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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 -
The British Journal of General Practice... Jun 2024It is estimated 20-70% of those living with a dementia diagnosis experience dementia-related psychosis (D-RP). D-RP results in decreased quality of life, increased carer...
BACKGROUND
It is estimated 20-70% of those living with a dementia diagnosis experience dementia-related psychosis (D-RP). D-RP results in decreased quality of life, increased carer burden, increased rapid cognitive decline, increased need for primary care support, and earlier care/nursing home admission, all which come at a considerable cost to the NHS. Antipsychotic medications prescribed by primary care services are typically used as treatment but have short-term efficacy and dangerous side effects. Effective management with the use of non-pharmacological interventions could safely improve the quality of life of those living with dementia, as well as reduce burden on primary care services and GPs.
AIM
To evaluate the effectiveness of non-pharmacological interventions in the management of D-RP. Studies that measure the effect of non-pharmacological interventions on patient or caregiver quality of life or determine the cost-effectiveness and safety of non-pharmacological interventions against antipsychotic medications will also be included.
METHOD
A global systematic literature review was conducted in Medline, Embase, PsychInfo, CINAHL, Web of Science, and CENTRAL. Included studies were analysed using meta-analysis and narrative synthesis. The protocol is registered with PROSPERO (ID: CRD42022294750).
RESULTS
Data extraction of 18 included papers revealed 4 interventions to show evidence of efficacy in improving D-RP in older adults. Person-centred care, robot pets, cognitive rehabilitation, and music therapy significantly decreased psychosis in care homes and in participants living at home. These results are discussed, and implications noted.
CONCLUSION
Future RCTs should focus on specifically improving D-RP, as this was not the primary aim for many interventions.
Topics: Humans; Dementia; Psychotic Disorders; Quality of Life; Caregivers; Primary Health Care; Antipsychotic Agents; Cost-Benefit Analysis
PubMed: 38902088
DOI: 10.3399/bjgp24X737445 -
The Lancet. Psychiatry Jul 2024Many patients with schizophrenia have symptoms that do not respond to antipsychotics. This condition is called treatment-resistant schizophrenia and has not received... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Many patients with schizophrenia have symptoms that do not respond to antipsychotics. This condition is called treatment-resistant schizophrenia and has not received specific attention as opposed to general schizophrenia. Psychological and psychosocial interventions as an add-on treatment to pharmacotherapy could be useful, but their role and comparative efficacy to each other and to standard care in this population are not known. We investigated the efficacy, acceptability, and tolerability of psychological and psychosocial interventions for patients with treatment-resistant schizophrenia.
METHODS
In this systematic review and network meta-analysis (NMA), we searched for published and unpublished randomised controlled trials (RCTs) through a systematic database search in BIOSIS, CINAHL, Embase, LILACS, MEDLINE, PsychInfo, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform for articles published from inception up to Jan 31, 2020. We also searched the Cochrane Schizophrenia Group registry for studies published from inception up to March 31, 2022, and PubMed and Cochrane CENTRAL for studies published from inception up to July 31, 2023. We included RCTs that included patients with treatment-resistant schizophrenia. The primary outcome was overall symptoms. We did random-effects pairwise meta-analyses and NMAs to calculate standardised mean differences (SMDs) or risk ratios with 95% CIs. No people with lived experience were involved throughout the research process. The study protocol was registered in PROSPERO, CRD42022358696.
FINDINGS
We identified 30 326 records, excluding 24 526 by title and abstract screening. 5762 full-text articles were assessed for eligibility, of which 5540 were excluded for not meeting the eligibility criteria, and 222 reports corresponding to 60 studies were included in the qualitative synthesis. Of these, 52 RCTs with 5034 participants (1654 [33·2%] females and 3325 [66·8%] males with sex indicated) comparing 20 psychological and psychosocial interventions provided data for the NMA. Mean age of participants was 38·05 years (range 23·10-48·50). We aimed to collect ethnicity data, but they were scarcely reported. According to the quality of evidence, cognitive behavioural therapy for psychosis (CBTp; SMD -0·22, 95% CI -0·35 to -0·09, 35 trials), virtual reality intervention (SMD -0·41, -0·79 to -0·02, four trials), integrated intervention (SMD -0·70, -1·18 to -0·22, three trials), and music therapy (SMD -1·27, -1·83 to -0·70, one study) were more efficacious than standard care in reducing overall symptoms. No indication of publication bias was identified.
