Limitations to enhancing the speed of onset of antidepressants - are rapid action antidepressants possible?

Existing antidepressant treatments suffer from a limited efficacy and a slow onset of action. Some first-generation antidepressant drugs are still among the most effective treatments. Several neurobiological adaptive mechanisms are involved in the delayed action of antidepressants. Among these, a negative feed-back involving somatodendritic autoreceptors plays an important role in such delay. In the case of the SSRIs, the prevention of this effect with 5-HT(1A) autoreceptor antagonists enhances their effects at experimental level. Open-label and placebo-controlled trials with the mixed beta-adrenoceptor/5-HT(1A) antagonist pindolol support that this agent reduces the latency to achieve a clinical improvement when used in combination with SSRIs. Displacement studies support that this action is mediated by its interaction with 5-HT(1A) receptors. The design of clinical trials for the evaluation of fast-acting antidepressants is critical. The use of loose criteria of response may result in a poor discriminating power. Conversely, stringent clinical criteria may be more helpful in revealing the differences between treatments. The data of a double-blind, placebo-controlled trial comparing fluoxetine plus placebo and fluoxetine plus pindolol suggests that the use of sustained response (i.e., one maintained until the end of the trial) is critical for the establishment of differences between treatments. Other factors, such as a placebo lead-in phase or the frequency of visits, appear to play a minor role. Overall, these data indicate that faster antidepressant drugs can be obtained through a better knowledge of their actions in CNS. Copyright 2001 John Wiley & Sons, Ltd.