Improvement In Negative Symptoms Research Articles

The Effects of Art Therapy and Psychosocial Skills Training on Symptoms and Social Functioning in Patients with Schizophrenia and Their Relatives.

The effects of antipsychotics on negative symptoms are limited. The most appropriate approach in the treatment of schizophrenia is the integration of drug therapy with psychological and social interventions. The purpose of this study was to evaluate and compare the effects of art therapy and psychosocial skills training (PSST) in the treatment of schizophrenia. A total of 15 patients diagnosed with schizophrenia according to the criteria in DSM-5 and 12 patient relatives were included in the study. The patients were randomly divided into 2 groups, 7 were included in the art therapy program and 8 were included in the PSST program for schizophrenia. 90-minute sessions of art therapy and PSST were carried out once a week for 17 weeks. Participants with schizophrenia were evaluated with the Positive and Negative Syndrome Scale (PANSS), Social Functioning Scale (SFS) and the Calgary Depression Scale for Schizophrenia and the relatives were given Beck Depression Inventory, Beck Anxiety Inventory and Zarit Burden Interview. There was a significant decrease in the PANSS negative symptoms, PANSS general psychopathology, SFS pro-social activities and SFS recreation scores in both groups, while the SFS social withdrawal scores decreased significantly only in the art therapy group. In the PANSS negative symptoms subscale, passive social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation and stereotyped thinking scores were significantly lower in the art therapy group. In the PSST group only the score for difficulty in abstract thinking declined significantly. The findings of the present study suggest that art therapy and PSST have positive effects on the improvement of negative symptoms as well as improvements in social and cognitive functionality in schizophrenia.

Activation of Metabotropic Glutamate Receptor 3 Modulates Thalamo-accumbal Transmission and Rescues Schizophrenia-Like Physiological and Behavioral Deficits

BackgroundPolymorphisms in the gene encoding for metabotropic glutamate receptor 3 (mGlu3) are associated with an increased likelihood of schizophrenia diagnosis and can predict improvements in negative symptoms following treatment with antipsychotics. However, the mechanisms by which mGlu3 can regulate brain circuits involved in schizophrenia pathophysiology are not clear. MethodsWe employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, slice optogenetics, and fiber photometry to investigate the effects of mGlu3 activation on phencyclidine (PCP)-induced impairments in thalamo-accumbal transmission and sociability deficits. A chemogenetic approach was used to evaluate the role of thalamo-accumbal transmission in PCP-induced sociability deficits. ResultsWe first established that PCP treatment augmented excitatory transmission onto dopamine D1 receptor–expressing medium spiny neurons (D1-MSNs) in the nucleus accumbens (NAc) and induced sociability deficits. Our studies revealed a selective increase in glutamatergic synaptic transmission from thalamic afferents to D1-MSNs in the NAc shell. Chemogenetic silencing of thalamo-accumbal inputs rescued PCP-induced sociability deficits. Pharmacological activation of mGlu3 normalized PCP-induced impairments in thalamo-accumbal transmission and sociability deficits. Mechanistic studies revealed that mGlu3 activation induced robust long-term depression at synapses from the thalamic projections onto D1-MSNs in the NAc shell. ConclusionsThese data demonstrate that activation of mGlu3 decreases thalamo-accumbal transmission and thereby rescues sociability deficits in mouse modeling schizophrenia-like symptoms. These findings provide novel insights into the NAc-specific mechanisms and suggest that agents modulating glutamatergic signaling in the NAc may provide a promising approach for treating negative symptoms in schizophrenia.

