**2.2 Antipsychotic drugs and mechanisms of neuroplasticity**

Antipsychotic medication is the mainstay of effective management of psychosis where schizophrenia is the most prevalent among psychotic disorders. Most of what we know about antipsychotic drugs action is at the receptor level, where abnormalities in neurotransmission constitute either an excess or a deficiency of neurotransmitters, including dopamine, serotonin, and glutamate. Therein firstgeneration drugs act as antagonists of dopamine D2 receptors and target most positive symptoms such as hallucinations and delusions. The receptor-binding profile of second-generation drugs extends beyond D2 affinity antagonism to other neuroreceptors including serotonin 5-HT2A in the frontal lobe, thus accounting for superior efficacy of these drugs in the pathophysiology of negative symptoms and cognitive disorganization [15, 16]. Overall, treatment response has been shown to be associated to the level of D2 occupancy, which is the target of all currently licensed antipsychotics [17]. To delineate therapeutic mechanism of clinically effective drugs beyond receptor level, research has focused on neural systems effects before and after pharmacotherapy in medication-naïve patients with firstepisode psychosis. Functional MRI studies revealed pre-treatment functional alterations within frontostriatal circuitry, marked by patterns of hypoactivity within the dorsolateral/medial prefrontal cortex coupled with hyperactivity in the hippocampus and striatum [18–20]. Thus, aberrant frontostriatal circuitry might represent a potential system- level mechanism of psychosis and a candidate for treatment target with antipsychotics. Post-treatment findings lend some evidence to validate this model, showing increases in task-related frontal cortical activation in patients who underwent 12 weeks of quetiapine fumarate treatment compared to a drug-naive group [21, 22], and in a small group of patients with schizophrenia medicated with risperidone [23]. A similar study on cortical structure and function alterations within 1 year of psychosis onset in unmedicated schizophrenia patients versus patients under short-term therapy with atypical antipsychotics revealed a more complex relationship [20]. Although the treatment was associated with enhanced cognitive control and increased prefrontal, middle temporal, parietal, and occipital activity, it also revealed post-treatment prefrontal cortical thinning in the treatment group. The mechanism by which antipsychotics are associated with the loss of gray matter remains unclear, however neuroinflammatory models posit elevations in proinflammatory cytokine levels [24], microglia activation [25], and increased extracellular volume in white and gray matter [26]. Thus, the study adds to the growing literature on therapeutic mechanisms of antipsychotics, mediated by normalization of aberrant frontal cortical function, and suggests that caution must be exercised in interpreting neuroanatomical changes as being potentially deleterious to brain function.
