B R A I N S T O R M S Clinical Neuroscience Update Are Two Antidepressant Mechanisms Better Than One? © Copyright 1997Stephen Physicians M. Stahl, M.D., Postgraduate Ph.D. Press, Inc. Issue: A drug that combines two or more synergistic mechanisms of action may yield superior therapeutic efficacy or tolerability compared to a single therapeutic mechanism of highly selective agents. he classical antidepressants,One thatpersonal combining copy mechanisms may be isprinted always New drugs with multiple mecha- namely tricyclic antidepres- undesirable. Two drugs in which mul- nisms may not only be able to reduce T sants (TCAs) and monoam- tiple mechanisms reduce undesired side effects, they might even im- ine oxidase inhibitors, have multiple actions rather than cause them are prove antidepressant efficacy. There pharmacologic mechanisms, but only nefazodone and mirtazapine. Both is a troubling clinical notion, espe- those increasing the availability of se- agents increase serotonin, as do the cially among some investigators, rotonin (5-HT) and norepinephrine SSRIs.1,2 However, the anxiety, sexual that the SSRIs are not as powerful (NE) explain antidepressant actions.1 dysfunction, and sleep disturbance as- as the TCAs for treating patients Their other actions, such as anticho- sociated with SSRIs and mediated by who have severe depression or who linergic properties, are responsible for stimulating 5-HT2 receptors can be are resistant to prior trials of antide- 1 side effects. This profile has given prevented by the 5-HT2 antagonists pressants. Looking at the pharma- rise to the notion that multiple mecha- nefazodone and mirtazapine; the nau- cology of the favorite Europe TCA nisms mean “dirty drugs” and that the sea associated with SSRIs and medi- clomipramine, we see that it is both best drugs should be “smart bombs” ated by stimulating 5-HT3 receptors a serotonin and a norepinephrine 1 attacking only a single receptor target. can also be prevented by the 5-HT3 reuptake inhibitor. Is it possible that Thus, the classical antidepressants antagonist mirtazapine.1,3,4 the SSRIs went too far by removing were replaced by the serotonin selec- tive reuptake inhibitors (SSRIs), which have essentially only a single neurotransmitter action, namely on 5-HT. Take-Home Points Some of the newest antidepres- sants, however, challenge the notion N Classical antidepressants are “dirty drugs” because their mul- tiple mechanisms cause side effects BRAINSTORMS is a monthly section of The Journal of Clinical Psychiatry aimed at providing N Newer antidepressants are clean compared with these dirty updates of novel concepts emerging from the neurosciences that have relevance to the drugs and produce a much improved side effect profile, but not practicing psychiatrist. improved antidepressant efficacy From the Clinical Neuroscience Research Center in San Diego and the Department of Psychiatry at the University of California San N “Designer” antidepressants with two or more mechanisms may Diego. Reprint requests to: Stephen M. Stahl, M.D., reduce side effects, improve antidepressant efficacy, or both Ph.D., Editor, BRAINSTORMS, 8899 University Center Lane, Suite 130, San Diego, CA 92122. 338339 J Clin Psychiatry 58:8, August 1997 B R A I N S T O R M S Clinical Neuroscience Update Single Selective Mechanisms = Loss of Side Effects SSRI SRI © Copyright 1997 Physicians Postgraduate Press, Inc. Multiple Multiple Therapeutic Mechanisms = Mechanisms = SRI Side Effects SNRI Improved Efficacy NRI H 1 SRI TCA 2 M 1 NRI NaSSA H 5HT 3 Are Two Antidepressant Mechanisms 5HT2 Better Than One? the NE-enhancing properties of theOne ingpersonal for a long copy time mayto treat be patients printed un- much more efficacy than either agent TCAs? able to respond to or tolerate different alone. In other words, sometimes 1 + Some evidence indeed suggests that antidepressants. That is, they have 1 = 10. On the other hand, combining this is so,5–9 although not everyone been combining therapeutic mecha- therapeutic agents may also reduce agrees.9–10 The dual 5-HT/NE-action nisms by using multiple simultaneous the side effects of each agent. In that TCA clomipramine has proved to be therapeutic agents. This brings to mind case, 1 + 1 = 0. superior to various single 5-HT-action the old saying that there are three types Where this all leads no one knows SSRIs in several trials (e.g., references of psychopharmacologists: those who for sure, but the clear mandate for fu- 5 and 6). The dual (5-HT/NE)-action can count and those who can’t. Wise ture antidepressants will be to en- agent venlafaxine preserves both the clinicians suggest that the best ones hance efficacy, not just tolerability. NE- and 5-HT-enhancing properties are those who can’t count: that is, com- Perhaps bad mathematics is the an- (especially at high doses) of the TCAs bining therapeutic agents may yield swer. N while cleaning up their undesired pharmacology.1 One study suggests enhanced efficacy or more rapid onset of action for venlafaxine compared REFERENCES with an SSRI.7 Similarly, the dual (5-HT/NE)-action agent mirtazapine 1.Stahl SM. Essential Psychopharmacology. tor showing better tolerance but weaker antide- may also have enhanced efficacy over New York, NY: Cambridge University Press; pressant effect than clomipramine in a con- an SSRI.8 Although more research is 1996 trolled multicenter study. J Affect Disord 1990; 2. de Boer T. The effects of mirtazapine on cen- 18:289–299 clearly needed for all dual-acting tral noradrenergic and serotonergic neu- 7. Clerc GE, Ruimy P, Verdeau-Pailles J, on behalf drugs, it would not be surprising if rotransmission. Int Clin Psychopharmacol of the Venlafaxine French Inpatient Study these observations eventually hold up 1995;10(suppl 4):19–23 Group. A double-blind comparison of venlafax- 3. Stimml GL, Dopheide JA, Stahl SM. 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