Watch for nonpsychotropics causing psychiatric side effects Look behind the scenes for drugs that play a supporting role in new mood symptoms r. J, age 52, has a history of opioid® dependence.Dowden Health Media Four weeks after starting interferon therapy for Mhepatitis C, he presents to the outpatient mental health clinic with depressedCopyright mood, irritability,For personal decreased use only energy, poor concentration, insomnia, anhedonia, and suicidal ideation. Because Mr. J has no history of depression, the psychia- trist diagnoses him with depressive disorder secondary to interferon. Interferon is stopped. Mr. J’s mood improves, HIATRY but he wants to restart interferon. c 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 in- terferon with a combination of sertraline and supportive psychotherapy. BLAIR KELLY BLAIRFOR CURRENT KELLY PSY Recognizing a medication as the possible cause of your Kanwaldeep S. Sidhu, MD patient’s psychiatric symptoms can avoid inaccurate Third-year resident diagnosis and nonindicated psychiatric treatment. Dil- Richard Balon, MD Professor igently evaluating patients for drug-related psychiatric side effects is critical because complications usually are reversed when the offending drug is discontinued. Department of Psychiatry and Behavioral Neurosciences Wayne State University Unfortunately, a thin line separates available evidence Detroit, MI 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 Current Psychiatry behavioral disturbances. Vol. 7, No. 4 61 continued For mass reproduction, content licensing and permissions contact Dowden Health Media. Table New-onset psychiatric symptoms? Check patient’s drug list Symptom Documented as a possible cause Psychosis/ Anabolic androgenic steroids, antihistamines, clonidine, corticosteroids, agitation decongestants, didanosine, ethionamide, H2 blockers, isoniazid, nitrates, NSAIDs, Nonpsychotropic opioids, proton pump inhibitors, quinolones, salbutamol, skeletal muscle relaxants, medications 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 Clinical Point Delirium ACE inhibitors, anabolic androgenic steroids, antibiotics (most), anticholinergics, beta blockers, centrally acting antihypertensives such as methyldopa and Beta blockers such reserpine, cimetidine, clonidine, corticosteroids, didanosine, digoxin, H2 blockers, as metoprolol and lidocaine, naltrexone, nitrates, NSAIDs, opioids propranolol can Insomnia Aminophylline, anabolic androgenic steroids, clonidine, corticosteroids, decongestants, didanosine, opioid antagonists, proton pump inhibitors, quinolone cause delirium and antibiotics, salbutamol, skeletal muscle relaxants, tetracyclines psychosis 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 A wide range of drugs can cause psycho- Metoprolol and propranolol can induce sis, agitation, anxiety, depression, delirium, delirium and psychosis.4,5 Psychiatric side or insomnia (Table). On the other hand, cer- effects with metoprolol are frequent,4 and tain psychiatric side effects of nonpsycho- propranolol has been associated with: tropics can be beneficial Box( 1). • sedation (affecting >10% of patients) Improve your assessments by examin- • nightmares ing the evidence linking psychiatric side • visual impairment effects to commonly prescribed and over- • hallucinations the-counter (OTC) compounds, including: • delirium • cardiovascular medications • depression.5 • steroids (prescription and illegal) In 1967, it was reported that up to 50% • hormones of patients taking propranolol may experi- • interferons ence dysphoria and at times severe depres- • antimicrobials. sion.6 These effects may occur acutely or develop gradually. 