Kanwaldeep S. Sidhu, MD

Comment on this article

Mrs. S, age 44, is on leave from her job as a bank cashier because depressive symptoms interfered with her performance. At a university-based psychiatric clinic she reports feeling depressed, reduced interest in daily activities, problems with sleep onset and maintenance, inconsistent appetite, low energy, hopelessness, and decreased memory and concentration.

The resident psychiatrist diagnoses major depressive disorder (MDD) and starts Mrs. S on sertraline, 50 mg/d. The dosage is gradually titrated to 200 mg/d, and after 8 weeks she reports substantial improvement.

Mrs. S returns to her job but experiences residual low energy, lethargy, and inconsistent sleep. Her work schedule and caring for her 2 children at home prevent her from continuing weekly cognitive-behavioral therapy (CBT), but she soon notices that she feels more energetic. She reports that because of high gasoline prices she has been walking several miles daily to commute by train to work. The resident psychiatrist sees this as an opportunity to reinforce the benefits of exercise for depression.

Antidepressants alone do not adequately treat many patients with depression. In the STAR*D Project—which compared long-term outcomes of various depression treatments—only 28% to 33% of outpatients achieved remission with selective serotonin reuptake inhibitor (SSRI) monotherapy. Rates were somewhat higher with bupropion or serotonin norepinephrine reuptake inhibitor (SNRI) monotherapy, but greater benefit was obtained from augmenting SSRIs.¹

Combining antidepressants with psychotherapy² and lifestyle changes—particularly exercise—makes sense intuitively and is supported by well-designed studies:

• The 60% of adults in the National Comorbidity Survey who said they exercised regularly reported lower rates of depression and anxiety, compared with less active adults.³
• A meta-analysis of 11 randomized, controlled trials supports the use of exercise as an effective intervention for clinical depression.⁴

Box 1

This article examines the evidence supporting exercise for treating and preventing clinical depression. We begin by addressing clinicians’ concerns about motivating depressed patients to exercise.

Overcoming barriers

Physician issues. Busy physicians often omit discussions about exercise during brief office visits. Only 34% of 9,299 patients in a population-based survey⁵ reported that their doctors counseled them about exercise during their most recent visits. Counseling patients does not have to be time-intensive, however. A study of the Physician-based Assessment and Counseling for Exercise (PACE) project showed that 70% of physicians could provide exercise counseling in 3 to 5 minutes, and most patients reported following their physicians’ advice.⁶

Highly depressed individuals are at risk to quit when they encounter barriers to exercise and to respond to difficulties with frustration and self-disappointment. Thus, depressed patients may need support and encouragement to initiate and maintain regular exercise routines.⁷ Set small, realistic goals for them, and discuss how to solve problems and remove barriers to increase their likelihood to exercise.

Interventions are most likely to be effective when you counsel patients about exercise as prescription and discuss exercise at each visit.⁸ Previously sedentary patients have shown short-term moderate increases in physical activity in response to physician counseling. In a study of 212 adults (mean age 39, 84% female), the PACE project significantly increased minutes of weekly walking.⁹ More than one-half (52%) of patients increased their physical activity, compared with 12% of controls whose physicians did not provide the PACE intervention.

Patient issues. Lack of time and no appropriate space to exercise are common complaints, particularly among residents of regions with long, cold winters. Some patients perceive regular exercise as monotonous or boring, and others may lack the necessary initiative because of poor physical health, fear, negative experiences, or lack of knowledge about exercising. These barriers can be pronounced in older depressed persons. In a cross-sectional study of 645 residents of Jyväskylä, Finland, those age >75 with depressive symptoms were more than twice as likely to be physically inactive as nondepressed residents.¹⁰

An intensive exercise program is not the optimal starting point for many patients. Even walking or light jogging can be an effective exercise for depressed individuals with physical limitations. For these patients, a consultation with their primary physician may be necessary if a more intensive program has to be recommended.

Exercise as monotherapy

A dose-response relationship? Various mechanisms have been suggested for the benefits of exercise in depression (Box 1). Exercise alone—without medication—may be an effective treatment for mild and in some cases moderate MDD, and aerobic exercise may reduce depressive symptoms in a dose-response relationship.¹¹

 

A study of exercise in a supervised laboratory setting demonstrated this relationship in 80 adults age 20 to 45 with mild-to-moderate depressive symptoms. Subjects were randomly assigned to an exercise control group (3 days/week of flexibility exercise) or 1 of 4 aerobic exercise groups that varied in total energy expenditure (a “low dose” of 7.0 kcal/kg/week or a “public health dose” of 17.5 kcal/kg/week). The 17-item Hamilton Rating Scale for Depression (HRSD) was the primary outcome measure.

After 12 weeks, HRSD scores declined from baseline by 47% in subjects engaged in the public health dose of aerobic exercise—a significant reduction. Depressive symptoms declined by 30% in the low-dose exercisers, but this was comparable to the 29% reduction in the control group.

Comment. The effective exercise dose in this study is similar to the public health recommendation of 30 minutes of moderate-to-vigorous activity on all or most days per week (see Related Resources). Antidepressant effects have been associated with more modest physical activity, however, which may be easier to initiate and maintain for individuals with depression. The study did not find significant differences in outcomes based on the subjects’ age, gender, or exercise frequency. Nevertheless, the exercise dose may be important to produce an antidepressant effect.

An inverse relationship? Compared with occasional exercise, habitual physical activity usually is associated with greater cardiorespiratory fitness. Whether habitual activity also results in fewer depressive symptoms and greater emotional well-being remains to be seen.

A large, cross-sectional, National Institutes of Health-funded study of 5,451 men and 1,277 women¹² suggests an inverse relationship between physical activity and depressive symptoms. Subjects underwent a treadmill exercise test to evaluate physical fitness. A 20-point self-report scale assessed depressive symptoms, and the General Well-Being Schedule¹³ was used to assess emotional well-being. Depressive symptoms were more severe in “inactive” and “insufficiently active” subjects compared with “sufficiently active” and “highly active” subjects.

On the other hand, although regular exercise may be associated with reduced depressive symptoms in the population at large, no cause-effect relationship was found in a population-based, longitudinal study of 5,952 twins.¹⁴

A prospective, randomized, controlled trial¹⁵ suggests that exercise could be an important treatment tool in patients diagnosed with MDD. The 202 adult subjects (153 women, 49 men) were randomly assigned to 1 of 4 treatments:

• supervised exercise in a group setting
• home-based exercise
• antidepressant medication (sertraline, 50 to 200 mg/d)
• placebo pills.

Patients underwent the structured clinical interview for depression and completed the HRSD. After 16 weeks, 41% of participants achieved remission, defined as no longer meeting MDD criteria and a HRSD score <8. Compared with placebo controls, patients receiving active treatments tended to have higher remission rates:

• 45% with supervised exercise
• 40% with home-based exercise
• 47% with medication
• 31% with placebo.

Comment. The placebo response rate was relatively high in this study, and antidepressant dosages might not have been optimal. These factors could explain why remission rates with supervised exercise and antidepressant medication were comparable. The study might have been more reliable if it had included a medication plus exercise arm. Patients treated in an office setting might not fare as well as these study subjects whose exercise was supervised.

Postpartum depression occurs in an estimated 13% of new mothers.¹⁶ In a controlled trial, 80 women with depression at 4 weeks postpartum were assigned to either:

• an exercise support program (1 hour supervised exercise and 2 sessions at home each week for 3 months)
• standard care.

Box 2

 

No subjects received medication. Women in the exercise support program were less likely to have high scores on the Edinburgh Postnatal Depression Scale, compared with controls. Women who exercised also reported a greater sense of well-being. Differences between the 2 groups were not statistically significant at 4 weeks post partum but achieved significance at 5 months.¹⁷

Depressive symptoms may exacerbate fatigue in postpartum women.¹⁸ A study of 88 women with postpartum depression showed the benefits of a home-based exercise program on physical and mental fatigue.¹⁹ This finding may be important because fatigue often is associated with treatment-resistant depression and may increase the likelihood of relapse in women with postpartum depression.²⁰

Late-life depression. Exercise can benefit the depressed elderly as well. In a 10-week randomized, controlled trial²¹ of volunteers age ≥60 with major or minor depression or dysthymia, progressive resistance training (PRT) significantly reduced depression, as measured by the Beck Depression Inventory (BDI) and HRSD. PRT also improved quality of life, vitality, social functioning, and emotional well-being when compared with a control group (Box 2).

A dose-response relationship of exercise for treating late-life depression was shown in a blinded, controlled trial²² of 60 community-dwelling, depressed subjects age >60. These patients were randomly assigned to high-intensity PRT, low-intensity PRT, or standard care by a general practitioner (GP). A ≥50% reduction in HRSD score was achieved by:

• 61% of the high-intensity PRT group
• 29% of the low-intensity PRT group
• 21% of the GP care group.

Sleep quality improved in all participants, with the greatest relative change in the high-intensity PRT group.

Exercise vs psychotherapy. The benefits of exercise may be comparable or superior to those of cognitive or group psychotherapy.^23,24 This may be good news for patients such as Mrs. S who lack time or financial resources for regular psychotherapy.

Adjunctive exercise

In depressed patients, exercise may increase the perceived quality of life when combined with medication. This was demonstrated in a randomized, 32-week naturalistic study of 30 women, age 40 to 60, with treatment-resistant MDD.²⁵ The 10 women who received various antidepressants plus physical exercise showed significantly greater long-term improvement in depression symptoms, as measured by the HRSD and Global Assessment of Functioning (GAF) scores, compared with 20 women who received pharmacotherapy alone.²⁶ Study limitations included the absence of a placebo arm, small sample size, and inclusion of subjects with comorbid anxiety disorders.

Group aerobic exercise programs can be an effective and feasible treatment for depression, particularly for older adults. In a controlled trial,²⁷ 156 men and women age >50 with MDD were randomly assigned to 3 groups: a program of aerobic exercise; sertraline, ≤200 mg/d; or exercise plus sertraline. HRSD and BDI scores before and after treatment were the primary outcome measures. Secondary measures included aerobic capacity, life satisfaction, self-esteem, anxiety, and dysfunctional cognitions. After 16 weeks of treatment, similar percentages of patients in each group no longer met DSM-IV-TR criteria for MDD:

• 60.4% of patients in the exercise-only group
• 68.8% of patients in the medication-only group
• 65.5% of patients receiving exercise plus medication.

Depression severity appeared to predict the rate of response to the different treatments. Patients who received medication alone seemed to have the most rapid response to treatment. Patients with less severe depression appeared to respond more quickly to exercise plus medication than those with more severe depression.

Long-term benefits

Because depression is a chronic, relapsing illness, any treatment will be widely accepted only if its benefits are long-term. A study of aerobic exercise in 156 adults age ≥50 with MDD²⁸ found that benefits were sustained for >6 months.

Participants were randomly assigned to 4 months of aerobic exercise; sertraline, ≤200 mg/d; or a combination of exercise and sertraline. Aerobic exercise consisted of 30 minutes of brisk walking and jogging on a treadmill, with training ranges equivalent to 70% to 85% of individuals’ maximum heart rate. Appropriate warm-up and cool-down sessions of 5 to 10 minutes were included.

Depressive symptoms improved significantly from baseline in all 3 groups—as assessed by clinical interview, HRSD, and BDI—and after 4 months a comparable number in each group no longer met diagnostic criteria for MDD. When subjects were reassessed 6 months later, the exercisers had significantly lower relapse rates than those receiving medication (P=.01). Those who continued to exercise also were less likely to meet MDD criteria at the end of the 10-month study.

Box 3

 

Even when unsupervised, exercise can have long-term benefits—as was shown in a randomized, blinded, controlled study of 32 elderly subjects.²⁹ An active treatment group underwent 10 weeks of supervised weight lifting, followed by 10 weeks of unsupervised exercise. Controls received no active treatment. Depression scores as measured by BDI were significantly lower at 20 weeks and 26 months in exercisers compared with controls. An antidepressant effect was seen in 73% of exercisers vs 36% of controls at 20 weeks of treatment.

Comment. These studies show that exercise can maintain an anti depressant effect for 10 to 26 months, but additional randomized controlled studies are needed.

Preventing depression? Inactive nondepressed individuals may be at greater risk to develop depression compared with active individuals, according to a 29-year longitudinal study of Californians age 17 to 94. This association was somewhat diminished when findings were adjusted for the Alameda County residents’ physical health, socioeconomic status, social supports, life events, and other health habits.³⁰ The authors recommended that exercise programs be offered in community mental health programs.

