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The Lancet. Psychiatry Mar 2024There are no recommendations based on the efficacy of specific drugs for the treatment of psychotic depression. To address this evidence gap, we did a network... (Meta-Analysis)
Meta-Analysis
BACKGROUND
There are no recommendations based on the efficacy of specific drugs for the treatment of psychotic depression. To address this evidence gap, we did a network meta-analysis to assess and compare the efficacy and safety of pharmacological treatments for psychotic depression.
METHODS
In this systematic review and network meta-analysis, we searched ClinicalTrials.gov, CENTRAL, Embase, PsycINFO, PubMed, Scopus, and Web of Science from inception to Nov 23, 2023 for randomised controlled trials published in any language that assessed pharmacological treatments for individuals of any age with a diagnosis of a major depressive episode with psychotic features, in the context of major depressive disorder or bipolar disorder in any setting. We excluded continuation or maintenance trials. We screened the study titles and abstracts identified, and we extracted data from relevant studies after full-text review. If full data were not available, we requested data from study authors twice. We analysed treatments for individual drugs (or drug combinations) and by grouping them on the basis of mechanisms of action. The primary outcomes were response rate (ie, the proportion of participants who responded to treatment) and acceptability (ie, the proportion who discontinued treatment for any reason). We calculated risk ratios and did separate frequentist network meta-analyses by using random-effects models. The risk of bias of individual studies was assessed with the Cochrane risk-of-bias tool and the confidence in the evidence with the Confidence-In-Network-Meta-Analysis (CINeMA). This study was registered with PROSPERO, CRD42023392926.
FINDINGS
Of 6313 reports identified, 16 randomised controlled trials were included in the systematic review, and 14 were included in the network meta-analyses. The 16 trials included 1161 people with psychotic depression (mean age 50·5 years [SD 11·4]). 516 (44·4%) participants were female and 422 (36·3%) were male; sex data were not available for the other 223 (19·2%). 489 (42·1%) participants were White, 47 (4·0%) were African American, and 12 (1·0%) were Asian; race or ethnicity data were not available for the other 613 (52·8%). Only the combination of fluoxetine plus olanzapine was associated with a higher proportion of participants with a treatment response compared with placebo (risk ratio 1·91 [95% CI 1·27-2·85]), with no differences in terms of safety outcomes compared with placebo. When treatments were grouped by mechanism of action, the combination of a selective serotonin reuptake inhibitor with a second-generation antipsychotic was associated with a higher proportion of treatment responses than was placebo (1·89 [1·17-3·04]), with no differences in terms of safety outcomes. In head-to-head comparisons of active treatments, a significantly higher proportion of participants had a response to amitriptyline plus perphenazine (3·61 [1·23-10·56]) and amoxapine (3·14 [1·01-9·80]) than to perphenazine, and to fluoxetine plus olanzapine compared with olanzapine alone (1·60 [1·09-2·34]). Venlafaxine, venlafaxine plus quetiapine (2·25 [1·09-4·63]), and imipramine (1·95 [1·01-3·79]) were also associated with a higher proportion of treatment responses overall. In head-to-head comparisons grouped by mechanism of action, antipsychotic plus antidepressant combinations consistently outperformed monotherapies from either drug class in terms of the proportion of participants with treatment responses. Heterogeneity was low. No high-risk instances were identified in the bias assessment for our primary outcomes.
INTERPRETATION
According to the available evidence, the combination of a selective serotonin reuptake inhibitor and a second-generation antipsychotic-and particularly of fluoxetine and olanzapine-could be the optimal treatment choice for psychotic depression. These findings should be taken into account in the development of clinical practice guidelines. However, these conclusions should be interpreted cautiously in view of the low number of included studies and the limitations of these studies.
FUNDING
None.
Topics: Male; Female; Humans; Middle Aged; Depressive Disorder, Major; Fluoxetine; Perphenazine; Network Meta-Analysis; Bipolar Disorder; Venlafaxine Hydrochloride; Selective Serotonin Reuptake Inhibitors; Depression; Antipsychotic Agents; Olanzapine
PubMed: 38360024
DOI: 10.1016/S2215-0366(24)00006-3 -
Cureus Jan 2024Antipsychotics are considered a gold standard treatment for schizophrenia. However, there is considerable variation in antipsychotic medication choice. Factors...
