Psychiatrists empirically recognize that excessive or chronic psychological stress can result in long-lasting impairments of brain functions that partly involve neuronal cell damages. Recent studies begin to elucidate the molecular pathways activated/inhibited by psychological stress. Activation of the HPA axis under psychological stress causes inflammatory oxidative stresses in the brain, in part due to elevation of cytokines. Psychological stress or neuropathological conditions (e.g., accumulation of β-amyloids) trigger ‘cellular stress responses,’ which promotes up-regulation of molecular chaperones to protect macromolecules from degradation. The unfolded protein response (UPR), the endoplasmic reticulum (ER)-specific cellular stress response, has been recently implicated in the pathophysiology of neuropsychiatric disorders and the pharmacology of certain clinically used drugs. The sigma-1 receptor is an ER protein whose ligands are shown to exert antidepressant-like and neuroprotective actions. Recent studies found that the sigma-1 receptor is a novel ligand-operated ER chaperone that regulates bioenergetics, free radical generation, oxidative stress, UPR and cytokine signaling. The sigma-1 receptor also regulates morphogenesis of neuronal cells, such as neurite outgrowth, synaptogenesis, and myelination that can be perturbed by cellular stress. The sigma-1 receptor may thus contribute to a cellular defense system that protects nervous systems against chronic psychological stress. Findings from the sigma receptor research provide an implication that not only the cell surface monoamine effectors but also intracellular molecules, especially those at the ER, may provide novel therapeutic targets of future drug developments.
Endogenous sigma-1 agonists have been shown to rapidly modulate the HPA axis through σ-1Rs  The σ-1R modulates the function of voltage-gated and ligand-gated ion channels, likely by protein–protein interactions 
“σ-1Rs are distributed throughout the brain. At the subcellular level, σ-1Rs are mainly localized at the endoplasmic reticulum (ER)/mitochondrial associated membranes (MAM) and at very low levels in post-synaptic thickenings of the neuron.
…the σ-1R interacts with numerous cellular components, e.g., different classes of ion channels, kinases, G-protein coupled receptors (GPCRs), etc. The σ-1R associates with voltage-gated ion channels, e.g., Na+, K+, and Ca2+. Interaction of the σ-1R with voltage-gated K+ and Ca2+ channels results in either inhibition or enhancement in the activities of these ion channels, whereas σ-1R interaction with voltage-gated Na+ channels results in inhibition of the channel activity. On the other hand, σ-1R enhances the activity of N-methyl-D-aspartate receptors (NMDARs) (a ligand-gated ion channel) and dopamine D1 receptors (a GPCR).
Various other research suggests that the σ1R is a novel target for schizophrenia:
“Clinical studies suggested that σ1R ligands might not possess anti-psychotic-like effects against positive symptoms but rather; they may ameliorate the negative symptoms that are mainly related to NMDAR dysfunction. Interestingly, the severity of the negative symptoms of schizophrenic patients is correlated with alterations in the plasma levels of neurosteroids, the putative ligands of this ligand-operated chaperone/receptor. Neurosteroids produce multiple effects on the nervous system, making it difficult to dissect out the processes mediated by σ1R. Nevertheless, pregnenolone levels are altered in post-mortem brains obtained from schizophrenia patients and adjunct treatment with pregnenolone diminishes their negative symptoms. Collectively, these findings suggest that σ1R ligands may be useful in ameliorating specific symptoms of schizophrenia.
The potential anti-psychotic activity of σ1R ligands is believed to result from their antagonistic activity, although our data indicate that the term agonist or antagonist is not clear when considering the control of NMDAR hypofunction. The selective σ1R antagonist S1RA displayed the highest activity in this paradigm and its effect was counterbalanced by the agonist PRE084. However, several other σ1R ligands behaved as partial agonists that reduced the activity of S1RA in this context, such as NE100 and BD1063. The mixed agonist-antagonist activity of these compounds may also account for the complex σ1R pharmacology, which is further complicated by the neurosteroids that show multiple activities outside of this system.” 