INTERPRETATION
We provide robust findings that CBTp can reduce the overall symptoms of patients with treatment-resistant schizophrenia, and therefore clinicians can prioritise this intervention in their clinical practice. Other psychological and psychosocial interventions showed promising results but need further investigation.
FUNDING
DAAD-ASFE.
Topics: Humans; Network Meta-Analysis; Psychosocial Intervention; Schizophrenia, Treatment-Resistant; Randomized Controlled Trials as Topic; Psychotherapy; Antipsychotic Agents; Treatment Outcome; Schizophrenia
PubMed: 38879276
DOI: 10.1016/S2215-0366(24)00136-6 -
Schizophrenia Bulletin Jun 2024Antipsychotics are the treatment of choice for schizophrenia, but they often induce akathisia. However, comparative efficacy of treatment strategies for akathisia...
BACKGROUND
Antipsychotics are the treatment of choice for schizophrenia, but they often induce akathisia. However, comparative efficacy of treatment strategies for akathisia remains unclear.
DESIGN
We performed a systematic review and network meta-analyses (PROSPERO CRD42023450720). We searched multiple databases on July 24, 2023. We included randomized clinical trials comparing 1 or more treatment strategies for antipsychotic-induced akathisia against each other or control conditions. We included adults with schizophrenia or other psychiatric disorders treated with antipsychotics. The primary outcome was akathisia severity at posttreatment. Secondary outcomes included akathisia response, all-cause dropout, psychotic symptoms, and long-term akathisia severity. We synthesized data in random effects frequentist network meta-analyses and assessed confidence in the evidence using CINeMA.
RESULTS
We identified 19 trials with 661 randomized participants (mean age 35.9 [standard deviation 12.0]; 36.7% [195 of 532] women). No trials examined dose reduction or switching of antipsychotics. Findings suggested 5-HT2A antagonists (k = 6, n = 108; standardized mean difference [SMD] -1.07 [95% confidence interval, -1.42; -0.71]) and beta-blockers (k = 8, n = 105; SMD -0.46 [-0.85; -0.07]) may improve akathisia severity, but confidence in the evidence was deemed low. We also found that benzodiazepines (k = 2, n = 13; SMD -1.62 [-2.64; -0.59]) and vitamin B6 (k = 3, n = 67; SMD -0.99 [-1.49; -0.50]) might also be beneficial, but confidence in the evidence was very low. Analyses of secondary outcomes did not provide additional insights.
CONCLUSIONS
Our findings suggest that 5-HT2A antagonists, beta-blockers, and with a lesser certainty, benzodiazepines, and vitamin B6 might improve akathisia. Given the low to very low confidence in the evidence of add-on agents and the absence of evidence of their long-term efficacy, careful consideration of side effects is warranted. These recommendations are extremely preliminary and further trials are needed.
PubMed: 38869177
DOI: 10.1093/schbul/sbae098 -
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 -
Psychiatry Research Aug 2024An association between psychiatric medications and falls and fractures in people taking them has been demonstrated, but which class or medication leads to the greatest... (Meta-Analysis)
Meta-Analysis Comparative Study Review
An association between psychiatric medications and falls and fractures in people taking them has been demonstrated, but which class or medication leads to the greatest risk of falls or fractures should be further investigated. The aim of this study was to compare and rank the magnitude of risk of falls and fractures due to different psychiatric medications. Eight databases were searched for this meta-analysis and evaluated using a frequency-based network meta-analysis. The results included a total of 28 papers with 14 medications from 5 major classes, involving 3,467,314 patients. The results showed that atypical antipsychotics were the class of medications with the highest risk of falls, and typical antipsychotics were the class of medications with the highest risk of resulting in fractures. Quetiapine ranked first in the category of 13 medications associated with risk of falls, and class Z drugs ranked first in the category of 6 medications associated with risk of fractures. The available evidence suggests that atypical antipsychotics and typical antipsychotics may be the drugs with the highest risk of falls and fractures, respectively. Quetiapine may be the medication with the highest risk of falls, and class Z drugs may be the medication with the highest risk of fractures.
Topics: Humans; Accidental Falls; Antipsychotic Agents; Fractures, Bone; Network Meta-Analysis
PubMed: 38833938
DOI: 10.1016/j.psychres.2024.115974 -
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 -
General Hospital Psychiatry 2024Evidence suggests that inflammatory processes play a role in the pathophysiology of schizophrenia. Statins exert anti-inflammatory and antioxidant effects and may be... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Evidence suggests that inflammatory processes play a role in the pathophysiology of schizophrenia. Statins exert anti-inflammatory and antioxidant effects and may be effective in improving the symptoms of schizophrenia. This study explored whether statins, as an adjunctive therapy, can alleviate the symptoms of schizophrenia.
