Psychedelics for treatment of negative symptoms and depressive symptoms in schizophrenia spectrum disorder: A narrative review

Serotonergic psychedelics, which are being explored for treatment-resistant depression, might also help with depressive and negative symptoms in schizophrenia spectrum disorders (SSDs). Schizophrenia and depression share some underlying brain disturbances, including problems with dopamine, glutamate, and neuroplasticity, as well as abnormal brain network connectivity. Depressive symptoms in SSDs may combine features of both disorders, and psychedelics could potentially recalibrate maladaptive brain networks. Preclinical studies show psychedelics increase dendritic spines and BDNF and restore reward sensitivity. Clinical evidence is limited: uncontrolled psychedelic use is linked to increased psychosis, but controlled administration may be tolerated in stable individuals. Only one early-phase trial with MDMA in schizophrenia is ongoing; no randomized trials have tested psilocybin or LSD in SSDs. The authors conclude that psychedelics are biologically plausible but unproven for these symptoms.

Study at a glance

Abstract

Serotonergic psychedelics are re-emerging as therapeutic candidates across psychiatry, particularly for treatment-resistant depression. Their rapid and sustained antidepressant effects, alongside evidence for neuroplastic, dopaminergic, and glutamatergic modulation, have prompted interest in whether they could address depressive and negative symptoms in schizophrenia spectrum disorders (SSDs). This narrative review summarizes mechanistic, preclinical, and early clinical findings relevant to psychedelic use in SSDs. Schizophrenia and major depressive disorder share disturbances in dopamine, glutamate, and neuroplasticity, and both involve large-scale network abnormalities. Schizophrenia is associated with widespread dysconnectivity, mesocortical hypodopaminergia, and striatal hyperdopaminergia linked to NMDA receptor hypofunction. Depression is characterized by fronto-limbic and default mode network hyperconnectivity, mesolimbic hypodopaminergia, and reduced cortical glutamatergic tone. Depressive symptoms within SSDs may reflect an intermediate phenotype combining depressive-like hyperconnectivity with schizophrenia-related global dysconnectivity, suggesting that psychedelics' capacity to transiently increase network flexibility and recalibrate maladaptive connectivity may be clinically relevant. Preclinical studies show increased dendritic spine density, enhanced BDNF expression, restored reward sensitivity, and modulation of network dynamics after psychedelic administration. Clinically, uncontrolled exposure appears associated with increased psychosis-related presentations, whereas limited case reports suggest controlled administration may be tolerated in carefully selected, clinically stable individuals with SSDs. To date, only one early-phase trial (MDMA in schizophrenia) is ongoing, and no randomized trials have evaluated psilocybin or LSD in SSDs. Overall, psychedelics are biologically and mechanistically plausible but remain unproven for depressive and negative symptoms in SSDs, which partially overlap. Carefully designed, safety-focused early-phase studies in clinically stable patients are therefore a prerequisite for broader clinical application.