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JAMA Network Open Mar 2024There is an absence of mortality risk assessment tools in first-episode psychosis (FEP) that could enable personalized interventions.
IMPORTANCE
There is an absence of mortality risk assessment tools in first-episode psychosis (FEP) that could enable personalized interventions.
OBJECTIVE
To examine the feasibility of machine learning (ML) in discerning mortality risk in FEP and to assess whether such risk predictions can inform pharmacotherapy choices.
DESIGN, SETTING, AND PARTICIPANTS
In this prognostic study, Swedish nationwide cohort data (from July 1, 2006, to December 31, 2021) were harnessed for model development and validation. Finnish cohort data (from January 1, 1998, to December 31, 2017) were used for external validation. Data analyses were completed between December 2022 and December 2023.
MAIN OUTCOMES AND MEASURES
Fifty-one nationwide register variables, encompassing demographics and clinical and work-related histories, were subjected to ML to predict future mortality risk. The ML model's performance was evaluated by calculating the area under the receiver operating characteristic curve (AUROC). The comparative effectiveness of pharmacotherapies in patients was assessed and was stratified by the ML model to those with predicted high mortality risk (vs low risk), using the between-individual hazard ratio (HR). The 5 most important variables were then identified and a model was retrained using these variables in the discovery sample.
RESULTS
This study included 24 052 Swedish participants (20 000 in the discovery sample and 4052 in the validation sample) and 1490 Finnish participants (in the validation sample). Swedish participants had a mean (SD) age of 29.1 (8.1) years, 62.1% were men, and 418 died with 2 years. Finnish participants had a mean (SD) age of 29.7 (8.0) years, 61.7% were men, and 31 died within 2 years. The discovery sample achieved an AUROC of 0.71 (95% CI, 0.68-0.74) for 2-year mortality prediction. Using the 5 most important variables (ie, the top 10% [substance use comorbidities, first hospitalization duration due to FEP, male sex, prior somatic hospitalizations, and age]), the final model resulted in an AUROC of 0.70 (95% CI, 0.63-0.76) in the Swedish sample and 0.67 (95% CI, 0.56-0.78) in the Finnish sample. Individuals with predicted high mortality risk had an elevated 15-year risk in the Swedish sample (HR, 3.77 [95% CI, 2.92-4.88]) and an elevated 20-year risk in the Finnish sample (HR, 3.72 [95% CI, 2.67-5.18]). For those with predicted high mortality risk, long-acting injectable antipsychotics (HR, 0.45 [95% CI, 0.23-0.88]) and mood stabilizers (HR, 0.64 [95% CI, 0.46-0.90]) were associated with decreased mortality risk. Conversely, for those predicted to survive, only oral aripiprazole (HR, 0.38 [95% CI, 0.20-0.69]) and risperidone (HR, 0.38 [95% CI, 0.18-0.82]) were associated with decreased mortality risk.
CONCLUSIONS AND RELEVANCE
In this prognostic study, an ML-based model was developed and validated to predict mortality risk in FEP. These findings may help to develop personalized interventions to mitigate mortality risk in FEP.
Topics: Humans; Male; Adult; Female; Death; Psychotic Disorders; Anticonvulsants; Antipsychotic Agents; Machine Learning
PubMed: 38497965
DOI: 10.1001/jamanetworkopen.2024.0640 -
Innovations in Clinical Neuroscience 2024Clinical practice guidelines support efforts to improve functioning in patients with schizophrenia. Discrepancies in the perception of cognitive status between...
BACKGROUND
Clinical practice guidelines support efforts to improve functioning in patients with schizophrenia. Discrepancies in the perception of cognitive status between clinicians, patients with schizophrenia, and their caregivers have been associated with impaired functional abilities in patients; medication side effects might worsen both cognition and daily functioning. We assessed daily/social functioning and cognition in stable patients with schizophrenia who switched to the long-acting injectable (LAI) antipsychotic aripiprazole lauroxil (AL).
