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Symptoms of hostility in patients during acute exacerbations of schizophrenia have been associated with aggressive behavior. Data suggest that some second-generation antipsychotics have specific anti-hostility effects, independent of sedation and positive symptom improvement. Two post hoc analyses were performed to examine the efficacy of lurasidone for reducing hostility in patients with schizophrenia. One analysis pooled adults (Nâ =â 1168) from 5 placebo-controlled, 6-week trials of lurasidone (40-160â mg). Another analysis pooled younger patients (up to age 25â years, Nâ =â 427) from the adult studies and a similarly designed trial of lurasidone (40 or 80â mg) in adolescent patients (13-17â years old). The outcome measure was mean change in the hostility item (P7) of the Positive and Negative Syndrome Scale (PANSS). To address pseudospecificity, results were adjusted for positive symptom change and sedation. In adults with a baseline PANSS hostility score ≥2, significant improvement in hostility was observed for all doses with a dose-related increase in effect size (Cohen's d): lurasidone 40â mgâ =â 0.18, 80â mgâ =â 0.24, 120â mgâ =â 0.36, and 160â mgâ =â 0.53. The same dose-response pattern was observed for the more severe hostility subgroups (P7: ≥3, ≥4), and in the early-onset population. Results suggest that lurasidone has specific, dose-related anti-hostility effects.
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INTRODUCTION: Long-acting injectable (LAI) antipsychotic medications can help improve treatment adherence in patients with schizophrenia and bipolar disorder. Despite this, they are underutilized. In 2003, intramuscular risperidone became the first available LAI atypical antipsychotic medication, and since then, a number of competing long-acting risperidone formulations have been brought to market, with additional options under active development. These include intramuscular, subcutaneous, long-acting oral, and implantable formulations. AREAS COVERED: This review summarizes currently available and emerging long-acting risperidone formulations, including efficacy and safety data, and practical considerations aimed to help prescribers distinguish one formulation from another. EXPERT OPINION: There is an expanding number of currently available LAI antipsychotic medications giving patients and providers an opportunity to personalize and individualize care. Rates of adherence to treatment in patients with schizophrenia and bipolar disorder are low, and individualizing care can help improve this. The risperidone LAI treatment landscape includes five options approved by the U.S. Food and Drug Administration, with others under clinical development. These options differ in regard to mode of administration, approved indications, available dose strengths, injection intervals, needle size, injection volume, storage, and other variables. Prescribers should be familiar with these differing options to help patients find the best fit for their individual needs.
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Antipsicóticos , Transtorno Bipolar , Preparações de Ação Retardada , Risperidona , Esquizofrenia , Humanos , Esquizofrenia/tratamento farmacológico , Risperidona/administração & dosagem , Risperidona/uso terapêutico , Antipsicóticos/uso terapêutico , Antipsicóticos/administração & dosagem , Transtorno Bipolar/tratamento farmacológicoRESUMO
OBJECTIVES: Appraise the evidence for daridorexant 50 mg and 25 mg versus placebo when treating chronic insomnia disorder in terms of number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). METHODS: NNT, NNH, and LHH were calculated from a 3-month pivotal Phase 3 study (N = 930; randomized 1:1:1 to daridorexant 50 mg, daridorexant 25 mg, or placebo once nightly). Wakefulness after sleep onset, latency to persistent sleep, self-reported total sleep time, Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), and Insomnia Severity Index were used for the NNT efficacy analysis. NNH safety analysis was performed using rates of adverse events (AEs) occurring in >1% of the participants in any arm. LHH was assessed for all NNT estimates, contrasting them with NNH estimates for somnolence, headache, and fatigue AEs. RESULTS: NNT estimates for daridorexant 50 mg versus placebo were <10 for clinically meaningful thresholds across all outcomes. NNT estimates for daridorexant 25 mg versus placebo were not as robust as those observed for daridorexant 50 mg, with many values exceeding 10. NNH estimates for daridorexant 50 mg and 25 mg versus placebo did not show a statistically significant treatment difference except for falls, where NNH was negative for the daridorexant 50 mg group (-44 [95% CI -328; -21]; rate of falls was greater with placebo than for daridorexant 50 mg). All LHH ratios at Months 1 and 3 were >1 (except for daridorexant 25 mg for the IDSIQ alert/cognition domain), indicating that patients were more likely to respond to daridorexant 50 mg and 25 mg than to experience an AE of somnolence, headache, or fatigue. CONCLUSION: Daridorexant 50 mg and 25 mg have a favorable benefit-risk ratio over 3 months. Daridorexant 50 mg demonstrated more robust (lower) NNT estimates versus placebo than daridorexant 25 mg.
