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Military Medical Research Jun 2023Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable...
BACKGROUND
Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers. Previous studies have indicated the association between treatment response and genetic and epigenetic factors, but no effective biomarkers have been identified. Hence, further research is imperative to enhance precision medicine in SCZ treatment.
METHODS
Participants with SCZ were recruited from two randomized trials. The discovery cohort was recruited from the CAPOC trial (n = 2307) involved 6 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, and Haloperidol/Perphenazine (subsequently equally assigned to one or the other) groups. The external validation cohort was recruited from the CAPEC trial (n = 1379), which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, and Aripiprazole groups. Additionally, healthy controls (n = 275) from the local community were utilized as a genetic/epigenetic reference. The genetic and epigenetic (DNA methylation) risks of SCZ were assessed using the polygenic risk score (PRS) and polymethylation score, respectively. The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis, methylation quantitative trait loci, colocalization, and promoter-anchored chromatin interaction. Machine learning was used to develop a prediction model for treatment response, which was evaluated for accuracy and clinical benefit using the area under curve (AUC) for classification, R for regression, and decision curve analysis.
RESULTS
Six risk genes for SCZ (LINC01795, DDHD2, SBNO1, KCNG2, SEMA7A, and RUFY1) involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response. The developed and externally validated prediction model, which incorporated clinical information, PRS, genetic risk score (GRS), and proxy methylation level (proxyDNAm), demonstrated positive benefits for a wide range of patients receiving different APDs, regardless of sex [discovery cohort: AUC = 0.874 (95% CI 0.867-0.881), R = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841-0.861), R = 0.507].
CONCLUSIONS
This study presents a promising precision medicine approach to evaluate treatment response, which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ ), 18. Aug 2009 retrospectively registered: CAPOC-ChiCTR-RNC-09000521 ( https://www.chictr.org.cn/showproj.aspx?proj=9014 ), CAPEC-ChiCTR-RNC-09000522 ( https://www.chictr.org.cn/showproj.aspx?proj=9013 ).
Topics: Humans; Antipsychotic Agents; Schizophrenia; Olanzapine; Risperidone; Aripiprazole; Precision Medicine; Multiomics; Benzodiazepines; Randomized Controlled Trials as Topic; Phospholipases
PubMed: 37269009
DOI: 10.1186/s40779-023-00459-7 -
World Psychiatry : Official Journal of... Jun 2023Most acute phase antipsychotic drug trials in schizophrenia last only a few weeks, but patients must usually take these drugs much longer. We examined the long-term...
Most acute phase antipsychotic drug trials in schizophrenia last only a few weeks, but patients must usually take these drugs much longer. We examined the long-term efficacy of antipsychotic drugs in acutely ill patients using network meta-analysis. We searched the Cochrane Schizophrenia Group register up to March 6, 2022 for randomized, blinded trials of at least 6-month duration on all second-generation and 18 first-generation antipsychotics. The primary outcome was change in overall symptoms of schizophrenia; secondary outcomes were all-cause discontinuation; change in positive, negative and depressive symptoms; quality of life, social functioning, weight gain, antiparkinson medication use, akathisia, serum prolactin level, QTc prolongation, and sedation. Confidence in the results was assessed by the CINeMA (Confidence in Network Meta-Analysis) framework. We included 45 studies with 11,238 participants. In terms of overall symptoms, olanzapine was on average more efficacious than ziprasidone (standardized mean difference, SMD=0.37, 95% CI: 0.26-0.49), asenapine (SMD=0.33, 95% CI: 0.21-0.45), iloperidone (SMD=0.32, 95% CI: 0.15-0.49), paliperidone (SMD=0.28, 95% CI: 0.11-0.44), haloperidol (SMD=0.27, 95% CI: 0.14-0.39), quetiapine (SMD=0.25, 95% CI: 0.12-0.38), aripiprazole (SMD=0.16, 95% CI: 0.04-0.28) and risperidone (SMD=0.12, 95% CI: 0.03-0.21). The 95% CIs for olanzapine versus aripiprazole and risperidone included the possibility of trivial effects. The differences between olanzapine and lurasidone, amisulpride, perphenazine, clozapine and zotepine were either small or uncertain. These results were robust in sensitivity analyses and in line with other efficacy outcomes and all-cause discontinuation. Concerning weight gain, the impact of olanzapine was higher than all other antipsychotics, with a mean difference ranging from -4.58 kg (95% CI: -5.33 to -3.83) compared to ziprasidone to -2.30 kg (95% CI: -3.35 to -1.25) compared to amisulpride. Our data suggest that olanzapine is more efficacious than a number of other antipsychotic drugs in the longer term, but its efficacy must be weighed against its side effect profile.
