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Purpose of Review Schizophrenia (SZ) is a debilitating mental illness; existing treatments are partially effective and associated with significant side effect burden, largely due to our limited understanding of disease mechanisms and the trajectory of disease progression. Accumulating evidence suggests that metabolic changes associated with glucose metabolism, mitochondrial dysfunction, and redox imbalance play an important role in the pathophysiology of schizophrenia. However, the molecular mechanisms associated with these abnormalities in the brains of schizophrenia patients and the ways in which they change over time remain unclear. This paper aims to review the current literature on molecular mechanisms and in vivo magnetic resonance spectroscopy (MRS) studies of impaired energy metabolism in patients at clinical high risk for psychosis, with first-episode SZ, and with chronic SZ. Our review covers research related to high-energy phosphate metabolism, lactate, intracellular pH, redox ratio, and the antioxidant glutathione. Recent Findings Both first-episode and chronic SZ patients display a significant reduction in creatine kinase reaction activity and redox (NAD + /NADH) ratio in the prefrontal cortex. Chronic, but not first-episode, SZ patients also show a trend toward increased lactate levels and decreased pH value. These findings suggest a progressive shift from oxidative phosphorylation to glycolysis for energy production over the course of SZ, which is associated with redox imbalance and mitochondrial dysfunction. Summary Accumulating evidence indicates that aberrant brain energy metabolism associated with mitochondrial dysfunction and redox imbalance plays a critical role in SZ and will be a promising target for future treatments.

Abstract Background Foundational models of the psychoses included course as a core element differentiating patients. Current models, ICD-11 and DSM-5, only require symptom criteria to be met to make a diagnosis. We explore the proposition that making course designation essential, again, would improve the categorization of patients with psychotic disorders. Study Design We briefly discuss the history by which symptoms, alone, became the primary elements required for diagnosis. We review past and recent evidence on the best models for differentiating among psychoses. Study Results The use of course designations, along with symptoms, produces the best fit to the way in which psychotic disorders present and progress. It also matches how clinicians assess patients and choose therapeutic interventions. A model including course as a factor is more accurate and complete than models using symptoms alone. And it produces groups of patients that are likely to be more homogeneous than purely symptom-based models. The degree of heterogeneity among patients classified together within current International Classification of Diseases (ICD) and Diagnostic and Statistical Manual of Mental Disorders (DSM) categories can lead to false findings in research and a lack of clarity on the best treatment in individual cases. Increasing homogeneity in diagnostic groups, by including course designations, could advantage clinical care, clinical trials, and research on underlying pathogenic mechanisms. Conclusions Adding a course as a diagnostic element is practical. Clinicians already consider it. Specifying courses can be required in making a diagnosis. Doing so is evidence based and enhances the accuracy and value of diagnoses. We recommend restoring the course as a core element of any new diagnostic system.

Multiple psychiatric disorders are characterized by a failure to suppress default-mode network (DMN) activity during tasks and by weaker anti-correlations between DMN and other brain networks at rest. However, the cellular and molecular mechanisms underlying this phenomenon are poorly understood. At the cellular level, neuronal activity is regulated by multiple neurochemical processes including cycling of glutamate and GABA, the major excitatory and inhibitory neurotransmitters in brain. By combining functional MRI and magnetic resonance spectroscopy techniques, it has been shown that the neurotransmitter concentrations in DMN modulate not only functional activity during cognitive tasks, but also the functional connectivity between DMN and other brain networks such as frontoparietal executive control network (CN) at rest in the healthy brain. In the current study, we extend previous research to first episode psychosis (FEP) patients and their relatives. We detected higher glutamate (Glu) levels in the medial prefrontal cortex (MPFC) in FEP compared to healthy controls without a significant difference in GABA. We also observed a significantly lower functional anti-correlated connectivity between critical nodes within the DMN (MPFC) and CN (DLPFC) in FEP. Furthermore, the relationship between MPFC Glu and GABA concentrations and the functional anti-correlation that is seen in healthy people was absent in FEP patients. These findings imply that both the DMN Glu level and the interaction between DMN and CN are affected by the illness, as is the association between neurochemistry and functional connectivity. A better understanding of this observation could provide opportunities for developing novel treatment strategies for psychosis.

