Symptom Domains Of Schizophrenia Research Articles

Variations of Sleep Patterns and Their Relations with Positive and Negative Domains of Schizophrenia in Eastern Indian Population

Abstract Objectives: Schizophrenia is a persistent and incapacitating psychiatric condition characterized by symptoms with positive, negative, affective, and cognitive domains. Sleep disturbances represent an important facet of this disorder, impacting both the quality of life and influencing its overall outcome. In the cross-sectional study, we intended to investigate the polysomnographic findings of patients with schizophrenia showing predominantly positive symptoms as opposed to those presenting with predominantly negative symptoms and also as compared to normal population. Methods: This study had a cross-sectional design, involving the recruitment of 60 medication-naive patients diagnosed with schizophrenia according to the ICD-10 criteria and 30 study participants representing normal population. The cases were subdivided into two groups: one characterized by predominantly positive symptoms and the other characterized by predominantly negative symptoms. Both the groups received overnight polysomnography, and study variables were recorded. Results: All the sleep parameters were deranged in patients with schizophrenia as compared to normal controls in the general population, with significantly more pronounced differences found in those with predominant positive symptoms for most variables (p < 0.001). The only exception was the duration of N3 (slow-wave sleep) which was significantly decreased in patients with negative symptoms compared to those with positive symptoms (p < 0.001). But no significant differences were found between the negative and positive symptom domain groups in mean rapid eye movement (REM) latency, duration of N1 and N2 sleep, and total percentage of REM sleep. Conclusion: This study highlights substantial variations in sleep patterns between the negative and positive symptom domains of schizophrenia and also as compared to the general population. Further study is imperative to explore the link between circadian integrity and symptoms of the various domains of schizophrenia.

A Study of Neurological Soft Signs and Cognition in Schizophrenia.

Neurological soft signs (NSS) are delicate neurological abnormalities that comprise deficits in motor coordination, problems with the sequencing of complex motor acts, and sensory integration difficulties. These are nonspecific with no specific localization in the brain. NSS are found in many patients with Schizophrenia. Cognitive dysfunctions are also present in more than two-thirds of patients with Schizophrenia. This study aims at assessing the NSS and its association with cognitive impairment in patients with Schizophrenia. A total of 100 Schizophrenia patients were included in the study. The Heidelberg scale was used for assessing the NSS. The Montreal Cognitive Assessment Scale(MoCA) for cognitive impairment, the Positive and Negative Syndrome Scale(PANSS) for Schizophrenia, and the Brief Psychiatric Rating Scale (BPRS) were used to assess the severity. Statistical analysis was performed by Pearson's Chi-square test, Kruskal-Wallis test, Wilcoxon rank testsand Spearman rank correlation along with mean and standard deviation. NSS were present in 68% (N=68) of the patients with motor coordination being maximally affected. Cognitive impairment was found in 73% (N=73) of patients with a MoCA score <26. Patients with predominant negative symptoms had higher NSS scores and lower MoCA scores. A "statistically significant" correlation was observed between cognitive impairment and NSS. Most patients with NSS and impaired cognition were in the "markedly ill" category of BPRS. A significant association was observed between cognitive deficits, negative symptoms, and NSS in Schizophrenia.NSS and cognitive dysfunctions are integral parts of Schizophrenia symptomdomains and need to be assessed as the negative symptoms and severity of illness are associated with NSS, especially problems with motor coordination and cognitive dysfunctions.

Effects of independent versus dependent stressful life events on major symptom domains of schizophrenia