A miR-137–Related Biological Pathway of Risk for Schizophrenia Is Associated With Human Brain Emotion Processing

BackgroundmiR-137 is a microRNA involved in brain development, regulating neurogenesis and neuronal maturation. Genome-wide association studies have implicated miR-137 in schizophrenia risk but do not explain its involvement in brain function and underlying biology. Polygenic risk for schizophrenia mediated by miR-137 targets is associated with working memory, although other evidence points to emotion processing. We characterized the functional brain correlates of miR-137 target genes associated with schizophrenia while disentangling previously reported associations of miR-137 targets with working memory and emotion processing. MethodsUsing RNA sequencing data from postmortem prefrontal cortex (N = 522), we identified a coexpression gene set enriched for miR-137 targets and schizophrenia risk genes. We validated the relationship of this set to miR-137 in vitro by manipulating miR-137 expression in neuroblastoma cells. We translated this gene set into polygenic scores of coexpression prediction and associated them with functional magnetic resonance imaging activation in healthy volunteers (n1 = 214; n2 = 136; n3 = 2075; n4 = 1800) and with short-term treatment response in patients with schizophrenia (N = 427). ResultsIn 4652 human participants, we found that 1) schizophrenia risk genes were coexpressed in a biologically validated set enriched for miR-137 targets; 2) increased expression of miR-137 target risk genes was mediated by low prefrontal miR-137 expression; 3) alleles that predict greater gene set coexpression were associated with greater prefrontal activation during emotion processing in 3 independent healthy cohorts (n1, n2, n3) in interaction with age (n4); and 4) these alleles predicted less improvement in negative symptoms following antipsychotic treatment in patients with schizophrenia. ConclusionsThe functional translation of miR-137 target gene expression linked with schizophrenia involves the neural substrates of emotion processing.

Baseline BMI is associated with clinical symptom improvements in first-episode schizophrenia: a longitudinal study.

Background: There is sufficient evidence of the high prevalence of obesity in schizophrenia (SZ) compared to the general population. Previous studies have reported that weight gain correlated with the response to antipsychotics in patients with SZ. Nonetheless, the relationship between body mass index (BMI) and therapeutic benefits remains unclear. This study was designed to investigate the association between baseline BMI and improvements in clinical symptoms after treatment with antipsychotics in first-episode and medication-naïve SZ (FEMNS). Methods: A total of 241 FEMNS patients were enrolled and received risperidone over 12weeks. The severity of symptoms was assessed by the Positive and Negative Syndrome Scale (PANSS) and BMI was measured at baseline and 12-week follow-up. Results: We found that risperidone treatment raised the body weight of FEMNS patients and baseline BMI was negatively correlated with the improvement in negative symptoms (r = -0.14, p = 0.03) after 12-week treatment. Linear regression analysis indicated that baseline BMI was an independent predictor of response to risperidone in the early stage of SZ. Conclusion: The current study suggests a close relationship between baseline BMI and improvement in negative symptoms in SZ.

High-definition transcranial direct current stimulation for treating cognitive and negative symptoms in chronic schizophrenia – A sham-controlled proof of concept study

Objectives: Cognitive and negative symptoms are core symptoms of schizophrenia affecting interpersonal and socio-occupational functioning. Impaired dorsolateral prefrontal cortex (DLPFC) function is implicated in negative and cognitive symptoms. Conventional transcranial direct current stimulation (tDCS) to DLPFC has attracted interest as an add-on treatment for these symptoms. High-definition tDCS (HD-tDCS), an optimized form of tDCS, has the potential for more focalized neuromodulation. Studies suggest that an increased number of sessions may increase the effectiveness of stimulation. Hence, we aimed to evaluate the efficacy of 20 sessions of HD-tDCS over the left DLPFC in the improvement of cognitive and negative symptoms in chronic schizophrenia (>2 years continuous illness). Material and Methods: Twenty patients with chronic schizophrenia with predominantly cognitive and negative symptoms were enrolled in this sham-controlled trial. Participants received 20 sessions of HD-tDCS at 2 mA for 20 min, that is, twice daily over 10 days. Montreal cognitive assessment and scale for assessment of negative symptoms were used to assess outcome variables. Assessments were carried out at baseline, 2 weeks, and 6 weeks, respectively. Results: Significant improvement was noted in both active and sham groups across all outcome variables over time. However, a statistically significant decrease in negative symptoms in the active group was noted, which was maintained at the end of 6 weeks, but there was no statistically significant improvement in cognitive symptoms between the active and sham groups at 6 weeks. The stimulation protocol was well tolerated. Conclusion: HD-tDCS has substantial potential in the treatment of negative symptoms; however, its role in cognitive symptoms needs further evaluation.

