While The Medical Letter relates several neuropsychiatric side effects with most drugs on the list, it emphasizes the association of depression with calcium channel blockers by indicating only this condition with this drug category. This, despite a single report of hallucinations with verapamil (Isoptin) as the only neuropsychiatric symptom of a calcium channel blocker included on the 1993 list.
A new warning about the occurrences of depression, suicide and psychosis in patients receiving the acne medication isotretinoin (Accutane) is being added to the product labeling, according to an announcement by the manufacturer, Hoffmann-La Roche.
After receiving a letter in March from the U.S. Food and Drug Administration, which took issue with Accutane advertising, Roche also announced that it will stop ads which imply that treatment with Accutane is useful for the "psychological trauma" and "emotional suffering" that is associated with acne.
The previous labeling had noted reports of depression, including some cases in which symptoms resolved and then re-emerged when the medication was stopped and restarted. The FDA sought the stronger warning when, according to a Wall Street Journal story, they had accumulated over a dozen reports correlating reoccurrence of neuro-psychiatric symptoms with medication rechallenge, in addition to 12 reports since 1989 of patients committing suicide while receiving the medication.
Neither the FDA nor the manufacturer find that a causal relationship is established by the reports, however. John Wilkin, M.D., head of the FDA Division of Dermatologic and Dental Drugs, commented to the Wall Street Journal, "there is enough of a signal right now, we thought it'd be prudent to put something in the labeling."
Kellie McLaughlin, a Roche spokeswoman, commented that teen-agers, the largest age group using Accutane, have "a higher incidence of depression than most." McLaughlin suggested that the adolescents with severe, recalcitrant acne for which isotretinoin is indicated might be at heightened risk for depression, independent of taking the medication.
The revised FDA-approved labeling, commencing with product packaging in March, elaborates on the seriousness and persistence of depression, and the possible occurrence of suicide. It warns that discontinuation of Accutane therapy may be insufficient to address the symptoms, and that further evaluation and treatment may be necessary.
Other Drugs Implicated
Coincidentally, during the week prior to this announced warning, The Medical Letter updated its list of drugs and drug categories (139 in current list) reported to cause psychiatric symptoms (The Medical Letter, Inc., 1998). Isotretinoin is among 33 drugs on that list to be associated with depression (see sidebar).
Also in proximity to the Accutane announcement, the following week Swedish researchers commented to the press that the calcium channel blocker cardiovascular drugs "should be considered as possible cause of depression and suicide." Their study of 3,397 outpatients in 152 Swedish municipalities, published in the British Medical Journal, revealed a fivefold greater incidence of suicide among those using calcium channel blockers than patients using other antihypertensive medications (Lindberg et al., 1998).
While The Medical Letter relates several neuropsychiatric side effects with most drugs on the list, it emphasizes the association of depression with calcium channel blockers by indicating only this condition with this drug category. This, despite a single report of hallucinations with verapamil (Isoptin) as the only neuropsychiatric symptom of a calcium channel blocker included on the 1993 list (The Medical Letter, Inc., 1993).
In addition to isotretinoin and calcium channel blockers, among the 33 drugs and drug categories listed for depressive symptom side effects, the "statin" cholesterol-lowering agents and other antihypertensives are widely associated with, if not implicated as the cause of, depressive symptoms--with varying levels of evidence, as reviewed below.
Depression as Adverse Drug Reaction
One of the earliest reports of depression occurring with isotretinoin was of six patients (four women, two men; mean age 28.5 years, range 20 to 42 years) in a series of 110 patients with acne or keratinizing disorders (Hazen et al., 1983). Only one of the six patients had a previous history of depression. The dermatologists reported that depressive symptoms manifested within two weeks of starting isotretinoin, and included crying spells (in three of six patients), malaise (three of six) and forgetfulness (one of six). In only one of the six patients were the symptoms sufficiently severe to necessitate discontinuing the drug.