Daridorexant, a dual orexin receptor antagonist, is a new treatment for chronic insomnia disorder. This analysis examined the effect and safety of daridorexant 50 and 25 mg, using data from a 3-month Phase 3 study (NCT03545191) to measure 'number needed to treat' (NNT) and 'number needed to harm' (NNH).NNT estimates how many patients need to be treated over a specific period to see one more beneficial response. Estimates versus placebo <10 indicate an effective treatment. Daridorexant 50 mg estimates were <10 for all objective and subjective measurements of insomnia assessed in this analysis, including evaluation of daytime functioning. NNT estimates for daridorexant 25 mg versus placebo were not as robust as daridorexant 50 mg, with values >10.NNH is calculated in the same way as NNT but estimates harmful outcomes rather than benefits. Estimates versus placebo >10 means the treatment is reasonably well tolerated.Using NNT and NNH, the 'likelihood to be helped or harmed' (LHH) ratio was calculated, determining how more likely a patient is to benefit versus experiencing harm from a treatment (LHH of >1 denotes a positive benefitrisk ratio). Both daridorexant doses had a favorable benefitrisk ratio over 3 months with LHH > 1.This analysis supports daridorexant 50 mg as the optimal dose to treat insomnia in adults, offering improved effectiveness compared with daridorexant 25 mg, with a similarly good safety profile.
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Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Números Necessários para Tratar , Método Duplo-Cego , Idoso , Adulto Jovem , Imidazóis , PirrolidinasRESUMO
PURPOSE/BACKGROUND: Using data from KINECT® 4, a phase 3, 48-week study of valbenazine, post hoc analyses were conducted to assess long-term outcomes that are relevant to the real-world management of tardive dyskinesia (TD). METHODS/PROCEDURES: Post hoc analyses of the participants of the KINECT 4 study who completed 48 weeks of open-label valbenazine (40 or 80 mg) treatment were conducted. Valbenazine effects on TD were evaluated using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD (CGI-TD), and Patient Global Impression of Change (PGIC). FINDINGS/RESULTS: Of 103 participants completing 48 weeks of treatment, 55% experienced clinically meaningful improvement (defined as ≥2-point reduction in AIMS total score [sum of items 1 - 7, evaluated by site raters]) by week 4; at week 48, 97% met this threshold. The percentage of completers who achieved AIMS total score response thresholds of ≥10% to ≥90% increased over time, with 86% of completers reaching ≥50% improvement. Of the 40 (39%) completers with AIMS ≥50% response at week 8, 38 (95%) sustained this response at week 48; 81% of those who did not meet this threshold at week 8 had achieved it by week 48. At week 48, more than 85% of completers achieved CGI-TD and PGIC ratings of "much improved" or "very much improved." IMPLICATIONS/CONCLUSIONS: The majority of participants who completed 48 weeks of treatment with once-daily valbenazine experienced substantial clinically meaningful and sustained TD improvements. These findings indicate that valbenazine can be a highly effective long-term treatment in patients with TD.
