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BackgroundLatinos are more likely than non-Latino Whites to develop dementia and be prescribed antipsychotics for dementia-related behavioral symptoms. Antipsychotics have significant risks yet are often overprescribed. Our understanding of how Latino caregivers of Latino older adults living with dementia perceive and address behavioral issues is limited, impeding our ability to address the root causes of antipsychotic overprescribing.MethodsWe interviewed Latino older adults' caregivers and community-based organization workers serving older adults with cognitive impairment (key informants), focusing on the management of behavioral symptoms and experiences with health services.ResultsWe interviewed 8 caregivers and 2 key informants. Caregivers were the spouses, children, or grandchildren of the older adult living with cognitive impairment; their ages ranged from 30 to 95. We identified three categories of how caregivers learned about, managed, and coped with behavioral symptoms: caregivers often faced shortcomings with dementia care in the medical system, receiving limited guidance and support; caregivers found community organizations and senior day centers to be lifelines, as they received relevant, timely advice and support, caregivers often devised their own creative strategies to manage behavioral symptoms.ConclusionIn-depth interviews suggest that the healthcare system is failing to provide support for behavioral symptoms from dementia; caregivers of Latino older adults rely on community organizations instead.

Background Case Presentation Conclusions Ischemic priapism is a rare pathological condition, and delayed intervention can result in irreversible sequelae. Most cases are attributed to the use of antipsychotics. The blockade of α1‐adrenergic receptors is thought to be associated with the disease onset, although data supporting this hypothesis are lacking. No consensus regarding the optimal choice of medication is available.A 59‐year‐old man with schizophrenia, who had been receiving long‐acting injections of risperidone, developed ischemic priapism after receiving paliperidone treatment. Following improvement in ischemic priapism, we administered a combination of aripiprazole and olanzapine, which improved his psychiatric symptoms. We did not observe any recurrence of ischemic priapism.Switching the antipsychotic drug causing ischemic priapism to patients having a relatively low affinity for α1‐adrenergic receptors may enable the treatment of schizophrenia without recurrence of ischemic priapism. In addition to the affinity for α1‐adrenergic receptor, differences in metabolic enzyme types and antipsychotic doses may be involved in the occurrence of ischemic priapism. Accumulating evidence is necessary to establish guidelines for selecting medication of patients with ischemic priapism. [ABSTRACT FROM AUTHOR]

Background: Lumateperone has been approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia in adults since 2019, however, there is still a lack of data report on adverse reactions in real-world settings. Conducting data mining on adverse events (AEs) associated with Lumateperone and investigating the risk factors for serious AEs can provide valuable insights for its clinical practice. Methods: AE reports in the FDA Adverse Event Reporting System (FAERS) from 2019 Q4 (FDA approval of Lumateperone) to 2024 Q1 were collected and analyzed. Disproportionality in Lumateperone-associated AEs was evaluated using the following parameters: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). Univariate and multivariate logistic regression analyses were conducted to identify the risk factors for Lumateperone-induced severe AEs. Results: A total of 2,644 reports defined Lumateperone as the primary suspected drug was collected, including 739 reports classified as severe AEs and 1905 reports as non-severe AEs. The analysis revealed that 130 preferred terms (PTs) with significant disproportionality were based on the four algorithms, 67 (51.53%) of which were not included in the product labeling, affecting 6 systems and organs. In addition, dizziness (81 cases) was the most reported Lumateperone-associated severe AEs, and tardive dyskinesia showed the strongest signal (ROR = 186.24). Logistic regression analysis indicated that gender, bipolar II disorder, and concomitant drug use are independent risk factors for Lumateperone-associated severe AEs. Specifically, female patients had a 1.811-fold increased risk compared with male patients (OR = 1.811 [1.302, 2.519], p = 0.000), while patients with bipolar II disorder had a 1.695-fold increased risk compared with patients diagnosed with bipolar disorder (OR = 1.695 [1.320, 2.178], p = 0.000). Conversely, concomitant use of CYP3A4 inhibitors or drugs metabolized by CYP3A4 was associated with a decreased risk of severe AEs (OR = 0.524 [0.434, 0.633], P = 0.000). Conclusion: Collectively, this study provides critical insights into the safety profile of Lumateperone. It highlights the need for cautious use in high-risk populations, such as females and individuals with bipolar II disorder, and emphasizes the importance of monitoring for AEs, including dizziness and tardive dyskinesia. Healthcare also should remain alert to potential AEs not listed in the prescribing information to ensure medical safety. [ABSTRACT FROM AUTHOR]

Objective: The incidence of neuroleptic malignant syndrome (NMS), a rare, potentially fatal adverse effect of antipsychotics, among children and youth is unknown. This cohort study estimated NMS incidence in antipsychotic users age 5–24 years and described its variation according to patient and antipsychotic characteristics. Methods: We used national Medicaid data (2004–2013) to identify patients beginning antipsychotic treatment and calculated the incidence of NMS during antipsychotic current use. Adjusted hazard ratios (HRs) assessed the independent contribution of patient and antipsychotic characteristics to NMS risk. Results: The 1,032,084 patients had 131 NMS cases during 1,472,558 person-years of antipsychotic current use, or 8.9 per 100,000 person-years. The following five factors independently predicted increased incidence: age 18–24 years (HR [95% CI] = 2.45 [1.65–3.63]), schizophrenia spectrum and other psychotic disorders (HR = 5.86 [3.16–10.88]), neurodevelopmental disorders (HR = 7.11 [4.02–12.56]), antipsychotic dose >200mg chlorpromazine-equivalents (HR = 1.71 [1.15–2.54]), and first-generation antipsychotics (HR = 4.32 [2.74–6.82]). NMS incidence per 100,000 person-years increased from 1.8 (1.1–3.0) for those with none of these factors to 198.1 (132.8–295.6) for those with 4 or 5 factors. Findings were essentially unchanged in sensitivity analyses that restricted the study data to second-generation antipsychotics, children age 5–17 years, and the 5 most recent calendar years. Conclusion: In children and youth treated with antipsychotics, five factors independently identified patients with increased NMS incidence: age 18–24 years, schizophrenia spectrum and other psychotic disorders, neurodevelopmental disorders, first-generation drugs, and antipsychotic doses greater than 200 mg chlorpromazine-equivalents. Patients with 4 or 5 of these factors had more than 100 times the incidence of those with none. These findings could improve early identification of children and youth with elevated NMS risk, potentially leading to earlier detection and improved outcomes. [ABSTRACT FROM AUTHOR]

Introduction While antipsychotics are often prescribed for behavioral and psychological symptoms of dementia (BPSD), typically on an off-label basis, these medications have serious adverse effects. This study investigated the long-term use of antipsychotics among inpatients with dementia displaying severe BPSD, focusing on how prescriptions change over time. Methods Medical charts at Kusakabe Memorial Hospital were retrospectively reviewed from October 2012 to September 2021. The study included patients diagnosed with dementia, admitted for BPSD, and were continuing antipsychotics at 3 months of their admission. Antipsychotic dosages were categorized as high (≥300 mg/d), medium (100–300 mg/d), and low (<100 mg/d) based on chlorpromazine equivalents and tracked until 15 months during hospitalization. Binary logistic regression was used to identify factors associated with dosage reductions between months 3 and 6. Results This study involved 188 patients, with an average age of 81.2 years, 67% of whom were diagnosed with Alzheimer's dementia. At 3 months, 15.4% were taking high, 44.1% on medium, and 40.4% on low dosages of antipsychotics. The highest average dosage was observed at 3 months, with a subsequent decrease over time. By the 12th month, 20–30% of patients in all dosage categories had stopped their antipsychotic medication. Significant factors for dosage reduction included higher initial doses (OR 1.003, 95%Cl: 1.001–1.006, P=0.01) and male gender (OR 2.481, 95%Cl: 1.251–4.918, P=0.009). Discussion A trajectory of antipsychotic dosage in inpatients with severe BPSD has rarely been reported. This research emphasizes the need for personalized strategies in managing long-term pharmacotherapy for this vulnerable group of patients. [ABSTRACT FROM AUTHOR]

