Psychiatry - December 2008 - (Page 30)

INTRODUCTION In the past two years alone, the US Food and Drug Administration (FDA) has issued alerts concerning suicidal ideation linked to the drug varenicline (Chantix®)1 as well as to numerous antiepileptic drugs.2 Meanwhile, the antiobesity drug rimonabant (Accomplia®)—not yet available in the US—was given a vote of no confidence by an FDA advisory panel,3 owing in part to the drug’s association with suicidality. All this occurs against the backdrop of intense controversy surrounding newer antidepressants and their possible association with increased suicidal ideation in a small percentage of younger patients.4 The notion of a “depressogenic” drug is hardly new to medical practitioners. More than a half century ago, Freis5 first reported on “mental depression” in association with the antihypertensive drug, reserpine. And in his classic, Anatomy of Melancholy (1621), the English scholar Robert Burton identified alcohol as one cause of melancholy. Indeed, if alcohol is considered a drug, the concept of drug-induced depression (DID) may be traced to antiquity: In the Old Testament, for example, we read: “Who has woe? Who has sorrow? Those who tarry long over wine…” (Proverbs 23:29–30). In our own time, numerous medications and classes of medications have been implicated in DID, sometimes called substance-induced depression or drug-related depression. DID has important medical, medicolegal, and commercial implications. Any physician who has observed steroid-related mood swings—either mania or depression— knows that DID can drastically affect a patient’s clinical course. For example, one of us (R.P.) reported a case in which a young woman appeared to develop persistent bipolar mood swings after a single course of corticosteroids for treatment of ulcerative colitis.6 The legal implications of alleged or apparent DID are also becoming clear. It is now easy to find online advertisements from law firms with solicitations such as, “If you or a loved 30 Psychiatry 2008 [ V O L U M E 5, NUMBER one took [antidepressant x] and suffered side effects, please fill out the form at the right for a free case evaluation by a qualified drug side effects attorney.”7 It is obvious that pharmaceutical firms stand to suffer major financial consequences from lawsuits alleging that their product “caused” a patient to become suicidal. As we will see, however, the task of establishing a causal link between a drug and a patient’s subsequent depression or suicide is daunting. In this paper, we review DID in relation to drugs used mainly in primary care and internal medicine. We do not cover the burgeoning area of depression or “suicidality” in relation to antidepressants or to other agents with FDA labeling for use in psychiatric disorders (e.g., antipsychotics, anxiolytics, and moodstabilizers, including anticonvulsants). The reader is referred to recent reviews of depression and other putative side effects associated with psychotropic agents.8–10 That said, there is substantial overlap in the pharmacological “territories” now covered by psychiatrists, family practitioners, internists, and neurologists. Most antidepressant prescriptions, for example, are written by primary care physicians (PCP), not psychiatrists.11 And, not uncommonly, psychiatrists nowadays are prescribing agents usually associated with neurologists, such as anticonvulsants or drugs for neuropathic pain. In this paper, we first review methodological issues in assessing DID; the epidemiology of DID; and hypotheses concerning the pathophysiology of DID. We then review, by general class or specific agent, the medications associated with DID. We attempt to categorize the data according to “strength of evidence,” and conclude with some practical recommendations for PCPs and other physicians. METHODOLOGICAL PROBLEMS, “CAUSALITY,” AND LEVELS OF EVIDENCE Let’s say that Dr. Jones prescribes a beta-blocking antihypertensive agent for Mr. Smith. A month later, 12, DECEMBER] Mr. Smith complains that he is “feeling really down lately,” lacks energy, and is having some difficulty with sexual performance. It is understandable that Dr. Jones might implicate the recently prescribed beta blocker in the genesis of Mr. Smith’s complaints. But suppose Mr. Smith has a history of recurrent major depression—with eight previous episodes over the past 12 years, all characterized by low mood, anergia, and loss of libido. Now the culprit is not so clear, and the risk of post-hoc fallacy (“after this drug, therefore because of this drug”) is very real. Indeed, as we shall see, epidemiologic studies of beta blockers do not clearly implicate them in DID, notwithstanding many suggestive case reports to the contrary.12 On the other hand, a recent review concluded that, “Evidence from case reports should be carefully considered when relevant, randomized, controlled trials have not been adequately designed to detect adverse effects.”13 Indeed, large epidemiological studies and meta-analyses cannot always reveal the “outlier” who has an idiosyncratic—but quite genuine— depressive reaction to a drug. The Naranjo causality scale14 for adverse drug reactions (Figure 1) is one instrument that can assist clinicians in assessing the likelihood that a drug is responsible for the onset of depressive or suicidal ideation. Another factor in assessing the likelihood of a drug’s depressogenic effect is the type and quality of studies used in the determination. The general principles of “evidencebased medicine” hold that the evidentiary value of clinical and experimental data should be judged hierarchically. Thus, the randomized, prospective, double-blind, placebocontrolled study is usually held up as the “gold standard” of evidence.15 Meta-analyses, uncontrolled studies (including observational epidemiological studies), and case series are considered lower-level evidence, with the lowly, single-case report occupying the bottom rung. In

Table of Contents Feed for the Digital Edition of Psychiatry - December 2008

Psychiatry - December 2008 Editor’s Message Contents Editorial Advisory Board Antidepressant Prescribing by Specialty and Treatment of Premenstrual Dysmorphic Disorder Pain, Pain, Go Away: Antidepressants and Pain Management Why Psychotherapy Helps the Patient in Chronic Pain General Medical Drugs Associated with Depression Katatonia: A New Conceptual Understanding of Catatonia and a New Rating Scale Thermoregulation and the Role of Calcium Signalling in Neurotransmission Cognition and Schizophrenia: Is There a Role for Cognitive Assessments in Diagnosis and Treatment? Journal Watch Information for Authors

Psychiatry - December 2008

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