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Discinesia Tardia , Tetrabenazina , Valina , Humanos , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacologia , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Discinesia Tardia/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Valina/análogos & derivados , Valina/administração & dosagem , Valina/farmacologia , Valina/efeitos adversos , Idoso , Resultado do Tratamento , Adulto , Escala de Movimento Involuntário Anormal , Antipsicóticos/efeitos adversos , Antipsicóticos/administração & dosagemRESUMO
BACKGROUND: Hostility, irritability, and agitation are common in patients with bipolar I disorder. Post hoc analyses evaluated the effect of cariprazine on these symptoms in patients with bipolar I mania. METHODS: Data were pooled from three randomized, double-blind, placebo-controlled phase 3 cariprazine trials in adults with bipolar I manic/mixed episodes (NCT00488618, NCT01058096, NCT01058668); pooled cariprazine doses (3-12 mg/d) were analyzed. Patients were categorized into hostility/irritability and agitation subgroups by baseline scores: Young Mania Rating Scale (YMRS) irritability and disruptive-aggressive behavior items score ≥ 2; Positive and Negative Syndrome Scale (PANSS) hostility item ≥ 2; PANSS-Excited Component (PANSS-EC) total score ≥ 14 and score ≥ 4 on ≥ 1 individual item. Changes from baseline to week 3 in hostility/irritability- and agitation-related outcomes were evaluated. Adjustments were made for the presence of other manic symptoms, sedation, and akathisia. RESULTS: Most patients met subgroup inclusion criteria (YMRS hostility = 930; PANSS hostility = 841, PANSS-EC agitation = 486). In the YMRS subgroup, least squares mean differences in change from baseline were statistically significant for cariprazine versus placebo on YMRS hostility/irritability-related items (irritability [-0.93], disruptive-aggressive behavior [-0.79], combined [-1.75]; P ≤ 0.001 each), YMRS total score (-5.92, P ≤ 0.0001), and all individual YMRS items (-0.25 to -0.93, P ≤ 0.0001); differences remained significant after adjustment for other manic symptoms, sedation, and akathisia. Differences in PANSS hostility and PANSS-EC subgroups were significant for cariprazine versus placebo (P ≤ 0.001). LIMITATIONS: Post hoc analysis. CONCLUSION: Cariprazine demonstrated specific antihostility/irritability and anti-agitation effects in patients with manic/mixed episodes of bipolar I disorder and baseline hostility, irritability, or agitation.
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Transtorno Bipolar , Hostilidade , Humor Irritável , Mania , Piperazinas , Agitação Psicomotora , Humanos , Transtorno Bipolar/tratamento farmacológico , Agitação Psicomotora/tratamento farmacológico , Agitação Psicomotora/etiologia , Masculino , Humor Irritável/efeitos dos fármacos , Feminino , Adulto , Piperazinas/uso terapêutico , Método Duplo-Cego , Pessoa de Meia-Idade , Mania/tratamento farmacológico , Antipsicóticos/uso terapêutico , Escalas de Graduação Psiquiátrica , Resultado do Tratamento , Agressão/efeitos dos fármacosRESUMO
Introduction: HP-3070, a once-daily asenapine transdermal system, is the first antipsychotic "patch" formulation FDA approved for adults with schizophrenia. Positive and Negative Syndrome Scale (PANSS) score items can be grouped into a five-factor structure to describe specific schizophrenia symptom domains. This post hoc analysis of data from a pivotal study evaluated HP-3070's efficacy by examining these factors. Methods: In a phase 3 study, adults with an acute exacerbation of schizophrenia were randomized to six weeks of treatment with HP-3070 3.8mg/24h, 7.6mg/24h, or placebo. An analysis was performed using the five PANSS factor domains (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, anxiety/depression). Mixed-model repeated-measures (MMRM) analysis included change from baseline (CFB) in PANSS factor score as the repeated dependent variable, with country, treatment, visit, treatment by visit interaction, and baseline PANSS score as covariates. Results: The analysis included 607 patients. Treatment with HP-3070 3.8mg/24h resulted in a statistically significant LS mean CFB (improvement) vs placebo at Weeks 4-6 for all domains except for anxiety/depression, where a numerical difference was observed in favor of active treatments. Among the domains, the positive symptom factor demonstrated the numerically greatest LS mean (SE) difference from placebo in CFB, which for HP-3070 7.6mg/24h was -2.0 [0.57] and for HP-3070 3.8mg/24h was -2.3 [0.57]; P<0.001 for both. Treatment effect size for the positive symptom factor using Cohen's d (95% confidence intervals) was 0.39 (0.17, 0.61) for HP-3070 7.6mg/24h and 0.45 (0.20, 0.64) for HP-3070 3.8mg/24h. Discussion: Post hoc analysis using a PANSS five-factor model suggests that HP-3070 may address a broad range of symptoms in people with schizophrenia.
