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Pharmacological Research Feb 2022Antipsychotics represent the mainstay of schizophrenia pharmacological therapy, and their role has been expanded in the last years to mood disorders treatment. Although...
Antipsychotics represent the mainstay of schizophrenia pharmacological therapy, and their role has been expanded in the last years to mood disorders treatment. Although introduced in 1952, many years of research were required before an accurate picture of how antipsychotics work began to emerge. Despite the well-recognized characterization of antipsychotics in typical and atypical based on their liability to induce motor adverse events, their main action at dopamine D2R to elicit the "anti-psychotic" effect, as well as the multimodal action at other classes of receptors, their effects on intracellular mechanisms starting with receptor occupancy is still not completely understood. Significant lines of evidence converge on the impact of these compounds on multiple molecular signaling pathways implicated in the regulation of early genes and growth factors, dendritic spine shape, brain inflammation, and immune response, tuning overall the function and architecture of the synapse. Here we present, based on PRISMA approach, a comprehensive and systematic review of the above mechanisms under a translational perspective to disentangle those intracellular actions and signaling that may underline clinically relevant effects and represent potential targets for further innovative strategies in antipsychotic therapy.
Topics: Animals; Antipsychotic Agents; Brain; Chromatin Assembly and Disassembly; Epigenesis, Genetic; Gene Expression Regulation; Genes, Immediate-Early; Humans; Neuronal Plasticity; Neuroprotective Agents; Neurotransmitter Transport Proteins
PubMed: 35026403
DOI: 10.1016/j.phrs.2022.106078 -
NPJ Schizophrenia May 2021Early intervention is essential for favorable long-term outcomes in schizophrenia. However, there is limited guidance in the scientific literature on how best to choose... (Review)
Review
Early intervention is essential for favorable long-term outcomes in schizophrenia. However, there is limited guidance in the scientific literature on how best to choose between dopamine D receptor (DR) partial agonists and DR antagonists in early stages of schizophrenia. The aim of this meta-analysis was to directly compare DR partial agonists with DR antagonists for efficacy and tolerability, using randomized controlled trials (RCTs) that involved participants diagnosed with first-episode psychosis, schizophrenia, or related psychotic disorders with a duration of illness ≤5 years. Fourteen RCTs, involving 2494 patients, were included in the meta-analysis. Aripiprazole was the only identified DR partial agonist, and was not significantly different from pooled DR antagonists for overall symptom reduction or all-cause discontinuation. However, aripiprazole was more favorable than pooled DR antagonists for depressive symptoms, prolactin levels, and triglyceride levels. Specifically, aripiprazole was more favorable than paliperidone for triglyceride levels and more favorable than risperidone and olanzapine, but less favorable than ziprasidone, for weight gain. In addition, aripiprazole was less favorable for akathisia compared with second-generation DR antagonists, in particular olanzapine and quetiapine, and less favorable for discontinuation due to inefficacy than risperidone. Lastly, aripiprazole was more favorable than haloperidol for various efficacy and tolerability outcomes. In conclusion, aripiprazole's efficacy did not differ substantially from DR antagonists in the early course of schizophrenia, whereas differential tolerability profiles were noted. More double-blind RCTs are required comparing the efficacy and tolerability of aripiprazole as well as other DR partial agonists with DR antagonists in early stages of schizophrenia.
PubMed: 34035313
DOI: 10.1038/s41537-021-00158-z -
Scientific Reports Mar 2021We compared the efficacy, safety, and acceptability of lurasidone at different doses to establish the dose-response relationships of lurasidone therapeutic and adverse... (Comparative Study)
Comparative Study Meta-Analysis
We compared the efficacy, safety, and acceptability of lurasidone at different doses to establish the dose-response relationships of lurasidone therapeutic and adverse effects in acute schizophrenia. Included trials were 4- to 16-week, fixed-dose, randomized controlled trials of lurasidone in adults with acute schizophrenia. Different doses of lurasidone, other antipsychotics, and placebo were considered as independent treatments. Apart from all-cause dropout rates, four therapeutic and four adverse outcomes were included in the frequentist network meta-analysis (NMA). Lurasidone 160, 120, 80, 40, and 20 mg/day were studied in ten trials of 3,366 adults with schizophrenia exacerbation. Lurasidone 160 mg/day reduced Positive and Negative Syndrome Scale (PANSS) total scores significantly more than lurasidone 120, 80, 40, and 20 mg/day (mean differences = - 7.63, - 7.04, - 8.83, and - 12.25, respectively). All-cause dropout rates were significantly lower in participants receiving lurasidone 160 mg/day and 80 mg/day compared with those taking placebo. The half-maximal effective doses of lurasidone for PANSS total, PANSS positive, and MADRS score reductions were higher than 80 mg/day. The confidence of all NMA estimates was low or very low. Lurasidone 160 mg/day is currently the most efficacious and acceptable dose for acute schizophrenia. Its maximal effective doses may be higher than 160 mg/day.
