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Current Issues in Molecular Biology May 2024Among the pathophysiological correlates of schizophrenia, recent research suggests a potential role for the Hedgehog (Hh) signalling pathway, which has been... (Review)
Review
Is the Hedgehog Pathway Involved in the Pathophysiology of Schizophrenia? A Systematic Review of Current Evidence of Neural Molecular Correlates and Perspectives on Drug Development.
Among the pathophysiological correlates of schizophrenia, recent research suggests a potential role for the Hedgehog (Hh) signalling pathway, which has been traditionally studied in embryonic development and oncology. Its dysregulation may impact brain homeostasis, neuroplasticity, and potential involvement in neural processes. This systematic review provides an overview of the involvement of Hh signalling in the pathophysiology of schizophrenia and antipsychotic responses. We searched the PubMed and Scopus databases to identify peer-reviewed scientific studies focusing on Hh and schizophrenia, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, finally including eight studies, including three articles focused on patients with schizophrenia, two animal models of schizophrenia, two animal embryo studies, and one cellular differentiation study. The Hh pathway is crucial in the development of midbrain dopaminergic neurons, neuroplasticity mechanisms, regulating astrocyte phenotype and function, brain-derived neurotrophic factor expression, brain glutamatergic neural transmission, and responses to antipsychotics. Overall, results indicate an involvement of Hh in the pathophysiology of schizophrenia and antipsychotic responses, although an exiguity of studies characterises the literature. The heterogeneity between animal and human studies is another main limitation. Further research can lead to better comprehension and the development of novel personalised drug treatments and therapeutic interventions.
PubMed: 38920990
DOI: 10.3390/cimb46060318 -
Drugs & Aging Jun 2024International guidelines discourage antipsychotic use for delirium; however, concerns persist about their continued use in clinical practice.
BACKGROUND
International guidelines discourage antipsychotic use for delirium; however, concerns persist about their continued use in clinical practice.
OBJECTIVES
We aimed to describe the prevalence and patterns of antipsychotic use in delirium management with regard to best-practice recommendations. Primary outcomes investigated were prevalence of use, antipsychotic type, dosage and clinical indication.
METHODS
Eligibility criteria: studies of any design that examined antipsychotic use to manage delirium in adults in critical care, acute care, palliative care, rehabilitation, and aged care were included. Studies of patients in acute psychiatric care, with psychiatric illness or pre-existing antipsychotic use were excluded.
INFORMATION SOURCES
we searched five health databases on 16 August, 2023 (PubMed, CINAHL, Embase, APA PsycInfo, ProQuest Health and Medical Collection) using MeSH terms and relevant keywords, including 'delirium' and 'antipsychotic'. Risk of bias: as no included studies were randomised controlled trials, all studies were assessed for methodological quality using the Mixed Methods Appraisal Tool.
SYNTHESIS OF RESULTS
descriptive data were extracted in Covidence and synthesised in Microsoft Excel.
RESULTS
Included studies: 39 studies published between March 2004 and August 2023 from 13 countries (n = 1,359,519 patients). Most study designs were retrospective medical record audits (n = 16).
SYNTHESIS OF RESULTS
in 18 studies, participants' mean age was ≥65 years (77.79, ±5.20). Palliative care had the highest average proportion of patients with delirium managed with antipsychotics (70.87%, ±33.81%); it was lower and varied little between intensive care unit (53.53%, ±19.73%) and non-intensive care unit settings [medical, surgical and any acute care wards] (56.93%, ±26.44%) and was lowest in in-patient rehabilitation (17.8%). Seventeen different antipsychotics were reported on. In patients aged ≥65 years, haloperidol was the most frequently used and at higher than recommended mean daily doses (2.75 mg, ±2.21 mg). Other antipsychotics commonly administered were olanzapine (mean 11 mg, ±8.54 mg), quetiapine (mean 64.23 mg, ±43.20 mg) and risperidone (mean 0.97 mg, ±0.64 mg).
CONCLUSIONS
The use of antipsychotics to manage delirium is strongly discouraged in international guidelines. Antipsychotic use in delirium care is a risk for adverse health outcomes and a longer duration of delirium, especially in older people. However, this study has provided evidence that clinicians continue to use antipsychotics for delirium management, the dose, frequency and duration of which are often outside evidence-based guideline recommendations. Clinicians continue to choose antipsychotics to manage delirium symptoms to settle agitation and maintain patient and staff safety, particularly in situations where workload pressures are high. Sustained efforts are needed at the individual, team and organisational levels to educate, train and support clinicians to prioritise non-pharmacological interventions early before deciding to use antipsychotics. This could prevent delirium and avert escalation in behavioural symptoms that often lead to antipsychotic use.