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INTRODUCTION: Antipsychotics are the foundation of pharmacologic treatment for schizophrenia. There are many oral antipsychotics available and given that these medications are generally considered comparably efficacious when titrated to an adequate dose, their varied tolerability, and safety profiles become critically important for medication selection. AREAS COVERED: This paper reviews tolerability and safety considerations for first-line second-generation oral antipsychotics currently approved for the treatment of schizophrenia in the USA. Excluded from consideration are clozapine and non-oral formulations. EXPERT OPINION: Among antipsychotics, there are many differences in adverse reactions observed in clinical trials, such as variable likelihood to cause sedation vs insomnia, weight gain and abnormalities in glucose/lipid metabolism, hyperprolactinemia, potential for impact on the QT interval, and motoric adverse effects. Additional safety data that can help with medication selection include safety in pregnancy and lactation, and potential for drug-drug interactions. Ultimately, working with patients to personalize treatment by focusing on safety and individual tolerability considerations for various adverse effects can help in building a therapeutic alliance and improving patients' outcomes.
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Antipsicóticos , Clozapina , Hiperprolactinemia , Esquizofrenia , Humanos , Antipsicóticos/efeitos adversos , Esquizofrenia/tratamento farmacológico , Clozapina/uso terapêutico , Hiperprolactinemia/induzido quimicamente , Tiazóis/uso terapêuticoRESUMO
Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are drug-induced parkinsonism (DIP), dystonia, akathisia, and tardive dyskinesia (TD). Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening consequence of DRBA exposure. Recommendations for anticholinergic use in patients with DIMDs were developed on the basis of a roundtable discussion with healthcare professionals with extensive expertise in DIMD management, along with a comprehensive literature review. The roundtable agreed that "extrapyramidal symptoms" is a non-specific term that encompasses a range of abnormal movements. As such, it contributes to a misconception that all DIMDs can be treated in the same way, potentially leading to the misuse and overprescribing of anticholinergics. DIMDs are neurobiologically and clinically distinct, with different treatment paradigms and varying levels of evidence for anticholinergic use. Whereas evidence indicates anticholinergics can be effective for DIP and dystonia, they are not recommended for TD, akathisia, or NMS; nor are they supported for preventing DIMDs except in individuals at high risk for acute dystonia. Anticholinergics may induce serious peripheral adverse effects (e.g., urinary retention) and central effects (e.g., impaired cognition), all of which can be highly concerning especially in older adults. Appropriate use of anticholinergics therefore requires careful consideration of the evidence for efficacy (e.g., supportive for DIP but not TD) and the risks for serious adverse events. If used, anticholinergic medications should be prescribed at the lowest effective dose and for limited periods of time. When discontinued, they should be tapered gradually.