We evaluated two models to link stressful life events (SLEs) with the psychopathology of schizophrenia spectrum disorders (SSD). We separated SLEs into independent (iSLEs, unlikely influenced by one’s behavior) and dependent (dSLEs, likely influenced by one’s behavior). Stress-diathesis and stress generation models were evaluated for the relationship between total, i- and d- SLEs and the severity of positive, negative, and depressive symptoms in participants with SSD. Participants with SSD (n = 286; 196 males; age = 37.5 ± 13.5 years) and community controls (n = 121; 83 males; 35.4 ± 13.9 years) completed self-report of lifetime negative total, i- and d- SLEs. Participants with SSD reported a significantly higher number of total SLEs compared to controls (B = 1.11, p = 6.4 × 10–6). Positive symptom severity was positively associated with the total number of SLEs (β = 0.20, p = 0.001). iSLEs (β = 0.11, p = 0.09) and dSLEs (β = 0.21, p = 0.0006) showed similar association with positive symptoms (p = 0.16) suggesting stress-diathesis effects. Negative symptom severity was negatively associated with the number of SLEs (β = –0.19, p = 0.003) and dSLEs (β = −0.20, p = 0.001) but not iSLEs (β = –0.04, p = 0.52), suggesting stress generation effects. Depressive symptom severity was positively associated with SLEs (β = 0.34, p = 1.0 × 10–8), and the association was not statistically stronger for dSLEs (β = 0.33, p = 2.7 × 10–8) than iSLEs (β = 0.21, p = 0.0006), p = 0.085, suggesting stress-diathesis effects. The SLE – symptom relationships in SSD may be attributed to stress generation or stress-diathesis, depending on symptom domain. Findings call for a domain-specific approach to clinical intervention for SLEs in SSD.

Molecular insights into orphan G protein-coupled receptors relevant to schizophrenia.

Schizophrenia remains a sizable socio-economic burden that continues to be treated with therapeutics based on 70-year old science. All currently approved therapeutics primarily target the dopamine D2 receptor to achieve their efficacy. Whilst dopaminergic dysregulation is a key feature in this disorder, the targeting of dopaminergic machinery has yielded limited efficacy and an appreciable side effect burden. Over the recent decades, numerous drugs that engage non-dopaminergic G protein-coupled receptors (GPCRs) have yielded a promise of efficacy without the deleterious side effect profile, yet none have successfully completed clinical studies and progressed to the market. More recently, there has been increased attention around non-dopaminergic GPCR-targeting drugs, which demonstrated efficacy in some schizophrenia symptom domains. This provides renewed hope that effective schizophrenia treatment may lie outside of the dopaminergic space. Despite the potential for muscarinic receptor- (and other well-characterised GPCR families) targeting drugs to treat schizophrenia, they are often plagued with complications such as lack of receptor subtype selectivity and peripheral on-target side effects. Orphan GPCR studies have opened a new avenue of exploration with many demonstrating schizophrenia-relevant mechanisms and a favourable expression profile, thus offering potential for novel drug development. This review discusses centrally expressed orphan GPCRs: GPR3, GPR6, GPR12, GPR52, GPR85, GPR88 and GPR139 and their relationship to schizophrenia. We review their expression, signalling mechanisms and cellular function, in conjunction with small molecule development and structural insights. We seek to provide a snapshot of the growing evidence and development potential of new classes of schizophrenia therapeutics. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.

How Obsessive-Compulsive Symptoms Correlate with other Symptoms and Quality of Life in Schizophrenia? A Cross-Sectional Study.

Early psychiatrists inferred that obsessive-compulsive symptoms (OCS) represent a defense against psychosis and prevent the progression of schizophrenia. However, recent clinical research has yielded inconsistent results across studies regarding the link between OCS and the symptom domains of schizophrenia and the influence OCS have on a patient's functioning and quality of life (QOL).This study aimed to determine whether OCS has any association with the symptom severity, functioning, and QOL of schizophrenia patients. This cross-sectional study done in a tertiary care hospital consecutively recruited 85 outpatients of schizophrenia in clinical remission over one year. Positive and Negative Syndrome Scale (PANSS), Yale-Brown Obsessive Compulsive Scale (Y-BOCS), WHO Quality of Life Brief Version (WHO QOL-BREF), and Global Assessment of Functioning (GAF) scales were applied. Eighteen patients (21.2%) had OCS (Y-BOCS score of ≥8). Patients with OCS had higher PANSS scores (mean±SD of total score 77.16± 16.4, P < 0.001), suggestive of more severe psychosis, poor functioning overall (mean GAF score 37.35 ± 15.62, P < 0.001), and poor QOL in the psychological domain (P < 0.001). In addition, significant associations were present between the Y-BOCS score and the PANSS (r = 0.65), GAF (r = -0.61), and WHO QOL BREF scores in the physical (r = -0.39), and psychological domains (r = -0.41) (P < 0.001 on all of the above). Patients with OCS have more severe symptoms and a lower QOL. A significant association exists between the intensity of OCS and schizophrenia symptoms, global functioning, and QOL.

