Search

Dopamine (DA) and glutamate neurotransmission are strongly implicated in schizophrenia pathophysiology. While most studies focus on contributions of neurons that release only DA or glutamate, neither DA nor glutamate models alone recapitulate the full spectrum of schizophrenia pathophysiology. Similarly, therapeutic strategies limited to either system cannot effectively treat all three major symptom domains of schizophrenia: positive, negative, and cognitive symptoms. Increasing evidence suggests extensive interactions between the DA and glutamate systems and more effective treatments may therefore require the targeting of both DA and glutamate signaling. This offers the possibility that disrupting DA-glutamate circuitry between these two systems, particularly in the striatum and forebrain, culminate in schizophrenia pathophysiology. Yet, the mechanisms behind these interactions and their contributions to schizophrenia remain unclear. In addition to circuit- or system-level interactions between neurons that solely release either DA or glutamate, here we posit that functional alterations involving a subpopulation of neurons that co-release both DA and glutamate provide a novel point of integration between DA and glutamate systems, offering a key missing link in our understanding of schizophrenia pathophysiology. Better understanding of mechanisms underlying DA/glutamate co-release from these neurons may therefore shed new light on schizophrenia pathophysiology and lead to more effective therapeutics., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Previous studies on psychiatric patients infected with COVID-19 have reported a more severe course of disease and higher rates of mortality compared with the general population. This cohort study linked Israeli national databases including all individuals ever hospitalized for a psychiatric disorder (cases), and COVID-19 testing, infection, hospitalization, mortality, and vaccinations, between March 1 st 2020 and March 31 st 2021. Cases were 125,273 individuals aged 18 and above ever hospitalized in a psychiatric facility (ICD-10 F10-F69 or F90-F99), compared to the total population, n = 6,143,802. Compared with the total population, cases were less likely to be tested for COVID-19, 51.2% (95% CI: 50.8-51.7) vs 62.3% (95% CI 62.2-62.4) and had lower rates of confirmed COVID infection, 5.9% (95% CI: 5.8-6.1) vs 8.9% (95% CI: 8.9-8.9). Among those infected, risks for COVID-19 hospitalization, COVID-19 attributed mortality and all-cause mortality were higher for cases than the total population, adjusted odds ratios were 2.10; (95% CI: 1.96-2.25), 1.76; (95% CI: 1.54-2.01) and 2.02; (95% CI: 1.80-2.28), respectively. These risks were even higher for cases with non-affective psychotic disorders and bipolar disorder. Age adjusted rates of vaccination were lower in cases, 60.4% (95% CI: 59.9-60.8) vs 74.9% (95% CI: 74.8-75.0) in the total population, and particularly low for cases with non-affective psychotic disorders, 56.9% (95% CI: 56.3-57.6). This study highlights the need to increase testing for COVID-19 in individuals ever hospitalized for a psychiatric disorder, closely monitor those found positive, and to reach out to encourage vaccination., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Anhedonia and amotivation are debilitating symptoms and represent unmet therapeutic needs in a range of clinical conditions. The gut-microbiome-endocannabinoid axis might represent a potential modifiable target for interventions. Based on results obtained from animal models, we tested the hypothesis that the endocannabinoid system mediates the association between gut-microbiome diversity and anhedonia/amotivation in a general population cohort. We used longitudinal data collected from 786 volunteer twins recruited as part the TwinsUK register. Our hypothesis was tested with a multilevel mediation model using family structure as random intercept. The model was set using alpha diversity (within-individual gut-microbial diversity) as predictor, serum and faecal levels of the endocannabinoid palmitoylethanolamide (PEA) as mediator, and anhedonia/amotivation as outcome. PEA is considered the endogenous equivalent of cannabidiol, with increased serum levels believed to have anti-depressive effects, while increased stool PEA levels, reflecting increased excretion, are believed to have opposite, detrimental, effects on mental health. We therefore expected that either reduced serum PEA or increased stool PEA would mediate the association between microbial diversity and anhedonia amotivation. Analyses were adjusted for obesity, diet, antidepressant use, sociodemographic and technical covariates. Data were imputed using multiple imputation by chained equations. Mean age was 65.2 ± 7.6; 93% of the sample were females. We found a direct, significant, association between alpha diversity and anhedonia/amotivation (β = -0.37; 95%CI: -0.71 to -0.03; P = 0.03). Faecal, but not serum, levels of the endocannabinoid palmitoylethanolamide (PEA) mediated this association: the indirect effect was significant (β = -0.13; 95%CI: -0.24 to -0.01; P = 0.03), as was the total effect (β = -0.38; 95%CI: -0.72 to -0.04; P = 0.03), whereas the direct effect of alpha diversity on anhedonia/amotivation was attenuated fully (β = -0.25; 95%CI: -0.60 to 0.09; P = 0.16). Our results suggest that gut-microbial diversity might contribute to anhedonia/amotivation via the endocannabinoid system. These findings shed light on the biological underpinnings of anhedonia/amotivation and suggest the gut microbiota-endocannabinoid axis as a promising therapeutic target in an area of unmet clinical need., (© 2021. The Author(s).)

