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Neuroscience and Biobehavioral Reviews Jan 2022Schizophrenia is associated with substantial unmet needs, highlighting the necessity for new treatments. This narrative review compares the pharmacology, clinical trial... (Review)
Review
Schizophrenia is associated with substantial unmet needs, highlighting the necessity for new treatments. This narrative review compares the pharmacology, clinical trial data and tolerability of novel medications to representative antipsychotics. Cariprazine, brexpiprazole and brilaroxazine are partial dopamine agonists effective in acute relapse. Lumateperone (serotonin and dopamine receptor antagonist) additionally benefits asocial and depressive symptoms. F17464 (D3 antagonist and 5-HT1A partial agonist) has one positive phase II study. Lu AF35700 (dopamine and serotonin receptor antagonist) was tested in treatment-resistance with no positive results. Pimavanserin, roluperidone, ulotaront and xanomeline do not act directly on the D2 receptor at clinical doses. Initial studies indicate pimavanserin and roluperidone improve negative symptoms. Ulotaront and xanomeline showed efficacy for positive and negative symptoms of schizophrenia in phase II trials. BI 409306, BI 425809 and MK-8189 target glutamatergic dysfunction in schizophrenia, though of these only BI 425809 showed efficacy. These medications largely have favourable cardiometabolic side-effect profiles. Overall, the novel pharmacology, clinical trial and tolerability data indicate these compounds are promising new additions to the therapeutic arsenal.
Topics: Antipsychotic Agents; Benzopyrans; Clinical Trials, Phase II as Topic; Humans; Piperazines; Schizophrenia; Sulfonamides
PubMed: 34838528
DOI: 10.1016/j.neubiorev.2021.11.032 -
The Journal of Clinical Psychiatry Mar 2020Many individuals with schizophrenia experience multiple relapses, which are associated with serious and potentially fatal outcomes. Nonadherence to antipsychotic...
Many individuals with schizophrenia experience multiple relapses, which are associated with serious and potentially fatal outcomes. Nonadherence to antipsychotic medications is a major contributor to relapse. By using reliable strategies to measure adherence and identify patients who are not taking their medications as prescribed, clinicians can intervene to possibly prevent relapse or decrease its severity.
Topics: Adult; Antipsychotic Agents; Humans; Medication Adherence; Prevalence; Recurrence; Schizophrenia; Secondary Prevention
PubMed: 32237296
DOI: 10.4088/JCP.MS19053BR1C -
The Journal of Clinical Psychiatry May 2022To evaluate Positive and Negative Syndrome Scale (PANSS) categorical response rates, time course of response, and symptom subdomains of response with the combination...
Antipsychotic Efficacy of KarXT (Xanomeline-Trospium): Post Hoc Analysis of Positive and Negative Syndrome Scale Categorical Response Rates, Time Course of Response, and Symptom Domains of Response in a Phase 2 Study.