METHODS
Clinically stable adults with residual symptoms of schizophrenia or intolerance following three or more doses of paliperidone palmitate or risperidone LAI were switched to flexibly dosed open-label AL treatment (441mg, 662mg, or 882mg every 4 weeks or 882mg every 6 weeks) for six months (ClinicalTrials.gov identifier: NCT02634320). Daily/social functioning was assessed using the Personal and Social Performance Scale (PSP); total and subscale scores were summarized using descriptive statistics. The cognitive status of patients was assessed using the New York Assessment of Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) at baseline and Month 6 or early termination, providing patient, caregiver, and clinician perspectives. A analysis assessed level of agreement in ratings of cognitive status among respondents, evaluated at baseline and last assessment, using weighted kappa coefficients (0.01-0.20, slight agreement; 0.21-0.40, fair agreement; 0.41-0.60, moderate agreement; 0.61-0.80, substantial agreement.).
RESULTS
All 51 enrolled patients received one or more AL doses; 35 completed the study, and 45 contributed data at last assessment. Mean age was 40.6 years; 72.5 percent of patients were male. Based on PSP total score, functioning was maintained from baseline (mean [standard deviation (SD)]: 55.1 [10.5]) through six months of AL treatment (mean [SD]: 57.7 [13.2]). Proportions of patients rating personal and social functioning issues as "not present" or "mild" remained stable between baseline and Month 6 for each PSP subscale. At baseline (n=50), cognitive difficulties were most commonly rated "not present" or "mild" in all NY-AACENT domains by patients (58-86% across domains), clinicians (62-94%), and caregivers (50-92%), and these rates were maintained or increased at last assessment for all reporters. Weighted kappa coefficients indicated fair-to-substantial agreement between patients and clinicians across domains at last assessment (0.32-0.64; baseline: 0.14-0.55); patient-caregiver agreement ranged from 0.07 to 0.50 at last assessment (baseline: 0.25-0.60).
CONCLUSION
In clinically stable patients with schizophrenia who initiated AL, self-reported functioning was maintained over six months of treatment. Clinician-, caregiver-, and patient-reported cognitive function was stable at baseline and maintained in all NY-AACENT domains; patient-clinician agreement on level of cognitive impairment increased over six months of treatment with AL.
PubMed: 38495608
DOI: No ID Found -
ClinicoEconomics and Outcomes Research... 2024Patients with Parkinson's disease psychosis (PDP) treated with pimavanserin (PIM) versus other atypical antipsychotics (AAPs) including quetiapine (QUE) may have...
Analysis of Medicare Patients Treated with Pimavanserin versus Other Atypical Antipsychotics: A Cost-Offset Model Evaluating Skilled Nursing Facility Stays and Long-Term Care Admissions in Parkinson's Disease Psychosis.
BACKGROUND
Patients with Parkinson's disease psychosis (PDP) treated with pimavanserin (PIM) versus other atypical antipsychotics (AAPs) including quetiapine (QUE) may have health-care cost savings due to fewer skilled nursing facility-stays (SNF-stays) and long-term care admissions (LTCA).
METHODS
A decision analytic model was developed using the 2019 Medicare Patient Driven Payment Model (PDPM) to estimate SNF-stays and LTCA associated per-patient- per-year (PPPY) facility and rehabilitation costs among patients that initiated PIM vs QUE or vs other-AAPs (i.e, quetiapine, risperidone, olanzapine, aripiprazole). Model inputs were derived for: (i) annual SNF-stay and LTCA rates from an analysis of Medicare beneficiaries with PDP, and (ii) annual mean rehabilitation and resident care-stay costs from PDPM case-mix adjusted value-based payment rates for 5 rehabilitation components (ie, physical-therapy, occupational-therapy, nursing, speech-language pathology, non-therapy ancillary), and an additional variable-per-diem for room/board services. PPPY costs were estimated from (i) SNF-stay and (ii) LTCA rates multiplied by annual mean costs of stay in 2022 USD. Probabilistic sensitivity analysis (PSA) was performed using 1000 Monte Carlo simulations.
