检索问题
阿立哌唑相比于其他精神病类药物，有哪些临床优势？
阿立哌唑（Aripiprazole）在与其他精神病药物的比较中，展现出多方面的临床优势，这些优势涵盖了疗效、耐受性、安全性以及在特定疾病和患者群体中的应用。
1. 在精神分裂症治疗中的优势：
- 疗效与安全性平衡： 在急性期精神分裂症的治疗中，阿立哌唑与口服奥氮平（olanzapine）和利培酮（risperidone）具有相似的症状改善效果，但与奥氮平相比，其引发体重的增加程度较低，且不伴有显著的QTc间期延长风险 。一项研究表明，阿立哌唑在改善阴性症状和抑郁症状方面优于氟哌啶醇（haloperidol）。
- 长效注射剂型（LAI）的优势： 阿立哌唑有长效注射剂型（如阿立哌唑一水合物和阿立哌唑月桂酯），这些剂型在治疗急性期精神分裂症方面与口服制剂具有相似的疗效，但在某些副作用方面可能优于口服制剂 。长效注射剂型对于那些依从性差、容易复发的患者尤其有益，并且提供多种给药间隔选项（每月一次、每6周一次或每2个月一次），方便个体化治疗 。
- 锥体外系症状（EPS）和催乳素升高的风险较低： 与氟哌啶醇等第一代抗精神病药物相比，阿立哌唑引发锥体外系症状的风险较低，与利培酮和安慰剂相似 。此外，阿立哌唑显著降低血清催乳素水平，并且在考察的剂量范围内，高剂量阿立哌唑与较低的催乳素水平相关 。这对于需要长期服用抗精神病药物的患者，尤其是出现抗精神病药物性高催乳素血症的患者，是一个重要的优势 。在催乳素水平超过50 ng/ml的患者中，辅助使用阿立哌唑（5 mg、10 mg或10 mg以上）能显著降低催乳素水平 。
- 体重增加风险较低： 阿立哌唑在引起体重增加方面的风险较小，与其他非典型抗精神病药物相比，它不易导致显著的体重增加 。这对于关注代谢健康和心血管风险的患者来说是一个重要考量 。
2. 在双相情感障碍治疗中的优势：
- 广泛推荐作为一线治疗： 在双相I型障碍的急性躁狂期和维持治疗中，阿立哌唑被加拿大情绪和焦虑治疗网络（CANMAT）和国际双相情感障碍学会（ISBD）2018指南推荐为一线治疗药物，可单独使用或与其他药物联合使用 。
- 儿童和青少年中的应用： 阿立哌唑被批准用于10-17岁儿童和青少年躁狂或混合状态的双相情感障碍治疗 。
3. 在Tourette's 综合征治疗中的优势：
- 有效缓解抽动症状： 针对儿童、青少年和年轻Tourette's综合征患者，阿立哌唑在减轻抽动症状方面表现出显著疗效，优于安慰剂，且与利培酮（risperidone）相比，其效果也优于可乐定（clonidine）。
4. 在痴呆行为和精神症状（BPSD）治疗中的优势：
- 良好的可接受性： 在对痴呆行为和精神症状（BPSD）的治疗中，阿立哌唑在可接受性方面表现最佳，优于安慰剂和brexpiprazole，并且在耐受性方面优于奥氮平 。
5. 代谢参数和QTc间期影响小：
- 心血管安全性： 阿立哌唑在QTc间期延长和代谢参数（如体重增加、血糖和血脂）方面的改变不显著，这使其在心血管安全性方面优于一些其他抗精神病药物 。真实世界的研究也支持阿立哌唑与较低的QTc间期延长风险相关 。
6. 对抗精神病药物引起的高催乳素血症的治疗作用：
- 降低催乳素： 阿立哌唑能够有效降低由其他抗精神病药物引起的高催乳素血症，特别是在催乳素水平较高的患者中 。这使其成为一种重要的辅助治疗选择，尤其是在患者需要继续服用其他抗精神病药物时 。
- 多巴胺D2受体部分激动剂特性： 作为多巴胺D2受体部分激动剂，阿立哌唑的独特作用机制使其在治疗过程中对催乳素水平的影响较小，甚至能够降低高催乳素水平，这与传统的D2受体阻断剂不同 。
7. 潜在的成瘾治疗前景：
- 减少奖励效应： 初步研究表明，阿立哌唑作为多巴胺D2受体部分激动剂，在一些动物模型中显示出对兴奋剂和阿片类药物成瘾的辅助疗效，它可以减弱阿片类药物的奖励特性而不影响其镇痛效果，并且具有较低的滥用倾向 。
总结 阿立哌唑的临床优势主要体现在其对多种精神疾病的有效治疗，包括精神分裂症、双相情感障碍和Tourette's综合征。其独特的药理学特性，如多巴胺D2受体部分激动剂作用，赋予了它较低的锥体外系症状、代谢副作用和高催乳素血症风险，以及良好的心血管安全性。此外，阿立哌唑在应对其他抗精神病药物引起的高催乳素血症方面具有辅助治疗作用。长效注射剂型的可用性也为提高患者依从性、预防复发提供了更多选择。然而，在某些情况下，阿立哌唑也可能引起强迫症症状，因此仍需根据患者的具体情况进行个体化选择和监测 。
References
1Comparative efficacy, tolerability, and acceptability of pharmacological interventions for the treatment of children, adolescents, and young adults with Tourette's syndrome: a systematic review and network meta-analysis.PubMed
Luis C Farhat, Emily Behling, Angeli Landeros-Weisenberger, et al.