Topics: Humans; Delirium; Antipsychotic Agents; Aged; Adult; Hospitals
PubMed: 38856874
DOI: 10.1007/s40266-024-01122-z -
Therapeutic Advances in... 2024Antipsychotic medications are associated with weight gain and metabolic derangement. However, comprehensive evidence for the efficacy of co-commenced pharmacological...
BACKGROUND
Antipsychotic medications are associated with weight gain and metabolic derangement. However, comprehensive evidence for the efficacy of co-commenced pharmacological treatments to mitigate initial weight gain is limited. Metformin has been shown to be effective in reducing weight among people on antipsychotic medications who are already overweight, but the potential benefits of metformin co-commencement in mitigating antipsychotic-induced weight gain has not been systematically reviewed.
METHOD
We conducted a systematic review of PubMed, EMBASE, PsychInfo, CINAHL, the Cochrane database, and China National Knowledge Infrastructure from inception to 18 November 2023. We undertook a meta-analysis of concomitant commencement of metformin placebo for attenuation of weight gain and metabolic syndrome for people with schizophrenia commencing a new antipsychotic.
RESULTS
Fourteen studies from Australia, United States, Venezuela, and China with 1126 participants were included. We found that metformin was superior to placebo in terms of attenuating weight gain (-3.12 kg, 95% CI -4.22 to -2.01 kg). Metformin also significantly attenuated derangement of fasting glucose levels, total cholesterol, and total triglyceride levels. Sensitivity analysis on study quality, duration, and antipsychotic agent did not impact the results. Meta-analysis was also conducted on adverse drug reactions (ADR) reported in each study which showed no significant difference in ADR incidence between metformin and placebo groups. Subgroup analysis on antipsychotic-naïve participants and participants switching to new antipsychotic did not impact the results.
CONCLUSION
Metformin led to statistically significant and clinically meaningful attenuation of weight gain as well as attenuation of several other metabolic parameters when commenced concomitantly with antipsychotic medications. Co-commencement of metformin with antipsychotic medications, where tolerated, should be considered in the clinical setting with aim to improve long-term cardiometabolic outcomes for patients with long-term need of antipsychotic treatments.
PubMed: 38827016
DOI: 10.1177/20451253241255476 -
Progress in Neuro-psychopharmacology &... Jul 2024Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment outcomes. The aim of this study was to quantify the pregnancy impact on the ASM pharmacokinetics.
METHODS
A systematic literature search was conducted in PubMed/EMBASE in November 2022 and updated in August 2023 for studies comparing levels of ASM in the same individuals during pregnancy and in the preconception/postpartum period. Alteration ratios between the 3rd trimester and baseline were estimated. We also performed a random-effects meta-analysis calculating between-timepoint differences in mean differences (MDs) and 95% confidence intervals (95%CIs) for dose-adjusted plasma concentrations (C/D ratios). Study quality was assessed using the ClinPK guidelines.
RESULTS
A total of 65 studies investigating 15 ASMs in 674 pregnancies were included. The largest differences were reported for lamotrigine, oxcarbazepine and levetiracetam (alteration ratio 0.42, range 0.07-2.45, 0.42, range 0.08-0.82 and 0.52, range 0.04-2.77 respectively): accordingly, C/D levels were lower in the 3rd trimester for lamotrigine, levetiracetam and the main oxcarbazepine metabolite monohydroxycarbazepine (MD = -12.33 × 10, 95%CI = -16.08 to -8.58 × 10 (μg/mL)/(mg/day), p < 0.001, MD = -7.16 (μg/mL)/(mg/day), 95%CI = -9.96 to -4.36, p < 0.001, and MD = -4.87 (μg/mL)/(mg/day), 95%CI = -9.39 to -0.35, p = 0.035, respectively), but not for oxcarbazepine (MD = 1.16 × 10 (μg/mL)/(mg/day), 95%CI = -2.55 to 0.24 × 10, p = 0.10). The quality of studies was acceptable with an average rating score of 11.5.
CONCLUSIONS
Data for lamotrigine, oxcarbazepine (and monohydroxycarbazepine) and levetiracetam demonstrate major changes in pharmacokinetics during pregnancy, suggesting the importance of therapeutic drug monitoring to assist clinicians in optimizing treatment outcomes.