Antipsychotics are considered a gold standard treatment for schizophrenia. However, there is considerable variation in antipsychotic medication choice. Factors considered involved include symptomatology, prior response, and adverse reactions. This case report presents a 38-year-old male patient with schizophrenia in acute psychosis refractory to several antipsychotics. Hypotheses for the mechanism of action of antipsychotics and psychopharmacology are discussed, and treatment resistance is defined. The patient's psychiatric, medical, and social history and past antipsychotic medications are reviewed. Afterward, the rationale for initiating perphenazine is discussed, and the patient's improvement with this medication is examined. Current literature on perphenazine's efficacy is also reviewed and discussed alongside its limitations.
PubMed: 38313962
DOI: 10.7759/cureus.51593 -
Frontiers in Psychiatry 2023Our objective was to conduct a systematic review and meta-analysis of adverse effects on sleep in patients with schizophrenia receiving antipsychotic treatment.
INTRODUCTION
Our objective was to conduct a systematic review and meta-analysis of adverse effects on sleep in patients with schizophrenia receiving antipsychotic treatment.
METHODS
A systematic search was performed in PubMed, Cochrane Central, Embase, Toxline, Ebsco, Virtual Health Library, Web of Science, SpringerLink, and in Database of abstracts of Reviews of Effects of Randomized Clinical Trials to identify eligible studies published from January 1990 to October 2021. The methodological quality of the studies was evaluated using the CONSORT list, and the Cochrane bias tool. Network meta-analysis was performed using the Bayesian random-effects model, with multivariate meta-regression to assess the association of interest.
RESULTS
87 randomized clinical trials were identified that met the inclusion criteria, and 70 articles were included in the network meta-analysis. Regarding the methodological quality of the studies, 47 had a low or moderate bias risk. The most common adverse effects on sleep reported in the studies were insomnia, somnolence, and sedation. The results of the network meta-analysis showed that ziprasidone was associated with an increased risk of insomnia (OR, 1.56; 95% credible interval CrI, 1.18-2.06). Several of the included antipsychotics were associated with a significantly increased risk of somnolence; haloperidol (OR, 1.90; 95% CrI, 1.12-3.22), lurasidone (OR, 2.25; 95% CrI, 1.28-3.97) and ziprasidone (OR, 1.79; 95% CrI, 1.06-3.02) had the narrowest confidence intervals. In addition, perphenazine (OR, 5.33; 95% CrI, 1.92-14.83), haloperidol (OR, 2.61; 95% CrI, 1.14-5.99), and risperidone (OR, 2.41; 95% CrI, 1.21-4.80) were associated with an increased risk of sedation compared with placebo, and other antipsychotics did not differ. According to the SUCRAs for insomnia, chlorpromazine was ranked as the lowest risk of insomnia (57%), followed by clozapine (20%), while flupentixol (26 %) and perospirone (22.5%) were associated with a lower risk of somnolence. On the other hand, amisulpride (89.9%) was the safest option to reduce the risk of sedation.
DISCUSSION
Insomnia, sedation, and somnolence were the most frequent adverse effects on sleep among the different antipsychotics administered. The evidence shows that chlorpromazine, clozapine, flupentixol, perospirone, and amisulpride had favorable safety profiles. In contrast, ziprasidone, perphenazine, haloperidol, and risperidone were the least safe for sleep.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42017078052, identifier: PROSPERO 2017 CRD42017078052.
PubMed: 37441144
DOI: 10.3389/fpsyt.2023.1189768 -
The Role of Total White Blood Cell Count in Antipsychotic Treatment for Patients with Schizophrenia.Current Neuropharmacology 2024Total white blood cell count (TWBCc), an index of chronic and low-grade inflammation, is associated with clinical symptoms and metabolic alterations in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial Clinical Trial
BACKGROUND
Total white blood cell count (TWBCc), an index of chronic and low-grade inflammation, is associated with clinical symptoms and metabolic alterations in patients with schizophrenia. The effect of antipsychotics on TWBCc, predictive values of TWBCc for drug response, and role of metabolic alterations require further study.
METHODS
Patients with schizophrenia were randomized to monotherapy with risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perphenazine or haloperidol in a 6-week pharmacological trial. We repeatedly measured clinical symptoms, TWBCc, and metabolic measures (body mass index, blood pressure, waist circumference, fasting blood lipids and glucose). We used mixed-effect linear regression models to test whether TWBCc can predict drug response. Mediation analysis to investigate metabolic alteration effects on drug response.
RESULTS
At baseline, TWBCc was higher among patients previously medicated. After treatment with risperidone, olanzapine, quetiapine, perphenazine, and haloperidol, TWBCc decreased significantly ( < 0.05). Lower baseline TWBCc predicted greater reductions in Positive and Negative Syndrome Scale (PANSS) total and negative scores over time ( < 0.05). We found significant mediation of TWBCc for effects of waist circumference, fasting low-density lipoprotein cholesterol, and glucose on reductions in PANSS total scores and PANSS negative subscale scores ( < 0.05).
