Neuropharmacology of Antipsychotic Treatments in Schizophrenia

Schizophrenia is characterised by positive, negative and cognitive symptoms arising from dysregulated neurotransmitter systems. Traditional antipsychotic drugs act primarily through dopamine D2 receptor antagonism, effectively reducing hallucinations and delusions but often causing extrapyramidal side effects and providing limited relief for cognitive and negative symptoms. Atypical agents incorporate serotonin 5-HT2A receptor antagonism alongside D2 blockade, improving tolerability and addressing affective disturbances with modest cognitive benefits. Recent neuropharmacological research has expanded targets to include glutamatergic modulation, notably through metabotropic glutamate receptors, and lipid-signalling pathways such as sphingomyelinase activity. Investigations into intracellular cascades—including cAMP-PKA, AKT-GSK3β and CREB signalling—have shed light on synaptic plasticity and neuronal survival mechanisms that underpin both disease progression and therapeutic response. Biomarker-driven strategies, utilising neuroimaging, genetic profiling and peripheral assays, are guiding personalised treatments and the repurposing of existing medicines to mitigate oxidative stress and enhance neuroprotection. Despite these advances, treatment resistance and persistent functional deficits continue to pose significant clinical challenges, underscoring the need for multi-target pharmacotherapies that integrate neurotransmitter modulation with intracellular network regulation.

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Neuropharmacology of Antipsychotic Treatments in Schizophrenia publication trend

The graph below shows the total number of articles in neuropharmacology of antipsychotic treatments in schizophrenia across all publications each year (not limited to Nature Index journals).

Technical terms

Dopamine D2 receptor: A G protein-coupled receptor that mediates dopaminergic signalling; blockade alleviates positive psychotic symptoms.

Serotonin 5-HT2A receptor: A neurotransmitter receptor implicated in mood regulation and psychosis; antagonism contributes to the profile of atypical antipsychotics.

Metabotropic glutamate receptor 2 (mGluR2): A receptor that modulates glutamate release; positive allosteric modulation can reduce excitotoxicity and synaptic overactivity.

Allosteric modulator: A compound that binds to a site distinct from the neurotransmitter active site on a receptor, altering its functional response.

Oxidative stress marker: A biomolecule indicating an imbalance between reactive oxygen species production and antioxidant defences, often linked to cellular damage.

Extrapyramidal side effects: Movement disorders such as dystonia, akathisia and parkinsonism, commonly arising from dopamine receptor blockade.

Sphingomyelinase: An enzyme involved in sphingolipid metabolism; abnormal activity may affect membrane composition and neuronal signalling in schizophrenia.

References

1. Acid sphingomyelinase activity suggests a new antipsychotic pharmaco-treatment strategy for schizophrenia. Molecular Psychiatry (2025).
2. Drug Repurposing of Metformin for the Treatment of Haloperidol-Related Behavior Disorders and Oxidative Stress: A Preliminary Study. Pharmaceutics (2024).
3. Neurotoxic/Neuroprotective Effects of Clozapine and the Positive Allosteric Modulator of mGluR2 JNJ-46356479 in Human Neuroblastoma Cell Cultures. International Journal of Molecular Sciences (2023).
4. Assessing NH300094, a novel dopamine and serotonin receptor modulator with cognitive enhancement property for treating schizophrenia. Frontiers in Pharmacology (2024).
5. cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia. Frontiers in Molecular Neuroscience (2018).
6. AKT/GSK3 signaling pathway and schizophrenia. Frontiers in Molecular Neuroscience (2012).
7. Unique Effects of Acute Aripiprazole Treatment on the Dopamine D2 Receptor Downstream cAMP-PKA and Akt-GSK3β Signalling Pathways in Rats. PLOS ONE (2015).