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Clinical Pharmacology of Antidepressants and Mood-Stabilizers


Types of antidepressants

Antidepressants currently fall into five major categories: [1] tertiary amine tricyclics (amitriptyline, clomipramine, doxepin, imipramine, trimipramine), secondary amine tricyclics (amoxapine, desipramine, maprotiline, nortriptyline, protriptyline); [2] monoamine oxidase (MAO) inhibitors (phenelzine, tranylcypromine, selegiline [(-)-deprenyl], and experimental short-acting MAO-A inhibitors (eg,, moclobemide [Manerex], marketed in Canada); [3] serotonin-reuptake inhibitors: (SSRIs) clomipramine, citalopram, []-fluoxetine, fluvoxamine, sertraline, paroxetine, and the mixed 5-HT/NE uptake inhibitor venlafaxine (plus the withdrawn zimelidine; [4] stimulant-like dopaminergic as well as noradrenergic agents: bupropion (and the withdrawn nomifensine); [5] the atypical antidepressant mirtazapine (Remeron; a sedating antidepressant chemically related to mianserin, with indirect adrenergic and serotonergic actions as an a2 and serotonin 5-HT2 and 5-HT3 antagonist that enhances release of both NE and 5-HT) and [6] sedative-anxiolytics: including the triazolopyridines trazodone and nefazodone, but probably not high-potency benzodiazepines.

Efficacy of antidepressants

The evidence of antidepressant efficacy of most antidepressants is much less compelling than most other classes of psychotropic agents. Indeed, virtually all types have outperformed a placebo in only about 60%-70% of comparisons. In part, this limited evidence of efficacy reflects ambiguities surrounding currently broad definitions of depressive syndromes, particularly the relatively loose contemporary category of "major" depression, such that rates of response to a placebo may be as high as 20%-40% and that to other relatively nonspecific treatments (including sedative-anxiolytics) is even higher (40%-50%), while typical responses to an antidepressant range.

Dosing of antidepressants

Dose-response relationships of most antidepressants remain insecure, and there is a divergence of opinion about dosing between US and European clinical investigators. Some studies support use of aggressive daily dosing above the equivalent of 150 mg of a standard agent.


The problem of apparent "treatment-resistance" in depression requires further study, but many cases respond when a patient actually is willing to follow a previously recommended treatment, or high doses are accepted and pursued for at least 6-8 weeks. Some cases may represent destabilizing effects of overly aggressive antidepressant treatment of patients with overlooked bipolarity, but many others are truly treatment-unresponsive unipolar depressions. In cases of convincing treatment resistance, or loss of response over time (tolerance), evidence that important gains are to be found in exploring a series of similar agents is lacking.

Long-term treatment

Long-term maintenance treatment of recurrent unipolar major depression with antidepressants has a complex body of research findings. Continuation of such agents in nearly full doses as are given short-term is probably effective in preventing early relapse in the 6-12 months.

recovery from an acute episode, and this is a widely accepted clinical practice. However, studies of more prolonged prophylactic benefit over several years of maintenance treatment are limited and suggest diminishing evidence of efficacy with duration of follow-up, perhaps in part due to limited compliance with generally poorly tolerated TCAs. An influential study in which compliance with high doses (ca. 200 mg of imipramine daily) and blood TCA concentrations of imipramine was assured, there was convincing evidence of benefit over a placebo in outpatients treated up to 5 years, whereas (possibly inadequately vigorous) psychotherapy added little. Several recent trials provide support for long-term use of SSRIs. Long-term use of antidepressants is more secure with more previous episodes, and even in dysthymia or chronic depression. Rapid dose-reduction or discontinuation of maintenance antidepressant treatment appears to carry a high risk of early recurrence of depression, particularly within six months, and even following several years of stable mood.

Alternative applications of "antidepressants"

Although the evidence of efficacy of antidepressants, as a class, is not as convincing as for other types of drugs, there is growing clinical and research evidence to support a widening range of potential indications of these drugs. The partial success of the SSRIs as a group in ameliorating

OCD is encouraging, as is the utility of TCAs (especially imipramine) and MAO inhibitors (less so fluoxetine, not bupropion) in blocking the episodic, acute autonomic expression of panic. The range of disorders suspected of being related to OCD and in which serotonin-enhancing treatments are being explored, includes eating disorders, hair-pulling (trichotillomania) and other repetitive habits, compulsive gambling, kleptomania, premenstrual dysphoria, and perhaps body dysmorphic disorder. Antidepressants have a scientifically demonstrated but incompletely defined place in the overall management of patients with bulimia nervosa and may have an

Suicide risk

The relationship of antidepressant treatment and suicidal behavior remains unclear. It was formerly suspected that inadequate antidepressant treatment may carry a higher mortality risk due to suicide or medical illness, but this apparent association now appears to be an artifact of more conservative treatment in high-risk, especially elderly and medically infirm, patients. Suicidal behavior is not uncommon in patients with a mood disorder, and potentially lethal antidepressants (TCAs and MAO inhibitors) have been common vehicles of attempted or successful self-destruction. However, evidence that specific treatments (notably, fluoxetine or akathisia-inducing neuroleptics) may increase the risk of dangerous or violent acts more than other alternatives (other agents, undertreatment, no treatment) remains unconvincing. Since newer antidepressants are less lethal in overdose, they are more safely given to potentially suicidal patients. There have been tentative suggestions that serotonin-facilitating antidepressants may be more beneficial against suicidal behavior than



Efficacy of lithium salts

Lithium salts (carbonate or citrate) are relatively specific for the treatment of mania but their onset of useful action is slow (5-10 days). For this reason, and due to the limited margin of safety (therapeutic index) of lithium in acutely disturbed, poorly cooperative, and metabolically compromised patients, many are not treated immediately or primarily with lithium in acute mania. Instead, they are treated temporarily with an antipsychotic agent (often more dramatically effective in mania than in schizophrenia) or a sedative (usually a high-potency benzodiazepine, such as lorazepam [Ativan] or clonazepam [Klonopin]). Lithium salts can then be added safely in gradually increasing doses. Short-term effectiveness in mania is best established in young adults (in whom placebo response rates are surprisingly

Evidence for efficacy of lithium in acute nonbipolar depression is much weaker than for bipolar depression. Some beneficial effects of lithium in depression may be due to underdiagnosis of bipolar disorder and related conditions, or the possibility that some cases of apparent nonbipolar depression may be phenotypic variants of bipolar disorder ("pseudounipolar" depression hypothesis). It is also very

Surprisingly, lithium is the only form of maintenance treatment in recurring major affective disorders with substantial evidence of reduced suicidal risk (including anticonvulsants, antidepressants, ECT, and psychotherapy, but perhaps not clozapine which has reduced suicide risk in schizophrenia, at least). Recent direct comparisons of lithium with TCA maintenance in unipolar depression and carbamazepine in

Newer antimanic, putative mood-stabilizing agents

Innovative alternatives to lithium include certain anticonvulsant agents which have been found especially useful also in "psychomotor," "partial complex," or "temporal lobe" forms of epilepsy. Carbamazepine (Tegretol) has been used longer than other alternatives, including in a few long-term maintenance trials, although its efficacy and tolerability (sedation, confusion, nausea, blood dyscrasias) as a monotherapy (at doses providing plasma concentrations of 6-12 gg/ml) appear to be limited, and there is some evidence that it is less 

Valproate (as the generic valproic acid or Depakene, or the preferred, enteric-coated monosodium salt divalproex, Depakote, or other preparations of sodium valproate), at plasma concentrations of 50125 g/ml) is highly effective in mania, and can act rapidly at loading