Background: Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid symptoms such as psychosis and cognitive dysfunction. Serotonin (5-HT) neurotransmission is involved in a wide variety of psychiatric diseases and its potential as a drug target continues to attract attention. Objectives: The present study elucidates the effects of a novel 5-HT modulator, DSP-6745, on depression and its comorbid symptoms. Results: In vitro radioligand binding and functional assays showed that DSP-6745 is a potent inhibitor of 5-HT transporter and 5-HT2A, 5-HT2C, and 5-HT7 receptors. In vivo, DSP-6745 (6.4 and 19.1 mg/kg as free base, p.o.) increased the release of not only 5-HT, norepinephrine, and dopamine, but also glutamate in the medial prefrontal cortex. The results of in vivo mouse phenotypic screening by SmartCube® suggested that DSP-6745 has a behavioral signature combined with antidepressant-, anxiolytic-, and antipsychotic-like signals. A single oral dose of DSP-6745 (6.4 and 19.1 mg/kg) showed rapid antidepressant-like efficacy in the rat forced swim test, even at 24 h post-dosing, and anxiolytic activity in the rat social interaction test. Moreover, DSP-6745 (12.7 mg/kg, p.o.) led to an improvement in the apomorphine-induced prepulse inhibition deficit in rats. In the marmoset object retrieval with detour task, which is used to assess cognitive functions such as attention and behavioral inhibition, DSP-6745 (7.8 mg/kg, p.o.) enhanced cognition. Conclusions: These data suggest that DSP-6745 is a multimodal 5-HT receptor antagonist and a 5-HT transporter inhibitor and has the potential to be a rapid acting antidepressant with efficacies in mitigating the comorbid symptoms of depression. [ABSTRACT FROM AUTHOR]

Neurochemical dysregulations resulting from N-methyl-D-aspartate hypofunction (NMDA), are exacerbated by neuroimmune and oxidative stress and are known risk factors for neuropsychiatric disorders like schizophrenia-like diseases. Here, we investigate the protective and curative effects, and mechanisms of silymarin, a polyphenolic flavonoid with neuroprotective functions in preventive-reversal model of ketamine, an NMDA antagonist in mice. Mice were grouped into 6 cohorts (n = 9). In the pre-treatment, groups 1 and 2 received saline (10 mL/kg/p.o.), groups 3 and 4 (silymarin, 50 and 100 mg/kg/p.o.), and group 5 (risperidone, 0.5 mg/kg/p.o.) consecutively for 14 days, then combined with ketamine (20 mg/kg/i.p.) injection in groups 2–5 from days 8–14. However, mice in reversal study received intraperitoneal injection of ketamine for 14 days before silymarin (50 and 100 mg/kg, p.o) and risperidone (0.5 mg/kg, p.o.) treatment between days 8–14. The consequences on schizophrenia-like behavior, neurochemistry, inflammation, and oxidative/nitrergic stress markers were evaluated in critical brain regions of the disease. Silymarin prevented and reversed ketamine-induced increase in dopamine, 5-hydroxyltryptamine, acetylcholinesterase, malondialdehyde and nitrite levels in the striatum, prefrontal-cortex and hippocampus. These were accompanied by improvement in hyperlocomotion, stereotypy, memory, and social impairments, notably devoid of cataleptogenic potential. Complementarily, silymarin reduced myeloperoxidase, tumor-necrosis factor-α, and interleukin-6 concentrations relative to the ketamine group. Moreover, ketamine-induced decreased brain-derived neurotrophic factor, glutathione, catalase, superoxide-dismutase levels were normalized by silymarin in the brain regions relative to ketamine. Overall, these findings suggest that silymarin's antipsychotic effect might be primarily associated, among other mechanisms, with the normalization of neurochemical and neurotrophic changes in the mice brains. [ABSTRACT FROM AUTHOR]

Long‐term sample stability of five atypical antipsychoticdrugs risperidone, paliperidone, clozapine, quetiapine and olanzapine and the antidepressant drug mirtazapine in serum was studied by use of a newly developed and validated analytical method based on solid‐phase extraction and liquid chromatography–tandem mass spectrometry. Ascorbic acid was used as an antioxidative agent to stabilize olanzapine during storage and sample preparation. We assessed analyte stability on long‐term storage in serum samples at 25°C, 5°C, −20°C and −80°C, and during five freeze–thaw cycles. Analytes were stable for 23 days at room temperature except for olanzapine and mirtazapine (17 days). All analytes were stable for at least 30 days at 5°C. All analytes were stable for 270 days at −20°C, except for paliperidone and mirtazapine with 60 days and 180 days, respectively. All analytes were stable for 270 days at −80°C. Furthermore, all analytes were stable for five freeze–thaw cycles. We recommend storage at −80°C when samples drawn for analysis of antipsychotic drugs are stored for more than 60 days, whereas a temperature of −20°C is sufficient for storage less than 60 days. [ABSTRACT FROM AUTHOR]

Background and Hypothesis The World Health Organization's (WHOs) Mental Health Gap Action Programme (mhGAP) aims to improve healthcare for mental, neurological, and substance use disorders in nonspecialized settings, with a focus on low- and middle-income countries (LMICs). mhGAP includes guidelines for the treatment of psychoses (including schizophrenia), which were recently updated in 2023. The complexity of the WHO guideline update process and the updated recommendations on psychoses are presented. Study Design The WHO guideline development process is outlined as well as the evidence appraisal and the translation of the evidence into recommendations following the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. The guideline update process includes a review of the literature, a compilation of systematic reviews, and extracting data related to critical and important outcomes. The updated recommendations and the justifying evidence are discussed. Study Results The WHO mhGAP guidelines for psychoses are adapted to LMICs, and consist of 13 recommendations in 2023, whereof 5 were updated, and 1 recommendation was newly developed. Background information on how these recommendations were obtained, and significant changes since the previous guideline update in 2015 are provided. Conclusions Unlike other guidelines, the WHO must consider various countries, contextual factors, and the WHO Model Lists of Essential Medicines when developing its guidelines. A transformation of the WHO guideline for psychoses into a living guideline would ensure always up-to-date recommendations and facilitate shared decision-making. [ABSTRACT FROM AUTHOR]

Objective: Over time, most patients with schizophrenia wish to reduce or discontinue their antipsychotic medication treatment. In Denmark, a specialized government-funded outpatient clinic was established to offer guided antipsychotic dose reduction. This study aimed to provide data on motivations for and previous experiences with antipsychotic tapering among patients attending the clinic. Methods: Patients completed an open-ended survey on their motivations for discontinuing or tapering antipsychotic medication and recorded their expectations about these outcomes. They also provided information on previous experiences with discontinuing medication and their level of symptoms, functioning, and side effects. Results: The survey was completed by 76 (86%) of 88 patients. The main motivations for discontinuing antipsychotics were adverse effects (71%) and uncertainty about the necessity of taking antipsychotics (29%). Other factors included concerns about long-term effects, disagreeing with the diagnosis, experiencing an insufficient effect, and feeling stigmatized by taking medication. Previous experience with discontinuation of antipsychotics was reported by 42 patients, of whom 23 reported relapse as the outcome. Most patients believed they could succeed in dose reduction (N=73 of 75, 97%) or discontinuation (N=62 of 75, 83%). Conclusions: Motivational factors reported for professionally guided antipsychotic dose reduction align with previous studies examining patients choosing to discontinue these medications. Despite reports of relapse during prior discontinuation attempts, most patients still reported motivation for and belief in successful dose reduction or discontinuation. An understanding of patients' motivations and beliefs is paramount to an optimal treatment alliance. Offering guided dose reduction may reduce sudden and unsupported discontinuation of antipsychotics. [ABSTRACT FROM AUTHOR]

Schizophrenia is serious and prevalent psychotic condition in which patients misinterpret the real conditions and might cause combination of symptoms like hallucinations, delusions, and extremely disordered thinking and impaired behavior during daily functioning. People who are suffering from schizophrenia require lifelong treatment. The scientists are elucubrating round the clock to contribute novel pharmacological compounds in the hopes of improving the "quality of life" of schizophrenia patients. The antipsychotics drugs which are currently available in the market for management of schizophrenia needs reformulation into lipid vesicular nanocarrier systems with tremendous potential to provide superior platform as cutting-edge therapeutic strategies to target the brain via intranasal administration and thereby reduced the systemic adverse effects. The development of nanoformulation also provides sustained or prolonged drug delivery systems which might be helpful in reducing necessitate of frequent dosage administration. The transferosomes are types of vesicular nanocarriers which have been explored extensively in previous decades to address the flaws of conventional drug delivery systems and currently aregaining significant relevance in therapeutics owing to their capacity to conquer drug penetration challenges via biological membranes which acts by squeezing the vesicular structure into intercellular lipid barrier of biological membrane. The non-invasive intranasal delivery of drugs via nanotransferosomal vesicles acts as valuable tool for drugs with poor bioavailability. This review article addresses the risk factors for schizophrenia; key challenges faced with conventional medicines and the significance of nanotransferosomes in intranasal drug delivery for the management of schizophrenia which might advance the quality of living of patients suffering from schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia and substance use disorders (SUDs) are often comorbid conditions that present clinical challenges due to their heterogeneity and the difficulties associated with poor physical health, low medication adherence, high relapse and hospitalization rates, and increased risk of mortality. This is often exacerbated by a fragmented health care system that treats addiction and mental illness separately, leading to delays in proper diagnosis and treatment. Main text: The aim of this narrative review, based on an extensive literature search and experts' clinical experience, is to synthesize evidence on the psychopathological and clinical characteristics of patients, the burden and management at the level of healthcare system, and possible gaps in the treatment of schizophrenia with comorbid SUD in order to understand and address the needs of patients. Treatment options, differences between antipsychotic medications, and the benefits of long-acting formulations and partial dopaminergic agonists are described. Partial dopamine agonists (aripiprazole, cariprazine, and brexpiprazole) have demonstrated good control of psychotic symptoms and SUDs with a favorable safety profile. Conclusion: Pharmacological interventions should be accompanied by psychosocial support within an integrated and multidisciplinary approach that promotes shared decision-making and a good therapeutic alliance between the entire medical team and the patient. [ABSTRACT FROM AUTHOR]