Box 4

Simple steps to build physical activity into daily life

The American Heart Association offers helpful tips for increasing daily exercise at home, at work, and at play. For additional suggestions, go to www.americanheart.org.
At home	At the office	At play
Do housework yourself instead of hiring someone else to do it	Brainstorm project ideas with a coworker while taking a walk	Plan family outings and vacations that include physical
Work in the garden or mow the grass (using a riding mower doesn’t count); rake leaves, prune, dig, and pick up trash	Stand while talking on the telephone	activity (hiking, backpacking, swimming, etc.)
Go out for a short walk before breakfast, after dinner or both; start with 5 to 10 minutes and work up to 30 minutes	Walk down the hall to speak with someone rather than using the telephone	See the sights in new cities by walking, jogging, or bicycling
Walk or bike to the corner store instead of driving	Take the stairs instead of the elevator, or get off a few floors early and take the stairs the rest of the way	Make a date with a friend to enjoy your favorite physical activities, and do them regularly
When walking, increase the pace from leisurely to brisk; choose a hilly route	Schedule exercise time on your business calendar, and treat it as any other important appointment	Play your favorite music while exercising, something that motivates you
		Dance with someone or by yourself; take dancing lessons
		Join a recreational club that emphasizes physical activity
		When golfing, walk the course instead of using a cart

CASE CONTINUED: Removing barriers to exercise

The resident psychiatrist treating Mrs. S encourages her to join an aerobic exercise class at the nearby fitness facility. Because cost is a potential barrier, he helps her negotiate a discount for the first 6 months of membership. Her husband agrees in a joint counseling session to help more with the care of their children so that she can attend the classes.

With continued sertraline, 200 mg/d, and aerobic exercise, Mrs. S’s residual depressive symptoms gradually improve. She still has days when she is unable to attend the exercise classes, but she benefits from the program and is functioning better at work and home.

Getting started

We recommend that psychiatrists inquire about physical activity at every visit to gauge patients’ perception and motivation to exercise. Find ways to overcome patients’ fears and negative experiences with exercise. Provide information to help increase physical activity among patients with depressive symptoms¹⁰ (see Related Resources).

Encourage patients to take steps each day to increase their physical activity (Box 3). Depending on the severity of the individual’s depression and inactivity, a realistic starting point may be to take the stairs instead of an elevator, play with children and pets, or take short brisk walks in the yard or neighborhood (Box 4). Consider stationary bikes or swimming as alternatives for physically handicapped individuals and patients who have undergone knee replacements.

Related resources

• 2008 physical activity guidelines for Americans. U.S. Department of Health and Human Services; 2008:vi-viii. www.health.gov/paguidelines.
• American College of Sports Medicine/American Health Association physical activity guidelines and keys to exercise success. www.acsm.org.
• American Heart Association. www.americanheart.org.
• U.S. Department of Health and Human Services. Quick Guide for Healthy Living. Get Active. www.healthfinder.gov/prevention/ViewTopic.aspx?topicID=22.

 

Drug brand names

• Bupropion • Wellbutrin
• Sertraline • Zoloft

Disclosure

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

Comment on this article

Mrs. S, age 44, is on leave from her job as a bank cashier because depressive symptoms interfered with her performance. At a university-based psychiatric clinic she reports feeling depressed, reduced interest in daily activities, problems with sleep onset and maintenance, inconsistent appetite, low energy, hopelessness, and decreased memory and concentration.

The resident psychiatrist diagnoses major depressive disorder (MDD) and starts Mrs. S on sertraline, 50 mg/d. The dosage is gradually titrated to 200 mg/d, and after 8 weeks she reports substantial improvement.

Mrs. S returns to her job but experiences residual low energy, lethargy, and inconsistent sleep. Her work schedule and caring for her 2 children at home prevent her from continuing weekly cognitive-behavioral therapy (CBT), but she soon notices that she feels more energetic. She reports that because of high gasoline prices she has been walking several miles daily to commute by train to work. The resident psychiatrist sees this as an opportunity to reinforce the benefits of exercise for depression.

Antidepressants alone do not adequately treat many patients with depression. In the STAR*D Project—which compared long-term outcomes of various depression treatments—only 28% to 33% of outpatients achieved remission with selective serotonin reuptake inhibitor (SSRI) monotherapy. Rates were somewhat higher with bupropion or serotonin norepinephrine reuptake inhibitor (SNRI) monotherapy, but greater benefit was obtained from augmenting SSRIs.¹

Combining antidepressants with psychotherapy² and lifestyle changes—particularly exercise—makes sense intuitively and is supported by well-designed studies:

• The 60% of adults in the National Comorbidity Survey who said they exercised regularly reported lower rates of depression and anxiety, compared with less active adults.³
• A meta-analysis of 11 randomized, controlled trials supports the use of exercise as an effective intervention for clinical depression.⁴

Box 1

This article examines the evidence supporting exercise for treating and preventing clinical depression. We begin by addressing clinicians’ concerns about motivating depressed patients to exercise.

Overcoming barriers

Physician issues. Busy physicians often omit discussions about exercise during brief office visits. Only 34% of 9,299 patients in a population-based survey⁵ reported that their doctors counseled them about exercise during their most recent visits. Counseling patients does not have to be time-intensive, however. A study of the Physician-based Assessment and Counseling for Exercise (PACE) project showed that 70% of physicians could provide exercise counseling in 3 to 5 minutes, and most patients reported following their physicians’ advice.⁶

Highly depressed individuals are at risk to quit when they encounter barriers to exercise and to respond to difficulties with frustration and self-disappointment. Thus, depressed patients may need support and encouragement to initiate and maintain regular exercise routines.⁷ Set small, realistic goals for them, and discuss how to solve problems and remove barriers to increase their likelihood to exercise.

Interventions are most likely to be effective when you counsel patients about exercise as prescription and discuss exercise at each visit.⁸ Previously sedentary patients have shown short-term moderate increases in physical activity in response to physician counseling. In a study of 212 adults (mean age 39, 84% female), the PACE project significantly increased minutes of weekly walking.⁹ More than one-half (52%) of patients increased their physical activity, compared with 12% of controls whose physicians did not provide the PACE intervention.

Patient issues. Lack of time and no appropriate space to exercise are common complaints, particularly among residents of regions with long, cold winters. Some patients perceive regular exercise as monotonous or boring, and others may lack the necessary initiative because of poor physical health, fear, negative experiences, or lack of knowledge about exercising. These barriers can be pronounced in older depressed persons. In a cross-sectional study of 645 residents of Jyväskylä, Finland, those age >75 with depressive symptoms were more than twice as likely to be physically inactive as nondepressed residents.¹⁰

An intensive exercise program is not the optimal starting point for many patients. Even walking or light jogging can be an effective exercise for depressed individuals with physical limitations. For these patients, a consultation with their primary physician may be necessary if a more intensive program has to be recommended.

Exercise as monotherapy

A dose-response relationship? Various mechanisms have been suggested for the benefits of exercise in depression (Box 1). Exercise alone—without medication—may be an effective treatment for mild and in some cases moderate MDD, and aerobic exercise may reduce depressive symptoms in a dose-response relationship.¹¹

 

A study of exercise in a supervised laboratory setting demonstrated this relationship in 80 adults age 20 to 45 with mild-to-moderate depressive symptoms. Subjects were randomly assigned to an exercise control group (3 days/week of flexibility exercise) or 1 of 4 aerobic exercise groups that varied in total energy expenditure (a “low dose” of 7.0 kcal/kg/week or a “public health dose” of 17.5 kcal/kg/week). The 17-item Hamilton Rating Scale for Depression (HRSD) was the primary outcome measure.

After 12 weeks, HRSD scores declined from baseline by 47% in subjects engaged in the public health dose of aerobic exercise—a significant reduction. Depressive symptoms declined by 30% in the low-dose exercisers, but this was comparable to the 29% reduction in the control group.

Comment. The effective exercise dose in this study is similar to the public health recommendation of 30 minutes of moderate-to-vigorous activity on all or most days per week (see Related Resources). Antidepressant effects have been associated with more modest physical activity, however, which may be easier to initiate and maintain for individuals with depression. The study did not find significant differences in outcomes based on the subjects’ age, gender, or exercise frequency. Nevertheless, the exercise dose may be important to produce an antidepressant effect.

An inverse relationship? Compared with occasional exercise, habitual physical activity usually is associated with greater cardiorespiratory fitness. Whether habitual activity also results in fewer depressive symptoms and greater emotional well-being remains to be seen.

A large, cross-sectional, National Institutes of Health-funded study of 5,451 men and 1,277 women¹² suggests an inverse relationship between physical activity and depressive symptoms. Subjects underwent a treadmill exercise test to evaluate physical fitness. A 20-point self-report scale assessed depressive symptoms, and the General Well-Being Schedule¹³ was used to assess emotional well-being. Depressive symptoms were more severe in “inactive” and “insufficiently active” subjects compared with “sufficiently active” and “highly active” subjects.

On the other hand, although regular exercise may be associated with reduced depressive symptoms in the population at large, no cause-effect relationship was found in a population-based, longitudinal study of 5,952 twins.¹⁴

A prospective, randomized, controlled trial¹⁵ suggests that exercise could be an important treatment tool in patients diagnosed with MDD. The 202 adult subjects (153 women, 49 men) were randomly assigned to 1 of 4 treatments:

• supervised exercise in a group setting
• home-based exercise
• antidepressant medication (sertraline, 50 to 200 mg/d)
• placebo pills.

Patients underwent the structured clinical interview for depression and completed the HRSD. After 16 weeks, 41% of participants achieved remission, defined as no longer meeting MDD criteria and a HRSD score <8. Compared with placebo controls, patients receiving active treatments tended to have higher remission rates:

• 45% with supervised exercise
• 40% with home-based exercise
• 47% with medication
• 31% with placebo.

Comment. The placebo response rate was relatively high in this study, and antidepressant dosages might not have been optimal. These factors could explain why remission rates with supervised exercise and antidepressant medication were comparable. The study might have been more reliable if it had included a medication plus exercise arm. Patients treated in an office setting might not fare as well as these study subjects whose exercise was supervised.

Postpartum depression occurs in an estimated 13% of new mothers.¹⁶ In a controlled trial, 80 women with depression at 4 weeks postpartum were assigned to either:

• an exercise support program (1 hour supervised exercise and 2 sessions at home each week for 3 months)
• standard care.

Box 2

 

No subjects received medication. Women in the exercise support program were less likely to have high scores on the Edinburgh Postnatal Depression Scale, compared with controls. Women who exercised also reported a greater sense of well-being. Differences between the 2 groups were not statistically significant at 4 weeks post partum but achieved significance at 5 months.¹⁷

Depressive symptoms may exacerbate fatigue in postpartum women.¹⁸ A study of 88 women with postpartum depression showed the benefits of a home-based exercise program on physical and mental fatigue.¹⁹ This finding may be important because fatigue often is associated with treatment-resistant depression and may increase the likelihood of relapse in women with postpartum depression.²⁰

Late-life depression. Exercise can benefit the depressed elderly as well. In a 10-week randomized, controlled trial²¹ of volunteers age ≥60 with major or minor depression or dysthymia, progressive resistance training (PRT) significantly reduced depression, as measured by the Beck Depression Inventory (BDI) and HRSD. PRT also improved quality of life, vitality, social functioning, and emotional well-being when compared with a control group (Box 2).

A dose-response relationship of exercise for treating late-life depression was shown in a blinded, controlled trial²² of 60 community-dwelling, depressed subjects age >60. These patients were randomly assigned to high-intensity PRT, low-intensity PRT, or standard care by a general practitioner (GP). A ≥50% reduction in HRSD score was achieved by:

• 61% of the high-intensity PRT group
• 29% of the low-intensity PRT group
• 21% of the GP care group.

Sleep quality improved in all participants, with the greatest relative change in the high-intensity PRT group.

Exercise vs psychotherapy. The benefits of exercise may be comparable or superior to those of cognitive or group psychotherapy.^23,24 This may be good news for patients such as Mrs. S who lack time or financial resources for regular psychotherapy.

Adjunctive exercise

In depressed patients, exercise may increase the perceived quality of life when combined with medication. This was demonstrated in a randomized, 32-week naturalistic study of 30 women, age 40 to 60, with treatment-resistant MDD.²⁵ The 10 women who received various antidepressants plus physical exercise showed significantly greater long-term improvement in depression symptoms, as measured by the HRSD and Global Assessment of Functioning (GAF) scores, compared with 20 women who received pharmacotherapy alone.²⁶ Study limitations included the absence of a placebo arm, small sample size, and inclusion of subjects with comorbid anxiety disorders.

Group aerobic exercise programs can be an effective and feasible treatment for depression, particularly for older adults. In a controlled trial,²⁷ 156 men and women age >50 with MDD were randomly assigned to 3 groups: a program of aerobic exercise; sertraline, ≤200 mg/d; or exercise plus sertraline. HRSD and BDI scores before and after treatment were the primary outcome measures. Secondary measures included aerobic capacity, life satisfaction, self-esteem, anxiety, and dysfunctional cognitions. After 16 weeks of treatment, similar percentages of patients in each group no longer met DSM-IV-TR criteria for MDD:

• 60.4% of patients in the exercise-only group
• 68.8% of patients in the medication-only group
• 65.5% of patients receiving exercise plus medication.

Depression severity appeared to predict the rate of response to the different treatments. Patients who received medication alone seemed to have the most rapid response to treatment. Patients with less severe depression appeared to respond more quickly to exercise plus medication than those with more severe depression.

Long-term benefits

Because depression is a chronic, relapsing illness, any treatment will be widely accepted only if its benefits are long-term. A study of aerobic exercise in 156 adults age ≥50 with MDD²⁸ found that benefits were sustained for >6 months.

