Schizophenia

Symptoms, signs, and diagnosis of schizophrenia

A decreased expression of specific interneuron subtypes, containing either the calcium binding protein parvalbumin (PV) or the neurotransmitter somatostatin (SST), are observed in the cortex and hippocampus of both patients with schizophrenia and rodent models used to study the disorder. Moreover, preclinical studies suggest that this loss of inhibitory function is a key pathological mechanism underlying the symptoms of schizophrenia. Interestingly, decreased expression of Lhx6, a key transcriptional regulator specific to the development and migration of PV and SST interneurons, is seen in human postmortem studies and following multiple developmental disruptions used to model schizophrenia preclinically. These results suggest that disruptions in interneuron development in utero may contribute to the pathology of the disorder. To recapitulate decreased Lhx6 expression during development, we used in utero electroporation to introduce an Lhx6 shRNA plasmid and knockdown Lhx6 expression in the brains of rats on gestational day 17. We then examined schizophrenia-like neurophysiological and behavioral alterations in the offspring once they reached adulthood. In utero Lhx6 knockdown resulted in increased ventral tegmental area (VTA) dopamine neuron population activity and a sex-specific increase in locomotor response to a psychotomimetic, consistent with positive symptomology of schizophrenia. However, Lhx6 knockdown had no effect on social interaction or spatial working memory, suggesting behaviors associated with negative and cognitive symptom domains were unaffected. These results suggest that knockdown of Lhx6 during development results in neurophysiological and behavioral alterations consistent with the positive symptom domain of schizophrenia in adult rats.

In schizophrenia spectrum disorders, improvement in symptoms varies between patients with short and long durations of illness. In this meta-analysis we provided an overview of both short- and long-term symptomatic improvement for patients with schizophrenia spectrum disorders with distinct durations of illness. We included 82 longitudinal studies assessing the course of positive, negative, depressive and disorganization symptoms. We analyzed effect sizes of change in four subgroups based on durations of illness at baseline: <2 years, 2–5 years, 5–10 years, >10 years. Potential moderators were explored using meta-regression and sensitivity analyses. Overall, we found large improvements of positive symptoms and small improvements of negative, depressive, and disorganization symptoms. Positive and disorganization symptoms improved relatively stronger for patients earlier in the course of illness, whereas negative and depressive symptoms showed modest improvement regardless of duration of illness. Improvement of symptoms was associated with higher baseline severity of positive symptoms, a younger age, a smaller subsample with schizophrenia, and, specifically for negative symptoms, higher baseline severity of depressive symptoms. Future research should focus on exploring ways to optimize improvement in negative and depressive symptoms for patients with schizophrenia spectrum disorders.

Schizophrenia and autism spectrum disorders (ASD) are among the neurodevelopmental disorders that have recently been conceptualized as disorders of brain energy metabolism. A variety of pathophysiological mechanisms might concur to the development of the disorders, to include altered brain glucose metabolism resulting in inefficient processing of glucose as the primary source of metabolic energy (ATP) via glycolysis as well as the abnormal functioning of the mitochondria. The ketogenic diet is a very low-carbohydrate, high-protein, and high-fat diet that induces a physiological state of ketosis in humans and other mammals. In the absence of glycolysis, ketone bodies enter the neural cell metabolism to produce ATP via the TCA cycle and might thus act as an alternative energy substrate. Preliminary data from preclinical and human studies confirm a measurable effect of dietary interventions to re-establish efficient brain energy metabolism.

The current schizophrenia construct as delineated in the latest editions of the DSM and the ICD has some strengths, but also many weaknesses.

It improved the reliability of the diagnosis, made communication among clinicians, users and families less ambiguous, is useful for education and training, and for reimbursement and insurance purposes.

However, many serious weaknesses should be considered. The term “Schizophrenia” does not recognize the heterogeneity of the disorder and might nourish the belief that schizophrenia represents a unitary disease. In addition, there is no agreement on the existence and nature of a “core aspect” of the disorder. Stable dimensions, in particular negative symptoms and cognitive impairment, which are key determinants of functioning, are not de facto regarded as core aspects. Finally, the construct is associated to the notion of a poor outcome, to a high level of stigma and has acquired a derogatory connotation.

We are not ready but should be prepared to abandon the current schizophrenia construct. Clinicians and researchers should be encouraged to complement the ICD/DSM diagnosis with an in-depth characterization of the individual clinical picture, along with other variables, such as family history, comorbidities, vulnerability factors and personal trajectory. The “Primary Psychoses” construct, together with improved cross-sectional and longitudinal phenotypes from representative population and patient cohorts, and the availability of artificial intelligence methods, could lead to a new and more precise taxonomy of psychotic disorders, and increase the probability of identifying meaningful biomarkers to improve prevention, diagnosis, prognosis, and treatment for people suffering from psychotic disorders.