Moret thought to act on various neurotransmitter systems at the level of signal transduction mechanisms, leading to neuroplastic changes associated with stabilization of mood (see the review of Lenox and Hahn 2000). Lithium also plays a correcting role in the expression of some genes involved in the pathophysiology of bipolar disorder. Animal studies have shown that potentiation of antidepressant treatment by lithium may also be mediated through enhanced 5-HT neurotransmission (Haddjeri et al 2000). Neuroendocrine studies in humans also demonstrate that lithium augments the function of the serotonergic system (Bauer et al 2003). Although mood stabilizers are usually prescribed with antidepressants to avoid switching to mania in bipolar patients, some are used as augmentation agents in depression. Anticonvulsants, such as valproate, carbamazepine (see review of Dietrich and Emrich 1998), and lamotrigine (randomized, double-blind, placebo- controlled study, Barbosa et al 2003), combined with classical antidepressants appear to be well tolerated and effective in treatment-resistant depressed patients. Recently, venlafaxine combined with carbamazepine has proved to be effective in the treatment of depressed patients not responding to monotherapy with venlafaxine (open study, Ciusani et al 2004). Thyroid hormone The prevalence of thyroid dysfunction in women is high. Hypothyroidism is associated with depression, and correcting this endocrine dysfunction is beneficial when treating an associated depression (Larisch et al 2004). The addition of triiodothyronine (T3) to ongoing TCA treatment is an effective augmentation strategy in patients with refractory depression in a randomized, double-blind, placebo-controlled study (Joffe et al 1993) and in accelerating clinical response to TCAs in patients with nonrefractory depression, particularly women (meta- analysis, Altshuler et al 2001). For example, depressed patients unresponsive to the SSRI fluoxetine, responded to fluoxetine associated with T3 (open-label treatment, Agid and Lerer 2003). This augmentation effect of T3 on the antidepressant action (at least of the tricyclics) may be explained by the increased 5-HT levels in rat frontal cortex after chronic administration of T3, measured by microdialysis (Gur et al 1999). Chronic administration of clomipramine also resulted in increased levels of 5-HT in the frontal cortex. In rats treated with clomipramine and T3, cortical levels of 5-HT were higher than those of rats receiving only one treatment (Gur et al 1999). 5-HT1A receptor augmenting agents Clinical studies and genetic research in animals and humans have suggested that the activity of 5-HT1A receptors may be important in the pathophysiology of depression (Celada et al 2004; Neumeister et al 2004). The somatodendritic 5-HT1A autoreceptors located in the raphe nuclei are stimulated by increased serotonin concentrations that result from the inhibition of serotonin reuptake by antidepressants such as SSRIs given acutely. This results, through a negative feedback mechanism, in an inhibition of the firing activity of midbrain 5-HT neurones and the release of 5-HT by terminals in the forebrain. This leads to an attenuation of the increase in synaptic 5-HT produced by antidepressants in forebrain. The delayed onset of action of serotonergic antidepressants is considered to be, at least in part, the result of a reduction in the function, or desensitization, of 5-HT1A somatodendritic autoreceptors, which occurs following chronic treatment with these drugs. This delay of onset of action is similar to the time necessary for the desensitization of these 5-HT1A autoreceptors by the SSRIs to occur (Blier and de Montigny 1994). 5-HT1A receptor antagonists As explained above, only when the 5-HT1A autoreceptors are desensitized (after several weeks) is the full potential of serotonin reuptake inhibition obtained. The 5-HT1A receptor antagonists can remove this feedback and have been proposed as a means of accelerating and possibly potentiating antidepressant action (Pérez et al 2001; Serrats et al 2004). The β-adrenergic/5-HT1A receptor antagonist, pindolol, which binds to the 5-HT1A receptors in the human brain (Martinez et al 2001; Rabiner et al 2001), accelerates and may enhance the antidepressant effect of SSRIs (meta- analysis of Ballesteros and Callado 2004; review of Isaac 2004), such as fluoxetine (see review of Artigas et al 2001; controlled trial, Pérez et al 2001), or in paroxetine-refractory patients (placebo-controlled study, Sokolski et al 2004). Not all authors, however, have been able to replicate these findings (double-blind, placebo-controlled trial, Berman et al 1997). Preclinical studies that have examined the desensitization hypothesis and clinical studies that utilized pindolol as a test of this hypothesis in depressed patients have been reviewed by Kinney et al (2000). 304 Neuropsychiatric Disease and Treatment 2005:1(4)