic acid and carbamazepine.^28-30

Anticonvulsants

Trials. In a 1-week trial, 39 patients without previous psychiatric diagnosis or psychotropic use were randomly assigned to phenytoin, 300 mg/d, or placebo as prednisone therapy was initiated.¹⁰ Compared with placebo, the phenytoin group reported a smaller increase on the Internal State Scale Activation subscale (ACT), a self-report measure of mania symptom severity. No significant differences were found on the YMRS or HRSD scales. Based on the ACT scale finding, the authors concluded that phenytoin attenuated manic or hypomanic effects of prednisone.

A study of levetiracetam, 1500 mg/d, showed no significant change in HRSD, YMRS, or ACT scores from baseline to end point for either levetiracetam or placebo.¹¹

A 12-week, open-label trial of lamotrigine in 5 patients receiving corticosteroids continuously for 6 months showed no significant difference in mood changes as measured by the HRSD, YMRS, or the depression sub-scale of the Internal State Scale.¹²

Case reports show that lamotrigine and gabapentin have been used effectively to prevent manic symptoms in patients receiving corticosteroid therapy.^31,32

Treatment recommendations

Establishing a treatment algorithm for corticosteroid-induced psychosis is hampered by the lack of prospective placebo-controlled trials. However, most case reports describe benefit from administrating atypical antipsychotics and lithium.

Box

Consider adding a low-dose atypical antipsychotic with which case studies report quick symptom resolution and patients tolerating these agents. Monitor carefully for metabolic changes, a risk associated with antipsychotics and corticosteroids. Lithium would be a good second-line therapy because of its demonstrated benefit for both prophylaxis and treatment of psychiatric disturbances.

Lithium use can be complicated and dangerous in patients who have underlying diseases associated with renal dysfunction, however—such as nephrotic syndromes and SLE—leading some authors to suggest valproic acid or carbamazepine instead.³³ In addition, corticosteroid-induced changes in sodium balance could increase the risk of lithium toxicity.³⁴

When patients cannot tolerate atypical antipsychotics or lithium, case reports support the use of valproic acid, carbamazepine, lamotrigine, or gabapentin to treat symptoms of corticosteroid-induced psychosis.

Related resources

• Cerullo MA. Expect psychiatric side effects from corticosteroid use in the elderly. Geriatrics. 2008;63(1):15-18.
• Sirois F. Steroid psychosis: a review. Gen Hosp Psychiatry. 2003;25:27-33.
• Patten SB, Neutel CI. Corticosteroid-induced adverse psychiatric effects: incidence, diagnosis, and management. Drug Safety. 2000;22(2):111-122.
• Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. Mayo Clin Proc. 2006;81(10):1361-1367.

Drug brand names

• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Corticotropin • Acthar
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Lithium • Lithobid, Eskalith, others
• Methylprednisolone • Medrol
• Olanzapine • Zyprexa
• Phenytoin • Dilantin
• Prednisone • Deltasone
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

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

Mrs. E, age 31, develops rapid, pressured speech and insomnia for 4 consecutive nights, but reports a normal energy level after receiving high-dose methylprednisolone for an acute flare of systemic lupus erythematosus (SLE).

Her medical history indicates an overlap syndrome between SLE and systemic sclerosis for the last 5 years, migraine headaches, and 4 spontaneous miscarriages, but she has no psychiatric history. Her family history is negative for psychiatric illness and positive for diabetes mellitus, hypertension, and coronary artery disease.

Mrs. E lives with her husband and 10-year-old son. She admits to multiple stressors, including her health problems and financial dificulties, which recently led to the family’s decision to move to her mother-in-law’s house. Mrs. E denies using illicit drugs, cigarettes, or alcohol.

Mrs. E is admitted to the hospital, and her corticosteroid dosage is reduced with a switch to prednisone, 60 mg/d. She is started on risperidone, 1 mg at bedtime, which is titrated without adverse effect. Her psychotic symptoms improve over 4 days, and she is discharged on prednisone, 60 mg/d, and risperidone, 0.5 mg in the morning and 2 mg at night.

After completing her corticosteroid course, Mrs. E experiences complete resolution of psychiatric symptoms and is tapered off risperidone after 6 months.

Corticosteroid use can cause a variety of psychiatric syndromes, including mania, psychosis, depression, and delirium. A meta-analysis reports severe psychotic reactions in 5.7% of patients taking corticosteroids and mild-to-moderate reactions in 28% of patients.¹ Hypomania, mania, and psychosis are the most common psychiatric reactions to acute corticosteroid therapy.² This article reviews case reports and open-label trials of antipsychotics, mood stabilizers, and anticonvulsants to treat corticosteroid-induced mania and psychosis and outlines treatment options.

Symptoms

Corticosteroid-induced psychosis represents a spectrum of psychological changes that can occur at any time during treatment. Mild-to-moderate symptoms include agitation, anxiety, insomnia, irritability, and restlessness, whereas severe symptoms include mania, depression, and psychosis.³ Case reports reveal:

• mania and hypomania in 35% of patients with corticosteroid-induced psychosis
• acute psychotic disorder in 24% of patients, with hallucinations reported in one-half of these cases
• depression, which is more common with chronic corticosteroid therapy, in 28% of patients.⁴

Delirium and cognitive deficits also have been reported, although these symptoms generally subside with corticosteroid reduction or withdrawal.^4,5

Psychiatric symptoms often develop after 4 days of corticosteroid therapy, although they can occur late in therapy or after treatment ends.⁶ Delirium often resolves within a few days, psychosis within 7 days, and mania within 2 to 3 weeks, whereas depression can last for more than 3 weeks.⁴ A 3-level grading system can gauge severity of corticosteroid-induced psychosis; grade 2 or 3 warrants treatment (Table 1).⁴

Table 1

Grading scale for corticosteroid-induced psychiatric symptoms

Risk factors

High corticosteroid dose is the primary risk factor for psychosis. The Boston Collaborative Drug Surveillance Program reported that among individuals taking prednisone, psychiatric disturbances are seen in:

• 1.3% of patients taking <40 mg/d
• 4.6% of patients taking 40 to 80 mg/d
• 18.4% of patients taking >80 mg/d.⁷

However, the corticosteroid dosage does not predict onset, severity, type of reaction, or duration.^3,7 Female patients are at higher risk of corticosteroid-induced psychosis, even after one controls for medical conditions diagnosed more often in women, such as SLE and rheumatoid arthritis.³ Previous episodes of corticosteroid-induced psychosis, history of psychiatric illness, and age are not associated with corticosteroid-induced psychosis.³

Treatment

Management includes tapering corticosteroids, with or without adding medications to treat the acute state. Decreasing corticosteroids to the lowest dose possible—<40 mg/d—or gradually discontinuing therapy to prevent triggering adrenal insufficiency may improve psychotic symptoms and avoids the risk of adverse effects from adjunctive medications.

Psychopharmacologic treatment may be necessary, depending on the severity of psychosis or the underlying disease, particularly if corticosteroids cannot be tapered or discontinued. Evidence from open-label trials (Table 2)^8-12 and case reports indicates that psychotic symptoms could be prevented and treated with off-label antipsychotics, mood stabilizers, and anticonvulsants.

Consider your patient’s underlying medical condition when selecting psychotropics. For example, try to avoid prescribing:

• antipsychotics to patients with cardiac conduction abnormalities
• lithium to patients who need diuretic or angiotensin-converting enzyme inhibitor therapy or those with underlying renal insufficiency.

When appropriate, collaborate with the provider who prescribed the corticosteroids because tapering or discontinuation might not be possible.

Table 2

Corticosteroid-induced psychosis: Adjunctive treatment studies

Antipsychotics

Open-label trial. Olanzapine reduced psychiatric symptoms in a 5-week, open-label trial of 12 outpatients experiencing manic or mixed symptoms secondary to corticosteroids.⁸ At baseline, patients had a mean score of 15.25 on the Young Mania Rating Scale (YMRS) on a mean prednisone dose of 14.4 mg/d. After receiving olanzapine, 2.5 mg/d titrated to a maximum 20 mg/d (mean 8.5 mg/d), subjects demonstrated a significant decrease on the YMRS (P=.002), Hamilton Rating Scale for Depression (HRSD) (P=.005), and Brief Psychiatric Rating Scale (BPRS) (P=.006) with no change in extrapyramidal side-effect scales, weight, or glucose measurements.

Case reports. Among antipsychotics, olanzapine has the greatest number of case reports for treating corticosteroid-induced psychosis, mainly for mania.^13-15 Benefit with olanzapine was demonstrated at dosages from 2.5 to 15 mg/d and improvement occurred within days to weeks. Several patients remained symptom-free with olanzapine and continued corticosteroid therapy.

Other reports describe benefit with risperidone for a variety of psychiatric symptoms—including hypomania, hallucinations, and delusions—associated with corticosteroid therapy.^16-19 Risperidone dosing ranged from 1 to 4 mg/d, and symptoms improved within days to weeks.

One case report describes quetiapine for the treatment of corticosteroid-induced mania.²⁰ The patient’s symptoms improved within 10 hours of initiating quetiapine, 25 mg/d, and YMRS score decreased from 31 before therapy to 5 at discharge. No case reports exist for ziprasidone or aripiprazole.

Mood stabilizers

Cohort study. One study suggests that lithium may be effective for preventing and treating corticosteroid-induced psychosis. A retrospective cohort study examined records of patients diagnosed with multiple sclerosis or retrobulbar neuritis who were treated with corticotropin.⁹ Corticotropin has been reported to cause psychotic reactions in up to 11% of patients through a mechanism thought to mirror corticosteroid-induced psychosis (Box).^21-23 Psychiatric symptoms developed in 38% of patients treated with lithium compared with 62% of controls. No patients pretreated with lithium maintained at 0.8 to 1.2 mEq/L reported mood disturbances or psychotic reactions.

Case reports. Among mood stabilizers, lithium has the greatest number of case reports on its use for prevention and treatment of corticosteroid-induced psychosis. In these reports, patients pretreated with lithium did not experience a relapse of psychosis related to chronic corticosteroid therapy.^24-27 Case reports also describe benefit with valproic acid and carbamazepine.^28-30

Anticonvulsants

Trials. In a 1-week trial, 39 patients without previous psychiatric diagnosis or psychotropic use were randomly assigned to phenytoin, 300 mg/d, or placebo as prednisone therapy was initiated.¹⁰ Compared with placebo, the phenytoin group reported a smaller increase on the Internal State Scale Activation subscale (ACT), a self-report measure of mania symptom severity. No significant differences were found on the YMRS or HRSD scales. Based on the ACT scale finding, the authors concluded that phenytoin attenuated manic or hypomanic effects of prednisone.

A study of levetiracetam, 1500 mg/d, showed no significant change in HRSD, YMRS, or ACT scores from baseline to end point for either levetiracetam or placebo.¹¹

A 12-week, open-label trial of lamotrigine in 5 patients receiving corticosteroids continuously for 6 months showed no significant difference in mood changes as measured by the HRSD, YMRS, or the depression sub-scale of the Internal State Scale.¹²

Case reports show that lamotrigine and gabapentin have been used effectively to prevent manic symptoms in patients receiving corticosteroid therapy.^31,32

Treatment recommendations

Establishing a treatment algorithm for corticosteroid-induced psychosis is hampered by the lack of prospective placebo-controlled trials. However, most case reports describe benefit from administrating atypical antipsychotics and lithium.

Box

Consider adding a low-dose atypical antipsychotic with which case studies report quick symptom resolution and patients tolerating these agents. Monitor carefully for metabolic changes, a risk associated with antipsychotics and corticosteroids. Lithium would be a good second-line therapy because of its demonstrated benefit for both prophylaxis and treatment of psychiatric disturbances.

Lithium use can be complicated and dangerous in patients who have underlying diseases associated with renal dysfunction, however—such as nephrotic syndromes and SLE—leading some authors to suggest valproic acid or carbamazepine instead.³³ In addition, corticosteroid-induced changes in sodium balance could increase the risk of lithium toxicity.³⁴

When patients cannot tolerate atypical antipsychotics or lithium, case reports support the use of valproic acid, carbamazepine, lamotrigine, or gabapentin to treat symptoms of corticosteroid-induced psychosis.

Related resources

• Cerullo MA. Expect psychiatric side effects from corticosteroid use in the elderly. Geriatrics. 2008;63(1):15-18.
• Sirois F. Steroid psychosis: a review. Gen Hosp Psychiatry. 2003;25:27-33.
• Patten SB, Neutel CI. Corticosteroid-induced adverse psychiatric effects: incidence, diagnosis, and management. Drug Safety. 2000;22(2):111-122.
• Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. Mayo Clin Proc. 2006;81(10):1361-1367.

Drug brand names

• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Corticotropin • Acthar
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Lithium • Lithobid, Eskalith, others
• Methylprednisolone • Medrol
• Olanzapine • Zyprexa
• Phenytoin • Dilantin
• Prednisone • Deltasone
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

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

Mrs. E, age 31, develops rapid, pressured speech and insomnia for 4 consecutive nights, but reports a normal energy level after receiving high-dose methylprednisolone for an acute flare of systemic lupus erythematosus (SLE).

Her medical history indicates an overlap syndrome between SLE and systemic sclerosis for the last 5 years, migraine headaches, and 4 spontaneous miscarriages, but she has no psychiatric history. Her family history is negative for psychiatric illness and positive for diabetes mellitus, hypertension, and coronary artery disease.

Mrs. E lives with her husband and 10-year-old son. She admits to multiple stressors, including her health problems and financial dificulties, which recently led to the family’s decision to move to her mother-in-law’s house. Mrs. E denies using illicit drugs, cigarettes, or alcohol.

Mrs. E is admitted to the hospital, and her corticosteroid dosage is reduced with a switch to prednisone, 60 mg/d. She is started on risperidone, 1 mg at bedtime, which is titrated without adverse effect. Her psychotic symptoms improve over 4 days, and she is discharged on prednisone, 60 mg/d, and risperidone, 0.5 mg in the morning and 2 mg at night.

After completing her corticosteroid course, Mrs. E experiences complete resolution of psychiatric symptoms and is tapered off risperidone after 6 months.

Corticosteroid use can cause a variety of psychiatric syndromes, including mania, psychosis, depression, and delirium. A meta-analysis reports severe psychotic reactions in 5.7% of patients taking corticosteroids and mild-to-moderate reactions in 28% of patients.¹ Hypomania, mania, and psychosis are the most common psychiatric reactions to acute corticosteroid therapy.² This article reviews case reports and open-label trials of antipsychotics, mood stabilizers, and anticonvulsants to treat corticosteroid-induced mania and psychosis and outlines treatment options.

Symptoms

Corticosteroid-induced psychosis represents a spectrum of psychological changes that can occur at any time during treatment. Mild-to-moderate symptoms include agitation, anxiety, insomnia, irritability, and restlessness, whereas severe symptoms include mania, depression, and psychosis.³ Case reports reveal:

• mania and hypomania in 35% of patients with corticosteroid-induced psychosis
• acute psychotic disorder in 24% of patients, with hallucinations reported in one-half of these cases
• depression, which is more common with chronic corticosteroid therapy, in 28% of patients.⁴

Delirium and cognitive deficits also have been reported, although these symptoms generally subside with corticosteroid reduction or withdrawal.^4,5

Psychiatric symptoms often develop after 4 days of corticosteroid therapy, although they can occur late in therapy or after treatment ends.⁶ Delirium often resolves within a few days, psychosis within 7 days, and mania within 2 to 3 weeks, whereas depression can last for more than 3 weeks.⁴ A 3-level grading system can gauge severity of corticosteroid-induced psychosis; grade 2 or 3 warrants treatment (Table 1).⁴

Table 1

Grading scale for corticosteroid-induced psychiatric symptoms

Risk factors

High corticosteroid dose is the primary risk factor for psychosis. The Boston Collaborative Drug Surveillance Program reported that among individuals taking prednisone, psychiatric disturbances are seen in:

• 1.3% of patients taking <40 mg/d
• 4.6% of patients taking 40 to 80 mg/d
• 18.4% of patients taking >80 mg/d.⁷

However, the corticosteroid dosage does not predict onset, severity, type of reaction, or duration.^3,7 Female patients are at higher risk of corticosteroid-induced psychosis, even after one controls for medical conditions diagnosed more often in women, such as SLE and rheumatoid arthritis.³ Previous episodes of corticosteroid-induced psychosis, history of psychiatric illness, and age are not associated with corticosteroid-induced psychosis.³

Treatment

Management includes tapering corticosteroids, with or without adding medications to treat the acute state. Decreasing corticosteroids to the lowest dose possible—<40 mg/d—or gradually discontinuing therapy to prevent triggering adrenal insufficiency may improve psychotic symptoms and avoids the risk of adverse effects from adjunctive medications.

Psychopharmacologic treatment may be necessary, depending on the severity of psychosis or the underlying disease, particularly if corticosteroids cannot be tapered or discontinued. Evidence from open-label trials (Table 2)^8-12 and case reports indicates that psychotic symptoms could be prevented and treated with off-label antipsychotics, mood stabilizers, and anticonvulsants.

Consider your patient’s underlying medical condition when selecting psychotropics. For example, try to avoid prescribing:

• antipsychotics to patients with cardiac conduction abnormalities
• lithium to patients who need diuretic or angiotensin-converting enzyme inhibitor therapy or those with underlying renal insufficiency.