Topics: Acute Disease; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Lurasidone Hydrochloride; Network Meta-Analysis; Randomized Controlled Trials as Topic; Schizophrenia
PubMed: 33692392
DOI: 10.1038/s41598-021-84836-z -
Academic Emergency Medicine : Official... Dec 2022Agitation in children in acute care settings poses significant patient and staff safety concerns. While behavioral approaches are central to reducing agitation and oral... (Review)
Review
OBJECTIVE
Agitation in children in acute care settings poses significant patient and staff safety concerns. While behavioral approaches are central to reducing agitation and oral medications are preferred, parenteral medications are used when necessary to promote safety. The goal of this systematic review was to evaluate the effectiveness and safety of an ultra-short-acting parenteral medication, droperidol, for the management of acute, severe agitation in children in acute care settings.
METHODS
A systematic review of randomized controlled trials, observational studies, and case series/reports examined the effectiveness and safety of parenteral droperidol for management of acute agitation in patients ≤21 years old in acute care settings. Effectiveness outcomes included time to sedation and need for a subsequent dose of medication. Safety outcomes were adverse effects such as QTc prolongation, hypotension, respiratory depression, and dystonic reactions.
RESULTS
A total of 431 unique articles were identified. Six articles met inclusion criteria: two in the prehospital setting, one in the emergency department, and three in the inpatient hospital setting. The articles included a prospective observational study, three retrospective observational studies, and two case reports. The largest study reported a median time to sedation of 14 min (interquartile range 10-20 min); other studies reported a time to sedation of 15 min or less. Across studies, 8%-22% of patients required a second dose of medication for ongoing agitation. The most frequent adverse effects were dystonic reactions and transient hypotension. One patient had QTc prolongation and another developed respiratory depression, but both had significant comorbidities that may have contributed. The risk of bias in included studies ranged from moderate to critical.
CONCLUSIONS
Existing data on droperidol for management of acute agitation in children suggest that droperidol is both effective and safe for acute, severe agitation in children. Data are limited by study designs that may introduce bias.
Topics: Humans; Child; Young Adult; Adult; Droperidol; Retrospective Studies; Emergency Service, Hospital; Prospective Studies; Respiratory Insufficiency; Psychomotor Agitation; Observational Studies as Topic
PubMed: 35490341
DOI: 10.1111/acem.14515 -
Revista Brasileira de Psiquiatria (Sao... May 2023To summarize evidence-based pharmacological treatments and provide guidance on clinical interventions for adult patients with obsessive-compulsive disorder (OCD).
Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders guidelines for the treatment of adult obsessive-compulsive disorder. Part I: pharmacological treatment.
OBJECTIVES
To summarize evidence-based pharmacological treatments and provide guidance on clinical interventions for adult patients with obsessive-compulsive disorder (OCD).
METHODS
The American Psychiatric Association (APA) guidelines for the treatment of OCD (2013) were updated with a systematic review assessing the efficacy of pharmacological treatments for adult OCD, comprising monotherapy with selective serotonin reuptake inhibitors (SSRIs), clomipramine, serotonin and norepinephrine reuptake inhibitors (SNRIs), and augmentation strategies with clomipramine, antipsychotics, and glutamate-modulating agents. We searched for the literature published from 2013-2020 in five databases, considering the design of the study, primary outcome measures, types of publication, and language. Selected articles had their quality assessed with validated tools. Treatment recommendations were classified according to levels of evidence developed by the American College of Cardiology and the American Heart Association (ACC/AHA).
RESULTS
We examined 57 new studies to update the 2013 APA guidelines. High-quality evidence supports SSRIs for first-line pharmacological treatment of OCD. Moreover, augmentation of SSRIs with antipsychotics (risperidone, aripiprazole) is the most evidence-based pharmacological intervention for SSRI-resistant OCD.
CONCLUSION
SSRIs, in the highest recommended or tolerable doses for 8-12 weeks, remain the first-line treatment for adult OCD. Optimal augmentation strategies for SSRI-resistant OCD include low doses of risperidone or aripiprazole. Pharmacological treatments considered ineffective or potentially harmful, such as monotherapy with antipsychotics or augmentation with ketamine, lamotrigine, or N-acetylcysteine, have also been detailed.
