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Lancet (London, England) Sep 2019Schizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is... (Meta-Analysis)
Meta-Analysis
Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis.
BACKGROUND
Schizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials.
METHODS
We did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to Jan 8, 2019. Two authors independently selected studies and extracted data. We included randomised controlled trials in adults with acute symptoms of schizophrenia or related disorders. We excluded studies in patients with treatment resistance, first episode, predominant negative or depressive symptoms, concomitant medical illnesses, and relapse-prevention studies. Our primary outcome was change in overall symptoms measured with standardised rating scales. We also extracted data for eight efficacy and eight safety outcomes. Differences in the findings of the studies were explored in metaregressions and sensitivity analyses. Effect size measures were standardised mean differences, mean differences, or risk ratios with 95% credible intervals (CrIs). Confidence in the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). The study protocol is registered with PROSPERO, number CRD42014014919.
FINDINGS
We identified 54 417 citations and included 402 studies with data for 53 463 participants. Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from -0·89 (95% CrI -1·08 to -0·71) for clozapine to -0·03 (-0·59 to 0·52) for levomepromazine (40 815 participants). Standardised mean differences compared with placebo for reduction of positive symptoms (31 179 participants) varied from -0·69 (95% CrI -0·86 to -0·52) for amisulpride to -0·17 (-0·31 to -0·04) for brexpiprazole, for negative symptoms (32 015 participants) from -0·62 (-0·84 to -0·39; clozapine) to -0·10 (-0·45 to 0·25; flupentixol), for depressive symptoms (19 683 participants) from -0·90 (-1·36 to -0·44; sulpiride) to 0·04 (-0·39 to 0·47; flupentixol). Risk ratios compared with placebo for all-cause discontinuation (42 672 participants) ranged from 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide), for sedation (30 770 participants) from 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol), for use of antiparkinson medication (24 911 participants) from 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide). Mean differences compared to placebo for weight gain (28 317 participants) ranged from -0·16 kg (-0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevation (21 569 participants) from -77·05 ng/mL (-120·23 to -33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from -2·21 ms (-4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole). Conclusions for the primary outcome did not substantially change after adjusting for possible effect moderators or in sensitivity analyses (eg, when excluding placebo-controlled studies). The confidence in evidence was often low or very low.
INTERPRETATION
There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the importance of each outcome, the patients' medical problems, and preferences.
FUNDING
German Ministry of Education and Research and National Institute for Health Research.
Topics: Administration, Oral; Antipsychotic Agents; Comparative Effectiveness Research; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome
PubMed: 31303314
DOI: 10.1016/S0140-6736(19)31135-3 -
The Annals of Pharmacotherapy Nov 2016To review evidence for the treatment of neuroleptic malignant syndrome (NMS) and to discuss how to rechallenge patients with neuroleptics when continued pharmacotherapy... (Review)
Review
OBJECTIVE
To review evidence for the treatment of neuroleptic malignant syndrome (NMS) and to discuss how to rechallenge patients with neuroleptics when continued pharmacotherapy for chronic psychological illness is required.
DATA SOURCES
A PubMed search was conducted through March 2016 using available medical subject heading (MeSH) terms and keywords that included neuroleptic malignant syndrome, treatment, dantrolene, and bromocriptine. A manual search of article reference sections followed.
STUDY SELECTION AND DATA EXTRACTION
Case reports and case series in English that discussed NMS and atypical NMS treatment as well as neuroleptic rechallenge were included for review.
DATA SYNTHESIS
The reported incidence of NMS was 0.02% to 0.03%, with a mortality rate of 5.6%. Current literature on NMS is primarily retrospective and emphasizes diagnostic criteria, causative agents, and potential pharmacotherapy. Details regarding timing of administration, dose, and duration of pharmacotherapy are inconsistently reported. Reported dosing strategies and outcomes have been summarized. Instances of rechallenge were infrequently reported but demonstrate that recurrence may happen at any time after NMS resolution. Recommendations regarding safe rechallenge are provided.
CONCLUSION
NMS is a rare adverse drug reaction, with a complex pathophysiology and presentation. Timely diagnosis and discontinuation of antipsychotic therapy is the first-line treatment, followed by supportive care and pharmacotherapy. Antipsychotic rechallenge is often required and should be attempted only after a drug-free period and with a different agent, slowly titrated with close monitoring.