When appropriate, collaborate with the provider who prescribed the corticosteroids because tapering or discontinuation might not be possible.

Table 2

Corticosteroid-induced psychosis: Adjunctive treatment studies

Antipsychotics

Open-label trial. Olanzapine reduced psychiatric symptoms in a 5-week, open-label trial of 12 outpatients experiencing manic or mixed symptoms secondary to corticosteroids.⁸ At baseline, patients had a mean score of 15.25 on the Young Mania Rating Scale (YMRS) on a mean prednisone dose of 14.4 mg/d. After receiving olanzapine, 2.5 mg/d titrated to a maximum 20 mg/d (mean 8.5 mg/d), subjects demonstrated a significant decrease on the YMRS (P=.002), Hamilton Rating Scale for Depression (HRSD) (P=.005), and Brief Psychiatric Rating Scale (BPRS) (P=.006) with no change in extrapyramidal side-effect scales, weight, or glucose measurements.

Case reports. Among antipsychotics, olanzapine has the greatest number of case reports for treating corticosteroid-induced psychosis, mainly for mania.^13-15 Benefit with olanzapine was demonstrated at dosages from 2.5 to 15 mg/d and improvement occurred within days to weeks. Several patients remained symptom-free with olanzapine and continued corticosteroid therapy.

Other reports describe benefit with risperidone for a variety of psychiatric symptoms—including hypomania, hallucinations, and delusions—associated with corticosteroid therapy.^16-19 Risperidone dosing ranged from 1 to 4 mg/d, and symptoms improved within days to weeks.

One case report describes quetiapine for the treatment of corticosteroid-induced mania.²⁰ The patient’s symptoms improved within 10 hours of initiating quetiapine, 25 mg/d, and YMRS score decreased from 31 before therapy to 5 at discharge. No case reports exist for ziprasidone or aripiprazole.

Mood stabilizers

Cohort study. One study suggests that lithium may be effective for preventing and treating corticosteroid-induced psychosis. A retrospective cohort study examined records of patients diagnosed with multiple sclerosis or retrobulbar neuritis who were treated with corticotropin.⁹ Corticotropin has been reported to cause psychotic reactions in up to 11% of patients through a mechanism thought to mirror corticosteroid-induced psychosis (Box).^21-23 Psychiatric symptoms developed in 38% of patients treated with lithium compared with 62% of controls. No patients pretreated with lithium maintained at 0.8 to 1.2 mEq/L reported mood disturbances or psychotic reactions.

Case reports. Among mood stabilizers, lithium has the greatest number of case reports on its use for prevention and treatment of corticosteroid-induced psychosis. In these reports, patients pretreated with lithium did not experience a relapse of psychosis related to chronic corticosteroid therapy.^24-27 Case reports also describe benefit with valproic acid and carbamazepine.^28-30

Anticonvulsants

Trials. In a 1-week trial, 39 patients without previous psychiatric diagnosis or psychotropic use were randomly assigned to phenytoin, 300 mg/d, or placebo as prednisone therapy was initiated.¹⁰ Compared with placebo, the phenytoin group reported a smaller increase on the Internal State Scale Activation subscale (ACT), a self-report measure of mania symptom severity. No significant differences were found on the YMRS or HRSD scales. Based on the ACT scale finding, the authors concluded that phenytoin attenuated manic or hypomanic effects of prednisone.

A study of levetiracetam, 1500 mg/d, showed no significant change in HRSD, YMRS, or ACT scores from baseline to end point for either levetiracetam or placebo.¹¹

A 12-week, open-label trial of lamotrigine in 5 patients receiving corticosteroids continuously for 6 months showed no significant difference in mood changes as measured by the HRSD, YMRS, or the depression sub-scale of the Internal State Scale.¹²

Case reports show that lamotrigine and gabapentin have been used effectively to prevent manic symptoms in patients receiving corticosteroid therapy.^31,32

Treatment recommendations

Establishing a treatment algorithm for corticosteroid-induced psychosis is hampered by the lack of prospective placebo-controlled trials. However, most case reports describe benefit from administrating atypical antipsychotics and lithium.

Box

Consider adding a low-dose atypical antipsychotic with which case studies report quick symptom resolution and patients tolerating these agents. Monitor carefully for metabolic changes, a risk associated with antipsychotics and corticosteroids. Lithium would be a good second-line therapy because of its demonstrated benefit for both prophylaxis and treatment of psychiatric disturbances.

Lithium use can be complicated and dangerous in patients who have underlying diseases associated with renal dysfunction, however—such as nephrotic syndromes and SLE—leading some authors to suggest valproic acid or carbamazepine instead.³³ In addition, corticosteroid-induced changes in sodium balance could increase the risk of lithium toxicity.³⁴

When patients cannot tolerate atypical antipsychotics or lithium, case reports support the use of valproic acid, carbamazepine, lamotrigine, or gabapentin to treat symptoms of corticosteroid-induced psychosis.

Related resources

• Cerullo MA. Expect psychiatric side effects from corticosteroid use in the elderly. Geriatrics. 2008;63(1):15-18.
• Sirois F. Steroid psychosis: a review. Gen Hosp Psychiatry. 2003;25:27-33.
• Patten SB, Neutel CI. Corticosteroid-induced adverse psychiatric effects: incidence, diagnosis, and management. Drug Safety. 2000;22(2):111-122.
• Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. Mayo Clin Proc. 2006;81(10):1361-1367.

Drug brand names

• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Corticotropin • Acthar
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Lithium • Lithobid, Eskalith, others
• Methylprednisolone • Medrol
• Olanzapine • Zyprexa
• Phenytoin • Dilantin
• Prednisone • Deltasone
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

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

Individuals who abuse substances often have comorbid psychiatric disorders—80% of alcoholics have another axis I disorder¹—and the reverse also is true. More than one-half of schizophrenia patients and 30% of anxiety and affective disorder patients abuse substances.¹

In addition to worsening psychiatric illnesses and interfering with proper treatment, alcohol and other substances can lead to serious cardiac, neurologic, pulmonary, or gastrointestinal complications that can linger even after your patient stops abusing drugs. This article provides an overview of common medical complications related to using alcohol, marijuana, cocaine, methamphetamines, and opioids.

Alcohol

Because some consequences of alcohol abuse (Table 1) are thought to be dose-dependent, ask about your patient’s alcohol consumption. Moderate drinking is defined as up to 2 drinks/day for men and 1 drink/day for women.² Heavy drinking is ≥5 drinks/day (or ≥15 drinks/week) for men and ≥4/day (or ≥8/week) for women.³ A drink contains 12.5 grams of ethanol and is defined as:

• 12 oz (360 mL) of beer or wine cooler
• 5 oz (150 mL) of wine
• 1.5 oz (45 mL) of 80-proof distilled spirits.³

Gastrointestinal effects. Chronic heavy alcohol consumption can lead to fatty liver (steatosis), alcoholic hepatitis, and cirrhosis. Steatosis—the first stage of alcoholic liver disease—can occur from heavy drinking for just a few days but can be reversed with abstinence from alcohol. Prolonged use can lead to alcoholic hepatitis. Symptoms include nausea, lack of appetite, vomiting, fatigue, abdominal pain and tenderness, spider-like blood vessels, and increased bleeding times.

Abstinence might not reverse liver damage from alcoholic hepatitis, and cirrhosis can still develop. Up to 70% of patients with alcoholic hepatitis will develop cirrhosis.^4,5 Common physical manifestations of cirrhosis include generalized weakness, fatigue, malaise, anorexia with signs of malnutrition, and increased bleeding.

Laboratory findings of elevated aspartate aminotransferase/alanine aminotransferase, gamma-glutamyltransferase, and carbohydrate-deficient transferrin also point to heavy alcohol use.⁶

Acute pancreatitis—the most common cause of hospitalization from alcohol-related GI complications—is seen more often than liver disease.⁷

Cardiovascular effects. Light to moderate drinking may be cardioprotective, but heavy alcohol consumption increases the risk of hypertension and ischemic heart disease.⁸ Incidence of hypertension is two-fold greater in individuals who have >2 drinks/day and highest in those who have >5 drinks/day.⁹

Prolonged excessive alcohol consumption is the leading cause of nonischemic dilated cardiomyopathy. Symptoms of alcoholic cardiomyopathy include fatigue; dyspnea, including paroxysmal nocturnal dyspnea and orthopnea; loss of appetite; irregular pulse; productive cough with pink/frothy material; lower extremity edema; and nocturia.¹⁰ Cardiac function can recover with early diagnosis and alcohol abstinence.¹¹

Cognitive decline. The effects of light drinking on cognitive function are controversial, but heavy consumption—especially at ≥30 drinks/week—is known to cause impairment.¹² Alcohol-dependent individuals have been shown to have impaired verbal fluency, working memory, and frontal function as is seen in Alzheimer’s disease.¹³ One possible factor contributing to cognitive dysfunction is cortical volume loss in chronic alcoholics.¹²

To read how nicotine plus alcohol increases the risk of heart disease and brain atrophy, click here.

To read about the medical complications of nicotine, click here.

Table 1

Medical complications of alcohol abuse

Marijuana

Marijuana is the most commonly abused illicit substance worldwide, and data show an increasing prevalence of marijuana abuse and dependence (32% of U.S. 12th graders endorsed its use in 2007).¹⁴

In many populations marijuana use seems to precede use of cocaine, opioids, or other substances.¹⁵ Although the concept of marijuana as a “gateway drug” is still debated, consider the possibility that your patients who use marijuana also are using other illicit substances. In a 2004 survey, 19% of marijuana users admitted to use of other illicit drugs.¹⁶ Although many people consider marijuana a “safe” drug, it can cause adverse effects (Table 2).

Pulmonary complications. Even infrequent marijuana use can lead to burning and stinging of the mouth and throat, usually accompanied by a heavy cough. Regular users may develop complications similar to chronic tobacco use: daily cough, chronic phlegm production, susceptibility to lung infections (such as acute bronchitis), and potential for airway obstruction.^17,18

Marijuana use can double or triple the risk of cancer of the respiratory tract and lungs.¹⁹ Tetrahydrocannabinol—the active chemical in marijuana—might contribute to this risk because it can augment oxidative stress, lead to mitochondrial dysfunction, and inhibit apoptosis.¹⁹

Cardiac complications. Acute marijuana use causes tachycardia, increases supine blood pressure, and decreases standing blood pressure, resulting in dizziness, syncope, falls, and possible injuries.^20,21 Increased cardiac output and cardiac work—coupled with a decreased capacity to carry oxygen—can lead to angina or acute coronary syndrome, especially in older adults with preexisting cardiovascular disease.²¹ Growing evidence shows that marijuana use could lead to cardiac arrhythmias, such as atrial fibrillation.²⁰ Long-term heavy users seem to develop tolerance to some cardiovascular effects, but blood volume overall increases, heart rate slows, and circulatory responses to exercise are diminished.¹⁸

Cognitive impairment. Chronic marijuana users might experience cognitive impairment—particularly on memory of word lists and attention tasks²²—but there is debate as to whether these deficits are stable or temporary. Some studies show persistent cognitive impairments in longer-term cannabis users, even after 2 years of abstinence.²² However, most studies suggest that marijuana-associated cognitive deficits are reversible and related to recent exposure.¹⁸

Table 2

Medical complications of marijuana use

Cocaine

Cocaine is the most frequent cause of drug-related death, particularly when combined with alcohol.²³

Chronic nasal insufflations can cause loss of sense of smell, nosebleeds, dysphagia, hoarseness, and overall irritation of the nasal septum, which in turn can lead to chronic mucosal inflammation and rhinorrhea.²⁴ Intravenous users often have puncture marks or “tracks,” usually on the forearms, and are predisposed to infectious diseases such as human immunodeficiency virus (HIV) and other blood-borne infections.^24,25 Regular cocaine ingestion can lead to bowel gangrene because of reduced blood flow and orofacial complications.²⁴ Asking about how your patient ingests cocaine will guide your evaluation of possible medical complications (Table 3).

Cardiac complications. Recent cocaine use is a common cause of chest pain. A 2002 survey reported that 25% of patients in urban hospitals and 13% in rural settings presenting with nontraumatic chest pain tested positive for cocaine use.²⁶ Although cocaine can lead to ventricular fibrillation, tachycardia, and increased blood pressure, its main mechanism for inducing chest pain and myocardial infarction (MI) is coronary vasospasm, especially of diseased vessels. The acute risk of MI is increased by a factor of 24 in the first 60 minutes after cocaine use.²³ Chronic use promotes thrombus formation, leading to atherosclerotic disease.²³ Recurrent chest pain in a young, otherwise healthy individual could indicate cocaine abuse.

Neurologic complications. Headache is the most common neurologic complication of cocaine use. Although usually associated with intoxication or withdrawal, headaches can become chronic with chronic use.²⁵ Reduced seizure threshold also has been reported with cocaine use, particularly in patients with cerebral lesions, and most seizures occur with first-time use. Isolated events might not require anticonvulsant therapy, although referral to a neurologist is recommended.²⁷

Cocaine use puts individuals at higher risk for subarachnoid hemorrhage, intracerebral bleed, ischemic stroke, and transient ischemic attacks. The route of cocaine ingestion seems to influence the type of stroke: IV and intranasal use are associated with hemorrhagic stroke, and inhalation with ischemic stroke.²⁵

Table 3

Medical complications of cocaine use

Methamphetamine

Like many illicit substances, methamphetamine can be taken in many forms.

• “Speed,” a powder form, can be snorted or injected.
• “Base” is a powder with higher purity.
• “Ice,” also known as “crystal,” has very high purity and can be smoked, “chased” (cooked on aluminum foil and smoked), mixed with marijuana, or injected.²⁸

Evaluate meth-abusing patients for many of the same medical complications associated with cocaine and other stimulants. Acute effects include hypertension, tachycardia, and arrhythmias; chronic effects include stroke and cardiac valve sclerosis. Pulmonary hypertension can occur when the drug is smoked (Table 4).²⁸

Dental complications. Originally believed to result from the acidity of methamphetamine, advanced tooth decay or “meth mouth” is thought to be caused by decreased production of saliva—a consequence of increased sympathetic activity—combined with overall decreased oral intake, sugar and soft drink consumption, and poor oral hygiene. Methamphetamine abusers often experience bruxism, which exacerbates tooth decay.²⁹

Neurologic changes. Chronic methamphetamine use is characterized by poor cognitive functioning and emotional changes such as paranoia and depression.²⁹ These are believed to be caused by neuropathologic changes in the cortex, striatum, and hippocampus.

Table 4

Medical complications of methamphetamine abuse

Opioids

Prescriptions of opioid analgesics for chronic pain—and their subsequent diversion—are the main conduit to nonmedical use.³⁰ IV heroin use is the most common cause of illicit drug overdose.³¹ Opioids are used by:

• ingestion, usually of synthetic analgesics (prescription drugs)
• parenteral administration, often IV heroin
• inhalation, a pure form that is heated and burned.

Infectious complications. Injection drug use—especially with unsterilized shared needles—is an efficient vector for blood-borne infections. Needle sharing is the most common cause of new HIV and viral hepatitis infections.³² All IV drug users should be routinely tested for these viral infections. Chronic IV drug use can cause vein sclerosis, leading to visible “track marks” and, rarely, thromboembolic events. Be alert for integumentary infections—especially in patients who “skin pop” drugs by injecting them under the skin—or systemic infectious diseases, such as skin abscesses, cellulitis, septicemia, botulism, or bacterial endocarditis (Table 5).³³

Pulmonary complications. Overstimulation of opioid receptors in the brainstem and carotid bodies can cause slow and irregular respiration and decreased gag and coughing reflex during acute intoxication. The rate of opioid intake appears to play a role; a gradual increase in opioid blood levels leads to progressive respiratory depression by causing gradual hypercapnia, and a quick rise in receptor occupancy can lead to rapid apnea. Therefore opioids with slow receptor binding, such as buprenorphine, may be safer than those that bind more quickly, such as fentanyl. However, all opioids can cause this dangerous side effect.³⁴ Inhaled forms of heroin have also been shown to lead to status asthmaticus.³⁵

Table 5

Medical complications of opioid abuse

Cardiac and neurologic complications. Methadone use could prolong the QTc interval, leading to dysrhythmias such as torsades de pointes. Higher doses increase the incidence of syncope.³⁶ Ongoing monitoring of the QTc interval is warranted for all patients on methadone.

Neurologic effects of opioids include:

• delayed leukoencephalopathy with IV overdose and inhaled preheated heroin, known as ”chasing the dragon”
• widespread cortical dysfunction (abulia, lack of volition, hemineglect,³⁷ and deficits in executive functioning and emotional processing) leading to impaired decision-making.³⁸

Related resources

• National Institute on Drug Abuse. www.nida.nih.gov.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• Johnston LD, O’Malley PM, Bachman JG, et al. Monitoring the Future national survey results on drug use, 1975-2008. Volume I: Secondary school students. Bethesda, MD: National Institute on Drug Abuse; 2009. NIH Publication No. 09-7402.

Drug brand names

• Buprenorphine • Subutex
• Fentanyl • Actiq, Duragesic, others
• Methadone • Dolophine, Methadose

Disclosures

Drs. Khan and Morrow report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. McCarron is a consultant to Eli Lilly and Company.

