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Review
, 2019 (1), 149-168
eCollection

Comparative Psychopharmacology of Autism and Psychotic-Affective Disorders Suggests New Targets for Treatment

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Review

Comparative Psychopharmacology of Autism and Psychotic-Affective Disorders Suggests New Targets for Treatment

Bernard J Crespi. Evol Med Public Health.

Abstract

The first treatments showing effectiveness for some psychiatric disorders, such as lithium for bipolar disorder and chlorpromazine for schizophrenia, were discovered by accident. Currently, psychiatric drug design is seen as a scientific enterprise, limited though it remains by the complexity of brain development and function. Relatively few novel and effective drugs have, however, been developed for many years. The purpose of this article is to demonstrate how evolutionary biology can provide a useful framework for psychiatric drug development. The framework is based on a diametrical nature of autism, compared with psychotic-affective disorders (mainly schizophrenia, bipolar disorder and depression). This paradigm follows from two inferences: (i) risks and phenotypes of human psychiatric disorders derive from phenotypes that have evolved along the human lineage and (ii) biological variation is bidirectional (e.g. higher vs lower, faster vs slower, etc.), such that dysregulation of psychological traits varies in two opposite ways. In this context, the author review the evidence salient to the hypothesis that autism and psychotic-affective disorders represent diametrical disorders in terms of current, proposed and potential psychopharmacological treatments. Studies of brain-derived neurotrophic factor, the PI3K pathway, the NMDA receptor, kynurenic acid metabolism, agmatine metabolism, levels of the endocannabinoid anandamide, antidepressants, anticonvulsants, antipsychotics, and other treatments, demonstrate evidence of diametric effects in autism spectrum disorders and phenotypes compared with psychotic-affective disorders and phenotypes. These findings yield insights into treatment mechanisms and the development of new pharmacological therapies, as well as providing an explanation for the longstanding puzzle of antagonism between epilepsy and psychosis. Lay Summary: Consideration of autism and schizophrenia as caused by opposite alterations to brain development and function leads to novel suggestions for pharmacological treatments.

Keywords: autism; evolution; psychopharmacology; psychosis; schizophrenia.

Figures

Figure 1.
Figure 1.
Model of autism and psychotic-affective conditions as diametric (opposite) disorders with diametric treatments and psychopharmacological patterns related to treatments. Optimal levels of treatment lead to normal, balanced cognition, while ‘too much’ treatment leads to phenotypes typical of the opposite disorder or disorders. See text for details. Leo Kanner is known for describing autism, and Emil Kraepelin for describing schizophrenia
Figure 2.
Figure 2.
Highly simplified depiction of the inter-relationships of the BDNF-TrkB, NMDA-mGLur5, and PI3K- mTOR systems, that impact upon pathways highly relevant to autism and psychotic-affective conditions. Arrows refer to activation, and the blunt tip refers to negative regulation (reducing activation). NMDA antagonists cause psychological and physiological shifts in the direction of the phenotypes of psychosis. Dashed line refers to synaptic cell membrane. See text for details
Figure 3.
Figure 3.
Simplified depiction of kynurenic acid pathway metabolism, which mediates risk and phenotypes of autism and schizophrenia via effects on NMDA receptor activity levels

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