BACKGROUND: In clinical practice guidelines there is no consensus about the medications that should be initially offered to children and young people with Tourette's syndrome. To provide a rigorous evidence base that could help guide decision making and guideline development, we aimed to compare the efficacy, tolerability, and acceptability of pharmacological interventions for Tourette's syndrome. METHODS: For this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, Embase, PsycINFO, PubMed, Web of Science, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov, for published and unpublished studies from database inception to Nov 19, 2021. We included double-blind randomised controlled trials of any medication administered as a monotherapy for at least 1 week against another medication or placebo in children and adolescents (aged ≥4 years and ≤18 years), adults (>18 years), or both, diagnosed with Tourette's syndrome according to standardised criteria. We excluded studies that exclusively recruited participants with comorbid attention-deficit hyperactivity disorder or obsessive-compulsive disorder. The primary outcome was change in severity of tic symptoms (efficacy). Secondary outcomes were treatment discontinuations due to adverse events (tolerability) and for any reason (acceptability). Pharmacological interventions were examined considering medication categories and medications individually in separate analyses. Summary data were extracted and pooled with a random-effects network meta-analysis to calculate standardised mean differences for efficacy and odds ratios for tolerability and acceptability, with 95% CIs. The Confidence in Network Meta-Analysis (CINeMA) framework was used to assess the certainty of evidence. The protocol was pre-registered in PROSPERO (CRD42022296975). FINDINGS: Of the 12 088 records identified through the database search, 88 records representing 39 randomised controlled trials were included in the network meta-analysis; these 39 randomised controlled trials comprised 4578 participants (mean age 11·8 [SD 4·5] years; 3676 [80·8%] male participants) and evaluated 23 individual medications distributed across six medication categories. When considering medication categories, first-generation (standardised mean difference [SMD] -0·65 [95% CI -0·79 to -0·51]; low certainty of evidence) and second-generation (-0·71 [-0·88 to -0·54]; moderate certainty of evidence) antipsychotic drugs, as well as α-2 agonists (-0·21 [-0·39 to -0·03]; moderate certainty of evidence), were more efficacious than placebo. First-generation and second-generation antipsychotic drugs did not differ from each other (SMD 0·06 [95% CI -0·14 to 0·25]; low certainty of evidence). However, both first-generation (SMD 0·44 [95% CI 0·21 to 0·66]) and second-generation (0·49 [0·25 to 0·74]) antipsychotic drugs outperformed α-2 agonists, with moderate certainty of evidence. Similar findings were observed when individual medications were considered: aripiprazole (SMD -0·60 [95% CI -0·83 to -0·38]), haloperidol (-0·51 [-0·88 to -0·14]), olanzapine (-0·83 [-1·49 to -0·18]), pimozide (-0·48 [-0·84 to -0·12]), risperidone (-0·66 [-0·98 to -0·34]), and clonidine (-0·20 [-0·37 to -0·02]) all outperformed placebo, with moderate certainty of evidence. Antipsychotic medications did not differ from each other, but there was low to very low certainty of evidence for these comparisons. However, aripiprazole (SMD -0·40 [95% CI -0·69 to -0·12]) and risperidone (-0·46 [-0·82 to -0·11]) outperformed clonidine, with moderate certainty of evidence. Heterogeneity or inconsistency only emerged for a few comparisons. In terms of tolerability and acceptability, there were no relevant findings for any of the efficacious medication categories or individual medications against each other or placebo, but there was low to very low certainty of evidence associated with these comparisons. INTERPRETATION: Our analyses show that antipsychotic drugs are the most efficacious intervention for Tourette's syndrome, while α-2 agonists are also more efficacious than placebo and could be chosen by those who elect not to take antipsychotic drugs. Shared decision making about the degree of tic-related severity and distress or impairment, the trade-offs of efficacy and safety between antipsychotic drugs and α-2 agonists, and other highly relevant individual factors that could not be addressed in the present analysis, should guide the choice of medication for children and young people with Tourette's syndrome. FUNDING: None.
2Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.PubMed
Stefan Leucht, Andrea Cipriani, Loukia Spineli, et al.
BACKGROUND: The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs. METHODS: We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation. FINDINGS: We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73-1·03; amisulpride 0·66, 0·53-0·78; olanzapine 0·59, 0·53-0·65; risperidone 0·56, 0·50-0·63; paliperidone 0·50, 0·39-0·60; zotepine 0·49, 0·31-0·66; haloperidol 0·45, 0·39-0·51; quetiapine 0·44, 0·35-0·52; aripiprazole 0·43, 0·34-0·52; sertindole 0·39, 0·26-0·52; ziprasidone 0·39, 0·30-0·49; chlorpromazine 0·38, 0·23-0·54; asenapine 0·38, 0·25-0·51; lurasidone 0·33, 0·21-0·45; and iloperidone 0·33, 0·22-0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from -0·09 for the best drug (haloperidol) to -0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to -1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to -0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses. INTERPRETATION: Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines. FUNDING: None.
3Pharmacological treatment strategies for antipsychotic-induced hyperprolactinemia: a systematic review and network meta-analysis.PubMed
Zhe Lu, Yaoyao Sun, Yuyanan Zhang, et al.
Antipsychotic-induced hyperprolactinemia (AP-induced HPRL) occurs overall in up to 70% of patients with schizophrenia, which is associated with hypogonadism and sexual dysfunction. We summarized the latest evidence for the benefits of prolactin-lowering drugs. We performed network meta-analyses to summarize the evidence and applied Grading of Recommendations Assessment, Development, and Evaluation frameworks (GRADE) to rate the certainty of evidence, categorize interventions, and present the findings. The search identified 3,022 citations, 31 studies of which with 1999 participants were included in network meta-analysis. All options were not significantly better than placebo among patients with prolactin (PRL) less than 50 ng/ml. However, adjunctive aripiprazole (ARI) (5 mg: MD = -64.26, 95% CI = -87.00 to -41.37; 10 mg: MD = -59.81, 95% CI = -90.10 to -29.76; more than 10 mg: MD = -68.01, 95% CI = -97.12 to -39.72), switching to ARI in titration (MD = -74.80, 95% CI = -134.22 to -15.99) and adjunctive vitamin B6 (MD = -91.84, 95% CI = -165.31 to -17.74) were associated with significant decrease in AP-induced PRL among patients with PRL more than 50 ng/ml with moderated (adjunctive vitamin B6) to high (adjunctive ARI) certainty of evidence. Pharmacological treatment strategies for AP-induced HPRL depends on initial PRL level. No effective strategy was found for patients with AP-induced HPRL less than 50 ng/ml, while adjunctive ARI, switching to ARI in titration and adjunctive high-dose vitamin B6 showed better PRL decrease effect on AP-induced HPRL more than 50 ng/ml.
4Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder.PubMed
Lakshmi N Yatham, Sidney H Kennedy, Sagar V Parikh, et al.
The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment-emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second- line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence-based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-line treatments for acute mania. First-line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.
5Antipsychotics and risk of QT prolongation: a pharmacovigilance study.PubMed
Constance Bordet, Philippe Garcia, Francesco Salvo, et al.
RATIONALE: While meta-analyses of clinical trials found that lurasidone and partial dopamine agonists (brexpiprazole and aripiprazole) were the antipsychotics less likely to cause QTc prolongation, and sertindole, amisulpride, and ziprasidone were the most frequently associated with this adverse drug reaction; no real-world studies have investigated this risk between the different antipsychotics. OBJECTIVES AND METHODS: Using data recorded from 1967 to 2019 in VigiBase®, the World Health Organization's Global Individual Case Safety Reports database, we performed disproportionality analysis to investigate the risk of reporting QT prolongation between 20 antipsychotics. RESULTS: Sertindole had the highest risk of reporting QT prolongation, followed by ziprasidone and amisulpride. Lurasidone was associated with the lowest risk. First-generation antipsychotics were associated with a greater QT prolongation reporting risk (ROR, 1.21; 95%CI, 1.10-1.33) than second-generation antipsychotics. A positive correlation was found between the risk of reporting QT prolongation and affinity for hERG channel (R = 0.14, slope = Pearson coefficient = 0.41, p value = 0.1945). CONCLUSIONS: This large study in a real-world setting suggests that sertindole and ziprasidone were the antipsychotics drugs associated with the highest risk of QT prolongation reporting. Our results suggest that lurasidone is less associated with QT interval prolongation reports. Our study also suggests that antipsychotics with the higher hERG affinity are more associated with to QT prolongations reports.