Topics: Antipsychotic Agents; Dantrolene; Diagnosis, Differential; Humans; Mental Disorders; Neuroleptic Malignant Syndrome; Recurrence
PubMed: 27423483
DOI: 10.1177/1060028016657553 -
Drugs Jul 2021Schizophrenia is a debilitating illness with a lifetime prevalence estimate of 0.6% and consists of symptoms from the positive, negative, and cognitive domains. Social... (Review)
Review
Schizophrenia is a debilitating illness with a lifetime prevalence estimate of 0.6% and consists of symptoms from the positive, negative, and cognitive domains. Social support, therapy, psychoeducation, and overall case management are very important aspects of the treatment of schizophrenia. However, as abnormalities in neurotransmission are one of the key findings of schizophrenia pathology, pharmacotherapies are cornerstones of the management of schizophrenia. Antipsychotics have been used as the primary pharmacological treatment of schizophrenia. These agents often have a good effect on reducing positive symptoms, but may not markedly improve negative symptoms or cognitive defects. However, at least 20% of individuals with schizophrenia do not experience a substantial response from monotherapy with antipsychotics. Further, despite evolving treatment protocols and advances in early recognition of the disorder, 70% of patients with schizophrenia require long-term, even lifetime, medication to control their symptoms and do not achieve complete recovery. To address these shortcomings, clinicians and research scientists have explored different combinations of treatments, polypharmacy, to improve the treatment of patients. Antipsychotic polypharmacy has been shown to cause more side effects than monotherapy, which is the main reason why most treatment guidelines caution against it. Antipsychotic monotherapy should be strived for and clozapine should be tried at the latest if two monotherapy trials with other antipsychotics have failed and no absolute contraindications exist. If residual symptoms exist despite trials of adequate dose and duration, other reasons that may reduce treatment effect should be ruled out. Long-acting injectables or blood concentration measurements should be considered to affirm compliance and proper serum levels. Antipsychotic polypharmacy should be considered and discussed with patients from whom the aforementioned procedures do not produce a satisfactory treatment result. In some cases, antipsychotic polypharmacy may produce better results than other forms of treatment augmentation, such as benzodiazepines. In particular, combining aripiprazole with clozapine may be effective in reducing treatment side effects or residual symptoms, and this is likely to hold true for combining other partial dopamine D agonists with clozapine as well, although currently scant data exist. More research is needed, both in controlled but also real-world settings, to define optimal antipsychotic polypharmacy and/or other psychotropic treatment augmentation strategies for specific patient groups and situations.
Topics: Antipsychotic Agents; Drug Therapy, Combination; Humans; Practice Guidelines as Topic; Schizophrenia
PubMed: 34196945
DOI: 10.1007/s40265-021-01556-4 -
The Psychiatric Clinics of North America Jun 2023Treatment-resistant depression (TRD) affects one in three patients with major depressive disorder and is associated with increased risk of all-cause mortality. Studies... (Review)
Review
Treatment-resistant depression (TRD) affects one in three patients with major depressive disorder and is associated with increased risk of all-cause mortality. Studies of real-world practices suggest that antidepressant monotherapy continues to be the most widely used treatment after inadequate response to a first-line treatment. However, rates of remission with antidepressants in TRD are suboptimal. Atypical antipsychotics are the most widely studied augmentation agent and aripiprazole, brexpiprazole, cariprazine, quetiapine extended-release, and olanzapine-fluoxetine combination are approved for depression. Benefits of using atypical antipsychotics for TRD has to be weighted against their potential adverse events, such as weight gain, akathisia, and tardive dyskinesia.
Topics: Humans; Antipsychotic Agents; Depressive Disorder, Major; Depression; Antidepressive Agents; Quetiapine Fumarate; Drug Therapy, Combination
PubMed: 37149344
DOI: 10.1016/j.psc.2023.02.012 -
Clinical Pharmacokinetics Dec 2018Therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding side effects by maintaining long-term exposure to minimally... (Review)
Review
Therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding side effects by maintaining long-term exposure to minimally effective blood concentrations. The rationale for using therapeutic drug monitoring in relation to second-generation antipsychotics is still being discussed at least with regard to the real clinical utility, but there is evidence that it can improve efficacy, especially when patients do not respond or develop side effects using therapeutic doses. Furthermore, drug plasma concentration determinations can be of some utility in medico-legal problems. This review concentrates on the clinical pharmacokinetic data related to clozapine, risperidone, paliperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole, sertindole, asenapine, iloperidone, lurasidone, brexpiprazole and cariprazine and briefly considers the main aspects of their pharmacodynamics. Optimal plasma concentration ranges are proposed for clozapine, risperidone, paliperidone and olanzapine because the studies of quetiapine, amisulpride, asenapine, iloperidone and lurasidone provide only limited information and there is no direct evidence concerning ziprasidone, aripiprazole, sertindole, brexpiprazole and cariprazine: the few reported investigations need to be confirmed and extended.
