Antipsychotics in bipolar depression: in reply

Krishnadas & Livingston (2010) make the case for caution when interpreting the results of our metaanalysis showing the efficacy of some secondgeneration antipsychotics in bipolar depression, as well as their apparent rapid onset of action While we generally agree that in the case of olanzapine the only items that significantly separated from placebo were those assessing sleep, inner tension and appetite Starting with olanzapine, it should be noted that if instead of MMRM analysis Moreover, the effect size, while modest, is in the same range as for many approved drugs, such as antidepressants in unipolar depression. In the case of quetiapine, Krishnadas & Livingston (2010) acknowledge that the studies show unequivocal antidepressant effects. We do not believe that the rapid onset of action of olanzapine and quetiapine can only be ascribed to their sedative properties ; in fact, rapid onset of action was also seen with two non-sedative antipsychotics, aripiprazole and ziprasidone, which failed to sustain antidepressant effects over 8 wk In our opinion, the rapid onset of antidepressant action that can be seen with all modern antipsychotics that have been tested in bipolar depression, and not with other drugs such as lithium, lamotrigine or antidepressants, is likely to be related to increased serotonin-receptormediated dopamine outflow combined with a moderate D 2 antagonism. Other mechanisms, such as H 1 antagonism (olanzapine and quetiapine), which may account for the effects on sleep, anxiety and appetite, or noradrenaline transporter inhibition (quetiapine/ norquetiapine and, to some extent, ziprasidone) might contribute but as they are not shared by all the compounds, would not explain why all the tested modern antipsychotics act so quickly.