Topics: Humans; Pregnancy; Anticonvulsants; Female; Pregnancy Complications; Levetiracetam; Lamotrigine; Epilepsy; Oxcarbazepine
PubMed: 38762161
DOI: 10.1016/j.pnpbp.2024.111030 -
Psychiatry Research Jul 2024Brain-derived neurotrophic factor (BDNF) is an important regulatory protein in the pathophysiology of psychiatric disorders. Several studies have reported the... (Meta-Analysis)
Meta-Analysis
Brain-derived neurotrophic factor (BDNF) is an important regulatory protein in the pathophysiology of psychiatric disorders. Several studies have reported the relationship between peripheral BDNF concentrations and the use of psychoactive drugs. However, the results remain controversial. This study aimed to evaluate the effects of psychoactive drugs on BDNF concentrations and to explore the association between changes in BDNF concentrations and improvements in clinical scores. A systematic review and meta-analysis were conducted. Six electronic databases, including PubMed, Scopus, Medline, Web of Science, Google Scholar and Science Direct, were searched. Changes in BDNF concentrations were compared before and after psychoactive treatment, using the standardized mean difference (SMD) and 95 % confidence interval (95 % CI). Twenty-three studies were included. A significant increase in serum BDNF concentrations was observed after treatment with antipsychotics (SMD=0.43; 95 %CI: 0.26, 0.60) and antidepressants (SMD=0.49; 95 %CI: 0.23, 0.74). However, the plasma BDNF concentration was not affected by antidepressant and antipsychotic medication. Although an improvement in clinical scores was observed after treatment, no significant association was observed between changes in BDNF concentrations and the changes in the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Depression Rating Scale (HAM-D) scores. In conclusion, antidepressants and antipsychotics increase serum BDNF concentrations.
Topics: Humans; Brain-Derived Neurotrophic Factor; Antidepressive Agents; Antipsychotic Agents
PubMed: 38703562
DOI: 10.1016/j.psychres.2024.115946 -
PloS One 2024To report the first and largest systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy and safety of aripiprazole or... (Meta-Analysis)
Meta-Analysis
Efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression or major depressive disorder: A systematic review and meta-analysis of randomized controlled trials.
OBJECTIVES
To report the first and largest systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression (TRD) or major depressive disorder(MDD).
METHODS
We conducted a systematic literature retrieval via PubMed, Embase, Web of Science, and Cochrane until April 2023 for RCT, which evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching for patients with TRD or MDD. Outcomes measured were changes in the Montgomery-Asberg Depression Rating Scale (MADRS), response and remission rate, and serious adverse events.
RESULTS
Five RCTs, including 4480 patients, were included for meta-analysis. Among them, two RCTs were rated as "high risk" in three aspects (allocation concealment, blinding of participants and personnel and blinding of outcome assessment) because of the non-blind method, and the quality evaluation of the remaining works of literature was "low risk". Augmentation treatment with Aripiprazole (A-ARI) was associated with a significant higher response rate compared with augmentation treatment with bupropion (A-BUP) (RR: 1.15; 95% CI: 1.05, 1.25; P = 0.0007; I2 = 23%). Besides, A-ARI had a significant higher remission rate compared with switching to bupropion (S-BUP) (RR: 1.22; 95% CI: 1.00, 1.49; P = 0.05; I2 = 59%) and A-BUP had a significant higher remission rate compared with S-BUP (RR: 1.20; 95% CI: 1.06, 1.36; P = 0.0004; I2 = 0%). In addition, there was no significant difference in remission rate(RR: 1.05; 95% CI: 0.94, 1.17; P = 0.42; I2 = 33%), improvement of MADRS(WMD: -2.07; 95% CI: -5.84, 1.70; P = 0.28; I2 = 70%) between A-ARI and A-BUP. No significant difference was observed in adverse events and serious adverse events among the three treatment strategies.
CONCLUSIONS
A-ARI may be a better comprehensive antidepressant treatment strategy than A-BUP or S-BUP for patients with TRD or MDD. More large-scale, multi-center, double-blind RCTs are needed to further evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching treatment strategies.