6Advances in Mood Disorder Pharmacotherapy: Evaluating New Antipsychotics and Mood Stabilizers for Bipolar Disorder and Schizophrenia.PubMed
Emilia Kowalczyk, Sylwia Koziej, Ewelina Soroka
This article provides a narrative review of recent developments in mood-stabilizing drugs, considering their mechanism of action, efficacy, safety, and therapeutic potential in the treatment of mood disorders, particularly bipolar disorder and schizophrenia. The review focuses on the mechanism and clinical aspects of second-generation antipsychotic medications; aripiprazole, classified as a third-generation antipsychotic medication; lamotrigine, as a representative of antiepileptic drugs; and lurasidone, a novel second-generation antipsychotic medication. Moreover, the article refers to one of the newest and most highly effective normothymic drugs, cariprazine. The potential of new mood stabilizer candidates lumateperone and brexpiprazole is also presented. Covered topics include the clinical efficacy of new drugs in reducing manic and depressive symptoms during acute episodes, as well as their role in preventing relapse. In addition, we analyzed the incidence of adverse effects of each drug. Many of the new drugs have strong potential to be beneficial and safe in cases of many comorbidities, as they do not cause many adverse effects and do not require high doses of use. The results underscore the importance of ongoing and future research to better understand the action and efficacy of these mood stabilizers and their implications in the treatment of mood disorders, aiming to achieve euthymia and improve the quality of life of affected patients. In this article, we aim to review current drug treatments for the management of mood disorders, including bipolar disorder and schizophrenia.
7Efficacy, acceptability and side-effects of oral versus long-acting- injectables antipsychotics: Systematic review and network meta-analysis.PubMed
Dongfang Wang, Johannes Schneider-Thoma, Spyridon Siafis, et al.
Long-acting injectable antipsychotics (LAIs) are primarily used for relapse prevention, but in some settings and situations, they may also be useful for acute treatment of schizophrenia. We conducted a systematic review and frequentist network meta-analysis of randomized-controlled trials (RCTs), focusing on adult patients in the acute phase of schizophrenia. Interventions were risperidone, paliperidone, aripiprazole, olanzapine, and placebo, administered either orally or as LAI. We synthesized data on overall symptoms, complemented by 17 other efficacy and tolerability outcomes. Confidence in the evidence was assessed with the Confidence-in-Network-Meta-Analysis-framework (CINeMA). We included 115 RCTs with 25,550 participants. All drugs were significantly more efficacious than placebo with the following standardized mean differences and their 95 % confidence intervals: olanzapine LAI -0.66 [-1.00; -0.33], risperidone LAI -0.59[-0.73;-0.46], olanzapine oral -0.55[-0.62;-0.48], aripiprazole LAI -0.54[-0.71; -0.37], risperidone oral -0.48[-0.55;-0.41], paliperidone oral -0.47[-0.58;-0.37], paliperidone LAI -0.45[-0.57;-0.33], aripiprazole oral -0.40[-0.50; -0.31]. There were no significant efficacy differences between LAIs and oral formulations. Sensitivity analyses of the primary outcome overall symptoms largely confirmed these findings. Moreover, some side effects were less frequent under LAIs than under their oral counterparts. Confidence in the evidence was moderate for most comparisons. LAIs are efficacious for acute schizophrenia and may have some benefits compared to oral formulations in terms of side effects. These findings assist clinicians with insights to weigh the risks and benefits between oral and injectable agents when treating patients in the acute phase.
8Antipsychotic-Related Prolactin Changes: A Systematic Review and Dose-Response Meta-analysis.PubMed
Xiao Lin, Spyridon Siafis, Jing Tian, et al.