Background: Appropriate use of medication is a key indicator of the quality of care provided in long-term care (LTC). The objective of this study was to determine whether resident-facility language concordance/discordance is associated with the odds of potentially inappropriate prescribing of antipsychotics (PIP-AP) in LTC. Methods: We conducted a population-based, retrospective cohort study of LTC residents in Ontario, Canada from 2010 to 2019. We obtained resident language from standardized resident assessments, and derived facility language by determining the proportion of residents belonging to each linguistic group within individual LTC homes. Using linked administrative databases, we identified all instances of PIP-AP during a 1-year follow-up period. PIP-AP was defined using the STOPP-START criteria, which have previously been shown to predict adverse clinical events such as emergency department (ED) visits and hospitalizations. The association between linguistic factors and PIP-AP was assessed using adjusted multivariable logistic regression analysis. Results: We identified 198,729 LTC residents consisting of 162,814 Anglophones (81.9%), 6,230 Francophones (3.1%), and 29,685 Allophones (14.9%). The odds of PIP-AP of were higher for both Francophones (aOR 1.15, 95% CI 1.08–1.23) and Allophones (aOR 1.11, 95% CI 1.08–1.15) when compared to Anglophones. When compared to English LTC homes, French LTC homes had greater odds of PIP-AP (aOR 1.12, 95% CI 1.05–1.20), while Allophone homes had lower odds of PIP-AP (aOR 0.82, 95% CI 0.77–0.86). Residents living in language-discordant LTC homes had higher odds of PIP-AP when compared to LTC residents living in language-concordant LTC homes (aOR 1.07, 95% CI 1.04–1.10). Conclusion: This study identified linguistic factors related to the odds of PIP-AP in LTC, suggesting that the linguistic environment may have an impact on the quality of care provided to residents. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion Long‐acting injectable antipsychotics (LAIs) are not routinely offered to patients living with bipolar disorder type I (BP‐I), despite widespread evidence that supports their benefits over oral antipsychotics, particularly in early disease.A round‐table meeting of psychiatrists convened to discuss barriers and opportunities and provide consensus recommendations around the early use of LAIs for BP‐I.LAIs are rarely prescribed to treat BP‐I unless a patient has severe symptoms, sub‐optimal adherence to oral antipsychotics, or has experienced multiple relapses. Beyond country‐specific accessibility issues (e.g., healthcare infrastructure and availability/approval status), primary barriers to the effective use of LAIs were identified as attitudinal and knowledge/experience‐based. Direct discussions between healthcare providers and patients about treatment preferences may not occur due to a preconceived notion that patients prefer oral antipsychotics. Moreover, as LAIs have historically been limited to the treatment of schizophrenia and the most severe cases of BP‐I, healthcare providers might be unaware of the benefits LAIs provide in the overall management of BP‐I. Improved treatment adherence associated with LAIs compared to oral antipsychotics may support improved outcomes for patients (e.g., reduced relapse and hospitalization). Involvement of all stakeholders (healthcare providers, patients, and their supporters) participating in the patient journey is critical in early and shared decision‐making processes. Clinical and database studies could potentially bridge knowledge gaps to facilitate acceptance of LAIs.This review discusses the benefits of LAIs in the management of BP‐I and identifies barriers to use, while providing expert consensus recommendations for potential solutions to support informed treatment decision‐making. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion To explore the optimal dose of blonanserin transdermal patch (BNS‐P) based on baseline psychiatric symptomatic characteristics during acute schizophrenia.A post hoc cluster analysis was conducted using data from a 6‐week randomized, double‐blind, placebo‐controlled study of BNS‐P (40 or 80 mg/day) in acute schizophrenia. We classified patients into three clusters based on baseline psychiatric symptoms. Efficacy was assessed using the change from baseline to week 6 in the PANSS total score. Safety was assessed by the incidence of adverse events.Among 577 patients, three clusters were identified, characterized by severe psychiatric (Cluster‐S; n = 122), predominant negative (Cluster‐N; n = 191), and predominant positive (Cluster‐P; n = 264) symptoms. In Cluster‐P, both BNS‐P 40 and 80 mg/day reduced PANSS total score significantly more than placebo (p = 0.036, effect size = 0.342; p < 0.001, effect size = 0.687, respectively). In Cluster‐S and ‐N, only BNS‐P 80 mg/day reduced PANSS total score significantly more than placebo (p = 0.045, effect size = 0.497; p = 0.034, effect size = 0.393, respectively). The effect size was greater at 80 mg/day than at 40 mg/day across all clusters. The most common treatment‐emergent adverse events were akathisia and skin‐related adverse events in all clusters.BNS‐P exhibited a dose‐dependent antipsychotic effect in all clusters, particularly highlighting its efficacy in patients with predominant positive symptoms, even at lower doses. These findings provide novel and valuable insights for determining BNS‐P dose tailoring to individual symptomatic characteristics in real‐world practice. [ABSTRACT FROM AUTHOR]

Risperidone extended‐release injectable suspension (R‐ERIS; marketed as RYKINDO) is a novel immediate‐release version of risperidone formulated as extended‐release microspheres for biweekly intramuscular injection to treat schizophrenia in adults. The pharmacokinetics (PK) and safety of R‐ERIS were evaluated in a multicenter, randomized, open‐label, multiple‐dose study in patients with stable schizophrenia or schizoaffective disorder. Eligible patients (N = 108) 18 to 65 years old were randomized (1:1) to receive IM injections of R‐ERIS 25 mg or the comparator, a biweekly risperidone long‐acting injectable (BW‐RLAI; marketed as RISPERDAL CONSTA) 25 mg for a total of 5 injections. The primary objective was to evaluate the relative bioavailability of active moiety (risperidone plus 9‐hydroxyrisperidone) at steady state. Blood samples were analyzed for risperidone and 9‐hydroxyrisperidone using a validated, specific, and sensitive liquid chromatography with tandem mass spectrometry method. Plasma concentration–time data were analyzed using non‐compartmental methods. Pharmacokinetic parameters were calculated based on individual patient PK profiles. Safety was assessed using standard measures. At steady state, mean plasma concentrations of the active moiety were similar for R‐ERIS and BW‐RLAI. R‐ERIS rapidly released risperidone after the injection without apparent lag time. Plasma active moiety levels reached steady state after the second injection of R‐ERIS. The elimination of the drug was completed approximately 2 weeks earlier for R‐ERIS as compared to that for BW‐RLAI. R‐ERIS was safe and well tolerated. Overall, R‐ERIS exhibited a faster onset and offset than BW‐RLAI and statistical analysis of exposure parameters demonstrated bioequivalence at steady state. [ABSTRACT FROM AUTHOR]

Schizophrenia is a leading cause of global disease burden. Current drug treatments are associated with significant side effects and have limited efficacy for many patients, highlighting the need to develop new approaches that target other aspects of the neurobiology of schizophrenia. Preclinical, in vivo imaging, postmortem, genetic, and pharmacological studies have highlighted the key role of cortical GABAergic (gamma-aminobutyric acidergic)-glutamatergic microcircuits and their projections to subcortical dopaminergic circuits in the pathoetiology of negative, cognitive, and psychotic symptoms. Antipsychotics primarily act downstream of the dopaminergic component of this circuit. However, multiple drugs are currently in development that could target other elements of this circuit to treat schizophrenia. These include drugs for GABAergic or glutamatergic targets, including glycine transporters, D-amino acid oxidase, sodium channels, or potassium channels. Other drugs in development are likely to primarily act on pathways that regulate the dopaminergic system, such as muscarinic or trace amine receptors or 5-HT 2A receptors, while PDE10A inhibitors are being developed to modulate the downstream consequences of dopaminergic dysfunction. Our review considers where new drugs may act on this circuit and their latest clinical trial evidence in terms of indication, efficacy, and side effects. Limitations of the circuit model, including whether there are neurobiologically distinct subgroups of patients, and future directions are also considered. Several drugs based on the mechanisms reviewed have promising clinical data, with the muscarinic agonist KarXT most advanced. If these drugs are approved for clinical use, they have the potential to revolutionize understanding of the pathophysiology and treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

