Cognitive impairment is a core feature of patients with neuropsychiatric diseases such as
schizophrenia and psychotic depression. The drugs currently used to treat
cognitive impairment have significant limitations, ensuring that the search for more effective
therapies remains active. Endoplasmic reticulum
protein sigma-1 receptors are unique binding sites in the brain that exert a potent effect on multiple
neurotransmitter systems. Accumulating evidence suggests that sigma-1 receptors play a role in both the pathophysiology of neuropsychiatric diseases, and the mechanistic action of some therapeutic drugs, such as the
selective serotonin reuptake inhibitors (
SSRIs),
donepezil and
neurosteroids. Among
SSRIs,
fluvoxamine, a potent
sigma-1 receptor agonist, has the highest affinity at sigma-1 receptors.
Sigma-1 receptor agonists greatly potentiate
nerve-growth factor (
NGF)-induced neurite outgrowth in PC12 cells, an effect that is antagonized by treatment with the selective
sigma-1 receptor antagonist
NE-100. Furthermore,
phencyclidine (PCP)-induced
cognitive impairment, associated with animal models of
schizophrenia is significantly improved by sub-chronic administration of
sigma-1 receptor agonists such as
fluvoxamine,
SA4503 (
cutamesine) and
donepezil. This effect is antagonized by co-administration of
NE-100. A positron emission tomography (PET) study using the specific
sigma-1 receptor ligand [
11C]SA4503 demonstrates that
fluvoxamine and
donepezil bind to sigma-1 receptors in the healthy human brain. In clinical studies, some
sigma-1 receptor agonists, including
fluvoxamine,
donepezil and
neurosteroids, improve
cognitive impairment and clinical symptoms in neuropsychiatric diseases. In this article, we review the recent findings on
sigma-1 receptor agonists as potential therapeutic drugs for the treatment of
cognitive impairment in
schizophrenia and psychotic depression.