Psychedelics for treatment of negative symptoms and depressive symptoms in schizophrenia spectrum disorder: A narrative review
Year: 2026
Type: review
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.
Source: Schizophrenia Research
Authors: Michel Sabé, Paul Grof, Nathan B. Sackett, Sara Tai, Pamela Kryskow, Anya Bershad, Douglas Turkington, Matteo Buonarroti, Marco De Pieri, Pantelis Baniotopoulos, Mickael Eskinazi, Kerem Böge, Stefan Leucht, Federico Seragnoli, Léonice Furtado, Tatiana Aboulafia Brakha, Logos Curtis, Matthias Kirschner, Stefan Kaiser, Louise Penzenstadler, Daniele Zullino, Mikkel Højlund, Jade Gallo, Marco Solmi, Jacopo Sapienza, Marta Bosia, Joseph La Torre
Institutions: University of Geneva, University Hospital of Geneva, University of Toronto, University of Washington, University of Manchester, Vancouver Island University, University of California, Los Angeles, VA Greater Los Angeles Healthcare System, Cumbria Northumberland Tyne and Wear NHS Foundation Trust, Humboldt-Universität zu Berlin, Deutsches Zentrum für Psychische Gesundheit, Freie Universität Berlin, Charité - Universitätsmedizin Berlin, Technical University of Munich, University of Southern Denmark, Region of Southern Denmark, University of Ottawa, Ottawa Hospital, Ottawa Hospital Research Institute, Istituto Universitario di Studi Superiori di Pavia, Vita-Salute San Raffaele University, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele
Language: English
Subfield: Clinical Psychology
Field: Psychology
Domain: Social Sciences
Open Access status: hybrid
Estimated APC paid: $3,910
Funder: National Institutes of Health
OpenAlex ID: W7135185290