RESULTS
Overall SNF-stay rates of 20.2%, 31.4%, and 31.7%, and LTCA rates of 23.2%, 33.8%, 34.6% were observed for PIM, QUE, and other-AAPs, respectively. Based on annual mean costs, PPPY SNF-stay rehabilitation and resident related costs for PIM ($41,808) vs QUE ($65,172) or vs other-AAPs ($65,664), resulted in $23,364 and $23,856 PPPY cost savings, respectively. Similarly, PPPY LTCA rehabilitation and resident related costs for PIM ($47,957) vs QUE ($70,091) or vs other-AAPs ($71,566) resulted in $22,134 and $23,609 PPPY cost-savings for PIM, respectively. PSA suggested PIM would provide cost-savings vs QUE or other-AAPs in >99% of iterations.
CONCLUSION
In this analysis, PIM demonstrated nearly 36% and 32% lower PPPY SNF-stays and LTCA costs, respectively, vs QUE or other-AAPs. Research examining additional cost-offsets (i.e., fewer falls/fractures) associated with SNF-stay or LTCA may be needed.
PubMed: 38495124
DOI: 10.2147/CEOR.S452162 -
Journal of Psychopharmacology (Oxford,... Apr 2024Prescribing drugs for psychosis (antipsychotics) is challenging due to high rates of poor treatment outcomes, which are in part explained by an individual's genetics....
BACKGROUND
Prescribing drugs for psychosis (antipsychotics) is challenging due to high rates of poor treatment outcomes, which are in part explained by an individual's genetics. Pharmacogenomic (PGx) testing can help clinicians tailor the choice or dose of psychosis drugs to an individual's genetics, particularly psychosis drugs with known variable response due to CYP2D6 gene variants ('CYP2D6-PGx antipsychotics').
AIMS
This study aims to investigate differences between demographic groups prescribed 'CYP2D6-PGx antipsychotics' and estimate the proportion of patients eligible for PGx testing based on current pharmacogenomics guidance.
METHODS
A cross-sectional study took place extracting data from 243 patients' medical records to explore psychosis drug prescribing, including drug transitions. Demographic data such as age, sex, ethnicity, and clinical sub-team were collected and summarised. Descriptive statistics explored the proportion of 'CYP2D6-PGx antipsychotic' prescribing and the nature of transitions. We used logistic regression analysis to investigate associations between demographic variables and prescription of 'CYP2D6-PGx antipsychotic' versus 'non-CYP2D6-PGx antipsychotic'.
RESULTS
Two-thirds (164) of patients had been prescribed a 'CYP2D6-PGx antipsychotic' (aripiprazole, risperidone, haloperidol or zuclopenthixol). Over a fifth (23%) of patients would have met the suggested criteria for PGx testing, following two psychosis drug trials. There were no statistically significant differences between age, sex, or ethnicity in the likelihood of being prescribed a 'CYP2D6-PGx antipsychotic'.
CONCLUSIONS
This study demonstrated high rates of prescribing 'CYP2D6-PGx-antipsychotics' in an EIP cohort, providing a rationale for further exploration of how PGx testing can be implemented in EIP services to personalise the prescribing of drugs for psychosis.