To evaluate Positive and Negative Syndrome Scale (PANSS) categorical response rates, time course of response, and symptom subdomains of response with the combination oral agent KarXT (xanomeline-trospium) in the treatment of schizophrenia. Post hoc analysis was conducted for EMERGENT-1 (NCT03697252), a 5-week, inpatient, placebo-controlled, phase 2 study of acute psychosis in patients who met criteria for schizophrenia. The EMERGENT-1 study was conducted between September 2018 and August 2019. Categorical thresholds of response used were PANSS total score reductions of ≥ 20%, ≥ 30%, ≥ 40%, and ≥ 50% between baseline and study end. Number needed to treat (NNT) for each categorical threshold was calculated. The proportion of KarXT- and placebo-treated patients achieving each response threshold at weeks 2, 4, and 5 was assessed. Marder 5-factor analysis of PANSS assessed response with KarXT across symptom domains. A total of 83 patients in the KarXT group and 87 patients in the placebo group were included in the modified intent-to-treat analysis. Response rates with KarXT ranged from 59.0% for a ≥ 20% threshold to 15.7% for a ≥ 50% threshold. All response rates with KarXT were significantly higher than in the placebo arm ( < .05), with NNTs ranging from 3 (≥ 20% improvement) to 11 (≥ 50% improvement). KarXT was associated with a significantly higher response rate relative to placebo as early as 2 weeks for ≥ 20% ( = .0001) and ≥ 30% ( = .0022) thresholds and at 4 weeks for the ≥ 40% ( = .0049) and ≥ 50% ( = .0041) thresholds. Each of the Marder 5 factors showed significant differences favoring KarXT over placebo ( < .05) by 2 weeks and continuing through week 5 (endpoint Cohen effect sizes, 0.48-0.66). KarXT provided clinically meaningful responder rates on PANSS total score compared with placebo at each response threshold, providing further support of the successful primary and secondary endpoints. Response was demonstrated as early as 2 weeks relative to placebo. KarXT demonstrated improvements vs placebo in all 5 factors (positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility, and anxiety/depression). ClinicalTrials.gov identifier: NCT03697252.
Topics: Antipsychotic Agents; Double-Blind Method; Humans; Pyridines; Schizophrenia; Thiadiazoles; Treatment Outcome
PubMed: 35552528
DOI: 10.4088/JCP.21m14316 -
European Neuropsychopharmacology : the... Jan 2022Uncertainty remains regarding the relative efficacy of maintenance pharmacotherapy for bipolar disorder (BD), and available data require updating. The present systematic... (Meta-Analysis)
Meta-Analysis Review
Uncertainty remains regarding the relative efficacy of maintenance pharmacotherapy for bipolar disorder (BD), and available data require updating. The present systematic review and meta-analysis aims to consolidate the evidence from the highest quality randomized controlled trials (RCTs) published up to July 2021, overcoming the limitations of earlier reviews. The PubMed and the Cochrane Central Register of Controlled Trials were searched for double-blind RCTs involving lithium, mood stabilizing anticonvulsants (MSAs), antipsychotics, antidepressants, and other treatments. Rates of new mood episodes with test vs. reference treatments (placebo or alternative active agent) were compared by random-effects meta-analysis. Polarity index was calculated for each treatment type. Eligible trials involved ≥6 months of maintenance follow up. Of 2,158 identified reports, 22 met study eligibility criteria, and involved 7,773 subjects stabilized for 1-12 weeks and followed-up for 24-104 weeks. Psychotropic monotherapy overall (including lithium, MSAs, and second generation antipsychotics (SGA) was more effective in preventing new BD episodes than placebo (odds ratio, OR=0.42; 95% confidence interval, CI 0.34-0.51, p<0.00001). Significantly lower risk of new BD episodes was observed with the following individual drugs: aripiprazole, asenapine, lithium, olanzapine, quetiapine, and risperidone long-acting (ORs varied 0.19-0.46). Adding aripiprazole, divalproex, quetiapine, or olanzapine/risperidone to lithium or an MSA was more effective compared with lithium or MSA monotherapy (OR=0.37; 95%CI 0.25-0.55, p<0.00001). Active treatment favored prevention of mania over depression. The key limitations were "responder-enriched" design in most trials and high outcomes heterogeneity. PROSPERO registration number is CRD42020162663.
Topics: Adult; Anticonvulsants; Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Humans; Lithium; Olanzapine; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone
PubMed: 34489127
DOI: 10.1016/j.euroneuro.2021.08.264 -
Drugs Mar 2020Lumateperone (Caplyta) is a novel, orally available agent developed by Intra-Cellular Therapies (under a license from Bristol-Myers Squibb) for the treatment of... (Review)
Review
Lumateperone (Caplyta) is a novel, orally available agent developed by Intra-Cellular Therapies (under a license from Bristol-Myers Squibb) for the treatment of schizophrenia and other neuropsychiatric and neurological disorders. Lumateperone is a first-in-class selective and simultaneous modulator of serotonin, dopamine and glutamate. In December 2019, lumateperone received its first global approval in the USA for the treatment of schizophrenia in adults. The drug is also under clinical development for bipolar depression, behavioural disorders associated with dementia and Alzheimer's disease, sleep maintenance insomnia and major depressive disorders. This article summarizes the milestones in the development of lumateperone leading to this first approval for the treatment of schizophrenia.
Topics: Antipsychotic Agents; Drug Approval; Heterocyclic Compounds, 4 or More Rings; Humans; Schizophrenia
PubMed: 32060882
DOI: 10.1007/s40265-020-01271-6 -
Current Opinion in Psychiatry May 2020The gut microbiota has been speculated to underpin metabolic changes associated with chronic antipsychotic use. The change in the gut microbiota can also cause abnormal... (Review)
Review
PURPOSE OF REVIEW
The gut microbiota has been speculated to underpin metabolic changes associated with chronic antipsychotic use. The change in the gut microbiota can also cause abnormal absorbtion from the gut into the blood stream (leaky gut syndrome) that can lead to inflammatory reactions, and thus, secondary damage to the brain and central nervous system. Our article aims to highlight relevant research on antipsychotic's effect on the microbiota and to point out future directions.
RECENT FINDINGS
Antipsychtoic use can result in specific microbiota changes, and it is important to differentiate this from the innate microbiota of the patient. It is important to treat these microbiota changes, as they are correlated with obesity, which is a negative contributor to the cardiovascular health of those suffering with schizophrenia. Ways to prevent antipsychotic-induced side-effects include antibiotic treatment, histamine 3 receptor blockade and metformin use.
SUMMARY
Given the dearth of current literature, more research is needed, however, to determine, which comes first in people with schizophrenia--an abnormal gut microbiota that elevates one's risk for schizophrenia or psychopharmacologic treatment of schizophrenia leading to secondary microbiota abnormalities or the negative symptoms of schizophrenia leading to obesity and its associated microbiota changes.
Topics: Antipsychotic Agents; Gastrointestinal Microbiome; Humans; Inflammation; Psychotic Disorders
PubMed: 32068569
DOI: 10.1097/YCO.0000000000000594 -
Asian Journal of Psychiatry Jan 2023To integrate all evidence derived from randomized controlled trials (RCTs) of both pharmacological and nonpharmacological augmentation interventions for... (Meta-Analysis)
Meta-Analysis
Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia: A systematic review and network meta-analysis with normalized entropy assessment.
OBJECTIVE
To integrate all evidence derived from randomized controlled trials (RCTs) of both pharmacological and nonpharmacological augmentation interventions for clozapine-resistant schizophrenia (CRS).
METHODS
Six major electronic databases were systematically searched for RCTs published until July 10, 2021. The primary outcome was change in overall symptoms, and the secondary outcomes were positive and negative symptoms and acceptability. We performed random-effects network meta-analysis. Normalized entropy was calculated to examine the uncertainty of treatment ranking.
RESULTS
We identified 35 RCTs (1472 patients with 23 active augmentation treatments) with a mean daily clozapine dose of 440.80 (91.27) mg for 1168.22 (710.28) days. Network meta-analysis of overall symptoms (reported as standardized mean difference; 95 % confidence interval) with consistent results indicated that mirtazapine (-4.41; -5.61, -3.21), electroconvulsive therapy (ECT) (-4.32; -5.43, -3.21), and memantine (-2.02; -3.14, -0.91) were ranked as the best three treatments. For positive symptoms, ECT (-5.18; -5.86, -4.49) was ranked the best with less uncertainty. For negative symptoms, memantine (-3.38; -4.50, -2.26), duloxetine (-3.27; -4.25, -2.29), and mirtazapine (-1.73; -2.71, -0.74) were ranked the best three treatments with less uncertainty. All antipsychotics, N-methyl d-aspartate receptor agonists, and antiepileptics were not associated with more efficacy than placebo. Compared to placebo, only amisulpride had statistically significant lower discontinuation rate (risk ratio: 0.21; 95 % CI: 0.05, 0.93).
