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Understanding the Role of Sigma-1 Receptors in Psychotic Depression

(PSYCHIATRIC TIMES) - Psychosis occurs in 10% to 37.1% of patients with mood disorders (Johnson et al., 1991; Thakur et al., 1999). Psychotic depression is a clinical subtype of major depressive disorder and is characterized by psychosis accompanied by greater severity of depressive symptoms that include psychomotor impairment (retardation or agitation), morbid cognition (involving guilt and a sense of deserving punishment), suicidal idea and neuropsychological impairment (Jeste et al., 1996). Psychotic depression has been shown to have poor prognosis when compared to nonpsychotic depression (i.e., higher rates of recurrence, greater incapacitation, more frequent hospitalization, longer episodes and greater mortality) (Schatzberg, 2003; Vythilingam et al., 2003). Although several reports suggest abnormalities of endocrine, dopaminergic and/or serotonergic systems in psychotic depression (Hamner and Gold, 1998; Nelson and Davis, 1997), pathophysiology of psychotic depression is still unclear.

Psychotic depression has traditionally been treated with electroconvulsive therapy and/or typical antipsychotics in conjunction with tricyclic antidepressants. More recent studies have demonstrated the efficacy of atypical antipsychotics and selective serotonin reuptake inhibitors in treating psychotic depression (Hirschfeld, 1999; Masan, 2004). Interestingly, SSRI monotherapy, especially fluvoxamine (Luvox), has been shown effective against both the psychotic and depressive symptoms of this disorder (Gatti et al., 1996; Hirschfeld, 1999; Zanardi et al., 2000). Based on these findings, it has been recently proposed that SSRIs might have multiple action sites in the brain in addition to serotonin transporters. For example, σ-1 receptors might play a role in the therapeutic action of SSRIs (Stahl, 2005). This article will introduce recently defined biological actions of σ-1 receptors and suggest a potential role of σ-1 receptors in psychotic depression.

Treating Psychotic Depression

Compared to major depression without psychosis, psychotic depression often responds poorly to treatment with TCAs alone. Thus, psychotic depression requires a pharmacological treatment that is different from that for other mood disorders (Iwanami et al., 1999). Most studies report a better response to ECT for patients with psychosis and depression (Flint and Rifat, 1998) or a combined therapy of TCAs and antipsychotics when compared to TCA monotherapy (Schatzberg, 2003). However, the combined therapy significantly increases the risk of side effects (Keck et al., 2000). After recognizing the possible efficacy of amoxapine (Anton and Sexauer, 1983), an antidepressant that blocks both dopamine D2 and 5-HT2 receptors, benefits of atypical antipsychotics have been shown in the treatment of psychotic depression (Dassa et al., 1993; Miodownik and Lerner, 2000; Nelson et al., 2001; Ranjan and Meltzer, 1996; Rothschild et al., 1999). The glucocorticoid receptor antagonist mifepristone (Mifeprex) has also been shown to rapidly improve psychotic depression (Belanoff et al., 2001; Simpson et al., 2005).

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