Seventy Years of Antipsychotic Development: A Critical Review.

Since the mid-1950s discovery of the first effective antipsychotic medications (APM), we have only been able to improve the tolerability but not the overall efficacy of currently available APMs, as reflected by effectiveness trials in Europe and the United States. This inability to develop more effective APMs is attributable to multiple factors, including failure to create and use assessment tools to assess core symptom domains in schizophrenia, move beyond the dopaminergic hypothesis and to develop "me too" drugs, imposing ill-defined research domain criteria, and lacking federal funding for clinical trials. The classification of APMs is also confusing, including second-generation, partial agonists, and multimodal APMs in the same class of APMs, despite significant differences in their mechanisms of action. Other factors stagnating drug development include inadequate sample sizes to address heterogeneity, lack of statistical measures correlating with clinical significance, using the atheoretical basis of psychiatric diagnoses, failure to control placebo response, and high cost of newer and perhaps more tolerable APMs. Furthermore, there has been a failure to develop early predictors of antipsychotic response and various tools to optimize an APM response. Finally, some mental health providers are also responsible for the suboptimal use of APMs, by using excessive maintenance doses, often with irrational polypharmacy, further compromising effectiveness and medication adherence. However, some bright spots in antipsychotic development include improved tolerability of APMs and long-acting injectables to address the high prevalence of medication nonadherence. This review critically reviews 70 years of antipsychotic development, the reasons behind the failure to develop more effective APMs, and suggestions for future direction.

Resting-State Brain Activity Dysfunctions in Schizophrenia and Their Associations with Negative Symptom Domains: An fMRI Study.

The aim of the present study was to examine the neurobiological correlates of the two negative symptom domains of schizophrenia, the Motivational Deficit domain (including avolition, anhedonia, and asociality) and the Expressive Deficit domain (including blunted affect and alogia), focusing on brain areas that are most commonly found to be associated with negative symptoms in previous literature. Resting-state (rs) fMRI data were analyzed in 62 subjects affected by schizophrenia (SZs) and 46 healthy controls (HCs). The SZs, compared to the HCs, showed higher rs brain activity in the right inferior parietal lobule and the right temporoparietal junction, and lower rs brain activity in the right dorsolateral prefrontal cortex, the bilateral anterior dorsal cingulate cortex, and the ventral and dorsal caudate. Furthermore, in the SZs, the rs brain activity in the left orbitofrontal cortex correlated with negative symptoms (r = -0.436, p = 0.006), in particular with the Motivational Deficit domain (r = -0.424, p = 0.002), even after controlling for confounding factors. The left ventral caudate correlated with negative symptoms (r = -0.407, p = 0.003), especially with the Expressive Deficit domain (r = -0.401, p = 0.003); however, these results seemed to be affected by confounding factors. In line with the literature, our results demonstrated that the two negative symptom domains might be underpinned by different neurobiological mechanisms.

Opportunities and challenges for the development of M1 muscarinic receptor positive allosteric modulators in the treatment for neurocognitive deficits.

Targeting allosteric sites of M1 muscarinic acetylcholine receptors (M1 receptors) is a promising strategy to treat neurocognitive disorders, such as Alzheimer's disease and schizophrenia. Indeed, the last two decades have seen an impressive body of work focussing on the design and development of positive allosteric modulators (PAMs) for the M1 receptor. This has led to the identification of a structurally diverse range of highly selective M1 PAMs. In preclinical models, M1 PAMs have shown rescue of cognitive deficits and improvement of endpoints predictive of symptom domains of schizophrenia. Yet, to date only a few M1 PAMs have reached early-stage clinical trials, with many of them failing to progress further due to on-target mediated cholinergic adverse effects that have plagued the development of this class of ligand. This review covers the recent preclinical and clinical studies in the field of M1 receptor drug discovery for the treatment of Alzheimer's disease and schizophrenia, with a specific focus on M1 PAM, highlighting both the undoubted potential but also key challenges for the successful translation of M1 PAMs from bench-side to bedside. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.