Bipolar disorder is the fourth most debilitating psychiatric illness in the world regarding Disability Adjusted Life Years and manic episodes frequently lead to lengthy hospitalizations which restricts the freedom of patients. Therefore, decreasing the length of hospitalization with safer agents is of utmost importance in the treatment of manic episodes. Aripiprazole is a medication known for its efficacy in managing mania associated with bipolar disorder. Aripiprazole long‐acting injection is approved for the treatment of mania associated with bipolar disorder in adults and found efficacious as a maintenance treatment. In the treatment of schizophrenia, European Medicines Agency has approved a simplified starting strategy of aripiprazole once a month, with two 400 mg injections and a single oral 20 mg dose of aripiprazole. To the best of our knowledge, no previous study has reported the safety, tolerability, and efficacy of this regimen in adult bipolar disorder patients. We present a case series of eight patients who were admitted to the hospital in a manic episode with psychotic features. We observed that the double injection start regimen was effective in treating manic symptoms with no specific severe adverse events. We conclude from a small sample of manic patients that a double injection start regimen has good efficacy and tolerability. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Antipsychotics increase the risk of developing diabetes, but clinical trials are not generalizable with short follow‐up, while observational studies often lack important information, particularly hemoglobin A1c (HbA1c).We followed two Danish cohorts with schizophrenia. First, using Danish nationwide registers, we identified all individuals diagnosed with first‐episode schizophrenia (FES) between 1999 and 2019 (n = 31,856). Exposure was a redeemed prescription for an antipsychotic, and the outcome was diabetes, defined via hospital‐based diagnosis and redeemed prescriptions for glucose‐lowering drugs. Adjusted Cox regression calculated hazard rate ratios (HRR). Second, using data from the Central Denmark Region, we identified all individuals diagnosed with FES from October 2016 to September 2022 (n = 2671). Using a within‐subject design, we analyzed the change in HbA1c during the 2 years after initiation of specific antipsychotics compared to the 2 years before.In the nationwide cohort, 2543 (8.0%) individuals developed diabetes (incidence rate = 9.39 [95% CI = 9.03–9.76] per 1000 person‐years). Antipsychotics, compared to periods without, were associated with an increased risk of developing diabetes (HRR = 2.04, 95% CI = 1.75–2.38). We found a dose–response association, particularly for second‐generation antipsychotics, and different risk rates for specific antipsychotics. In the Central Denmark Region cohort, a total of 9.2% developed diabetes but mean HbA1c levels remained stable at 37 mmol/mol during the 2 years after initiation of antipsychotic medication.This comprehensive real‐world two‐cohort study emphasizes that diabetes affects almost 10% of patients with FES. Antipsychotics increase this risk, while HbA1c deterioration requires longer treatment. These findings are important for clinicians and young patients with FES. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusion Interpatient variability in bipolar I depression (BP‐D) symptoms challenges the ability to predict pharmacotherapeutic outcomes. A machine learning workflow was developed to predict remission after 8 weeks of pharmacotherapy (total score of ≤8 on the Montgomery Åsberg Depression Rating Scale [MADRS]).Supervised machine learning models were trained on data from BP‐D patients treated with olanzapine (N = 168) and were externally validated on patients treated with olanzapine/fluoxetine combination (OFC; N = 131) and lamotrigine (LTG; N = 126). Top predictors were used to develop a prognosis rule informing how many symptoms should change and by how much within 4 weeks to increase the odds of achieving remission.An AUC of 0.76 (NIR:0.59; p = 0.17) was established to predict remission in olanzapine‐treated subjects. These trained models achieved AUCs of 0.70 with OFC (NIR:0.52; p < 0.03) and 0.73 with LTG (NIR:0.52; p < 0.003), demonstrating external replication of prediction performance. Week‐4 changes in four MADRS symptoms (reported sadness, reduced sleep, reduced appetite, and concentration difficulties) were top predictors of remission. Across all pharmacotherapies, three or more of these symptoms needed to improve by ≥2 points at Week‐4 to have a 65% chance of achieving remission at 8 weeks (OR: 3.74, 95% CI: 2.45–5.76; p < 9.3E‐11).Machine learning strategies achieved cross‐trial and cross‐drug replication in predicting remission after 8 weeks of pharmacotherapy for BP‐D. Interpretable prognoses rules required only a limited number of depressive symptoms, providing a promising foundation for developing simple quantitative decision aids that may, in the future, serve as companions to clinical judgment at the point of care. [ABSTRACT FROM AUTHOR]

Objective: The authors used longitudinal biobank data with up to 25 years of follow-up on over 2,600 clozapine users to derive reliable estimates of the real-world burden of clozapine adverse drug events (ADEs). Methods: A total of 2,659 participants in the FinnGen biobank project had a schizophrenia diagnosis and clozapine purchases with longitudinal electronic health record follow-up for up to 25 years after clozapine initiation. Diseases and health-related events enriched during clozapine use were identified, adjusting for disease severity. The incidence and recurrence of ADEs over years of clozapine use, their effect on clozapine discontinuation and deaths, and their pharmacogenetics were studied. Results: Median follow-up time after clozapine initiation was 12.7 years. Across 2,157 diseases and health-related events, 27 were enriched during clozapine use, falling into five disease categories: gastrointestinal hypomotility, seizures, pneumonia, other acute respiratory tract infections, and tachycardia, along with a heterogeneous group including neutropenia and type 2 diabetes, among others. Cumulative incidence estimates for ileus (severe gastrointestinal hypomotility) and pneumonia were 5.3% and 29.5%, respectively, 20 years after clozapine initiation. Both events were significantly associated with increased mortality among clozapine users (ileus: odds ratio=4.5; pneumonia: odds ratio=2.8). Decreased genotype-predicted CYP2C19 and CYP1A2 activities were associated with higher pneumonia risk. Conclusions: Clozapine-induced ileus and pneumonia were notably more frequent than has previously been reported and were associated with increased mortality. Two CYP genes influenced pneumonia risk. Pneumonia and ileus call for improved utilization of available preventive measures. [ABSTRACT FROM AUTHOR]

Background: Sepsis constitutes a condition that involves life-threatening organ dysfunction induced by severe infection. This nested case–control study investigated risk factors for severe sepsis and whether antipsychotic use is associated with severe sepsis risk in patients with schizophrenia, a topic that has not been comprehensively explored in previous studies. Methods: We selected 39,432 patients with schizophrenia aged between 15 and 65 years from Taiwan's Psychiatric Inpatient Medical Claims database for the period 2000–2012. The case group comprised patients with severe sepsis after their first psychiatric admission (n = 1382). The case and control groups were randomly matched (1:4) by age, sex and first psychiatric admission (year) and finally comprised 1382 and 5528 individuals, respectively. We employed multivariable conditional logistic regression to identify (1) risk factors (physical illnesses and nonpsychiatric medications) and (2) antipsychotic–severe sepsis associations. Results: Higher numbers of psychiatric admissions and physical illnesses such as delirium, cerebrovascular disease and cancer were significantly associated with a higher risk of severe sepsis. Furthermore, severe sepsis was associated with the use of antithrombotic agents, systemic corticosteroids and agents targeting the renin–angiotensin system. Clozapine (adjusted risk ratio = 1.65) and quetiapine (adjusted risk ratio = 1.59) use were associated with an increased risk of severe sepsis. The use of more than one antipsychotic drug could further increase this risk. Conclusion: Several physical illnesses and nonpsychiatric medications increase the risk of severe sepsis in patients with schizophrenia. Specifically, clozapine or quetiapine use significantly increased the risk of severe sepsis in these patients. [ABSTRACT FROM AUTHOR]

Background: In the population of patients in the intensive care unit (ICU), most studies compared the use of atypical antipsychotics, such as quetiapine, with the use of traditional haloperidol in patients with delirium of various forms and etiologies. The role of such agents in patients with hyperactive delirium is not fully understood. This study compares the effectiveness of quetiapine with haloperidol in treating the hyperactive form of delirium in terms of their effects on the Delirium Rating Scale-Revised-98 (DRS-R-98), length of stay in the ICU, and mortality in critically ill patients. Methods: One hundred adult patients diagnosed with hyperactive delirium were randomly assigned to receive either oral quetiapine (25–50 mg/day) or haloperidol (1–2 mg/day). The response, defined as "a DRS-R-98 severity score reduction from baseline of 50% or more" and a DRS-R-98 severity score of 12 or less without relapse, was the primary outcome. Results: The mean age of all patients was 68 ± 6 years. The study population's overall response rate was 92%. Response rates for the two groups were remarkably equal (p = 0.609). Secondary outcomes were comparable in both groups, such as ICU mortality (p = 0.496), in-hospital mortality (p = 0.321), in-hospital stay (p = 0.310), and the need for mechanical ventilation (p > 0.99). But the quetiapine group showed a statistically reduced mean ICU stay (10.1 ± 2.0 vs. 11.7 ± 2.6 days, p = 0.018) and increased sleeping hours per night (p = 0.001). Conclusions: Quetiapine may be equally as effective as haloperidol in treating the symptoms of hyperactive delirium in critically ill patients, with no mortality benefit. [ABSTRACT FROM AUTHOR]

