Unraveling the mysteries of schizophrenia: Insights into prefrontal cortex dysfunction and therapeutic implications

Table 1 Therapeutic implications of prefrontal cortex dysfunction in schizophrenia

Category	Interventions	Examples	Target/mechanism	Key considerations
Pharmacological	First-generation antipsychotics	Haloperidol	D2 receptor antagonism (mesolimbic pathway)	Reduces positive symptoms (hallucinations/delusions); minimal impact on PFC-mediated cognitive/negative symptoms
	Second-generation antipsychotics	Risperidone, clozapine	D2 + serotonin 2A receptor modulation	Partial PFC dopaminergic enhancement; metabolic side effects (weight gain, diabetes)
	NMDA receptor modulators	Glycine transport inhibitors	Enhances glutamatergic signaling via NMDA co-agonism	Improves PFC excitatory-inhibitory balance; potential cognitive benefits
	α7 nicotinic acetylcholine receptor agonists	Varenicline	Boosts cholinergic signaling in PFC	Modest cognitive benefits; receptor desensitization remains a challenge
	TAAR1 agonists	Ulotaront, ralmitaront	Modulates PFC dopaminergic/glutamatergic transmission	Effective for positive, negative, and cognitive symptoms without D2-related side effects
	Folate supplementation	l-methylfolate	Corrects one-carbon metabolism deficits	Reduces psychosis risk/symptoms via metabolic-epigenetic interactions
Non-pharmacological	Neuromodulation	Repetitive TMS, tDCS, magnetic seizure therapy, ECT, DBS	Targets PFC-subcortical circuits	Enhances PFC connectivity; variable cognitive/negative symptom efficacy in resistant cases
	Cognitive remediation therapy	Working memory/executive function	Neuroplasticity-driven training	Improves functional outcomes; requires sustained engagement
Emerging/experimental	Stem cell-based strategies	GABAergic interneuron transplantation	Restores PFC microcircuitry via interneuron grafting	Preclinical rescue of behavioral deficits; ethical/technical challenges remain
	Psychedelic-assisted therapy	Psilocybin	Resets PFC connectivity via neuroplasticity	Potential benefits for mood/cognition; unproven in schizophrenia populations
Combination approaches	Integrated therapies	Pharmacological agents + neuromodulation + behavioral interventions	Synergistic targeting of PFC dysfunction	Addressing heterogeneity may improve functional outcomes and quality of life

PFC: Prefrontal cortex; NMDA: N-methyl-D-aspartate; TAAR1: Trace amine-associated receptor 1; TMS: Transcranial magnetic stimulation; tDCS: Transcranial direct current stimulation; ECT: Electroconvulsive therapy; DBS: Deep brain stimulation.