Topics: Animals; Antipsychotic Agents; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Medication Adherence
PubMed: 29915922
DOI: 10.1007/s40262-018-0664-3 -
Expert Opinion on Drug Safety Feb 2021: Management of patients with acute agitation or aggressive behavior can pose a significant challenge to health-care providers in emergency departments. : This article... (Review)
Review
: Management of patients with acute agitation or aggressive behavior can pose a significant challenge to health-care providers in emergency departments. : This article provides a comprehensive review of the pharmacologic properties, efficacy, and safety profiles of select intramuscular (IM) sedative agents (i.e., antipsychotics, benzodiazepines, and ketamine) for rapid tranquilization. : Using antipsychotics and benzodiazepines - whether a single agent or combined - will have similar efficacy in producing sedation. But there are differences in the time to sedation depending on which agent is used. Based upon the available studies, droperidol (5-10 mg IM) and midazolam (5-10 mg IM) have the fastest onset of sedation when either is used as a single agent. When combination therapy is used, using midazolam with an antipsychotic agent, instead of lorazepam, may result in faster sedative effect. QT prolongation and torsades de pointes are uncommon adverse drug effects of antipsychotic administration. Ketamine is often reserved as a second-line agent when antipsychotics and benzodiazepines fail to produce the desired tranquilization. However, ketamine (5 mg/kg IM) is more frequently associated with airway compromise requiring endotracheal intubation. A low-dose of ketamine (2 mg/kg IM) may reduce the risk of airway compromise while providing adequate sedation.
Topics: Acute Disease; Aggression; Antipsychotic Agents; Benzodiazepines; Delirium; Emergency Service, Hospital; Excitatory Amino Acid Antagonists; Humans; Ketamine; Psychomotor Agitation
PubMed: 33327811
DOI: 10.1080/14740338.2021.1865911 -
The New England Journal of Medicine Apr 2020An oral compound, SEP-363856, that does not act on dopamine D2 receptors but has agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
An oral compound, SEP-363856, that does not act on dopamine D2 receptors but has agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT) receptors, may represent a new class of psychotropic agent for the treatment of psychosis in schizophrenia.
METHODS
We performed a randomized, controlled trial to evaluate the efficacy and safety of SEP-363856 in adults with an acute exacerbation of schizophrenia. The patients were randomly assigned in a 1:1 ratio to receive once-daily treatment with SEP-363856 (50 mg or 75 mg) or placebo for 4 weeks. The primary end point was the change from baseline in the total score on the Positive and Negative Symptom Scale (PANSS; range, 30 to 210; higher scores indicate more severe psychotic symptoms) at week 4. There were eight secondary end points, including the changes from baseline in the scores on the Clinical Global Impressions Severity (CGI-S) scale and the Brief Negative Symptom Scale (BNSS).
RESULTS
A total of 120 patients were assigned to the SEP-363856 group and 125 to the placebo group. The mean total score on the PANSS at baseline was 101.4 in the SEP-363856 group and 99.7 in the placebo group, and the mean change at week 4 was -17.2 points and -9.7 points, respectively (least-squares mean difference, -7.5 points; 95% confidence interval, -11.9 to -3.0; P = 0.001). The reductions in the CGI-S and BNSS scores at week 4 were generally in the same direction as those for the primary outcome, but the results were not adjusted for multiple comparisons. Adverse events with SEP-363856 included somnolence and gastrointestinal symptoms; one sudden cardiac death occurred in the SEP-363856 group. The incidence of extrapyramidal symptoms and changes in the levels of lipids, glycated hemoglobin, and prolactin were similar in the trial groups.
CONCLUSIONS
In this 4-week trial involving patients with an acute exacerbation of schizophrenia, SEP-363856, a non-D2-receptor-binding antipsychotic drug, resulted in a greater reduction from baseline in the PANSS total score than placebo. Longer and larger trials are necessary to confirm the effects and side effects of SEP-363856, as well as its efficacy relative to existing drug treatments for patients with schizophrenia. (Funded by Sunovion Pharmaceuticals; ClinicalTrials.gov number, NCT02969382.).
