Antipsychotic drug development in the pre-human-genome era: a full circle

The term "psychosis" refers to a spectrum of mental disorders characterized by abnormal thoughts, perceptions, and behaviors. It can manifest as mood disorders, dementia, delirium with psychotic features, substance-induced psychosis with psychotic features, brief psychotic disorder, delusional disorder, schizoaffective disorder, and schizophrenia. Among all these disorders, schizophrenia is the most common psychotic disorder, affecting 1% of the worldwide population. Psychotic symptoms in all...

Schizophrenia is a neurodevelopmental disorder whose origins are rooted in complex genetic components. Despite our burgeoning understanding, the pathophysiology of this disorder remains incompletely deciphered.
Researchers have identified genetic factors that increase susceptibility to schizophrenia, underscoring the intricate interplay between genetics and environment in disease development. At the core of schizophrenia's pathophysiology is excessive dopaminergic neurotransmission within the...

Antipsychotic drugs are classified into first-generation (typical) drugs including phenothiazines; and second-generation (atypical) drugs. Chlorpromazine hydrochloride (Thorazine), a phenothiazine derivative, broadly impacts the central, autonomic, and endocrine systems. This drug, along with typical agents like haloperidol (Haldol), primarily works by antagonizing D2 receptors, thus reducing dopaminergic neurotransmission. However, typical antipsychotics can cause side effects such as sedation...

Antipsychotic drugs primarily block dopamine and serotonin receptors and cholinergic, adrenergic, and histaminergic receptors, thereby reducing hallucinations and delusions in conditions like schizophrenia. However, they can trigger unwanted extrapyramidal effects such as dystonias, Parkinson-like symptoms, and tardive dyskinesia.
Despite these side effects, antipsychotics are used therapeutically for various purposes, including managing schizophrenia, preventing nausea and vomiting, curbing...

Advances in genomics have profoundly influenced drug discovery by increasing both the speed and accuracy of pharmaceutical development. Pharmacogenomics, which examines how genetic variation influences drug response, facilitates the identification of novel therapeutic targets and enables patient stratification for personalized treatment. These strategies contribute to improved drug efficacy, minimized adverse effects, and more efficient clinical trial design.Mapping genetic differences...