Sarcosine May Induce EGF Production or Inhibit the Decline in EGF Concentrations in Patients with Chronic Schizophrenia (Results of the PULSAR Study).

Sarcosine (N-methylglycine), a glutamatergic modulator, reduces the primary negative symptoms of schizophrenia. These beneficial changes might be mediated by trophic factors such as epidermal growth factor (EGF). We assessed associations between initial serum EGF levels or changes in serum EGF levels and symptom severity during the addition of sarcosine to stable antipsychotic treatment and thereby evaluated the associations between glutamatergic modulation, clinical changes and peripheral EGF concentrations. Fifty-eight subjects with a diagnosis of chronic schizophrenia with dominant negative symptoms, stably treated with antipsychotics, completed a prospective 6-month, randomized, double-blind, placebo-controlled study. Subjects received orally 2 g of sarcosine (n = 28) or placebo (n = 30) daily. Serum EGF levels and symptom severity (using the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS)) were assessed at baseline, 6-week and 6-month follow-up. Augmentation antipsychotic treatment with sarcosine had no effect on EGF serum levels at any time points. Only the sarcosine group showed a significant improvement in negative symptoms, general psychopathology subscales and the overall PANSS score. We found a reduction in serum EGF levels in the placebo group, but levels in the sarcosine remained stable during the study. Our data indicate that improvement in negative symptoms due to sarcosine augmentation is not directly mediated by EGF, but effective treatment may induce the production or block the decrease in EGF concentrations, which indicates the neuroprotective effect of treatment and confirms the relationship between neuroprotection and EGF levels.

Optimizing antidepressant and clozapine co-prescription in clinical practice: A systematic review and expert recommendations

ObjectivesTo synthesize the information relevant for clinical practice on clozapine-antidepressant co-prescription concerning pharmacokinetic drug-drug interactions (DDI), adverse drug reactions (ADRs) associated with the co-prescription, antidepressant add-on for clozapine-resistant symptoms and antidepressant add-on for clozapine-induced ADRs. MethodsArticles were identified with MEDLINE, Web of Sciences and PsycINFO search from inception through April 2023. Data were synthesized narratively. ResultsADRs are most often induced by the co-prescription of antidepressants that inhibit CYP enzymes (fluvoxamine, fluoxetine, paroxetine). Fluvoxamine add-on is hazardous because of its potent inhibition of clozapine metabolism and has few indications (lowering daily number of clozapine tablets, reducing norclozapine-induced metabolic disturbances and other dose-dependent clozapine-induced ADRs). ADR frequency may be reduced by therapeutic drug monitoring and knowledge of other factors impacting clozapine metabolism (pneumonia, inflammation, smoking, etc.). Improvement of negative symptoms is the most documented beneficial effect of antidepressant add-on for clozapine-resistant psychotic symptoms. The add-on antidepressant should be chosen according to its safety profile regarding DDI with clozapine: antidepressants inhibiting clozapine metabolism or increasing the anticholinergic load should be avoided. Other indications of antidepressant add-on (affective or obsessive compulsive symptoms, sialorrhea, and enuresis) are poorly documented. ConclusionAntidepressant add-on to clozapine is associated with potential benefits in clozapine users as this strategy may contribute to reduce the burden of clozapine-resistant symptoms or of clozapine-induced ADRs. Further studies are needed to determine whether antidepressant add-on can reduce the risk of clozapine discontinuation.

Significant improvement of psychotic symptoms in treatment-resistant schizophrenia with clozapine in an adolescent with SHINE syndrome: a case report

This report highlights a rare single-gene cause of early-onset, treatment-resistant schizophrenia, and its unique responsiveness to clozapine therapy. This case describes a pediatric female who was diagnosed with early-onset schizophrenia and catatonia in her early adolescence, and was later found to have DLG4-related synaptopathy, also known as SHINE syndrome. SHINE syndrome is a rare neurodevelopmental disorder caused by dysfunction of the postsynaptic density protein-95 (PSD-95), encoded by the DLG4 gene. After failing three antipsychotic drug treatments, the patient was started on clozapine, which resulted in significant improvements in positive and negative symptoms. This case illustrates the impact of clozapine in treatment-resistant early-onset psychosis and exemplifies practical implications for genetic testing in early-onset schizophrenia.