PubMed: 37159349
DOI: 10.1002/wps.21089 -
Emergency Medicine International 2023To describe the clinical presentation of acute dystonia (AD) from drug abuse or misuse, as well as the emergency department (ED) management and outcomes in adolescents...
OBJECTIVES
To describe the clinical presentation of acute dystonia (AD) from drug abuse or misuse, as well as the emergency department (ED) management and outcomes in adolescents and young adults.
METHODS
This was a retrospective cohort study of patients aged 10-25 years who were admitted to the ED for AD due to intentional abuse or misuse from January 1, 2014, to June 30, 2017. Data were collected from electronic medical records by three investigators with excellent interrater reliability (0.87).
RESULTS
Sixty-two cases met the criteria with male predominance (85.5%); the mean age was 16.7 years. Perphenazine was the most common cause of AD (38.7%), followed by haloperidol (32.2%). The most common AD manifestations were torticollis (51.6%), oromandibular dystonia (45.2%), and oculogyric crisis (22.6%). Intravenous (IV) diazepam combined with oral trihexyphenidyl and IV diazepam alone were the most frequently used first treatment in our ED (41.7% and 35.0%, respectively). Overall, the improvement rates from IV diazepam alone or combined with trihexyphenidyl ranged from 46.2%-75.0%. These rates were inferior to those observed with IV benztropine (100%) alone or combined with trihexyphenidyl. All patients were treated on an outpatient basis, except for one who was admitted to a pediatric ward.
CONCLUSIONS
In recent years, drug-induced AD caused by intentional abuse among adolescents and young adults has become a concern in Thailand. The most common suspected drugs of abuse were first-generation antipsychotics, perphenazine, and haloperidol. The most effective treatment was benztropine.
PubMed: 37057297
DOI: 10.1155/2023/2725974 -
Pharmaceutics Feb 2023Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor....
Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor. Therapeutic reference ranges and dose-effect relation are the main requirements for this drug titration tool. Defining and updating therapeutic reference ranges are difficult, and there is no standardised method for the calculation and clinical qualification of these. The study presents a basic model for validating and selecting routine laboratory data. The programmed algorithm was applied on data sets of antidepressants and antipsychotics from three public hospitals in Denmark. Therapeutic analytical ranges were compared with the published therapeutic reference ranges by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) and in additional literature. For most of the drugs, the calculated therapeutic analytical ranges showed good concordance between the laboratories and to published therapeutic reference ranges. The exceptions were flupentixol, haloperidol, paroxetine, perphenazine, and venlafaxine + o-desmethyl-venlafaxine (total plasma concentration), where the range was considerably higher for the laboratory data, while the calculated range of desipramine, sertraline, ziprasidone, and zuclopenthixol was considerably lower. In most cases, we identified additional literature supporting our data, highlighting the need of a critical re-examination of current therapeutic reference ranges in Denmark. An automated approach can aid in the evaluation of current and future therapeutic reference ranges by providing additional information based on big data from multiple laboratories.
PubMed: 36839995
DOI: 10.3390/pharmaceutics15020673 -
ACS Chemical Neuroscience Jan 2023Alzheimer's disease is imposing a growing social and economic burden worldwide, and effective therapies are urgently required. One possible approach to modulation of the...
Alzheimer's disease is imposing a growing social and economic burden worldwide, and effective therapies are urgently required. One possible approach to modulation of the disease outcome is to use small molecules to limit the conversion of monomeric amyloid (Aβ42) to cytotoxic amyloid oligomers and fibrils. We have synthesized modulators of amyloid assembly that are unlike others studied to date: these compounds act primarily by sequestering the Aβ42 monomer. We provide kinetic and nuclear magnetic resonance data showing that these perphenazine conjugates divert the Aβ42 monomer into amorphous aggregates that are not cytotoxic. Rapid monomer sequestration by the compounds reduces fibril assembly, even in the presence of pre-formed fibrillar seeds. The compounds are therefore also able to disrupt monomer-dependent secondary nucleation, the autocatalytic process that generates the majority of toxic oligomers. The inhibitors have a modular design that is easily varied, aiding future exploration and use of these tools to probe the impact of distinct Aβ42 species populated during amyloid assembly.
Topics: Humans; Perphenazine; Amyloid beta-Peptides; Amyloid; Alzheimer Disease; Amyloidogenic Proteins; Peptide Fragments
PubMed: 36542544
DOI: 10.1021/acschemneuro.2c00498 -
Health Psychology Research 2022Phenothiazines, a diverse class of drugs, can be used to treat multiple mental health and physical conditions. Phenothiazines have been used for decades to treat mental...