Major neurocognitive psychosis: a novel schizophrenia endophenotype class that is based on machine learning and resembles Kraepelin's and Bleuler's conceptions.

The purpose of this study is to describe how to use the precision nomothetic psychiatry approach to (a) delineate the associations between schizophrenia symptom domains, including negative symptoms, psychosis, hostility, excitation, mannerism, formal thought disorders, psychomotor retardation (PHEMFP), and cognitive dysfunctions and neuroimmunotoxic and neuro-oxidative pathways and (b) create a new endophenotype class based on these features. We show that all symptom domains (negative and PHEMFP) may be used to derive a single latent trait called overall severity of schizophrenia (OSOS). In addition, neurocognitive test results may be used to extract a general cognitive decline (G-CoDe) index, based on executive function, attention, semantic and episodic memory, and delayed recall scores. According to partial least squares analysis, the impacts of adverse outcome pathways (AOPs) on OSOS are partially mediated by increasing G-CoDe severity. The AOPs include neurotoxic cytokines and chemokines, oxidative damage to proteins and lipids, IgA responses to neurotoxic tryptophan catabolites, breakdown of the vascular and paracellular pathways with translocation of Gram-negative bacteria, and insufficient protection through lowered antioxidant levels and impairments in the innate immune system. Unsupervised machine learning identified a new schizophrenia endophenotype class, named major neurocognitive psychosis (MNP), which is characterised by increased negative symptoms and PHEMFP, G-CoDe and the above-mentioned AOPs. Based on these pathways and phenome features, MNP is a distinct endophenotype class which is qualitatively different from simple psychosis (SP). It is impossible to draw any valid conclusions from research on schizophrenia that ignores the MNP and SP distinctions.

Relevance of interactions between dopamine and glutamate neurotransmission in schizophrenia.

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.

Selective mGlu1 Potentiation Reverses Cortical Disinhibition and Schizophrenia‐like Social and Cognitive Deficits

There is a critical need to develop novel therapeutic strategies for addressing the negative and cognitive symptom domains in schizophrenia (SCZ). Multiple clinical and preclinical studies support the hypothesis that loss of GABAergic inhibitory transmission in the prefrontal cortex (PFC) and other forebrain regions may play a critical role in the pathophysiological changes underlying cognitive and social behavioral deficits in SCZ patients. Recently, we demonstrated that activation of the mGlu1 subtype of metabotropic glutamate receptor increases inhibitory transmission in the PFC by selective excitation of somatostatin‐expressing GABA interneurons. Genetic studies in humans reveal an association between deleterious non‐synonymous single nucleotide polymorphisms (nsSNPS) in of the human gene encoding mGlu1 (GRM1) and SCZ, raising the possibility that mGlu1 signaling is critical to the function of brain circuits underlying symptoms associated with this disorder.Here, we examine whether novel positive allosteric modulators (PAMs) selective for mGlu1 reverse electrophysiological effects and behavioral deficits in an MK‐801‐induced animal model of SCZ. We used ex vivo whole‐cell patch‐clamp electrophysiology to show that MK‐801 decreased the frequency of spontaneous inhibitory postsynaptic currents onto layer V pyramidal cells of the PFC, and this cortical disinhibition was reversed by mGlu1 activation. Furthermore, acute MK‐801 treatment induces inhibitory deficits onto PFC‐basolateral amygdala (BLA), but not PFC‐nucleus accumbens, projecting layer V pyramidal cells that can be reversed by selective mGlu1 activation. PFC‐BLA projections are known to contribute functionally to social‐approach behavior, while the BLA plays a critical role in object recognition and cognition broadly. We found that the mGlu1 PAM VU6004909 effectively reversed MK801‐induced deficits in social interaction and social novelty preference in a three‐chamber assay. Additionally, VU6004909 restored novel object recognition following MK‐801 treatment. In combination with our previous reports that mGlu1 PAMs reverse deficits in inhibitory transmission in the PFC, the current study provides strong evidence for mGlu1 PAMs as a promising novel approach for the treatment of social and cognitive deficits in SCZ patients.