Individuals who abuse substances often have comorbid psychiatric disorders—80% of alcoholics have another axis I disorder¹—and the reverse also is true. More than one-half of schizophrenia patients and 30% of anxiety and affective disorder patients abuse substances.¹

In addition to worsening psychiatric illnesses and interfering with proper treatment, alcohol and other substances can lead to serious cardiac, neurologic, pulmonary, or gastrointestinal complications that can linger even after your patient stops abusing drugs. This article provides an overview of common medical complications related to using alcohol, marijuana, cocaine, methamphetamines, and opioids.

Alcohol

Because some consequences of alcohol abuse (Table 1) are thought to be dose-dependent, ask about your patient’s alcohol consumption. Moderate drinking is defined as up to 2 drinks/day for men and 1 drink/day for women.² Heavy drinking is ≥5 drinks/day (or ≥15 drinks/week) for men and ≥4/day (or ≥8/week) for women.³ A drink contains 12.5 grams of ethanol and is defined as:

• 12 oz (360 mL) of beer or wine cooler
• 5 oz (150 mL) of wine
• 1.5 oz (45 mL) of 80-proof distilled spirits.³

Gastrointestinal effects. Chronic heavy alcohol consumption can lead to fatty liver (steatosis), alcoholic hepatitis, and cirrhosis. Steatosis—the first stage of alcoholic liver disease—can occur from heavy drinking for just a few days but can be reversed with abstinence from alcohol. Prolonged use can lead to alcoholic hepatitis. Symptoms include nausea, lack of appetite, vomiting, fatigue, abdominal pain and tenderness, spider-like blood vessels, and increased bleeding times.

Abstinence might not reverse liver damage from alcoholic hepatitis, and cirrhosis can still develop. Up to 70% of patients with alcoholic hepatitis will develop cirrhosis.^4,5 Common physical manifestations of cirrhosis include generalized weakness, fatigue, malaise, anorexia with signs of malnutrition, and increased bleeding.

Laboratory findings of elevated aspartate aminotransferase/alanine aminotransferase, gamma-glutamyltransferase, and carbohydrate-deficient transferrin also point to heavy alcohol use.⁶

Acute pancreatitis—the most common cause of hospitalization from alcohol-related GI complications—is seen more often than liver disease.⁷

Cardiovascular effects. Light to moderate drinking may be cardioprotective, but heavy alcohol consumption increases the risk of hypertension and ischemic heart disease.⁸ Incidence of hypertension is two-fold greater in individuals who have >2 drinks/day and highest in those who have >5 drinks/day.⁹

Prolonged excessive alcohol consumption is the leading cause of nonischemic dilated cardiomyopathy. Symptoms of alcoholic cardiomyopathy include fatigue; dyspnea, including paroxysmal nocturnal dyspnea and orthopnea; loss of appetite; irregular pulse; productive cough with pink/frothy material; lower extremity edema; and nocturia.¹⁰ Cardiac function can recover with early diagnosis and alcohol abstinence.¹¹

Cognitive decline. The effects of light drinking on cognitive function are controversial, but heavy consumption—especially at ≥30 drinks/week—is known to cause impairment.¹² Alcohol-dependent individuals have been shown to have impaired verbal fluency, working memory, and frontal function as is seen in Alzheimer’s disease.¹³ One possible factor contributing to cognitive dysfunction is cortical volume loss in chronic alcoholics.¹²

To read how nicotine plus alcohol increases the risk of heart disease and brain atrophy, click here.

To read about the medical complications of nicotine, click here.

Table 1

Medical complications of alcohol abuse

Marijuana

Marijuana is the most commonly abused illicit substance worldwide, and data show an increasing prevalence of marijuana abuse and dependence (32% of U.S. 12th graders endorsed its use in 2007).¹⁴

In many populations marijuana use seems to precede use of cocaine, opioids, or other substances.¹⁵ Although the concept of marijuana as a “gateway drug” is still debated, consider the possibility that your patients who use marijuana also are using other illicit substances. In a 2004 survey, 19% of marijuana users admitted to use of other illicit drugs.¹⁶ Although many people consider marijuana a “safe” drug, it can cause adverse effects (Table 2).

Pulmonary complications. Even infrequent marijuana use can lead to burning and stinging of the mouth and throat, usually accompanied by a heavy cough. Regular users may develop complications similar to chronic tobacco use: daily cough, chronic phlegm production, susceptibility to lung infections (such as acute bronchitis), and potential for airway obstruction.^17,18

Marijuana use can double or triple the risk of cancer of the respiratory tract and lungs.¹⁹ Tetrahydrocannabinol—the active chemical in marijuana—might contribute to this risk because it can augment oxidative stress, lead to mitochondrial dysfunction, and inhibit apoptosis.¹⁹

Cardiac complications. Acute marijuana use causes tachycardia, increases supine blood pressure, and decreases standing blood pressure, resulting in dizziness, syncope, falls, and possible injuries.^20,21 Increased cardiac output and cardiac work—coupled with a decreased capacity to carry oxygen—can lead to angina or acute coronary syndrome, especially in older adults with preexisting cardiovascular disease.²¹ Growing evidence shows that marijuana use could lead to cardiac arrhythmias, such as atrial fibrillation.²⁰ Long-term heavy users seem to develop tolerance to some cardiovascular effects, but blood volume overall increases, heart rate slows, and circulatory responses to exercise are diminished.¹⁸

Cognitive impairment. Chronic marijuana users might experience cognitive impairment—particularly on memory of word lists and attention tasks²²—but there is debate as to whether these deficits are stable or temporary. Some studies show persistent cognitive impairments in longer-term cannabis users, even after 2 years of abstinence.²² However, most studies suggest that marijuana-associated cognitive deficits are reversible and related to recent exposure.¹⁸

Table 2

Medical complications of marijuana use

Cocaine

Cocaine is the most frequent cause of drug-related death, particularly when combined with alcohol.²³

Chronic nasal insufflations can cause loss of sense of smell, nosebleeds, dysphagia, hoarseness, and overall irritation of the nasal septum, which in turn can lead to chronic mucosal inflammation and rhinorrhea.²⁴ Intravenous users often have puncture marks or “tracks,” usually on the forearms, and are predisposed to infectious diseases such as human immunodeficiency virus (HIV) and other blood-borne infections.^24,25 Regular cocaine ingestion can lead to bowel gangrene because of reduced blood flow and orofacial complications.²⁴ Asking about how your patient ingests cocaine will guide your evaluation of possible medical complications (Table 3).

Cardiac complications. Recent cocaine use is a common cause of chest pain. A 2002 survey reported that 25% of patients in urban hospitals and 13% in rural settings presenting with nontraumatic chest pain tested positive for cocaine use.²⁶ Although cocaine can lead to ventricular fibrillation, tachycardia, and increased blood pressure, its main mechanism for inducing chest pain and myocardial infarction (MI) is coronary vasospasm, especially of diseased vessels. The acute risk of MI is increased by a factor of 24 in the first 60 minutes after cocaine use.²³ Chronic use promotes thrombus formation, leading to atherosclerotic disease.²³ Recurrent chest pain in a young, otherwise healthy individual could indicate cocaine abuse.

Neurologic complications. Headache is the most common neurologic complication of cocaine use. Although usually associated with intoxication or withdrawal, headaches can become chronic with chronic use.²⁵ Reduced seizure threshold also has been reported with cocaine use, particularly in patients with cerebral lesions, and most seizures occur with first-time use. Isolated events might not require anticonvulsant therapy, although referral to a neurologist is recommended.²⁷

Cocaine use puts individuals at higher risk for subarachnoid hemorrhage, intracerebral bleed, ischemic stroke, and transient ischemic attacks. The route of cocaine ingestion seems to influence the type of stroke: IV and intranasal use are associated with hemorrhagic stroke, and inhalation with ischemic stroke.²⁵

Table 3

Medical complications of cocaine use

Methamphetamine

Like many illicit substances, methamphetamine can be taken in many forms.

• “Speed,” a powder form, can be snorted or injected.
• “Base” is a powder with higher purity.
• “Ice,” also known as “crystal,” has very high purity and can be smoked, “chased” (cooked on aluminum foil and smoked), mixed with marijuana, or injected.²⁸

Evaluate meth-abusing patients for many of the same medical complications associated with cocaine and other stimulants. Acute effects include hypertension, tachycardia, and arrhythmias; chronic effects include stroke and cardiac valve sclerosis. Pulmonary hypertension can occur when the drug is smoked (Table 4).²⁸

Dental complications. Originally believed to result from the acidity of methamphetamine, advanced tooth decay or “meth mouth” is thought to be caused by decreased production of saliva—a consequence of increased sympathetic activity—combined with overall decreased oral intake, sugar and soft drink consumption, and poor oral hygiene. Methamphetamine abusers often experience bruxism, which exacerbates tooth decay.²⁹

Neurologic changes. Chronic methamphetamine use is characterized by poor cognitive functioning and emotional changes such as paranoia and depression.²⁹ These are believed to be caused by neuropathologic changes in the cortex, striatum, and hippocampus.

Table 4

Medical complications of methamphetamine abuse

Opioids

Prescriptions of opioid analgesics for chronic pain—and their subsequent diversion—are the main conduit to nonmedical use.³⁰ IV heroin use is the most common cause of illicit drug overdose.³¹ Opioids are used by:

• ingestion, usually of synthetic analgesics (prescription drugs)
• parenteral administration, often IV heroin
• inhalation, a pure form that is heated and burned.

Infectious complications. Injection drug use—especially with unsterilized shared needles—is an efficient vector for blood-borne infections. Needle sharing is the most common cause of new HIV and viral hepatitis infections.³² All IV drug users should be routinely tested for these viral infections. Chronic IV drug use can cause vein sclerosis, leading to visible “track marks” and, rarely, thromboembolic events. Be alert for integumentary infections—especially in patients who “skin pop” drugs by injecting them under the skin—or systemic infectious diseases, such as skin abscesses, cellulitis, septicemia, botulism, or bacterial endocarditis (Table 5).³³

Pulmonary complications. Overstimulation of opioid receptors in the brainstem and carotid bodies can cause slow and irregular respiration and decreased gag and coughing reflex during acute intoxication. The rate of opioid intake appears to play a role; a gradual increase in opioid blood levels leads to progressive respiratory depression by causing gradual hypercapnia, and a quick rise in receptor occupancy can lead to rapid apnea. Therefore opioids with slow receptor binding, such as buprenorphine, may be safer than those that bind more quickly, such as fentanyl. However, all opioids can cause this dangerous side effect.³⁴ Inhaled forms of heroin have also been shown to lead to status asthmaticus.³⁵

Table 5

Medical complications of opioid abuse

Cardiac and neurologic complications. Methadone use could prolong the QTc interval, leading to dysrhythmias such as torsades de pointes. Higher doses increase the incidence of syncope.³⁶ Ongoing monitoring of the QTc interval is warranted for all patients on methadone.

Neurologic effects of opioids include:

• delayed leukoencephalopathy with IV overdose and inhaled preheated heroin, known as ”chasing the dragon”
• widespread cortical dysfunction (abulia, lack of volition, hemineglect,³⁷ and deficits in executive functioning and emotional processing) leading to impaired decision-making.³⁸

Related resources

• National Institute on Drug Abuse. www.nida.nih.gov.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• Johnston LD, O’Malley PM, Bachman JG, et al. Monitoring the Future national survey results on drug use, 1975-2008. Volume I: Secondary school students. Bethesda, MD: National Institute on Drug Abuse; 2009. NIH Publication No. 09-7402.

Drug brand names

• Buprenorphine • Subutex
• Fentanyl • Actiq, Duragesic, others
• Methadone • Dolophine, Methadose

Disclosures

Drs. Khan and Morrow report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. McCarron is a consultant to Eli Lilly and Company.

Individuals who abuse substances often have comorbid psychiatric disorders—80% of alcoholics have another axis I disorder¹—and the reverse also is true. More than one-half of schizophrenia patients and 30% of anxiety and affective disorder patients abuse substances.¹

In addition to worsening psychiatric illnesses and interfering with proper treatment, alcohol and other substances can lead to serious cardiac, neurologic, pulmonary, or gastrointestinal complications that can linger even after your patient stops abusing drugs. This article provides an overview of common medical complications related to using alcohol, marijuana, cocaine, methamphetamines, and opioids.

Alcohol

Because some consequences of alcohol abuse (Table 1) are thought to be dose-dependent, ask about your patient’s alcohol consumption. Moderate drinking is defined as up to 2 drinks/day for men and 1 drink/day for women.² Heavy drinking is ≥5 drinks/day (or ≥15 drinks/week) for men and ≥4/day (or ≥8/week) for women.³ A drink contains 12.5 grams of ethanol and is defined as:

• 12 oz (360 mL) of beer or wine cooler
• 5 oz (150 mL) of wine
• 1.5 oz (45 mL) of 80-proof distilled spirits.³

Gastrointestinal effects. Chronic heavy alcohol consumption can lead to fatty liver (steatosis), alcoholic hepatitis, and cirrhosis. Steatosis—the first stage of alcoholic liver disease—can occur from heavy drinking for just a few days but can be reversed with abstinence from alcohol. Prolonged use can lead to alcoholic hepatitis. Symptoms include nausea, lack of appetite, vomiting, fatigue, abdominal pain and tenderness, spider-like blood vessels, and increased bleeding times.

Abstinence might not reverse liver damage from alcoholic hepatitis, and cirrhosis can still develop. Up to 70% of patients with alcoholic hepatitis will develop cirrhosis.^4,5 Common physical manifestations of cirrhosis include generalized weakness, fatigue, malaise, anorexia with signs of malnutrition, and increased bleeding.

Laboratory findings of elevated aspartate aminotransferase/alanine aminotransferase, gamma-glutamyltransferase, and carbohydrate-deficient transferrin also point to heavy alcohol use.⁶

Acute pancreatitis—the most common cause of hospitalization from alcohol-related GI complications—is seen more often than liver disease.⁷

Cardiovascular effects. Light to moderate drinking may be cardioprotective, but heavy alcohol consumption increases the risk of hypertension and ischemic heart disease.⁸ Incidence of hypertension is two-fold greater in individuals who have >2 drinks/day and highest in those who have >5 drinks/day.⁹

Prolonged excessive alcohol consumption is the leading cause of nonischemic dilated cardiomyopathy. Symptoms of alcoholic cardiomyopathy include fatigue; dyspnea, including paroxysmal nocturnal dyspnea and orthopnea; loss of appetite; irregular pulse; productive cough with pink/frothy material; lower extremity edema; and nocturia.¹⁰ Cardiac function can recover with early diagnosis and alcohol abstinence.¹¹

Cognitive decline. The effects of light drinking on cognitive function are controversial, but heavy consumption—especially at ≥30 drinks/week—is known to cause impairment.¹² Alcohol-dependent individuals have been shown to have impaired verbal fluency, working memory, and frontal function as is seen in Alzheimer’s disease.¹³ One possible factor contributing to cognitive dysfunction is cortical volume loss in chronic alcoholics.¹²

To read how nicotine plus alcohol increases the risk of heart disease and brain atrophy, click here.

To read about the medical complications of nicotine, click here.

Table 1

Medical complications of alcohol abuse

Marijuana

Marijuana is the most commonly abused illicit substance worldwide, and data show an increasing prevalence of marijuana abuse and dependence (32% of U.S. 12th graders endorsed its use in 2007).¹⁴

In many populations marijuana use seems to precede use of cocaine, opioids, or other substances.¹⁵ Although the concept of marijuana as a “gateway drug” is still debated, consider the possibility that your patients who use marijuana also are using other illicit substances. In a 2004 survey, 19% of marijuana users admitted to use of other illicit drugs.¹⁶ Although many people consider marijuana a “safe” drug, it can cause adverse effects (Table 2).

Pulmonary complications. Even infrequent marijuana use can lead to burning and stinging of the mouth and throat, usually accompanied by a heavy cough. Regular users may develop complications similar to chronic tobacco use: daily cough, chronic phlegm production, susceptibility to lung infections (such as acute bronchitis), and potential for airway obstruction.^17,18

Marijuana use can double or triple the risk of cancer of the respiratory tract and lungs.¹⁹ Tetrahydrocannabinol—the active chemical in marijuana—might contribute to this risk because it can augment oxidative stress, lead to mitochondrial dysfunction, and inhibit apoptosis.¹⁹

Cardiac complications. Acute marijuana use causes tachycardia, increases supine blood pressure, and decreases standing blood pressure, resulting in dizziness, syncope, falls, and possible injuries.^20,21 Increased cardiac output and cardiac work—coupled with a decreased capacity to carry oxygen—can lead to angina or acute coronary syndrome, especially in older adults with preexisting cardiovascular disease.²¹ Growing evidence shows that marijuana use could lead to cardiac arrhythmias, such as atrial fibrillation.²⁰ Long-term heavy users seem to develop tolerance to some cardiovascular effects, but blood volume overall increases, heart rate slows, and circulatory responses to exercise are diminished.¹⁸

Cognitive impairment. Chronic marijuana users might experience cognitive impairment—particularly on memory of word lists and attention tasks²²—but there is debate as to whether these deficits are stable or temporary. Some studies show persistent cognitive impairments in longer-term cannabis users, even after 2 years of abstinence.²² However, most studies suggest that marijuana-associated cognitive deficits are reversible and related to recent exposure.¹⁸

Table 2

Medical complications of marijuana use

Cocaine

Cocaine is the most frequent cause of drug-related death, particularly when combined with alcohol.²³

Chronic nasal insufflations can cause loss of sense of smell, nosebleeds, dysphagia, hoarseness, and overall irritation of the nasal septum, which in turn can lead to chronic mucosal inflammation and rhinorrhea.²⁴ Intravenous users often have puncture marks or “tracks,” usually on the forearms, and are predisposed to infectious diseases such as human immunodeficiency virus (HIV) and other blood-borne infections.^24,25 Regular cocaine ingestion can lead to bowel gangrene because of reduced blood flow and orofacial complications.²⁴ Asking about how your patient ingests cocaine will guide your evaluation of possible medical complications (Table 3).