5 The relationship between depressive Cardiovascular medications symptoms and beta blockers has been in- Beta blockers have CNS effects—some of creasingly questioned, however. One study which cause psychiatric syndromes—that did not find a higher prevalence of depres- might depend on an ancillary property sion in patients receiving beta blockers vs such as lipophilicity.2 Unlike hydrophilic those receiving other medications, although agents such as atenolol that are excreted this trial had major methodologic limita- unchanged by the kidneys, lipophilic tions.7 One large study found no significant drugs such as metoprolol and propranolol association between beta-blocker use and are metabolized by the liver and are be- major depression, regardless of patient age, lieved to enter the brain. Metoprolol has a gender, or race.8 brain/plasma concentration ratio about 20 These studies stress the importance of Current Psychiatry 62 April 2008 times higher than that of atenolol.3 carefully assessing the individual patient before assigning neurotoxicity to beta block- Box 1 ers, as these drugs have considerable ben- efits for cardiovascular disease.9 Not all psychiatric side effects are harmful Angiotensin-converting enzyme (ACE) inhibitors also affect the CNS. About 4% n some instances, mood-elevating side effects of nonpsychotropic medications to 8% of patients taking an ACE inhibitor I might be beneficial. This might be the experience altered mental status—typically case if your patient experiences a sudden, increased arousal and psychomotor activ- otherwise unexplainable improvement. ity—although <2% discontinue the medica- tion because of neuropsychiatric side effects. CASE Helped by corticosteroids These include: Ms. Q, age 44, has a history of asthma and • anxiety major depressive disorder and is being • mania treated by a resident psychiatrist with • insomnia a combination of paroxetine, 60 mg/d, • fatigue mirtazapine, 15 mg at night, and cognitive- • paresthesias behavioral therapy. Her treatment has been Clinical Point • hallucinations.5 challenging, and the psychiatrist has tried Mood changes Sedation occurs in about 5% of patients multiple medications and psychotherapy modalities. are the most taking ACE inhibitors. Depression and sui- At a recent psychotherapy session, Ms. cide ideation as a result of ACE inhibition common psychiatric Q says she has been feeling much better, have been reported;13 however, ACE inhibi- symptoms caused by with improved mood and greater energy. tors have also been known to improve de- Upon further questioning, she reports corticosteroids pression. Episodes of frank delirium have having an asthma exacerbation a week 5 been reported. before that resulted in hospitalization. During her stay, Ms. Q was started on Clonidine is a centrally acting alpha- a tapering dose of prednisone, which agonist. The alpha-adrenergic system regu- elevated her mood. Depressive symptoms lates arousal and has an important role in returned when the effects of the major depression, anxiety states, and other prednisone wore off. arousal disorders. Prednisone is not indicated for depression and has harmful effects when More than one-third (35%) of patients tak- used long term. The psychiatrist adds ing clonidine experience sedation or lethar- bupropion, 300 mg/d, to Ms. Q’s regimen, gy; less commonly, the drug causes anxiety and her symptoms improve. (3%), agitation (3%), depression (1%), and insomnia (1%).5 Acute confusion, delirium, hypomania, and psychosis related to cloni- suicide, but the evidence is inconclusive. dine use have long been recognized, occur- Some studies have supported this link,10,11 ring in <1% of patients—primarily those whereas others have strongly refuted it12,13 with preexisting cerebrovascular disease.5 or had mixed results.14 A recent review15 rec- ommends being vigilant for psychiatric side Other cardiovascular drugs. Side effects of effects in patients taking these drugs. nitrates/nitrites include delirium, psychosis (including delusions), anxiety, restlessness, agitation, and hypomania.5 Digoxin can Steroids: prescription and illegal cause cardiac glycoside-induced encepha- Corticosteroids are prescribed for a variety lopathy, which may present as sedation, of immune system-related diseases, includ- apathy, depression, and psychosis. Patients ing asthma, allergic rhinitis, rheumatoid may develop delirium, even when digoxin/ arthritis, inflammatory bowel disease, and digitoxin serum levels are within a thera- dermatologic disorders. Mood changes are peutic range. the most common psychiatric symptoms Cholesterol-lowering statins might be caused by corticosteroid use; delirium is less Current Psychiatry linked to an increased risk of depression and common. Psychiatric side effects include: Vol. 7, No. 4 63 • lethargy cases or situations in which