Sigma receptor ligands in selected affective disorders, psychoses, and addictions - a narrative review.

Sigma receptors (SRs), comprising the sigma 1 (S1R) and sigma 2 (S2R) subtypes, represent a distinct class of intracellular proteins that differ fundamentally from classical neurotransmitter receptors. S1Rs act as ligand-operated molecular chaperones primarily localized at mitochondria-associated membranes (MAM) of the endoplasmic reticulum (ER), whereas S2Rs, identified as transmembrane protein 97 (TMEM97), function as modulators of cellular homeostasis. Both subtypes are densely expressed in brain regions critical for emotional and cognitive processing, including the prefrontal cortex (PFC), hippocampus (HIP), amygdala (AMG), and basal ganglia. SRs play a pivotal role in regulating neuronal excitability, synaptic plasticity, and ER stress responses, thereby influencing oxidative stress, synaptogenesis, and neuronal survival. Moreover, their interactions with endogenous neurosteroids and the immune-endocrine system highlight their involvement in complex neuropsychiatric pathophysiology. Consequently, SRs are increasingly recognized as promising targets for pharmacological intervention. Preclinical evidence indicates that S1R agonists exert antidepressant, anxiolytic, and pro-cognitive effects, whereas S1R antagonism or genetic deletion induces behavioural phenotypes relevant to depression and schizophrenia. S2R modulation, in turn, influences psychostimulant sensitivity and emotional regulation, although its underlying mechanisms remain less well defined. Notably, the clinical efficacy of several widely used antidepressants (e.g., fluvoxamine) and antipsychotics have been increasingly attributed to their significant affinity for SRs, suggesting that SR engagement may contribute to their therapeutic profiles. This narrative review synthesizes core molecular and neurophysiological findings and critically evaluates the potential of SR-targeting compounds as next-generation pharmacological strategies for treatment-resistant depression, psychotic disorders, and addiction. Given the continuous emergence of new research, this work provides an updated overview of the current state of knowledge for both researchers and clinicians.