Understanding the Role of Sigma-1 Receptors in Psychotic Depression

October 1, 2005

Selective serotonin reuptake inhibitors have been shown effective in the treatment of depression with psychosis. This efficacy appears to correlate with the SSRIs’ level of affinity at the sigma-1 receptors in the brain. What role does the sigma-1 receptor play in psychotic depression? Based on this role, are there implications for other treatments?

Psychiatric Times

October 2005

Vol. XXII

Issue 11

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).

The efficacy of SSRIs in combination with antipsychotics, especially the atypicals, in treating psychotic depression has been reported (Bonomo and Fogliani, 2000; Matthews et al., 2002; Wolfersdorf et al., 1995). Furthermore, a line of clinical studies demonstrated that the monotherapy of SSRIs, particularly fluvoxamine, is effective in treating psychotic depression. Gatti et al. (1996) reported that, of the 57 participants with psychotic depression, 84.2% recovered after a six-week treatment of fluvoxamine in an open trial. They found improvements of rating scores in both the Hamilton Rating Scale for Depression (HAM-D) and the Dimensions of Delusional Experience rating scale (DDERS).

Another study also showed the efficacy of fluvoxamine (300 mg/day) in the maintenance therapy of psychotic depression (Zanardi et al., 1997). The efficacy of fluvoxamine in psychotic depression has also been demonstrated in a double-blind controlled study (Zanardi et al., 2000). The clinical efficacy of venlafaxine (Effexor), a serotonin norepinephrine reuptake blocker, was also tested in that study, however, fluvoxamine seemed to be more promising. Further, another study showed a lower efficacy of sertraline (Zoloft) in the treatment of psychotic depression (Simpson et al., 2003), suggesting that each SSRI might have a different spectrum of effectiveness in the treatment of psychotic depression, and that the mechanism of their actions may involve other neuronal system(s) in addition to the serotonergic system. Based on these findings, Stahl (2005) very recently proposed that σ-1 receptors might be involved in pathophysiology of psychotic depression and that the action of SSRIs, especially those of fluvoxamine, may be related to their high affinities for σ-1 receptors.

Pathophysiology

Certain studies have demonstrated the possible link of psychotic depression to dysregulation of neurotransmitters, such as dopamine and serotonin; abnormality of brain lipid ganglioside; or hyperactivation of the neuroendocrine system (Hamner, 1998; Meyers et al., 1999). In elderly patients with psychotic depression, lower activities of dopamine-β-dehydrogenase have been reported (Meyers et al., 1999).

Certain studies have suggested that the abnormality of cortisol responses to the dexamethasone suppression test is more prevalent in psychotic depression than in nonpsychotic depression (Nelson and Davis, 1997; Schatzberg et al., 1984). Although it was hypothesized that psychotic symptoms in depression could be due to increased dopamine activity secondary to hypothalamic-pituitary-adrenal (HPA) axis overactivity, some studies failed to replicate the direct link between dopaminergic dysfunction and HPA axis in psychotic depression (Duval et al., 2000; Lykouras et al., 2000). However, the fact that psychotic depression frequently appears in patients with neuroendocrine diseases such as Cushing's syndrome supports the involvement of the abnormalities of the endocrine system in psychotic depression (Chu et al., 2001). The rapid and potent efficacy of mifepristone for psychotic depression further strengthens this hypothesis (Belanoff et al., 2001; Simpson et al., 2005).

Sigma-1 Receptors

The σ receptor was originally proposed as a subtype of opioid receptors (σ opioid receptors) and was suggested to contribute to delusion and psychosis induced by benzomorphans such as SKF-10047 and pentazocine (Martin et al., 1976). However, later studies confirmed that σ receptors are nonopioid receptors, and they are now called σ receptors instead of σ opioid receptors to distinguish the protein from opioid receptors (Quirion et al., 1992; Su, 1982).

Sigma receptors consist of at least two subtypes, σ-1 and -2 receptors (Bowen et al., 1989; Kitaichi et al., 2000). Sigma-1 receptors have been cloned (Hanner et al., 1996), and their biological and physiological roles have been more intensively examined; σ-2 receptors have not. The σ-1 receptor gene is located on human chromosome 9, band p13, and it encodes 25 kDa membrane proteins that have no homology to any mammalian protein (Hanner et al., 1996; Prasad et al., 1998). Sigma-1 receptors are intracellular receptors mainly localized on the endoplasmic reticulum, and they dynamically translocate inside cells (Hayashi and Su, 2003a, 2003b). Sigma-1 receptors are expressed in specific regions of the brain such as layers of the cortex, hippocampus, hypothalamic nuclei, substantia nigra and Purkinje cells in the cerebellum (Heroux et al., 1992; Kitaichi et al., 2000). Although the exact molecular action of σ-1 receptors is still unclear, a number of studies have demonstrated that they play a role as a modulator of ion channels (K+ channels; N-methyl-D-aspartate receptors [NMDA]; inositol 1,3,5 trisphosphate receptors) (Hayashi and Su, 2001; Hayashi et al., 2000; Monnet et al., 1992; Wilke et al, 1999). Studies also suggest that σ-1 receptors regulate lipid transport/metabolism, neuritogenesis, cellular differentiation and myelination in the brain (Hayashi and Su, 2004b, 2003b).