Cardiac complications. Recent cocaine use is a common cause of chest pain. A 2002 survey reported that 25% of patients in urban hospitals and 13% in rural settings presenting with nontraumatic chest pain tested positive for cocaine use.²⁶ Although cocaine can lead to ventricular fibrillation, tachycardia, and increased blood pressure, its main mechanism for inducing chest pain and myocardial infarction (MI) is coronary vasospasm, especially of diseased vessels. The acute risk of MI is increased by a factor of 24 in the first 60 minutes after cocaine use.²³ Chronic use promotes thrombus formation, leading to atherosclerotic disease.²³ Recurrent chest pain in a young, otherwise healthy individual could indicate cocaine abuse.

Neurologic complications. Headache is the most common neurologic complication of cocaine use. Although usually associated with intoxication or withdrawal, headaches can become chronic with chronic use.²⁵ Reduced seizure threshold also has been reported with cocaine use, particularly in patients with cerebral lesions, and most seizures occur with first-time use. Isolated events might not require anticonvulsant therapy, although referral to a neurologist is recommended.²⁷

Cocaine use puts individuals at higher risk for subarachnoid hemorrhage, intracerebral bleed, ischemic stroke, and transient ischemic attacks. The route of cocaine ingestion seems to influence the type of stroke: IV and intranasal use are associated with hemorrhagic stroke, and inhalation with ischemic stroke.²⁵

Table 3

Medical complications of cocaine use

Methamphetamine

Like many illicit substances, methamphetamine can be taken in many forms.

• “Speed,” a powder form, can be snorted or injected.
• “Base” is a powder with higher purity.
• “Ice,” also known as “crystal,” has very high purity and can be smoked, “chased” (cooked on aluminum foil and smoked), mixed with marijuana, or injected.²⁸

Evaluate meth-abusing patients for many of the same medical complications associated with cocaine and other stimulants. Acute effects include hypertension, tachycardia, and arrhythmias; chronic effects include stroke and cardiac valve sclerosis. Pulmonary hypertension can occur when the drug is smoked (Table 4).²⁸

Dental complications. Originally believed to result from the acidity of methamphetamine, advanced tooth decay or “meth mouth” is thought to be caused by decreased production of saliva—a consequence of increased sympathetic activity—combined with overall decreased oral intake, sugar and soft drink consumption, and poor oral hygiene. Methamphetamine abusers often experience bruxism, which exacerbates tooth decay.²⁹

Neurologic changes. Chronic methamphetamine use is characterized by poor cognitive functioning and emotional changes such as paranoia and depression.²⁹ These are believed to be caused by neuropathologic changes in the cortex, striatum, and hippocampus.

Table 4

Medical complications of methamphetamine abuse

Opioids

Prescriptions of opioid analgesics for chronic pain—and their subsequent diversion—are the main conduit to nonmedical use.³⁰ IV heroin use is the most common cause of illicit drug overdose.³¹ Opioids are used by:

• ingestion, usually of synthetic analgesics (prescription drugs)
• parenteral administration, often IV heroin
• inhalation, a pure form that is heated and burned.

Infectious complications. Injection drug use—especially with unsterilized shared needles—is an efficient vector for blood-borne infections. Needle sharing is the most common cause of new HIV and viral hepatitis infections.³² All IV drug users should be routinely tested for these viral infections. Chronic IV drug use can cause vein sclerosis, leading to visible “track marks” and, rarely, thromboembolic events. Be alert for integumentary infections—especially in patients who “skin pop” drugs by injecting them under the skin—or systemic infectious diseases, such as skin abscesses, cellulitis, septicemia, botulism, or bacterial endocarditis (Table 5).³³

Pulmonary complications. Overstimulation of opioid receptors in the brainstem and carotid bodies can cause slow and irregular respiration and decreased gag and coughing reflex during acute intoxication. The rate of opioid intake appears to play a role; a gradual increase in opioid blood levels leads to progressive respiratory depression by causing gradual hypercapnia, and a quick rise in receptor occupancy can lead to rapid apnea. Therefore opioids with slow receptor binding, such as buprenorphine, may be safer than those that bind more quickly, such as fentanyl. However, all opioids can cause this dangerous side effect.³⁴ Inhaled forms of heroin have also been shown to lead to status asthmaticus.³⁵

Table 5

Medical complications of opioid abuse

Cardiac and neurologic complications. Methadone use could prolong the QTc interval, leading to dysrhythmias such as torsades de pointes. Higher doses increase the incidence of syncope.³⁶ Ongoing monitoring of the QTc interval is warranted for all patients on methadone.

Neurologic effects of opioids include:

• delayed leukoencephalopathy with IV overdose and inhaled preheated heroin, known as ”chasing the dragon”
• widespread cortical dysfunction (abulia, lack of volition, hemineglect,³⁷ and deficits in executive functioning and emotional processing) leading to impaired decision-making.³⁸

Related resources

• National Institute on Drug Abuse. www.nida.nih.gov.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• Johnston LD, O’Malley PM, Bachman JG, et al. Monitoring the Future national survey results on drug use, 1975-2008. Volume I: Secondary school students. Bethesda, MD: National Institute on Drug Abuse; 2009. NIH Publication No. 09-7402.

Drug brand names

• Buprenorphine • Subutex
• Fentanyl • Actiq, Duragesic, others
• Methadone • Dolophine, Methadose

Disclosures

Drs. Khan and Morrow report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. McCarron is a consultant to Eli Lilly and Company.

Comment on this article

Ms. G, age 56, presents with the chief complaint of “depression.” Review of symptoms reveals 6 months of depressed mood, anhedonia, tearfulness, 30-pound weight gain, low energy, and bilateral ankle edema. Her psychiatrist orders a thyroid stimulating hormone (TSH) level, which shows 9.51 mU/L (normal range 0.35 to 4.94 mU/L), indicating hypothyroidism. After 1 month of treatment with levothyroxine, Ms. G’s mood symptoms and edema resolve and her weight stabilizes.

A patient who comes to you for treatment of depression might also present with physical symptoms (such as, fatigue, nausea, balance problems, etc.) that could point to a medical illness. Endocrine, neurologic, infectious, and malignant processes (Table 1) and vitamin deficiencies (Table 2) could be causing your patient’s depression. To help differentiate various etiologies of depressive symptoms, we review common medical causes of depression, their distinguishing characteristics, and pertinent treatment issues.

DSM-IV-TR considers major depression secondary to a general medical condition to be diagnostically separate from a major depressive episode. When considering nonpsychiatric causes of depression, begin with a thorough medical history including current and past medications (Table 3),^1-7 illicit substance use, review of systems, and a detailed neurologic exam.

Table 1

Medical conditions with evidence of causing depression

Table 2

Vitamin deficiencies that can lead to depression

Table 3

Medications that may be linked to depressive symptoms

Endocrine disorders

Hypothyroidism increases a patient’s risk of a mood disorder 7-fold, compared with the general population.⁸

Signs and symptoms. Patients with hypothyroidism may complain of constipation, thinning hair, dry skin, edema, sensitivity to cold, goiter, thyroid nodule, or hoarse voice. Symptoms such as fatigue, weight gain, and sleep disturbance overlap with depressive symptoms. A TSH value >4.94 mU/L indicates hypothyroidism and warrants referral to a primary care provider or endocrinologist.

Although the pathophysiology is unclear, 1 study found elevated thyroid peroxide antibodies in depressed postmenopausal women who had abnormal thyroid function tests, suggesting an autoimmune link between depression and hypothyroidism.⁹ In another study, 2.5% of depressed patients had abnormal serum TSH or thyroxine levels indicating hypothyroidism.¹⁰ Thyroid hormones have been used to augment treatment of refractory depression.¹¹

Hyperparathyroidism. “Moans, groans, stones, and psychiatric overtones” describes the constellation of hyperparathyroidism symptoms. As serum calcium levels rise, mood and physical symptoms worsen (Table 4).

Signs and symptoms. Elevated serum calcium (normal range 8.7 to 10.7 mg/dL) and parathyroid hormone (PTH) levels support the diagnosis. Depressive symptoms may diminish or even resolve when calcium levels return to normal after parathyroidectomy.¹²

Cushing’s syndrome (CS). As many as 80% of patients exhibit depressive symptoms when CS is active.¹³

Signs and symptoms. Distinguishing CS symptoms include:

• hirsutism
• truncal obesity
• acne
• hypertension
• facial flushing
• purple striae.

Elevated serum cortisol, the condition’s hallmark, may be caused by pituitary adenomas, adrenal tumors or hyperplasia, or ectopic adrenocorticotropic hormone secretion. The most common cause is exogenous administration of glucocorticoids. A dexamethasone suppression test or 24-hour urine cortisol confirms CS diagnosis.

Depressed CS patients often experience poor concentration, early morning waking, and decreased libido. Compared with nondepressed individuals with CS, those with depression tend to be older (average age 37.5) and more likely to be female, have more severe CS-related symptoms, and exhibit higher urine cortisol levels at diagnosis (average 1.694 pmol/L).^14,15

Antidepressants typically will not resolve depression in patients with CS unless you also correct the hypercorticalism.¹⁶

Addison’s disease (AD). Major depressive disorder is >2 times more prevalent in AD patients compared with matched controls.¹⁷

Signs and symptoms. Hyperpigmentation, salt cravings, low blood pressure, nausea, and vomiting are AD hallmarks. AD patients present with fatigue, vegetative symptoms, weight loss, and weakness that mimics a major depressive episode.

AD is caused by damage to the adrenal cortex. These patients do not have enough of the mineralocorticoid aldosterone, which maintains sodium and potassium balance and regulates blood pressure via the renin-angiotensin-aldosterone pathway. Decreased morning serum cortisol level, hyponatremia, and hyperkalemia confirm the diagnosis. AD can be serious—possibly fatal—so prompt referral to an endocrinologist is warranted.

Table 4

Clinical symptoms of hyperparathyroidism

Neurologic disorders

Stroke. Post-stroke depressive symptoms generally do not differ from endogenous depression. Apathy, catastrophic reactions, hyper emotionalism, and diurnal mood variations are more prevalent in stroke patients,¹⁸ although some of these features have been noted in other neurologic conditions.

Signs and symptoms. Look for depression onset or a change in existing depression symptoms that occurs in the context of a clinically apparent stroke.¹⁹ Antidepressants such as serotonin reuptake inhibitors may relieve post-stroke depression.

Seizures. Depressive symptoms could appear before or after a seizure or may be the clinical presentation of a simple or complex partial seizure.¹

Signs and symptoms. Episodic, short-lived depression that resolves rapidly may warrant a seizure evaluation. Prodromal depressive symptoms such as irritability, depression, fear, or anger²⁰ may precede a seizure by 1 to 3 days and could improve after the seizure.

Caused by a simple partial seizure, ictal depression is characterized by guilt, anhedonia, or sudden-onset suicidal ideation without an environmental trigger. Symptoms are fairly short-lived, lasting from a few hours to a few days.⁵

Depressive symptoms also may develop minutes before a complex partial seizure or a secondarily generalized seizure.² Mood changes typically are brief, stereotypical, and associated with other ictal phenomena. Interictal depression involves mild chronic symptoms similar to dysthymia. Postictal depression may last for several days.

Prodromal and ictal depression often improve when antiepileptic therapy reduces seizure frequency.

Huntington’s disease (HD) is a hereditary chorea caused by expanded trinucleotide repeats and characterized by abnormal movements, cognitive impairment, and neuropsychiatric symptoms. The suicide rate among HD patients is 4 times higher than in the general population.²¹

Signs and symptoms. Depression concurrent with neurologic symptoms such as chorea or dystonia may warrant an HD evaluation. Patients may present with psychiatric complaints such as depression, apathy, insomnia, or anxiety that may coincide with or precede other neurologic symptoms.²² Mood-congruent delusions and auditory hallucinations also have been reported.²³ In one study, 98% of HD patients exhibited psychiatric symptoms—including dysphoria, agitation, irritability, apathy, and anxiety—that occurred irrespective of cognitive or motor symptoms.²⁴

Research into the cause of HD’s neuropsychiatric symptoms has focused on abnormalities in frontostriatal brain circuitry.²⁵ Depressive symptoms might respond to any class of antidepressant.

Wilson’s disease—caused by copper accumulation in the liver and basal ganglia—is characterized by degenerative changes in the brain, liver disease, and golden-brown or green Kayser-Fleischer rings in the cornea.

Signs and symptoms. Hepatic symptoms include hepatomegaly, hepatitis, and cirrhosis. Psychiatric symptoms—which include personality changes, depression, irritability, and psychosis—may occur alone or concurrent with neurologic symptoms such as tremor or dystonia.²⁶ Neuropsychiatric symptoms—the initial presentation in up to one-third of Wilson’s disease patients—may respond to anticopper therapies.²⁶

Multiple sclerosis (MS). Up to 50% of MS patients experience depression, although it is unclear if symptoms are caused by the disease or the impact of having a progressive chronic illness.

Signs and symptoms. MS may cause weakness, visual loss, incontinence, paresthesias, and speech disturbances. MS symptoms such as fatigue, insomnia, and poor concentration overlap with DSM-IV-TR criteria for major depression. Depressive symptoms may worsen during disease flare-ups and with advanced neurologic disease.

Depression may be more prevalent in MS patients with brain lesions compared with those with spinal cord lesions.²⁹ Imaging studies indicate that depressed MS patients are more likely to have hyperintense lesions in the left inferior frontal regions of the brain and greater atrophy of the left anterior temporal region,³⁰ indicating that the disease may play a role in depressive symptoms.

Parkinson’s disease (PD). Nearly one-half of PD patients experience depression, which recent research suggests is related to neuroanatomic degeneration and not a reaction to having the illness.³¹

Signs and symptoms. Because PD can present with sleep disturbances, bradykinesia, restricted range of facial expression, and apathy, it initially might be mistaken for a depressive disorder.

Other neurologic disorders. Depression in Alzheimer’s disease typically involves prominent anhedonia, irritability, apathy, and anxiety, rather than suicidal ideation and guilt.³² In traumatic brain injury, the most common psychiatric disturbance is a depressive syndrome resembling endogenous depression.³² Progressive supranuclear palsy—a degenerative disorder of the basal ganglia, brainstem, and cerebellar nuclei—is associated with cognitive impairments and personality changes and may present as depression.³³

Infectious disease

Human immunodeficiency virus (HIV). Depression affects 22% to 45% of HIV patients, particularly women, homosexual men, intravenous drug users, and patients with a history of depression.³⁴ The cause of depression in HIV infection is unclear because studies are complicated by factors such as:

• social stigma and isolation associated with HIV
• side effects (such as fatigue) of antiretroviral medications
• comorbid opportunistic CNS infections, such as tuberculosis or cryptococcal meningitis
• the virus itself, which is known to affect the brain.³⁵

Certain sociodemographic factors are associated with depression in HIV patients, but Gibbie et al³⁶ found that CD4 count and viral load are not. This suggests that HIV does not directly cause depression, although research is ongoing. Comorbid substance dependence and AIDS-related dementia can complicate the clinical picture.

The depressive syndrome in patients with HIV typically does not precede the diagnosis of HIV. Diagnosing depression in HIV patients—regardless of the cause—is crucial because of its effect on quality of life, productivity, medication adherence, and mortality.³⁷

West Nile virus. Among the one-third of patients who report new-onset depression after West Nile infection, 75% experience mild-to-severe depression as measured on a depression scale.³⁸ Studies of depression in West Nile virus infection are complicated by recall bias, illness-related disability, and fatigue that interferes with psychiatric assessment. Similar to HIV, a depression diagnosis typically is made following a known West Nile virus infection.

Lyme disease. More than one-third of patients diagnosed with post-Lyme syndrome—chronic symptoms that persist after antibiotic treatment—will have depression during their lifetime.³⁹ One report that attempted to determine a causal relationship between Lyme disease and depression found a similar lifetime incidence of depression in those with Lyme disease and in the general population. Even so, the incidence of depression doubled in this sample after the onset of Lyme disease. Studies of this relationship are confounded by other effects of Lyme disease, small numbers of subjects, and recall bias.

Signs and symptoms. Exposure to ticks, cranial nerve involvement, arthralgias, memory deficits, and psychotic depression may suggest Lyme disease.

Creutzfeldt-Jakob disease is a rare prion disease that can be genetic, spontaneous, or acquired via contaminated beef, corneal transplants, or dural transplants. Patients may present with cognitive impairment, fatigue, emotional lability, and depression.

