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?
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.
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).
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).
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.
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.
Anton RF, Sexauer JD (1983), Efficacy of amoxapine in psychotic depression. Am J Psychiatry 140(10):1344-1347.
Baulieu EE, Robel P, Schumacher M (2001), Neurosteroids: beginning of the story. Int Rev Neurobiol 46:1-32.
Belanoff JK, Flores BH, Kalezhan M et al. (2001), Rapid reversal of psychotic depression using mifepristone. J Clin Psychopharmacol 21(5):516-521.
Bermack JE, Debonnel G (2005), The role of sigma receptors in depression. J Pharmacol Sci 97(3):317-336.
Bonomo V, Fogliani AM (2000), Citalopram and haloperidol for psychotic depression. Am J Psychiatry 157(10):1706-1707.
Borison RL, Diamond BI, Dren AT (1991), Does sigma receptor antagonism predict clinical antipsychotic efficacy? Psychopharmacol Bull 27(2):103-106.
Bowen WD, Hellewell SB, McGarry KA (1989), Evidence for a multi-site model of the rat brain sigma receptor. Eur J Pharmacol 163(2-3):309-318.
Chu JW, Matthias DF, Belanoff J et al. (2001), Successful long-term treatment of refractory Cushing's disease with high-dose mifepristone (RU 486). J Clin Endocrinol Metab 86(8):3568-3573.
Dassa D, Kaladjian A, Azorin JM, Giudicelli S (1993), Clozapine in the treatment of psychotic refractory depression. Br J Psychiatry 163:822-824.
Duval F, Mokrani MC, Crocq MA et al. (2000), Dopaminergic function and the cortisol response to dexamethasone in psychotic depression. Prog Neuropsychopharmacol Biol Psychiatry 24(2):207-225.
Flint AJ, Rifat SL (1998), The treatment of psychotic depression in later life: a comparison of pharmacotherapy and ECT. Int J Geriatr Psychiatry 13(1):23-28.
Frieboes RM, Murck H, Wiedemann K et al. (1997), Open clinical trial on the sigma ligand panamesine in patients with schizophrenia. Psychopharmacology (Berl) 132(1):82-88.
Gatti F, Bellini L, Gasperini M et al. (1996), Fluvoxamine alone in the treatment of delusional depression. Am J Psychiatry 153(3):414-416.
Gewirtz GR, Gorman JM, Volavka J et al. (1994), BMY 14802, a sigma receptor ligand for the treatment of schizophrenia. Neuropsychopharmacology 10(1):37-40.
Griffin LD, Mellon SH (1999), Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci U S A 96(23):13512-13517.
Hamner MB (1998), Recurrent psychotic depression associated with GM2 gangliosidosis. Psychosomatics 39(5):446-448.
Hamner MB, Gold PB (1998), Plasma dopamine beta-hydroxylase activity in psychotic and non-psychotic post-traumatic stress disorder. Psychiatry Res 77(3):175-181.
Hanner M, Moebius FF, Flandorfer A et al. (1996), Purification, molecular cloning, and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci U S A 93(15):8072-8077.
Hayashi T, Maurice T, Su TP (2000), Ca(2+) signaling via sigma(1)-receptors: novel regulatory mechanism affecting intracellular Ca(2+) concentration. J Pharmacol Exp Ther 293(3):788-798.
Hayashi T, Su TP (2001), Regulating ankyrin dynamics: roles of sigma-1 receptors. Proc Natl Acad Sci U S A 98(2):491-496.
Hayashi T, Su TP (2003a), Intracellular dynamics of sigma-1 receptors (sigma(1)- binding sites) in NG108-15 cells. J Pharmacol Exp Ther 306(2):726-733.
Hayashi T, Su TP (2003b), Sigma-1 receptors (sigma(1)-binding sites) form raft-like microdomains and target lipid droplets on the endoplasmic reticulum: roles in endoplasmic reticulum lipid compartmentalization and export. Pharmacol Exp Ther 306(2):718-725.
Hayashi T, Su TP (2004a), Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. CNS Drugs 18(5):269-284.
Hayashi T, Su TP (2004b), Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation. Proc Natl Acad Sci U S A 101(41):14949-14954.
Heroux JA, Tam SW, De Souza EB (1992), Autoradiographic identification and characterization of sigma receptors in guinea pig brain using [3H]1(cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl) piperidine ([3H]DuP 734), a novel sigma receptor ligand. Brain Res 598(1-2):76-86.