Objectives: The current study uses longitudinal data from the National Alzheimer's Coordinating Center (NACC) to assess the effects of antipsychotic medication use on changes in cognitive functioning among adults in the United States. Methods: Linear mixed models were conducted that included study visits, days between visits, sex, age, education, and medical history (i.e. diabetes, seizures, traumatic brain injury, stroke, and Parkinson's disease). The Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to create variables assessing changes in psychotic symptoms, manic symptoms, and agitation/disinhibition. Results: The results indicated that starting an antipsychotic medication was associated with a greater decline in semantic fluency (Fruit and Vegetable Naming), processing speed (Digit Symbol and Trail Making Test, Part A), and cognitive flexibility (Trail Making Test, Part B). Conversely, stopping an antipsychotic medication was protective against declines in the same cognitive skills. The effect of antipsychotic medications on cognitive functioning did not appear to differ by reported changes in psychiatric symptoms after adjusting for false discovery. Conclusion: The results suggest that prescribers should consider discontinuance of an antipsychotic if the patient is reporting cognitive problems and their symptoms are manageable off the medications. The findings hope to spark future research into the effects of antipsychotic use on biomarkers of progressive dementias (e.g. Alzheimer's disease). [ABSTRACT FROM AUTHOR]

Objectives: To describe nursing home (NH) characteristics associated with antipsychotic use and test whether associations changed after implementation of the National Partnership to Improve Dementia Care's antipsychotic reduction initiative (ARI). Methods: Longitudinal quasi-experimental design using data from multiple sources and piecewise linear mixed models were used for statistical analyses. Results: There was a significant decrease in monthly antipsychotic use across the study period (pre-ARI b = −0.0003, p <.001; post-ARI b = −0.0012, p <.001), which held after adjusting for NH characteristics. Registered nurse hours (b = −0.0026, p <.001), licensed practical nurse hours (b = −0.0019, p <.001), facility chain membership (b = −0.0013, p <.01), and health inspection ratings (b = −0.0003, p >.01) were associated with decreased antipsychotic use. Post-ARI changes in associations between NH characteristics and antipsychotic use were small and not statistically significant. Conclusions: Decreases in antipsychotic use were associated with most NH characteristics, and associations persisted post-ARI. Further research is warranted to examine the interactions between ARI policy and NH characteristics on antipsychotic prescribing, as well as other NH factors, such as facility prescribing cultures and clinical specialty of staff. Clinical Implications: Decreases in monthly antipsychotic use were observed following the ARI. The decreases in monthly antipsychotic use were associated with most NH characteristics, and these associations persisted during the post-ARI period. [ABSTRACT FROM AUTHOR]

Background and Objectives: Recent studies suggest that the binary categorization of first-generation antipsychotics (FGAs) as being primarily responsible for extrapyramidal symptoms (EPSs) and second-generation antipsychotics (SGAs) for cardiometabolic abnormalities is an oversimplification. SGAs also demonstrate antagonistic affinity for D2 receptors, indicating their potential to induce EPSs. This study utilized the Korea Adverse Event Reporting System (KAERS) database to explore adverse drug event (ADE) signals related to both FGAs and SGAs. Materials and Methods: Relevant ADE reports from January 2013 to December 2022 were extracted from the KAERS database and analyzed using disproportionality analysis, employing the proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC) with its 95% lower confidence interval (LCI) indices. Results: Of the initial dataset of 2,890,702 ADE reports, those with insufficient data and duplicates were removed, resulting in a final dataset of 5249 reports for analysis. Aripiprazole, an SGA, showed signals for movement disorders, including EPSs (PRR 4.7, ROR 4.8, IC 2.2), tremors (PRR 5.3, ROR 5.4, IC 2.4), and akathisia (PRR 18.6, ROR 19.3, IC 3.5). Notably, for quetiapine, cardiovascular signals were detected, including increased blood pressure (PRR 2.1, ROR 2.3, IC 0.5), and tachyarrhythmia (PRR 13.9, ROR 14.1, IC 1.8), along with peripheral edema (PRR 2.5, ROR 2.5, IC 0.2). Metabolic abnormalities, such as weight gain and increased appetite, were identified for four SGAs: aripiprazole, olanzapine, quetiapine, and risperidone. Safety signals related to movement disorders were not detectable for FGAs, likely due to the limited number of ADE reports available for analysis. Conclusions: Our study findings support that the distribution of ADEs between FGAs and SGAs is not strictly binary. Aripiprazole, despite being an SGA, showed signals for extrapyramidal movement disorders. Four SGAs (aripiprazole, olanzapine, quetiapine, and risperidone) were linked to metabolic side effects, while quetiapine was associated with cardiovascular safety signals. [ABSTRACT FROM AUTHOR]

Background Method Results Conclusion Nonadherence/discontinuation of antipsychotic (AP) medications represents an important clinical issue in patients across psychiatric disorders, including schizophrenia spectrum disorders (SSDs). While antipsychotic‐induced weight gain (AIWG) is a reported contributor to nonadherence, a systematic review of the association between AIWG and medication nonadherence/discontinuation has not been explored previously.A systematic search was conducted in MEDLINE, EMBASE, PsychINFO, CINAHL, and CENTRAL databases, among others, to help identify all studies which explored adherence, study dropouts, AP switching and/or discontinuations attributable to AIWG among individuals with severe mental illness. A meta‐analysis was also completed where applicable.We identified two categories of studies for the meta‐analysis. Category 1 included three studies, which compared measures of AP adherence or discontinuation across BMI classes/degrees of self‐reported weight gain. When compared to normal weight individuals receiving APs or those who did not report AIWG, individuals who were either overweight or obese or reported weight gain in relation to AP use had an increased odds of AP nonadherence (OR 2.37; 95% CI 1.51–3.73; p = 0.0002). Category 2 had 14 studies which compared measures of discontinuation related to weight gain reported as an adverse effect across different APs. Olanzapine was associated with a 3.32 times (95% CI 2.32–4.74; p < 0.00001) increased likelihood of nonadherence or discontinuation when compared to other APs with lower weight gain liabilities. Similarly, APs with moderate weight gain liability (paliperidone, risperidone, and quetiapine) increased the odds of nonadherence or discontinuation by 2.25 (95% CI 1.31–3.87; p = 0.003) when compared to APs considered to have lower weight gain liability (i.e. haloperidol and aripiprazole). The qualitative summary also confirmed these findings.This review and meta‐analysis suggests that AIWG influences medication nonadherence/discontinuation, whereby APs with higher weight gain liability are associated with nonadherence/discontinuation. Additional studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

The introduction of a new psychopharmaceutical medication instead of the previous one always poses a certain challenge. In the case of antipsychotics (AP), these problems are considerably more complicated and are mainly caused by the question of dose equivalents, but also by the pharmacokinetic properties of the drug. In the case of partial dopamine D2 agonists, an additional issue is the possibility of deterioration when switching from the previous D2 antagonists to these drugs. Cross-titration is therefore generally recommended. Finally, due to the capsule form, it is not possible to increase the dose of cariprazine by less than 1.5 mg during titration. In this paper, we have presented our proposal to replace the most commonly used second-generation APs with the third-generation AP cariprazine. We have taken into account the dose equivalents, the pharmacological forms of the drugs and their pharmacokinetic and pharmacodynamic properties. [ABSTRACT FROM AUTHOR]

Sex-related differences in psychopharmacology present unique challenges in both clinical and research settings. Recognition of sex differences in psychopharmacological treatment has increased in recent years, but a significant research gap regarding variations between men and women still exists. Biological factors, including hormonal fluctuations, genetic factors, and brain structure differences, contribute significantly to differential drug responses. Moreover, social determinants can influence the differential burden of psychiatric disorders between the sexes and may impact treatment plans. Incorporating sex as a key variable in personalized treatment programs and plans holds the potential to optimize efficacy and minimize adverse effects in psychopharmacology. Sex-related challenges in psychopharmacology necessitate a nuanced approach to treatment. Further research is needed to fully understand these differences and to develop guidelines for personalized medication management. By addressing these challenges, clinicians can improve treatment outcomes and enhance the quality of life of patients with psychiatric disorders. [ABSTRACT FROM AUTHOR]