BACKGROUND: Prolactin increase is a common and potentially problematic adverse event of antipsychotics. We aimed to discover the relationship between antipsychotic doses and changes in prolactin levels. OBJECTIVE: To examine the relationship between antipsychotic doses and changes in prolactin levels in adults with acutely exacerbated schizophrenia. METHODS: We searched the Cochrane Schizophrenia Group register (last search 26 July 2024) and previous reviews for fixed-dose, randomized controlled trials (RCTs) that investigated monotherapy of 21 antipsychotics in adults with acutely exacerbated schizophrenia. The primary outcome was mean prolactin change from baseline to study endpoint adopting mean differences (MD) in ng/mL as the effect size measure. The dose-response curves were estimated by conducting random-effects dose-response meta-analyses using the restricted cubic spline method. RESULTS: Among 165 eligible studies, 68 studies with 238 dose arms (23,128 participants, 35% female) reported on prolactin and were meta-analyzed. Of these, 94% lasted ≤ 3 months, and 90% of the studies used oral formulations. Participants in one study experienced their first episode, while all other studies also included multiepisode participants. The dose-response curves indicated that with aripiprazole, higher doses were significantly associated with lower prolactin levels than lower doses. Brexpiprazole, cariprazine, lumateperone, and quetiapine carried negligible risks for prolactin increase across examined doses. During treatment with most other antipsychotics, i.e., asenapine, haloperidol, iloperidone, lurasidone, olanzapine, paliperidone, risperidone, and ziprasidone, prolactin levels rose with increasing doses and then continued to increase or plateaued. The shape of the dose-response curves was similar in males and females, with generally larger amplitudes of the curves in females. CONCLUSIONS: The prolactin-increasing property varies among antipsychotics, is dose-related, and is greater in females. These findings in adults with acutely exacerbated schizophrenia can help clinicians titrate and adapt antipsychotic doses and consider patients' sex in treatment decisions. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO); registration no. CRD42020181467.
9Risk factors, prevention and treatment of weight gain associated with the use of antidepressants and antipsychotics: a state-of-the-art clinical review.PubMed
Marco Solmi, Alessandro Miola, Federico Capone, et al.
INTRODUCTION: People with severe mental illness have poor cardiometabolic health. Commonly used antidepressants and antipsychotics frequently lead to weight gain, which may further contribute to adverse cardiovascular outcomes. AREAS COVERED: We searched MEDLINE up to April 2023 for umbrella reviews, (network-)meta-analyses, trials and cohort studies on risk factors, prevention and treatment strategies of weight gain associated with antidepressants/antipsychotics. We developed 10 clinical recommendations. EXPERT OPINION: To prevent, manage, and treat antidepressant/antipsychotic-related weight gain, we recommend i) assessing risk factors for obesity before treatment, ii) monitoring metabolic health at baseline and regularly during follow-up, iii) offering lifestyle interventions including regular exercise and healthy diet based on patient preference to optimize motivation, iv) considering first-line psychotherapy for mild-moderate depression and anxiety disorders, v)choosing medications based on medications' and patient's weight gain risk, vi) choosing medications based on acute vs long-term treatment, vii) using effective, tolerated medications, viii) switching to less weight-inducing antipsychotics/antidepressants where possible, ix) using early weight gain as a predictor of further weight gain to inform the timing of intervention/switch options, and x) considering adding metformin or glucagon-like peptide-1 receptor agonists, or topiramate(second-line due to potential adverse cognitive effects) to antipsychotics, or aripiprazole to clozapine or olanzapine.
10Drug induced hypoprolactinemia.PubMed
Adriana G Ioachimescu, Fahrettin Kelestimur
Prolactin levels can be influenced by multiple medications primarily through the interaction with dopamine receptors which regulate its secretion. Unlike hyperprolactinemia which has a well-defined clinical phenotype, the effects of hypoprolactinemia beyond inability to lactate are incompletely understood. Recent studies have raised concerns regarding detrimental changes in glucose metabolism, sexual function and psychological profile in patients with low prolactin levels. In contrast with anatomic and genetic etiologies, drug-induced hypoprolactinemia is usually reversible after dose reduction of the offending medication. The most common clinical scenario of drug-induced hypoprolactinemia in the endocrine clinic pertains to patients treated with cabergoline or bromocriptine for prolactin-secreting or other types of pituitary adenomas. Also, data has accumulated regarding hypoprolactinemia in patients receiving aripiprazole for schizophrenia and other psychiatric disorders. These patients warrant careful evaluation for comorbidities. This review aims to increase awareness about the potentially detrimental effects of drug-induced hypoprolactinemia, which should be considered in clinical practice decisions.