CONCLUSION
Add-on mirtazapine, ECT, and memantine were the most efficacious augmentation options for CRS. Data on other important outcomes such as cognitive functioning or quality of life were rarely reported, making further large-scale, well-designed RCTs necessary. (PROSPERO number, CRD42021262197.).
Topics: Humans; Clozapine; Network Meta-Analysis; Entropy; Memantine; Mirtazapine; Antipsychotic Agents; Schizophrenia
PubMed: 36470132
DOI: 10.1016/j.ajp.2022.103375 -
Tijdschrift Voor Psychiatrie 2022
Topics: Antipsychotic Agents; Humans; Schizophrenia
PubMed: 35420139
DOI: No ID Found -
Neuropharmacology Jun 2023Schizophrenia is a severe brain disorder that usually produces a lifetime of disability. First generation or typical antipsychotics such as haloperidol and second... (Review)
Review
Schizophrenia is a severe brain disorder that usually produces a lifetime of disability. First generation or typical antipsychotics such as haloperidol and second generation or atypical antipsychotics such as clozapine and risperidone remain the current standard for schizophrenia treatment. In some patients with schizophrenia, antipsychotics produce complete remission of positive symptoms, such as hallucinations and delusions. However, antipsychotic drugs are ineffective against cognitive deficits and indeed treated schizophrenia patients have small improvements or even deterioration in several cognitive domains. This underlines the need for novel and more efficient therapeutic targets for schizophrenia treatment. Serotonin and glutamate have been identified as key parts of two neurotransmitter systems involved in fundamental brain processes. Serotonin (or 5-hydroxytryptamine) 5-HT receptor (5-HTR) and metabotropic glutamate 2 receptor (mGluR2) are G protein-coupled receptors (GPCRs) that interact at epigenetic and functional levels. These two receptors can form GPCR heteromeric complexes through which their pharmacology, function and trafficking becomes affected. Here we review past and current research on the 5-HTR-mGluR2 heterocomplex and its potential implication in schizophrenia and antipsychotic drug action. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".
Topics: Humans; Schizophrenia; Antipsychotic Agents; Serotonin; Glutamates; Receptor, Serotonin, 5-HT2A
PubMed: 36889432
DOI: 10.1016/j.neuropharm.2023.109489 -
BMJ Case Reports Mar 2023Olanzapine is a commonly used and effective second-generation antipsychotic agent used for the control of paranoia and agitation in schizophrenia and bipolar disorder as...
Olanzapine is a commonly used and effective second-generation antipsychotic agent used for the control of paranoia and agitation in schizophrenia and bipolar disorder as well as in the behavioural and psychological symptoms of dementia. Serious side effects of treatment are uncommon but spontaneous rhabdomyolysis represents a rare complication. We describe here a patient treated with a stable dose of olanzapine for more than 8 years who developed acute severe rhabdomyolysis without an identifiable trigger and without features suggestive of neuroleptic malignant syndrome. The rhabdomyolysis was atypical in its delayed onset and severity with a creatine kinase level of 345 125 U/L, the highest level reported in the available literature. We also describe the clinical manifestations of delayed-onset olanzapine-induced rhabdomyolysis and its differentiation from neuroleptic malignancy syndrome, and we highlight key aspects of management to prevent or minimise further complications such as acute kidney injury.
Topics: Humans; Olanzapine; Benzodiazepines; Antipsychotic Agents; Schizophrenia; Neuroleptic Malignant Syndrome; Rhabdomyolysis
PubMed: 36898712
DOI: 10.1136/bcr-2022-254377