… σ-1R activation leads to an increased interaction between GluN2 subunits and σ-1Rs and mediates trafficking of NMDARs to the cell surface. These results suggest that σ-1R may play an important role in NMDAR-mediated functions, such as learning and memory. It also opens new avenues for additional studies into a multitude of pathological conditions in which NMDARs are involved, including schizophrenia, dementia, and stroke.” 
Substances which function as sigma-1 agonists/antagonists include:
“…there are reports showing a reduction of sigma-1 receptors in the brains of schizophrenic patients postmortem, and the typical and widely used antipsychotic haloperidol has a very high affinity for sigma-1 receptors. Interestingly, it is also reported that sigma-1 receptors are engaged in modulating NMDA-type glutamate receptors, which might be involved in the pathophysiology of schizophrenia.
Clinical trials with rimcazole, BMY 14802, eliprodil (SL-82.0715) and panamesine (EMD57445) have been conducted. Unfortunately, most of these ligands show poor efficacy for the treatment of schizophrenia, and for acute symptoms their effects can even be negative. However, an open label study for eliprodil, performed with chronic schizophrenic patients with predominantly negative symptoms, improved the negative symptoms as assessed by the positive and negative syndrome scale. Panamesine improved both positive and negative symptoms, but as the metabolite of panamesine was found to have potent antidopaminergic properties which might explain these improving effects, this information must be taken with caution.
The prominence of cognitive impairments as core symptoms of schizophrenia has recently been reconsidered. A number of basic research studies have demonstrated the role of sigma-1 receptors in schizophrenic cognitive impairments. PCP is known to induce negative symptoms and cognitive impairments in healthy individuals, and is therefore used in animal models of schizophrenia. We reported that repeated administration of PCP caused the reduction of sigma-1 receptors in the frontal cortex and the hippocampus in the mouse brain, consistent with a previous report on postmortem brain samples from schizophrenia patients. The PCP-induced cognitive impairments could be improved by subsequent subchronic administration of fluvoxamine but not paroxetine or sertraline. In addition, the selective sigma-1 agonist SA4503 or neurosteroid dehydroepiandrosterone-sulfate (DHEA-S) improved PCP-induced cognitive deficits in mice. These effects were antagonized by coadministration of the selective sigma-1 receptor antagonist NE-100, suggesting that sigma-1 receptor agonism of these drugs might be involved in the mechanism of action. These results indicate that sigma-1 receptor agonists would be potential therapeutic drugs for the treatment of cognitive impairments in schizophrenia.
Adjunctive medication of fluvoxamine, a sigma-1 receptor agonist, has been reported to improve primary negative symptoms in chronic schizophrenia patients who had been treated with antipsychotics. Furthermore, Iyo and colleagues reported a case that demonstrated the efficacy of 50 mg/day-fluvoxamine, but not 20 mg/day-paroxetine, on cognitive deficits in a schizophrenic patient treated with risperidone (no affinity at sigma-1 receptors). Therefore, there is need of a further double-blind, placebo-controlled study of the effects of adjunctive fluvoxamine on cognitive impairments in patients with schizophrenia.
There are a few reports indicating that polymorphisms of the sigma-1 receptor gene (SIGMAR1) are associated with schizophrenia. Two functional polymorphisms of SIGMAR1, GC-241-240-TT and Gln2Pro, were identified and reported to have a significant association with schizophrenia. Subsequent studies failed to confirm this, but a study by Takizawa and colleagues using 52-channel near-infrared spectroscopy showed a significant association between the prefrontal hemodynamic response during a verbal fluency task and the Gln2Pro polymorphism of the sigma-1 receptor gene in schizophrenia patients.”
⇒ Other σ–antagonists also have been investigated as potential antipsychotic medications. 
Sigma-1 receptors may also modulate inflammatory responses :
“…sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10.”
The study concluded that σ-1R ligands may act as “systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptors” and could be “harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues”