Adult Schizophrenia Research Articles

Development and initial validation of a multivariable predictive Early Adversity Scale for Schizophrenia (EAS-Sz) using register data to quantify environmental risk for adult schizophrenia diagnosis after childhood exposure to adversity.

Additional to a child's genetic inheritance, environmental exposures are associated with schizophrenia. Many are broadly described as childhood adversity; modelling the combined impact of these is complex. We aimed to develop and validate a scale on childhood adversity, independent of genetic and other environmental liabilities, for use in schizophrenia risk analysis models, using data from cross-linked electronic health and social services registers. A cohort of N = 428 970 Western Australian children born 1980-2001 was partitioned into three samples: scale development sample (N = 171 588), and two scale validation samples (each N = 128 691). Measures of adversity were defined before a child's 10th birthday from five domains: discontinuity in parenting, family functioning, family structure, area-level socioeconomic/demographic environment and family-level sociodemographic status. Using Cox proportional hazards modelling of follow-up time from 10th birthday to schizophrenia diagnosis or censorship, weighted combinations of measures were firstly developed into scales for each domain, then combined into a final global scale. Discrimination and calibration performance were validated using Harrell's C and graphical assessment respectively. A weighted combination of 42 measures of childhood adversity was derived from the development sample. Independent application to identical measures in validation samples produced Harrell's Concordance statistics of 0.656 and 0.624. Average predicted time to diagnosis curves corresponded with 95% CI limits of observed Kaplan-Meier curves in five prognostic categories. Our Early Adversity Scale for Schizophrenia (EAS-Sz), the first using routinely collected register data, predicts schizophrenia diagnosis above chance, and has potential to help untangle contributions of genetic and environmental liability to schizophrenia risk.

Schizophrenia Hypothesis: Autonomic Nervous System Dysregulation of Fetal and Adult Immune Tolerance

The autonomic nervous system can control immune cell activation via both sympathetic adrenergic and parasympathetic cholinergic nerve release of norepinephrine and acetylcholine. The hypothesis put forward in this paper suggests that autonomic nervous system dysfunction leads to dysregulation of immune tolerance mechanisms in brain-resident and peripheral immune cells leading to excessive production of pro-inflammatory cytokines such as Tumor Necrosis Factor alpha (TNF-α). Inactivation of Glycogen Synthase Kinase-3β (GSK3β) is a process that takes place in macrophages and microglia when a toll-like receptor 4 (TLR4) ligand binds to the TLR4 receptor. When Damage-Associated Molecular Patterns (DAMPS) and Pathogen-Associated Molecular Patterns (PAMPS) bind to TLR4s, the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) pathway should be activated, leading to inactivation of GSK3β. This switches the macrophage from producing pro-inflammatory cytokines to anti-inflammatory cytokines. Acetylcholine activation of the α7 subunit of the nicotinic acetylcholine receptor (α7 nAChR) on the cell surface of immune cells leads to PI3K/Akt pathway activation and can control immune cell polarization. Dysregulation of this pathway due to dysfunction of the prenatal autonomic nervous system could lead to impaired fetal immune tolerance mechanisms and a greater vulnerability to Maternal Immune Activation (MIA) resulting in neurodevelopmental abnormalities. It could also lead to the adult schizophrenia patient’s immune system being more vulnerable to chronic stress-induced DAMP release. If a schizophrenia patient experiences chronic stress, an increased production of pro-inflammatory cytokines such as TNF-α could cause significant damage. TNF-α could increase the permeability of the intestinal and blood brain barrier, resulting in lipopolysaccharide (LPS) and TNF-α translocation to the brain and consequent increases in glutamate release. MIA has been found to reduce Glutamic Acid Decarboxylase mRNA expression, resulting in reduced Gamma-aminobutyric acid (GABA) synthesis, which combined with an increase of glutamate release could result in an imbalance of glutamate and GABA neurotransmitters. Schizophrenia could be a “two-hit” illness comprised of a genetic “hit” of autonomic nervous system dysfunction and an environmental hit of MIA. This combination of factors could lead to neurotransmitter imbalance and the development of psychotic symptoms.

Serum Levels and in vitro CX3CL1 (Fractalkine), CXCL8, and IL-10 Synthesis in Phytohemaglutinin-Stimulated and Non-stimulated Peripheral Blood Mononuclear Cells in Subjects With Schizophrenia.

IntroductionAlthough schizophrenia is a severe mental illness, whose etiology is still largely unknown, its pathogenesis may be associated with dysregulation of the immune mechanisms. The present study compares the levels of interleukin (IL)-10, interleukin-8 (CXCL8), and fractalkine (CX3CL1) between schizophrenia patients and healthy controls. It also assesses the ability of peripheral peripheral blood mononuclear cells (PBMCs) to produce these cytokines spontaneously and following mitogen-stimulation.Materials and MethodsA prospective study was performed of 60 adult schizophrenia patients and 32 controls. CXCL8, IL-10, and fractalkine concentrations were measured in serum and supernatants from cultured PBMCs. Anthropometric (BMI, WHR) and body composition measurements were taken using bioimpedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA).Results and ConclusionThe schizophrenia patients demonstrated significantly higher levels of serum CXCL8 (schizophrenia: 13.4 ± 15.7 pg/mL, control: 6.9 ± 4.2 pg/mL, p = 0.001) and lower level of serum fractalkine (schizophrenia: 22.8 ± 9.9 pg/mL, control: 45.4 ± 84.5 pg/mL, p = 0.041). Serum IL-10 levels did not significantly differ. No in vitro synthesis of fractalkine was observed. Neither unstimulated or PHA-stimulated CXCL8 secretion differed between the two groups (p >0.05). The patients not taking mood stabilizers (MS–) demonstrated significantly higher CXCL8 levels than those on mood stabilizers (MS+) (p = 0.03) and control (p < 0.001). In addition, the MS- sub-group demonstrated significantly lower serum fraktalkine than controls (p = 0.009). These effects could be described as pseudo-normalization of CXCL8 and fractalkine in schizophrenia patients taking mood stabilizers.

Aripiprazole lai two-injection start in a 16 year-old with Schizophrenia

IntroductionAripiprazole LAI is approved for the treatment of schizophrenia in adults. Recently, Europe and Canada approved the use of the two-injection start (TIS) regimen: two separate injections of 400 mg long-acting aripiprazole along with a single 20 mg dose of oral aripiprazole. Aripiprazole showed efficacy in the treatment of adolescents with acute schizophrenia in several controlled trials, leading to its approval for 13-17 year-old adolescents with schizophrenia by the EMA. However, the LAI formulation still remains off-label in adolescents.ObjectivesTo demonstrate the efficacy and safety of the TIS regimen of aripiprazole LAI formulation in a 16 year-old adolescent with schizophrenia.MethodsWe evaluated the symptoms of schizophrenia and general severity by means of the PANSS and CGI scales. The scales were administered at hospital admission, after 3 weeks, 5 weeks, and at 4-weeks follow-up.ResultsAt the admission the patient PANSS total score was 136, the CGI score of 7. Aripiprazole was started and up-titrated to 30 mg/day. After 3 weeks, the positive symptoms were significantly reduced; due to the persistence of negative symptoms, clozapine 100 mg/day was added. At week 5 the PANSS total score decreased to 81. Due to poor insight we proposed aripiprazole LAI with the two-injection start. One month later, global functioning and illness insight improved; PANSS score was 43, CGI score 2. There was no evidence of akathisia or other side effects.ConclusionsAripiprazole LAI showed good efficacy and tolerability in an adolescent with schizophrenia. The two-injection start regimen was a safe and viable option.DisclosureNo significant relationships.

Place of the partial dopamine receptor agonist aripiprazole in the management of schizophrenia in adults: a Delphi consensus study

BackgroundAripiprazole is a second-generation antipsychotic, efficacious in patients with schizophrenia during acute episodes. Due to its pharmacological profile, aripiprazole may be of interest in patients with specific clinical profiles who have not been studied extensively in randomised clinical trials.ObjectivesTo capture experience with aripiprazole in everyday psychiatric practice using the Delphi method in order to inform decision-making on the use of aripiprazole for the treatment of patients with schizophrenia in clinical situations where robust evidence from clinical trials is lacking.MethodsThe scope of the survey was defined as the management of schizophrenia in adults. A systematic literature review was performed to identify the different clinical situations in which aripiprazole has been studied, and to describe the level of clinical evidence. Clinical profiles to include in the Delphi survey were selected if there was a clear interest in terms of medical need but uncertainty over the efficacy of aripiprazole. For each clinical profile retained, five to seven specific statements were generated and included in a questionnaire. The final 41-item questionnaire was proposed to a panel of 406 French psychiatrists with experience in the treatment of schizophrenia. Panellists rated their level of agreement using a Likert scale. A second round of voting on eleven items was organised to clarify points for which a consensus was not obtained in the first round.ResultsFive clinical profiles were identified in the literature review (persistent negative symptoms, pregnancy, cognitive dysfunction, addictive comorbidity and clozapine resistance). Sixty-two psychiatrists participated in the first round of the Delphi survey and 33 in the second round. A consensus was obtained for 11 out of 41 items in the first round and for 9/11 items in the second round. According to the panellists’ clinical experience, aripiprazole can be used as maintenance treatment for pregnant women, is relevant to preserve cognitive function and can be considered an option in patients with a comorbid addictive disorder or with persistent negative symptoms.ConclusionThese findings may help physicians in choosing relevant ways to use aripiprazole and highlight areas where more research is needed to widen the evidence base.

Med Check: Adlarity Transdermal Patch; Qulipta; Nuplazid; and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Adlarity Transdermal Patch; Qulipta; Nuplazid; and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:26 Apr 2022https://doi.org/10.1176/appi.pn.2022.05.5.35Adlarity Transdermal Patch Approved for Treatment of Alzheimer’sIn March the U.S. Food and Drug Administration (FDA) approved Adlarity (donepezil transdermal system) as a treatment for patients with mild, moderate, or severe dementia associated with Alzheimer’s disease, Corium Inc. announced. Adlarity is a once-weekly patch that continuously delivers either 5 mg or 10 mg of donepezil through the skin per day. Either the patient or a caregiver may place the patch on the patient’s back, thigh, or buttocks.The FDA approved Adlarity based on a relative bioavailability study in healthy patients that compared the transdermal system to Aricept (donepezil hydrochloride) tablets. In the study, 60 healthy volunteers received 5 mg of Adlarity per day for five weeks, after which they received either 10 mg of Adlarity or oral donepezil per day for another five weeks. At the end of the study, exposure to donepezil was similar among patients who took Adlarity and those who took oral donepezil. Adlarity is expected to be available in the early fall. Qulipta Promising for Treatment of Chronic MigraineAdults with chronic migraine who took Qulipta (atogepant) in a phase 3 trial experienced fewer monthly migraine days compared with those who took placebo, AbbVie announced in March. Qulipta is currently approved for preventing episodic migraine in adults.In the trial, more than 750 patients with at least a one-year history of chronic migraine were randomized to receive 60 mg of atogepant once a day, 30 mg of atogepant twice a day, or placebo for 12 weeks. All patients had at least 15 headache days with at least eight migraine days in the 28 days before randomization. The trial consisted of two analyses based on regulatory agency feedback in the United States and European Union.The U.S. analysis revealed that patients in the 60 mg and 30 mg atogepant arms experienced a decrease of 6.88 and 7.46 monthly migraine days, respectively, compared with patients in the placebo arm, who experienced a decrease of 5.05 monthly migraine days. The European Union analysis revealed that patients in the 60 mg and 30 mg atogepant arms experienced a decrease of 6.75 and 7.33 monthly migraine days, respectively, compared with patients in the placebo arm, who experienced a decrease of 5.09 monthly migraine days. Acadia Resubmits Nuplazid for Treatment of Alzheimer’s PsychosisAcadia Pharmaceuticals in March announced that the FDA has set an action date for the company’s resubmitted supplemental New Drug Application (sNDA) for Nuplazid (pimavanserin) for the treatment of hallucinations and delusions associated with Alzheimer’s disease psychosis. The FDA’s Division of Psychiatry has also advised the company that it is planning to hold an advisory committee meeting in connection with its review.In April 2021 the FDA rejected pimavanserin for this indication, citing “a lack of statistical significance in some of the subgroups of dementia, and insufficient numbers of patients with certain less common dementia subtypes as lack of substantial evidence of effectiveness to support approval.”The resubmission provides additional analyses from two previously conducted clinical studies, HARMONY and Study-019, to support the proposed indication for the drug and addresses the issues raised in the FDA’s rejection last year.Pimavanserin is currently approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Vraylar sNDA Submitted for Adjunctive Treatment of Major Depressive DisorderIn February AbbVie announced that it has submitted an sNDA for Vraylar (cariprazine) for the adjunctive treatment of major depressive disorder in patients who are receiving ongoing antidepressant therapy. Cariprazine is currently approved for the treatment of schizophrenia in adults, the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, and the treatment of depressive episodes associated with bipolar I disorder in adults.In a phase 3 study of 759 adults with major depressive disorder, patients who took 1.5 mg cariprazine daily experienced a statistically significant change from baseline to week six in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score compared with those who took placebo. In a second study, patients who took 2 mg to 4.5 mg of cariprazine per day also experienced a significant change from baseline to week eight in the MADRS total score compared with those who took placebo. In both of these studies, no new safety events were identified. ■ ISSUES NewArchived

Benefit–Risk Assessment of Psychotropic Drugs in Older Patients with Chronic Obstructive Pulmonary Disease

Depression, anxiety, and other mental health disorders, including bipolar disorder and schizophrenia, occur commonly in older adults with chronic obstructive pulmonary disease (COPD), and they are often inadequately treated. We review the available evidence for benefits and risks of pharmacologic treatments (e.g. selective serotonin reuptake inhibitors [SSRIs], serotonin-noradrenaline reuptake inhibitors [SNRIs], tricyclic antidepressants [TCAs], antipsychotic drugs, and benzodiazepines) for common mental illnesses in older persons with COPD. Evidence to use both SSRIs/SNRIs and TCAs from randomized controlled trials is uncertain for treating major depression in patients with COPD. However, population-based findings indicate that they are widely used, and this valuable intervention (preferably SSRIs/SNRIs) should not be denied for selected patients after evaluating potential risks and benefits, especially patients presenting with major depression and suicidal ideation, when a collaborative-care approach is being used. Although there is some evidence for the short-term use of benzodiazepines for treating insomnia, breathlessness, and anxiety in patients with COPD, their long-term use should be closely monitored or avoided to reduce the increased rate of major adverse events. Currently, there are only limited data on the use of antipsychotic drugs for managing schizophrenia or bipolar disorder in older patients with COPD. Hence, clinicians should use extra caution when prescribing antipsychotic agents and be vigilant for symptoms of acute respiratory failure and other adverse effects. Psychotropic medications are clearly beneficial for younger, healthy persons with depression and anxiety; however, the risk-benefit calculation is not so clear for treating psychological problems, schizophrenia, and bipolar disorder in older adults with COPD, given older-adult sensitivity to medications and the mixed findings of relatively few controlled trials.

The First Baby Born After Polygenic Embryo Screening

The First Baby Born After Polygenic Embryo Screening

Adult neural stem cells and schizophrenia.

Schizophrenia (SCZ) is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits. Although many genetic risk factors have been identified, SCZ is also considered as a neurodevelopmental disorder. Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes. Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood. These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination, which have been shown to be closely linked with many psychiatric disorders, such as SCZ. Here in this review, we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors. We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets, which could facilitate the development of novel medication and treatment.

Treatment Approaches for First Episode and Early-Phase Schizophrenia in Adolescents and Young Adults: A Delphi Consensus Report from Europe.

PurposeAlthough first-episode psychosis (FEP) in youth, particularly early-onset schizophrenia (EOS), is managed similarly to adult-onset schizophrenia, few antipsychotics are approved for people aged 13–18 years. We aimed to explore areas of uncertainty in EOS management and provide evidence-based recommendations to mental health specialists. We used the Delphi methodology to gain knowledge in areas lacking evidence-based strategies. This standardized methodology consists of the development of a questionnaire by content experts, which is then submitted to a broader panel of professionals (panelists) to survey their level of agreement on the topics proposed.Materials and MethodsThe developed questionnaire covered patient management from diagnosis to maintenance treatment and was administered to a broader panel of specialists across Europe. Based on an analysis of responses received in this first round, the items that needed further insight were submitted to the panel for a second round and then reanalysed.ResultsAn initial set of 90 items was developed; in round I, consensus was reached for 83/90 items (92%), while it was reached for 7/11 (64%) of the items sent out for rerating in round II. Feedback for rounds I and II was obtained from 54/92 and 48/54 approached experts, respectively. There was broad agreement on diagnostic standards, multimodal approaches and focus on adverse events, but uncertainty in terms of pharmacological strategies (including clozapine) in case of failure and antipsychotic dosing in younger patients.ConclusionDespite knowledge about diagnostic clues and integrated management of EOS, this study highlights the lack of standardization in treating EOS, with safety arguments having a major role in the decision-making process. Targeted clinical trials and systematic dissemination across Europe of current scientific evidence on the value of early intervention services is hoped to contribute to standardized and improved quality care for patients with early-phase psychosis and schizophrenia.

POSA46 Cost Analysis of Lurasidone for the Treatment of Schizophrenia in Adults within the United Kingdom

An economic model was built to establish the incremental costs of lurasidone, a second-generation atypical antipsychotic, when introduced as a first-line adult schizophrenia treatment in the UK. The incremental cost of the following treatment sequences was estimated: lurasidone, cariprazine, brexpiprazole, clozapine versus cariprazine, brexpiprazole, lurasidone and clozapine. The costs of either lurasidone or cariprazine were compared as first-line options because there are currently no restrictions on treatment lines of schizophrenia therapy. A Markov model incorporating the following health states was developed: stable (receiving, or temporarily discontinued from, treatment) and relapse. Patient movement between health states was dependent on six-weekly probabilities of relapse and discontinuation due to intolerable side effects or any other reasons. All efficacy data were obtained from network meta-analyses. A six-week cycle length was used and a 3.5% discount rate was applied to costs over a five-year time horizon. Resource use and unit costs were reflective of the NHS and were obtained from published literature. Costs included treatment, outpatient, adverse events, primary and residential care. An increased mortality risk associated with schizophrenia was applied to all patients. Deterministic sensitivity analysis was undertaken to assess the uncertainty of the economic Results: The treatment sequence containing lurasidone as a first-line treatment resulted in a cost-saving of £816 per patient. First-line lurasidone was associated with increased treatment, stable health state and adverse event costs (£570, £107 and £6 per patient respectively). However, these costs were outweighed by the cost-savings within the relapse health state (savings of £1,499 per patient). Deterministic sensitivity analysis demonstrated the results were most sensitive to discontinuation rates, relapse rates and relapse residential costs. However, no variation in inputs caused first-line lurasidone to become cost-incurring. Lurasidone is a cost-saving intervention for the treatment of schizophrenia in adults when received first-line in a UK setting.

Abnormal patterns of regional homogeneity and functional connectivity across the adolescent first-episode, adult first-episode and adult chronic schizophrenia

Functional deficits in schizophrenia (SZ) are observed prior to the onset of psychosis and differ at different stages of SZ. However, there is a paucity of studies focused on adolescent first-episode SZ (AOS), adult first-episode SZ (AFES), and adult chronic SZ (CHSZ). In this study, we investigated regional activity and corresponding functional connectivity alterations that have aimed to compare the three disease stages simultaneously. The subjects comprised 49 patients with AOS, 57 patients with AFES, 51 patients with CHSZ, 41 adolescent healthy controls, and 138 adult healthy controls. We compared regional homogeneity (ReHo) between patients at each disease stage with matched healthy controls. We focused on the shared brain regions that showed significant differences between SZ patients at the three different disease stages and healthy controls. Further analysis was conducted to explore whether the patterns of the whole brain functional connectivity alterations were similar. The putamen and medial frontal gyrus (MFG) showed consistently abnormal patterns in AOS, AFES, and CHSZ. Commonly decreased ReHo values in the MFG and increased ReHo values in the bilateral putamen were found in AOS, AFES, and CHSZ. Functional connectivity of MFG remained common abnormality in different SZ stage. In conclusion, ReHo abnormalities in the MFG and the putamen may be common abnormal patterns of brain function in the three different stages of SZ. The vmPFC-dlPFC FC abnormality common occurs in adolescence and adulthood.. This study may provide a more comprehensive understanding of the neurodevelopmental abnormality across the AOS, AFES, and CHSZ.

Letter to the Editor: Rethinking The Cost Of Antipsychotic Treatment: The Average Cost Of The Drugs Used In Turkey In 2020.

Letter to the Editor: Rethinking The Cost Of Antipsychotic Treatment: The Average Cost Of The Drugs Used In Turkey In 2020.

Medication Error : Haloperidol Toxicity In A Child With Intellectual Disability

Haloperidol is a typical antipsychotic drug used in the treatment of schizophrenia and mania in adults, and for hyperactivity, behavioural and movement disorders in children. A common adverse effect of this drug is the development of extrapyramidal symptoms due to the blockage of dopamine receptors. Here we report a case of haloperidol toxicity due to medication error.

Real-world analysis of insurance churn among young adults with schizophrenia using the Colorado All-Payer Claims Database.

BACKGROUND: Most patients with schizophrenia are diagnosed in their early twenties and often have commercial insurance at diagnosis. These young adults can experience changes in insurance coverage, that is, "churn," which can lead to disruptions in care. OBJECTIVE: To examine the frequency, speed, and type of insurance churn events in a young adult schizophrenia population with commercial insurance coverage at diagnosis. METHODS: The Colorado All-Payer Claims Database, containing insurance claims data from commercial and public insurers for Colorado residents, was used for the study. Eligible patients were required to have at least 1 inpatient or 2 outpatient claims for schizophrenia or schizoaffective disorder, be of age 18-34 years at index, have previous insurance coverage for 12 consecutive months, and have commercial insurance at diagnosis. These patients were 1:5 propensity score matched (PSM) with nonschizophrenia members. Percentages of members on different insurance types were calculated monthly to assess churn events. Cohorts were compared using descriptive statistics, Cox proportional hazards, and generalized estimating equation models. RESULTS: The matched schizophrenia and nonschizophrenia cohorts comprised 501 and 2,510 members, respectively. Before PSM, cohorts were imbalanced (schizophrenia cohort had a younger median age and higher proportion of males). After matching, the cohorts were similar in terms of the matched baseline characteristics. Previous mental health disorders were more common in the schizophrenia cohort (75%) than in the nonschizophrenia cohort (26%). The proportion of members with at least 1 churn event for the schizophrenia and nonschizophrenia cohorts, respectively, were 53.8% vs 36.5% after 12 months and 84.6% vs 69.2% after 48 months. Time to first churn event was significantly shorter in the schizophrenia cohort (16 months) than the nonschizophrenia cohort (23 months; P < 0.001). Schizophrenia cohort members had 64.1 and 56.8 churn events per 1,000 members per month vs 43.0 (P ≤ 0.001) and 42.8 (P = 0.011) churn events for nonschizophrenia cohort members in the first and second 6-month periods, respectively. Proportions of members in the schizophrenia and nonschizophrenia cohorts on public insurance, respectively, were 22.9% vs 6.9% after 12 months and 52.4% and 10.7% after 48 months. In the schizophrenia cohort, the most common churn event type was from commercial to public insurance rather than to a different commercial insurance; notably, 41% of members were still on a commercial plan 4 years after diagnosis. CONCLUSIONS: Young adults with schizophrenia experienced churn events more rapidly and more frequently than those without schizophrenia for the first 4 years studied after the index date. These disruptions may be associated with reduced access to care and treatment gaps in this vulnerable patient population. DISCLOSURES: This research was sponsored by Janssen Scientific Affairs, LLC. Pesa, Benson, and Patel are employees of Janssen Scientific Affairs, LLC, and are stockholders of Johnson & Johnson. Potluri, Rotter, and Papademetriou are employees of SmartAnalyst Inc, and their work on this study was funded by Janssen Pharmaceuticals. A version of this study was presented as a poster at the Psych Congress 2020 Virtual Experience, September 10-13, 2020.

Long-term efficacy and safety of once-monthly Risperidone ISM® in the treatment of schizophrenia: Results from a 12-month open-label extension study

ObjectiveTo evaluate long-term efficacy, safety and tolerability of Risperidone ISM® in patients with schizophrenia, a multicenter, open-label extension of the PRISMA-3 study was conducted. MethodsEligible placebo (unstable) and Risperidone ISM® (stabilized) rollover patients from a previous 12-week double-blind phase and de novo stable patients received once-monthly intramuscular injections of Risperidone ISM® 75 or 100 mg for 12 months. The long term-efficacy assessment included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales. Safety evaluation included treatment-emergent adverse events (TEAEs), injection site reactions (ISR), laboratory tests and several safety scales. ResultsAltogether, 215 patients entered the study (55 unstable, 119 stabilized and 41 stable patients). Most patients (74.9%) completed, and discontinuation rates were broadly similar across the study subgroups, mainly due to withdrawal of consent (12.1%). PANSS total and subscales scores decreased from baseline to endpoint in all groups, with the largest decrease for unstable patients. Improvement from baseline to 12 months was also shown for CGI-S and CGI-I scores for both unstable and stabilized patients; the CGI-S and CGI-I scores remained almost unchanged for the stable group. At least one treatment-related TEAE was reported in 39.1% of patients; the most common were headache (12.1%), hyperprolactinemia (9.8%) and asthenia (5.1%). ISR were reported in 8 (0.3%) patients; injection site pain score was low across the 2355 doses assessed. ConclusionRisperidone ISM® is an effective, safe, and well-tolerated long-term treatment of schizophrenia in adults, regardless of the initial disease severity or whether patients were previously treated with Risperidone ISM® during an acute exacerbation or switched from stable doses of oral risperidone.

Risperidone for Extended-Release Injectable Suspension (Perseris)

&#x0D; CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.&#x0D; The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.&#x0D; This review assesses risperidone for extended-release injectable suspension (Perseris), powder for suspension, 90 mg or 120 mg subcutaneous injection.&#x0D; Indication: Treatment of schizophrenia in adults.&#x0D;

Risk of First-Episode Schizophrenia in Aged Adults Increased During COVID-19 Outbreak.

We noticed an unusual increase of aged adults in first-episode schizophrenia in January and February 2020 since the outbreak of COVID-19. This retrospective study aims to statistically validate this observation and find potential risk factors, if applicable. The demographics of schizophrenia in outpatients (both first-episode and follow-up) from January to March 2020 (36,624 records) and similar periods of 2017–2019 (114,141 records) were analyzed and compared to minimize seasonal influence. Limited personal information (age, gender, approximate residence) was investigated to find risk factors. After considering seasonal factors such as the Spring festival, the age of the first-episode schizophrenia was significantly increased in January (46.60 ± 15.14) and February (51.53 ± 14.74) but went back to normal in March 2020 (38.89 ± 14.59), compared with similar periods from 2017 to 2019 (Jan., 40.77 ± 15.26; Feb., 39.69 ± 15.10; Mar., 42.04 ± 15.83). Meanwhile, a slight but not significant change was found in the distribution of gender and approximate residence (urban/suburb). Our data supported that risk of first-episode schizophrenia in aged adults increased during the COVID-19 outbreak, which is consistent with the fact that COVID-19 is more lethal to elders. Public healthcare should prepare in advance for potential risks in public mental health, especially for elders.

Maternal immune activation downregulates schizophrenia genes in the foetal mouse brain.

Susceptibility to schizophrenia is mediated by genetic and environmental risk factors. Maternal immune activation by infections during pregnancy is hypothesized to be a key environmental risk factor. However, little is known about how maternal immune activation contributes to schizophrenia pathogenesis. In this study, we investigated if maternal immune activation influences the expression of genes associated with schizophrenia in foetal mouse brains. We found that two sets of schizophrenia genes were downregulated more than expected by chance in the foetal mouse brain following maternal immune activation, namely those genes associated with schizophrenia through genome-wide association study (fold change = 1.93, false discovery rate = 4 × 10−4) and downregulated genes in adult schizophrenia brains (fold change = 1.51, false discovery rate = 4 × 10−10). We found that these genes mapped to key biological processes, such as neuronal cell adhesion. We also identified cortical excitatory neurons and inhibitory interneurons as the most vulnerable cell types to the deleterious effects of this interaction. Subsequently, we used gene expression information from herpes simplex virus 1 infection of neuronal precursor cells as orthogonal evidence to support our findings and to demonstrate that schizophrenia-associated cell adhesion genes, PCDHA2, PCDHA3 and PCDHA5, were downregulated following herpes simplex virus 1 infection. Collectively, our results provide novel evidence for a link between genetic and environmental risk factors in schizophrenia pathogenesis. These findings carry important implications for early preventative strategies in schizophrenia.

Risperidone for Extended-Release Injectable Suspension (Perseris)

&#x0D; CADTH recommends that Perseris should be reimbursed by public drug plans for the treatment of schizophrenia in adults if certain conditions are met.&#x0D; Perseris should be covered by public drug plans in a similar manner to other long-acting injectable atypical antipsychotic drugs for the treatment of adults with schizophrenia.&#x0D; Perseris should only be reimbursed if the total monthly dose is not more than 120 mg and is not used in combination with other long-acting injectable antipsychotic drugs. Perseris should not cost more than other long-acting injectable (LAI) atypical antipsychotic drugs.&#x0D;