The Psychiatric Genomics Consortium-Schizophrenia Workgroup (PGC-SCZ) has recently published a genomewide association study (GWAS) identifying >100 genetic loci, encompassing a total of 341 protein-coding genes, attaining genomewide significance for susceptibility to schizophrenia. Given the extremely long time (12-15 years) and expense (>$1 billion) associated with the development of novel drug targets, repurposing of drugs with known and validated targets may be the most expeditious path toward deriving clinical utility from these GWAS findings. In the present study, we examined all genes within loci implicated by the PGC-SCZ GWAS against databases of targets of both approved and registered pharmaceutical compounds. We identified 20 potential schizophrenia susceptibility genes that encode proteins that are the targets of approved drugs. Of these, we prioritized genes/targets that are of clear neuropsychiatric interest and that are also sole members of the linkage disequilibrium block surrounding a PGC-SCZ GWAS hit. In addition to DRD2, 5 genes meet these criteria: CACNA1C, CACNB2, CACNA1I, GRIN2A and HCN1. An additional 20 genes coding for proteins that are the targets of drugs in registered clinical trials, but without approved indications, were also identified. Although considerable work is still required to fully explicate the biological implications of the PGC-SCZ GWAS results, pathways related to these known, druggable targets may represent a promising starting point. [ABSTRACT FROM AUTHOR]

Since the introduction of chlorpromazine and throughout the development of the new-generation antipsychotic drugs (APDs) beginning with clozapine, the D2 receptor has been the target for the development of APDs. Pharmacologic actions to reduce neurotransmission through the D2 receptor have been the only proven therapeutic mechanism for psychoses. A number of novel non-D2 mechanisms of action of APDs have been explored over the past 40 years but none has definitively been proven effective. At the same time, the effectiveness of treatments and range of outcomes for patients are far from satisfactory. The relative success of antipsychotics in treating positive symptoms is limited by the fact that a substantial number of patients are refractory to current medications and by their lack of efficacy for negative and cognitive symptoms, which often determine the level of functional impairment. In addition, while the newer antipsychotics produce fewer motor side effects, safety and tolerability concerns about weight gain and endocrinopathies have emerged. Consequently, there is an urgent need for more effective and better-tolerated antipsychotic agents, and to identify new molecular targets and develop mechanistically novel compounds that can address the various symptom dimensions of schizophrenia. In recent years, a variety of new experimental pharmacological approaches have emerged, including compounds acting on targets other than the dopamine D2 receptor. However, there is still an ongoing debate as to whether drugs selective for singe molecular targets (that is, 'magic bullets') or drugs selectively non-selective for several molecular targets (that is, 'magic shotguns', 'multifunctional drugs' or 'intramolecular polypharmacy') will lead to more effective new medications for schizophrenia. In this context, current and future drug development strategies can be seen to fall into three categories: (1) refinement of precedented mechanisms of action to provide drugs of comparable or superior efficacy and side-effect profiles to existing APDs; (2) development of novel (and presumably non-D2) mechanism APDs; (3) development of compounds to be used as adjuncts to APDs to augment efficacy by targeting specific symptom dimensions of schizophrenia and particularly those not responsive to traditional APD treatment. In addition, efforts are being made to determine if the products of susceptibility genes in schizophrenia, identified by genetic linkage and association studies, may be viable targets for drug development. Finally, a focus on early detection and early intervention aimed at halting or reversing progressive pathophysiological processes in schizophrenia has gained great influence. This has encouraged future drug development and therapeutic strategies that are neuroprotective. This article provides an update and critical review of the pharmacology and clinical profiles of current APDs and drugs acting on novel targets with potential to be therapeutic agents in the future. [ABSTRACT FROM AUTHOR]

It has been suggested that the superiority of antidepressants over placebo in controlled trials is merely a consequence of side effects enhancing the expectation of improvement by making the patient realize that he/she is not on placebo. We explored this hypothesis in a patient-level post hoc-analysis including all industry-sponsored, Food and Drug Administration-registered placebo-controlled trials of citalopram or paroxetine in adult major depression that used the Hamilton Depression Rating Scale (HDRS) and included a week 6 symptom assessment (n=15). The primary analyses, which compared completers on active treatment without early adverse events to completers on placebo (with or without adverse events) with respect to reduction in the HDRS depressed mood item showed larger symptom reduction in patients given active treatment, the effect sizes being 0.48 for citalopram and 0.33 for paroxetine. In actively treated subjects reporting early adverse events, who also outperformed those given placebo, the severity of the adverse events did not predict response. Several sensitivity analyses, for example, including (i) those using change of the sum of all HDRS-17 items as effect parameter, (ii) those excluding all subjects with adverse events (that is, also those on placebo) and (iii) those based on the intention-to-treat population, were all in line with the primary analyses. The finding that both paroxetine and citalopram are clearly superior to placebo also when not producing adverse events, as well as the lack of association between adverse event severity and response, argue against the theory that antidepressants outperform placebo solely or largely because of their side effects.