New Strategies in the Treatment of Schizophrenia

Reserves in the Treatment of Schizophrenia

As current research in psychiatry and neurobiology shows, dopamine dysfunction is not sufficient to explain the psychopathology of schizophrenia. Therefore, treatment primarily based on influencing the dopaminergic system is not ideal. The symptoms of schizophrenia show significant heterogeneity among patients, and the responses to specific treatments vary, leading to a trial-and-error therapeutic strategy. Current antipsychotics are highly effective in treating positive symptoms such as hallucinations and delusions. However, they are less effective against negative symptoms or cognitive deficits, which are significant predictors of social and occupational impairment. The pathophysiological processes in different stages of schizophrenia may vary, while pharmacological treatment remains fundamentally the same throughout the disease course. In the future, it is possible that new therapies targeting different phases of the disease will be developed.

Disorders in Other Neurotransmitter Systems

The dopamine theory must be supplemented with information about the influence of other neurotransmitter systems and their mutual interactions. Dysfunction in these systems may cause aberrant interneuron function, leading to deficits in cognitive, behavioral, and social areas. One of the pathophysiological mechanisms of schizophrenia could be glutamatergic dysfunction. Glutamate is an excitatory neurotransmitter whose pathways extend to the cortex, limbic system, and thalamic areas involved in the onset and development of schizophrenia. 

The serotonin (5-HT) hypothesis is also worth considering. According to current findings, serotonin antagonists reduce undesirable extrapyramidal symptoms induced by antipsychotics. There is increasing interest in 5-HT₃ antagonists (ondansetron, tropisetron, and granisetron) used as antiemetics. They could become part of the treatment for negative and cognitive symptoms.

Most patients with schizophrenia are heavy smokers. There is a correlation between the inclination to nicotine, the disease itself, and its treatment. Patients report sedative and procognitive effects of smoking, alleviation of negative symptoms, and reduction of treatment side effects. Smoking helps them overcome the deficit in nicotinic cholinergic receptors. In this context, the administration of selective agonists of the nicotinic receptor type α₇ is being considered.

Studies have shown that changes in the gamma-aminobutyric acid (GABA) system can contribute to the pathophysiology of schizophrenia. GABA is the main inhibitory neurotransmitter in the CNS. Allosteric agonists of GABA_A receptors, benzodiazepines, are often used in the treatment of psychoses and have been found to affect core symptoms of schizophrenia. Other areas of interest in the research of the pathophysiology of schizophrenia include inflammation and oxidative stress. A significant link has been found between inflammatory states and schizophrenia.

The Future in Understanding the Genetic Background

Treatment targeting negative or other non-psychotic symptoms, either alone or adjunctively, could solve the common problem of non-adherence, which significantly complicates the entire therapeutic process. Advancements in understanding the genetic background of the disease also hold promise. Genome-wide association studies continue to identify genes associated with the risk of schizophrenia, which may additionally interact with negative environmental factors. Prevention should focus on the early identification of at-risk individuals and the development of safe and effective interventions that can eliminate specific risks.

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Source: Yang A. C., Tsai S. J. New targets for schizophrenia treatment beyond the dopamine hypothesis. Int J Mol Sci 2017; 18 (8): 1689, doi: 10.3390/ijms18081689.