Topics: Humans; Adult; Antipsychotic Agents; Selective Serotonin Reuptake Inhibitors; Clomipramine; Aripiprazole; Risperidone; Brazil; Treatment Outcome; Obsessive-Compulsive Disorder
PubMed: 36749887
DOI: 10.47626/1516-4446-2022-2891 -
The Cochrane Database of Systematic... May 2021Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, seizures and neurodevelopmental problems.
OBJECTIVES
To assess the effectiveness and safety of using a sedative versus control (placebo, usual treatment or non-pharmacological treatment) for NAS due to withdrawal from opioids and determine which type of sedative is most effective and safe for NAS due to withdrawal from opioids.
SEARCH METHODS
We ran an updated search on 17 September 2020 in CENTRAL via CRS Web and MEDLINE via Ovid. We searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.
SELECTION CRITERIA
We included trials enrolling infants with NAS born to mothers with an opioid dependence with more than 80% follow-up and using randomised, quasi-randomised and cluster-randomised allocation to sedative or control.
DATA COLLECTION AND ANALYSIS
Three review authors assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of the evidence.
MAIN RESULTS
We included 10 trials (581 infants) with NAS secondary to maternal opioid use in pregnancy. There were multiple comparisons of different sedatives and regimens. There were limited data available for use in sensitivity analysis of studies at low risk of bias. Phenobarbital versus supportive care: one study reported there may be little or no difference in treatment failure with phenobarbital and supportive care versus supportive care alone (risk ratio (RR) 2.73, 95% confidence interval (CI) 0.94 to 7.94; 62 participants; very low-certainty evidence). No infant had a clinical seizure. The study did not report mortality, neurodevelopmental disability and adverse events. There may be an increase in days' hospitalisation and treatment from use of phenobarbital (hospitalisation: mean difference (MD) 20.80, 95% CI 13.64 to 27.96; treatment: MD 17.90, 95% CI 11.98 to 23.82; both 62 participants; very low-certainty evidence). Phenobarbital versus diazepam: there may be a reduction in treatment failure with phenobarbital versus diazepam (RR 0.39, 95% CI 0.24 to 0.62; 139 participants; 2 studies; low-certainty evidence). The studies did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be little or no difference in days' hospitalisation and treatment (hospitalisation: MD 3.89, 95% CI -1.20 to 8.98; 32 participants; treatment: MD 4.30, 95% CI -0.73 to 9.33; 31 participants; both low-certainty evidence). Phenobarbital versus chlorpromazine: there may be a reduction in treatment failure with phenobarbital versus chlorpromazine (RR 0.55, 95% CI 0.33 to 0.92; 138 participants; 2 studies; very low-certainty evidence), and no infant had a seizure. The studies did not report mortality and neurodevelopmental disability. One study reported there may be little or no difference in days' hospitalisation (MD 7.00, 95% CI -3.51 to 17.51; 87 participants; low-certainty evidence) and 0/100 infants had an adverse event. Phenobarbital and opioid versus opioid alone: one study reported no infants with treatment failure and no clinical seizures in either group (low-certainty evidence). The study did not report mortality, neurodevelopmental disability and adverse events. One study reported there may be a reduction in days' hospitalisation for infants treated with phenobarbital and opioid (MD -43.50, 95% CI -59.18 to -27.82; 20 participants; low-certainty evidence). Clonidine and opioid versus opioid alone: one study reported there may be little or no difference in treatment failure with clonidine and dilute tincture of opium (DTO) versus DTO alone (RR 0.09, 95% CI 0.01 to 1.59; 80 participants; very low-certainty evidence). All five infants with treatment failure were in the DTO group. There may be little or no difference in seizures (RR 0.14, 95% CI 0.01 to 2.68; 80 participants; very low-certainty evidence). All three infants with seizures were in the DTO group. There may be little or no difference in mortality after discharge (RR 7.00, 95% CI 0.37 to 131.28; 80 participants; very low-certainty evidence). All three deaths were in the clonidine and DTO group. The study did not report neurodevelopmental disability. There may be little or no difference in days' treatment (MD -4.00, 95% CI -8.33 to 0.33; 80 participants; very low-certainty evidence). One adverse event occurred in the clonidine and DTO group. There may be little or no difference in rebound NAS after stopping treatment, although all seven cases were in the clonidine and DTO group. Clonidine and opioid versus phenobarbital and opioid: there may be little or no difference in treatment failure (RR 2.27, 95% CI 0.98 to 5.25; 2 studies, 93 participants; very low-certainty evidence). One study reported one infant in the clonidine and morphine group had a seizure, and there were no infant mortalities. The studies did not report neurodevelopmental disability. There may be an increase in days' hospitalisation and days' treatment with clonidine and opioid versus phenobarbital and opioid(hospitalisation: MD 7.13, 95% CI 6.38 to 7.88; treatment: MD 7.57, 95% CI 3.97 to 11.17; both 2 studies, 91 participants; low-certainty evidence). There may be little or no difference in adverse events (RR 1.55, 95% CI 0.44 to 5.40; 2 studies, 93 participants; very low-certainty evidence). However, there was oversedation only in the phenobarbital and morphine group; and hypotension, rebound hypertension and rebound NAS only in the clonidine and morphine group.