For several decades, the dopamine hypothesis contributed to the discovery of numerous typical and atypical antipsychotics and was the sole hypothesis for the pathophysiology of schizophrenia. However, neither typical nor atypical antipsychotics, other than clozapine, have been effective in addressing negative symptoms and cognitive impairments, which are indices for the prognostic and disability outcomes of schizophrenia. Following the development of atypical antipsychotics, the therapeutic targets for antipsychotics expanded beyond the blockade of dopamine D2 and serotonin 5-HT2A receptors to explore the partial agonism of the D2 receptor and the modulation of new targets, such as D3, 5-HT1A, 5-HT7, and metabotropic glutamate receptors. Despite these efforts, to date, psychiatry has not successfully developed antipsychotics with antipsychotic properties proven to be superior to those of clozapine. The glutamate hypothesis, another hypothesis regarding the pathophysiology/pathomechanism of schizophrenia, was proposed based on clinical findings that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, such as phencyclidine and ketamine, induce schizophrenia-like psychotic episodes. Large-scale genome-wide association studies (GWASs) revealed that approximately 30% of the risk genes for schizophrenia (the total number was over one hundred) encode proteins associated with glutamatergic transmission. These findings supported the validation of the glutamate hypothesis, which was inspired by the clinical findings regarding NMDAR antagonists. Additionally, these clinical and genetic findings suggest that schizophrenia is possibly a syndrome with complicated pathomechanisms that are affected by multiple biological and genetic vulnerabilities. The glutamate hypothesis has been the most extensively investigated pathophysiology/pathomechanism hypothesis, other than the dopamine hypothesis. Studies have revealed the possibility that functional abnormalities of the NMDAR play important roles in the pathophysiology/pathomechanism of schizophrenia. However, no antipsychotics derived from the glutamatergic hypothesis have yet been approved for the treatment of schizophrenia or treatment-resistant schizophrenia. Considering the increasing evidence supporting the potential pro-cognitive effects of glutamatergic agents and the lack of sufficient medications to treat the cognitive impairments associated with schizophrenia, these previous setbacks cannot preclude research into potential novel glutamate modulators. Given this background, to emphasize the importance of the dysfunction of the NMDAR in the pathomechanism and/or pathophysiology of schizophrenia, this review introduces the increasing findings on the functional abnormalities in glutamatergic transmission associated with the NMDAR. [ABSTRACT FROM AUTHOR]

Treatment of schizophrenia with currently available drugs is often ineffective or results in several adverse reactions. In previous studies focusing on the search for new antipsychotic drugs, we designed and obtained a series of dopamine D2 and serotonin 5-HT1A and 5-HT2A receptor ligands that were pharmacologically evaluated and showed promising antipsychotic activity. Evaluation of ADMET parameters is an important issue in drug development and should be performed at its early stage to avoid developing molecules with poor pharmacokinetics, that are unlikely to enter the market. For this reason, in this work we focused on the assessment of physicochemical parameters of selected compounds from the series we obtained to assess their drug-like potential. The results of thermal analysis showed that most of the tested compounds are thermally stable above 200 °C, with one compound stable up to 190 °C. Permeability through biological membranes assessed in the parallel artificial membrane permeability assay indicated that all tested compounds effectively migrate through biological membranes by means of passive diffusion. The solubility of the tested compounds was determined in PBS, reflecting physiological pH, and 0.01 M HCl, indicating their low to moderate solubility in PBS, which was significantly improved in acidic environment. The lipophilicity of the studied compounds expressed as LogD falls within the range of 1.84–2.80, what suggest that they would show good oral absorption and the ability to cross lipid barriers. The studies were supplemented with in silico prediction of ADMET parameters, which also indicate the probable high drug-likeness of the tested compounds. [ABSTRACT FROM AUTHOR]

Aim: To establish significant risk factors for the development of adverse drug effects (ADEs) in children and adolescents with an acute psychotic episode taking antipsychotics. Materials and Methods: The research team randomly selected 15 patient records each month for 3 years (2016–2018). Overall, 450 patient records were included (223 boys and 227 girls, mean age was 14.52 ± 2.21 years). Adverse effects were identified using the standard algorithm of the Global Trigger Tool method. A "trigger" is an indication that an adverse reaction is likely to occur, e.g., an antihistamine prescription on a prescribing list. When a trigger was detected, the case history was studied in further detail to confirm the occurrence of ADEs. We divided patients into two groups: the "children" group (under 12 years old) and the "adolescents" group (13 years and older). Data were analyzed using the statistical package IBM SPSS Statistics 23.0. Results: Of the 450 patient records, 402 (89.3%) had at least one trigger detected. In total, 126 case histories contained evidence of ADE (28%). The total number of ADEs per 1000 patient days was 5.39 and the number of ADEs per 100 admissions was 32.0. Among adolescents, two or more triggers per patient were significantly more frequently identified (61.3% vs. 44.6%; p = 0.001). ADEs were rare in "Children" compared with "Adolescents" (13.8% vs. 30.4%; p = 0.006). The logistic regression analysis confirmed high predictive role of "Adolescence" (odds ratio [OR] = 2.58; 95% confidence interval [CI] 1.22–5.4; p = 0.013), "Polypharmacy" (OR = 1.96; 95% CI 1.23–3.1; p = 0.004), and "First-life hospitalization" (OR = 2.17; 95% CI 1.34–3.48; p = 0.001) for ADE fact in patient records. Conclusion: We found that significant risk factors for ADEs to antipsychotics in patients with acute psychotic episode were adolescence (13 years and older), polypharmacy, and first-life hospitalization. The fact that children (i.e., younger than 13 years of age) are less likely to experience ADEs was not associated with high-risk drugs or higher doses in our study. [ABSTRACT FROM AUTHOR]

Background: Antipsychotics carry a higher-risk profile than other psychotropic medications and may be prescribed for youth with conditions in which other first-line treatments are more appropriate. This study aimed to evaluate the population-level effect of the Safer Use of Antipsychotics in Youth (SUAY) trial, which aimed to reduce person-days of antipsychotic use among participants. Methods: We conducted an interrupted time series analysis using segmented regression to measure changes in prescribing trends of antipsychotic initiation rates pre-SUAY and post-SUAY trial at four U.S. health systems between 2013 and 2020. Results: In our overall model, adjusted for age and insurance type, antipsychotic initiation rates decreased by 0.73 (95% confidence interval [CI]: 0.30, 1.16, p = 0.002) prescriptions per 10,000 person-months before the SUAY trial. In the first quarter following the start of the trial, there was an immediate decrease in the rate of antipsychotic initiations of 6.57 (95% CI: 0.99, 12.15) prescriptions per 10,000 person-months. When comparing the posttrial period to the pretrial period, there was an increase of 1.09 (95% CI: 0.32, 1.85) prescriptions per 10,000 person-months, but the increasing rate in the posttrial period alone was not statistically significant (0.36 prescriptions per 10,000 person-months, 95% CI: −0.27, 0.99). Conclusion: The declining trend of antipsychotic initiation seen between 2013 and 2018 (pre-SUAY trial) may have naturally reached a level at which prescribing was clinically warranted and appropriate, resulting in a floor effect. The COVID-19 pandemic, which began in the final three quarters of the posttrial period, may also be related to increased antipsychotic medication initiation. [ABSTRACT FROM AUTHOR]

Antipsychotic-induced weight gain (AIWG) is a significant but frequently neglected adverse effect of first- and second-generation antipsychotic therapy, which may lead to cardiovascular disturbances. The present network meta-analysis (NMA) was conducted to evaluate and compare the effects of available treatment options in antipsychotic-induced weight gain (AIWG). The data was extracted from 68 relevant clinical trials after a literature search on MEDLINE/PubMed, Embase, Scopus, Cochrane databases and clinical trial registries. Random-effects Bayesian NMA was done to pool the effects across the interventions for the change in body weight from baseline. A network graph was built, a consistency model was run, node split analysis was performed, treatments were ranked as per the SUCRA score and meta-regression was done for the duration of therapy, baseline body weight and treatment strategy as the predictor variables. Finally, the results were sorted based on the certainty of evidence. The drugs showing significant reduction in body weight in order of magnitude of effect size include sibutramine 10 mg (−8.0 kg; −16. to −0.21), metformin 750 mg + lifestyle modification (−7.5 kg; −12 to −2.8), topiramate 200 mg (−7 kg; −10 to −3.4), metformin 750 mg (−5.7 kg; −9.3 to −2.1), topiramate 100 mg (−5.7 kg; −8.8 to −2.5), topiramate 50 mg (−5.2 kg; −10 to −0.57), liraglutide 1.8 mg (−5.2 kg; −10., −0.080), sibutramine 15 mg (−4.5 kg; −8.9 to −0.59), nizatidine 300 mg (−3.0 kg; −5.9 to −0.23) and metformin 1000 mg (−2.3 kg; −4.6 to −0.0046). There was no effect of duration of follow-up, baseline body weight and, preventive versus therapeutic strategy on weight reduction in AIWG. Metformin 750 mg with lifestyle modification was the most effective treatment for AIWG, followed by topiramate 200 mg, metformin 750 mg, and topiramate 100 mg with moderate certainty of evidence. • This network meta-analysis compared pharmacological agents used for antipsychotic-induced weight gain (AIWG) in schizophrenia. • Metformin (750 mg) with lifestyle modification is the best available treatment for AIWG, followed by topiramate (200 mg) and metformin (750 mg). • Other interventions which had a significant weight reduction effect were topiramate (50 mg and 100 mg), nizatidine 300 mg and metformin 1000 mg. • Liraglutide 3 mg had the highest magnitude of weight reduction as compared to placebo when meta-regression with baseline mean weight was done. [ABSTRACT FROM AUTHOR]