CONCLUSION
TWBCc is affected by certain antipsychotics among patients with schizophrenia, with decreases observed following short-term, but increases following long-term treatment. TWBCc is predictive of drug response, with lower TWBCc predicting better responses to antipsychotics. It also mediates the effects of certain metabolic measures on improvement of negative symptoms. This indicates that the metabolic state may affect clinical manifestations through inflammation.
Topics: Humans; Antipsychotic Agents; Schizophrenia; Olanzapine; Risperidone; Quetiapine Fumarate; Haloperidol; Perphenazine; Benzodiazepines; Glucose; Inflammation
PubMed: 36600620
DOI: 10.2174/1570159X21666230104090046 -
Molecular Pharmaceutics Dec 2023Mucus mechanically protects the intestinal epithelium and impacts the absorption of drugs, with a largely unknown role for bile. We explored the impacts of bile on...
Mucus mechanically protects the intestinal epithelium and impacts the absorption of drugs, with a largely unknown role for bile. We explored the impacts of bile on mucosal biomechanics and drug transport within mucus. Bile diffused with square-root-of-time kinetics and interplayed with mucus, leading to transient stiffening captured in Brillouin images and a concentration-dependent change from subdiffusive to Brownian-like diffusion kinetics within the mucus demonstrated by differential dynamic microscopy. Bile-interacting drugs, Fluphenazine and Perphenazine, diffused faster through mucus in the presence of bile, while Metoprolol, a drug with no bile interaction, displayed consistent diffusion. Our findings were corroborated by rat studies, where co-dosing of a bile acid sequestrant substantially reduced the bioavailability of Perphenazine but not Metoprolol. We clustered over 50 drugs based on their interactions with bile and mucin. Drugs that interacted with bile also interacted with mucin but not vice versa. This study detailed the dynamics of mucus biomechanics under bile exposure and linked the ability of a drug to interact with bile to its abbility to interact with mucus.
Topics: Rats; Animals; Bile; Elevators and Escalators; Perphenazine; Mucus; Mucins
PubMed: 37906224
DOI: 10.1021/acs.molpharmaceut.3c00550 -
Psychiatry and Clinical Neurosciences Sep 2023This study identified discrepant therapeutic outcomes of antipsychotics.
AIM
This study identified discrepant therapeutic outcomes of antipsychotics.
METHODS
A total of 5191 patients with schizophrenia were enrolled, 3030 as discovery cohort, 1395 as validation cohort, and 766 as multi-ancestry validation cohort. Therapeutic Outcomes Wide Association Scan was conducted. Types of antipsychotics (one antipsychotic vs other antipsychotics) were dependent variables, therapeutic outcomes including efficacy and safety were independent variables.
RESULTS
In discovery cohort, olanzapine related to higher risk of weight gain (AIWG, OR: 2.21-2.86), liver dysfunction (OR: 1.75-2.33), sedation (OR: 1.76-2.86), increased lipid level (OR: 2.04-2.12), and lower risk of extrapyramidal syndrome (EPS, OR: 0.14-0.46); risperidone related to higher risk of hyperprolactinemia (OR: 12.45-20.53); quetiapine related to higher risk of sedation (OR = 1.73), palpitation (OR = 2.87), increased lipid level (OR = 1.69), lower risk of hyperprolactinemia (OR: 0.09-0.11), and EPS (OR: 0.15-0.44); aripiprazole related to lower risk of hyperprolactinemia (OR: 0.09-0.14), AIWG (OR = 0.44), sedation (OR: 0.33-0.47), and QTc prolongation (β = -2.17); ziprasidone related to higher risk of increased QT interval (β range: 3.11-3.22), nausea (OR: 3.22-3.91), lower risk of AIWG (OR: 0.27-0.46), liver dysfunction (OR: 0.41-0.38), and increased lipid level (OR: 0.41-0.55); haloperidol related to higher risk of EPS (OR: 2.64-6.29), hyperprolactinemia (OR: 5.45-9.44), and increased salivation (OR: 3.50-3.68). Perphenazine related to higher risk of EPS (OR: 1.89-2.54). Higher risk of liver dysfunction in olanzapine and lower risk of hyperprolactinemia in aripiprazole were confirmed in validation cohort, and higher risk of AIWG in olanzapine and hyperprolactinemia in risperidone were confirmed in multi-ancestry validation cohort.