Participants were randomly assigned to 4 months of aerobic exercise; sertraline, ≤200 mg/d; or a combination of exercise and sertraline. Aerobic exercise consisted of 30 minutes of brisk walking and jogging on a treadmill, with training ranges equivalent to 70% to 85% of individuals’ maximum heart rate. Appropriate warm-up and cool-down sessions of 5 to 10 minutes were included.

Depressive symptoms improved significantly from baseline in all 3 groups—as assessed by clinical interview, HRSD, and BDI—and after 4 months a comparable number in each group no longer met diagnostic criteria for MDD. When subjects were reassessed 6 months later, the exercisers had significantly lower relapse rates than those receiving medication (P=.01). Those who continued to exercise also were less likely to meet MDD criteria at the end of the 10-month study.

Box 3

 

Even when unsupervised, exercise can have long-term benefits—as was shown in a randomized, blinded, controlled study of 32 elderly subjects.²⁹ An active treatment group underwent 10 weeks of supervised weight lifting, followed by 10 weeks of unsupervised exercise. Controls received no active treatment. Depression scores as measured by BDI were significantly lower at 20 weeks and 26 months in exercisers compared with controls. An antidepressant effect was seen in 73% of exercisers vs 36% of controls at 20 weeks of treatment.

Comment. These studies show that exercise can maintain an anti depressant effect for 10 to 26 months, but additional randomized controlled studies are needed.

Preventing depression? Inactive nondepressed individuals may be at greater risk to develop depression compared with active individuals, according to a 29-year longitudinal study of Californians age 17 to 94. This association was somewhat diminished when findings were adjusted for the Alameda County residents’ physical health, socioeconomic status, social supports, life events, and other health habits.³⁰ The authors recommended that exercise programs be offered in community mental health programs.

Box 4

Simple steps to build physical activity into daily life

The American Heart Association offers helpful tips for increasing daily exercise at home, at work, and at play. For additional suggestions, go to www.americanheart.org.
At home	At the office	At play
Do housework yourself instead of hiring someone else to do it	Brainstorm project ideas with a coworker while taking a walk	Plan family outings and vacations that include physical
Work in the garden or mow the grass (using a riding mower doesn’t count); rake leaves, prune, dig, and pick up trash	Stand while talking on the telephone	activity (hiking, backpacking, swimming, etc.)
Go out for a short walk before breakfast, after dinner or both; start with 5 to 10 minutes and work up to 30 minutes	Walk down the hall to speak with someone rather than using the telephone	See the sights in new cities by walking, jogging, or bicycling
Walk or bike to the corner store instead of driving	Take the stairs instead of the elevator, or get off a few floors early and take the stairs the rest of the way	Make a date with a friend to enjoy your favorite physical activities, and do them regularly
When walking, increase the pace from leisurely to brisk; choose a hilly route	Schedule exercise time on your business calendar, and treat it as any other important appointment	Play your favorite music while exercising, something that motivates you
		Dance with someone or by yourself; take dancing lessons
		Join a recreational club that emphasizes physical activity
		When golfing, walk the course instead of using a cart

CASE CONTINUED: Removing barriers to exercise

The resident psychiatrist treating Mrs. S encourages her to join an aerobic exercise class at the nearby fitness facility. Because cost is a potential barrier, he helps her negotiate a discount for the first 6 months of membership. Her husband agrees in a joint counseling session to help more with the care of their children so that she can attend the classes.

With continued sertraline, 200 mg/d, and aerobic exercise, Mrs. S’s residual depressive symptoms gradually improve. She still has days when she is unable to attend the exercise classes, but she benefits from the program and is functioning better at work and home.

Getting started

We recommend that psychiatrists inquire about physical activity at every visit to gauge patients’ perception and motivation to exercise. Find ways to overcome patients’ fears and negative experiences with exercise. Provide information to help increase physical activity among patients with depressive symptoms¹⁰ (see Related Resources).

Encourage patients to take steps each day to increase their physical activity (Box 3). Depending on the severity of the individual’s depression and inactivity, a realistic starting point may be to take the stairs instead of an elevator, play with children and pets, or take short brisk walks in the yard or neighborhood (Box 4). Consider stationary bikes or swimming as alternatives for physically handicapped individuals and patients who have undergone knee replacements.

Related resources

• 2008 physical activity guidelines for Americans. U.S. Department of Health and Human Services; 2008:vi-viii. www.health.gov/paguidelines.
• American College of Sports Medicine/American Health Association physical activity guidelines and keys to exercise success. www.acsm.org.
• American Heart Association. www.americanheart.org.
• U.S. Department of Health and Human Services. Quick Guide for Healthy Living. Get Active. www.healthfinder.gov/prevention/ViewTopic.aspx?topicID=22.

 

Drug brand names

• Bupropion • Wellbutrin
• Sertraline • Zoloft

Disclosure

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

Comment on this article

Mrs. S, age 44, is on leave from her job as a bank cashier because depressive symptoms interfered with her performance. At a university-based psychiatric clinic she reports feeling depressed, reduced interest in daily activities, problems with sleep onset and maintenance, inconsistent appetite, low energy, hopelessness, and decreased memory and concentration.

The resident psychiatrist diagnoses major depressive disorder (MDD) and starts Mrs. S on sertraline, 50 mg/d. The dosage is gradually titrated to 200 mg/d, and after 8 weeks she reports substantial improvement.

Mrs. S returns to her job but experiences residual low energy, lethargy, and inconsistent sleep. Her work schedule and caring for her 2 children at home prevent her from continuing weekly cognitive-behavioral therapy (CBT), but she soon notices that she feels more energetic. She reports that because of high gasoline prices she has been walking several miles daily to commute by train to work. The resident psychiatrist sees this as an opportunity to reinforce the benefits of exercise for depression.

Antidepressants alone do not adequately treat many patients with depression. In the STAR*D Project—which compared long-term outcomes of various depression treatments—only 28% to 33% of outpatients achieved remission with selective serotonin reuptake inhibitor (SSRI) monotherapy. Rates were somewhat higher with bupropion or serotonin norepinephrine reuptake inhibitor (SNRI) monotherapy, but greater benefit was obtained from augmenting SSRIs.¹

Combining antidepressants with psychotherapy² and lifestyle changes—particularly exercise—makes sense intuitively and is supported by well-designed studies:

• The 60% of adults in the National Comorbidity Survey who said they exercised regularly reported lower rates of depression and anxiety, compared with less active adults.³
• A meta-analysis of 11 randomized, controlled trials supports the use of exercise as an effective intervention for clinical depression.⁴

Box 1

This article examines the evidence supporting exercise for treating and preventing clinical depression. We begin by addressing clinicians’ concerns about motivating depressed patients to exercise.

Overcoming barriers

Physician issues. Busy physicians often omit discussions about exercise during brief office visits. Only 34% of 9,299 patients in a population-based survey⁵ reported that their doctors counseled them about exercise during their most recent visits. Counseling patients does not have to be time-intensive, however. A study of the Physician-based Assessment and Counseling for Exercise (PACE) project showed that 70% of physicians could provide exercise counseling in 3 to 5 minutes, and most patients reported following their physicians’ advice.⁶

Highly depressed individuals are at risk to quit when they encounter barriers to exercise and to respond to difficulties with frustration and self-disappointment. Thus, depressed patients may need support and encouragement to initiate and maintain regular exercise routines.⁷ Set small, realistic goals for them, and discuss how to solve problems and remove barriers to increase their likelihood to exercise.

Interventions are most likely to be effective when you counsel patients about exercise as prescription and discuss exercise at each visit.⁸ Previously sedentary patients have shown short-term moderate increases in physical activity in response to physician counseling. In a study of 212 adults (mean age 39, 84% female), the PACE project significantly increased minutes of weekly walking.⁹ More than one-half (52%) of patients increased their physical activity, compared with 12% of controls whose physicians did not provide the PACE intervention.

Patient issues. Lack of time and no appropriate space to exercise are common complaints, particularly among residents of regions with long, cold winters. Some patients perceive regular exercise as monotonous or boring, and others may lack the necessary initiative because of poor physical health, fear, negative experiences, or lack of knowledge about exercising. These barriers can be pronounced in older depressed persons. In a cross-sectional study of 645 residents of Jyväskylä, Finland, those age >75 with depressive symptoms were more than twice as likely to be physically inactive as nondepressed residents.¹⁰

An intensive exercise program is not the optimal starting point for many patients. Even walking or light jogging can be an effective exercise for depressed individuals with physical limitations. For these patients, a consultation with their primary physician may be necessary if a more intensive program has to be recommended.

Exercise as monotherapy

A dose-response relationship? Various mechanisms have been suggested for the benefits of exercise in depression (Box 1). Exercise alone—without medication—may be an effective treatment for mild and in some cases moderate MDD, and aerobic exercise may reduce depressive symptoms in a dose-response relationship.¹¹

 

A study of exercise in a supervised laboratory setting demonstrated this relationship in 80 adults age 20 to 45 with mild-to-moderate depressive symptoms. Subjects were randomly assigned to an exercise control group (3 days/week of flexibility exercise) or 1 of 4 aerobic exercise groups that varied in total energy expenditure (a “low dose” of 7.0 kcal/kg/week or a “public health dose” of 17.5 kcal/kg/week). The 17-item Hamilton Rating Scale for Depression (HRSD) was the primary outcome measure.

After 12 weeks, HRSD scores declined from baseline by 47% in subjects engaged in the public health dose of aerobic exercise—a significant reduction. Depressive symptoms declined by 30% in the low-dose exercisers, but this was comparable to the 29% reduction in the control group.

Comment. The effective exercise dose in this study is similar to the public health recommendation of 30 minutes of moderate-to-vigorous activity on all or most days per week (see Related Resources). Antidepressant effects have been associated with more modest physical activity, however, which may be easier to initiate and maintain for individuals with depression. The study did not find significant differences in outcomes based on the subjects’ age, gender, or exercise frequency. Nevertheless, the exercise dose may be important to produce an antidepressant effect.

An inverse relationship? Compared with occasional exercise, habitual physical activity usually is associated with greater cardiorespiratory fitness. Whether habitual activity also results in fewer depressive symptoms and greater emotional well-being remains to be seen.

A large, cross-sectional, National Institutes of Health-funded study of 5,451 men and 1,277 women¹² suggests an inverse relationship between physical activity and depressive symptoms. Subjects underwent a treadmill exercise test to evaluate physical fitness. A 20-point self-report scale assessed depressive symptoms, and the General Well-Being Schedule¹³ was used to assess emotional well-being. Depressive symptoms were more severe in “inactive” and “insufficiently active” subjects compared with “sufficiently active” and “highly active” subjects.

On the other hand, although regular exercise may be associated with reduced depressive symptoms in the population at large, no cause-effect relationship was found in a population-based, longitudinal study of 5,952 twins.¹⁴

A prospective, randomized, controlled trial¹⁵ suggests that exercise could be an important treatment tool in patients diagnosed with MDD. The 202 adult subjects (153 women, 49 men) were randomly assigned to 1 of 4 treatments:

• supervised exercise in a group setting
• home-based exercise
• antidepressant medication (sertraline, 50 to 200 mg/d)
• placebo pills.

Patients underwent the structured clinical interview for depression and completed the HRSD. After 16 weeks, 41% of participants achieved remission, defined as no longer meeting MDD criteria and a HRSD score <8. Compared with placebo controls, patients receiving active treatments tended to have higher remission rates:

• 45% with supervised exercise
• 40% with home-based exercise
• 47% with medication
• 31% with placebo.

Comment. The placebo response rate was relatively high in this study, and antidepressant dosages might not have been optimal. These factors could explain why remission rates with supervised exercise and antidepressant medication were comparable. The study might have been more reliable if it had included a medication plus exercise arm. Patients treated in an office setting might not fare as well as these study subjects whose exercise was supervised.

Postpartum depression occurs in an estimated 13% of new mothers.¹⁶ In a controlled trial, 80 women with depression at 4 weeks postpartum were assigned to either:

• an exercise support program (1 hour supervised exercise and 2 sessions at home each week for 3 months)
• standard care.

Box 2

 

No subjects received medication. Women in the exercise support program were less likely to have high scores on the Edinburgh Postnatal Depression Scale, compared with controls. Women who exercised also reported a greater sense of well-being. Differences between the 2 groups were not statistically significant at 4 weeks post partum but achieved significance at 5 months.¹⁷

Depressive symptoms may exacerbate fatigue in postpartum women.¹⁸ A study of 88 women with postpartum depression showed the benefits of a home-based exercise program on physical and mental fatigue.¹⁹ This finding may be important because fatigue often is associated with treatment-resistant depression and may increase the likelihood of relapse in women with postpartum depression.²⁰

Late-life depression. Exercise can benefit the depressed elderly as well. In a 10-week randomized, controlled trial²¹ of volunteers age ≥60 with major or minor depression or dysthymia, progressive resistance training (PRT) significantly reduced depression, as measured by the Beck Depression Inventory (BDI) and HRSD. PRT also improved quality of life, vitality, social functioning, and emotional well-being when compared with a control group (Box 2).