Signs and symptoms include changes in the brain seen on an MRI, rapid physical and mental decline, and myoclonus and ataxia signs that occur late in the disease. Depression caused by this incurable disease often fails to respond to treatment.

Neurosyphilis patients may experience personality changes, irritability, psychosis, and decreased self-care, which may be interpreted as anhedonia or depressed mood.

Signs and symptoms. Common physical signs include dysarthria, hyperreflexia, cognitive decline, hallucinations, tremor, tabes dorsalis, and Argyll Robertson pupils. Neurosyphilis is confirmed by positive venereal disease research laboratory test of cerebrospinal fluid and treated with high-dose penicillin. Consensus is lacking on the role of psychotropic medications for the management of psychiatric symptoms.⁴⁰

Hepatitis C patients have a higher lifetime prevalence of major depression compared with controls.⁴¹ Although evidence does not support a causal link between hepatitis C infection and depression, anecdotal reports persist.⁴² Studies of comorbid depression and hepatitis C are complicated by hepatic encephalopathy, fatigue, medication side effects, and social and economic factors associated with hepatitis C. Physical symptoms include decreased appetite, fatigue, fever, nausea, vomiting, abdominal pain, clay-colored stool, joint pain, and jaundice.

Interferon (IFN) treatment for chronic, active hepatitis C has been associated with increased depressive symptoms and suicidal behavior. In a study of 31 hepatitis C patients, 23% experienced depressive episodes concurrent with IFN alfa treatment.⁴³ Depressive symptoms seem to be related to dose and treatment duration and may take several weeks to develop.

Malignancy

Cancer patients often report depressive symptoms, although a causal relationship between malignancy and depression remains unclear. Some evidence suggests that pancreatic cancer and paraneoplastic syndromes can cause depression. In a retrospective study, depression preceded a pancreatic cancer diagnosis more often than with other gastrointestinal or non-gastrointestinal cancers.⁴⁴ Typically, depression starts >1 year before the cancer is discovered. It is unclear, however, if the cancer leads to depression or depression predisposes a person to pancreatic cancer.

Signs and symptoms. New-onset depression, dramatic unintended weight loss, and predominant sleep disturbance warrant further evaluation for malignancy. In patients diagnosed with cancer, depressive symptoms may be caused by reactive depression, an acute stress reaction, or adjustment disorder with depressed mood.

Paraneoplastic syndromes can cause depression, behavior and personality changes, and memory deficits.⁴⁵ These syndromes are commonly found in breast, lung, and testicular cancer, all of which might not be discovered when psychiatric symptoms develop.⁴⁶

The immune system’s reaction to cancer produces antibodies that attack the nervous system. Diagnosis of the resulting limbic encephalitis thought to underlie psychiatric symptoms is by CSF-positive antibodies (anti-Yo antibodies, anti-Ma2 antibodies, or anti-Hu) and abnormalities in brain MRI. Psychiatric symptoms often improve when the underlying malignancy is treated.

Related resources

• Blumenfield M, Strain JJ. Psychosomatic medicine. Philadelphia, PA: Lippincott, Williams, & Wilkins; 2006.
• Ferrando SJ, Freyberg Z. Neuropsychiatric aspects of infectious diseases. Crit Care Clin. 2008;24:889-919.

Drug brand names

• Bupropion • Wellbutrin, Zyban
• Felbamate • Felbatol
• Interferon alfa • Intron, Roferon
• Interferon beta • Avonex, Rebif
• Isotretinoin • Accutane
• Levetiracetam • Keppra
• Phenytoin • Dilantin
• Primidone • Mysoline
• Propranolol • Inderal
• Tiagabine • Gabitril Roferon
• Topiramate • Topamax
• Verapamil • Isoptin
• Vigabatrin • Sabril
• Varenicline • Chantix

Disclosures

Dr. Carroll reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Rado receives research support from Eli Lilly and Company, Neuronetics, and Otsuka, and is a speaker for Eli Lilly and Company.

Comment on this article

Ms. G, age 56, presents with the chief complaint of “depression.” Review of symptoms reveals 6 months of depressed mood, anhedonia, tearfulness, 30-pound weight gain, low energy, and bilateral ankle edema. Her psychiatrist orders a thyroid stimulating hormone (TSH) level, which shows 9.51 mU/L (normal range 0.35 to 4.94 mU/L), indicating hypothyroidism. After 1 month of treatment with levothyroxine, Ms. G’s mood symptoms and edema resolve and her weight stabilizes.

A patient who comes to you for treatment of depression might also present with physical symptoms (such as, fatigue, nausea, balance problems, etc.) that could point to a medical illness. Endocrine, neurologic, infectious, and malignant processes (Table 1) and vitamin deficiencies (Table 2) could be causing your patient’s depression. To help differentiate various etiologies of depressive symptoms, we review common medical causes of depression, their distinguishing characteristics, and pertinent treatment issues.

DSM-IV-TR considers major depression secondary to a general medical condition to be diagnostically separate from a major depressive episode. When considering nonpsychiatric causes of depression, begin with a thorough medical history including current and past medications (Table 3),^1-7 illicit substance use, review of systems, and a detailed neurologic exam.

Table 1

Medical conditions with evidence of causing depression

Table 2

Vitamin deficiencies that can lead to depression

Table 3

Medications that may be linked to depressive symptoms

Endocrine disorders

Hypothyroidism increases a patient’s risk of a mood disorder 7-fold, compared with the general population.⁸

Signs and symptoms. Patients with hypothyroidism may complain of constipation, thinning hair, dry skin, edema, sensitivity to cold, goiter, thyroid nodule, or hoarse voice. Symptoms such as fatigue, weight gain, and sleep disturbance overlap with depressive symptoms. A TSH value >4.94 mU/L indicates hypothyroidism and warrants referral to a primary care provider or endocrinologist.

Although the pathophysiology is unclear, 1 study found elevated thyroid peroxide antibodies in depressed postmenopausal women who had abnormal thyroid function tests, suggesting an autoimmune link between depression and hypothyroidism.⁹ In another study, 2.5% of depressed patients had abnormal serum TSH or thyroxine levels indicating hypothyroidism.¹⁰ Thyroid hormones have been used to augment treatment of refractory depression.¹¹

Hyperparathyroidism. “Moans, groans, stones, and psychiatric overtones” describes the constellation of hyperparathyroidism symptoms. As serum calcium levels rise, mood and physical symptoms worsen (Table 4).

Signs and symptoms. Elevated serum calcium (normal range 8.7 to 10.7 mg/dL) and parathyroid hormone (PTH) levels support the diagnosis. Depressive symptoms may diminish or even resolve when calcium levels return to normal after parathyroidectomy.¹²

Cushing’s syndrome (CS). As many as 80% of patients exhibit depressive symptoms when CS is active.¹³

Signs and symptoms. Distinguishing CS symptoms include:

• hirsutism
• truncal obesity
• acne
• hypertension
• facial flushing
• purple striae.

Elevated serum cortisol, the condition’s hallmark, may be caused by pituitary adenomas, adrenal tumors or hyperplasia, or ectopic adrenocorticotropic hormone secretion. The most common cause is exogenous administration of glucocorticoids. A dexamethasone suppression test or 24-hour urine cortisol confirms CS diagnosis.

Depressed CS patients often experience poor concentration, early morning waking, and decreased libido. Compared with nondepressed individuals with CS, those with depression tend to be older (average age 37.5) and more likely to be female, have more severe CS-related symptoms, and exhibit higher urine cortisol levels at diagnosis (average 1.694 pmol/L).^14,15

Antidepressants typically will not resolve depression in patients with CS unless you also correct the hypercorticalism.¹⁶

Addison’s disease (AD). Major depressive disorder is >2 times more prevalent in AD patients compared with matched controls.¹⁷

Signs and symptoms. Hyperpigmentation, salt cravings, low blood pressure, nausea, and vomiting are AD hallmarks. AD patients present with fatigue, vegetative symptoms, weight loss, and weakness that mimics a major depressive episode.

AD is caused by damage to the adrenal cortex. These patients do not have enough of the mineralocorticoid aldosterone, which maintains sodium and potassium balance and regulates blood pressure via the renin-angiotensin-aldosterone pathway. Decreased morning serum cortisol level, hyponatremia, and hyperkalemia confirm the diagnosis. AD can be serious—possibly fatal—so prompt referral to an endocrinologist is warranted.

Table 4

Clinical symptoms of hyperparathyroidism

Neurologic disorders

Stroke. Post-stroke depressive symptoms generally do not differ from endogenous depression. Apathy, catastrophic reactions, hyper emotionalism, and diurnal mood variations are more prevalent in stroke patients,¹⁸ although some of these features have been noted in other neurologic conditions.

Signs and symptoms. Look for depression onset or a change in existing depression symptoms that occurs in the context of a clinically apparent stroke.¹⁹ Antidepressants such as serotonin reuptake inhibitors may relieve post-stroke depression.

Seizures. Depressive symptoms could appear before or after a seizure or may be the clinical presentation of a simple or complex partial seizure.¹

Signs and symptoms. Episodic, short-lived depression that resolves rapidly may warrant a seizure evaluation. Prodromal depressive symptoms such as irritability, depression, fear, or anger²⁰ may precede a seizure by 1 to 3 days and could improve after the seizure.

Caused by a simple partial seizure, ictal depression is characterized by guilt, anhedonia, or sudden-onset suicidal ideation without an environmental trigger. Symptoms are fairly short-lived, lasting from a few hours to a few days.⁵

Depressive symptoms also may develop minutes before a complex partial seizure or a secondarily generalized seizure.² Mood changes typically are brief, stereotypical, and associated with other ictal phenomena. Interictal depression involves mild chronic symptoms similar to dysthymia. Postictal depression may last for several days.

Prodromal and ictal depression often improve when antiepileptic therapy reduces seizure frequency.

Huntington’s disease (HD) is a hereditary chorea caused by expanded trinucleotide repeats and characterized by abnormal movements, cognitive impairment, and neuropsychiatric symptoms. The suicide rate among HD patients is 4 times higher than in the general population.²¹

Signs and symptoms. Depression concurrent with neurologic symptoms such as chorea or dystonia may warrant an HD evaluation. Patients may present with psychiatric complaints such as depression, apathy, insomnia, or anxiety that may coincide with or precede other neurologic symptoms.²² Mood-congruent delusions and auditory hallucinations also have been reported.²³ In one study, 98% of HD patients exhibited psychiatric symptoms—including dysphoria, agitation, irritability, apathy, and anxiety—that occurred irrespective of cognitive or motor symptoms.²⁴

Research into the cause of HD’s neuropsychiatric symptoms has focused on abnormalities in frontostriatal brain circuitry.²⁵ Depressive symptoms might respond to any class of antidepressant.

Wilson’s disease—caused by copper accumulation in the liver and basal ganglia—is characterized by degenerative changes in the brain, liver disease, and golden-brown or green Kayser-Fleischer rings in the cornea.

Signs and symptoms. Hepatic symptoms include hepatomegaly, hepatitis, and cirrhosis. Psychiatric symptoms—which include personality changes, depression, irritability, and psychosis—may occur alone or concurrent with neurologic symptoms such as tremor or dystonia.²⁶ Neuropsychiatric symptoms—the initial presentation in up to one-third of Wilson’s disease patients—may respond to anticopper therapies.²⁶

Multiple sclerosis (MS). Up to 50% of MS patients experience depression, although it is unclear if symptoms are caused by the disease or the impact of having a progressive chronic illness.

Signs and symptoms. MS may cause weakness, visual loss, incontinence, paresthesias, and speech disturbances. MS symptoms such as fatigue, insomnia, and poor concentration overlap with DSM-IV-TR criteria for major depression. Depressive symptoms may worsen during disease flare-ups and with advanced neurologic disease.

Depression may be more prevalent in MS patients with brain lesions compared with those with spinal cord lesions.²⁹ Imaging studies indicate that depressed MS patients are more likely to have hyperintense lesions in the left inferior frontal regions of the brain and greater atrophy of the left anterior temporal region,³⁰ indicating that the disease may play a role in depressive symptoms.

Parkinson’s disease (PD). Nearly one-half of PD patients experience depression, which recent research suggests is related to neuroanatomic degeneration and not a reaction to having the illness.³¹

Signs and symptoms. Because PD can present with sleep disturbances, bradykinesia, restricted range of facial expression, and apathy, it initially might be mistaken for a depressive disorder.

Other neurologic disorders. Depression in Alzheimer’s disease typically involves prominent anhedonia, irritability, apathy, and anxiety, rather than suicidal ideation and guilt.³² In traumatic brain injury, the most common psychiatric disturbance is a depressive syndrome resembling endogenous depression.³² Progressive supranuclear palsy—a degenerative disorder of the basal ganglia, brainstem, and cerebellar nuclei—is associated with cognitive impairments and personality changes and may present as depression.³³

Infectious disease

Human immunodeficiency virus (HIV). Depression affects 22% to 45% of HIV patients, particularly women, homosexual men, intravenous drug users, and patients with a history of depression.³⁴ The cause of depression in HIV infection is unclear because studies are complicated by factors such as:

• social stigma and isolation associated with HIV
• side effects (such as fatigue) of antiretroviral medications
• comorbid opportunistic CNS infections, such as tuberculosis or cryptococcal meningitis
• the virus itself, which is known to affect the brain.³⁵

Certain sociodemographic factors are associated with depression in HIV patients, but Gibbie et al³⁶ found that CD4 count and viral load are not. This suggests that HIV does not directly cause depression, although research is ongoing. Comorbid substance dependence and AIDS-related dementia can complicate the clinical picture.

The depressive syndrome in patients with HIV typically does not precede the diagnosis of HIV. Diagnosing depression in HIV patients—regardless of the cause—is crucial because of its effect on quality of life, productivity, medication adherence, and mortality.³⁷

West Nile virus. Among the one-third of patients who report new-onset depression after West Nile infection, 75% experience mild-to-severe depression as measured on a depression scale.³⁸ Studies of depression in West Nile virus infection are complicated by recall bias, illness-related disability, and fatigue that interferes with psychiatric assessment. Similar to HIV, a depression diagnosis typically is made following a known West Nile virus infection.

Lyme disease. More than one-third of patients diagnosed with post-Lyme syndrome—chronic symptoms that persist after antibiotic treatment—will have depression during their lifetime.³⁹ One report that attempted to determine a causal relationship between Lyme disease and depression found a similar lifetime incidence of depression in those with Lyme disease and in the general population. Even so, the incidence of depression doubled in this sample after the onset of Lyme disease. Studies of this relationship are confounded by other effects of Lyme disease, small numbers of subjects, and recall bias.

Signs and symptoms. Exposure to ticks, cranial nerve involvement, arthralgias, memory deficits, and psychotic depression may suggest Lyme disease.

Creutzfeldt-Jakob disease is a rare prion disease that can be genetic, spontaneous, or acquired via contaminated beef, corneal transplants, or dural transplants. Patients may present with cognitive impairment, fatigue, emotional lability, and depression.

Signs and symptoms include changes in the brain seen on an MRI, rapid physical and mental decline, and myoclonus and ataxia signs that occur late in the disease. Depression caused by this incurable disease often fails to respond to treatment.

Neurosyphilis patients may experience personality changes, irritability, psychosis, and decreased self-care, which may be interpreted as anhedonia or depressed mood.

Signs and symptoms. Common physical signs include dysarthria, hyperreflexia, cognitive decline, hallucinations, tremor, tabes dorsalis, and Argyll Robertson pupils. Neurosyphilis is confirmed by positive venereal disease research laboratory test of cerebrospinal fluid and treated with high-dose penicillin. Consensus is lacking on the role of psychotropic medications for the management of psychiatric symptoms.⁴⁰

Hepatitis C patients have a higher lifetime prevalence of major depression compared with controls.⁴¹ Although evidence does not support a causal link between hepatitis C infection and depression, anecdotal reports persist.⁴² Studies of comorbid depression and hepatitis C are complicated by hepatic encephalopathy, fatigue, medication side effects, and social and economic factors associated with hepatitis C. Physical symptoms include decreased appetite, fatigue, fever, nausea, vomiting, abdominal pain, clay-colored stool, joint pain, and jaundice.

Interferon (IFN) treatment for chronic, active hepatitis C has been associated with increased depressive symptoms and suicidal behavior. In a study of 31 hepatitis C patients, 23% experienced depressive episodes concurrent with IFN alfa treatment.⁴³ Depressive symptoms seem to be related to dose and treatment duration and may take several weeks to develop.

Malignancy

Cancer patients often report depressive symptoms, although a causal relationship between malignancy and depression remains unclear. Some evidence suggests that pancreatic cancer and paraneoplastic syndromes can cause depression. In a retrospective study, depression preceded a pancreatic cancer diagnosis more often than with other gastrointestinal or non-gastrointestinal cancers.⁴⁴ Typically, depression starts >1 year before the cancer is discovered. It is unclear, however, if the cancer leads to depression or depression predisposes a person to pancreatic cancer.

Signs and symptoms. New-onset depression, dramatic unintended weight loss, and predominant sleep disturbance warrant further evaluation for malignancy. In patients diagnosed with cancer, depressive symptoms may be caused by reactive depression, an acute stress reaction, or adjustment disorder with depressed mood.