AUTHORS' CONCLUSIONS
There is very low-certainty evidence that phenobarbital increases duration of hospitalisation and treatment, but reduces days to regain birthweight and duration of supportive care each day compared to supportive care alone. There is low-certainty evidence that phenobarbital reduces treatment failure compared to diazepam and very low-certainty evidence that phenobarbital reduces treatment failure compared to chlorpromazine. There is low-certainty evidence of an increase in days' hospitalisation and days' treatment with clonidine and opioid compared to phenobarbital and opioid. There are insufficient data to determine the safety and incidence of adverse events for infants treated with combinations of opioids and sedatives including phenobarbital and clonidine.
Topics: Bias; Chlorpromazine; Clonidine; Diazepam; Humans; Hypnotics and Sedatives; Infant, Newborn; Narcotics; Neonatal Abstinence Syndrome; Opioid-Related Disorders; Phenobarbital; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 34002380
DOI: 10.1002/14651858.CD002053.pub4 -
Biomedicine & Pharmacotherapy =... Dec 2020Individual response to medication depends on several factors (age, gender, body weight, general clinical condition, genetics, diet, hydration status, comorbidities,...
Individual response to medication depends on several factors (age, gender, body weight, general clinical condition, genetics, diet, hydration status, comorbidities, co-administered drugs and their mode of administration, smoking, alcohol overuse, environmental factors, e.g. sunlight) that may contribute to adverse drug reactions even at therapeutic doses. Patients in palliative care are at increased risk of these reactions. Unwanted drug effects diminish the quality of life and may lead to a suboptimal dying process. Haloperidol is one of the three most commonly used drugs in palliative care and the most commonly employed typical antipsychotic. It has also been recommended for inclusion into the palliative care emergency kit of home care teams. As such, it is important to be fully conversant with the indications, benefits, and risks of haloperidol, especially in the context of palliative care.
Topics: Antipsychotic Agents; Haloperidol; Humans; Palliative Care; Quality of Life; Risk Factors
PubMed: 33068931
DOI: 10.1016/j.biopha.2020.110772 -
Human Psychopharmacology Nov 2021Depressive symptoms occur in several psychiatric disorders, often in the absence of a formal diagnosis of depression. We aimed to evaluate the efficacy and the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Depressive symptoms occur in several psychiatric disorders, often in the absence of a formal diagnosis of depression. We aimed to evaluate the efficacy and the tolerability of amisulpride, both alone and as augmentation therapy, in the treatment of depressive symptoms in individuals with any major psychiatric disorder.
METHODS
We searched PubMed, Embase, PsycINFO, GreyLit, OpenGrey and ProQuest up to March 2020 for randomised controlled trials focussing on the treatment of an acute depressive episode in any major psychiatric disorder. A random-effect meta-analysis was performed to synthesize the findings on depressive symptoms (primary outcome), response rate and tolerability.
RESULTS
We retrieved 11 studies including 2065 patients with a diagnosis of dysthymia (eight studies), major depression (one study) or schizophrenia (two studies). Amisulpride 50 mg/day was associated with a larger reduction of depressive symptoms compared to placebo (standardised mean difference [SMD] = -0.70, CI 95% -0.92, -0.49; I = 0.0%), and was found to be comparable to selective serotonin reuptake inhibitors (SSRIs; SMD = -0.08, CI 95% -0.23, 0.06, I = 0.0%), amineptine, imipramine and amitriptyline in the treatment of dysthymia (three studies, not pooled). In individuals with schizophrenia, amisulpride administered at higher doses (>400 mg/day) was comparable to olanzapine and risperidone (two studies, not pooled). In terms of tolerability, amisulpride was superior to placebo for dysthymia (odds ratio [OR] = 3.94, CI 95% 1.07, 14.48; I = 0.0) and comparable with SSRIs (OR = 0.94, CI 95% 0.55, 1.62; I = 0.0%).