A dose-response relationship of exercise for treating late-life depression was shown in a blinded, controlled trial²² of 60 community-dwelling, depressed subjects age >60. These patients were randomly assigned to high-intensity PRT, low-intensity PRT, or standard care by a general practitioner (GP). A ≥50% reduction in HRSD score was achieved by:

• 61% of the high-intensity PRT group
• 29% of the low-intensity PRT group
• 21% of the GP care group.

Sleep quality improved in all participants, with the greatest relative change in the high-intensity PRT group.

Exercise vs psychotherapy. The benefits of exercise may be comparable or superior to those of cognitive or group psychotherapy.^23,24 This may be good news for patients such as Mrs. S who lack time or financial resources for regular psychotherapy.

Adjunctive exercise

In depressed patients, exercise may increase the perceived quality of life when combined with medication. This was demonstrated in a randomized, 32-week naturalistic study of 30 women, age 40 to 60, with treatment-resistant MDD.²⁵ The 10 women who received various antidepressants plus physical exercise showed significantly greater long-term improvement in depression symptoms, as measured by the HRSD and Global Assessment of Functioning (GAF) scores, compared with 20 women who received pharmacotherapy alone.²⁶ Study limitations included the absence of a placebo arm, small sample size, and inclusion of subjects with comorbid anxiety disorders.

Group aerobic exercise programs can be an effective and feasible treatment for depression, particularly for older adults. In a controlled trial,²⁷ 156 men and women age >50 with MDD were randomly assigned to 3 groups: a program of aerobic exercise; sertraline, ≤200 mg/d; or exercise plus sertraline. HRSD and BDI scores before and after treatment were the primary outcome measures. Secondary measures included aerobic capacity, life satisfaction, self-esteem, anxiety, and dysfunctional cognitions. After 16 weeks of treatment, similar percentages of patients in each group no longer met DSM-IV-TR criteria for MDD:

• 60.4% of patients in the exercise-only group
• 68.8% of patients in the medication-only group
• 65.5% of patients receiving exercise plus medication.

Depression severity appeared to predict the rate of response to the different treatments. Patients who received medication alone seemed to have the most rapid response to treatment. Patients with less severe depression appeared to respond more quickly to exercise plus medication than those with more severe depression.

Long-term benefits

Because depression is a chronic, relapsing illness, any treatment will be widely accepted only if its benefits are long-term. A study of aerobic exercise in 156 adults age ≥50 with MDD²⁸ found that benefits were sustained for >6 months.

Participants were randomly assigned to 4 months of aerobic exercise; sertraline, ≤200 mg/d; or a combination of exercise and sertraline. Aerobic exercise consisted of 30 minutes of brisk walking and jogging on a treadmill, with training ranges equivalent to 70% to 85% of individuals’ maximum heart rate. Appropriate warm-up and cool-down sessions of 5 to 10 minutes were included.

Depressive symptoms improved significantly from baseline in all 3 groups—as assessed by clinical interview, HRSD, and BDI—and after 4 months a comparable number in each group no longer met diagnostic criteria for MDD. When subjects were reassessed 6 months later, the exercisers had significantly lower relapse rates than those receiving medication (P=.01). Those who continued to exercise also were less likely to meet MDD criteria at the end of the 10-month study.

Box 3

 

Even when unsupervised, exercise can have long-term benefits—as was shown in a randomized, blinded, controlled study of 32 elderly subjects.²⁹ An active treatment group underwent 10 weeks of supervised weight lifting, followed by 10 weeks of unsupervised exercise. Controls received no active treatment. Depression scores as measured by BDI were significantly lower at 20 weeks and 26 months in exercisers compared with controls. An antidepressant effect was seen in 73% of exercisers vs 36% of controls at 20 weeks of treatment.

Comment. These studies show that exercise can maintain an anti depressant effect for 10 to 26 months, but additional randomized controlled studies are needed.

Preventing depression? Inactive nondepressed individuals may be at greater risk to develop depression compared with active individuals, according to a 29-year longitudinal study of Californians age 17 to 94. This association was somewhat diminished when findings were adjusted for the Alameda County residents’ physical health, socioeconomic status, social supports, life events, and other health habits.³⁰ The authors recommended that exercise programs be offered in community mental health programs.

Box 4

Simple steps to build physical activity into daily life

The American Heart Association offers helpful tips for increasing daily exercise at home, at work, and at play. For additional suggestions, go to www.americanheart.org.
At home	At the office	At play
Do housework yourself instead of hiring someone else to do it	Brainstorm project ideas with a coworker while taking a walk	Plan family outings and vacations that include physical
Work in the garden or mow the grass (using a riding mower doesn’t count); rake leaves, prune, dig, and pick up trash	Stand while talking on the telephone	activity (hiking, backpacking, swimming, etc.)
Go out for a short walk before breakfast, after dinner or both; start with 5 to 10 minutes and work up to 30 minutes	Walk down the hall to speak with someone rather than using the telephone	See the sights in new cities by walking, jogging, or bicycling
Walk or bike to the corner store instead of driving	Take the stairs instead of the elevator, or get off a few floors early and take the stairs the rest of the way	Make a date with a friend to enjoy your favorite physical activities, and do them regularly
When walking, increase the pace from leisurely to brisk; choose a hilly route	Schedule exercise time on your business calendar, and treat it as any other important appointment	Play your favorite music while exercising, something that motivates you
		Dance with someone or by yourself; take dancing lessons
		Join a recreational club that emphasizes physical activity
		When golfing, walk the course instead of using a cart

CASE CONTINUED: Removing barriers to exercise

The resident psychiatrist treating Mrs. S encourages her to join an aerobic exercise class at the nearby fitness facility. Because cost is a potential barrier, he helps her negotiate a discount for the first 6 months of membership. Her husband agrees in a joint counseling session to help more with the care of their children so that she can attend the classes.

With continued sertraline, 200 mg/d, and aerobic exercise, Mrs. S’s residual depressive symptoms gradually improve. She still has days when she is unable to attend the exercise classes, but she benefits from the program and is functioning better at work and home.

Getting started

We recommend that psychiatrists inquire about physical activity at every visit to gauge patients’ perception and motivation to exercise. Find ways to overcome patients’ fears and negative experiences with exercise. Provide information to help increase physical activity among patients with depressive symptoms¹⁰ (see Related Resources).

Encourage patients to take steps each day to increase their physical activity (Box 3). Depending on the severity of the individual’s depression and inactivity, a realistic starting point may be to take the stairs instead of an elevator, play with children and pets, or take short brisk walks in the yard or neighborhood (Box 4). Consider stationary bikes or swimming as alternatives for physically handicapped individuals and patients who have undergone knee replacements.

Related resources

• 2008 physical activity guidelines for Americans. U.S. Department of Health and Human Services; 2008:vi-viii. www.health.gov/paguidelines.
• American College of Sports Medicine/American Health Association physical activity guidelines and keys to exercise success. www.acsm.org.
• American Heart Association. www.americanheart.org.
• U.S. Department of Health and Human Services. Quick Guide for Healthy Living. Get Active. www.healthfinder.gov/prevention/ViewTopic.aspx?topicID=22.

 

Drug brand names

• Bupropion • Wellbutrin
• Sertraline • Zoloft

Disclosure

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

Mr. J, age 52, has a history of opioid dependence. Four weeks after starting interferon therapy for hepatitis C, he presents to the outpatient mental health clinic with depressed mood, irritability, decreased energy, poor concentration, insomnia, anhedonia, and suicidal ideation.

Because Mr. J has no history of depression, the psychiatrist diagnoses him with depressive disorder secondary to interferon. Interferon is stopped. Mr. J’s mood improves, but he wants to restart interferon.

The psychiatrist starts Mr. J on sertraline, 50 mg/d, then gradually increases the dose to 150 mg/d as Mr. J’s mood symptoms return. Subsequently, the patient continues interferon with a combination of sertraline and supportive psychotherapy.

Recognizing a medication as the possible cause of your patient’s psychiatric symptoms can avoid inaccurate diagnosis and nonindicated psychiatric treatment. Diligently evaluating patients for drug-related psychiatric side effects is critical because complications usually are reversed when the offending drug is discontinued. Unfortunately, a thin line separates available evidence from anecdotal myths about psychiatric complications of nonpsychotropics.

Almost two-thirds (65%) of drugs included in the Physicians’ Desk Reference list potential psychiatric side effects, according to a random sample review.¹ In some patients, such as Mr. J, these effects can exacerbate mood symptoms and result in perceptual, cognitive, or behavioral disturbances.

A wide range of drugs can cause psychosis, agitation, anxiety, depression, delirium, or insomnia (Table). On the other hand, certain psychiatric side effects of nonpsychotropics can be beneficial (Box 1).

Improve your assessments by examining the evidence linking psychiatric side effects to commonly prescribed and over-the-counter (OTC) compounds, including:

• cardiovascular medications
  
• steroids (prescription and illegal)
  
• hormones
  
• interferons
  
• antimicrobials.
  

Table

New-onset psychiatric symptoms? Check patient’s drug list

Symptom	Documented as a possible cause
Psychosis/agitation	Anabolic androgenic steroids, antihistamines, clonidine, corticosteroids, decongestants, didanosine, ethionamide, H2 blockers, isoniazid, nitrates, NSAIDs, opioids, proton pump inhibitors, quinolones, salbutamol, skeletal muscle relaxants, sulfonamides/trimethoprim
Anxiety	Acyclovir, anabolic androgenic steroids, clonidine, corticosteroids, cyclosporine, decongestants, didanosine, serotonin 5-HT1 agonists such as sumatriptan, foscarnet, ganciclovir, nitrates, ondansetron, penicillins, skeletal muscle relaxants
Depression	Anabolic androgenic steroids, beta blockers, chloramphenicol, clonidine, corticosteroids, didanosine, digoxin, efavirenz, foscarnet, GnRH agonists, H2 blockers, interferons, isoniazid, isotretinoin, NSAIDs, quinolones, statins, tetracyclines
Delirium	ACE inhibitors, anabolic androgenic steroids, antibiotics (most), anticholinergics, beta blockers, centrally acting antihypertensives such as methyldopa and reserpine, cimetidine, clonidine, corticosteroids, didanosine, digoxin, H2 blockers, lidocaine, naltrexone, nitrates, NSAIDs, opioids
Insomnia	Aminophylline, anabolic androgenic steroids, clonidine, corticosteroids, decongestants, didanosine, opioid antagonists, proton pump inhibitors, quinolone antibiotics, salbutamol, skeletal muscle relaxants, tetracyclines
NSAIDs: nonsteroidal anti-inflammatory drugs; ACE: angiotensin-converting enzyme; GnRH: gonadotropin-releasing hormone
Source: Prepared for Current Psychiatry by Drs. Sidhu and Balon from references cited in this article

Cardiovascular medications

Beta blockers have CNS effects—some of which cause psychiatric syndromes—that might depend on an ancillary property such as lipophilicity.² Unlike hydrophilic agents such as atenolol that are excreted unchanged by the kidneys, lipophilic drugs such as metoprolol and propranolol are metabolized by the liver and are believed to enter the brain. Metoprolol has a brain/plasma concentration ratio about 20 times higher than that of atenolol.³

Metoprolol and propranolol can induce delirium and psychosis.^4,5 Psychiatric side effects with metoprolol are frequent,⁴ and propranolol has been associated with:

• sedation (affecting >10% of patients)
  
• nightmares
  
• visual impairment
  
• hallucinations
  
• delirium
  
• depression.⁵
  

In 1967, it was reported that up to 50% of patients taking propranolol may experience dysphoria and at times severe depression.⁶ These effects may occur acutely or develop gradually. ⁵

The relationship between depressive symptoms and beta blockers has been increasingly questioned, however. One study did not find a higher prevalence of depression in patients receiving beta blockers vs those receiving other medications, although this trial had major methodologic limitations.⁷ One large study found no significant association between beta-blocker use and major depression, regardless of patient age, gender, or race.⁸

These studies stress the importance of carefully assessing the individual patient before assigning neurotoxicity to beta blockers, as these drugs have considerable benefits for cardiovascular disease.⁹

Angiotensin-converting enzyme (ACE) inhibitors also affect the CNS. About 4% to 8% of patients taking an ACE inhibitor experience altered mental status—typically increased arousal and psychomotor activity—although

• anxiety
  
• mania
  
• insomnia
  
• fatigue
  
• paresthesias
  
• hallucinations.⁵
  

Sedation occurs in about 5% of patients taking ACE inhibitors. Depression and suicide ideation as a result of ACE inhibition have been reported;¹³ however, ACE inhibitors have also been known to improve depression. Episodes of frank delirium have been reported.⁵

Clonidine is a centrally acting alpha-agonist. The alpha-adrenergic system regulates arousal and has an important role in major depression, anxiety states, and other arousal disorders.