Topics: Acute Disease; Administration, Oral; Adult; Antipsychotic Agents; Double-Blind Method; Drug Administration Schedule; Female; Humans; Least-Squares Analysis; Male; Receptors, Dopamine D2; Receptors, G-Protein-Coupled; Schizophrenia; Schizophrenic Psychology; Serotonin 5-HT1 Receptor Agonists; Severity of Illness Index; Treatment Outcome
PubMed: 32294346
DOI: 10.1056/NEJMoa1911772 -
Neuropharmacology Aug 2020Antipsychotic drugs are central to the treatment of schizophrenia and other psychotic disorders but are ineffective for some patients and associated with side-effects... (Review)
Review
Antipsychotic drugs are central to the treatment of schizophrenia and other psychotic disorders but are ineffective for some patients and associated with side-effects and nonadherence in others. We review the in vitro, pre-clinical, clinical and molecular imaging evidence on the mode of action of antipsychotics and their side-effects. This identifies the key role of striatal dopamine D2 receptor blockade for clinical response, but also for endocrine and motor side-effects, indicating a therapeutic window for D2 blockade. We consider how partial D2/3 receptor agonists fit within this framework, and the role of off-target effects of antipsychotics, particularly at serotonergic, histaminergic, cholinergic, and adrenergic receptors for efficacy and side-effects such as weight gain, sedation and dysphoria. We review the neurobiology of schizophrenia relevant to the mode of action of antipsychotics, and for the identification of new treatment targets. This shows elevated striatal dopamine synthesis and release capacity in dorsal regions of the striatum underlies the positive symptoms of psychosis and suggests reduced dopamine release in cortical regions contributes to cognitive and negative symptoms. Current drugs act downstream of the major dopamine abnormalities in schizophrenia, and potentially worsen cortical dopamine function. We consider new approaches including targeting dopamine synthesis and storage, autoreceptors, and trace amine receptors, and the cannabinoid, muscarinic, GABAergic and glutamatergic regulation of dopamine neurons, as well as post-synaptic modulation through phosphodiesterase inhibitors. Finally, we consider treatments for cognitive and negative symptoms such dopamine agonists, nicotinic agents and AMPA modulators before discussing immunological approaches which may be disease modifying. This article is part of the issue entitled 'Special Issue on Antipsychotics'.
Topics: Antipsychotic Agents; Humans; Mental Disorders
PubMed: 31299229
DOI: 10.1016/j.neuropharm.2019.107704 -
Dialogues in Clinical Neuroscience Sep 2019Despite effective pharmacological treatments for psychotic symptoms (eg, hallucinations, delusions), functional outcomes for people with psychotic disorders are often... (Review)
Review
Despite effective pharmacological treatments for psychotic symptoms (eg, hallucinations, delusions), functional outcomes for people with psychotic disorders are often disappointing. Although it is not included in the diagnostic criteria for psychotic disorders, cognitive impairment is one of the strongest determinants of community functioning in this clinical population, and thus it is an important target for intervention. In this review, we discuss the major areas of research regarding impaired cognition in psychotic illness. The specific topics covered include: (i) the prevalence of cognitive impairment in psychotic disorders; (ii) the profile and magnitude of cognitive impairment in psychotic disorders; (iii) the developmental course of cognitive impairment; (iv) the longitudinal stability of cognitive impairment; and (v) treatment approaches to improve cognitive performance in people with psychotic disorders. .
Topics: Antipsychotic Agents; Cognitive Behavioral Therapy; Cognitive Dysfunction; Humans; Nootropic Agents; Prevalence; Psychotic Disorders; Treatment Outcome
PubMed: 31749648
DOI: 10.31887/DCNS.2019.21.3/amccleery -
Nature Dec 2023Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis. They recognize diverse... (Comparative Study)
Comparative Study
Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis. They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders. However, the molecular mechanisms underlying its ability to recognize different ligands remain largely unclear. Here we present nine cryo-electron microscopy structures, with eight showing human and mouse TAAR1 in a complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine and two identified catecholamine agonists, and one showing 5-HTR in a complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to endogenous trace amine stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G-protein selectivity by TAAR1, which may help in the discovery of ligands or therapeutic strategies for neurological and metabolic disorders.
Topics: Animals; Humans; Mice; Amines; Amphetamine; Antipsychotic Agents; Binding Sites; Catecholamines; Cryoelectron Microscopy; GTP-Binding Proteins; Ligands; Molecular Dynamics Simulation; Mutation; Polypharmacology; Receptors, G-Protein-Coupled; Species Specificity; Substrate Specificity
PubMed: 37935376
DOI: 10.1038/s41586-023-06804-z