Among 221,846 young adults who received a stimulant for attention deficit–hyperactivity disorder, the percentage of patients who had an episode of psychosis within 60 days after starting the medication was higher among amphetamine users (0.21%) than among methylphenidate users (0.10%).

Abstract Microstructural abnormalities in the white matter (WM) are implicated in the pathophysiology of psychosis. In vivo magnetic resonance spectroscopy (MRS) can probe the brain’s intracellular microenvironment through the measurement of transverse relaxation and diffusion of neurometabolites and possibly provide cell-specific information. In our previous studies, we observed differential metabolite signal abnormalities in first episode and chronic stages of psychosis. In the present work, longitudinal data were presented for the first time on white matter cell-type specific abnormalities using a combination of diffusion tensor spectroscopy (DTS), T2 MRS, and diffusion tensor imaging (DTI) from a group of 25 first episode psychosis patients and nine matched controls scanned at baseline and one and two years of follow-up. We observed significantly reduced choline ADC in the year 1 of follow-up (0.194 µm2/ms) compared to baseline (0.229 µm2/ms), followed by a significant increase in NAA ADC in the year 2 follow-up (0.258 µm2/ms) from baseline (0.222 µm2/ms) and year 1 follow-up (0.217 µm2/ms). In contrast, NAA T2 relaxation, reflecting a related but different aspect of microenvironment from diffusion, was reduced at year 1 follow-up (257 ms) compared to baseline (278 ms). These abnormalities were observed in the absence of any abnormalities in water relaxation and diffusion at any timepoint. These findings indicate that abnormalities are seen in in glial-enriched (choline) signals in early stages of psychosis, followed by the subsequent emergence of neuronal-enriched (NAA) diffusion abnormalities, all in the absence of nonspecific water signal abnormalities.

Anhedonia is a prominent symptom in neuropsychiatric disorders, most markedly in major depressive disorder (MDD) and schizophrenia (SZ). Emerging evidence indicates an overlap in the neural substrates of anhedonia between MDD and SZ, which supported a transdiagnostic approach. Therefore, we used activation likelihood estimation (ALE) meta-analysis of functional magnetic resonance imaging studies in MDD and SZ to examine the neural bases of three subdomains of anhedonia: consummatory anhedonia, anticipatory anhedonia and emotional processing. ALE analysis focused specifically on MDD or SZ was used later to dissociate specific anhedonia-related neurobiological impairments from potential disease general impairments. ALE results revealed that consummatory anhedonia was associated with decreased activation in ventral basal ganglia areas, while anticipatory anhedonia was associated with more substrates in frontal-striatal networks except the ventral striatum, which included the dorsal anterior cingulate, middle frontal gyrus and medial frontal gyrus. MDD and SZ patients showed similar neurobiological impairments in anticipatory and consummatory anhedonia, but differences in the emotional experience task, which may also involve affective/mood general processing. These results support that anhedonia is characterized by alterations in reward processing and relies on frontal-striatal brain circuitry. The transdiagnostic approach is a promising way to reveal the overall neurobiological framework that contributes to anhedonia and could help to improve targeted treatment strategies.

Thought disorder may be associated with subtle language abnormalities. Binomials are pairs of words of the same grammatical type that are joined by a conjunction that often have a preferred order (for example, “up and down” is more common than “down and up”). We analyzed speech transcripts from patients with first-episode psychosis and found that atypical ordering of binomial pairs was associated with thought disorder but not with other psychosis symptoms. These results illustrate the potential to generate objective, quantifiable measures of disorganized speech.

This study examined the impact of Patient-Centered Communication (PCC), Open Dialogue-inspired changes to rounding practices and culture, on patient perceptions of care on an inpatient psychotic disorders unit. A retrospective cohort analysis was conducted based on medical records, restraint and seclusion records, and hospital Perceptions of Care (PoC) surveys. The analysis compared data from 6-month periods before and after implementation of PCC to quantify whether the implementation of PCC was associated with more positive care ratings. There were trends toward improvement suggestive of an effect on patients’ perception that their care was adequately explained, that they felt involved in care, that they felt respected, and that they were supported during hospitalization, although improvements did not achieve statistical significance. Greater improvement was observed for teams that incorporated a greater number of interventions. Dialogic practice-inspired changes on an acute inpatient unit may improve patient perceptions of inclusion and respect in their care.