Diverse classes of psychotropic drugs bind to σ-1 receptors (Table). Among antipsychotics, haloperidol (Haldol) has the highest affinity for the σ-1 receptors (Takebayashi et al., 2004). Selective serotonin reuptake inhibitors also have high affinities for σ-1 receptors, while TCAs have less (Narita et al., 1996; Takebayashi et al., 2004). In early studies in the 1980s and 1990s, it was hard to characterize an agonist-antagonist fashion of σ-1 ligands. Recent in vitro and animal studies, however, indicate that haloperidol is a potent σ-1 antagonist, whereas antidepressants that possess affinities for σ-1 receptors are agonists of the receptor (Table).

Steroid hormones are proposed as endogenous ligands of σ-1 receptors (Su, 1991; Su et al., 1988). Particularly, progesterone has a moderate affinity close to its physiological concentration (Su et al., 1988). These hormones are synthesized de novo in the brain (termed neurosteroids) and regulate activities of NMDA receptors, γ-aminobutyric acid (A) receptor-coupled channels and σ-1 receptors (Baulieu et al., 2001). Brain levels of neurosteroids are known to change by aging, emotion and certain pathophysiological states (Baulieu et al., 2001). Studies have demonstrated the importance of neurosteroids in learning and memory, depression, and negative symptoms of schizophrenia (Baulieu et al., 2001; Strous et al., 2003; van Broekhoven and Verkes, 2003).

In animal studies, σ-1 receptor antagonists show antipsychotic effects. Although some σ-1 antagonists were shown to inhibit apomorphine- or amphetamine-induced behavioral alterations, some studies demonstrated that selective σ-1 receptor antagonists more specifically inhibit the phencyclidine-induced behaviors (Hayashi and Su, 2004a; Okuyama and Nakazato, 1996). Sigma-1 receptor antagonists rimcazole and BMY-14802 have been tested in clinical trials of acute psychotic symptoms of schizophrenia; however, apparent antipsychotic actions of these compounds were not confirmed (Borison et al., 1991; Gewirtz et al., 1994). Recently synthesized σ-1 ligands SL82.0715 and EMD 57445 (panamesine) were shown to improve negative symptoms in open clinical trials (Frieboes et al., 1997; Modell et al., 1996; Muller et al., 1999).

Although certain σ-1 receptor ligands show antipsychotic actions, the roles of σ-1 receptors in memory, cognition and depression have been examined more extensively. A number of animal studies demonstrated that σ-1 ligands, especially agonists, have potent anti-amnesic actions and that the cognition-improving action of neurosteroids is mediated via σ-1 receptors (Maurice and Lockhart, 1997; Maurice et al., 2001). Sigma-1 agonists also exert antidepressant-like actions in the forced swimming test faster than TCAs (Bermack and Debonnel, 2005). Only one σ-1 receptor agonist, JO-1784 (igmesine), has been tested in a clinical trial. It significantly improved depression in an open trial, but the effect was not confirmed in a Phase II trial (Pande et al., 1998).

Receptor Affinity

Fluvoxamine, showing the utmost potent effectiveness in the treatment of psychotic depression, has the highest affinity for σ-1 receptors (Ki=36 nM) among SSRIs (Narita et al., 1996). Indeed, the efficacy of SSRIs in psychotic depression appears to correlate better with their affinities for σ-1 receptors than with those for serotonin transporters (Hirano et al., 2005; Narita et al., 1996; Zanardi et al., 1996). In an in vitro study, chronic fluvoxamine was shown to cause an upregulation of σ-1 receptors and to potentiate the neuritogenesis in a σ-1 receptor-dependent, but serotonin-independent, manner (Takebayashi et al., 2002). Studies have also demonstrated that chronic fluvoxamine increases--in a serotonin-independent manner--neurosteroid allopregnanolone in rat brains and in the cerebrospinal fluid of patients with depression (Griffin and Mellon, 1999; Uzunova et al., 1998). One study demonstrated a statistically significant correlation between symptomatology improvement and the increase in allopregnanolone after fluoxetine (Prozac) or fluvoxamine treatment (Uzunova et al., 1998).

These findings clearly indicate that some SSRIs possess other action site(s) in addition to being the serotonin transporter blocker, and they suggest that neurosteroids could potentially mediate the unique serotonin-independent action of SSRIs. Sigma-1 receptors are known to bind neurosteroids and were proposed to link the central nervous system to the endocrine system (Su, 1991). Furthermore, it was demonstrated that selective σ-1 receptor ligands potently stimulate adrenocorticotropic hormone release after central or peripheral administrations in rats (Iyengar et al., 1990). Therefore, it is possible that one of the action sites of fluvoxamine may involve σ-1 receptors that regulate the neuroendocrine system in the brain. Investigation is warranted for whether fluvoxamine specifically affects the dysfunction of the HPA axis in psychotic depression and whether σ-1 receptors play a role in this action of fluvoxamine.

Conclusion

The possible involvement of σ-1 receptors in the unique action of fluvoxamine in psychotic depression has been recently proposed (Stahl, 2005). Although a number of preclinical and clinical studies are needed to confirm this hypothesis, the hypothesis may shed light on the uniqueness of the pharmacological actions of SSRIs and may thus provide a potential algorithmic approach to the treatment of psychotic depression. Further, the link of σ-1 receptors to psychotic depression may suggest the potential involvement of neurosteroids in pathogenesis of this psychiatric disorder.

Dr. Hayashi is a staff scientist at the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.

Dr. Su is chief of the cellular pathobiology unit at NIH's NIDA.

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