Hirano K, Kimura R, Sugimoto Y et al. (2005), Relationship between brain serotonin transporter binding, plasma concentration and behavioural effect of selective serotonin reuptake inhibitors. Br J Pharmacol 144(5):695-702.
Hirschfeld RM (1999), Efficacy of SSRIs and newer antidepressants in severe depression: comparison with TCAs. J Clin Psychiatry 60(5):326-335.
Iwanami A, Oyamada S, Shirayama Y, Kamijima K (1999), Algorithms for the pharmacotherapy psychotic depression. Psychiatry Clin Neurosci 53(suppl):S45-S48.
Iyengar S, Mick S, Dilworth V et al. (1990), Sigma receptors modulate the hypothalamic-pituitary-adrenal (HPA) axis centrally: evidence for a functional interaction with NMDA receptors, in vivo. Neuropharmacology 29(3):299-303.
Jeste DV, Heaton SC, Paulsen JS et al. (1996), Clinical and neuropsychological comparison of psychotic depression with nonpsychotic depression and schizophrenia. Am J Psychiatry 153(4):490-496 [see comment].
Johnson J, Horwath E, Weissman MM (1991), The validity of major depression with psychotic features based on a community study. Arch Gen Psychiatry 48(12):1075-1081.
Keck PE Jr, McElroy SL, Strakowski SM, Soutullo CA (2000), Antipsychotics in the treatment of mood disorders and risk of tardive dyskinesia. J Clin Psychiatry 61(suppl 4):33-38.
Kitaichi K, Chabot JG, Moebius FF et al. (2000), Expression of the purported sigma(1) (sigma(1)) receptor in the mammalian brain and its possible relevance in deficits induced by antagonism of the NMDA receptor complex as revealed using an antisense strategy. J Chem Neuroanat 20(3-4):375-387.
Lykouras L, Markianos M, Hatzimanolis J et al. (2000), Prolactin secretion in response to haloperidol challenge in delusional (psychotic) and non-delusional depression. Eur Psychiatry 15(8):480-482.
Martin WR, Eades CG, Thompson JA et al. (1976), The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197(3):517-532.
Masan PS (2004), Atypical antipsychotics in the treatment of affective symptoms: a review. Ann Clin Psychiatry 16(1):3-13.
Matthews JD, Bottonari KA, Polania LM et al. (2002), An open study of olanzapine and fluoxetine for psychotic major depressive disorder: interim analyses. J Clin Psychiatry 63(12):1164-1170.
Maurice T, Lockhart BP (1997), Neuroprotective and anti-amnesic potentials of sigma (sigma) receptor ligands. Prog Neuropsychopharmacol Biol Psychiatry 21(1):69-102.
Maurice T, Urani A, Phan VL, Romieu P (2001), The interaction between neuroactive steroids and the sigma1 receptor function: behavioral consequences and therapeutic opportunities. Brain Res Brain Res Rev 37(1-3):116-132.
Meyers BS, Alexopoulos GS, Kakuma T et al. (1999), Decreased dopamine beta-hydroxylase activity in unipolar geriatric delusional depression. Biol Psychiatry 45(4):448-452.
Miodownik C, Lerner V (2000), Risperidone in the treatment of psychotic depression. Clin Neuropharmacol 23(6):335-337.
Modell S, Naber D, Holzbach R (1996), Efficacy and safety of an opiate sigma-receptor antagonist (SL 82.0715) in schizophrenic patients with negative symptoms: an open dose-range study. Pharmacopsychiatry 29(2):63-66.
Monnet FP, Debonnel G, de Montigny C (1992), In vivo electrophysiological evidence for a selective modulation of N-methyl-D-aspartate-induced neuronal activation in rat CA3 dorsal hippocampus by sigma ligands. J Pharmacol Exp Ther 261(1):123-130.
Muller MJ, Grunder G, Wetzel H et al. (1999), Antipsychotic effects and tolerability of the sigma ligand EMD 57445 (panamesine) and its metabolites in acute schizophrenia: an open clinical trial. Psychiatry Res 89(3):275-280.
Narita N, Hashimoto K, Tomitaka S, Minabe Y (1996), Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain. Eur J Pharmacol 307(1):117-119.
Nelson EB, Rielage E, Welge JA, Keck PE Jr (2001), An open trial of olanzapine in the treatment of patients with psychotic depression. Ann Clin Psychiatry 13(3):147-151.
Nelson JC, Davis JM (1997), DST studies in psychotic depression: a meta-analysis. Am J Psychiatry 54(11):1497-1503.
Okuyama S, Nakazato A (1996), NE-100: a novel sigma receptor antagonist. CNS Drug Reviews 2(2):226-237.