Phenothiazines, a diverse class of drugs, can be used to treat multiple mental health and physical conditions. Phenothiazines have been used for decades to treat mental illnesses, including schizophrenia, mania in bipolar disorder, and psychosis. Additionally, these drugs offer relief for physical illnesses, including migraines, hiccups, nausea, and vomiting in both adults and children. Further research is needed to prove the efficacy of phenothiazines in treating physical symptoms. Phenothiazines are dopaminergic antagonists that inhibit D2 receptors with varying potency. High potency phenothiazines such as perphenazine are used to treat various psychiatric conditions such as the positive symptoms of schizophrenia, the symptoms of psychosis, and mania that can occur with bipolar disorder. Low/mid potency phenothiazines such as chlorpromazine antipsychotic drugs that have been used to treat schizophrenia and schizophrenia-like disorders since the 1950s and are utilized in numerous disease states. The present investigation aims to elucidate the effects of phenothiazines in clinical practice.
PubMed: 36425230
DOI: 10.52965/001c.38930 -
Current Neuropharmacology 2023Since the early clinical efficacy of antipsychotics has not yet been well perceived, this study sought to decide whether the efficacy of antipsychotics at week 2 can... (Randomized Controlled Trial)
Randomized Controlled Trial Clinical Trial
BACKGROUND
Since the early clinical efficacy of antipsychotics has not yet been well perceived, this study sought to decide whether the efficacy of antipsychotics at week 2 can predict subsequent responses at week 6 and identify how such predictive capacities vary among different antipsychotics and psychotic symptoms.
METHODS
A total of 3010 patients with schizophrenia enrolled in a randomized controlled trial (RCT) and received a 6-week treatment with one antipsychotic drug randomly chosen from five atypical antipsychotics (risperidone 2-6 mg/d, olanzapine 5-20 mg/d, quetiapine 400-750 mg/d, aripiprazole 10-30 mg/d, and ziprasidone 80-160 mg/d) and two typical antipsychotics (perphenazine 20-60 mg/d and haloperidol 6-20 mg/d). Early efficacy was defined as the reduction rate using the Positive and Negative Syndrome Scale (PANSS) total score at week 2. With cut-offs at 50% reduction, logistic regression, receiver operating characteristic (ROC) and random forests were adopted.
RESULTS
The reduction rate of PANSS total score and improvement of psychotic symptoms at week 2 enabled subsequent responses to 7 antipsychotics to be predicted, in which improvements in delusions, lack of judgment and insight, unusual thought content, and suspiciousness/ persecution were endowed with the greatest weight.
CONCLUSION
It is robust enough to clinically predict treatment responses to antipsychotics at week 6 using the reduction rate of PANSS total score and symptom relief at week 2. Psychiatric clinicians had better determine whether to switch the treatment plan by the first 2 weeks.
Topics: Humans; Antipsychotic Agents; Benzodiazepines; Schizophrenia; Aripiprazole; Olanzapine; Risperidone; Quetiapine Fumarate; Haloperidol; Treatment Outcome
PubMed: 36411567
DOI: 10.2174/1570159X21666221118164612 -
Scientific Reports Oct 2022Organophosphates (OPs) are inhibitors of acetylcholinesterase and have deleterious effects on the central nervous system. Clinical manifestations of OP poisoning include...
Organophosphates (OPs) are inhibitors of acetylcholinesterase and have deleterious effects on the central nervous system. Clinical manifestations of OP poisoning include convulsions, which represent an underlying toxic neuro-pathological process, leading to permanent neuronal damage. This neurotoxicity is mediated through the cholinergic, GABAergic and glutamatergic (NMDA) systems. Pharmacological interventions in OP poisoning are designed to mitigate these specific neuro-pathological pathways, using anticholinergic drugs and GABAergic agents. Benactyzine is a combined anticholinergic, anti-NMDA compound. Based on previous development of novel GABA derivatives (such as prodrugs based on perphenazine for the treatment of schizophrenia and nortriptyline against neuropathic pain), we describe the synthesis and preliminary testing of a mutual prodrug ester of benactyzine and GABA. It is assumed that once the ester crosses the blood-brain-barrier it will undergo hydrolysis, releasing benactyzine and GABA, which are expected to act synergistically. The combined release of both compounds in the brain offers several advantages over the current OP poisoning treatment protocol: improved efficacy and safety profile (where the inhibitory properties of GABA are expected to counteract the anticholinergic cognitive adverse effects of benactyzine) and enhanced chemical stability compared to benactyzine alone. We present here preliminary results of animal studies, showing promising results with early gabactyzine administration.
Topics: Animals; Benactyzine; Antidotes; Prodrugs; Organophosphates; Acetylcholinesterase; Chemical Warfare Agents; Cholinergic Antagonists; Esters; gamma-Aminobutyric Acid; Organophosphate Poisoning; Cholinesterase Inhibitors
PubMed: 36302937
DOI: 10.1038/s41598-022-23141-9