Paraneoplastic syndromes can cause depression, behavior and personality changes, and memory deficits.⁴⁵ These syndromes are commonly found in breast, lung, and testicular cancer, all of which might not be discovered when psychiatric symptoms develop.⁴⁶

The immune system’s reaction to cancer produces antibodies that attack the nervous system. Diagnosis of the resulting limbic encephalitis thought to underlie psychiatric symptoms is by CSF-positive antibodies (anti-Yo antibodies, anti-Ma2 antibodies, or anti-Hu) and abnormalities in brain MRI. Psychiatric symptoms often improve when the underlying malignancy is treated.

Related resources

• Blumenfield M, Strain JJ. Psychosomatic medicine. Philadelphia, PA: Lippincott, Williams, & Wilkins; 2006.
• Ferrando SJ, Freyberg Z. Neuropsychiatric aspects of infectious diseases. Crit Care Clin. 2008;24:889-919.

Drug brand names

• Bupropion • Wellbutrin, Zyban
• Felbamate • Felbatol
• Interferon alfa • Intron, Roferon
• Interferon beta • Avonex, Rebif
• Isotretinoin • Accutane
• Levetiracetam • Keppra
• Phenytoin • Dilantin
• Primidone • Mysoline
• Propranolol • Inderal
• Tiagabine • Gabitril Roferon
• Topiramate • Topamax
• Verapamil • Isoptin
• Vigabatrin • Sabril
• Varenicline • Chantix

Disclosures

Dr. Carroll reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Rado receives research support from Eli Lilly and Company, Neuronetics, and Otsuka, and is a speaker for Eli Lilly and Company.

Comment on this article

Ms. G, age 56, presents with the chief complaint of “depression.” Review of symptoms reveals 6 months of depressed mood, anhedonia, tearfulness, 30-pound weight gain, low energy, and bilateral ankle edema. Her psychiatrist orders a thyroid stimulating hormone (TSH) level, which shows 9.51 mU/L (normal range 0.35 to 4.94 mU/L), indicating hypothyroidism. After 1 month of treatment with levothyroxine, Ms. G’s mood symptoms and edema resolve and her weight stabilizes.

A patient who comes to you for treatment of depression might also present with physical symptoms (such as, fatigue, nausea, balance problems, etc.) that could point to a medical illness. Endocrine, neurologic, infectious, and malignant processes (Table 1) and vitamin deficiencies (Table 2) could be causing your patient’s depression. To help differentiate various etiologies of depressive symptoms, we review common medical causes of depression, their distinguishing characteristics, and pertinent treatment issues.

DSM-IV-TR considers major depression secondary to a general medical condition to be diagnostically separate from a major depressive episode. When considering nonpsychiatric causes of depression, begin with a thorough medical history including current and past medications (Table 3),^1-7 illicit substance use, review of systems, and a detailed neurologic exam.

Table 1

Medical conditions with evidence of causing depression

Table 2

Vitamin deficiencies that can lead to depression

Table 3

Medications that may be linked to depressive symptoms

Endocrine disorders

Hypothyroidism increases a patient’s risk of a mood disorder 7-fold, compared with the general population.⁸

Signs and symptoms. Patients with hypothyroidism may complain of constipation, thinning hair, dry skin, edema, sensitivity to cold, goiter, thyroid nodule, or hoarse voice. Symptoms such as fatigue, weight gain, and sleep disturbance overlap with depressive symptoms. A TSH value >4.94 mU/L indicates hypothyroidism and warrants referral to a primary care provider or endocrinologist.

Although the pathophysiology is unclear, 1 study found elevated thyroid peroxide antibodies in depressed postmenopausal women who had abnormal thyroid function tests, suggesting an autoimmune link between depression and hypothyroidism.⁹ In another study, 2.5% of depressed patients had abnormal serum TSH or thyroxine levels indicating hypothyroidism.¹⁰ Thyroid hormones have been used to augment treatment of refractory depression.¹¹

Hyperparathyroidism. “Moans, groans, stones, and psychiatric overtones” describes the constellation of hyperparathyroidism symptoms. As serum calcium levels rise, mood and physical symptoms worsen (Table 4).

Signs and symptoms. Elevated serum calcium (normal range 8.7 to 10.7 mg/dL) and parathyroid hormone (PTH) levels support the diagnosis. Depressive symptoms may diminish or even resolve when calcium levels return to normal after parathyroidectomy.¹²

Cushing’s syndrome (CS). As many as 80% of patients exhibit depressive symptoms when CS is active.¹³

Signs and symptoms. Distinguishing CS symptoms include:

• hirsutism
• truncal obesity
• acne
• hypertension
• facial flushing
• purple striae.

Elevated serum cortisol, the condition’s hallmark, may be caused by pituitary adenomas, adrenal tumors or hyperplasia, or ectopic adrenocorticotropic hormone secretion. The most common cause is exogenous administration of glucocorticoids. A dexamethasone suppression test or 24-hour urine cortisol confirms CS diagnosis.

Depressed CS patients often experience poor concentration, early morning waking, and decreased libido. Compared with nondepressed individuals with CS, those with depression tend to be older (average age 37.5) and more likely to be female, have more severe CS-related symptoms, and exhibit higher urine cortisol levels at diagnosis (average 1.694 pmol/L).^14,15

Antidepressants typically will not resolve depression in patients with CS unless you also correct the hypercorticalism.¹⁶

Addison’s disease (AD). Major depressive disorder is >2 times more prevalent in AD patients compared with matched controls.¹⁷

Signs and symptoms. Hyperpigmentation, salt cravings, low blood pressure, nausea, and vomiting are AD hallmarks. AD patients present with fatigue, vegetative symptoms, weight loss, and weakness that mimics a major depressive episode.

AD is caused by damage to the adrenal cortex. These patients do not have enough of the mineralocorticoid aldosterone, which maintains sodium and potassium balance and regulates blood pressure via the renin-angiotensin-aldosterone pathway. Decreased morning serum cortisol level, hyponatremia, and hyperkalemia confirm the diagnosis. AD can be serious—possibly fatal—so prompt referral to an endocrinologist is warranted.

Table 4

Clinical symptoms of hyperparathyroidism

Neurologic disorders

Stroke. Post-stroke depressive symptoms generally do not differ from endogenous depression. Apathy, catastrophic reactions, hyper emotionalism, and diurnal mood variations are more prevalent in stroke patients,¹⁸ although some of these features have been noted in other neurologic conditions.

Signs and symptoms. Look for depression onset or a change in existing depression symptoms that occurs in the context of a clinically apparent stroke.¹⁹ Antidepressants such as serotonin reuptake inhibitors may relieve post-stroke depression.

Seizures. Depressive symptoms could appear before or after a seizure or may be the clinical presentation of a simple or complex partial seizure.¹

Signs and symptoms. Episodic, short-lived depression that resolves rapidly may warrant a seizure evaluation. Prodromal depressive symptoms such as irritability, depression, fear, or anger²⁰ may precede a seizure by 1 to 3 days and could improve after the seizure.

Caused by a simple partial seizure, ictal depression is characterized by guilt, anhedonia, or sudden-onset suicidal ideation without an environmental trigger. Symptoms are fairly short-lived, lasting from a few hours to a few days.⁵

Depressive symptoms also may develop minutes before a complex partial seizure or a secondarily generalized seizure.² Mood changes typically are brief, stereotypical, and associated with other ictal phenomena. Interictal depression involves mild chronic symptoms similar to dysthymia. Postictal depression may last for several days.

Prodromal and ictal depression often improve when antiepileptic therapy reduces seizure frequency.

Huntington’s disease (HD) is a hereditary chorea caused by expanded trinucleotide repeats and characterized by abnormal movements, cognitive impairment, and neuropsychiatric symptoms. The suicide rate among HD patients is 4 times higher than in the general population.²¹

Signs and symptoms. Depression concurrent with neurologic symptoms such as chorea or dystonia may warrant an HD evaluation. Patients may present with psychiatric complaints such as depression, apathy, insomnia, or anxiety that may coincide with or precede other neurologic symptoms.²² Mood-congruent delusions and auditory hallucinations also have been reported.²³ In one study, 98% of HD patients exhibited psychiatric symptoms—including dysphoria, agitation, irritability, apathy, and anxiety—that occurred irrespective of cognitive or motor symptoms.²⁴

Research into the cause of HD’s neuropsychiatric symptoms has focused on abnormalities in frontostriatal brain circuitry.²⁵ Depressive symptoms might respond to any class of antidepressant.

Wilson’s disease—caused by copper accumulation in the liver and basal ganglia—is characterized by degenerative changes in the brain, liver disease, and golden-brown or green Kayser-Fleischer rings in the cornea.

Signs and symptoms. Hepatic symptoms include hepatomegaly, hepatitis, and cirrhosis. Psychiatric symptoms—which include personality changes, depression, irritability, and psychosis—may occur alone or concurrent with neurologic symptoms such as tremor or dystonia.²⁶ Neuropsychiatric symptoms—the initial presentation in up to one-third of Wilson’s disease patients—may respond to anticopper therapies.²⁶

Multiple sclerosis (MS). Up to 50% of MS patients experience depression, although it is unclear if symptoms are caused by the disease or the impact of having a progressive chronic illness.

Signs and symptoms. MS may cause weakness, visual loss, incontinence, paresthesias, and speech disturbances. MS symptoms such as fatigue, insomnia, and poor concentration overlap with DSM-IV-TR criteria for major depression. Depressive symptoms may worsen during disease flare-ups and with advanced neurologic disease.

Depression may be more prevalent in MS patients with brain lesions compared with those with spinal cord lesions.²⁹ Imaging studies indicate that depressed MS patients are more likely to have hyperintense lesions in the left inferior frontal regions of the brain and greater atrophy of the left anterior temporal region,³⁰ indicating that the disease may play a role in depressive symptoms.

Parkinson’s disease (PD). Nearly one-half of PD patients experience depression, which recent research suggests is related to neuroanatomic degeneration and not a reaction to having the illness.³¹

Signs and symptoms. Because PD can present with sleep disturbances, bradykinesia, restricted range of facial expression, and apathy, it initially might be mistaken for a depressive disorder.

Other neurologic disorders. Depression in Alzheimer’s disease typically involves prominent anhedonia, irritability, apathy, and anxiety, rather than suicidal ideation and guilt.³² In traumatic brain injury, the most common psychiatric disturbance is a depressive syndrome resembling endogenous depression.³² Progressive supranuclear palsy—a degenerative disorder of the basal ganglia, brainstem, and cerebellar nuclei—is associated with cognitive impairments and personality changes and may present as depression.³³

Infectious disease

Human immunodeficiency virus (HIV). Depression affects 22% to 45% of HIV patients, particularly women, homosexual men, intravenous drug users, and patients with a history of depression.³⁴ The cause of depression in HIV infection is unclear because studies are complicated by factors such as:

• social stigma and isolation associated with HIV
• side effects (such as fatigue) of antiretroviral medications
• comorbid opportunistic CNS infections, such as tuberculosis or cryptococcal meningitis
• the virus itself, which is known to affect the brain.³⁵

Certain sociodemographic factors are associated with depression in HIV patients, but Gibbie et al³⁶ found that CD4 count and viral load are not. This suggests that HIV does not directly cause depression, although research is ongoing. Comorbid substance dependence and AIDS-related dementia can complicate the clinical picture.

The depressive syndrome in patients with HIV typically does not precede the diagnosis of HIV. Diagnosing depression in HIV patients—regardless of the cause—is crucial because of its effect on quality of life, productivity, medication adherence, and mortality.³⁷

West Nile virus. Among the one-third of patients who report new-onset depression after West Nile infection, 75% experience mild-to-severe depression as measured on a depression scale.³⁸ Studies of depression in West Nile virus infection are complicated by recall bias, illness-related disability, and fatigue that interferes with psychiatric assessment. Similar to HIV, a depression diagnosis typically is made following a known West Nile virus infection.

Lyme disease. More than one-third of patients diagnosed with post-Lyme syndrome—chronic symptoms that persist after antibiotic treatment—will have depression during their lifetime.³⁹ One report that attempted to determine a causal relationship between Lyme disease and depression found a similar lifetime incidence of depression in those with Lyme disease and in the general population. Even so, the incidence of depression doubled in this sample after the onset of Lyme disease. Studies of this relationship are confounded by other effects of Lyme disease, small numbers of subjects, and recall bias.

Signs and symptoms. Exposure to ticks, cranial nerve involvement, arthralgias, memory deficits, and psychotic depression may suggest Lyme disease.

Creutzfeldt-Jakob disease is a rare prion disease that can be genetic, spontaneous, or acquired via contaminated beef, corneal transplants, or dural transplants. Patients may present with cognitive impairment, fatigue, emotional lability, and depression.

Signs and symptoms include changes in the brain seen on an MRI, rapid physical and mental decline, and myoclonus and ataxia signs that occur late in the disease. Depression caused by this incurable disease often fails to respond to treatment.

Neurosyphilis patients may experience personality changes, irritability, psychosis, and decreased self-care, which may be interpreted as anhedonia or depressed mood.

Signs and symptoms. Common physical signs include dysarthria, hyperreflexia, cognitive decline, hallucinations, tremor, tabes dorsalis, and Argyll Robertson pupils. Neurosyphilis is confirmed by positive venereal disease research laboratory test of cerebrospinal fluid and treated with high-dose penicillin. Consensus is lacking on the role of psychotropic medications for the management of psychiatric symptoms.⁴⁰

Hepatitis C patients have a higher lifetime prevalence of major depression compared with controls.⁴¹ Although evidence does not support a causal link between hepatitis C infection and depression, anecdotal reports persist.⁴² Studies of comorbid depression and hepatitis C are complicated by hepatic encephalopathy, fatigue, medication side effects, and social and economic factors associated with hepatitis C. Physical symptoms include decreased appetite, fatigue, fever, nausea, vomiting, abdominal pain, clay-colored stool, joint pain, and jaundice.

Interferon (IFN) treatment for chronic, active hepatitis C has been associated with increased depressive symptoms and suicidal behavior. In a study of 31 hepatitis C patients, 23% experienced depressive episodes concurrent with IFN alfa treatment.⁴³ Depressive symptoms seem to be related to dose and treatment duration and may take several weeks to develop.

Malignancy

Cancer patients often report depressive symptoms, although a causal relationship between malignancy and depression remains unclear. Some evidence suggests that pancreatic cancer and paraneoplastic syndromes can cause depression. In a retrospective study, depression preceded a pancreatic cancer diagnosis more often than with other gastrointestinal or non-gastrointestinal cancers.⁴⁴ Typically, depression starts >1 year before the cancer is discovered. It is unclear, however, if the cancer leads to depression or depression predisposes a person to pancreatic cancer.

Signs and symptoms. New-onset depression, dramatic unintended weight loss, and predominant sleep disturbance warrant further evaluation for malignancy. In patients diagnosed with cancer, depressive symptoms may be caused by reactive depression, an acute stress reaction, or adjustment disorder with depressed mood.

Paraneoplastic syndromes can cause depression, behavior and personality changes, and memory deficits.⁴⁵ These syndromes are commonly found in breast, lung, and testicular cancer, all of which might not be discovered when psychiatric symptoms develop.⁴⁶

The immune system’s reaction to cancer produces antibodies that attack the nervous system. Diagnosis of the resulting limbic encephalitis thought to underlie psychiatric symptoms is by CSF-positive antibodies (anti-Yo antibodies, anti-Ma2 antibodies, or anti-Hu) and abnormalities in brain MRI. Psychiatric symptoms often improve when the underlying malignancy is treated.

Related resources

• Blumenfield M, Strain JJ. Psychosomatic medicine. Philadelphia, PA: Lippincott, Williams, & Wilkins; 2006.
• Ferrando SJ, Freyberg Z. Neuropsychiatric aspects of infectious diseases. Crit Care Clin. 2008;24:889-919.

Drug brand names

• Bupropion • Wellbutrin, Zyban
• Felbamate • Felbatol
• Interferon alfa • Intron, Roferon
• Interferon beta • Avonex, Rebif
• Isotretinoin • Accutane
• Levetiracetam • Keppra
• Phenytoin • Dilantin
• Primidone • Mysoline
• Propranolol • Inderal
• Tiagabine • Gabitril Roferon
• Topiramate • Topamax
• Verapamil • Isoptin
• Vigabatrin • Sabril
• Varenicline • Chantix

Disclosures

Dr. Carroll reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Rado receives research support from Eli Lilly and Company, Neuronetics, and Otsuka, and is a speaker for Eli Lilly and Company.

Dr. Gagliardi is assistant professor of psychiatry and behavioral sciences and assistant clinical professor of medicine, Duke University School of Medicine, Durham, NC.

Principal Source: Johnson L, Sabel A, Burman WJ, et al. Emergence of fluoroquinolone resistance in outpatient urinary Escherichia coli isolates. Am J Med. 2008;121:876-884.

More than 8 million urinary tract infections (UTIs) are diagnosed annually in the United States¹ and UTI is thought to be the most common bacterial infection.² Half of all women report having a UTI at some time in their lives.^2,3 UTI is rare in men, occurring in an estimated 5 to 8 of every 10,000 young to middle-aged men,⁴ but increases with age such that UTI rates in men age >70 are approximately one-third the rates in women.²

Up to 85% percent of UTIs are attributed to Escherichia coli.³ The hallmark symptoms of bacterial cystitis are dysuria and urinary frequency; additional symptoms include urgency, suprapubic pain, and hematuria.⁵

Being familiar with UTI symptoms can help expedite diagnosis and treatment because you might be a psychiatric patient’s primary contact with the healthcare system. Also, psychiatric inpatients could test positive for UTIs during routine medical screening. A 1-day urinalysis study of psychiatric inpatients without urinary catheters detected UTIs in approximately 5% of patients.⁶ In addition, UTI is a common cause of delirium.