Metabotropic Glutamate Receptors As Emerging Targets for the Treatment of Schizophrenia.

Accumulating evidence of glutamatergic abnormalities in the brains of schizophrenia patients has led to efforts to target various components of glutamatergic signaling as potential new approaches for schizophrenia. Exciting research suggests that metabotropic glutamate (mGlu) receptors could provide a fundamentally new approach for better symptomatic relief in patients with schizophrenia. In preclinical studies, the mGlu5 receptor positive allosteric modulators (PAMs) show efficacy in animal models relevant for all symptom domains in schizophrenia. Interestingly, biased pure mGlu5 receptor PAMs that do not potentiate coupling of mGlu5 receptors to N-methyl-D-aspartate (NMDA) receptors lack neurotoxic effects associated with mGlu5 PAMs that enhance coupling to NMDA receptors or have allosteric agonist activity. This provides a better therapeutic profile for treating schizophrenia-like symptoms. Additionally, the mGlu1 receptor PAMs modulate dopamine release in the striatum, which may contribute to their antipsychotic-like effects. Besides group I mGlu (mGlu1 and mGlu5) receptors, agonists of mGlu2/3 receptors also induce robust antipsychotic-like and procognitive effects in rodents and may be effective in treating symptoms of schizophrenia in a selective group of patients. Additionally, mGlu2/4 receptor heterodimers modulate glutamatergic neurotransmission in the prefrontal cortex at selective synapses activated in schizophrenia and therefore hold potential as novel antipsychotics. Excitingly, the mGlu3 receptor activation can enhance cognition in rodents, suggesting that mGlu3 receptor agonist/PAM could provide a novel approach for the treatment of cognitive deficits in schizophrenia. Collectively, the development of mGlu receptor-specific ligands may provide an alternative approach to meet the clinical need for safer and more efficacious therapeutics for schizophrenia. SIGNIFICANCE STATEMENT: The currently available antipsychotic medications do not show significant efficacy for treating negative symptoms and cognitive deficits in schizophrenia. Emerging preclinical and clinical literature suggests that pharmacological targeting of metabotropic glutamate receptors could potentially provide an alternative approach for designing safer and more efficacious therapeutics for treating schizophrenia.

Prof M. Murugappan Poster Award

Background:Neurological soft signs (NSS) are those minute sensory and motor function impairments which are found to be frequently associated with Schizophrenia. Frontal Release Signs (FRS) are a subset of NSS, whose pattern of association in schizophrenia has been understudied.Aim and Objectives:To evaluate the pattern of NSS and FRS in particular, in patients of schizophrenia and their first-degree relatives (FDR) and their association in both groups.Methodology:62 patients who were clinically diagnosed to have schizophrenia currently in remission using ICD-10 research criteria presenting our hospital and one of their normal FDR (62 FDRs) were selected for the study. Both the groups were rated on Neurological Evaluation Scale (Original version) for NSS and Brief psychiatric rating scale and were compared. Statistical analysis was done using SPSS-Version 16.Results:Neurological soft signs were significantly more common in patients with schizophrenia than their first-degree relatives. Mean total NSS score was 13.11±6.78 in schizophrenia patients which was significantly more than 6.55±4.24 (p<0.0001) in FDRs. Mean sub-score on FRS was 1.48±1.44 in schizophrenia patients which was significantly more than 0.31±0.61 (p<0.0001) in FDRs. Mean sub-score on glabellar reflex showed most significant association with patients (0.85±0.69) than their FDRs (0.23±0.49, p<0.00001).Discussion:Previous studies have also shown a similar pattern of distribution of NSS among patients of schizophrenia and their FDRs. Significant association of FRS especially glabellar reflex with patient group suggests that NSS, with FRS in particular may be considered as a biological marker of schizophrenia across all the culture groups.Conclusion:The association of NSS, particularly the FRS with Schizophrenia patients and their first-degree relatives strengthens the neurodevelopmental theory of schizophrenia. Further studies should be carried out to assess the relationship between symptom domains of schizophrenia and FRS in particular.

Thought Disorder as a Neglected Dimension in Schizophrenia.

