Partial agonists of dopamine receptors: receptor theory and the dopamine hypothesis of psychosis

SUMMARY This article discusses dopamine partial agonism, which is the main mechanism of action of the psychiatric drugs aripiprazole, brexpiprazole and cariprazine. It outlines the principles of receptor theory and the structure of dopamine receptors; characterises agonists, antagonists and partial agonists; and summarises the dopamine hypothesis of psychosis and the role of dopamine and serotonin in depression.

Pharmaco-Magnetic Resonance as a Tool for Monitoring the Medication-Related Effects in the Brain May Provide Potential Biomarkers for Psychotic Disorders

The neurodegenerative and neurodevelopmental hypotheses represent the basic etiological framework for the origin of schizophrenia. Additionally, the dopamine hypothesis, adopted more than two decades ago, has repeatedly asserted the position of dopamine as a pathobiochemical substrate through the action of psychostimulants and neuroleptics on the mesolimbic and mesocortical systems, giving insight into the origin of positive and negative schizophrenic symptoms. Meanwhile, cognitive impairments in schizophrenia remain incompletely understood but are thought to be present during all stages of the disease, as well as in the prodromal, interictal and residual phases. On the other hand, observations on the effects of NMDA antagonists, such as ketamine and phencyclidine, reveal that hypoglutamatergic neurotransmission causes not only positive and negative but also cognitive schizophrenic symptoms. This review aims to summarize the different hypotheses about the origin of psychoses and to identify the optimal neuroimaging method that can serve to unite them in an integral etiological framework. We systematically searched Google scholar (with no concern to the date published) to identify studies investigating the etiology of schizophrenia, with a focus on impaired central neurotransmission. The complex interaction between the dopamine and glutamate neurotransmitter systems provides the long-needed etiological concept, which combines the neurodegenerative hypothesis with the hypothesis of impaired neurodevelopment in schizophrenia. Pharmaco-magnetic resonance imaging is a neuroimaging method that can provide a translation of scientific knowledge about the neural networks and the disruptions in and between different brain regions, into clinically applicable and effective therapeutic results in the management of severe psychotic disorders.

Pharmaco-Magnetic Resonance as Tool for Monitoring the Medication-Related Effects in the Brain May Provide Potential Biomarkers for Psychotic Disorders

Psychotic disorders occur as a result of pathobiochemical processes in the brain, which disrupt the central neurotransmission of molecules such as dopamine and glutamate. The dopamine hypothesis, adopted more than 2 decades ago, has repeatedly asserted its position as an etiopathogenetic substrate through the action of psychostimulants and neuroleptics on the mesolimbic and mesocortical systems, giving insight into the origin of positive and negative schizophrenic symptoms. On the other hand, cognitive impairments in schizophrenia remain not fully understood but are thought to be present during all stages of the disease, as well as in the prodromal the interictal and residual phases. Over the last decade, functional magnetic resonance imaging has focused on research of brain networks like the Default mode network, the Salience network and Central executive network, enabling a deeper understanding of cognitive deficits, as well as other phenomena such as disorganization of thought and behavior. The study of the nodes of these networks, such as the precuneus and insula, informs about their complex significant roles as structures responsible for important cognitive domains such as concentration, attention, ability to understand and reproduce information, as well as memory functions. It is suggested that the neurotransmission of dopamine and glutamate play a key role in these processes and their successful modulation in the correct brain regions through psychopharmacological and biomedical instrumental methods may lead to a significant reversal of conventional paradigms. Pharmaco-magnetic resonance imaging is a neuroimaging method that can provide the translation of scientific knowledge about the neural networks and the disruptions in and between different brain regions, into clinically applicable and effective therapeutic results in the management of severe psychotic disorders.

Holistic Solutions to Schizophrenia Management in Geriatric Populations

Schizophrenia is a psychiatric condition characterized by dysfunction in thoughts, behavior, and emotions. The illness is typically diagnosed in late adolescence to early adulthood, and generally lasts throughout a patient’s lifetime. This debilitating condition affects approximately 25% of adults aged 55 years old and older. With numbers of elderly adults afflicted by psychiatric illnesses increasing in the future, special precautions need to be taken to address this underserved population. This increase in schizophrenia frequency among elderly populations also has repercussions not just for future healthcare, but health costs as well, with schizophrenia expenses being costly in comparison to other psychiatric ailments. A major theory explaining the genetic and physiological basis of schizophrenia is the dopamine hypothesis, which describes a disruption in the normal transmission of the dopaminergic pathway as well as the mesolimbic system. Current treatments of schizophrenia often involve pharmacological interventions that create heightened side effects in the elderly. There is a need for more research into efficient and effective treatments for the future, especially treatments that can be safe for elderly use such as brain stimulating interventions. Destigmatizing mental health issues and advocating for safer and more efficient therapies are the key to improving outcomes of geriatric schizophrenic patients