Pande AC, Geneve J, Scherrer B et al. (1998), Igmesine, a novel sigma ligand, has antidepressant properties. No. SM 0505, p30S. Presented at the Congress of Collegium Internationale Neuro-Psychopharmacologicum. Glasgow, Scotland; July 5-10.
Prasad PD, Li HW, Fei YJ et al. (1998), Exon-intron structure, analysis of promoter region, and chromosomal localization of the human type 1 sigma receptor gene. J Neurochem 70(2):443-451.
Quirion R, Bowen WD, Itzhak Y et al. (1992), A proposal for the classification of sigma binding sites. Trends Pharmacol Sci 13(3):85-86.
Ranjan R, Meltzer HY (1996), Acute and long-term effectiveness of clozapine in treatment-resistant psychotic depression. Biol Psychiatry 40(4):253-258.
Rothschild AJ, Bates KS, Boehringer KL, Syed A (1999), Olanzapine response in psychotic depression. J Clin Psychiatry 60(2):116-118.
Schatzberg AF (2003), New approaches to managing psychotic depression. J Clin Psychiatry 64(suppl 1):19-23.
Schatzberg AF, Rothschild AJ, Bond TC, Cole JO (1984), The DST in psychotic depression: diagnostic and pathophysiologic implications. Psychopharmacol Bull 20(3):362-364.
Simpson GM, El Sheshai A, Loza N et al. (2005), An 8-week open-label trial of a 6-day course of mifepristone for the treatment of psychotic depression. J Clin Psychiatry 66(5):598-602.
Simpson GM, El Sheshai A, Rady A et al. (2003), Sertraline as monotherapy in the treatment of psychotic and nonpsychotic depression. J Clin Psychiatry 64(8):959-965.
Stahl SM (2005), Antidepressant treatment of psychotic major depression: potential role of the sigma receptor. CNS Spectr 10(4):319-323.
Strous RD, Maayan R, Lapidus R et al. (2003), Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatry 60(2):133-141.
Su TP (1982), Evidence for sigma opioid receptor: binding of [3H]SKF-10047 to etorphine-inaccessible sites in guinea-pig brain. J Pharmacol Exp Ther 223(2):284-290.
Su TP (1991), Sigma receptors. Putative links between nervous, endocrine and immune systems. Eur J Biochem 200(3):633-642.
Su TP, London ED, Jaffe JH (1988), Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Science 240(4849):219-221 [see comment].
Takebayashi M, Hayashi T, Su TP (2002), Nerve growth factor-induced neurite sprouting in PC12 cells involves sigma-1 receptors: implications for antidepressants. J Pharmacol Exp Ther 303(3):1227-1237.
Takebayashi M, Hayashi T, Su TP (2004), A perspective on the new mechanism of antidepressants: neuritogenesis through sigma-1 receptors. Pharmacopsychiatry 37(suppl 3):S208-S213.
Thakur M, Hays J, Ranga K, Krishnan R (1999), Clinical, demographic and social characteristics of psychotic depression. Psychiatry Res 86(2):99-106.
Uzunova V, Sheline Y, Davis JM et al. (1998), Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci U S A 95(6):3239-3244.
van Broekhoven F, Verkes RJ (2003), Neurosteroids in depression: a review. Psychopharmacology (Berl) 165(2):97-110.
Vythilingam M, Chen J, Bremner JD et al. (2003), Psychotic depression and mortality. Am J Psychiatry 160(3):574-576 [see comment].
Wilke RA, Lupardus PJ, Grandy DK et al. (1999), K+ channel modulation in rodent neurohypophysial nerve terminals by sigma receptors and not by dopamine receptors. J Physiol 517(pt 2):391-406.
Wolfersdorf M, Barg T, Konig F et al. (1995), Paroxetine as antidepressant in combined antidepressant-neuroleptic therapy in delusional depression: observation of clinical use. Pharmacopsychiatry 28(2):56-60.
Zanardi R, Franchini L, Gasperini M et al. (1996), Double-blind controlled trial of sertraline versus paroxetine in the treatment of delusional depression. Am J Psychiatry 153(12):1631-1633 [see comment].
Zanardi R, Franchini L, Gasperini M et al. (1997), Long-term treatment of psychotic (delusional) depression with fluvoxamine: an open pilot study. Int Clin Psychopharmacol 12(4):195-197.
Zanardi R, Franchini L, Serretti A et al. (2000), Venlafaxine versus fluvoxamine in the treatment of delusional depression: a pilot double-blind controlled study. J Clin Psychiatry 61(1):26-29 [see comment].