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Evidence-Based Reviews

Watch for nonpsychotropics causing psychiatric side effects

Look behind the scenes for drugs that play a supporting role in new mood symptoms

Vol. 7, No. 4 / April 2008

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.


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


Documented as a possible cause


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


Acyclovir, anabolic androgenic steroids, clonidine, corticosteroids, cyclosporine, decongestants, didanosine, serotonin 5-HT1 agonists such as sumatriptan, foscarnet, ganciclovir, nitrates, ondansetron, penicillins, skeletal muscle relaxants


Anabolic androgenic steroids, beta blockers, chloramphenicol, clonidine, corticosteroids, didanosine, digoxin, efavirenz, foscarnet, GnRH agonists, H2 blockers, interferons, isoniazid, isotretinoin, NSAIDs, quinolones, statins, tetracyclines


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


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 <2% discontinue the medication because of neuropsychiatric side effects. These include:

  • 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 <1% of patients—primarily those with preexisting cerebrovascular disease.5

Box 1

Not all psychiatric side effects are harmful

In some instances, mood-elevating side effects of nonpsychotropic medications might be beneficial. This might be the case if your patient experiences a sudden, otherwise unexplainable improvement.

CASE Helped by corticosteroids

Ms. Q, age 44, has a history of asthma and major depressive disorder and is being treated by a resident psychiatrist with a combination of paroxetine, 60 mg/d, mirtazapine, 15 mg at night, and cognitive-behavioral therapy. Her treatment has been challenging, and the psychiatrist has tried multiple medications and psychotherapy modalities.

At a recent psychotherapy session, Ms. Q says she has been feeling much better, with improved mood and greater energy. Upon further questioning, she reports having an asthma exacerbation a week before that resulted in hospitalization. During her stay, Ms. Q was started on a tapering dose of prednisone, which elevated her mood. Depressive symptoms returned when the effects of the prednisone wore off.

Prednisone is not indicated for depression and has harmful effects when used long term. The psychiatrist adds bupropion, 300 mg/d, to Ms. Q’s regimen, and her symptoms improve.

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 it12,13 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.


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


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

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