11Brexpiprazole: A Review in Schizophrenia.PubMed
James E Frampton
Brexpiprazole (Rxulti, Rexulti) is an oral atypical antipsychotic agent approved for the treatment of schizophrenia in the EU (in adult patients) and the USA, as well as in some other countries, including Japan. Like aripiprazole, it is a partial agonist at dopamine D and serotonin 5-HT receptors and an antagonist at serotonin 5-HT receptors. However, brexpiprazole displays less intrinsic activity at D receptors and, coupled with actions at 5HT, 5HT and noradrenaline α receptors that are at least as potent as its action at D receptors, is predicted to demonstrate a lower propensity for activating adverse events and extrapyramidal symptoms than aripiprazole. Brexpiprazole 2-4 mg/day produced statistically significant and clinically meaningful improvements in overall symptomatology and psychosocial functioning compared with placebo in adults with acute exacerbation of schizophrenia. As maintenance treatment, brexpiprazole 1-4 mg/day significantly delayed the time to relapse compared with placebo in patients who were already stabilized on the drug and was associated with stabilization or continued improvement in patients' symptoms and functioning. Brexpiprazole was generally well tolerated, exhibiting an adverse event profile characterized by a relatively low incidence of activating and sedating adverse effects, small changes in QT interval and metabolic parameters that were not clinically significant, and moderate weight gain. Clinical evidence to date suggests it usefully extends the range of therapeutic options for schizophrenia.
12Efficacy, acceptability and tolerability of second-generation antipsychotics for behavioural and psychological symptoms of dementia: a systematic review and network meta-analysis.PubMed
Wenqi Lü, Fangzhou Liu, Yuwei Zhang, et al.
BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD) are highly prevalent in people living with dementia. Second-generation antipsychotics (SGAs) are commonly used to treat BPSD, but their comparative efficacy and acceptability are unknown. METHODS: The standard mean difference (SMD) was used to pool the fixed effects of continuous outcomes. We calculated ORs with corresponding 95% credible intervals (CI) for the categorical variable. Efficacy was defined as the scores improved on the standardised scales. Acceptability was defined as the all-cause dropout rate. Tolerability was defined as the discontinuation rate due to adverse effects (AEs). The relative treatment rankings were reported with the surface under the cumulative curve. The AE outcomes included mortality, cerebrovascular adverse events (CVAEs), falls, sedation, extrapyramidal symptoms and urinary symptoms. RESULTS: Twenty randomised controlled trials with a total of 6374 individuals containing 5 types of SGAs (quetiapine, olanzapine, risperidone, brexpiprazole and aripiprazole) with intervention lengths ranging from 6 weeks to 36 weeks were included in this network meta-analysis. For the efficacy outcome, compared with the placebo, brexpiprazole (SMD=-1.77, 95% CI -2.80 to -0.74) was more efficacious, and brexpiprazole was better than quetiapine, olanzapine and aripiprazole. Regarding acceptability, only aripiprazole (OR=0.72, 95% CI 0.54 to 0.96) was better than the placebo, and aripiprazole was also better than brexpiprazole (OR=0.61, 95% CI 0.37 to 0.99). In terms of tolerability, olanzapine was worse than placebo (OR=6.02, 95% CI 2.87 to 12.66), risperidone (OR=3.67, 95% CI 1.66 to 8.11) and quetiapine (OR=3.71, 95% CI 1.46 to 9.42), while aripiprazole was better than olanzapine (OR=0.25, 95% CI 0.08 to 0.78). Quetiapine presented good safety in CVAE. Brexpiprazole has better safety in terms of falls and showed related safety in sedation among included SGAs. CONCLUSION: Brexpiprazole showing great efficacy in the treatment of BPSD, with aripiprazole showing the highest acceptability and olanzapine showing the worst tolerability. The results of this study may be used to guide decision-making.
13Dopamine agonists and antipsychotics.PubMed
Mark E Molitch
There can potentially be a number of clinical interactions that could adversely affect patient outcomes in a patient with a prolactinoma and psychiatric disease that might require antipsychotic and dopamine agonist treatment. Dopamine agonists stimulate the dopamine D2 receptor, resulting in a decrease in prolactin (PRL) levels and in prolactinoma size but action on dopamine receptors in the meso-limbic system may rarely cause psychosis and more commonly cause impulse control disorders. The psychiatric benefits of antipsychotic agents involve blocking the D2 and other dopamine receptors but this blockade often also causes hyperprolactinemia. In patients with macroprolactinomas and psychosis, observation, estrogen/progestin replacement, and surgery can be considered in addition to dopamine agonists. In those who require dopamine agonists for PRL and tumor size control, the introduction of antipsychotics may blunt this effect, so that higher doses of the dopamine agonists may be needed. Alternatively, antipsychotics that have less of a blocking effect at the D2 receptor, such as aripiprazole, can be tried, if appropriate. For patients already on antipsychotic drugs who are found to have a macroprolactinoma for which dopamine agonists are required, dopamine agonists can be initiated at low dose and the dose escalated slowly. However, such patients require careful monitoring of psychiatric status to avoid the rare complication of exacerbation of the underlying psychosis. Again, if appropriate, use of antipsychotics that have less of a blocking effect at the D2 receptor may allow lower doses of dopamine agonists to be used in this situation.