More severe depression was found in three of seven patients experiencing such symptoms among 700 patients receiving isotretinoin in premarket clinical trials, according to a report from the Dermatology Branch of the National Cancer Institute, National Institutes of Health (Scheinman et al., 1990). In the three cases, the initial depressive symptom presentations were determined by a psychiatrist to have evolved into major depression. Their symptoms included fatigue, inability to concentrate, lack of motivation, forgetfulness and crying spells. In four other patients, the symptoms rapidly resolved when isotretinoin was discontinued, prior to the psychiatric assessment.
In one of the patients who initially improved, depressive symptoms returned when rechallenged with the medication. The symptoms had developed during the tenth week of the initial course of treatment, resolved within seven days after discontinuation, reemerged 10 weeks after treatment was resumed, and resolved again within seven days after the drug was stopped.
Until the recent epidemiologic evidence linking calcium channel blockers with depression onset and suicide, the association was made, as it is more commonly, by individual case report.
Joseph Hullett, M.D., and colleagues from the department of psychiatry at the University of California, Irvine, described four cases in which "substantial" depression manifested with the use of nifedipine (Procardia, Adalat). In one patient already under treatment with the antidepressant nortriptyline (Pamelor, Aventyl), the depression worsened when nifedipine was introduced. In each patient, the depression or exacerbation of depression resolved following discontinuation of the calcium channel blocker (Hullett et al., 1988).
Hullett et al. suggest that calcium channel blockers may influence limbic functioning in the brain by blocking calcium-dependent neurotransmitter release and attenuating the usual neurotransmission amplification through the second-messenger system. They also speculate that these agents could blunt norepinephrine effects. In addition, they note that nifedipine, but not verapamil or diltiazem (Cardizem), binds competitively to central benzodiazepine receptor sites.
The calcium channel blockers have also been differentiated by their degrees of potency in displacing phencyclidine and inhibiting dihydropyridine binding in rat brain studies which, according to Hullett et al., "may account for the varied and, at times, almost paradoxical pharmacological effects of the calcium channel blocking drugs."
The depression occurring with the statin HMG-CoA reductase inhibitor cholesterol-lowering agents is thought by Robert Rosenson, M.D., and Nancy Goranson, Ph.D., of Rush Presbyterian-St. Luke's Medical Center in Chicago, to be more likely with the more lipophilic lovastatin (Mevacor), which enters the central nervous system with greater ease, than with the more hydrophilic pravastatin (Pravachol).
In two cases of patients experiencing persistent sleep disturbance, anxious mood and impaired coping skills after receiving lovastatin, each promptly improved when the drug was discontinued and remained free of depressive symptoms after treatment was resumed with pravastatin (Rosenson and Goranson, 1993).
Others have linked depressive symptoms with pravastatin as well (Lechleitner et al., 1992). However, the association is contested by the drug manufacturer based on 14 controlled registration trials (Kassler-Taub et al., 1993) that showed that the incidence of depression did not differ significantly in 2,485 patients treated with either pravastatin or resin. Clinicians from the department of psychiatry at the Free University of Amsterdam suggest that cholesterol-lowering agents may provoke depression by disturbing cerebral serotonin metabolism (Duits and Bos, 1993).
-Blocker's Role Questioned
With the exception of angiotensin converting enzyme inhibitors and, possibly, the newer class of angiotensin II receptor antagonists, most antihypertensive agents--notably the -adrenergic blockers--have been associated with depression and other neuropsychiatric effects (Rauch et al., 1991).
Famihiko Okada, M.D., of Hokkaido University in Sapporo, Japan, pointed out over a decade ago that even thiazide diuretics can produce such symptoms, although their potential for doing so is often overlooked because they are commonly used in combination with antihypertensives having greater liability for depressive symptoms (Okada, 1985). Okada suggests, however, that thiazide diuretics may affect central adrenergic systems, noting that decreased plasma catecholamines have been found in animal studies with long-term thiazide administration.
The adrenergic blockade of the -blocker drugs is commonly assumed to dispose patients to depressive symptom side effects, even when administered as an ophthalmic (Hugues and LeJeunne, 1993). A contrarian view has emerged, however, from several studies.
