Psychiatry - December 2008 - (Page 32)

TABLE 1. Some possible mechanisms of drug-induced depression DRUG OR DRUG CLASS POSSIBLE MECHANISM FOR DID Block slow influx of calcium into the cell, inhibiting calcium-dependent neurotransmitter release and reducing neurotransmitter amplification through the second-messenger system20 Nifedipine, other calcium channel blockers Benzodiazepines Based on rodent studies: decreased release of serotonin in hippocampus (except with alprazolam)23 Exogenous corticosteroids Based on rodent development studies: dexamethasone administration leads to deficits in the number and size of neural cells; reduced function of G-protein-coupled catecholaminergic or cholinergic receptors24 Displaces nicotine from acetylcholine receptors, produces low-to-moderate levels of dopamine release, and stimulates mesolimbic dopamine system. May upset the balance in cholinergic-adrenergic tone potentially leading to depression or mania25 been criticized by Baumeister et al22 who have argued that reserpine is not depressogenic and that “the reason for perpetuation of this myth is reluctance to discard the monoamine hypothesis.” Nonetheless, reduction or depletion of biogenic amines continues to be adduced as one possible mechanism for DID and has by no means been ruled out.17 Other putative mechanisms20,23–25 for DID are listed in Table 1, but must be considered highly speculative at this time. This uncertainty is brought home by the observation that one and the same drug—e.g., dexamethasone or varenicline—may be associated with either depressive or manic-like symptoms.25 Finally, the development of DID appears to be more likely in a person who has a predisposition to depression.17 Varenicline DRUGS AND DID: WHERE THE EVIDENCE LIES We have identified more than a dozen classes of medications with putative depressive effects. Some have provoked official alerts from the FDA, whereas others have elicited isolated case-reports of DID. A listing of the agents is presented in Table 2, where we also indicate the level of evidence associated with each class. One should note that the level of evidence may vary within a therapeutic class. This may in part be explained by differences in pharmacokinetic parameters among the drugs within a given class. For example, lipophilic drugs are able to penetrate the blood brain barrier more readily than hydrophilic compounds and as a result may have more profound central nervous system (CNS) effects. Much of the literature comes by way of case reports, but some is available from large-scale trials in which depression was assessed. The variations in identification of a DID in these trials is worth mentioning. Certain reports extrapolate from patients on both drug X and an antidepressant (prescription symmetry), whereas others actually screen for depressive symptoms at 2,646 elderly subjects in the Netherlands yielded some relevant findings.20 Using a combination of structured interviews for depression and careful determination of medication use, the researchers were able to determine the Population Attributable Risk percentage (PAR%) for various drug classes. The PAR% is not a direct measure of incidence or prevalence; rather, it is a quantitative estimate of the proportion of disease in the population that is directly attributable to a particular risk factor.21 The authors concluded that the PAR% for nonselective beta blockers is 2.5 percent, for calcium antagonists five percent; for benzodiazepines 15.42 percent; and for systemic corticosteroids, 2.95 percent. If these figures are at all representative of actual DID prevalence, we are dealing with a significant public health problem in the elderly and perhaps in younger populations as well. 32 Psychiatry 2008 [ V O L U M E 5, NUMBER PUTATIVE PATHOPHYSIOLOGY OF DID Given the plethora of drugs implicated in DID, there is no reason to presume that all drugs produce depression via a common pathophysiological mechanism. And, in as much as the pathophysiology of “ordinary” or idiopathic depression remains uncertain, it would be presumptuous to make confident claims regarding the genesis of DID. Nonetheless, specific depressogenic drugs may induce depression via mechanisms that have been investigated in other contexts. The classic example is that of reserpine, perhaps the first putative depressogenic drug to be the focus of a professional journal report.5 Since in-vitro investigations have shown reserpine to be an “aminedepleting agent,” it was plausible to hypothesize that reserpine induces depression by reducing neuronal stores of biogenic amines. However, this plausible notion has recently 12, DECEMBER]

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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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