Buspirone The partial 5-HT1A receptor agonist (full agonist at 5-HT1A autoreceptors and partial agonist at postsynaptic 5-HT1A receptors) buspirone, which is used principally in generalized anxiety disorder, has also been shown to produce marked clinical improvement when used as an augmenting agent in depressed patients who are initially unresponsive to the SSRIs such as fluoxetine, paroxetine, or citalopram (open trial, Dimitriou and Dimitriou 1998; see review of Shayegan and Stahl 2000). Results from a randomized, double-blind, placebo-controlled study showed that severely depressed patients had a better response when buspirone (compared with placebo) was added to their fluoxetine or citalopram treatment (Appelberg et al 2001). However, another double-blind, placebo-controlled trial (Landen et al 1998) failed to demonstrate any difference in the extra efficacy resulting from the addition of buspirone or placebo to their SSRI therapy. An unusually high placebo response may explain this result. The effect of buspirone is thought to be via enhancement of the activation of postsynaptic 5-HT1A receptors in the presence of 5-HT1A autoreceptors, which have already been desensitized by the antidepressant. Estrogen Vulnerability to mood disorders is increased during perimenopause and postmenopause (Soares and Cohen 2001). Because fluctuating estrogen levels accompany the perimenopausal transition, estrogen replacement therapy (ERT) has been suggested as a possibly effective adjunctive treatment for mood disorders occurring during peri- menopause (Soares and Cohen 2001). Discontinuation of hormone therapy appears to be associated with the rapid recurrence of depression in some women with a history of depression (Stewart et al 2004). Small studies have shown that in depressed women who have minimal response to a SSRI, ERT may augment response (open trial, Rasgon et al 2002; randomized comparative study, Westlund and Parry 2003). Fluoxetine combined with ERT in a recent randomized, open-label, parallel trial was effective in the treatment of menopausal depressed women (Liu et al 2004). Inhibitors of steroid synthesis Young et al (2004) have reported that the corticosteroid receptor antagonist mifepristone can exert an antidepressive effect. Following these preliminary results, Jahn et al (2004) have shown in a double-blind, placebo-controlled trial that Augmentation strategies in depression metyrapone, an inhibitor of cortisol synthesis and associated with nefazodone or fluvoxamine, gives a better outcome than the antidepressants alone, with an earlier onset of action and a sustained effect in patients with major depression. Methylphenidate The antidepressant response to monotherapy is often inadequate in the elderly and especially in patients with extensive psychomotor slowing. The addition of a stimulant action can be particularly beneficial in this fragile population by accelerating and intensifying the response. The indirect dopaminergic agonist and psychostimulant methylphenidate (for review, see Leonard 2004) combined with MAOIs still represents an alternative after other options have failed (see review of Feinberg 2004; case study, Shelton Clauson 2004). Methylphenidate has also been shown by Lavretsky et al (2003) in an open-label trial to accelerate the response to the SSRI citalopram in this population. Atypical antipsychotics In subjects with recurrent major depression (non-bipolar) without psychotic features and who are unresponsive to conventional antidepressant therapy, it has been demonstrated that the efficacy of olanzapine plus fluoxetine is superior for treating their resistant depression than either agent alone (double-blind, comparative study, Shelton et al 2001; retrospective chart review, Barbee et al 2004). Similar results were obtained with ziprasidone in association with the SSRIs, fluoxetine, paroxetine, citalopram, or sertraline (Barbee et al 2004; open trial, Papakostas et al 2004). An augmentation therapy of milnacipran with risperidone has been found to considerably improve recovery in patients with depression who only partially responded to milnacipran alone, and also in some treatment-refractory patients (case series, Tani et al 2004). In addition, the response to the addition of risperidone was very rapid (less than 5 days), in agreement with previous reports (case series, Ostroff and Nelson 1999; Shelton et al 2001). This augmentation effect is thought to result in part from the blockade of 5-HT2A receptors and may be explained by the results of animal studies. The combination of olanzapine and other antipsychotics with the SSRI fluoxetine produced robust, sustained increases of extracellular levels of dopamine and noradrenaline in rat prefrontal cortex and hypothalamus as measured by microdialysis, greater than with either drug alone (Zhang et al 2000; Koch et al 2004). Blocking simultaneously the 5-HT transporter and 5-HT2A receptors Neuropsychiatric Disease and Treatment 2005:1(4) 305