METHODS
PubMed, EMBASE, and the Cochrane Library were searched for articles published up to March 2023. The risk-of-bias tool for randomized trials was used to assess study quality. Two researchers independently assessed the risks of bias and extracted data. Pooled data on Positive and Negative Syndrome Scale (PANSS) scores were analyzed. A random-effects model was employed to calculate pooled effect sizes. Statistical heterogeneity across studies was assessed using the I statistic. All analyses were performed using RevMan5 and Comprehensive Meta-Analysis software.
RESULTS
Nine trials enrolling 533 patients in total were included. Add-on statin therapy was found to be associated with a significantly better total PANSS score [standardized mean difference (SMD) = -0.42, 95% confidence interval (CI) -0.75 to -0.09, I = 72%; P = 0.01] and PANSS negative subscale score (SMD = -0.26, 95% CI -0.45 to -0.07, I = 0%; P = 0.009) in comparison with placebo. However, add-on statin therapy did not appear to improve scores for the PANSS positive and general subscales at the study-defined endpoint (6-24 weeks).
CONCLUSIONS
Our meta-analysis indicates that adjunctive statin therapy may confer benefits in ameliorating PANSS negative and total scores. It needs more solid data to confirm the results are related to clinical improvement and functioning.
Topics: Humans; Schizophrenia; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Outcome Assessment, Health Care; Drug Therapy, Combination; Antipsychotic Agents
PubMed: 38824832
DOI: 10.1016/j.genhosppsych.2024.05.001 -
Journal of Clinical Psychopharmacology
Topics: Humans; Antipsychotic Agents; Lurasidone Hydrochloride; Asthma; Piperazines; Female; Male; Schizophrenia; Adult
PubMed: 38820328
DOI: 10.1097/JCP.0000000000001871 -
Journal of Psychiatric Practice May 2024Prolactinomas-pituitary tumors that overproduce prolactin-can cause various troublesome symptoms. Dopamine agonists (DAs) reduce prolactin production in the prolactin...
OBJECTIVE
Prolactinomas-pituitary tumors that overproduce prolactin-can cause various troublesome symptoms. Dopamine agonists (DAs) reduce prolactin production in the prolactin pathway, making them the first-line treatment for prolactinomas. However, the main side effect of DA treatment, hyperdopaminergia, is an explicit etiology for psychiatric side effects. Psychiatric conditions are often treated with dopamine antagonists, which can induce hyperprolactinemia. This presents a challenge for patients with both a prolactinoma and a preexisting psychiatric condition, as treatment of one condition could worsen the other. This review seeks to identify an adequate therapeutic regimen for patients with coexisting prolactinomas and psychiatric symptoms.
METHODS
This review examined PubMed citations from 1960 to 2023 published in English and involving human subjects. Case reports, case series, and cohort studies involving patients with concomitant prolactinomas and psychiatric symptoms, as validated by brain imaging, serologic prolactin levels, and medical history or chart reports of psychiatric symptoms, were included.
RESULTS
Thematic analysis included 23 reports involving 42 participants; 27 of the 42 patients experienced a significant reduction in prolactin levels and psychiatric symptoms (64%). Treatment of those 42 patients included discontinuing or altering antipsychotic/dopamine antagonist therapy or discontinuing DA therapy to reduce psychiatric symptoms, with surgery or radiation postpharmacotherapy as a last-line strategy. However, in some cases (reported in Tables 2 to 4), either psychiatric or prolactin-related symptoms recurred despite adjustment.
CONCLUSIONS
Clinicians may find it beneficial to prioritize specific antipsychotics (aripiprazole, olanzapine, ziprasidone, or clozapine) over others (risperidone, thioridazine, thiothixene, and remoxipride). Discontinuing DA medication at least periodically until the patient's condition improves may also be advisable. If these 2 initial approaches do not yield a significant improvement in symptom management, surgery or radiation therapy may be considered. As patients may respond differently to these therapies, our study still recommends a patient-centered approach.
Topics: Humans; Prolactinoma; Pituitary Neoplasms; Mental Disorders; Dopamine Agonists; Antipsychotic Agents; Dopamine Antagonists
PubMed: 38819244
DOI: 10.1097/PRA.0000000000000783