Screening

The utility of routine screening urinalysis is under debate, and testing is best used in cases of suspected UTI. However, medical disorders frequently are not recognized in psychiatric patients, especially in older patients⁷ or those with risk factors for UTI. Sexually transmitted diseases (STDs) are not major contributors to UTI risk; however, they may share common symptoms and urinalysis findings. If patients report symptoms of UTI (urgency, dysuria, frequency), urinalysis is indicated. In a urinalysis, >2 to 5 leukocytes per high-powered field in an uncontaminated centrifuged urine specimen without a high number of squamous epithelial cells suggest UTI.

In patients with abnormal urinalysis, ask about dysuria, urinary frequency, history of UTIs, and use of antibiotics. Antibiotic use in the preceding 12 months is associated with increased risk of bacterial resistance.¹ Assess for symptoms of complicated UTI such as fever, flank pain, nausea, and vomiting. Urine culture is not recommended for uncomplicated UTI but may be necessary when symptoms do not resolve or signs of complicated UTI emerge. Consider possible STDs in patients with sterile pyuria.⁵

Treatment and antibiotic resistance

For patients with uncomplicated UTI, a short course of empiric antibiotics is appropriate even in the absence of confirmatory culture data. Fluoroquinolones (FQs), such as ciprofloxacin and levofloxacin, have been used as a first-line treatment. However, FQs are associated with:

• QTc-prolongation, a concern when co-administered with antipsychotics⁸
• delirium
• increased risk of tendinitis and tendon rupture⁹
• antibiotic resistance.

A study of a comprehensive urban public health system in Denver, CO, showed that rates of FQ-resistant E coli increased after levofloxacin was established as first-line therapy for UTIs. This occurred after E coli strains developed high resistance to an earlier first-line therapy, trimethoprim/sulfamethoxazole (TMP/SMZ).¹ Using pharmacy and laboratory databases, investigators found that as levofloxacin prescriptions increased, rates of FQ-resistant E coli rose almost 10-fold, from 1% in 1999 to 9.4% in 2005. A detailed analysis of 2005 E coli isolates showed that previous levofloxacin prescription was strongly associated with FQ resistance (odds ratio 5.6, 95% confidence interval: 2.1 to 27.5). Levofloxacin-resistant strains of E coli also were more likely than levofloxacin-sensitive strains to be resistant to other antibiotics—90% compared with 43% for control specimens (Table).

Table

Antibiotic resistance among levofloxacin-resistant and levofloxacin-susceptible strains of E coli*

The use of FQs as first-line treatment of UTIs also is leading to resistant strains of Streptococcus pneumoniae,¹⁰ Salmonella,^11,12 Neisseria meningitides,¹³ and other bacteria. From an individual and public health perspective, it is important that psychiatrists monitor local resistance patterns and treatment recommendations.

In areas without widespread bacterial resistance to TMP/SMZ, a 3-day course of TMP/SMZ could be considered first-line treatment for uncomplicated UTI in patients without allergies or contraindications. However, in areas where resistance to TMP/SMZ is high, a 7-day course of nitrofurantoin is recommended for uncomplicated cystitis. Resistance patterns can vary from hospital to hospital and even among units in the same hospital;¹⁴ therefore, refer to local microbiology labs for “antibiograms” or information regarding resistance patterns.

Related resource

• National Guideline Clearinghouse. Urinary tract infection. www.guidelines.gov/summary/summary.aspx?doc_id=7407.

Drug brand names

• Ampicillin • Principen
• Cefazolin • Ancef
• Ceftriaxone • Rocephin
• Ciprofloxacin • Ciloxan, Cipro, Cipro XR, ProQuin XR
• Gentamicin • Garamycin
• Levofloxacin • Levaquin
• Nitrofurantoin • Furadantin, Macrodantin, Macrobid, Urotoin
• Trimethoprim/Sulfamethoxazole • Bacter-Aid DS, Bactrim, Septra, Sulfatrim, Sultrex
• Tobramycin • Nebcin

Disclosure

Dr. Gagliardi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Gagliardi is assistant professor of psychiatry and behavioral sciences and assistant clinical professor of medicine, Duke University School of Medicine, Durham, NC.

Principal Source: Johnson L, Sabel A, Burman WJ, et al. Emergence of fluoroquinolone resistance in outpatient urinary Escherichia coli isolates. Am J Med. 2008;121:876-884.

More than 8 million urinary tract infections (UTIs) are diagnosed annually in the United States¹ and UTI is thought to be the most common bacterial infection.² Half of all women report having a UTI at some time in their lives.^2,3 UTI is rare in men, occurring in an estimated 5 to 8 of every 10,000 young to middle-aged men,⁴ but increases with age such that UTI rates in men age >70 are approximately one-third the rates in women.²

Up to 85% percent of UTIs are attributed to Escherichia coli.³ The hallmark symptoms of bacterial cystitis are dysuria and urinary frequency; additional symptoms include urgency, suprapubic pain, and hematuria.⁵

Being familiar with UTI symptoms can help expedite diagnosis and treatment because you might be a psychiatric patient’s primary contact with the healthcare system. Also, psychiatric inpatients could test positive for UTIs during routine medical screening. A 1-day urinalysis study of psychiatric inpatients without urinary catheters detected UTIs in approximately 5% of patients.⁶ In addition, UTI is a common cause of delirium.

Screening

The utility of routine screening urinalysis is under debate, and testing is best used in cases of suspected UTI. However, medical disorders frequently are not recognized in psychiatric patients, especially in older patients⁷ or those with risk factors for UTI. Sexually transmitted diseases (STDs) are not major contributors to UTI risk; however, they may share common symptoms and urinalysis findings. If patients report symptoms of UTI (urgency, dysuria, frequency), urinalysis is indicated. In a urinalysis, >2 to 5 leukocytes per high-powered field in an uncontaminated centrifuged urine specimen without a high number of squamous epithelial cells suggest UTI.

In patients with abnormal urinalysis, ask about dysuria, urinary frequency, history of UTIs, and use of antibiotics. Antibiotic use in the preceding 12 months is associated with increased risk of bacterial resistance.¹ Assess for symptoms of complicated UTI such as fever, flank pain, nausea, and vomiting. Urine culture is not recommended for uncomplicated UTI but may be necessary when symptoms do not resolve or signs of complicated UTI emerge. Consider possible STDs in patients with sterile pyuria.⁵

Treatment and antibiotic resistance

For patients with uncomplicated UTI, a short course of empiric antibiotics is appropriate even in the absence of confirmatory culture data. Fluoroquinolones (FQs), such as ciprofloxacin and levofloxacin, have been used as a first-line treatment. However, FQs are associated with:

• QTc-prolongation, a concern when co-administered with antipsychotics⁸
• delirium
• increased risk of tendinitis and tendon rupture⁹
• antibiotic resistance.

A study of a comprehensive urban public health system in Denver, CO, showed that rates of FQ-resistant E coli increased after levofloxacin was established as first-line therapy for UTIs. This occurred after E coli strains developed high resistance to an earlier first-line therapy, trimethoprim/sulfamethoxazole (TMP/SMZ).¹ Using pharmacy and laboratory databases, investigators found that as levofloxacin prescriptions increased, rates of FQ-resistant E coli rose almost 10-fold, from 1% in 1999 to 9.4% in 2005. A detailed analysis of 2005 E coli isolates showed that previous levofloxacin prescription was strongly associated with FQ resistance (odds ratio 5.6, 95% confidence interval: 2.1 to 27.5). Levofloxacin-resistant strains of E coli also were more likely than levofloxacin-sensitive strains to be resistant to other antibiotics—90% compared with 43% for control specimens (Table).

Table

Antibiotic resistance among levofloxacin-resistant and levofloxacin-susceptible strains of E coli*

The use of FQs as first-line treatment of UTIs also is leading to resistant strains of Streptococcus pneumoniae,¹⁰ Salmonella,^11,12 Neisseria meningitides,¹³ and other bacteria. From an individual and public health perspective, it is important that psychiatrists monitor local resistance patterns and treatment recommendations.

In areas without widespread bacterial resistance to TMP/SMZ, a 3-day course of TMP/SMZ could be considered first-line treatment for uncomplicated UTI in patients without allergies or contraindications. However, in areas where resistance to TMP/SMZ is high, a 7-day course of nitrofurantoin is recommended for uncomplicated cystitis. Resistance patterns can vary from hospital to hospital and even among units in the same hospital;¹⁴ therefore, refer to local microbiology labs for “antibiograms” or information regarding resistance patterns.

Related resource

• National Guideline Clearinghouse. Urinary tract infection. www.guidelines.gov/summary/summary.aspx?doc_id=7407.

Drug brand names

• Ampicillin • Principen
• Cefazolin • Ancef
• Ceftriaxone • Rocephin
• Ciprofloxacin • Ciloxan, Cipro, Cipro XR, ProQuin XR
• Gentamicin • Garamycin
• Levofloxacin • Levaquin
• Nitrofurantoin • Furadantin, Macrodantin, Macrobid, Urotoin
• Trimethoprim/Sulfamethoxazole • Bacter-Aid DS, Bactrim, Septra, Sulfatrim, Sultrex
• Tobramycin • Nebcin

Disclosure

Dr. Gagliardi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Gagliardi is assistant professor of psychiatry and behavioral sciences and assistant clinical professor of medicine, Duke University School of Medicine, Durham, NC.

Principal Source: Johnson L, Sabel A, Burman WJ, et al. Emergence of fluoroquinolone resistance in outpatient urinary Escherichia coli isolates. Am J Med. 2008;121:876-884.

More than 8 million urinary tract infections (UTIs) are diagnosed annually in the United States¹ and UTI is thought to be the most common bacterial infection.² Half of all women report having a UTI at some time in their lives.^2,3 UTI is rare in men, occurring in an estimated 5 to 8 of every 10,000 young to middle-aged men,⁴ but increases with age such that UTI rates in men age >70 are approximately one-third the rates in women.²

Up to 85% percent of UTIs are attributed to Escherichia coli.³ The hallmark symptoms of bacterial cystitis are dysuria and urinary frequency; additional symptoms include urgency, suprapubic pain, and hematuria.⁵

Being familiar with UTI symptoms can help expedite diagnosis and treatment because you might be a psychiatric patient’s primary contact with the healthcare system. Also, psychiatric inpatients could test positive for UTIs during routine medical screening. A 1-day urinalysis study of psychiatric inpatients without urinary catheters detected UTIs in approximately 5% of patients.⁶ In addition, UTI is a common cause of delirium.

Screening

The utility of routine screening urinalysis is under debate, and testing is best used in cases of suspected UTI. However, medical disorders frequently are not recognized in psychiatric patients, especially in older patients⁷ or those with risk factors for UTI. Sexually transmitted diseases (STDs) are not major contributors to UTI risk; however, they may share common symptoms and urinalysis findings. If patients report symptoms of UTI (urgency, dysuria, frequency), urinalysis is indicated. In a urinalysis, >2 to 5 leukocytes per high-powered field in an uncontaminated centrifuged urine specimen without a high number of squamous epithelial cells suggest UTI.

In patients with abnormal urinalysis, ask about dysuria, urinary frequency, history of UTIs, and use of antibiotics. Antibiotic use in the preceding 12 months is associated with increased risk of bacterial resistance.¹ Assess for symptoms of complicated UTI such as fever, flank pain, nausea, and vomiting. Urine culture is not recommended for uncomplicated UTI but may be necessary when symptoms do not resolve or signs of complicated UTI emerge. Consider possible STDs in patients with sterile pyuria.⁵

Treatment and antibiotic resistance

For patients with uncomplicated UTI, a short course of empiric antibiotics is appropriate even in the absence of confirmatory culture data. Fluoroquinolones (FQs), such as ciprofloxacin and levofloxacin, have been used as a first-line treatment. However, FQs are associated with:

• QTc-prolongation, a concern when co-administered with antipsychotics⁸
• delirium
• increased risk of tendinitis and tendon rupture⁹
• antibiotic resistance.

A study of a comprehensive urban public health system in Denver, CO, showed that rates of FQ-resistant E coli increased after levofloxacin was established as first-line therapy for UTIs. This occurred after E coli strains developed high resistance to an earlier first-line therapy, trimethoprim/sulfamethoxazole (TMP/SMZ).¹ Using pharmacy and laboratory databases, investigators found that as levofloxacin prescriptions increased, rates of FQ-resistant E coli rose almost 10-fold, from 1% in 1999 to 9.4% in 2005. A detailed analysis of 2005 E coli isolates showed that previous levofloxacin prescription was strongly associated with FQ resistance (odds ratio 5.6, 95% confidence interval: 2.1 to 27.5). Levofloxacin-resistant strains of E coli also were more likely than levofloxacin-sensitive strains to be resistant to other antibiotics—90% compared with 43% for control specimens (Table).

Table

Antibiotic resistance among levofloxacin-resistant and levofloxacin-susceptible strains of E coli*

The use of FQs as first-line treatment of UTIs also is leading to resistant strains of Streptococcus pneumoniae,¹⁰ Salmonella,^11,12 Neisseria meningitides,¹³ and other bacteria. From an individual and public health perspective, it is important that psychiatrists monitor local resistance patterns and treatment recommendations.

In areas without widespread bacterial resistance to TMP/SMZ, a 3-day course of TMP/SMZ could be considered first-line treatment for uncomplicated UTI in patients without allergies or contraindications. However, in areas where resistance to TMP/SMZ is high, a 7-day course of nitrofurantoin is recommended for uncomplicated cystitis. Resistance patterns can vary from hospital to hospital and even among units in the same hospital;¹⁴ therefore, refer to local microbiology labs for “antibiograms” or information regarding resistance patterns.

Related resource

• National Guideline Clearinghouse. Urinary tract infection. www.guidelines.gov/summary/summary.aspx?doc_id=7407.

Drug brand names

• Ampicillin • Principen
• Cefazolin • Ancef
• Ceftriaxone • Rocephin
• Ciprofloxacin • Ciloxan, Cipro, Cipro XR, ProQuin XR
• Gentamicin • Garamycin
• Levofloxacin • Levaquin
• Nitrofurantoin • Furadantin, Macrodantin, Macrobid, Urotoin
• Trimethoprim/Sulfamethoxazole • Bacter-Aid DS, Bactrim, Septra, Sulfatrim, Sultrex
• Tobramycin • Nebcin

Disclosure

Dr. Gagliardi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discussants: Sarah K. Rivelli, MD, and Andrew J. Muzyk, PharmD

Dr. Rivelli is associate program director, internal medicine-psychiatry residency, departments of internal medicine and psychiatry, and Dr. Muzyk is a clinical pharmacist, Duke University Medical Center, Durham, NC.

Principal Source: Richards JB, Papaioannou A, Adachi JD, et al, and the Canadian Multicentre Osteoporosis Study Research Group. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007;167(2):188-194.

An increased risk of developing osteoporosis may be a hazard of some psychiatric medications and disorders. Osteoporosis is common among postmenopausal women, and additional risk factors for women and men include certain psychiatric disorders (anorexia nervosa and alcohol abuse) and medications such as lithium and some anticonvulsants. In addition:

• Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) are associated with decreased bone mineral density and increased risk of hip fractures.^1,2
• A population-based prospective cohort study found that community-dwelling adults age ≥50 who took SSRIs had double the risk of incident fragility fractures over 5 years,¹ although corticosteroid and anticonvulsant use was more common among those taking SSRIs compared with controls and may have contributed to the higher risk.
• Some studies have suggested that depression may be associated with bone loss.³

Osteoporosis is diagnosed by the presence of a low-impact fracture, a spontaneous fracture—also called fragility fracture—or by decreased bone mineral density testing measured by dual x-ray absorptiometry (DXA) of the lumbar spine and proximal femur.⁴ Bone mineral density measured by DXA that is ≥2.5 standard deviations below the young adult female reference mean—called a T-score ≤-2.5—is consistent with a osteoporosis diagnosis. Blood tests are not necessary for diagnosis but may detect abnormal calcium or phosphorus metabolism related to comorbid disorders.

The U.S. Preventive Services Task Force recommends osteoporosis screening for all women age ≥65 and women age <65 who have risk factors for fracture (Table 1).⁵ There is no consensus on when to screen men, although all adults with a fragility fracture should undergo bone mineral density testing.

Consider screening men and women age >65 if secondary causes of osteoporosis—such as hypogonadism, hyperparathyroidism, hyperthyroidism, Cushing’s syndrome, inflammatory bowel disease, inflammatory arthritis, and hematologic cancers—are present.⁴

Table 1

Osteoporosis risk factors*

Prevention. A diet rich in calcium and vitamin D is essential for healthy bone growth.⁴ Daily requirements increase with age and are highest among adults age >50 (Table 2).⁶ Because the typical U.S. diet has poor calcium content, most adults and children will need calcium supplementation to meet daily requirements. Additional healthy bone lifestyle measures include avoiding caffeine and limiting alcohol consumption to <2 drinks/day.