14Aripiprazole long-acting injectable formulations for schizophrenia: aripiprazole monohydrate and aripiprazole lauroxil.PubMed
Leslie Citrome
Aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL) are two different long-acting injectable formulations of aripiprazole. AM 400 mg administered once monthly demonstrated efficacy in an acute, double-blind, placebo-controlled, randomized clinical trial, as well as in a double-blind, placebo-controlled, randomized-withdrawal maintenance study, and in two non-inferiority maintenance studies. AL is a prodrug of aripiprazole and available in 441 mg, 662 mg or 882 mg strengths. AL 441 mg and 882 mg administered once monthly demonstrated efficacy in an acute, double-blind, placebo-controlled, randomized clinical trial. The pharmacokinetic profile of AL also led to approval of dosing intervals of every 6 weeks for the 882 mg dose. The overall tolerability profiles of both products are consistent with what is known about oral aripiprazole.
15Antipsychotic-Induced Weight Gain: Dose-Response Meta-Analysis of Randomized Controlled Trials.PubMed
Hui Wu, Spyridon Siafis, Tasnim Hamza, et al.
BACKGROUND: Weight gain is among the most important side-effects of antipsychotics. It is, however, unclear whether it is associated with antipsychotic doses. We aimed to fill this gap with a dose-response meta-analysis. METHODS: We searched multiple electronic databases (last update search June 2021) for all fixed-dose studies that investigated 16 second-generation antipsychotics and haloperidol in adults with acute exacerbation of schizophrenia or with negative symptoms. We estimated the dose-response curves by conducting random-effects dose-response meta-analyses. We used the restricted cubic spline to model the dose-response relationship. The primary outcome was mean weight gain in kg from baseline to endpoint, the secondary outcome was the number of patients with clinically important weight gain. FINDINGS: Ninety-seven studies with 333 dose arms (36 326 participants) provided data for meta-analyses. Most studies were short-term with median duration of 6 weeks (range 4 to 26 weeks). In patients with acute exacerbation, amisulpride, aripiprazole, brexpiprazole, cariprazine, haloperidol, lumateperone, and lurasidone produced mild weight gain in comparison to placebo (mean difference at any dose≤1 kg), while more significant weight gain was observed by all other drugs. For most drugs, dose-response curves showed an initial dose-related increase in weight which plateaued at higher doses, while for others there was no plateau and some even had bell-shaped curves, meaning less weight gain to be associated with higher doses. INTERPRETATION: Second-generation antipsychotics do not only differ in their propensity to produce weight gain, but also in the shapes of their dose-response curves. This information is important for dosing decisions in clinical practice.
16Aripiprazole-induced obsessive-compulsive symptoms.PubMed
Dilshana Nafisa, Anil Kakunje
Aripiprazole is a novel antipsychotic with a unique pharmacological profile as a dopamine partial agonist. It is indicated for treatment of schizophrenia and bipolar disorder. This new antipsychotic has low rate of extrapyramidal side effects, metabolic changes and no significant adverse effect on serum prolactin concentration. In addition,it is not associated with significant weight gain like other atypical antipsychotics. As a reason, when other antipsychotics cause these adverse events, it's not uncommon to switch to Aripiprazole. Obsessive compulsive symptoms have been untoward sequel of a few second-generation antipsychotics. Among the second generation antipsychotics Clozapine, Olanzapine, and Risperidone are the most prominent agents associated with these sequelae, according to case reports. More recently, a handful of case reports indicated development of Obsessive-compulsive symptoms with Aripiprazole. We report a case that exhibited similar unexpected adverse effects after administration of Aripiprazole. Keywords: Aripiprazole, Second generation antipsychotics, Obsessive-compulsive symptoms (OCS).
17Dopamine receptor partial agonists and addiction.PubMed
Fabricio A Moreira, Jeffrey W Dalley
Many drugs abused by humans acutely facilitate, either directly or indirectly, dopamine neurotransmission in the mesolimbic pathway. As a consequence dopamine receptor agonists and antagonists have been widely investigated as putative pharmacological therapies for addiction. This general strategy, however, has had only limited success due in part to poor treatment adherence and efficacy and the significant adverse effects of dopaminergic medications. In this perspective, we discuss the potential therapeutic use of dopamine receptor partial agonists in addiction, developed initially as antipsychotic agents. Recent research indicates that the dopamine D2 receptor partial agonists, such as aripiprazole, also shows useful ancillary efficacy in several animal models of psychostimulant and opioid addiction. Notably, these findings suggest that unlike full dopamine receptor agonists and antagonists these compounds have low abuse liability and are generally well tolerated. Indeed, partial dopamine agonists attenuate the rewarding properties of opioids without interfering with their analgesic effects. Herein we discuss the utility and potential of dopamine receptor partial agonists as treatments for both stimulant and non-stimulant drug addiction.