Topics: Aripiprazole; Bupropion; Humans; Depressive Disorder, Major; Randomized Controlled Trials as Topic; Depressive Disorder, Treatment-Resistant; Treatment Outcome; Drug Therapy, Combination
PubMed: 38669232
DOI: 10.1371/journal.pone.0299020 -
Journal of Psychiatric Research Jun 2024Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and... (Review)
Review
Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and risperidone are two commonly prescribed antipsychotics, metabolized primarily through CYP2D6. Here, we aimed to provide an overview of the effect of CYP2C19 and CYP2D6 on side-effects of aripiprazole and risperidone, and expand on existing literature by critically examining methodological issues associated with pharmacogenetic studies. A PRISMA compliant search of six electronic databases (Pubmed, PsychInfo, Embase, Central, Web of Science, and Google Scholar) identified pharmacogenetic studies on aripiprazole and risperidone. 2007 publications were first identified, of which 34 were included. Quality of literature was estimated using Newcastle-Ottowa Quality Assessment Scale (NOS) and revised Cochrane Risk of Bias tool. The average NOS score was 5.8 (range: 3-8) for risperidone literature and 5 for aripiprazole (range: 4-6). All RCTs on aripiprazole were rated as high risk of bias, and four out of six for risperidone literature. Study populations ranged from healthy volunteers to inpatient individuals in psychiatric units and included adult and pediatric samples. All n = 34 studies examined CYP2D6. Only one study genotyped for CYP2C19 and found a positive association with neurological side-effects of risperidone. Most studies did not report any relationship between CYP2D6 and any side-effect outcome. Heterogeneity between and within studies limited the ability to synthesize data and draw definitive conclusions. Studies lacked statistical power due to small sample size, selective genotyping methods, and study design. Large-scale randomized trials with multiple measurements, providing robust evidence on this topic, are suggested.
Topics: Humans; Aripiprazole; Cytochrome P-450 CYP2D6; Risperidone; Cytochrome P-450 CYP2C19; Antipsychotic Agents
PubMed: 38631139
DOI: 10.1016/j.jpsychires.2024.04.001 -
Health Technology Assessment... Mar 2024The indication for this assessment is the use of the KardiaMobile six-lead electrocardiogram device for the assessment of QT interval-based cardiac risk in service users...
BACKGROUND
The indication for this assessment is the use of the KardiaMobile six-lead electrocardiogram device for the assessment of QT interval-based cardiac risk in service users prior to the initiation of, or for the monitoring of, antipsychotic medications, which are associated with an established risk of QT interval prolongation.
OBJECTIVES
To provide an early value assessment of whether KardiaMobile six-lead has the potential to provide an effective and safe alternative to 12-lead electrocardiogram for initial assessment and monitoring of QT interval-based cardiac risk in people taking antipsychotic medications.
REVIEW METHODS
Twenty-seven databases were searched to April/May 2022. Review methods followed published guidelines. Where appropriate, study quality was assessed using appropriate risk of bias tools. Results were summarised by research question; accuracy/technical performance; clinical effects (on cardiac and psychiatric outcomes); service user acceptability/satisfaction; costs of KardiaMobile six-lead.
RESULTS
We did not identify any studies which provided information about the diagnostic accuracy of KardiaMobile six-lead, for the detection of corrected QT-interval prolongation, in any population. All studies which reported information about agreement between QT interval measurements (corrected and/or uncorrected) with KardiaMobile six-lead versus 12-lead electrocardiogram were conducted in non-psychiatric populations, used cardiologists and/or multiple readers to interpret electrocardiograms. Where reported or calculable, the mean difference in corrected QT interval between devices (12-lead electrocardiogram vs. KardiaMobile six-lead) was generally small (≤ 10 ms) and corrected QT interval measured using KardiaMobile six-lead was consistently lower than that measured using 12-lead electrocardiogram. All information about the use of KardiaMobile six-lead, in the context of QT interval-based cardiac risk assessment for service users who require antipsychotic medication, was taken from retrospective surveys of staff and service users who had chosen to use KardiaMobile six-lead during pilots, described in two unpublished project reports. It is important to note that both these project reports relate to pilot studies which were not intended to be used in wider evaluations of KardiaMobile six-lead for use in the NHS. Both reports included survey results which indicated that the use of KardiaMobile six-lead may be associated with reductions in the time taken to complete an electrocardiogram and costs, relative to 12-lead electrocardiogram, and that KardiaMobile six-lead was preferred over 12-lead electrocardiogram by almost all responding staff and service users.
LIMITATIONS
There was a lack of published evidence about the efficacy of KardiaMobile six-lead for initial assessment and monitoring of QT interval-based cardiac risk in people taking antipsychotic medications.
CONCLUSIONS
There is insufficient evidence to support a full diagnostic assessment evaluating the clinical and cost effectiveness of KardiaMobile six-lead, in the context of QT interval-based cardiac risk assessment for service users who require antipsychotic medication. The evidence to inform the aims of this early value assessment (i.e. to assess whether the device has the potential to be clinically effective and cost-effective) was also limited. This report includes a comprehensive list of research recommendations, both to reduce the uncertainty around this early value assessment and to provide the additional data needed to inform a full diagnostic assessment, including cost-effectiveness modelling.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42022336695.
