Abstract
Schizophrenia is a severe neuropsychiatric disorder that affects approximately 0.5–1% of the population. Response to antipsychotic therapy is highly variable, and it is not currently possible to predict those patients who will or will not respond to antipsychotic medication. Furthermore, a high percentage of patients, approximately 30%, are classified as treatment-resistant (treatment-resistant schizophrenia; TRS). TRS is defined as a non-response to at least two trials of antipsychotic medication of adequate dose and duration. These patients are usually treated with clozapine, the only evidence-based pharmacotherapy for TRS. However, clozapine is associated with severe adverse events. For these reasons, there is an increasing interest to identify better targets for drug development of new compounds and to establish better biomarkers for existing medications. The ability of antipsychotics to improve psychotic symptoms is dependent on their antagonist and reverse agonist activities at different neuroreceptors, and some genetic association studies of TRS have focused on different pharmacodynamic factors. Some genetic studies have shown an association between antipsychotic response or TRS and neurodevelopment candidate genes, antipsychotic mechanisms of action (such as dopaminergic, serotonergic, GABAergic, and glutamatergic) or pharmacokinetic factors (i.e., differences in the cytochrome families). Moreover, there is a growing body of literature on the structural and functional neuroimaging research into TRS. Neuroimaging studies can help to uncover the underlying neurobiological reasons for such resistance and identify resistant patients earlier. Studies examining the neuropharmacological mechanisms of antipsychotics, including clozapine, can help to improve our knowledge of their action on the central nervous system, with further implications for the discovery of biomarkers and the development of new treatments. The identification of the underlying mechanisms of TRS is a major challenge for developing personalized medicine in the psychiatric field for schizophrenia treatment. The main goal of precision medicine is to use genetic and brain-imaging information to improve the safety, effectiveness, and health outcomes of patients via more efficiently targeted risk stratification, prevention, and tailored medication and treatment management approaches. The aim of this review is to summarize the state of art of pharmacogenetic, pharmacogenomic and neuroimaging studies in TRS.
Highlights
Schizophrenia is a disabling disease and many patients who are affected will not be able to achieve their goals in most areas of life
It is well established that positive symptoms explain only a small part of the variance of psychosocial functioning and that the greatest contribution to the functional outcome of schizophrenia is given by negative symptoms, cognitive and social cognitive impairment, as well as anxiety and depression (Galderisi et al, 2014, 2016)
Interesting data have come from pharmacogenetics, neuroimaging and the interaction of both fields of study, few converging findings are available that describe the antipsychotic treatment response and resistance mechanisms in schizophrenia (DeLisi and Fleischhacker, 2016)
Summary
Schizophrenia is a disabling disease and many patients who are affected will not be able to achieve their goals in most areas of life. Despite the presence of effective antipsychotic drugs and the introduction of evidencebased psychosocial interventions, the course of schizophrenia is characterized by the alternation of remissions and relapses and only a few patients are classified as meeting recovery criteria (Zipursky and Agid, 2015). All this evidence leads to the conclusion that, regardless of the crucial role of antipsychotics, some patients who don’t achieve clinical and functional recovery are defined as treatment-resistant schizophrenia (TRS) patients.
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