It is widely believed that relapse in first-episode psychosis (FEP) causes illness progression, with previous reviews suggesting that treatment non-response develops in one in six patients who relapse. This belief contributes to the primary treatment goal in FEP being relapse-prevention, often in favor of other recovery-oriented goals. However, previous reviews primarily reported on naturalistic studies in chronic schizophrenia and predated multiple major studies with higher-quality designs. We conducted a narrative review of studies of any design that examine the impact of relapse on medication response and other symptomatic and functional outcomes in FEP. We identified eight relevant studies, five of these published since the last major review on this topic. Observational studies show a clear association between relapses and worse response to medication, but poorly control for confounding. Three higher-quality studies (two randomized) generally do not find worse symptomatic or functional outcomes among medication reduction/discontinuation arms compared to maintenance controls, despite significantly higher initial rates of relapse. While the social and psychological consequences of a relapse should not be dismissed, clinicians should demand high-quality evidence about the risks of relapse on long-term outcomes. The conventional notion that relapse leads to treatment non-response or worse long-term outcomes is generally not supported by the highest quality studies. These findings can help clinicians and patients weigh the risks and benefits of competing treatment strategies in FEP. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction is commonly observed in schizophrenia spectrum disorders (SSDs). The causes of metabolic comorbidity in SSDs are complex and include intrinsic or biological factors linked to the disorder, which are compounded by antipsychotic (AP) medications. The exact mechanisms underlying SSD pathophysiology and AP-induced metabolic dysfunction are unknown, but dysregulated lipid metabolism may play a role. Lipidomics, which detects lipid metabolites in a biological sample, represents an analytical tool to examine lipid metabolism. This systematic review aims to determine peripheral lipid signatures that are dysregulated among individuals with SSDs (1) with minimal exposure to APs and (2) during AP treatment. To accomplish this goal, we searched MEDLINE, Embase, and PsychINFO databases in February 2024 to identify all full-text articles written in English where the authors conducted lipidomics in SSDs. Lipid signatures reported to significantly differ in SSDs compared to controls or in relation to AP treatment and the direction of dysregulation were extracted as outcomes. We identified 46 studies that met our inclusion criteria. Most of the lipid metabolites that significantly differed in minimally AP-treated patients vs. controls comprised glycerophospholipids, which were mostly downregulated. In the AP-treated group vs. controls, the significantly different metabolites were primarily fatty acyls, which were dysregulated in conflicting directions between studies. In the pre-to-post AP-treated patients, the most impacted metabolites were glycerophospholipids and fatty acyls, which were found to be primarily upregulated and conflicting, respectively. These lipid metabolites may contribute to SSD pathophysiology and metabolic dysfunction through various mechanisms, including the modulation of inflammation, cellular membrane permeability, and metabolic signaling pathways. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Transgender and nonbinary (TGNB) individuals are highly stigmatized members of society and are significantly at higher risk of having mood or anxiety-related disorders compared to non-TGNB individuals. METHODS: In this retrospective cohort study, antidepressant prescribing data were collected from TGNB adults diagnosed with gender dysphoria (GD) and mood or anxiety-related disorder between January 2005 and October 2021. The primary outcome was to compare the number of active outpatient antidepressant prescriptions at the time of GD diagnosis between gender identities. The secondary outcomes were to compare antidepressant class utilization between gender identities as well as the prevalence of concurrent mood or anxiety-related disorder diagnoses between gender identities. RESULTS: Of 131 patients who met inclusion criteria, there was no significant difference in number of active antidepressant prescriptions between gender identities at the time of the GD diagnosis (p = .357). However, transgender females were prescribed bupropion at significantly higher rates than other gender identities (p = .046). Approximately 38% of patients did not have an active antidepressant prescription at the time of GD diagnosis despite concurrent mood or anxiety-related diagnoses. The prevalence of generalized anxiety disorder was significantly greater among transgender males (p = .044). DISCUSSION: Although the number of active antidepressant prescriptions between gender identities were similar in this study, we found 38% of patients were not prescribed any antidepressants at time of GD and mood or anxiety-related disorders. This serendipitous finding elucidates a potential gap in mental health care among transgender adults.

Abstract Background Schizophrenia and substance use disorders (SUDs) are often comorbid conditions that present clinical challenges due to their heterogeneity and the difficulties associated with poor physical health, low medication adherence, high relapse and hospitalization rates, and increased risk of mortality. This is often exacerbated by a fragmented health care system that treats addiction and mental illness separately, leading to delays in proper diagnosis and treatment. Main text The aim of this narrative review, based on an extensive literature search and experts’ clinical experience, is to synthesize evidence on the psychopathological and clinical characteristics of patients, the burden and management at the level of healthcare system, and possible gaps in the treatment of schizophrenia with comorbid SUD in order to understand and address the needs of patients. Treatment options, differences between antipsychotic medications, and the benefits of long-acting formulations and partial dopaminergic agonists are described. Partial dopamine agonists (aripiprazole, cariprazine, and brexpiprazole) have demonstrated good control of psychotic symptoms and SUDs with a favorable safety profile. Conclusion Pharmacological interventions should be accompanied by psychosocial support within an integrated and multidisciplinary approach that promotes shared decision-making and a good therapeutic alliance between the entire medical team and the patient.

Abstract Background Appropriate use of medication is a key indicator of the quality of care provided in long-term care (LTC). The objective of this study was to determine whether resident-facility language concordance/discordance is associated with the odds of potentially inappropriate prescribing of antipsychotics (PIP-AP) in LTC. Methods We conducted a population-based, retrospective cohort study of LTC residents in Ontario, Canada from 2010 to 2019. We obtained resident language from standardized resident assessments, and derived facility language by determining the proportion of residents belonging to each linguistic group within individual LTC homes. Using linked administrative databases, we identified all instances of PIP-AP during a 1-year follow-up period. PIP-AP was defined using the STOPP-START criteria, which have previously been shown to predict adverse clinical events such as emergency department (ED) visits and hospitalizations. The association between linguistic factors and PIP-AP was assessed using adjusted multivariable logistic regression analysis. Results We identified 198,729 LTC residents consisting of 162,814 Anglophones (81.9%), 6,230 Francophones (3.1%), and 29,685 Allophones (14.9%). The odds of PIP-AP of were higher for both Francophones (aOR 1.15, 95% CI 1.08–1.23) and Allophones (aOR 1.11, 95% CI 1.08–1.15) when compared to Anglophones. When compared to English LTC homes, French LTC homes had greater odds of PIP-AP (aOR 1.12, 95% CI 1.05–1.20), while Allophone homes had lower odds of PIP-AP (aOR 0.82, 95% CI 0.77–0.86). Residents living in language-discordant LTC homes had higher odds of PIP-AP when compared to LTC residents living in language-concordant LTC homes (aOR 1.07, 95% CI 1.04–1.10). Conclusion This study identified linguistic factors related to the odds of PIP-AP in LTC, suggesting that the linguistic environment may have an impact on the quality of care provided to residents.

Abstract The caudate nucleus is a part of the striatum, and striatal hyperdopaminergia is considered central to the pathophysiology of schizophrenia. How caudate volume is affected in schizophrenia and what role antipsychotics play remains unclear. In early-onset schizophrenia (EOS), where psychosis emerges during a neurodevelopmentally critical phase, the caudate may exhibit a heightened vulnerability to the effects of antipsychotic medications. We hypothesized effects of both antipsychotic medication use and age of onset on caudate in schizophrenia. We included adult patients with EOS (n = 83) and adult-onset schizophrenia (AOS) (n = 246), adult healthy controls (HC, n = 774), adolescent patients with non-affective psychosis (n = 56) and adolescent HC (n = 97). We obtained T1-weighted MRI scans using a 1.5T Siemens scanner and General Electric 3T scanners. In our main analysis, we tested for main and interaction effects of diagnosis and current antipsychotic medication use on caudate volume. Adult patients with EOS (p

BackgroundSecond-generation antipsychotics (SGAs) are frontline treatments for serious mental illness. Often, individual patients benefit only from some SGAs and not others. The mechanisms underlying this unpredictability in treatment efficacy remain unclear. All SGAs bind the dopamine D3 receptor (D3R) and are traditionally considered antagonists for dopamine receptor signaling.MethodsHere, we used a combination of two-photon calcium imaging, in vitro signaling assays, and mouse behavior to assess signaling by SGAs at D3R.ResultsWe report that some clinically important SGAs function as arrestin-3 agonists at D3R, resulting in modulation of calcium channels localized to the site of action potential initiation in prefrontal cortex pyramidal neurons. We further show that chronic treatment with an arrestin-3 agonist SGA, but not an antagonist SGA, abolishes D3R function through postendocytic receptor degradation by GASP1 (G protein-coupled receptor-associated sorting protein-1).ConclusionsThese results implicate D3R-arrestin-3 signaling as a source of SGA variability, highlighting the importance of including arrestin-3 signaling in characterizations of drug action. Furthermore, they suggest that postendocytic receptor trafficking that occurs during chronic SGA treatment may contribute to treatment efficacy.