CONCLUSION
Future precision medicine should focus on personalized side-effects.
Topics: Humans; Antipsychotic Agents; Aripiprazole; Hyperprolactinemia; Lipids; Olanzapine; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Treatment Outcome
PubMed: 37210704
DOI: 10.1111/pcn.13567 -
International Journal of Clinical... Jun 2024To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling.
MATERIALS AND METHODS
We included randomized controlled studies, quasi-randomized trials, case reports, clinical trials, systematic reviews, and meta-analyses assessing the use of atropine in patients with sialorrhea or drooling. The endpoints were reduction in salivary flow rate, amount of saliva secreted, reduction in clinical symptoms of sialorrhea, death rattle intensity, or reduction in drooling intensity as measured by an objective scale such as the drooling intensity scale.
RESULTS
A total of 56 studies with 2,378 patients were included in the systematic review. The underlying disease states included brain injury, amyotrophic lateral sclerosis, cerebral palsy, clozapine- and perphenazine-induced sialorrhea, Parkinson's disease, and terminal illness. The routes of atropine administration included sublingual, intravenous, subcutaneous, oral tablet or solution, and direct injection of atropine into parotid glands or at the base of the tongue. The generalized estimated equation regression models showed that sublingual administration is superior to oral and subcutaneous routes.
CONCLUSION
Atropine is efficacious in managing sialorrhea in most disease states. Sublingual administration of atropine is superior to other routes of administration in reducing salivary flow in patients with sialorrhea.
Topics: Sialorrhea; Humans; Atropine; Treatment Outcome; Salivation
PubMed: 38577753
DOI: 10.5414/CP204538 -
Frontiers in Psychiatry 2023Depression is widespread global problem that not only severely impacts individuals' physical and mental health but also imposes a heavy disease burden on nations and...
BACKGROUND
Depression is widespread global problem that not only severely impacts individuals' physical and mental health but also imposes a heavy disease burden on nations and societies. The role of inflammation in the pathogenesis and pathophysiology of depression has received much attention, but the precise relationship between the two remains unclear. This study aims to investigate the correlation between depression and inflammation using a network medicine approach.
METHODS
We utilized a degree-preserving approach to identify the large connected component (LCC) of all depression-related proteins in the human interactome. The LCC was deemed as the disease module for depression. To measure the association between depression and other diseases, we calculated the overlap between these disease protein modules using the Sab algorithm. A smaller Sab value indicates a stronger association between diseases. Building on the results of this analysis, we further explored the correlation between inflammation and depression by conducting enrichment and pathway analyses of critical targets. Finally, we used a network proximity approach to calculate drug-disease proximity to predict the efficacy of drugs for the treatment of depression. We calculated and ranked the distances between depression disease modules and 6,100 drugs. The top-ranked drugs were selected to explore their potential for treating depression based on the hypothesis that their antidepressant effects are related to reducing inflammation.
RESULTS
In the human interactome, all depression-related proteins are clustered into a large connected component (LCC) consisting of 202 proteins and multiple small subgraphs. This indicates that depression-related proteins tend to form clusters within the same network. We used the 202 LCC proteins as the key disease module for depression. Next, we investigated the potential relationships between depression and 299 other diseases. Our analysis identified over 18 diseases that exhibited significant overlap with the depression module. Where S = -0.075 for the vascular disease and depressive disorders module, S = -0.070 for the gastrointestinal disease and depressive disorders module, and S = -0.062 for the endocrine system disease and depressive disorders module. The distance between them S < 0 implies that the pathogenesis of depression is likely to be related to the pathogenesis of its co-morbidities of depression and that potential therapeutic approaches may be derived from the disease treatment libraries of these co-morbidities. Further, considering that the inflammation is ubiquitous in some disease, we calculate the overlap between the collected inflammation module (236 proteins) and the depression module (202 proteins), finding that they are closely related (S = -0.358) in the human protein interaction network. After enrichment and pathway analysis of key genes, we identified the HIF-1 signaling pathway, PI3K-Akt signaling pathway, Th17 cell differentiation, hepatitis B, and inflammatory bowel disease as key to the inflammatory response in depression. Finally, we calculated the -score to determine the proximity of 6,100 drugs to the depression disease module. Among the top three drugs identified by drug-disease proximity analysis were Perphenazine, Clomipramine, and Amitriptyline, all of which had a greater number of targets in the network associated with the depression disease module. Notably, these drugs have been shown to exert both anti-inflammatory and antidepressant effects, suggesting that they may modulate depression through an anti-inflammatory mechanism. These findings demonstrate a correlation between depression and inflammation at the network medicine level, which has important implications for future elucidation of the etiology of depression and improved treatment outcomes.