Thought disorder (TD) is one of the main symptom domains of schizophrenia. TD is a construct that can be seen in both acute and chronic periods in patients with schizophrenia. It is associated with a poor prognosis and relapses, and it disrupts social-occupational functioning. TD also shows a strong familial aggregation and increases the risk of transition to schizophrenia in subjects with ultra-high risk. Although TD was once thought to be pathognomonic to schizophrenia, now it is known that it is a transdiagnostic symptom that is seen not only in schizophrenia but also in other psychiatric disorders. This article reviews the concept of thought disorder in terms of its history, clinical evaluation, neurocognitive features and clinical course in patients with schizophrenia.

Deep Brain Structure Volume and Cortical Thickness Associations With Negative Symptom Domains in Schizophrenia

Prior work has shown widespread associations between cortical thickness and total negative symptom severity in schizophrenia but associations with more refined negative symptom domains remain unknown.

Increased random exploration in schizophrenia is associated with inflammation

One aspect of goal-directed behavior, which is known to be impaired in patients with schizophrenia (SZ), is balancing between exploiting a familiar choice with known reward value and exploring a lesser known, but potentially more rewarding option. Despite its relevance to several symptom domains of SZ, this has received little attention in SZ research. In addition, while there is increasing evidence that SZ is associated with chronic low-grade inflammation, few studies have investigated how this relates to specific behaviors, such as balancing exploration and exploitation. We therefore assessed behaviors underlying the exploration–exploitation trade-off using a three-armed bandit task in 45 patients with SZ and 19 healthy controls (HC). This task allowed us to dissociate goal-unrelated (random) from goal-related (directed) exploration and correlate them with psychopathological symptoms. Moreover, we assessed a broad range of inflammatory proteins in the blood and related them to bandit task behavior. We found that, compared to HC, patients with SZ showed reduced task performance. This impairment was due to a shift from exploitation to random exploration, which was associated with symptoms of disorganization. Relative to HC, patients with SZ showed a pro-inflammatory blood profile. Furthermore, high-sensitivity C-reactive protein (hsCRP) positively correlated with random exploration, but not with directed exploration or exploitation. In conclusion, we show that low-grade inflammation in patients with SZ is associated with random exploration, which can be considered a behavioral marker for disorganization. hsCRP may constitute a marker for severity of, and a potential treatment target for maladaptive exploratory behaviors.

Antidepressive Effect of Antipsychotics in the Treatment of Schizophrenia: Meta-Regression Analysis of Randomized Placebo-Controlled Trials.

BackgroundAntipsychotics improve the positive symptoms of schizophrenia. However, little is known about the extent of antidepressive effects of antipsychotics and their correlation with effects on other symptom domains in schizophrenia. The aim was to investigate whether antidepressive effects of antipsychotics have a significant correlation with the effects on specific symptom domains of schizophrenia.MethodsElectronic databases were searched to identify eligible studies that reported antidepressive effects of antipsychotics for the treatment of adult patients with schizophrenia in double-blind, randomized placebo-controlled trials (RCTs). Mean change from baseline in depressive symptoms was meta-analyzed, and the correlation with the effects on other symptom domains was examined through meta-regression analysis.ResultsThirty-five RCTs (13 890 patients) were included in this meta-analysis. Overall, antipsychotics showed greater efficacy than placebo in reducing depressive symptoms, with small to medium effect sizes (standardized mean difference = −0.27, 95% confidence interval −0.32 to −0.22, P < .001). All the antipsychotics, except for chlorpromazine, haloperidol, and ziprasidone, were associated with significantly greater decreases in depressive symptoms compared with placebo (standardized mean difference = −0.19 to −0.40). A higher antidepressive effect was significantly correlated with a higher improvement in Positive and Negative Syndrome Scale/Brief Psychiatric Rating Scale total, positive, and negative, and Positive and Negative Syndrome Scale-general psychopathology symptoms (β = .618, P < .001; β = .476, P < .001; β = .689, P < .001; β = .603, P < .001, respectively).ConclusionsSecond-generation antipsychotics (except for ziprasidone) were associated with small to medium effects sizes on improvement in depressive symptoms among adult patients with schizophrenia. The antidepressive effect of antipsychotics was significantly correlated with improvement in other symptom domains, with the highest correlation observed for improvement in negative symptoms.PROSPERO registration numberCRD42019133015

Current Treatment Options and Emerging Agents for Schizophrenia.