 

More than one-third (35%) of patients taking clonidine experience sedation or lethargy; less commonly, the drug causes anxiety (3%), agitation (3%), depression (1%), and insomnia (1%).⁵ Acute confusion, delirium, hypomania, and psychosis related to clonidine use have long been recognized, occurring in 5

Box 1

Other cardiovascular drugs. Side effects of nitrates/nitrites include delirium, psychosis (including delusions), anxiety, restlessness, agitation, and hypomania.⁵ Digoxin can cause cardiac glycoside-induced encephalopathy, which may present as sedation, apathy, depression, and psychosis. Patients may develop delirium, even when digoxin/digitoxin serum levels are within a therapeutic range.

Cholesterol-lowering statins might be linked to an increased risk of depression and suicide, but the evidence is inconclusive. Some studies have supported this link,^10,11 whereas others have strongly refuted it^12,13 or had mixed results.¹⁴ A recent review¹⁵ recommends being vigilant for psychiatric side effects in patients taking these drugs.

Steroids: prescription and illegal

Corticosteroids are prescribed for a variety of immune system-related diseases, including asthma, allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease, and dermatologic disorders. Mood changes are the most common psychiatric symptoms caused by corticosteroid use; delirium is less common. Psychiatric side effects include:

• lethargy
  
• insomnia
  
• euphoria
  
• depression
  
• psychosis
  
• “personality changes”
  
• anxiety
  
• agitation.⁵
  

Multiple studies have linked corticosteroids and mood symptoms. The Boston Collaborative Drug Surveillance Program¹⁶ confirmed a direct relationship between corticosteroid dosage and psychiatric effects. More than 18% of patients had severe psychiatric symptoms at corticosteroid dosages >80 mg/d.

A prospective study of asthma patients found statistically significant changes in mood—primarily manic symptoms—during brief corticosteroid courses at modest dosages. Depressed persons did not become more depressed during prednisone therapy, however; in fact, some improved. Some patients with posttraumatic stress disorder reported increased depression and memories of the traumatic event during prednisone therapy.¹⁷

In a study of 50 ophthalmologic patients who did not have psychiatric illness receiving prednisolone (mean starting dose 119 mg/d) for 8 days, 26% developed mania and 10% depression.¹⁸ None reported psychotic symptoms.

The most common adverse effects of short-term corticosteroid therapy are euphoria and hypomania. Long-term therapy tends to induce depressive symptoms.¹⁹ A review of 79 cases of psychiatric syndromes induced by corticosteroids found that 41% reported depression, 28% mania, 6% mixed symptoms, and 14% psychosis.²⁰

A group of 16 healthy volunteers receiving 80 mg/d of prednisone over 5 days exhibited depressed or elevated mood, irritability, lability, increased energy, anxiety, and depersonalization.²¹ Numerous case studies have reported anxiety, agitation, mania, and psychotic symptoms in children and adults taking inhaled corticosteroids.

In general, psychiatric side effects of corticosteroids occur within 2 weeks of starting therapy and resolve with dosage reduction or discontinuation. In severe cases or situations in which the dosage cannot be reduced, the patient may require antipsychotics or mood stabilizers.¹⁹

Female gender and past psychiatric history might be risk factors for developing psychiatric symptoms with corticosteroids,²² although not all studies have confirmed these findings.¹⁸

Anabolic androgenic steroids (AAS) have limited therapeutic benefits but are used illegally by some bodybuilders, wrestlers, and other amateur and professional athletes to increase muscle mass, enhance performance, and gain a competitive edge. AAS can cause acute paranoia, delirium, mania or hypomania, homicidal rage, aggression, and extreme mood swings, as well as a marked increase in libido, irritability, agitation, and anger.

In a large observational cohort study of 320 bodybuilding amateur and recreational athletes,²³ AAS use induced many of these psychiatric side effects. The extent intensified as the abuse escalated. A study that used the Structured Clinical Interview for DSM-III-R to compare 88 athletes using steroids with 68 nonusers found that 23% of the AAS users reported major mood syndromes, including mania, hypomania, and major depression.²⁴

 

In a 2-week, double-blind, fixed-order, placebo-controlled, crossover study of healthy male inpatient volunteers, AAS had both:

• mood-elevating effects—euphoria (“steroid rush”), increased energy, and increased sexual arousal and drive
  
• mood-dysphoric effects, such as irritability, mood swings, increasingly violent feelings, increased hostility, and cognitive impairments.²⁵
  

As with corticosteroids, psychiatric symptoms from AAS become more prevalent and severe as dosage increases. They usually resolve within a few weeks after users discontinue steroids but may persist for up to 1 month, even if adequately treated with antipsychotic medication.

Hormones

Gonadotropin-releasing hormone (GnRH) agonists such as leuprolide and nafarelin are approved for treating endometriosis, advanced prostate cancer, precocious puberty, and uterine leiomyomata. Some studies and case reports suggest that these agents cause depressive symptoms.²⁶

Progestins have complex and variable psychiatric effects. Clinical trials have investigated the antidepressant effects of exogenous estrogens on psychiatric patients, but results have been inconsistent—possibly because of small numbers of subjects and design flaws.²⁶ Some studies suggest a link between estrogen and depression in premenopausal and menopausal women with and without psychiatric illness, but findings remain controversial because other studies have found that estrogens have positive effects on mood.^26,27

Interferon

Various forms of interferon are used to treat hepatitis C, melanoma, multiple sclerosis, chronic myelogenous leukemia, and other illnesses. Psychiatric complications—particularly depression—are the most frequent side effect of interferon therapy and mainly occur within the first 12 weeks of therapy.²⁸

In a prospective observational study of veterans undergoing interferon-alfa/ribavirin treatment for chronic hepatitis C:

• 48% of patients not receiving psychiatric care at baseline required treatment for neuropsychiatric side effects
  
• 23% developed symptoms of major depression.²⁹
  

Treatment with a selective serotonin reuptake inhibitor stabilized these symptoms and allowed patients to continue hepatitis treatment.

Because patients who receive interferon are far more likely to require psychiatric intervention if they have a family history of mood disorders, closely monitor them for depressive symptoms and treat such symptoms aggressively. Also closely monitor patients with multiple psychiatric diagnoses receiving interferon-alfa therapy.³⁰

Jeungling et al³¹ speculated that hypometabolism in the prefrontal cortex may predispose patients to interferon-associated neuropsychological syndromes. Neuropsychiatric symptoms may be a characteristic of hepatitis C, interferon treatment, or both.³²

Antimicrobial agents

Antibiotic and antiviral drugs can cause psychiatric side effects:

• directly by affecting neuronal functions
  
• indirectly by entering the brain rapidly, taking advantage of the compromised blood-brain barrier during sepsis or infection.
  

Delirium is the most common psychiatric complication associated with these agents.⁵

Antibiotics. Penicillin and its analogues are associated with sedation, anxiety, and hallucinations. Delirium has been reported as a side effect of most cephalosporins, especially in patients with compromised renal function. Quinolones such as ciprofloxacin and ofloxacin rarely cause restlessness, irritability, lethargy, tremors, insomnia, mania, depression, psychosis, delirium, seizures, or catatonia (incidence ≤1%).⁵ Though not commonly used, chloramphenicol may cause depression, confusion, and delirium. Many case reports have strongly associated clarithromycin with delirium.³³

Isoniazid is one of the most commonly used antibiotics that can cause psychiatric side effects; it has been linked to delirium, mania, depression, and psychosis. Ethionamide is associated with sedation, irritability, depression, restlessness, and psychosis. Tetracyclines have been known to cause depression, insomnia, and irritability at high dosages.

Sulfonamides can cause delirium. Psychosis and confusion also have been reported, especially when sulfa drugs are combined with trimethoprim.⁵

Antivirals. When used intravenously and at high doses, acyclovir and ganciclovir can cause lethargy, anxiety, hallucinations, and frank delirium.⁵ Foscarnet—an antiviral used to treat herpes viruses—can cause depression, anxiety, hallucinations, and aggressive irritability.

Didanosine—an antiretroviral agent to treat HIV infections—can cause lethargy (5% to 7% of patients), depression (2%), anxiety (2%), emotional lability (25%), delirium (2%), insomnia (1%), and psychotic delusions (1%).⁵ Efavirenz treatment may be associated with major depression and severe suicidal ideation.³⁴ Tenofovir, a nucleotide reverse transcriptase inhibitor, has not been associated with psychiatric side effects.²⁷

Antifungals. Psychiatric side effects are rare.

OTC and other agents

Many common nonprescription agents can cause psychiatric symptoms. The most frequently used classes include cold and allergy preparations, reflux medications, and analgesics (Box 2).^5,35

Cold preparations. Combined antihistamines and decongestants—such as phenylpropanolamine, azatadine, loratadine, ephedrine, phenylephrine, pseudoephedrine, and naphazoline—can cause an atropine-like psychosis that typically manifests as confusion, disorientation, agitation, hallucinations, and memory problems. Decongestants can cause dangerously high levels of norepinephrine when combined with monoamine oxidase inhibitors (MAOIs) and are contraindicated in patients taking MAOIs. Ephedrine can induce restlessness, dysphoria, irritability, anxiety, and insomnia.

 

Reflux medications. Two primary classes of reflux medications are proton pump inhibitors (omeprazole and lansoprazole) and H₂ receptor antagonists (famotidine, nizatidine, ranitidine, and cimetidine). Although generally considered to have a benign side-effect profile, these medications have been reported to cause serious neuropsychiatric complications—including mental confusion, agitation, depression, and hallucinations—mainly in geriatric patients with impaired hepatic-renal function.³⁶ These occur in only 37

Time to onset of psychiatric side effects from H₂ antagonists varies. Ranitidine can cause depression 4 to 8 weeks after treatment begins. Cimetidine has been reported to cause adverse events within 2 to 3 weeks and delirium within 24 to 48 hours.³⁸ These effects usually resolve within 3 days of discontinuing the drug. Cimetidine is also associated with sexual dysfunction.

Discontinuing ranitidine or cimetidine can induce a withdrawal syndrome that includes anxiety, insomnia, and irritability.³⁹ Cimetidine can increase the blood level and action of tricyclic antidepressants. Blood levels of these antidepressants can become toxic, resulting in tachycardia and other adverse effects.

Other medications. Ondansetron is a 5-hydroxytryptamine subclass 3 (5-HT₃) antagonist used for antiemetic therapy. In case reports, it has been strongly associated with anxiety.⁴⁰ This association is complex, however, and studies are evaluating 5-HT₃ receptor antagonists for the treatment of anxiety, depression, phobia, and schizophrenia.

Isotretinoin—a retinoid used for severe acne—can cause severe depression and suicidal behavior.⁴¹

Aminophylline and salbutamol are associated with agitation, insomnia, euphoria, and delirium. Methotrexate is known to cause personality changes, irritability, and delirium.²⁷

Box 2

Treating drug-related mood effects

If you suspect a nonpsychotropic medication is causing your patient’s psychiatric symptoms, discuss this with the patient and the prescribing physician. Switching to another similar agent may be an option. If this is not possible:

• work closely with the patient’s primary physician
  
• treat mood symptoms with appropriate psychotropics.
  

Related resources

• Turjanski N, Lloyd GG. Psychiatric side-effects of medications: recent developments. Advances in Psychiatric Treatment 2005;11:58-70.
  
• Brown TM, Stoudemire A. Psychiatric side effects of prescription and over-the-counter medications. Recognition and management. Washington, DC: American Psychiatric Publishing; 1998.
  
• Physicians’ Desk Reference. www.pdr.net.
  

Drug brand name

• Acyclovir • Zovirax
  
• Aminophylline • Phyllocontin, Truphylline
  
• Atenolol • Tenormin
  
• Azatadine • Optimine
  
• Baclofen • Lioresal
  
• Chloramphenicol • Chloromycetin
  
• Cimetidine • Tagamet
  
• Ciprofloxacin • Cipro
  
• Clarithromycin • Biaxin
  
• Clonidine • Catapres
  
• Cyclosporine • Neoral, Sandimmune, others
  
• Dantrolene • Dantrium
  
• Didanosine • Videx
  
• Efavirenz • Sustiva
  
• Ethionamide • Trecator
  
• Famotidine • Pepcid
  
• Foscarnet • Foscavir
  
• Ganciclovir • Cytovene
  
• Indomethacin • Indocin
  
• Interferon alfa • Intron, Roferon
  
• Isoniazid • Nydrazid
  
• Isotretinoin • Accutane
  
• Lansoprazole • Prevacid
  
• Leuprolide • Lupron
  
• Lidocaine • Xylocaine, Xylocard
  
• Loratadine • Claritin
  
• Methotrexate • Rheumatrex, Trexall
  
• Methyldopa • Aldomet
  
• Metoprolol • Lopressor
  
• Mirtazapine • Remeron
  
• Nafarelin • Synarel
  
• Naloxone • Suboxone
  
• Naltrexone • Vivitrol
  
• Naphazoline • Naphcon-A, Clearine
  
• Naproxen • Aleve, others
  
• Nizatidine • Axid
  
• Ofloxacin • Floxin
  
• Omeprazole • Prilosec
  
• Ondansetron • Zofran
  
• Paroxetine • Paxil
  
• Peginterferon alfa • PEG-Intron, Pegasys
  
• Phenylephrine • Neo-Synephrine
  
• Prednisolone • Blephamide, Pred Forte, others
  
• Propranolol • Inderal
  
• Pseudoephedrine • Actifed, Sudafed
  
• Ranitidine • Zantac
  
• Reserpine • Serpasi
  
• Ribavirin • Copegus, Rebetol
  
• Salbutamol • Aerolin, Airomir, others
  
• Sertraline • Zoloft
  
• Sumatriptan • Imitrex
  
• Tenofovir • Viread
  
• Trimethoprim • Proloprim
  

Disclosure

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

Mr. J, age 52, has a history of opioid dependence. Four weeks after starting interferon therapy for hepatitis C, he presents to the outpatient mental health clinic with depressed mood, irritability, decreased energy, poor concentration, insomnia, anhedonia, and suicidal ideation.

