Efficacy, antidepressant drugs

Chinese depressed patients appeared to require lower dosages, with consequently lower plasma concentrations of sertraline compared to Caucasian patients to achieve clinical efficacy (Ng et al, 2006). Again, this finding has supported the fact that Asian patients, especially Chinese, need lower doses of antidepressant drugs than their Western counterparts. 

Clomipramine (Anafranil) also a member of the tricyclic family, possesses similar pharmacology and antidepressant efficacy. This agent, however, has Food and Drug (FDA) approval only for use in the treatment of obsessive-compulsive disorder and is not included in this discussion of antidepressant drugs. 

Furthermore, clinical trials are performed in various cultural and geographical settings. Transcultural differences may play a significant role in drug efficacy e.g. oriental populations require much lower doses of antipsychotic drugs compared with Caucasian patient populations. Phase IV trials also may be performed to explore possible novel uses for compounds approved and marketed in other indications (e.g. treatment of anxiety disorders with antidepressants, treatment of bipolar disorder with anticonvulsants, etc.). 

Lithium carbonate and lithium citrate are the most commonly used compounds. Lithium has effects on cation transport, on individual neurotransmitters (including 5-HT) and on intracellular second messenger systems. Which of these is key to its therapeutic efficacy is not entirely clear but, as for the antidepressant drugs, the net effects seem to be to enhance serotonin function and to stabilise the noradrenergic system. Once lithium treatment is established it is very important that it is not suddenly stopped as this may result in rebound hypomania. 

The depressive phase of manic-depressive disorder often requires concurrent use of an antidepressant drug (see Chapter 30). Tricyclic antidepressant agents have been linked to precipitation of mania, with more rapid cycling of mood swings, although most patients do not show this effect. Selective serotonin reuptake inhibitors are less likely to induce mania but may have limited efficacy. Bupropion has shown some promise but—like tricyclic antidepressants—may induce mania at higher doses. As shown in recent controlled trials, the anticonvulsant lamotrigine is effective for many patients with bipolar depression. For some patients, however, one of the older monoamine oxidase inhibitors may be the antidepressant of choice. Quetiapine and the combination of olanzapine and fluoxetine has been approved for use in bipolar depression. 

It is interesting to note that despite the very widespread use and the generally accepted efficacy of antidepressants in pain therapy, at present not all antidepressant drugs are formally approved for the treatment of pain. Thus, the widespread use of these drugs is, to some extent, off-label, and there does not seem to be much effort in the pharmaceutical industry to market antidepressants explicitley as analgesic drugs. 

How has deregulation worked A meta-analysis of the herb St John s wort (Hypericum perforatum) for mild and moderately severe depression, published in 1996 by German and American physicians, concluded that it was more effective than a placebo and was as effective as standard antidepressants but with fewer side effects. However, the authors of the analysis raised questions about the methods employed and cautioned about its efficacy in seriously depressed patients. The active chemical in the herb, they claimed, was not appropriately standardized. Furthermore, the study only compared St John s wort with antidepressant drugs that were given at or below their lowest level of efficacy. And, finally, patients were treated for only 6 weeks. An accompanying editorial concluded that longer term studies are needed before it can be recommended in major depression. ... 

By the mid-60s there was a strong consensus that depression, at least in its severe endogenous form, was caused by an abnormal biochemical state consisting of reduced levels of monoamines in the brain. The theory was set out systematically in a well-known paper by Schildkraut (1965), who concentrated on the role of noradrenalin (Schildkraut 1965). Other authors focused on serotonin (Coppen 1967). Schildkraut asserted that some if not all depressions are associated with an absolute or relative deficiency of catecholamines, particularly norepinephrine. .. elation may conversely be associated with an excess of such amines (Schildkraut 1965, p. 509). The primary justification for the theory was the belief that stimulants and antidepressant drugs acted to increase monoamine levels. Schildkraut referred to how the supposed efficacy of imipramine had initially cast doubt on the theory, but the riddle had been solved by Axelrod s research on its ability to block tissue reuptake of noradrenalin. 

Freemantle, N., Anderson, I. M., Young, P. 2000, Predictive value of pharmacological activity for the relative efficacy of antidepressant drugs. Meta-regression analysis, Br.J.Psychiatry, vol. 177, pp. 292-302. 

Other antidepressant drugs that primarily affect serotonin reuptake include trazodone [TRAZ oh done], fluvoxamine [floo VOX a meen], nefazodone [ne FAZ oh don], paroxetine [pah ROX a teen], sertraline [SIR trah leen], and venlafaxine [vin lah FACKS in]. These SSRIs differ from fluoxetine in their relative effects on the reuptake of serotonin and norepinephrine. They do not seem to be more efficacious than fluoxetine, but their profiles of side effects are somewhat different. There is a high variability among patients in the rate of elimination of these drugs (including fluoxetine), and failure to tolerate one drug should not preclude a trial of another SSRI. 

Society-wide epidemiological studies cannot realistically answer empirical questions about drug efficacy and adverse effects it is hard enough to do so in carefully controlled clinical trials. And besides, the empirical question has already been answered by the clinical trials. Antidepressants increase suicidality in children and youth as well as adults. But it is guaranteed that these same ACNP so-called experts will start producing flimsy and even ridiculous epidemiological studies in an attempt to undermine the far more reliable data generated in controlled clinical trials. 

Approval [of Zoloft] may, however, for the reasons enumerated above, come under attack by constituencies that do not believe the agency is as demanding as it ought to be in regard to its standard for establishing the efficacy of antidepressant drug products. 

Antidepressant drugs of various classes (tricyclics, monoamine oxidase inhibitors, SSRIs) have broad efficacy in generalized anxiety and in panic disorder, for which they are the treatments of choice (6,7). While not likely to cause benzodiazepine-like dependence or abuse, they do have a significant therapeutic latency, and the older drugs are very toxic in overdose. 

Provided antidepressant drugs are prescribed at an adequate dose and taken regularly, 60-70% of patients with moderate or severe depression should respond within 3-i weeks. Meta-analyses have shown little evidence that any particular drug or class of antidepressant is more efficacious than others, but there are four possible exceptions to this general statement. 

When they occur, depressive symptoms should be treated actively using a combination of cognitive-behavioral therapy and an antidepressant drug. Of the available antidepressants, selective serotonin reuptake inhibitors (SSRIs) have the most favourable combination of efficacy and side-effect profile for the elderly, regardless of the presence of medical co-morbidities. Although the dual agent venlafaxine has been proposed as an alternative agent for older patients who are either non-responders or partial responders to SSRIs, the frail elderly may be particularly vulnerable to its side effects (Hayes 2004). 

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