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The American Journal of Hospice &... Mar 2017Delirium is a palliative care emergency where patients experience changes in perception, awareness, and behavior. Common features include changes in the sleep-wake... (Review)
Review
Delirium is a palliative care emergency where patients experience changes in perception, awareness, and behavior. Common features include changes in the sleep-wake cycle, emotional lability, delusional thinking, and language and thought disorders. Delirium results from neurotransmitter imbalances involving several neurotransmitters such as dopamine, glutamate, norepinephrine, acetylcholine, gamma-aminobutyric acid, and serotonin. Untreated delirium causes significant morbidity and mortality. Nonpharmacologic and pharmacologic approaches treat delirium. Current pharmacologic management of delirium involves using agents such as haloperidol or second-generation antipsychotics. Third-generation atypical antipsychotic drugs have emerged as a potential choice for delirium management. Aripiprazole is a third-generation antipsychotic with a dopamine receptor-binding profile distinct from other second-generation antipsychotics. Aripiprazole acts as partial agonist at dopamine D and 5-hydroxytryptamine (5-HT) receptors, stabilizing the dopamine receptor leading to improvement in symptoms. The article reviews the pharmacology, pharmacodynamics, metabolism, and evidence of clinical efficacy for this new antipsychotic agent. This article explores possible roles in palliative care.
Topics: Alzheimer Disease; Antipsychotic Agents; Aripiprazole; Delirium; Humans; Psychotic Disorders
PubMed: 26589880
DOI: 10.1177/1049909115612800 -
The American Journal of Psychiatry Mar 2018Research in both animals and humans indicates that cannabidiol (CBD) has antipsychotic properties. The authors assessed the safety and effectiveness of CBD in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Research in both animals and humans indicates that cannabidiol (CBD) has antipsychotic properties. The authors assessed the safety and effectiveness of CBD in patients with schizophrenia.
METHOD
In an exploratory double-blind parallel-group trial, patients with schizophrenia were randomized in a 1:1 ratio to receive CBD (1000 mg/day; N=43) or placebo (N=45) alongside their existing antipsychotic medication. Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Global Assessment of Functioning scale (GAF), and the improvement and severity scales of the Clinical Global Impressions Scale (CGI-I and CGI-S).
RESULTS
After 6 weeks of treatment, compared with the placebo group, the CBD group had lower levels of positive psychotic symptoms (PANSS: treatment difference=-1.4, 95% CI=-2.5, -0.2) and were more likely to have been rated as improved (CGI-I: treatment difference=-0.5, 95% CI=-0.8, -0.1) and as not severely unwell (CGI-S: treatment difference=-0.3, 95% CI=-0.5, 0.0) by the treating clinician. Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance (BACS: treatment difference=1.31, 95% CI=-0.10, 2.72) and in overall functioning (GAF: treatment difference=3.0, 95% CI=-0.4, 6.4). CBD was well tolerated, and rates of adverse events were similar between the CBD and placebo groups.
CONCLUSIONS
These findings suggest that CBD has beneficial effects in patients with schizophrenia. As CBD's effects do not appear to depend on dopamine receptor antagonism, this agent may represent a new class of treatment for the disorder.
Topics: Adult; Antipsychotic Agents; Cannabidiol; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia
PubMed: 29241357
DOI: 10.1176/appi.ajp.2017.17030325 -
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 -
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 -
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 -
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 -
The Lancet. Psychiatry Dec 2023TV-46000 is a long-acting, subcutaneous, antipsychotic agent that combines risperidone and an innovative, copolymer-based drug delivery technology in a suspension that... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of TV-46000, a long-acting, subcutaneous, injectable formulation of risperidone, for schizophrenia: a randomised clinical trial in the USA and Bulgaria.
BACKGROUND
TV-46000 is a long-acting, subcutaneous, antipsychotic agent that combines risperidone and an innovative, copolymer-based drug delivery technology in a suspension that was approved in April, 2023 for subcutaneous use. The aim of the phase 3 Risperidone Subcutaneous Extended-release (RISE) study was to evaluate the efficacy of TV‑46000 in schizophrenia.
METHODS
The RISE study consisted of two treatment stages: a 12-week, open-label stabilisation phase with oral risperidone (stage 1), and an open-ended, randomised, double-blind, placebo-controlled, relapse-prevention phase with subcutaneous TV-46000 (stage 2) done at 69 clinical sites across the USA and Bulgaria. Patients diagnosed with schizophrenia more than 1 year before screening by DSM-5 criteria and confirmed at screening by the Structured Clinical Interview for DSM-5 and who had at least one relapse within 24 months before screening were eligible for enrolment. Patients who were outpatients and stabilised in stage 1 continued to stage 2 and were randomly assigned 1:1:1 by a computer-generated randomisation list to receive either subcutaneous TV-46000 once monthly, TV-46000 once every 2 months, or placebo until relapse, early discontinuation, or the study was stopped because the prespecified stopping criterion of at least 90 relapse events was met. The primary endpoint was time to impending relapse of the intention-to-treat patient population in stage 2. This study is registered with ClinicalTrials.gov, number NCT03503318, and is complete.