Because Mr. J has no history of depression, the psychiatrist diagnoses him with depressive disorder secondary to interferon. Interferon is stopped. Mr. J’s mood improves, but he wants to restart interferon.

The psychiatrist starts Mr. J on sertraline, 50 mg/d, then gradually increases the dose to 150 mg/d as Mr. J’s mood symptoms return. Subsequently, the patient continues interferon with a combination of sertraline and supportive psychotherapy.

Recognizing a medication as the possible cause of your patient’s psychiatric symptoms can avoid inaccurate diagnosis and nonindicated psychiatric treatment. Diligently evaluating patients for drug-related psychiatric side effects is critical because complications usually are reversed when the offending drug is discontinued. Unfortunately, a thin line separates available evidence from anecdotal myths about psychiatric complications of nonpsychotropics.

Almost two-thirds (65%) of drugs included in the Physicians’ Desk Reference list potential psychiatric side effects, according to a random sample review.¹ In some patients, such as Mr. J, these effects can exacerbate mood symptoms and result in perceptual, cognitive, or behavioral disturbances.

A wide range of drugs can cause psychosis, agitation, anxiety, depression, delirium, or insomnia (Table). On the other hand, certain psychiatric side effects of nonpsychotropics can be beneficial (Box 1).

Improve your assessments by examining the evidence linking psychiatric side effects to commonly prescribed and over-the-counter (OTC) compounds, including:

• cardiovascular medications
  
• steroids (prescription and illegal)
  
• hormones
  
• interferons
  
• antimicrobials.
  

Table

New-onset psychiatric symptoms? Check patient’s drug list

Symptom	Documented as a possible cause
Psychosis/agitation	Anabolic androgenic steroids, antihistamines, clonidine, corticosteroids, decongestants, didanosine, ethionamide, H2 blockers, isoniazid, nitrates, NSAIDs, opioids, proton pump inhibitors, quinolones, salbutamol, skeletal muscle relaxants, sulfonamides/trimethoprim
Anxiety	Acyclovir, anabolic androgenic steroids, clonidine, corticosteroids, cyclosporine, decongestants, didanosine, serotonin 5-HT1 agonists such as sumatriptan, foscarnet, ganciclovir, nitrates, ondansetron, penicillins, skeletal muscle relaxants
Depression	Anabolic androgenic steroids, beta blockers, chloramphenicol, clonidine, corticosteroids, didanosine, digoxin, efavirenz, foscarnet, GnRH agonists, H2 blockers, interferons, isoniazid, isotretinoin, NSAIDs, quinolones, statins, tetracyclines
Delirium	ACE inhibitors, anabolic androgenic steroids, antibiotics (most), anticholinergics, beta blockers, centrally acting antihypertensives such as methyldopa and reserpine, cimetidine, clonidine, corticosteroids, didanosine, digoxin, H2 blockers, lidocaine, naltrexone, nitrates, NSAIDs, opioids
Insomnia	Aminophylline, anabolic androgenic steroids, clonidine, corticosteroids, decongestants, didanosine, opioid antagonists, proton pump inhibitors, quinolone antibiotics, salbutamol, skeletal muscle relaxants, tetracyclines
NSAIDs: nonsteroidal anti-inflammatory drugs; ACE: angiotensin-converting enzyme; GnRH: gonadotropin-releasing hormone
Source: Prepared for Current Psychiatry by Drs. Sidhu and Balon from references cited in this article

Cardiovascular medications

Beta blockers have CNS effects—some of which cause psychiatric syndromes—that might depend on an ancillary property such as lipophilicity.² Unlike hydrophilic agents such as atenolol that are excreted unchanged by the kidneys, lipophilic drugs such as metoprolol and propranolol are metabolized by the liver and are believed to enter the brain. Metoprolol has a brain/plasma concentration ratio about 20 times higher than that of atenolol.³

Metoprolol and propranolol can induce delirium and psychosis.^4,5 Psychiatric side effects with metoprolol are frequent,⁴ and propranolol has been associated with:

• sedation (affecting >10% of patients)
  
• nightmares
  
• visual impairment
  
• hallucinations
  
• delirium
  
• depression.⁵
  

In 1967, it was reported that up to 50% of patients taking propranolol may experience dysphoria and at times severe depression.⁶ These effects may occur acutely or develop gradually. ⁵

The relationship between depressive symptoms and beta blockers has been increasingly questioned, however. One study did not find a higher prevalence of depression in patients receiving beta blockers vs those receiving other medications, although this trial had major methodologic limitations.⁷ One large study found no significant association between beta-blocker use and major depression, regardless of patient age, gender, or race.⁸

These studies stress the importance of carefully assessing the individual patient before assigning neurotoxicity to beta blockers, as these drugs have considerable benefits for cardiovascular disease.⁹

Angiotensin-converting enzyme (ACE) inhibitors also affect the CNS. About 4% to 8% of patients taking an ACE inhibitor experience altered mental status—typically increased arousal and psychomotor activity—although

• anxiety
  
• mania
  
• insomnia
  
• fatigue
  
• paresthesias
  
• hallucinations.⁵
  

Sedation occurs in about 5% of patients taking ACE inhibitors. Depression and suicide ideation as a result of ACE inhibition have been reported;¹³ however, ACE inhibitors have also been known to improve depression. Episodes of frank delirium have been reported.⁵

Clonidine is a centrally acting alpha-agonist. The alpha-adrenergic system regulates arousal and has an important role in major depression, anxiety states, and other arousal disorders.

 

More than one-third (35%) of patients taking clonidine experience sedation or lethargy; less commonly, the drug causes anxiety (3%), agitation (3%), depression (1%), and insomnia (1%).⁵ Acute confusion, delirium, hypomania, and psychosis related to clonidine use have long been recognized, occurring in 5

Box 1

Other cardiovascular drugs. Side effects of nitrates/nitrites include delirium, psychosis (including delusions), anxiety, restlessness, agitation, and hypomania.⁵ Digoxin can cause cardiac glycoside-induced encephalopathy, which may present as sedation, apathy, depression, and psychosis. Patients may develop delirium, even when digoxin/digitoxin serum levels are within a therapeutic range.

Cholesterol-lowering statins might be linked to an increased risk of depression and suicide, but the evidence is inconclusive. Some studies have supported this link,^10,11 whereas others have strongly refuted it^12,13 or had mixed results.¹⁴ A recent review¹⁵ recommends being vigilant for psychiatric side effects in patients taking these drugs.

Steroids: prescription and illegal

Corticosteroids are prescribed for a variety of immune system-related diseases, including asthma, allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease, and dermatologic disorders. Mood changes are the most common psychiatric symptoms caused by corticosteroid use; delirium is less common. Psychiatric side effects include:

• lethargy
  
• insomnia
  
• euphoria
  
• depression
  
• psychosis
  
• “personality changes”
  
• anxiety
  
• agitation.⁵
  

Multiple studies have linked corticosteroids and mood symptoms. The Boston Collaborative Drug Surveillance Program¹⁶ confirmed a direct relationship between corticosteroid dosage and psychiatric effects. More than 18% of patients had severe psychiatric symptoms at corticosteroid dosages >80 mg/d.

A prospective study of asthma patients found statistically significant changes in mood—primarily manic symptoms—during brief corticosteroid courses at modest dosages. Depressed persons did not become more depressed during prednisone therapy, however; in fact, some improved. Some patients with posttraumatic stress disorder reported increased depression and memories of the traumatic event during prednisone therapy.¹⁷

In a study of 50 ophthalmologic patients who did not have psychiatric illness receiving prednisolone (mean starting dose 119 mg/d) for 8 days, 26% developed mania and 10% depression.¹⁸ None reported psychotic symptoms.

The most common adverse effects of short-term corticosteroid therapy are euphoria and hypomania. Long-term therapy tends to induce depressive symptoms.¹⁹ A review of 79 cases of psychiatric syndromes induced by corticosteroids found that 41% reported depression, 28% mania, 6% mixed symptoms, and 14% psychosis.²⁰

A group of 16 healthy volunteers receiving 80 mg/d of prednisone over 5 days exhibited depressed or elevated mood, irritability, lability, increased energy, anxiety, and depersonalization.²¹ Numerous case studies have reported anxiety, agitation, mania, and psychotic symptoms in children and adults taking inhaled corticosteroids.

In general, psychiatric side effects of corticosteroids occur within 2 weeks of starting therapy and resolve with dosage reduction or discontinuation. In severe cases or situations in which the dosage cannot be reduced, the patient may require antipsychotics or mood stabilizers.¹⁹

Female gender and past psychiatric history might be risk factors for developing psychiatric symptoms with corticosteroids,²² although not all studies have confirmed these findings.¹⁸

Anabolic androgenic steroids (AAS) have limited therapeutic benefits but are used illegally by some bodybuilders, wrestlers, and other amateur and professional athletes to increase muscle mass, enhance performance, and gain a competitive edge. AAS can cause acute paranoia, delirium, mania or hypomania, homicidal rage, aggression, and extreme mood swings, as well as a marked increase in libido, irritability, agitation, and anger.

In a large observational cohort study of 320 bodybuilding amateur and recreational athletes,²³ AAS use induced many of these psychiatric side effects. The extent intensified as the abuse escalated. A study that used the Structured Clinical Interview for DSM-III-R to compare 88 athletes using steroids with 68 nonusers found that 23% of the AAS users reported major mood syndromes, including mania, hypomania, and major depression.²⁴

 

In a 2-week, double-blind, fixed-order, placebo-controlled, crossover study of healthy male inpatient volunteers, AAS had both:

• mood-elevating effects—euphoria (“steroid rush”), increased energy, and increased sexual arousal and drive
  
• mood-dysphoric effects, such as irritability, mood swings, increasingly violent feelings, increased hostility, and cognitive impairments.²⁵
  

As with corticosteroids, psychiatric symptoms from AAS become more prevalent and severe as dosage increases. They usually resolve within a few weeks after users discontinue steroids but may persist for up to 1 month, even if adequately treated with antipsychotic medication.

Hormones

Gonadotropin-releasing hormone (GnRH) agonists such as leuprolide and nafarelin are approved for treating endometriosis, advanced prostate cancer, precocious puberty, and uterine leiomyomata. Some studies and case reports suggest that these agents cause depressive symptoms.²⁶

Progestins have complex and variable psychiatric effects. Clinical trials have investigated the antidepressant effects of exogenous estrogens on psychiatric patients, but results have been inconsistent—possibly because of small numbers of subjects and design flaws.²⁶ Some studies suggest a link between estrogen and depression in premenopausal and menopausal women with and without psychiatric illness, but findings remain controversial because other studies have found that estrogens have positive effects on mood.^26,27

Interferon

Various forms of interferon are used to treat hepatitis C, melanoma, multiple sclerosis, chronic myelogenous leukemia, and other illnesses. Psychiatric complications—particularly depression—are the most frequent side effect of interferon therapy and mainly occur within the first 12 weeks of therapy.²⁸

In a prospective observational study of veterans undergoing interferon-alfa/ribavirin treatment for chronic hepatitis C:

• 48% of patients not receiving psychiatric care at baseline required treatment for neuropsychiatric side effects
  
• 23% developed symptoms of major depression.²⁹
  

Treatment with a selective serotonin reuptake inhibitor stabilized these symptoms and allowed patients to continue hepatitis treatment.

Because patients who receive interferon are far more likely to require psychiatric intervention if they have a family history of mood disorders, closely monitor them for depressive symptoms and treat such symptoms aggressively. Also closely monitor patients with multiple psychiatric diagnoses receiving interferon-alfa therapy.³⁰

Jeungling et al³¹ speculated that hypometabolism in the prefrontal cortex may predispose patients to interferon-associated neuropsychological syndromes. Neuropsychiatric symptoms may be a characteristic of hepatitis C, interferon treatment, or both.³²

Antimicrobial agents

Antibiotic and antiviral drugs can cause psychiatric side effects:

• directly by affecting neuronal functions
  
• indirectly by entering the brain rapidly, taking advantage of the compromised blood-brain barrier during sepsis or infection.
  