Topics: Humans; Antipsychotic Agents; Pharmacogenetics; Cytochrome P-450 CYP2D6; Cross-Sectional Studies; Psychotic Disorders; Psychoses, Substance-Induced
PubMed: 38494658
DOI: 10.1177/02698811241238283 -
European Neuropsychopharmacology : the... Jun 2024Long-acting injectable antipsychotics (LAIs) are primarily used for relapse prevention, but in some settings and situations, they may also be useful for acute treatment... (Meta-Analysis)
Meta-Analysis Review
Long-acting injectable antipsychotics (LAIs) are primarily used for relapse prevention, but in some settings and situations, they may also be useful for acute treatment of schizophrenia. We conducted a systematic review and frequentist network meta-analysis of randomized-controlled trials (RCTs), focusing on adult patients in the acute phase of schizophrenia. Interventions were risperidone, paliperidone, aripiprazole, olanzapine, and placebo, administered either orally or as LAI. We synthesized data on overall symptoms, complemented by 17 other efficacy and tolerability outcomes. Confidence in the evidence was assessed with the Confidence-in-Network-Meta-Analysis-framework (CINeMA). We included 115 RCTs with 25,550 participants. All drugs were significantly more efficacious than placebo with the following standardized mean differences and their 95 % confidence intervals: olanzapine LAI -0.66 [-1.00; -0.33], risperidone LAI -0.59[-0.73;-0.46], olanzapine oral -0.55[-0.62;-0.48], aripiprazole LAI -0.54[-0.71; -0.37], risperidone oral -0.48[-0.55;-0.41], paliperidone oral -0.47[-0.58;-0.37], paliperidone LAI -0.45[-0.57;-0.33], aripiprazole oral -0.40[-0.50; -0.31]. There were no significant efficacy differences between LAIs and oral formulations. Sensitivity analyses of the primary outcome overall symptoms largely confirmed these findings. Moreover, some side effects were less frequent under LAIs than under their oral counterparts. Confidence in the evidence was moderate for most comparisons. LAIs are efficacious for acute schizophrenia and may have some benefits compared to oral formulations in terms of side effects. These findings assist clinicians with insights to weigh the risks and benefits between oral and injectable agents when treating patients in the acute phase.
Topics: Humans; Antipsychotic Agents; Administration, Oral; Schizophrenia; Delayed-Action Preparations; Network Meta-Analysis; Randomized Controlled Trials as Topic; Injections; Treatment Outcome
PubMed: 38490016
DOI: 10.1016/j.euroneuro.2024.03.003 -
Neuropsychiatric Disease and Treatment 2024Olanzapine has already been used to treat schizophrenia patients; however, the initial dosage recommendation when multiple drugs are used in combination, remains...
OBJECTIVE
Olanzapine has already been used to treat schizophrenia patients; however, the initial dosage recommendation when multiple drugs are used in combination, remains unclear. The purpose of this study was to explore the drug-drug interaction (DDI) of multiple drugs combined with olanzapine and to recommend the optimal administration of olanzapine in schizophrenia patients.
METHODS
In this study, we obtained olanzapine concentrations from therapeutic drug monitoring (TDM) database. In addition, related medical information, such as physiological, biochemical indexes, and concomitant drugs was acquired using medical log. Sixty-five schizophrenia patients were enrollmented for analysis using population pharmacokinetic model by means of nonlinear mixed effect (NONMEM).
RESULTS
Weight and combined use of aripiprazole significantly affected olanzapine clearance. Without aripiprazole, for once-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40-70, and 70-100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40-60, and 60-100 kg schizophrenia patients, respectively. With aripiprazole, for once-daily olanzapine administration dosages, 0.4, 0.3 mg/kg/day were recommended for 40-53, and 53-100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.4 mg/kg/day was recommended for 40-100 kg schizophrenia patients, respectively.
CONCLUSION
Aripiprazole significantly affected olanzapine clearance, and when schizophrenia patients use aripiprazole, the olanzapine dosages need adjust. Meanwhile, we firstly recommended the optimal initial dosages of olanzapine in schizophrenia patients.
PubMed: 38469209
DOI: 10.2147/NDT.S455183 -
European Review For Medical and... Feb 2024Aripiprazole, risperidone, atomoxetine, and methylphenidate are drugs commonly prescribed for many psychiatric conditions and can be used alone or in combination in...
OBJECTIVE
Aripiprazole, risperidone, atomoxetine, and methylphenidate are drugs commonly prescribed for many psychiatric conditions and can be used alone or in combination in children and adolescents. This study aimed to investigate comparatively the possible genotoxic effects or genoprotective potentials of these drugs on human lymphocytes and HepG2 cells.
