Evidence-Based Reviews

Watch for nonpsychotropics causing psychiatric side effects

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



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

SymptomDocumented as a possible cause
Psychosis/agitationAnabolic androgenic steroids, antihistamines, clonidine, corticosteroids, decongestants, didanosine, ethionamide, H2 blockers, isoniazid, nitrates, NSAIDs, opioids, proton pump inhibitors, quinolones, salbutamol, skeletal muscle relaxants, sulfonamides/trimethoprim
AnxietyAcyclovir, anabolic androgenic steroids, clonidine, corticosteroids, cyclosporine, decongestants, didanosine, serotonin 5-HT1 agonists such as sumatriptan, foscarnet, ganciclovir, nitrates, ondansetron, penicillins, skeletal muscle relaxants
DepressionAnabolic androgenic steroids, beta blockers, chloramphenicol, clonidine, corticosteroids, didanosine, digoxin, efavirenz, foscarnet, GnRH agonists, H2 blockers, interferons, isoniazid, isotretinoin, NSAIDs, quinolones, statins, tetracyclines
DeliriumACE 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
InsomniaAminophylline, 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.


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