18Aripiprazole Lauroxil: A Review in Schizophrenia.PubMed
James E Frampton
Aripiprazole lauroxil long-acting injectable (LAI) [Aristada] is an intramuscularly administered, extended-release prodrug of aripiprazole, an established atypical antipsychotic agent that, in terms of its relative position within the class, is at the low end of the risk spectrum for metabolic side effects. In the USA, aripiprazole lauroxil LAI is indicated for the treatment of schizophrenia; approved doses of the drug can be injected once-monthly (q4w), every 6 weeks (q6w) or every 2 months (q8w). The efficacy of the 441 and 882 mg q4w dosages in the treatment of acute exacerbations of schizophrenia and as long-term maintenance therapy in stable schizophrenia has been directly demonstrated in a phase III clinical trial and extension, while the efficacy of the 662 mg q4w, 882 mg q6w and 1064 mg q8w dosing regimens has been established on the basis of pharmacokinetic bridging studies. Aripiprazole lauroxil LAI therapy was generally well tolerated, with an adverse event profile consistent with that of oral aripiprazole (with the exception of injection-site reactions), including a low propensity to cause metabolic disturbances. Thus, aripiprazole lauroxil LAI extends the treatment regimen options for patients with schizophrenia; as with other LAI formulations of antipsychotic agents, it can be particularly recommended for patients with recurrent relapses related to nonadherence to oral preparations and for those who prefer this mode of administration. Moreover, unlike aripiprazole monohydrate LAI, the only other commercially available long-acting formulation of aripiprazole, aripiprazole lauroxil LAI offers more than one dosing interval option, which may be a potential advantage in terms of tailoring therapy to the needs of individual patients.
19Pediatric Bipolar Disorder: Challenges in Diagnosis and Treatment.PubMed
Janet Wozniak, Hannah O'Connor, Maria Iorini, et al.
Despite an opportunity to prevent adult psychopathology associated with bipolar disorder through early diagnosis in children, there is insufficient information and awareness among healthcare providers about the unique features and treatment of mania and its comorbid conditions in children. Converging evidence from disparate sites describe a developmentally distinct presentation of bipolar disorder in youth that is highly morbid, persistent and responds to treatment with the mood stabilizer medications used in the treatment of adult bipolar disorder, such as divalproex sodium and carbamazepine. Some are additionally approved for use in pediatric populations including, for manic or mixed states, risperidone, aripiprazole, and asenapine for those aged 10-17 years and also including lithium and olanzapine for ages 13-17 years. Quetiapine is approved as monotherapy or as adjunct to lithium or divalproex sodium for manic states in those aged 10-17 years. Delayed or missed diagnosis, inappropriate treatment, worsening course, and treatment resistance unfortunately still occur. While an array of mood-stabilizing medications is available for treatment, such as second-generation antipsychotics, lithium, and anticonvulsants, these can be only partially effective and fraught with annoying and serious side effects. This article will review current practice in the diagnosis and treatment of pediatric bipolar disorder and its comorbid conditions, highlighting areas of need for future research.
20Aripiprazole.PubMed
Jane K McGavin, Karen L Goa
Aripiprazole is a quinolinone derivative and the first of a new class of atypical antipsychotics. The drug has partial agonist activity at dopamine D(2) and serotonin 5-HT(1A) receptors, and is also an antagonist at 5-HT(2A) receptors. In patients with acute relapse of schizophrenia or schizoaffective disorder, aripiprazole 15 to 30 mg/day was at least as effective as haloperidol 10 mg/day and had similar efficacy to risperidone 6 mg/day in well designed, 4-week, placebo-controlled trials. Negative symptoms improved earlier in the aripiprazole than the risperidone group. Efficacy of aripiprazole was observed at week 1 in several trials and was sustained throughout the study periods. Aripiprazole was superior to placebo in a 26-week trial in patients with stable, chronic schizophrenia. In a 52-week trial involving patients with acute relapsing disease, aripiprazole was similar to haloperidol as assessed by time to failure to maintain response and was superior in ameliorating negative and depressive symptoms. The incidence of extrapyramidal symptoms during aripiprazole therapy was similar to that with risperidone and placebo but lower than with haloperidol. Compared with placebo, the proportion of patients with increased plasma prolactin levels and QTc prolongation was similar in patients treated with aripiprazole 15 to 30 mg/day but was significantly increased with haloperidol and risperidone.