MATERIALS AND METHODS
Cytotoxicity analysis was performed with the cell viability test on human lymphocytes and HepG2 cells, and half-maximal inhibitory concentration (IC50) values of the drugs were determined, and three different doses (¼ IC50, ½ IC50, and IC50) were applied for genetic analysis. For the determined doses, cells with and without DNA damage were examined by comet analysis.
RESULTS
In lymphocytes, aripiprazole and risperidone increased DNA damage at moderate and maximum doses, whereas atomoxetine increased DNA damage only at the maximum dose. In HepG2 cells, risperidone reduced DNA damage at all doses, while atomoxetine increased DNA damage at all doses. On the other hand, in the DNA-damaged cells induced by hydrogen peroxide (H2O2), DNA damage decreased at all concentrations of all drugs in both lymphocytes and HepG2 cells.
CONCLUSIONS
As a result, the genotoxicity of the drugs was found to be dose-dependent, and all drugs showed a genoprotective effect on DNA-damaged cells.
Topics: Adolescent; Child; Humans; Antipsychotic Agents; Risperidone; Aripiprazole; Atomoxetine Hydrochloride; Methylphenidate; Hep G2 Cells; Hydrogen Peroxide; DNA Damage; Lymphocytes; DNA
PubMed: 38436168
DOI: 10.26355/eurrev_202402_35456 -
The Journal of Clinical Psychiatry Feb 2024Aripiprazole lauroxil (AL) 1064 mg every 2 months following initiation using the AL NanoCrystal Dispersion formulation (AL) plus 30-mg oral aripiprazole was efficacious... (Comparative Study)
Comparative Study Randomized Controlled Trial
Safety and Tolerability of Starting Aripiprazole Lauroxil With Aripiprazole Lauroxil NanoCrystal Dispersion in 1 Day Followed by Aripiprazole Lauroxil Every 2 Months Using Paliperidone Palmitate Monthly as an Active Control in Patients With Schizophrenia: A Post Hoc Analysis of a Randomized...
Aripiprazole lauroxil (AL) 1064 mg every 2 months following initiation using the AL NanoCrystal Dispersion formulation (AL) plus 30-mg oral aripiprazole was efficacious and well tolerated in a 25-week, randomized, double-blind phase 3 trial in adults with acute schizophrenia. This post hoc analysis further characterized the safety of AL 1064 mg administered every 2 months and that of active control paliperidone palmitate (PP) 156 mg monthly based on occurrence, timing, and severity of adverse events (AEs) associated with antipsychotic medications. This study was conducted between November 2017 and March 2019. AL or PP was initiated during an inpatient stay of ≥ 2 weeks with transition to outpatient treatment thereafter. Rates of AEs of clinical interest, including injection site reactions (ISRs), motor AEs, sedation, hypotension, prolactin level increase, weight gain, and suicidal ideation/behavior, were summarized through weeks 4, 9, and 25 for each treatment. Of 200 patients who received ≥ 1 dose of study treatment, 99 (49.5%) completed the study (AL, 57%; PP, 43%). Mean (SD) baseline Positive and Negative Syndrome Scale total scores were 94.1 (9.04) and 94.6 (8.41) in the AL and PP treatment groups, respectively. AEs were reported by 69/99 (70%) patients administered AL and 72/101 (71%) administered PP; most AEs were mild or moderate in severity. ISRs (AL, 18.2%; PP, 26.7%) occurred primarily on days 1 and 8. All akathisia/restlessness AEs (AL, 10.1%; PP, 11.9%) occurred during the first 4 weeks; <10% of patients (either treatment) experienced hypotension, sedation, or suicidal ideation/behavior events. Weight gain of ≥ 7% from baseline occurred in 9.3% of AL- and 23.8% of PP-treated patients. Median prolactin concentrations changed by -4.60 and -3.55 ng/mL among AL-treated males and females, respectively, and did not exceed 2 times normal levels in any AL-treated patients. In PP-treated patients, changes were 21.20 and 80.40 ng/mL and concentrations exceeded 2 times normal in 38% and 88% of males and females, respectively. No new early- or late-emerging safety concerns were observed through 25 weeks of treatment with AL 1064 mg every 2 months following initiation using AL plus 30-mg oral aripiprazole. Results were consistent with known safety profiles of AL and PP and support the safety of AL 1064 mg every 2 months initiated using AL plus 30-mg oral aripiprazole. ClinicalTrials.gov identifier: NCT03345979.
