Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future

Abstract

Schizophrenia is a chronic and debilitating neuropsychiatric disorder affecting approximately 1% of the world’s population. This disease is associated with considerable morbidity placing a major financial burden on society. Antipsychotics have been the mainstay of the pharmacological treatment of schizophrenia for decades. The traditional typical and atypical antipsychotics demonstrate clinical efficacy in treating positive symptoms, such as hallucinations and delusions, while are largely ineffective and may worsen negative symptoms, such as blunted affect and social withdrawal, as well as cognitive function. The inability to treat these latter symptoms may contribute to social function impairment associated with schizophrenia. The dysfunction of multiple neurotransmitter systems in schizophrenia suggests that drugs selectively targeting one neurotransmission pathway are unlikely to meet all the therapeutic needs of this heterogeneous disorder. Often, however, the unintentional engagement of multiple pharmacological targets or even the excessive engagement of intended pharmacological targets can lead to undesired consequences and poor tolerability. In this article, we will review marketed typical and atypical antipsychotics and new therapeutic agents targeting dopamine receptors and other neurotransmitters for the treatment of schizophrenia. Representative typical and atypical antipsychotic drugs and new investigational drug candidates will be systematically reviewed and compared by reviewing structure-activity relationships, pharmacokinetic properties, drug metabolism and safety, pharmacological properties, preclinical data in animal models, clinical outcomes and associated side effects.

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

“…The number of predicted targets for each drug are shown in Figure 2 by the light-shaded portions of the bars. Notably, 75 (out of 368) predicted pairs are consistent with already published experimental data [50][51][52]. Table 1 lists 20 of them, along with the corresponding experimentally measured binding affinities; and others can be seen from the entries in Supplementary Table S4 where experimental binding affinities are listed.…”

Atypical Antipsychotic Drug Olanzapine Deregulates Hepatic Lipid Metabolism and Aortic Inflammation and Aggravates Atherosclerosis

“…Targeting this pathway are typical antipsychotic drugs, also called first-generation antipsychotic drugs, which are reported to effectively attenuate positive symptoms of schizophrenia by blocking dopamine D 2 receptors on postsynaptic neurons [6]. However, because of their high affinity for dopamine D 2 receptors, typical antipsychotic drugs are associated with a high risk of extrapyramidal motor adverse effects [7].…”

Differential effects of typical and atypical antipsychotics on astroglial cells in vitro

“…Interestingly, it has been reported that anti‐inflammatory agents have antipsychotic effects and are beneficial for schizophrenia patients (Müller et al, 2010; Müller and Schwarz, 2008). Moreover, typical antipsychotics have demonstrated clinical efficacy in the reduction of positive symptoms, but are ineffective and may exacerbate negative symptoms and cognitive deficits associated with schizophrenia (Li et al, 2016). In this regard, the modulation of the astroglial inflammatory response by risperidone may improve its antipsychotic effectiveness, while haloperidol may potentiate the neuroinflammation associated with neuropsychiatric disorders, which in turn could lead to brain damage and cognitive impairment.…”

“…Antipsychotics are medications used in the treatment of neuropsychiatric disorders, such as schizophrenia. These medications can be classified as typical (first generation) and atypical (second generation), according to the receptors to which they bind (Li et al, 2016; Meltzer, 2013; Stockmeier et al, 1993). Chlorpromazine and haloperidol are well‐known typical antipsychotics, while clozapine, quetiapine and risperidone are common atypical antipsychotics (Li et al, 2016).…”

“…These medications can be classified as typical (first generation) and atypical (second generation), according to the receptors to which they bind (Li et al, 2016; Meltzer, 2013; Stockmeier et al, 1993). Chlorpromazine and haloperidol are well‐known typical antipsychotics, while clozapine, quetiapine and risperidone are common atypical antipsychotics (Li et al, 2016). Previously, our group reported that risperidone, but not haloperidol, can modulate astroglial functions (Quincozes‐Santos et al, 2010, 2009a).…”