Physical activity reduces the risk of falls and fractures by increasing muscle strength, coordination, and mobility. Weight-bearing exercise delays osteoporosis onset by promoting strong bone development. When possible, avoid prescribing medications that increase the risk of falls, such as sedative-hypnotics, benzodiazepines, and anticholinergics, or cause bone loss, such as phenytoin, glucocorticoids, and phenobarbital.

Table 2

Daily calcium and vitamin D requirements for adults by age

Treatment. First-line pharmacologic treatment of osteoporosis includes calcium plus vitamin D and a bisphosphonate.⁶

Calcium plus vitamin D increases calcium absorption and has been shown to significantly reduce fracture risk. Calcium typically is prescribed in a carbonate or citrate formulation.

• Calcium carbonate must be taken with meals because it requires an acidic environment for absorption.
• Calcium citrate may cause fewer gastrointestinal side effects, such as constipation.

Because one-time calcium absorption is limited to <600 mg, multiple daily dosing is required. The National Osteoporosis Foundation recommends >800 IU of vitamin D daily to reduce fracture risk in patients age >50 and in those with osteoporosis.⁷

Bisphosphonates have been shown to reduce fracture risk and increase bone mineral density, primarily in the spine and hip and sometimes within 6 months. Once-weekly alendronate and once-monthly risedronate and oral ibandronate are FDA-approved for prevention and treatment of osteoporosis in postmenopausal women. Quarterly ibandronate and once-yearly zoledronic acid injections are approved for osteoporosis treatment. Alendronate and risedronate also are approved to treat osteoporosis caused by glucocorticoid therapy and in men.

Although bisphosphonates do not cause adverse psychiatric effects or interactions with psychotropic medications, bisphosphonates must be taken at least 30 minutes before any other medications. Adverse effects from oral bisphosphonates often are gastrointestinal—such as nausea, heartburn, pain, irritation, and ulceration—and patients should take these medications with only a glass of water and remain upright for at least 30 minutes after ingestion.

Other therapeutic options include teriparatide—a synthetic form of parathyroid hormone injected daily—calcitonin, and raloxifene. Estrogen therapy increases bone density in postmenopausal women but is not recommended for routine use because of increased risk of stroke, thromboembolism, heart disease, and breast cancer.

Related resources

• World Health Organization Fracture Risk Assessment tool. www.shef.ac.uk/FRAX.
• National Osteoporosis Foundation. www.nof.org.

Drug brand names

• Alendronate • Fosamax
• Calcitonin • Miacalcin
• Ibandronate • Boniva
• Lithium • various
• Phenobarbital • various
• Phenytoin • Dilantin
• Prednisone • Deltasone, Meticorten
• Raloxifene • Evista
• Risedronate • Actonel
• Teriparatide • Forteo
• Valproic acid • Depakene
• Zoledronic acid • Reclast

Disclosure

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

Discussants: Sarah K. Rivelli, MD, and Andrew J. Muzyk, PharmD

Dr. Rivelli is associate program director, internal medicine-psychiatry residency, departments of internal medicine and psychiatry, and Dr. Muzyk is a clinical pharmacist, Duke University Medical Center, Durham, NC.

Principal Source: Richards JB, Papaioannou A, Adachi JD, et al, and the Canadian Multicentre Osteoporosis Study Research Group. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007;167(2):188-194.

An increased risk of developing osteoporosis may be a hazard of some psychiatric medications and disorders. Osteoporosis is common among postmenopausal women, and additional risk factors for women and men include certain psychiatric disorders (anorexia nervosa and alcohol abuse) and medications such as lithium and some anticonvulsants. In addition:

• Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) are associated with decreased bone mineral density and increased risk of hip fractures.^1,2
• A population-based prospective cohort study found that community-dwelling adults age ≥50 who took SSRIs had double the risk of incident fragility fractures over 5 years,¹ although corticosteroid and anticonvulsant use was more common among those taking SSRIs compared with controls and may have contributed to the higher risk.
• Some studies have suggested that depression may be associated with bone loss.³

Osteoporosis is diagnosed by the presence of a low-impact fracture, a spontaneous fracture—also called fragility fracture—or by decreased bone mineral density testing measured by dual x-ray absorptiometry (DXA) of the lumbar spine and proximal femur.⁴ Bone mineral density measured by DXA that is ≥2.5 standard deviations below the young adult female reference mean—called a T-score ≤-2.5—is consistent with a osteoporosis diagnosis. Blood tests are not necessary for diagnosis but may detect abnormal calcium or phosphorus metabolism related to comorbid disorders.

The U.S. Preventive Services Task Force recommends osteoporosis screening for all women age ≥65 and women age <65 who have risk factors for fracture (Table 1).⁵ There is no consensus on when to screen men, although all adults with a fragility fracture should undergo bone mineral density testing.

Consider screening men and women age >65 if secondary causes of osteoporosis—such as hypogonadism, hyperparathyroidism, hyperthyroidism, Cushing’s syndrome, inflammatory bowel disease, inflammatory arthritis, and hematologic cancers—are present.⁴

Table 1

Osteoporosis risk factors*

Prevention. A diet rich in calcium and vitamin D is essential for healthy bone growth.⁴ Daily requirements increase with age and are highest among adults age >50 (Table 2).⁶ Because the typical U.S. diet has poor calcium content, most adults and children will need calcium supplementation to meet daily requirements. Additional healthy bone lifestyle measures include avoiding caffeine and limiting alcohol consumption to <2 drinks/day.

Physical activity reduces the risk of falls and fractures by increasing muscle strength, coordination, and mobility. Weight-bearing exercise delays osteoporosis onset by promoting strong bone development. When possible, avoid prescribing medications that increase the risk of falls, such as sedative-hypnotics, benzodiazepines, and anticholinergics, or cause bone loss, such as phenytoin, glucocorticoids, and phenobarbital.

Table 2

Daily calcium and vitamin D requirements for adults by age

Treatment. First-line pharmacologic treatment of osteoporosis includes calcium plus vitamin D and a bisphosphonate.⁶

Calcium plus vitamin D increases calcium absorption and has been shown to significantly reduce fracture risk. Calcium typically is prescribed in a carbonate or citrate formulation.

• Calcium carbonate must be taken with meals because it requires an acidic environment for absorption.
• Calcium citrate may cause fewer gastrointestinal side effects, such as constipation.

Because one-time calcium absorption is limited to <600 mg, multiple daily dosing is required. The National Osteoporosis Foundation recommends >800 IU of vitamin D daily to reduce fracture risk in patients age >50 and in those with osteoporosis.⁷

Bisphosphonates have been shown to reduce fracture risk and increase bone mineral density, primarily in the spine and hip and sometimes within 6 months. Once-weekly alendronate and once-monthly risedronate and oral ibandronate are FDA-approved for prevention and treatment of osteoporosis in postmenopausal women. Quarterly ibandronate and once-yearly zoledronic acid injections are approved for osteoporosis treatment. Alendronate and risedronate also are approved to treat osteoporosis caused by glucocorticoid therapy and in men.

Although bisphosphonates do not cause adverse psychiatric effects or interactions with psychotropic medications, bisphosphonates must be taken at least 30 minutes before any other medications. Adverse effects from oral bisphosphonates often are gastrointestinal—such as nausea, heartburn, pain, irritation, and ulceration—and patients should take these medications with only a glass of water and remain upright for at least 30 minutes after ingestion.

Other therapeutic options include teriparatide—a synthetic form of parathyroid hormone injected daily—calcitonin, and raloxifene. Estrogen therapy increases bone density in postmenopausal women but is not recommended for routine use because of increased risk of stroke, thromboembolism, heart disease, and breast cancer.

Related resources

• World Health Organization Fracture Risk Assessment tool. www.shef.ac.uk/FRAX.
• National Osteoporosis Foundation. www.nof.org.

Drug brand names

• Alendronate • Fosamax
• Calcitonin • Miacalcin
• Ibandronate • Boniva
• Lithium • various
• Phenobarbital • various
• Phenytoin • Dilantin
• Prednisone • Deltasone, Meticorten
• Raloxifene • Evista
• Risedronate • Actonel
• Teriparatide • Forteo
• Valproic acid • Depakene
• Zoledronic acid • Reclast

Disclosure

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

Discussants: Sarah K. Rivelli, MD, and Andrew J. Muzyk, PharmD

Dr. Rivelli is associate program director, internal medicine-psychiatry residency, departments of internal medicine and psychiatry, and Dr. Muzyk is a clinical pharmacist, Duke University Medical Center, Durham, NC.

Principal Source: Richards JB, Papaioannou A, Adachi JD, et al, and the Canadian Multicentre Osteoporosis Study Research Group. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007;167(2):188-194.

An increased risk of developing osteoporosis may be a hazard of some psychiatric medications and disorders. Osteoporosis is common among postmenopausal women, and additional risk factors for women and men include certain psychiatric disorders (anorexia nervosa and alcohol abuse) and medications such as lithium and some anticonvulsants. In addition:

• Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) are associated with decreased bone mineral density and increased risk of hip fractures.^1,2
• A population-based prospective cohort study found that community-dwelling adults age ≥50 who took SSRIs had double the risk of incident fragility fractures over 5 years,¹ although corticosteroid and anticonvulsant use was more common among those taking SSRIs compared with controls and may have contributed to the higher risk.
• Some studies have suggested that depression may be associated with bone loss.³

Osteoporosis is diagnosed by the presence of a low-impact fracture, a spontaneous fracture—also called fragility fracture—or by decreased bone mineral density testing measured by dual x-ray absorptiometry (DXA) of the lumbar spine and proximal femur.⁴ Bone mineral density measured by DXA that is ≥2.5 standard deviations below the young adult female reference mean—called a T-score ≤-2.5—is consistent with a osteoporosis diagnosis. Blood tests are not necessary for diagnosis but may detect abnormal calcium or phosphorus metabolism related to comorbid disorders.

The U.S. Preventive Services Task Force recommends osteoporosis screening for all women age ≥65 and women age <65 who have risk factors for fracture (Table 1).⁵ There is no consensus on when to screen men, although all adults with a fragility fracture should undergo bone mineral density testing.

Consider screening men and women age >65 if secondary causes of osteoporosis—such as hypogonadism, hyperparathyroidism, hyperthyroidism, Cushing’s syndrome, inflammatory bowel disease, inflammatory arthritis, and hematologic cancers—are present.⁴

Table 1

Osteoporosis risk factors*

Prevention. A diet rich in calcium and vitamin D is essential for healthy bone growth.⁴ Daily requirements increase with age and are highest among adults age >50 (Table 2).⁶ Because the typical U.S. diet has poor calcium content, most adults and children will need calcium supplementation to meet daily requirements. Additional healthy bone lifestyle measures include avoiding caffeine and limiting alcohol consumption to <2 drinks/day.

Physical activity reduces the risk of falls and fractures by increasing muscle strength, coordination, and mobility. Weight-bearing exercise delays osteoporosis onset by promoting strong bone development. When possible, avoid prescribing medications that increase the risk of falls, such as sedative-hypnotics, benzodiazepines, and anticholinergics, or cause bone loss, such as phenytoin, glucocorticoids, and phenobarbital.

Table 2

Daily calcium and vitamin D requirements for adults by age

Treatment. First-line pharmacologic treatment of osteoporosis includes calcium plus vitamin D and a bisphosphonate.⁶

Calcium plus vitamin D increases calcium absorption and has been shown to significantly reduce fracture risk. Calcium typically is prescribed in a carbonate or citrate formulation.

• Calcium carbonate must be taken with meals because it requires an acidic environment for absorption.
• Calcium citrate may cause fewer gastrointestinal side effects, such as constipation.

Because one-time calcium absorption is limited to <600 mg, multiple daily dosing is required. The National Osteoporosis Foundation recommends >800 IU of vitamin D daily to reduce fracture risk in patients age >50 and in those with osteoporosis.⁷

Bisphosphonates have been shown to reduce fracture risk and increase bone mineral density, primarily in the spine and hip and sometimes within 6 months. Once-weekly alendronate and once-monthly risedronate and oral ibandronate are FDA-approved for prevention and treatment of osteoporosis in postmenopausal women. Quarterly ibandronate and once-yearly zoledronic acid injections are approved for osteoporosis treatment. Alendronate and risedronate also are approved to treat osteoporosis caused by glucocorticoid therapy and in men.

Although bisphosphonates do not cause adverse psychiatric effects or interactions with psychotropic medications, bisphosphonates must be taken at least 30 minutes before any other medications. Adverse effects from oral bisphosphonates often are gastrointestinal—such as nausea, heartburn, pain, irritation, and ulceration—and patients should take these medications with only a glass of water and remain upright for at least 30 minutes after ingestion.

Other therapeutic options include teriparatide—a synthetic form of parathyroid hormone injected daily—calcitonin, and raloxifene. Estrogen therapy increases bone density in postmenopausal women but is not recommended for routine use because of increased risk of stroke, thromboembolism, heart disease, and breast cancer.

Related resources

• World Health Organization Fracture Risk Assessment tool. www.shef.ac.uk/FRAX.
• National Osteoporosis Foundation. www.nof.org.

Drug brand names

• Alendronate • Fosamax
• Calcitonin • Miacalcin
• Ibandronate • Boniva
• Lithium • various
• Phenobarbital • various
• Phenytoin • Dilantin
• Prednisone • Deltasone, Meticorten
• Raloxifene • Evista
• Risedronate • Actonel
• Teriparatide • Forteo
• Valproic acid • Depakene
• Zoledronic acid • Reclast

Disclosure

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

Principal Source: Advisory Committee on Immunization Practices. Recommended adult immunization schedule: United States, October 2007-September 2008. Ann Intern Med. 2007;147:725-729.—Discussant: Daniel Goldsmith, MD

Dr. Goldsmith is associate director, internal medicine residency program, Capital Health System, Trenton, NJ.

Psychiatric patients who use drugs, alcohol, or tobacco and those who engage in high-risk sexual behaviors can be protected from acquiring viral infections such as hepatitis A and B, influenza, and human papillomavirus (HPV). The recently updated adult immunization schedule (Table)^1,2 from the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) gives mental health professionals the opportunity to recognize risk and refer patients for vaccinations as part of preventive care. (see Related Resources) for a link to the complete CDC vaccination recommendations.

Hepatitis A and B. Substance abuse and high-risk sexual behaviors contribute to the high prevalence of comorbid alcohol-related liver disease and viral hepatitis among psychiatric patients. Individuals with chronic liver disease—regardless of its cause—should be screened for hepatitis A and B infection and, if negative, offered the appropriate vaccination series. Acute viral hepatitis in patients with pre-existing chronic hepatitis from any cause, such as alcohol abuse or hepatitis C, is associated with severe hepatic dysfunction and liver failure.³

Hepatitis B screening and vaccination is recommended for psychiatric populations that include clients of substance abuse treatment centers and institutions and daycare facilities for developmental disabilities, as well as IV drug users. Anyone who uses illegal drugs—injectable or noninjectable—should be vaccinated for hepatitis A.

Only individuals susceptible to hepatitis A and B should be vaccinated.³ To determine immune status for hepatitis B, serum tests for hepatitis B surface antigen (HepBsAg), hepatitis B surface antibody IgG (HepBsAb), and hepatitis B core antibody IgG (HepBcAb) are necessary to differentiate among patients who:

• are susceptible to infection
• had an infection that cleared
• have chronic active infection
• already have been vaccinated.

The hepatitis A IgG serum test determines a patient’s hepatitis A immune status. A negative result shows no previous infection, and the patient is eligible for vaccination. A positive result indicates previous infection meaning vaccination has no benefit.³

Influenza. Tobacco use and subsequent chronic pulmonary disease is an indication for annual influenza vaccination.⁴ Most individuals will receive the injectable, inactivated vaccine. The intranasal, live attenuated vaccine is reserved for nonpregnant adults age ≤49 without high-risk medical conditions and who are not in close contact with immunocompromised persons.¹

Pneumococcal and influenza vaccinations also are recommended for persons with chronic liver disease.¹ Consider recommending influenza, pneumococcal, varicella, and hepatitis B vaccinations for psychiatric patients in long-term care facilities.¹

HPV. Cervical cancer is highly associated with HPV, a sexually transmitted organism, and the HPV vaccine can effectively prevent infection and subsequent neoplasia. All women age ≤26 are eligible for the vaccine. Women with evidence of HPV infection—such as abnormal Pap smear, genital warts, or a positive HPV DNA test—are still eligible to receive the HPV vaccine because several viral strains cause disease.¹ Because mental health providers may treat otherwise medically healthy young people, including those who engage in high-risk behaviors, psychiatrists have an opportunity to refer for vaccinations individuals who may not consistently utilize primary care.

Immunity screening considerations. Vaccines for HPV, influenza, and pneumonia are recommended regardless of evidence of immunity or prior infection. Hepatitis A and B vaccines require a history of never having had the illness or laboratory evidence of a lack of immunity.

Table

Updated CDC adult vaccination recommendations

Related resources

• Immunization Action Coalition: Vaccine information for health care professionals. www.immunize.org.
• Centers for Disease Control and Prevention. Adult immunization schedule. www.cdc.gov/vaccines/recs/schedules/adult-schedule.htm.

Disclosure

Dr. Goldsmith reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.