Predictors of cognitive changes in patients with schizophrenia undergoing electroconvulsive therapy.

Previous studies on the effects of electroconvulsive therapy (ECT) on cognition in schizophrenia have been inconclusive. This study aimed to identify factors that may predict cognitive improvement or deterioration in patients with schizophrenia after-ECT. Patients with schizophrenia or schizoaffective disorder with predominantly positive psychotic symptoms, who were treated with ECT at the Institute of Mental Health (IMH), Singapore, between January 2016 and January 2018, were assessed. Montreal Cognitive Assessment (MoCA), Brief Psychiatric Rating Scale (BPRS) and Global Assessment of Function (GAF) were performed before and after ECT. Patients with clinically significant improvement, deterioration or no change in MoCA scores were compared on demographics, concurrent clinical treatment and ECT parameters. Of the 125 patients analysed, 57 (45.6%), 36 (28.8%) and 32 (25.6%) showed improvements, deterioration and no change in cognition respectively. Age and voluntary admission predicted MoCA deterioration. Lower pre-ECT MoCA and female sex predicted MoCA improvement. Patients showed improvements in GAF, BPRS and BPRS subscale scores on average, except for the MoCA deterioration group, who did not show statistically significant improvement in negative symptom scores. Sensitivity analysis showed that nearly half the patients (48.3%) who were initially unable to complete MoCA pre-ECT were able to complete MoCA post-ECT. The majority of patients with schizophrenia demonstrate improved cognition with ECT. Patients with poor cognition pre-ECT are more likely to see improvement post-ECT. Advanced age may be a risk factor for cognitive deterioration. Finally, improvements in cognition may be associated with improvements in negative symptoms.

Effect of Music Therapy on The Improvement of Clinical Symptoms and Cognitive Functions of Schizophrenia Patients Receiving Risperidone Therapy

Background: Music therapy as a non-pharmacotherapy management has not been widely used. Data about effectiveness, ideal number of sessions and types/methods of music therapy have not been widely studied in Indonesia. Therefore, this study was designed to answer these problems so that music therapy can be applied appropriately. Objective : To determine the effect of music therapy on the improvement of clinical symptoms and cognitive function of schizophrenic patients that are receiving risperidone therapy. Methods : This study was an experimental study with comparative analysis. Sampling with consecutive sampling on the population of patients who were hospitalized in the Regional Special Hospital of South Sulawesi Province. The treatment group received risperidone therapy and music therapy (active and receptive) 6-8 sessions with a duration of 45 minutes/session, the control group only received risperidone 2-4 mg/day. The instruments used were the PANSS and the MoCA - Indonesian version, examined in the second and fourth weeks after music therapy. Results: There was a significant difference between the treatment group compared to the control group in decreasing the PANSS score for negative symptoms (p=0.000), general psychopathology (4th week p=0.011) and cognitive function (4th week p=0.000) especially on visuospatial components (p=0.001), attention (p=0.009) and abstraction (p=0.011). There was no significant difference between the treatment group compared to the control group in decreasing the PANSS score for positive symptoms (p=0.0.102) Conclusion: Music therapy can be a non-pharmacological therapy of choice to support the improvement of negative symptoms, cognitive function and general psychopathology in the stabilization phase of schizophrenic patients receiving risperidone.

Process-outcome relations in music therapy versus music listening for people with schizophrenia viewed through a mediational model: the role of the therapeutic alliance.

Examine whether change in clinical outcomes for patients with schizophrenia and negative symptoms randomized to either Music Therapy (MT) or Music Listening (ML) is associated to moderators and mediators, with focus on alliance, attendance and dropout. An exploratory post-hoc analysis of data from an original randomized controlled trial (RCT) investigating the effect of MT vs. ML for people with schizophrenia and negative symptoms. Inclusion to the study was implemented through screening of referred patients for symptoms of schizophrenia and negative symptoms. A total of 57 patients were randomly assigned, 28 to MT and 29 to ML. Session logs and notes were included in this study. Statistical analysis investigated moderator and mediator relation to outcome variables: Negative symptoms, functioning, quality of life, and retention to treatment. On average, participants in MT attended 18.86 sessions (SD = 7.17), whereas those in ML attended 12.26 (SD = 9.52), a statistically significant difference (p = 0.0078). Dropout at 25 weeks was predicted by intervention, with dropout being 2.65 (SE = 1.01) times more likely in ML than in music therapy (p = 0.009). Helping alliance score at weeks was explained by intervention, with mean score being 0.68 (SE = 0.32) points lower in ML than in MT (p = 0.042). The number of sessions attended was also explained by intervention, with participants in ML attending on average 6.17 (SE = 2.24) fewer sessions than those randomized to MT (p = 0.008). Though both groups improved significantly, improvements in negative symptoms, depression, and functioning tended to be higher in ML, whereas improvements in alliance and quality of life tended to be higher in MT. The analysis could not detect a direct link between helping alliance score and outcome variables. However, the analysis documented a stronger alliance developed in the MT group, a lower dropout rate, as well as higher attendance in treatment.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02942459.

Long-term effects of Roluperidone on negative symptoms of schizophrenia.

Roluperidone has antagonist properties for 5-HT2A, sigma2, α1A- and α1B-adrenergic receptors, but no dopaminergic binding affinities. In 2 randomized controlled trials (RCT), treatment improved negative symptoms of schizophrenia and social functioning among patients with moderate to severe negative symptoms. We report results of the protocol specified analysis of 2 open-label extension studies of 24 and 40weeks investigating whether improvement of negative symptoms was sustained without significant adverse effects or worsening of psychosis. Following 12-week double-blind phase of both RCTs, patients were eligible to receive monotherapy roluperidone 32mg/day or 64mg/day for 24weeks (trial 1) or 40weeks (trial 2) in open-label extension study. Trial 1 included 244 patients of whom 142 entered 24-week open-label extension and trial 2 included 513 patients of whom 341 entered 40-week open-label extension. Trial 1 had PANSS negative factor score of Pentagonal Structure Model as primary outcome. Trial 2 had Marder Negative Symptoms Factor Score as primary outcome measure and Personal and Social Performance (PSP) Total score as secondary outcome. During open-label extensions, continued improvements in negative symptoms and on PSP were observed. Overall rate of symptomatic worsening requiring discontinuation of roluperidone and treatment with an antipsychotic was <10%. Roluperidone was well tolerated with no meaningful changes in vital signs, laboratory values, weight gain, metabolic indices, or extrapyramidal symptoms. Results of 2 open-label extension trials support roluperidone as a treatment of negative symptoms and social functioning deficits in patients with moderate to severe negative symptoms of schizophrenia.

A randomized controlled trial of add-on naproxen, simvastatin and their combination for the treatment of schizophrenia or schizoaffective disorder

This large randomized controlled trial examined the effect of naproxen, simvastatin or both on patients with schizophrenia. This was a large multi-center, twelve-week, randomized, double-blind, placebo-controlled, four-arm clinical trial administering naproxen, simvastatin or both to 232 subjects with schizophrenia or schizoaffective disorder. The primary outcome was change in PANSS total score. ANCOVA and mixed model analyses of the PANSS total score change showed no significant difference between naproxen and placebo (adjusted p = 0.78), simvastatin and placebo (adjusted p = 0.38) or the combination of naproxen and simvastatin compared to placebo (adjusted p = 0.72). No statistically significant drug-placebo differences were found in the PANSS subscales, CGI or BACS between all groups. There was a near significant improvement in negative symptoms (p = 0.06), and an analysis of the 5 factor PANSS factors analysis found a significant improvement in simvastatin above placebo in withdrawal (p = 0.03). These finding were not significant after correcting for multiple comparisons. A meta-analysis on changes in total PANSS scores in studies on statins in schizophrenia, including the present study together with six other studies showed a significant improvement for statins compared to placebo (Hedges’ G of -0.245 (CI= -0.403, -0.086, p = 0.002). When one outlying study which showed particularly strong effects of statins was removed, part of the effect went away. In conclusion, in this study, naproxen and simvastatin alone or in combination were not efficacious in the treatment of symptoms in schizophrenia. However, the meta-analysis of all studies of simvastatin for schizophrenia indicates further research on this topic.

Effects of low-dose combined olanzapine and sertraline on negative and depressive symptoms in treatment-resistant outpatients with acute exacerbated schizophrenia.

Background: Treatment-resistant schizophrenia (TRS) is a major clinical challenge. Current antipsychotic medications do not adequately address negative and depressive symptoms in patients with TRS, and novel treatments are thus needed. This study examines the efficacy of low-dose combined olanzapine (OLA) and sertraline on depressive and negative symptoms in patients with TRS. Methods: A total of 34 TRS outpatients with acutely exacerbated schizophrenia were randomly assigned to OLA monotherapy (12.5-20mg/day) (control group) or low-dose combined OLA (7.5-10mg/day) and sertraline (50-100mg/day) (OS group). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and at the end of treatment in weeks 4, 8, 12, and 24. Depressive symptoms and social functioning were also assessed. Results: Compared to the control group, the OS group showed significant improvements in depressive and negative symptoms over time. In addition, the low-dose combination of OLA and sertraline significantly improved social functioning compared with OLA monotherapy. There were no significant between-group differences in psychotic symptom improvement. However, the reduction in Hamilton Depression Rating Scale total score and PANSS negative subscore were not associated with improvements in social functioning, suggesting that these effects of combined treatment are independent. Conclusion: Low-dose combined OLA and sertraline may be effective in the treatment of negative and depressive symptoms compared with standard OLA monotherapy in patients with TRS who are experiencing an acute exacerbation of schizophrenia. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT04076371].

Recovery of auditory evoked response attentional gain modulation following the first psychotic episode indexes improvements in symptom severity.

Attentional control of auditory N100/M100 gain is reduced in individuals with first-episode psychosis (FEP). Persistent problems with executive modulation of auditory sensory activity may impact multiple aspects of psychosis. As a follow-up to our prior work reporting deficits in attentional M100 gain modulation in auditory cortex, we examined changes in M100 gain modulation longitudinally, and further examined relationships between auditory M100 and symptoms of psychosis. We compared auditory M100 in auditory sensory cortex between 21 FEP and 29 matched healthy participants and between timepoints separated by 220 ± 100 days. Magnetoencephalography data were recorded while participants alternately attended or ignored tones in an auditory oddball task. M100 was measured as the average of 80-140 ms post-stimulus in source-localized evoked responses within bilateral auditory cortex. Symptoms were assessed using the PANSS and PSYRATS. M100 amplitudes, attentional modulation of M100 amplitudes, and symptom severity all improved in FEP over time. Further, improvement in M100 modulation correlated with improvements in negative symptoms (PANSS) as well as physical, cognitive, and emotional components of hallucinations (PSYRATS). Conversely, improvements in the overall size of the M100, rather than the difference between active and passive M100 amplitudes, were related to worsening of positive symptoms (PANSS) and physical components of hallucinations. Results indicate a link between symptoms (particularly auditory hallucinations) and auditory cortex neurophysiology in FEP, where auditory attention and auditory sensation have opposed relationships to symptom change. These findings may inform current models of psychosis etiology and could provide nonpharmaceutical avenues for early intervention.

Review of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist Ulotaront: Part II—Summary of Initial Clinical Efficacy/Safety Results

AbstractIntroductionUlotaront is a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity that has received FDA Breakthrough Therapy Designation for the treatment of schizophrenia. Here we summarize ongoing clinical research characterizing the efficacy and safety of ulotaront as a member of the novel trace amine-associated receptor 1 (TAAR1) agonist class.MethodsSummarized are results from a double-blind, placebo-controlled study to evaluate the efficacy and safety of ulotaront (50 mg or 75 mg) in an acute exacerbation of schizophrenia, and a 6-month, open-label follow-up study. Also summarized are post-hoc analyses evaluating negative symptom efficacy, and key safety and adverse event (AE) outcomes.ResultsIn the short-term study, treatment with ulotaront was associated with significant (p&lt;0.001) endpoint improvement in the PANSS total score (effect size [ES]: 0.45), the CGI-Severity score (ES: 0.52) and the Brief Negative Symptom Scale total score (ES: 0.48). The incidence of any AE was lower on ulotaront versus placebo (45.8% vs. 50.4%), and the number needed to harm (NNH) for individual AEs on ulotaront were all &gt;40. Ulotaront was associated with lower risk for antipsychotic class-related AEs (extrapyramidal symptoms, akathisia, somnolence, nausea/vomiting, increased weight/metabolic labs, prolactinemia). The 6-month study demonstrated further improvement, with a completion rate (67%) that was higher than reported for current dopamine D2 antipsychotics.ConclusionsThe emerging profile of ulotaront is characterized by significant improvement in positive and negative symptoms of schizophrenia. The safety and tolerability profile of ulotaront is markedly different with respect to antipsychotic class-related AEs. The benefit-risk profile of ulotaront, as a member of a novel TAAR1 agonist class, is distinguished from antipsychotics by lack of AEs related to D2 and serotonin 5-HT2A receptor blockade.FundingSunovion Pharmaceuticals, Inc., and Otsuka Pharmaceutical Development &amp; Commercialization, Inc.

Obesity, antioxidants and negative symptom improvement in first-episode schizophrenia patients treated with risperidone

Negative symptoms remain a main therapeutic challenge in patients with schizophrenia (SZ). Obesity is associated with more severe negative symptoms after the first episode of psychosis. Oxidative stress caused by an impaired antioxidant defense system is involved in the pathophysiology of SZ. Yet, it is unclear regarding the role of obesity and antioxidants in negative symptom improvements in SZ. Therefore, this longitudinal study was designed to assess the impact of obesity on antioxidant defenses and negative symptom improvements in first-episode SZ patients. A total of 241 medication-naive and first-episode patients with SZ were treated with risperidone for 3 months. Outcome measures including symptoms, body weight, and total antioxidant status (TAS) levels were measured at baseline and the end of the third month. We found that after 12 weeks of treatment with risperidone, the body weight increased and clinical symptoms significantly improved. Baseline body mass index (BMI) was negatively correlated with negative symptom improvement after treatment and an increase in TAS was negatively associated with an increase in BMI only in the high BMI group. More importantly, the TAS × BMI interaction at baseline was an independent predictor of negative symptom improvement. Our longitudinal study indicates that the improvement in negative symptoms by risperidone was associated with baseline BMI and TAS levels in patients with SZ. Baseline BMI and TAS may be a predictor for negative improvement in SZ patients after risperidone treatment.

A Novel Psychosocial Intervention for Motivational Negative Symptoms in Schizophrenia: Combined Motivational Interviewing and CBT.

Negative symptoms are a primary cause of disability in schizophrenia for which there are no established pharmacotherapies. This study evaluated a novel psychosocial intervention that combined two evidence-based practices-motivational interviewing and cognitive-behavioral therapy (MI-CBT)-for the treatment of motivational negative symptoms. Seventy-nine participants with schizophrenia and moderate to severe negative symptoms were included in a randomized controlled trial comparing the 12-session MI-CBT treatment with a mindfulness control condition. Participants were assessed at three time points through the study period, which included 12 weeks of active treatment and 12 weeks of follow-up. The primary outcome measures were motivational negative symptoms and community functioning; the secondary outcomes included a posited biomarker of negative symptoms: pupillometric response to cognitive effort. Compared with the control group, participants in the MI-CBT group showed significantly greater improvements in motivational negative symptoms over the acute treatment period. Their gains relative to baseline were maintained at follow-up, although the differential benefit relative to control subjects was attenuated. There were nonsignificant effects toward improvements in community functioning and differential change in the pupillometric markers of cognitive effort. The results show that combining motivational interviewing with CBT yields improvements in negative symptoms, a feature of schizophrenia generally thought of as resistant to intervention. Motivational negative symptoms not only responded to the novel treatment, but the gains were maintained over the follow-up period. Implications for future studies and for improving the generalization of the negative symptom gains to daily functioning domains are discussed.