The currently available antipsychotics mostly treat the positive symptoms of schizophrenia and have at least one adverse effect as a potential liability. Encouraging data suggest potential efficacy for a variety of new agents for the treatment of total symptoms and/or specific symptom domains of schizophrenia. Mechanisms of action that are under investigation include dopamine D3 antagonism/serotonin 5-HT1A partial agonism; combined dopamine, serotonin, and glutamate modulation; phosphodiesterase 10A inhibition; trace amine-associated receptor-1 (TAAR1) agonism plus 5-HT1A agonism; 5-HT2A inverse agonism; sigma-2/5-HT2A antagonism; D-amino acid oxidase (DAAO) inhibition; glycine transporter-1 inhibition; vesicular monoamine transporter-2 antagonism; mu opioid antagonism added to olanzapine; and novel long-acting injectable antipsychotic formulations. It is hoped that ongoing and recently completed trials for agents with known and/or novel mechanisms of action will lead to approved treatments that effectively target the various symptom domains of schizophrenia, minimize the risk for a broad range of clinically relevant adverse effects, and improve functional outcomes for patients. Some novel treatments have already received approval for use in patients with schizophrenia. This brief report discusses recently approved novel agents and potential new treatment options for schizophrenia that are being investigated.

Vitamin D and Neurotrophin Levels and Their Impact on the Symptoms of Schizophrenia

Introduction: Vitamin D is involved in brain development and functioning, as well as in regulation of neurotrophic factors. Changes in the expression of those factors are possibly responsible for morphologic abnormalities and symptoms in patients suffering from schizophrenia. Objective: The main goal of this research was to investigate the interrelationship between vitamin D, nerve growth factors (NGF, brain-derived neurotrophic factor [BDNF], and neuregulin-1 [NRG1]), and schizophrenia symptom domains. Methods: This research included 97 inpatients diagnosed with schizophrenia. Schizophrenia symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Blood samples were taken in order to analyze concentrations of vitamin D, BDNF, NRG1, and NGF growth factors. The obtained results were used in a multiple regression analysis. Results: The vitamin D concentration positively affected the concentration of NRG1 (F = 8.583, p = 0.005) but not the concentration of other investigated growth factors (BDNF and NGF). The clinical characteristics and symptom domains of schizophrenia seemed to be unaffected by the concentrations of vitamin D, BDNF, and NGF, while the NRG1 concentration significantly affected positive symptom domains of schizophrenia (F = 4.927, p = 0.030). Conclusion: The vitamin D concentration positively affected NRG1 levels but not schizophrenia symptomatology as measured by PANSS. The as­sociation between the two could be intermediated via NRG1.

Resistance training in patients with schizophrenia: Concept and proof of principle trial

Resistance training has been shown to contribute to the prevention and management of cardiovascular diseases, which is why it can help reducing morbidity and mortality in schizophrenia patients. Moreover, positive effects on different schizophrenia symptom domains have been proposed.However, a specific resistance training tailored to the needs of schizophrenia patients and its evaluation is still lacking. The objective in this proof of principle trial was to evaluate the feasibility and efficacy of a newly developed 12-week resistance program according to current recommendations of the WHO and the American College of Sports Medicine. We employed a single blind, parallel assignment clinical trial design with participants randomized to attend either a resistance training including three 50min units per week or a balance and tone program as control condition.The primary outcome was the impact on health-related difficulties assessed with the World Health Organization Disability Assessment Schedule (WHO-DAS). Secondary outcome parameters included the level of functioning, schizophrenia symptoms, selected cognitive parameters as well as risk factors for cardiovascular diseases.In our proof of principle trial, we could not find significant time or group effects of resistance training on the WHO-DAS. However, we could observe significant positive effects on the level of functioning assessed with the Global Assessment of Functioning Scale (GAF) over the course of time, which were more pronounced in the intervention group. Our findings indicated that patients with schizophrenia could safely participate in resistance training with relevant improvements in their level of functioning. Well-powered replication trials are needed to provide more efficacy data.