FINDINGS
The study enrolled the first patient on June 1, 2018, and the last patient completed on Dec 3, 2020. 1267 patients were screened, 863 enrolled, and 544 (male, n=332 [61%], female, n=212 [39%]; mean [SD] age, 49·3 [10·98] years; Black or African American, n=322 [59%]; White, n=206 [38%]; Asian, n=7 [1%]; Native Hawaiian or other Pacific Islander, n=2 [<1%]; race not reported, n=3 [<1%]; other race, n=4 [<1%]; Hispanic or Latinx, n=117 [22%]) randomly assigned to subcutaneous TV-46000 once monthly (n=183), TV-46000 once every 2 months (n=180), or placebo (n=181). Time to impending relapse was significantly prolonged by 5·0 times with TV-46000 once monthly (hazard ratio, 0·200 [95% CI 0·109-0·367]; p<0·0001) and by 2·7 times with TV-46000 once every 2 months (0·375 [0·227-0·618]; p<0·0001) versus placebo. Most frequently reported treatment-related adverse events (ie, ≥5% of patients in either TV-46000 group) that occurred more often in patients receiving TV-46000 (once monthly or once every 2 months) versus placebo were injection site nodules (7% for TV-46000 once monthly, 7% for TV-46000 once every 2 months, 3% for placebo), weight increased (4%, 6%, 2%, respectively), and extrapyramidal disorder (5%, 3%, 0% respectively). Serious adverse events were reported for eight (4%) patients in the TV-46000 once-monthly group, ten (6%) patients in the TV-46000 once-every-2-months group, and 14 (8%) patients in the placebo group. The safety profile of TV-46000 was consistent with other approved formulations of risperidone. No new safety signals were identified.
INTERPRETATION
In patients with schizophrenia, subcutaneous TV-46000 once monthly and once every 2 months significantly delayed impending relapse versus placebo. TV-46000 is an effective long-acting, subcutaneous, antipsychotic agent treatment option in adult patients with schizophrenia, with a favourable benefit-risk profile.
FUNDING
Teva Branded Pharmaceutical Products R&D.
Topics: Adult; Humans; Male; Female; Middle Aged; Risperidone; Schizophrenia; Antipsychotic Agents; Bulgaria; Treatment Outcome; Chronic Disease; Double-Blind Method; Recurrence
PubMed: 37924833
DOI: 10.1016/S2215-0366(23)00288-2 -
Der Nervenarzt Jan 2020Schizophrenia is a severe psychiatric disorder with variable therapeutic responses, the etiology and pathophysiology of which require further elucidation. (Review)
Review
BACKGROUND
Schizophrenia is a severe psychiatric disorder with variable therapeutic responses, the etiology and pathophysiology of which require further elucidation.
OBJECTIVE
To review which pharmacological options are effective and safe and for which treatment goals in schizophrenia.
MATERIAL AND METHODS
Narrative review of the pharmacological therapy of adults diagnosed with schizophrenia.
RESULTS
Despite heterogeneous therapeutic responses, to date only dopamine antagonists or partial agonists are approved for the treatment of schizophrenia. The efficacy of antipsychotic agents differs only gradually, with the exception of clozapine for treatment-resistant schizophrenia, whereas undesired adverse effects are more variable. Those antipsychotic agents that show gradual efficacy advantages in meta-analyses of acute and maintenance treatment (clozapine, amisulpride, olanzapine, risperidone) are also those where at least one undesired adverse effect is most severely expressed. Antipsychotic adverse effects occur in subgroups of patients and are generally tolerable or treatable, whereas the "side effect" of untreated schizophrenia affects almost all patients, including relapses, psychosocial deterioration, secondary treatment resistance and increased mortality. Therefore, in patients with a confirmed diagnosis of schizophrenia, a lifelong continuous therapy is currently most likely indicated, ideally with antipsychotic agents for which adherence is directly measurable and improved. In the case of treatment resistant clozapine is the agent of choice, followed by electroconvulsive therapy, which also has the best evidence as augmentation treatment in cases of clozapine resistance.
CONCLUSION
New therapeutic agents with improved efficacy and tolerability as well as effectiveness for negative symptoms and cognitive disturbance are needed.
Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Olanzapine; Risperidone; Schizophrenia
PubMed: 31919550
DOI: 10.1007/s00115-019-00858-z -
Drugs Feb 2019Brexpiprazole (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... (Review)
Review
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.
Topics: Antipsychotic Agents; Aripiprazole; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Approval; Humans; Japan; Quinolones; Schizophrenia; Serotonin Receptor Agonists; Thiophenes; United States
PubMed: 30671869
DOI: 10.1007/s40265-019-1052-5 -
Progress in Neuro-psychopharmacology &... Feb 2018Aggressive behavior complicates the presentation of many psychiatric illnesses, and is associated with significant morbidity. Antipsychotic medications are used to treat... (Meta-Analysis)
Meta-Analysis Review
Aggressive behavior complicates the presentation of many psychiatric illnesses, and is associated with significant morbidity. Antipsychotic medications are used to treat this symptom dimension across multiple diagnoses. In this meta-analysis we sought to identify the effect size of antipsychotic medications for the treatment of reactive-impulsive aggression in adults, and identify differences across underlying diagnosis and specific agent. A search was conducted of four databases, MEDLINE, PsychINFO, Embase and the Cochrane Library to end date of August 10, 2016. The search terms included "aggression", "irritable mood", "anger", "hostility" and "antipsychotic agents" or "dopamine antagonists". 505 results were found, of which 47 were reviewed in detail and 21 ultimately included in the analysis. Antipsychotics were broadly effective for the treatment of aggression, but with effect sizes similar to those for non-pharmacologic interventions (standard mean difference=0.29, 95% confidence interval 0.22-0.36, z=8.5, p<0.001). There was no evidence for differences according to choice of agent (χ=2.7, df=6, p=0.85), or conclusive evidence as to the importance of the underlying diagnosis (χ=3.2, df=3, p=0.36). A small but significant dose effect was identified (β=0.0002, 95% CI 0.0001-0.0004, p=0.038). Although antipsychotics appear to be effective for treatment of aggression, their small effect sizes in the context of their significant side-effects should be taken into account when making clinical decisions about their use.
Topics: Aggression; Antipsychotic Agents; Humans
PubMed: 28754408
DOI: 10.1016/j.pnpbp.2017.07.019