CONCLUSION
Treatment with amisulpride could be a valid choice for selected individuals with dysthymia or depressive symptoms in the context of schizophrenia. More studies on the efficacy and tolerability of amisulpride are needed to draw firm conclusions on its potential benefits in other psychiatric disorders.
Topics: Amisulpride; Antipsychotic Agents; Depression; Depressive Disorder, Major; Dysthymic Disorder; Humans
PubMed: 34727399
DOI: 10.1002/hup.2801 -
PloS One 2021Nausea and vomiting of pregnancy affects up to 80% of pregnant women, it typically occurs during the first trimester which is the most sensitive time for environmental... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Nausea and vomiting of pregnancy affects up to 80% of pregnant women, it typically occurs during the first trimester which is the most sensitive time for environmental exposures given organogenesis. Metoclopramide is an antiemetic drug used widely during NVP, but the findings of studies evaluating its safety of use in pregnancy is inconsistent. Therefore, we conducted a systematic review and meta-analysis to assess whether metoclopramide use during first trimester of pregnancy is associated with the risk of major congenital malformations.
METHODS
The systematic search using database included Pubmed, Embase, Web of science, and Cochrane library. Studies written in English, comprising with an exposed group and a control group, reporting major congenital malformation as an outcome were included.
RESULTS
Six studies assessing a total number of 33374 metoclopramide-exposed and 373498 controls infants were included in this meta-analysis. No significant increase in the rate of major congenital malformation was detected following metoclopramide use during first trimester (OR, 1.14; 95% CI, 0.93-1.38).
CONCLUSIONS
Metoclopramide use during first trimester of pregnancy was not associated with the risk of major congenital malformations.
Topics: Antiemetics; Congenital Abnormalities; Female; Humans; Metoclopramide; Nausea; Odds Ratio; Pregnancy; Pregnancy Trimester, First; Vomiting
PubMed: 34543335
DOI: 10.1371/journal.pone.0257584 -
Advances in Therapy Sep 2022Schizophrenia is a chronic mental disorder associated with substantial morbidity and mortality affecting 0.25-1.6% of adults in the USA. Antipsychotic treatment is the...
BACKGROUND
Schizophrenia is a chronic mental disorder associated with substantial morbidity and mortality affecting 0.25-1.6% of adults in the USA. Antipsychotic treatment is the standard of care for schizophrenia, but real-world treatment patterns and associated costs have not been systematically reviewed.
OBJECTIVE
We conducted a systematic review to summarize treatment patterns and associated costs related to oral antipsychotic treatment of patients with schizophrenia in the USA.
DATA SOURCES
We searched Medline (via PubMed) and Embase to identify relevant observational studies published from January 1, 2008, to June 1, 2018; costs were converted to 2018 US dollars.
STUDY ELIGIBILITY
Observational, real-world studies reporting on patterns of treatment and/or associated costs for adult patients with schizophrenia treated with oral antipsychotics in the USA were included.
RESULTS
Eighty-one studies were identified. Frequently prescribed oral second-generation antipsychotics were olanzapine (up to 50.9%), risperidone (up to 40.0%), and quetiapine (up to 30.7%). Suboptimal adherence was common across studies. Antipsychotic switching occurred in about half of patients, while antipsychotic combination therapy occurred in nearly 30%; all were associated with increased medication-related costs. Mean annual direct medical costs differed by treatment, with reported costs of $17,115 to $26,138 for patients treated with olanzapine, $18,395 for risperidone, and $17,656 to $28,101 for quetiapine.
LIMITATIONS
This systematic review is limited by the variations in definitions of schizophrenia-related clinical terms used between studies and by the inclusion of studies focused on only the US health care system.
CONCLUSIONS
In the treatment of schizophrenia, suboptimal adherence, antipsychotic switching, and antipsychotic augmentation were all associated with high costs of care in comparison to patients who were adherent and did not require antipsychotic switching or augmentation. These findings illustrate the need for the development of new treatments that address efficacy and adherence challenges of currently available therapies.
Topics: Adult; Antipsychotic Agents; Financial Stress; Humans; Olanzapine; Quetiapine Fumarate; Risperidone; Schizophrenia; United States
PubMed: 35844007
DOI: 10.1007/s12325-022-02232-z