Potential drug targets in the kynurenine pathway to treat acute schizophrenia

AimsSchizophrenia is a serious developmental psychiatric disorder with a neurodegenerative component that causes marked deterioration in social relationships and ability to work. Present treatments are not satisfactory. Meta-analysis of placebo-controlled studies in acute schizophrenia shows that only a minority of patients have a good response to current antipsychotic medications. Therefore, there is a need for more effective psychopharmacologic treatments for this disorder.MethodThe purpose of this paper is to provide new interpretations of existing data to provide a scaffolding for the development of novel drug targets for the treatment of schizophrenia. The causes of schizophrenia are most likely heterogeneous and involve both genetic and environmental factors. The authors examined a wide range of purported causes of schizophrenia to identify a common biochemical pathway that would contribute to this disorder. This review specifically did not consider pathways that supported the dopamine hypothesis of schizophrenia since historically drugs focused on dopaminergic mechanism, as noted in the aims, have not been successful for many patients with schizophrenia.ResultTwo prominent schizophrenia-associated factors that have been widely studied with significant supporting evidence are stress and inflammation. Stress and inflammation share a common biochemical pathway that converges on the kynurenine pathway of the metabolism of tryptophan, an essential amino acid. At one end of the pathway, recently hospitalized patients with schizophrenia have been found to have low plasma tryptophan levels, whereas chronic schizophrenics have not, suggesting stress- and/or inflammation-induced increased metabolism of tryptophan. At the other end of the pathway, there is increased level of cerebrospinal fluid kynurenic acid in patients with schizophrenia as compared with healthy controls. Salivary kynurenic acid is associated with stress intolerance in schizophrenia. Importantly, natural occurring compounds in this pathway have significant CNS effects that include neurotoxicity and altered neural transmitter behavior.ConclusionStress and inflammation, both associated as causes of schizophrenia, are linked by a common biochemical pathway involving kynurenine. Examination of specific elements of the kynurenine pathway may aid in the identification of drug targets for schizophrenia.

Decisions from experience: adaptive information search and choice in younger and older adults

In real-world decision making, choice outcomes, and their probabilities are often not known a priori but must be learned from experience. The dopamine hypothesis of cognitive aging predicts that component processes of experience-based decision making (information search and stimulus–reward association learning) decline with age. Many existing studies in this domain have used complex neuropsychological tasks that are not optimal for testing predictions about specific cognitive processes. Here we used an experimental sampling paradigm with real monetary payoffs that provided separate measures of information search and choice for gains and losses. Compared with younger adults, older adults sought less information about uncertain risky options. However, like younger adults, older participants also showed evidence of adaptive decision making. When the desirable outcome of the risky option was rare (p = 0.10 or 0.20), both age groups engaged in more information search and made fewer risky choices, compared with when the desirable outcome of the risky option was frequent (p = 0.80 or 0.90). Furthermore, loss options elicited more sampling and greater modulation of risk taking, compared with gain options. Overall, these findings support predictions of the dopamine hypothesis of cognitive aging, but they also highlight the need for additional research into the interaction of age and valence (gain vs. loss) on experience-based choice.

Decisions from experience: adaptive information search and choice in younger and older adults

In real-world decision making, choice outcomes, and their probabilities are often not known a priori but must be learned from experience. The dopamine hypothesis of cognitive aging predicts that component processes of experience-based decision making (information search and stimulus–reward association learning) decline with age. Many existing studies in this domain have used complex neuropsychological tasks that are not optimal for testing predictions about specific cognitive processes. Here we used an experimental sampling paradigm with real monetary payoffs that provided separate measures of information search and choice for gains and losses. Compared with younger adults, older adults sought less information about uncertain risky options. However, like younger adults, older participants also showed evidence of adaptive decision making. When the desirable outcome of the risky option was rare (p = 0.10 or 0.20), both age groups engaged in more information search and made fewer risky choices, compared with when the desirable outcome of the risky option was frequent (p = 0.80 or 0.90). Furthermore, loss options elicited more sampling and greater modulation of risk taking, compared with gain options. Overall, these findings support predictions of the dopamine hypothesis of cognitive aging, but they also highlight the need for additional research into the interaction of age and valence (gain vs. loss) on experience-based choice.

The Dopamine Hypothesis of Autism Spectrum Disorder Revisited: Current Status and Future Prospects

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by social deficits and stereotyped behaviors. Despite intensive research, its etiopathogenesis remains largely unclear. Although studies consistently reported dopaminergic anomalies, a coherent dopaminergic model of ASD was lacking until recently. In 2017, we provided a theoretical framework for a “dopamine hypothesis of ASD” which proposed that autistic behavior arises from a dysfunctional midbrain dopaminergic system. Namely, we hypothesized that malfunction of 2 critical circuits originating in the midbrain, that is, the mesocorticolimbic and nigrostriatal pathways, generates the core behavioral features of ASD. Moreover, we provided key predictions of our model along with testing means. Since then, a notable number of studies referenced our work and numerous others provided support for our model. To account for these developments, we review all these recent data and discuss their implications. Furthermore, in the light of these new insights, we further refine and reconceptualize our model, debating on the possibility that various etiologies of ASD converge upon a dysfunctional midbrain dopaminergic system. In addition, we discuss future prospects, providing new means of testing our hypothesis, as well as its limitations. Along these lines, we aimed to provide a model which, if confirmed, could provide a better understanding of the etiopathogenesis of ASD along with new therapeutic strategies.