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Antipsicóticos , Distonia , Distúrbios Distônicos , Transtornos dos Movimentos , Síndrome Maligna Neuroléptica , Discinesia Tardia , Humanos , Idoso , Distonia/induzido quimicamente , Distonia/tratamento farmacológico , Antagonistas Colinérgicos/efeitos adversos , Agitação Psicomotora/tratamento farmacológico , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/etiologia , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/tratamento farmacológico , Antipsicóticos/efeitos adversosRESUMO
Background: Aripiprazole lauroxil (AL) 1064 mg every 2 months following initiation using the AL NanoCrystal Dispersion formulation (ALNCD) plus 30-mg oral aripiprazole was efficacious and well tolerated in a 25-week, randomized, double-blind phase 3 trial in adults with acute schizophrenia. This post hoc analysis further characterized the safety of AL 1064 mg administered every 2 months and that of active control paliperidone palmitate (PP) 156 mg monthly based on occurrence, timing, and severity of adverse events (AEs) associated with antipsychotic medications.Methods: This study was conducted between November 2017 and March 2019. AL or PP was initiated during an inpatient stay of ≥ 2 weeks with transition to outpatient treatment thereafter. Rates of AEs of clinical interest, including injection site reactions (ISRs), motor AEs, sedation, hypotension, prolactin level increase, weight gain, and suicidal ideation/behavior, were summarized through weeks 4, 9, and 25 for each treatment.Results: Of 200 patients who received ≥ 1 dose of study treatment, 99 (49.5%) completed the study (AL, 57%; PP, 43%). Mean (SD) baseline Positive and Negative Syndrome Scale total scores were 94.1 (9.04) and 94.6 (8.41) in the AL and PP treatment groups, respectively. AEs were reported by 69/99 (70%) patients administered AL and 72/101 (71%) administered PP; most AEs were mild or moderate in severity. ISRs (AL, 18.2%; PP, 26.7%) occurred primarily on days 1 and 8. All akathisia/restlessness AEs (AL, 10.1%; PP, 11.9%) occurred during the first 4 weeks; <10% of patients (either treatment) experienced hypotension, sedation, or suicidal ideation/behavior events. Weight gain of ≥ 7% from baseline occurred in 9.3% of AL- and 23.8% of PP-treated patients. Median prolactin concentrations changed by -4.60 and -3.55 ng/mL among AL-treated males and females, respectively, and did not exceed 2 times normal levels in any AL-treated patients. In PP-treated patients, changes were 21.20 and 80.40 ng/mL and concentrations exceeded 2 times normal in 38% and 88% of males and females, respectively.Conclusions: No new early- or late-emerging safety concerns were observed through 25 weeks of treatment with AL 1064 mg every 2 months following initiation using ALNCD plus 30-mg oral aripiprazole. Results were consistent with known safety profiles of AL and PP and support the safety of AL 1064 mg every 2 months initiated using ALNCD plus 30-mg oral aripiprazole.Trial Registration: ClinicalTrials.gov identifier: NCT03345979.
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Antipsicóticos , Hipotensão , Nanopartículas , Doenças não Transmissíveis , Esquizofrenia , Adulto , Feminino , Humanos , Masculino , Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Preparações de Ação Retardada/uso terapêutico , Hipotensão/induzido quimicamente , Hipotensão/tratamento farmacológico , Doenças não Transmissíveis/tratamento farmacológico , Palmitato de Paliperidona , Prolactina , Esquizofrenia/tratamento farmacológico , Esquizofrenia/induzido quimicamente , Resultado do Tratamento , Aumento de Peso , Método Duplo-CegoRESUMO
Importance: The prompt effective treatment of acute agitation among patients with schizophrenia or bipolar disorder can alleviate distressing symptoms for the patient and decrease the risk of escalation to aggression and the potential for serious harm to the patient, health care providers, and others.Observations: A commonly used approach for the management of acute agitation has been the intramuscular administration of antipsychotic medications and/or benzodiazepines. However, US Food and Drug Administration-approved treatments with alternative routes of delivery now include inhaled loxapine powder and, more recently, dexmedetomidine sublingual film. Two formulations of intranasal olanzapine for acute agitation are in development.Conclusions and Relevance: Intranasal formulations offer the potential for favorable pharmacokinetics and onset of action combined with ease of delivery obviating the need for injections and are thus consistent with patient-centered factors such as preference and self-administration. In this review, alternative methods of medication delivery are discussed, with an emphasis on the potential for intranasal administration to treat acute agitation in adult patients with schizophrenia or bipolar disorder.Prim Care Companion CNS Disord 2024;26(1):23nr03596. Author affiliations are listed at the end of this article.