Delirium is the most common psychiatric complication associated with these agents.⁵

Antibiotics. Penicillin and its analogues are associated with sedation, anxiety, and hallucinations. Delirium has been reported as a side effect of most cephalosporins, especially in patients with compromised renal function. Quinolones such as ciprofloxacin and ofloxacin rarely cause restlessness, irritability, lethargy, tremors, insomnia, mania, depression, psychosis, delirium, seizures, or catatonia (incidence ≤1%).⁵ Though not commonly used, chloramphenicol may cause depression, confusion, and delirium. Many case reports have strongly associated clarithromycin with delirium.³³

Isoniazid is one of the most commonly used antibiotics that can cause psychiatric side effects; it has been linked to delirium, mania, depression, and psychosis. Ethionamide is associated with sedation, irritability, depression, restlessness, and psychosis. Tetracyclines have been known to cause depression, insomnia, and irritability at high dosages.

Sulfonamides can cause delirium. Psychosis and confusion also have been reported, especially when sulfa drugs are combined with trimethoprim.⁵

Antivirals. When used intravenously and at high doses, acyclovir and ganciclovir can cause lethargy, anxiety, hallucinations, and frank delirium.⁵ Foscarnet—an antiviral used to treat herpes viruses—can cause depression, anxiety, hallucinations, and aggressive irritability.

Didanosine—an antiretroviral agent to treat HIV infections—can cause lethargy (5% to 7% of patients), depression (2%), anxiety (2%), emotional lability (25%), delirium (2%), insomnia (1%), and psychotic delusions (1%).⁵ Efavirenz treatment may be associated with major depression and severe suicidal ideation.³⁴ Tenofovir, a nucleotide reverse transcriptase inhibitor, has not been associated with psychiatric side effects.²⁷

Antifungals. Psychiatric side effects are rare.

OTC and other agents

Many common nonprescription agents can cause psychiatric symptoms. The most frequently used classes include cold and allergy preparations, reflux medications, and analgesics (Box 2).^5,35

Cold preparations. Combined antihistamines and decongestants—such as phenylpropanolamine, azatadine, loratadine, ephedrine, phenylephrine, pseudoephedrine, and naphazoline—can cause an atropine-like psychosis that typically manifests as confusion, disorientation, agitation, hallucinations, and memory problems. Decongestants can cause dangerously high levels of norepinephrine when combined with monoamine oxidase inhibitors (MAOIs) and are contraindicated in patients taking MAOIs. Ephedrine can induce restlessness, dysphoria, irritability, anxiety, and insomnia.

 

Reflux medications. Two primary classes of reflux medications are proton pump inhibitors (omeprazole and lansoprazole) and H₂ receptor antagonists (famotidine, nizatidine, ranitidine, and cimetidine). Although generally considered to have a benign side-effect profile, these medications have been reported to cause serious neuropsychiatric complications—including mental confusion, agitation, depression, and hallucinations—mainly in geriatric patients with impaired hepatic-renal function.³⁶ These occur in only 37

Time to onset of psychiatric side effects from H₂ antagonists varies. Ranitidine can cause depression 4 to 8 weeks after treatment begins. Cimetidine has been reported to cause adverse events within 2 to 3 weeks and delirium within 24 to 48 hours.³⁸ These effects usually resolve within 3 days of discontinuing the drug. Cimetidine is also associated with sexual dysfunction.

Discontinuing ranitidine or cimetidine can induce a withdrawal syndrome that includes anxiety, insomnia, and irritability.³⁹ Cimetidine can increase the blood level and action of tricyclic antidepressants. Blood levels of these antidepressants can become toxic, resulting in tachycardia and other adverse effects.

Other medications. Ondansetron is a 5-hydroxytryptamine subclass 3 (5-HT₃) antagonist used for antiemetic therapy. In case reports, it has been strongly associated with anxiety.⁴⁰ This association is complex, however, and studies are evaluating 5-HT₃ receptor antagonists for the treatment of anxiety, depression, phobia, and schizophrenia.

Isotretinoin—a retinoid used for severe acne—can cause severe depression and suicidal behavior.⁴¹

Aminophylline and salbutamol are associated with agitation, insomnia, euphoria, and delirium. Methotrexate is known to cause personality changes, irritability, and delirium.²⁷

Box 2

Treating drug-related mood effects

If you suspect a nonpsychotropic medication is causing your patient’s psychiatric symptoms, discuss this with the patient and the prescribing physician. Switching to another similar agent may be an option. If this is not possible:

• work closely with the patient’s primary physician
  
• treat mood symptoms with appropriate psychotropics.
  

Related resources

• Turjanski N, Lloyd GG. Psychiatric side-effects of medications: recent developments. Advances in Psychiatric Treatment 2005;11:58-70.
  
• Brown TM, Stoudemire A. Psychiatric side effects of prescription and over-the-counter medications. Recognition and management. Washington, DC: American Psychiatric Publishing; 1998.
  
• Physicians’ Desk Reference. www.pdr.net.
  

Drug brand name

• Acyclovir • Zovirax
  
• Aminophylline • Phyllocontin, Truphylline
  
• Atenolol • Tenormin
  
• Azatadine • Optimine
  
• Baclofen • Lioresal
  
• Chloramphenicol • Chloromycetin
  
• Cimetidine • Tagamet
  
• Ciprofloxacin • Cipro
  
• Clarithromycin • Biaxin
  
• Clonidine • Catapres
  
• Cyclosporine • Neoral, Sandimmune, others
  
• Dantrolene • Dantrium
  
• Didanosine • Videx
  
• Efavirenz • Sustiva
  
• Ethionamide • Trecator
  
• Famotidine • Pepcid
  
• Foscarnet • Foscavir
  
• Ganciclovir • Cytovene
  
• Indomethacin • Indocin
  
• Interferon alfa • Intron, Roferon
  
• Isoniazid • Nydrazid
  
• Isotretinoin • Accutane
  
• Lansoprazole • Prevacid
  
• Leuprolide • Lupron
  
• Lidocaine • Xylocaine, Xylocard
  
• Loratadine • Claritin
  
• Methotrexate • Rheumatrex, Trexall
  
• Methyldopa • Aldomet
  
• Metoprolol • Lopressor
  
• Mirtazapine • Remeron
  
• Nafarelin • Synarel
  
• Naloxone • Suboxone
  
• Naltrexone • Vivitrol
  
• Naphazoline • Naphcon-A, Clearine
  
• Naproxen • Aleve, others
  
• Nizatidine • Axid
  
• Ofloxacin • Floxin
  
• Omeprazole • Prilosec
  
• Ondansetron • Zofran
  
• Paroxetine • Paxil
  
• Peginterferon alfa • PEG-Intron, Pegasys
  
• Phenylephrine • Neo-Synephrine
  
• Prednisolone • Blephamide, Pred Forte, others
  
• Propranolol • Inderal
  
• Pseudoephedrine • Actifed, Sudafed
  
• Ranitidine • Zantac
  
• Reserpine • Serpasi
  
• Ribavirin • Copegus, Rebetol
  
• Salbutamol • Aerolin, Airomir, others
  
• Sertraline • Zoloft
  
• Sumatriptan • Imitrex
  
• Tenofovir • Viread
  
• Trimethoprim • Proloprim
  

Disclosure

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

Mr. J, age 52, has a history of opioid dependence. Four weeks after starting interferon therapy for hepatitis C, he presents to the outpatient mental health clinic with depressed mood, irritability, decreased energy, poor concentration, insomnia, anhedonia, and suicidal ideation.

Because Mr. J has no history of depression, the psychiatrist diagnoses him with depressive disorder secondary to interferon. Interferon is stopped. Mr. J’s mood improves, but he wants to restart interferon.

The psychiatrist starts Mr. J on sertraline, 50 mg/d, then gradually increases the dose to 150 mg/d as Mr. J’s mood symptoms return. Subsequently, the patient continues interferon with a combination of sertraline and supportive psychotherapy.

Recognizing a medication as the possible cause of your patient’s psychiatric symptoms can avoid inaccurate diagnosis and nonindicated psychiatric treatment. Diligently evaluating patients for drug-related psychiatric side effects is critical because complications usually are reversed when the offending drug is discontinued. Unfortunately, a thin line separates available evidence from anecdotal myths about psychiatric complications of nonpsychotropics.

Almost two-thirds (65%) of drugs included in the Physicians’ Desk Reference list potential psychiatric side effects, according to a random sample review.¹ In some patients, such as Mr. J, these effects can exacerbate mood symptoms and result in perceptual, cognitive, or behavioral disturbances.

A wide range of drugs can cause psychosis, agitation, anxiety, depression, delirium, or insomnia (Table). On the other hand, certain psychiatric side effects of nonpsychotropics can be beneficial (Box 1).

Improve your assessments by examining the evidence linking psychiatric side effects to commonly prescribed and over-the-counter (OTC) compounds, including:

• cardiovascular medications
  
• steroids (prescription and illegal)
  
• hormones
  
• interferons
  
• antimicrobials.
  

Table

New-onset psychiatric symptoms? Check patient’s drug list

Symptom	Documented as a possible cause
Psychosis/agitation	Anabolic androgenic steroids, antihistamines, clonidine, corticosteroids, decongestants, didanosine, ethionamide, H2 blockers, isoniazid, nitrates, NSAIDs, opioids, proton pump inhibitors, quinolones, salbutamol, skeletal muscle relaxants, sulfonamides/trimethoprim
Anxiety	Acyclovir, anabolic androgenic steroids, clonidine, corticosteroids, cyclosporine, decongestants, didanosine, serotonin 5-HT1 agonists such as sumatriptan, foscarnet, ganciclovir, nitrates, ondansetron, penicillins, skeletal muscle relaxants
Depression	Anabolic androgenic steroids, beta blockers, chloramphenicol, clonidine, corticosteroids, didanosine, digoxin, efavirenz, foscarnet, GnRH agonists, H2 blockers, interferons, isoniazid, isotretinoin, NSAIDs, quinolones, statins, tetracyclines
Delirium	ACE inhibitors, anabolic androgenic steroids, antibiotics (most), anticholinergics, beta blockers, centrally acting antihypertensives such as methyldopa and reserpine, cimetidine, clonidine, corticosteroids, didanosine, digoxin, H2 blockers, lidocaine, naltrexone, nitrates, NSAIDs, opioids
Insomnia	Aminophylline, anabolic androgenic steroids, clonidine, corticosteroids, decongestants, didanosine, opioid antagonists, proton pump inhibitors, quinolone antibiotics, salbutamol, skeletal muscle relaxants, tetracyclines
NSAIDs: nonsteroidal anti-inflammatory drugs; ACE: angiotensin-converting enzyme; GnRH: gonadotropin-releasing hormone
Source: Prepared for Current Psychiatry by Drs. Sidhu and Balon from references cited in this article

Cardiovascular medications

Beta blockers have CNS effects—some of which cause psychiatric syndromes—that might depend on an ancillary property such as lipophilicity.² Unlike hydrophilic agents such as atenolol that are excreted unchanged by the kidneys, lipophilic drugs such as metoprolol and propranolol are metabolized by the liver and are believed to enter the brain. Metoprolol has a brain/plasma concentration ratio about 20 times higher than that of atenolol.³

Metoprolol and propranolol can induce delirium and psychosis.^4,5 Psychiatric side effects with metoprolol are frequent,⁴ and propranolol has been associated with:

• sedation (affecting >10% of patients)
  
• nightmares
  
• visual impairment
  
• hallucinations
  
• delirium
  
• depression.⁵
  

In 1967, it was reported that up to 50% of patients taking propranolol may experience dysphoria and at times severe depression.⁶ These effects may occur acutely or develop gradually. ⁵

The relationship between depressive symptoms and beta blockers has been increasingly questioned, however. One study did not find a higher prevalence of depression in patients receiving beta blockers vs those receiving other medications, although this trial had major methodologic limitations.⁷ One large study found no significant association between beta-blocker use and major depression, regardless of patient age, gender, or race.⁸

These studies stress the importance of carefully assessing the individual patient before assigning neurotoxicity to beta blockers, as these drugs have considerable benefits for cardiovascular disease.⁹

Angiotensin-converting enzyme (ACE) inhibitors also affect the CNS. About 4% to 8% of patients taking an ACE inhibitor experience altered mental status—typically increased arousal and psychomotor activity—although

• anxiety
  
• mania
  
• insomnia
  
• fatigue
  
• paresthesias
  
• hallucinations.⁵
  

Sedation occurs in about 5% of patients taking ACE inhibitors. Depression and suicide ideation as a result of ACE inhibition have been reported;¹³ however, ACE inhibitors have also been known to improve depression. Episodes of frank delirium have been reported.⁵

Clonidine is a centrally acting alpha-agonist. The alpha-adrenergic system regulates arousal and has an important role in major depression, anxiety states, and other arousal disorders.

 

More than one-third (35%) of patients taking clonidine experience sedation or lethargy; less commonly, the drug causes anxiety (3%), agitation (3%), depression (1%), and insomnia (1%).⁵ Acute confusion, delirium, hypomania, and psychosis related to clonidine use have long been recognized, occurring in 5

Box 1

Other cardiovascular drugs. Side effects of nitrates/nitrites include delirium, psychosis (including delusions), anxiety, restlessness, agitation, and hypomania.⁵ Digoxin can cause cardiac glycoside-induced encephalopathy, which may present as sedation, apathy, depression, and psychosis. Patients may develop delirium, even when digoxin/digitoxin serum levels are within a therapeutic range.