Online Left-Hemispheric In-Phase Frontoparietal Theta tACS Modulates Theta-Band EEG Source-Based Large-Scale Functional Network Connectivity in Patients with Schizophrenia: A Randomized, Double-Blind, Sham-Controlled Clinical Trial.

EEG studies indicated that schizophrenia patients had increased resting-state theta-band functional connectivity, which was associated with negative symptoms. We recently published the first study showing that theta (6 Hz) transcranial alternating current stimulation (tACS) over left prefrontal and parietal cortices during a working memory task for accentuating frontoparietal theta-band synchronization (in-phase theta-tACS) reduced negative symptoms in schizophrenia patients. Here, we hypothesized that in-phase theta-tACS can modulate theta-band large-scale networks connectivity in schizophrenia patients. In this randomized, double-blind, sham-controlled trial, patients received twice-daily, 2 mA, 20-min sessions of in-phase theta-tACS for 5 consecutive weekdays (n = 18) or a sham stimulation (n = 18). Resting-state electroencephalography data were collected at baseline, end of stimulation, and at one-week follow-up. Exact low resolution electromagnetic tomography (eLORETA) was used to compute intra-cortical activity. Lagged phase synchronization (LPS) was used to measure whole-brain source-based functional connectivity across 84 cortical regions at theta frequency (5-7 Hz). EEG data from 35 patients were analyzed. We found that in-phase theta-tACS significantly reduced the LPS between the posterior cingulate (PC) and the parahippocampal gyrus (PHG) in the right hemisphere only at the end of stimulation relative to sham (p = 0.0009, corrected). The reduction in right hemispheric PC-PHG LPS was significantly correlated with negative symptom improvement at the end of the stimulation (r = 0.503, p = 0.039). Our findings suggest that in-phase theta-tACS can modulate theta-band large-scale functional connectivity pertaining to negative symptoms. Considering the failure of right hemispheric PC-PHG functional connectivity to predict improvement in negative symptoms at one-week follow-up, future studies should investigate whether it can serve as a surrogate of treatment response to theta-tACS.

The efficacy of homestyle rehabilitation on negative symptoms in chronic schizophrenia: A randomized controlled trial.

Schizophrenia is a debilitating mental disorder with a high disability rate that is characterized by negative symptoms such as apathy, hyperactivity, and anhedonia that can make daily life challenging and impair social functioning. In this study, we aim to investigate the effectiveness of homestyle rehabilitation in mitigating these negative symptoms and associated factors. A randomized controlled trial was conducted to compare the efficacy of hospital rehabilitation and homestyle rehabilitation for negative symptoms in 100 individuals diagnosed with schizophrenia. The participants were divided randomly into two groups, each persisting for 3 months. The primary outcome measures were the Scale for Assessment of Negative Symptoms (SANS) and Global Assessment of Functioning (GAF). The secondary outcome measures included the Positive Symptom Assessment Scale (SAPS), Calgary Schizophrenia Depression Scale (CDSS), Simpson-Angus Scale (SAS), and Abnormal Involuntary Movement Scale (AIMS). The trial aimed to compare the effectiveness of the two rehabilitation methods. Homestyle rehabilitation for negative symptoms was found to be more effective than hospital rehabilitation, according to the changes in SANS (T = 2.07, p = 0.04). Further analysis using multiple regression indicated that improvements in depressive symptoms (T = 6.88, p < 0.001) and involuntary motor symptoms (T = 2.75, p = 0.007) were associated with a reduction in negative symptoms. Homestyle rehabilitation may have greater potential than hospital rehabilitation in improving negative symptoms, making it an effective rehabilitation model. Further research is necessary to investigate factors such as depressive symptoms and involuntary motor symptoms, which may be associated with the improvement of negative symptoms. Additionally, more attention should be given to addressing secondary negative symptoms in rehabilitation interventions.