CONCLUSION
Neuroimmune signaling pathways play an important role in the pathogenesis of depression, and many classes of antidepressants exhibiting anti-inflammatory properties. The pathogenesis of depression is closely related to inflammation.
PubMed: 37492068
DOI: 10.3389/fpsyt.2023.1184188 -
Heliyon Nov 2023Adverse events (AEs) of antipsychotic drugs include neuroleptic malignant syndrome (NMS), which presents complex clinical symptoms, resulting in a fatal outcome. In this...
Adverse events (AEs) of antipsychotic drugs include neuroleptic malignant syndrome (NMS), which presents complex clinical symptoms, resulting in a fatal outcome. In this study, the association between antipsychotic drugs and NMS was comprehensively evaluated by cluster and association analyses using the Japanese Adverse Drug Event Report (JADER) database. The analyses were performed using 20 typical antipsychotics (TAPs) alongside 9 atypical antipsychotics (AAPs). The Standardised MedDRA Queries (SMQ) database was used to analyze NMS (SMQ code: 20000044). Reporting odds ratios (RORs) were used for AE signal detection. The relationship between antipsychotic drugs and AEs for NMS was investigated by performing hierarchical cluster analysis using Ward's method. Between April 2004 and September 2021, the total number of JADER reports was 705,294. RORs (95 % confidence interval) of NMS for haloperidol, chlorpromazine, risperidone, and aripiprazole were 12.1 (11.1-13.3), 6.3 (5.7-7.0), 6.2 (5.8-6.6), and 4.7 (4.4-5.1), respectively. Three clusters were formed, with characteristics as follows: Cluster 1 consisted of only TAPs, such as bromperidol and fluphenazine, whilst having a high reporting rate of hypotension, tachycardia, dyskinesia, and dystonia. Cluster 2 consisted of all AAPs alongside several TAPs, such as haloperidol and chlorpromazine, with higher reporting rates of disturbance of consciousness, extrapyramidal disorders (excluding dyskinesia and dystonia), and serotonin syndrome. Cluster 3 consisted of only perphenazine, whilst having a higher reporting rate of coma, leukocytosis, and Parkinsonism. The results of this study may therefore aid in the management of NMS using antipsychotic drugs.
PubMed: 38034668
DOI: 10.1016/j.heliyon.2023.e21891 -
Immunity, Inflammation and Disease May 2024Esophageal cancer (ESCA) is a highly invasive malignant tumor with poor prognosis. This study aimed to discover a generalized and high-sensitivity immune prognostic...
BACKGROUND
Esophageal cancer (ESCA) is a highly invasive malignant tumor with poor prognosis. This study aimed to discover a generalized and high-sensitivity immune prognostic signature that could stratify ESCA patients and predict their overall survival, and to discover potential therapeutic drugs by the connectivity map.
METHODS
The key gene modules significantly related to clinical traits (survival time and state) of ESCA patients were selected by weighted gene coexpression network analysis (WCGNA), then the univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to construct a 15-immune-related gene prognostic signature.
RESULTS
The immune-related risk model was related to clinical and pathologic factors and remained an effective independent prognostic factor. Enrichment analyses revealed that the differentially expressed genes (DEGs) of the high- and low-risk groups were associated with tumor cell proliferation and immune mechanisms. Based on the gathered data, a small molecule drug named perphenazine (PPZ) was elected. The pharmacological analysis indicates that PPZ could help in adjuvant therapy of ESCA through regulation of metabolic process and cellular proliferation, enhancement of immunologic functions, and inhibition of inflammatory reactions. Furthermore, molecular docking was performed to explore and verify the PPZ-core target interactions.
CONCLUSION
We succeed in structuring the immune-related prognostic model, which could be used to distinguish and predict patients' survival outcome, and screening a small molecule drug named PPZ. Prospective studies also are needed to further validate its analytical accuracy for estimating prognoses and confirm the potential use of PPZ for treating ESCA.
Topics: Esophageal Neoplasms; Humans; Network Pharmacology; Prognosis; Computational Biology; Gene Regulatory Networks; Gene Expression Regulation, Neoplastic; Gene Expression Profiling; Biomarkers, Tumor; Molecular Docking Simulation; Antineoplastic Agents; Male; Female
PubMed: 38804848
DOI: 10.1002/iid3.1266