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Antipsicóticos , Transtorno Bipolar , Loxapina , Esquizofrenia , Adulto , Humanos , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Antipsicóticos/uso terapêutico , Transtorno Bipolar/complicações , Transtorno Bipolar/tratamento farmacológico , Agitação Psicomotora/tratamento farmacológico , Agitação Psicomotora/etiologia , Loxapina/efeitos adversosRESUMO
It has been previously reported that among patients with schizophrenia that long-acting injectable (LAI) antipsychotic formulations can delay time to relapse longer when compared to their oral equivalents when patients discontinue therapy. Unanswered is whether this same pattern would be observed for patients with bipolar disorder receiving maintenance treatment. A systematic review was undertaken to identify relevant studies of LAI antipsychotics in maintenance treatment of bipolar disorder, employing a placebo-controlled randomized withdrawal design, and where equivalent studies using the corresponding oral formulation were also available. We found five studies [one aripiprazole monohydrate once monthly (AOM) study, one oral aripiprazole (OARI) study, two 2 weeks risperidone-LAI (RIS-LAI) studies, and one oral paliperidone (OPAL) study]. Numerically lower recurrence rates at 2, 4, 6, 8, 12, 16, 20, and 26 weeks were observed when AOM was discontinued when compared with discontinuation from OARI. Numerically lower recurrence rates at 2, 4, 6, 8, and 16 weeks were observed when RIS-LAI was discontinued when compared with discontinuation from OPAL. These results can be interpreted as a substantial delay in time to recurrence with a LAI antipsychotics formulation compared to the oral equivalent when medication is discontinued in patients with mania who had been stabilized on LAI antipsychotics or corresponding oral antipsychotics.
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Antipsicóticos , Transtorno Bipolar , Esquizofrenia , Humanos , Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Aripiprazol/administração & dosagem , Aripiprazol/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/induzido quimicamente , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/uso terapêutico , Palmitato de Paliperidona/administração & dosagem , Palmitato de Paliperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , RecidivaRESUMO
Although uncommon, the risk of aggression and violence is greater in people with schizophrenia than in the general population. Clozapine is the "gold standard" pharmacologic treatment for the management of persistent agitation and aggression in people with schizophrenia and is consistently recommended by guidelines and reviews for this purpose. Although clozapine is indicated for treatment-resistant schizophrenia based on its superior efficacy, studies have proposed that clozapine may have specific properties that ameliorate aggression and hostility that are distinct from its antipsychotic effects. A literature review was conducted on June 3, 2023, using the US National Library of Medicine's PubMed resource to identify articles focusing on clozapine for the treatment of aggression, violence, and/or hostility in patients with schizophrenia or schizoaffective disorder. The majority of evidence, including from randomized control trials, supports the utilization of clozapine as maintenance treatment for persistent aggressive behavior in patients with schizophrenia, and supports that its anti-aggressive effects may be independent from its antipsychotic properties (e.g. - treatment of hallucinations and delusions). Future randomized control studies evaluating clozapine and clozapine serum levels with aggression as the primary outcome would be of benefit.
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Agressão , Antipsicóticos , Clozapina , Transtornos Psicóticos , Esquizofrenia , Violência , Humanos , Clozapina/uso terapêutico , Agressão/efeitos dos fármacos , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêuticoRESUMO
This Viewpoint describes the need for novel mechanism of action agents for schizophrenia to extend therapeutic options and improve outcomes.