Abstract The incidence of major depressive disorder (MDD) after heart transplantation is high; however, there are no reports on treatment options when antidepressant therapy fails to improve the condition. We herein report on the case of a woman with MDD after heart transplantation who partially improved with antidepressant treatment but continued to have a loss of appetite. Augmentation treatment with aripiprazole improved her appetite, and her MDD went into remission. When antidepressant treatment is not sufficiently effective for MDD after heart transplantation, augmentation treatment with antipsychotics, such as aripiprazole, should be considered.

Antipsychotics are drugs commonly prescribed to treat a variety of psychiatric conditions. They are classified as typical and atypical, depending on their affinity for dopaminergic and serotonergic receptors. Although neurons have been assumed to be the major mediators of the antipsychotic pharmacological effects, glia, particularly astrocytes, have emerged as important cellular targets for these drugs. In the present study, we investigated the effects of acute treatments with the antipsychotics risperidone and haloperidol of hippocampal slices and astrocyte cultures, focusing on neuron-glia communication and how antipsychotics act in astrocytes. For this, we obtained hippocampal slices and primary astrocyte cultures from 30-day-old Wistar rats and incubated them with risperidone or haloperidol (1 and 10 μM) for 30 min and 24 h, respectively. We evaluated metabolic and enzymatic activities, the glutathione level, the release of inflammatory and trophic factors, as well as the gene expression of signaling proteins. Haloperidol increased glucose metabolism; however, neither of the tested antipsychotics altered the glutathione content or glutamine synthetase and Na+K+-ATPase activities. Haloperidol induced a pro-inflammatory response and risperidone promoted an anti-inflammatory response, while both antipsychotics seemed to decrease trophic support. Haloperidol and risperidone increased Nrf2 and HO-1 gene expression, but only haloperidol upregulated NFκB and AMPK gene expression. Finally, astrocyte cultures confirmed the predominant effect of the tested antipsychotics on glia and their opposite effects on astrocytes. Therefore, antipsychotics cause functional alterations in the hippocampus. This information is important to drive future research for strategies to attenuate antipsychotics-induced neural dysfunction, focusing on glia. [ABSTRACT FROM AUTHOR]

Understanding the cardiac risks of antipsychotic use is crucial for clinicians managing psychiatric conditions in children and adolescents. However, the effects on the QT interval in pediatric populations have been poorly investigated. We performed a systematic review to provide clinicians an updated source on the effects of antipsychotic medications on QTc and guide drug’s choice. A literature search on the PubMed and Scopus databases was conducted from April 22, 1989, to May 28, 2023, for all studies investigating the effects of antipsychotic medications on the QTc interval in patients aged 0–18 years. A total of 10 articles including 523 patients and 7 different antipsychotic drugs met our search criteria. Among the included articles were three randomized clinical trials, five controlled trials without randomization or prospective comparative cohort trials, and two retrospective cohort studies. Clinical data emerging from these studies were classified according to the Oxford Centre for Evidence-Based Medicine. Risperidone and aripiprazole showed minimal to no significant QTc prolongation, whereas quetiapine, olanzapine, and ziprasidone showed variable effects on QTc. Haloperidol did not demonstrate significant QTc prolongation. In a prospective comparative cohort trial, pimozide exhibited significant QTc prolongation in a cohort with Tourette syndrome. Conclusion: Only 10 studies have carefully addressed the effect of antipsychotic medications on QTc among pediatric patients, underscoring the need for further research. Personalized risk assessment and regular cardiac monitoring should be integrated into clinical management of pediatric and adolescent patients receiving antipsychotics to facilitate early detection of repolarization abnormalities and potential intervention. What is known: • QT interval prolongation is a reported side effect of antipsychotics among adults especially with first-generation antipsychotics and parenteral infusion. • Understanding the effect of antipsychotics on QT is essential for clinical monitoring and avoidance of complications. What is new: • Risperidone and aripiprazole were the most studied antipsychotics in pediatric patients and showed minimal QT prolongation. • The absence of a standardized protocol for assessing the effects on the QT interval makes comparisons between studies challenging and emphasizes the need for further research. [ABSTRACT FROM AUTHOR]

Purpose: Antipsychotic-induced prolactin elevation may impede protective effects of estrogens in women with schizophrenia-spectrum disorders (SSD). Our study sought to confirm whether the use of prolactin-raising antipsychotics is associated with lower estrogen levels, and to investigate how estrogen and prolactin levels relate to symptom severity and cognition in premenopausal women with SSD. Methods: This cross-sectional study included 79 premenopausal women, divided in three groups of women with SSD treated with prolactin-sparing antipsychotics (n = 21) or prolactin-raising antipsychotics (n = 27), and age-matched women without SSD (n = 31). Circulating 17β-estradiol was compared among groups. In patients, we assessed the relationship between prolactin and 17β-estradiol, and the relationships of these hormones to symptom severity and cognition, using correlation analyses and backward regression models. Results: In women receiving prolactin-raising antipsychotics, 17β-estradiol levels were lower as compared to both other groups (H(2) = 8.34; p = 0.015), and prolactin was inversely correlated with 17β-estradiol (r=-0.42, p = 0.030). In the prolactin-raising group, 17β-estradiol correlated positively with verbal fluency (r = 0.52, p = 0.009), and 17β-estradiol and prolactin together explained 29% of the variation in processing speed (β17β−estradiol = 0.24, βprolactin = -0.45, F(2,25) = 5.98, p = 0.008). In the prolactin-sparing group, 17β-estradiol correlated negatively with depression/anxiety (r = -0.57, p = 0.014), and together with prolactin explained 26% of the variation in total symptoms (β17β−estradiol = -0.41, βprolactin = 0.32, F(2,18) = 4.44, p = 0.027). Conclusions: In women with SSD, antipsychotic-induced prolactin elevation was related to lower estrogen levels. Further, estrogens negatively correlated with symptom severity and positively with cognition, whereas prolactin levels correlated negatively with cognition. Our findings stress the clinical importance of maintaining healthy levels of prolactin and estrogens in women with SSD. [ABSTRACT FROM AUTHOR]

Objective: Antipsychotics remain the first‐line treatment for people diagnosed with psychotic disorders despite adverse effects which lead many people to stop their medication. Many stop without the support of the prescriber, who may fear relapse. The objective of this study is to better understand the process of withdrawal from antipsychotics, from the perspective of people taking antipsychotics. Design: Online survey. Methods: An international online survey elicited quantitative responses about pre‐withdrawal planning (560) and qualitative responses about what was helpful and unhelpful when withdrawing from antipsychotics (443). Responses came from users of antipsychotics in 29 countries. Results: Forty‐seven per cent did not consult their psychiatrist before discontinuing. Only 40% made preparations, most commonly making a plan, gathering information and informing family. The most frequently reported helpful factors were focussing on the benefits of getting off the drugs (including ending adverse effects and feeling more alive), information about withdrawal symptoms and how to withdraw safely, withdrawing slowly, and support from psychologists, counsellors and psychotherapists. The most common unhelpful factor was the psychiatrist/doctor, largely because of their lack of knowledge, refusal to support the patient's wishes and the threat or use of coercion. Conclusions: Evidence‐based, respectful, collaborative responses to patients' concerns about adverse effects and desires to withdraw would probably reduce relapse rates and improve long‐term outcomes. It would definitely help end pervasive breaching of the principle of informed consent and human rights legislation. [ABSTRACT FROM AUTHOR]

Objectives: To determine the efficacy and safety of antipsychotic medication for treating individuals with a dual diagnosis of intellectual disability (ID) and schizophrenia. Methods: We systematically reviewed the literature to explore the risks and benefits of antipsychotics for schizophrenia in ID. In addition, a cross-sectional retrospective study on the tolerance profiles of a representative ID and schizophrenia cohort was conducted. Results: From the systematic search, we retained 18 articles detailing information on 24 cases. In almost all cases, the antipsychotic improved psychotic symptoms (e.g., hallucinations, delusions, disorganization). Negative manifestations were also improved (blunted affects, amotivation, poor rapport), as were challenging behaviors in a few cases. The most commonly reported side effects were neurological (extra-pyramidal, movement disorder, epilepsy) and metabolic manifestations. In the retrospective cross-sectional study, we reported data on 112 participants with comorbid ID and schizophrenia. In all, 103 participants were antipsychotic-treated, of which 39% were on antipsychotic monotherapy. Of these, 35% were in the obesity range, 25% in the hyperglycemic range, and 25% in the dyslipidemia range. The body mass index did not differ between the groups. Conclusions: This study provides an initial evidence base underpinning the efficacy of antipsychotic drugs on schizophrenia in the ID population. Nevertheless, there may be an increased risk of metabolic side effects, hence, close monitoring of blood glucose, lipids, and weight should be implemented when prescribing antipsychotics to this population. [ABSTRACT FROM AUTHOR]