In one study involving 77 nonpsychiatric patients undergoing cardiac catheterization, 21% of patients who were receiving -blockers (most often propranolol [Inderal]) were found to have major depression by assessment with the Beck Depression Inventory, as were 33% of this group who were not on -blockers (Carney et al., 1987). The -blocker did not, then, appear to heighten the risk for depression in this population, in which the prevalence of depression was high. The investigators observed, in addition, that the -blockers appeared to lessen the degree of anxiety ex-perienced prior to undergoing the cardiac catheterization.
Another study utilized a battery of diagnostic instruments to ascertain the prevalence of depression among 52 ambulatory nonpsychiatric patients receiving propranolol and 75 controls, matched demographically in gender, age, marital status, level of education and physician visits (Bartles et al., 1998).
The overall prevalence of depression was not different between the groups, and depressive symptoms were actually less in the propranolol group on some measures. A similar lack of association of -blockers with depression was documented in patients receiving the medication after myocardial infarction, during a convalescent period that is frequently complicated by the presentation of depressive symptoms (Schleifer et al., 1991).
While the literature may not clearly implicate a drug for causing depression or other neuropsychiatric adverse effects, the onset of such symptoms within days or weeks after a patient begins receiving a new medication or an increased dosage should raise suspicion of this possibility. Modifying the medication regimen and following up with appropriate health treatment may then avert the morbidity of depressive symptoms and potential mortality of major depression.
Bartles D, Glasser M, Wang A, Swanson P (1988), Association between depression and propranolol use in ambulatory patients. Clin Pharm 7:146-150.
Carney RM, Rich MW, Tevelde A et al. (1987), Prevalence of major depressive disorder in patients receiving -blocker therapy versus other medication. Am J Med 83(2):223-236.
Duits N, Bos FM (1993), Depressive symptoms and cholesterol lowering drugs. Lancet 341:114. Letter. Comment in: Lancet 1992 (Oct 10) 340(8824):910.
Hazen PG, Carney JF, Walker AE, Stewart JJ (1983), Depression--a side effect of 13-cis-retinoic acid therapy. J Am Acad Derm 9:278-279. Letter.
Hugues F-C, LeJeunne C (1993), Systemic and local tolerability of ophthalmic drug formulations. Drug Safety 8:365-380.
Hullett FJ, Potkin SG, Levy AB, Ciasca R (1988), Depression associated with nifedipine-induced calcium channel blockade. Am J Psychiatry 145:1277-1279.
Kassler-Taub KB, Woodward T, Markowitz JS (1993), Depressive symptoms and pravastatin. Lancet 341:371-372. Letter. Comment.
Lechleitner M, Hoppichler F, Konwalinka G et al. (1992), Depressive symptoms in hypercholes-terolaemia patients treated with pravastatin. Lancet 340:910 Letter. Comment in: Lancet 1993 (Jan 9) 341(8837):114; Lancet 1993 (Feb 6) 341(8841):371-372.
Lindberg G, Bingefors K, RÅnstam J et al. (1998), Use of calcium channel blockers and risk of suicide: Ecological findings confirmed in population based cohort study. Br Med J 316:741.
Okada F (1985), Depression after treatment with thiazide diuretics for hypertension. Am J Psychiatry 142:1101-1102.
Rauch SL, Stern TA, Zusman RM (1991), Neuropsychiatric considerations in the treatment of hypertension. Intl J Psychiatry Med 19:291-308.
Rosenson RS, Goranson NL (1993), Lovastatin-associated sleep and mood disturbances. Am J Med 95:548-549. Comment in: Am J Med 1995 (Jul) 99(1):108-109.
Scheinman PL, Peck GL, Rubinow DR et al. (1990), Acute depression from isotretinoin. J Am Acad Derm 22:112-113.
Schleifer SJ, Slater WR, Macari-Hinson MM et al. (1991), Digitalis and -blocking agents: effects on depression following myocardial infarction. Am Heart J 121:1397-1402.
The Medical Letter, Inc. (1998), Drugs that cause psychiatric symptoms. Med Lett Drugs Ther 35:65-70.
The Medical Letter, Inc. (1998), Some drugs that cause psychiatric symptoms. Med Lett Drugs Ther 40:21-24.