FUNDING
This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135520) and is published in full in ; Vol. 28, No. 19. See the NIHR Funding and Awards website for further award information.
Topics: Humans; Antipsychotic Agents; Retrospective Studies; Electrocardiography; Cognition; National Health Programs; Cost-Benefit Analysis
PubMed: 38551306
DOI: 10.3310/TFHU0078 -
Schizophrenia Bulletin Apr 2024People with first-episode psychosis (FEP) in low- and lower-middle-income countries (LMIC) experience delays in receiving treatment, resulting in poorer outcomes and...
BACKGROUND AND HYPOTHESIS
People with first-episode psychosis (FEP) in low- and lower-middle-income countries (LMIC) experience delays in receiving treatment, resulting in poorer outcomes and higher mortality. There is robust evidence for effective and cost-effective early intervention in psychosis (EIP) services for FEP, but the evidence for EIP in LMIC has not been reviewed. We aim to review the evidence on early intervention for the management of FEP in LMIC.
STUDY DESIGN
We searched 4 electronic databases (Medline, Embase, PsycINFO, and CINAHL) to identify studies describing EIP services and interventions to treat FEP in LMIC published from 1980 onward. The bibliography of relevant articles was hand-searched. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed.
STUDY RESULTS
The search strategy produced 5074 records; we included 18 studies with 2294 participants from 6 LMIC countries. Thirteen studies (1553 participants) described different approaches for EIP. Pharmacological intervention studies (n = 4; 433 participants) found a high prevalence of metabolic syndrome among FEP receiving antipsychotics (P ≤ .005). One study found a better quality of life in patients using injectables compared to oral antipsychotics (P = .023). Among the non-pharmacological interventions (n = 3; 308 participants), SMS reminders improved treatment engagement (OR = 1.80, CI = 1.02-3.19). The methodological quality of studies evidence was relatively low.
CONCLUSIONS
The limited evidence showed that EIP can be provided in LMIC with adaptations for cultural factors and limited resources. Adaptations included collaboration with traditional healers, involving nonspecialist healthcare professionals, using mobile technology, considering the optimum use of long-acting antipsychotics, and monitoring antipsychotic side effects.
Topics: Humans; Psychotic Disorders; Developing Countries; Early Medical Intervention; Antipsychotic Agents
PubMed: 38525604
DOI: 10.1093/schbul/sbae025 -
Clinics (Sao Paulo, Brazil) 2024The antiemetic effectiveness of olanzapine, as a prophylactic off-label antiemetic drug, for Postoperative Nausea and Vomiting (PONV) is unknown. In this systematic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The antiemetic effectiveness of olanzapine, as a prophylactic off-label antiemetic drug, for Postoperative Nausea and Vomiting (PONV) is unknown. In this systematic review and meta-analysis, the authors evaluate the efficacy and side effects of olanzapine as a prophylactic antiemetic in adult patients who undergo general anesthesia and assess adverse effects.
METHODS
A systematic search was done on electronic bibliographic databases in July 2023. Randomized controlled trials of olanzapine as a prophylactic antiemetic for PONV in adults who underwent general anesthesia were included. The authors excluded non-RCTs and retracted studies. The authors set no date of publication or language limits. The outcomes were the incidence of PONV within 24 h postoperatively and the safety of olanzapine. The risk of bias was assessed according to the tool suggested by the National Heart, Lung, and Blood Institute.
RESULTS
Meta-analysis included 446 adult patients. Olanzapine reduced on average 38 % the incidence of PONV. The estimated risk ratio (95 % CI) of olanzapine versus control was 0.62 (0.42-0.90), p = 0.010, I = 67 %. In the subgroup meta-analysis, doses of olanzapine (10 mg) reduced on average 49 % of the incidence of PONV (RR = 0.51 [0.34-0.77], p = 0.001, I = 31 %).
CONCLUSIONS
This systematic review with meta-analysis indicated that olanzapine as a prophylactic antiemetic alone or combined with other antiemetic agents reduced the incidence of postoperative nausea and vomiting. However, this conclusion must be presented with some degree of uncertainty due to the small number of studies included. There was a lack of any evidence to draw conclusions on side effects.
Topics: Adult; Humans; Antiemetics; Postoperative Nausea and Vomiting; Olanzapine; Anesthesia, General
PubMed: 38513297
DOI: 10.1016/j.clinsp.2024.100345