Cholesterol-lowering statins might be linked to an increased risk of depression and suicide, but the evidence is inconclusive. Some studies have supported this link,^10,11 whereas others have strongly refuted it^12,13 or had mixed results.¹⁴ A recent review¹⁵ recommends being vigilant for psychiatric side effects in patients taking these drugs.

Steroids: prescription and illegal

Corticosteroids are prescribed for a variety of immune system-related diseases, including asthma, allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease, and dermatologic disorders. Mood changes are the most common psychiatric symptoms caused by corticosteroid use; delirium is less common. Psychiatric side effects include:

• lethargy
  
• insomnia
  
• euphoria
  
• depression
  
• psychosis
  
• “personality changes”
  
• anxiety
  
• agitation.⁵
  

Multiple studies have linked corticosteroids and mood symptoms. The Boston Collaborative Drug Surveillance Program¹⁶ confirmed a direct relationship between corticosteroid dosage and psychiatric effects. More than 18% of patients had severe psychiatric symptoms at corticosteroid dosages >80 mg/d.

A prospective study of asthma patients found statistically significant changes in mood—primarily manic symptoms—during brief corticosteroid courses at modest dosages. Depressed persons did not become more depressed during prednisone therapy, however; in fact, some improved. Some patients with posttraumatic stress disorder reported increased depression and memories of the traumatic event during prednisone therapy.¹⁷

In a study of 50 ophthalmologic patients who did not have psychiatric illness receiving prednisolone (mean starting dose 119 mg/d) for 8 days, 26% developed mania and 10% depression.¹⁸ None reported psychotic symptoms.

The most common adverse effects of short-term corticosteroid therapy are euphoria and hypomania. Long-term therapy tends to induce depressive symptoms.¹⁹ A review of 79 cases of psychiatric syndromes induced by corticosteroids found that 41% reported depression, 28% mania, 6% mixed symptoms, and 14% psychosis.²⁰

A group of 16 healthy volunteers receiving 80 mg/d of prednisone over 5 days exhibited depressed or elevated mood, irritability, lability, increased energy, anxiety, and depersonalization.²¹ Numerous case studies have reported anxiety, agitation, mania, and psychotic symptoms in children and adults taking inhaled corticosteroids.

In general, psychiatric side effects of corticosteroids occur within 2 weeks of starting therapy and resolve with dosage reduction or discontinuation. In severe cases or situations in which the dosage cannot be reduced, the patient may require antipsychotics or mood stabilizers.¹⁹

Female gender and past psychiatric history might be risk factors for developing psychiatric symptoms with corticosteroids,²² although not all studies have confirmed these findings.¹⁸

Anabolic androgenic steroids (AAS) have limited therapeutic benefits but are used illegally by some bodybuilders, wrestlers, and other amateur and professional athletes to increase muscle mass, enhance performance, and gain a competitive edge. AAS can cause acute paranoia, delirium, mania or hypomania, homicidal rage, aggression, and extreme mood swings, as well as a marked increase in libido, irritability, agitation, and anger.

In a large observational cohort study of 320 bodybuilding amateur and recreational athletes,²³ AAS use induced many of these psychiatric side effects. The extent intensified as the abuse escalated. A study that used the Structured Clinical Interview for DSM-III-R to compare 88 athletes using steroids with 68 nonusers found that 23% of the AAS users reported major mood syndromes, including mania, hypomania, and major depression.²⁴

 

In a 2-week, double-blind, fixed-order, placebo-controlled, crossover study of healthy male inpatient volunteers, AAS had both:

• mood-elevating effects—euphoria (“steroid rush”), increased energy, and increased sexual arousal and drive
  
• mood-dysphoric effects, such as irritability, mood swings, increasingly violent feelings, increased hostility, and cognitive impairments.²⁵
  

As with corticosteroids, psychiatric symptoms from AAS become more prevalent and severe as dosage increases. They usually resolve within a few weeks after users discontinue steroids but may persist for up to 1 month, even if adequately treated with antipsychotic medication.

Hormones

Gonadotropin-releasing hormone (GnRH) agonists such as leuprolide and nafarelin are approved for treating endometriosis, advanced prostate cancer, precocious puberty, and uterine leiomyomata. Some studies and case reports suggest that these agents cause depressive symptoms.²⁶

Progestins have complex and variable psychiatric effects. Clinical trials have investigated the antidepressant effects of exogenous estrogens on psychiatric patients, but results have been inconsistent—possibly because of small numbers of subjects and design flaws.²⁶ Some studies suggest a link between estrogen and depression in premenopausal and menopausal women with and without psychiatric illness, but findings remain controversial because other studies have found that estrogens have positive effects on mood.^26,27

Interferon

Various forms of interferon are used to treat hepatitis C, melanoma, multiple sclerosis, chronic myelogenous leukemia, and other illnesses. Psychiatric complications—particularly depression—are the most frequent side effect of interferon therapy and mainly occur within the first 12 weeks of therapy.²⁸

In a prospective observational study of veterans undergoing interferon-alfa/ribavirin treatment for chronic hepatitis C:

• 48% of patients not receiving psychiatric care at baseline required treatment for neuropsychiatric side effects
  
• 23% developed symptoms of major depression.²⁹
  

Treatment with a selective serotonin reuptake inhibitor stabilized these symptoms and allowed patients to continue hepatitis treatment.

Because patients who receive interferon are far more likely to require psychiatric intervention if they have a family history of mood disorders, closely monitor them for depressive symptoms and treat such symptoms aggressively. Also closely monitor patients with multiple psychiatric diagnoses receiving interferon-alfa therapy.³⁰

Jeungling et al³¹ speculated that hypometabolism in the prefrontal cortex may predispose patients to interferon-associated neuropsychological syndromes. Neuropsychiatric symptoms may be a characteristic of hepatitis C, interferon treatment, or both.³²

Antimicrobial agents

Antibiotic and antiviral drugs can cause psychiatric side effects:

• directly by affecting neuronal functions
  
• indirectly by entering the brain rapidly, taking advantage of the compromised blood-brain barrier during sepsis or infection.
  

Delirium is the most common psychiatric complication associated with these agents.⁵

Antibiotics. Penicillin and its analogues are associated with sedation, anxiety, and hallucinations. Delirium has been reported as a side effect of most cephalosporins, especially in patients with compromised renal function. Quinolones such as ciprofloxacin and ofloxacin rarely cause restlessness, irritability, lethargy, tremors, insomnia, mania, depression, psychosis, delirium, seizures, or catatonia (incidence ≤1%).⁵ Though not commonly used, chloramphenicol may cause depression, confusion, and delirium. Many case reports have strongly associated clarithromycin with delirium.³³

Isoniazid is one of the most commonly used antibiotics that can cause psychiatric side effects; it has been linked to delirium, mania, depression, and psychosis. Ethionamide is associated with sedation, irritability, depression, restlessness, and psychosis. Tetracyclines have been known to cause depression, insomnia, and irritability at high dosages.

Sulfonamides can cause delirium. Psychosis and confusion also have been reported, especially when sulfa drugs are combined with trimethoprim.⁵

Antivirals. When used intravenously and at high doses, acyclovir and ganciclovir can cause lethargy, anxiety, hallucinations, and frank delirium.⁵ Foscarnet—an antiviral used to treat herpes viruses—can cause depression, anxiety, hallucinations, and aggressive irritability.

Didanosine—an antiretroviral agent to treat HIV infections—can cause lethargy (5% to 7% of patients), depression (2%), anxiety (2%), emotional lability (25%), delirium (2%), insomnia (1%), and psychotic delusions (1%).⁵ Efavirenz treatment may be associated with major depression and severe suicidal ideation.³⁴ Tenofovir, a nucleotide reverse transcriptase inhibitor, has not been associated with psychiatric side effects.²⁷

Antifungals. Psychiatric side effects are rare.

OTC and other agents

Many common nonprescription agents can cause psychiatric symptoms. The most frequently used classes include cold and allergy preparations, reflux medications, and analgesics (Box 2).^5,35

Cold preparations. Combined antihistamines and decongestants—such as phenylpropanolamine, azatadine, loratadine, ephedrine, phenylephrine, pseudoephedrine, and naphazoline—can cause an atropine-like psychosis that typically manifests as confusion, disorientation, agitation, hallucinations, and memory problems. Decongestants can cause dangerously high levels of norepinephrine when combined with monoamine oxidase inhibitors (MAOIs) and are contraindicated in patients taking MAOIs. Ephedrine can induce restlessness, dysphoria, irritability, anxiety, and insomnia.

 

Reflux medications. Two primary classes of reflux medications are proton pump inhibitors (omeprazole and lansoprazole) and H₂ receptor antagonists (famotidine, nizatidine, ranitidine, and cimetidine). Although generally considered to have a benign side-effect profile, these medications have been reported to cause serious neuropsychiatric complications—including mental confusion, agitation, depression, and hallucinations—mainly in geriatric patients with impaired hepatic-renal function.³⁶ These occur in only 37

Time to onset of psychiatric side effects from H₂ antagonists varies. Ranitidine can cause depression 4 to 8 weeks after treatment begins. Cimetidine has been reported to cause adverse events within 2 to 3 weeks and delirium within 24 to 48 hours.³⁸ These effects usually resolve within 3 days of discontinuing the drug. Cimetidine is also associated with sexual dysfunction.

Discontinuing ranitidine or cimetidine can induce a withdrawal syndrome that includes anxiety, insomnia, and irritability.³⁹ Cimetidine can increase the blood level and action of tricyclic antidepressants. Blood levels of these antidepressants can become toxic, resulting in tachycardia and other adverse effects.

Other medications. Ondansetron is a 5-hydroxytryptamine subclass 3 (5-HT₃) antagonist used for antiemetic therapy. In case reports, it has been strongly associated with anxiety.⁴⁰ This association is complex, however, and studies are evaluating 5-HT₃ receptor antagonists for the treatment of anxiety, depression, phobia, and schizophrenia.

Isotretinoin—a retinoid used for severe acne—can cause severe depression and suicidal behavior.⁴¹

Aminophylline and salbutamol are associated with agitation, insomnia, euphoria, and delirium. Methotrexate is known to cause personality changes, irritability, and delirium.²⁷

Box 2

Treating drug-related mood effects

If you suspect a nonpsychotropic medication is causing your patient’s psychiatric symptoms, discuss this with the patient and the prescribing physician. Switching to another similar agent may be an option. If this is not possible:

• work closely with the patient’s primary physician
  
• treat mood symptoms with appropriate psychotropics.
  

Related resources

• Turjanski N, Lloyd GG. Psychiatric side-effects of medications: recent developments. Advances in Psychiatric Treatment 2005;11:58-70.
  
• Brown TM, Stoudemire A. Psychiatric side effects of prescription and over-the-counter medications. Recognition and management. Washington, DC: American Psychiatric Publishing; 1998.
  
• Physicians’ Desk Reference. www.pdr.net.
  

Drug brand name

• Acyclovir • Zovirax
  
• Aminophylline • Phyllocontin, Truphylline
  
• Atenolol • Tenormin
  
• Azatadine • Optimine
  
• Baclofen • Lioresal
  
• Chloramphenicol • Chloromycetin
  
• Cimetidine • Tagamet
  
• Ciprofloxacin • Cipro
  
• Clarithromycin • Biaxin
  
• Clonidine • Catapres
  
• Cyclosporine • Neoral, Sandimmune, others
  
• Dantrolene • Dantrium
  
• Didanosine • Videx
  
• Efavirenz • Sustiva
  
• Ethionamide • Trecator
  
• Famotidine • Pepcid
  
• Foscarnet • Foscavir
  
• Ganciclovir • Cytovene
  
• Indomethacin • Indocin
  
• Interferon alfa • Intron, Roferon
  
• Isoniazid • Nydrazid
  
• Isotretinoin • Accutane
  
• Lansoprazole • Prevacid
  
• Leuprolide • Lupron
  
• Lidocaine • Xylocaine, Xylocard
  
• Loratadine • Claritin
  
• Methotrexate • Rheumatrex, Trexall
  
• Methyldopa • Aldomet
  
• Metoprolol • Lopressor
  
• Mirtazapine • Remeron
  
• Nafarelin • Synarel
  
• Naloxone • Suboxone
  
• Naltrexone • Vivitrol
  
• Naphazoline • Naphcon-A, Clearine
  
• Naproxen • Aleve, others
  
• Nizatidine • Axid
  
• Ofloxacin • Floxin
  
• Omeprazole • Prilosec
  
• Ondansetron • Zofran
  
• Paroxetine • Paxil
  
• Peginterferon alfa • PEG-Intron, Pegasys
  
• Phenylephrine • Neo-Synephrine
  
• Prednisolone • Blephamide, Pred Forte, others
  
• Propranolol • Inderal
  
• Pseudoephedrine • Actifed, Sudafed
  
• Ranitidine • Zantac
  
• Reserpine • Serpasi
  
• Ribavirin • Copegus, Rebetol
  
• Salbutamol • Aerolin, Airomir, others
  
• Sertraline • Zoloft
  
• Sumatriptan • Imitrex
  
• Tenofovir • Viread
  
• Trimethoprim • Proloprim
  

Disclosure

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