Topics: Adult; Female; Humans; Male; Antipsychotic Agents; Aripiprazole; Delayed-Action Preparations; Hypotension; Nanoparticles; Noncommunicable Diseases; Paliperidone Palmitate; Prolactin; Schizophrenia; Treatment Outcome; Weight Gain; Double-Blind Method
PubMed: 38416865
DOI: 10.4088/JCP.23m15095 -
Tongue Biting Event in Patients with Sleep-Related Facial Mandibular Myoclonus: A Case Series Study.Nature and Science of Sleep 2024Sleep-related facial mandibular myoclonus (SRFMM) remains rare in clinical practice. The aim of this study was to provide a comprehensive understanding of the...
BACKGROUND
Sleep-related facial mandibular myoclonus (SRFMM) remains rare in clinical practice. The aim of this study was to provide a comprehensive understanding of the electroclinical manner, therapeutic regimen, and prognosis of SRFMM.
METHODS
Twenty-three patients who were diagnosed with SRFMM by clinical manifestation, video-electroencephalography (EEG) and electromyography over bilateral masseter and temporalis muscles were enrolled. Clinical and electrophysiological evaluation as well as follow-up information were recorded and analyzed.
RESULTS
The cohort involved 4 infants and 19 adults with a mean onset age of 43.5 years for SRFMM, among whom 19 were male. Twenty-one patients complained of tongue injuries and disturbed night-time sleep. SRFMM in 4 patients were ascribed to oral aripiprazole, brainstem ischemia and brain trauma. In 62 SRFMM episodes, 93.5% occurred in NREM sleep and 6.5% in REM sleep, and all events were associated with EEG arousals. In 13 patients with or without clonazepam, the motor events gradually disappeared, and the rest turned to be sporadic.
CONCLUSION
SRFMM is a characteristic parasomnia manifested by tongue biting and accompanying facial mandibular myoclonus, leading to disrupted sleep. Besides adults, infants can also experience SRFMM with spontaneous remission. Most patients respond well to clonazepam, eventually with favorable prognosis.
PubMed: 38410526
DOI: 10.2147/NSS.S433628 -
Cureus Jan 2024Background Major depressive disorder (MDD) has many facets including mixed or atypical depression that requires personalized care to improve treatment-related outcomes....
Background Major depressive disorder (MDD) has many facets including mixed or atypical depression that requires personalized care to improve treatment-related outcomes. Second-generation antipsychotics (SGAs) offer complementary mechanisms for clinical roles in difficult-to-treat depression and treatment-resistant depression cases. Aim/objective To further delineate a consensus on the clinical positioning of SGAs for MDD, mixed, or atypical depression, a Knowledge Attitude Perception (KAP)-mediated Delphi Statement was planned. Material/methods A literature review for the definition, diagnosis, and management of MDD, mixed, and atypical depression as treatment-resistant depression (TRD) or difficult-to-treat depression (DTD) was conducted by a steering committee of academic and clinical experts (n=6) while developing a validated KAP questionnaire. Scientific statements as clinical recommendations were evolved using the Delphi methodology before building a clinical expert consensus with an online survey (n=24). Results Twenty-four psychiatrists highlighted DTD to offer a multidimensional approach to assess treatment strategies involving selective serotonin reuptake inhibitors (SSRIs) or SGAs, while ensuring symptom, functional, and quality of life (QoL) domain improvement for improved outcomes and remission rates. MDD cases with anxiety, anhedonia, comorbidities, and risk traits require personalized care with early induction of SGAs for severe cases or symptom persisters with functional impairment. Early augmentation with SGAs including aripiprazole or cariprazine can provide a favorable risk-benefit profile for clinical cases of MDD with or without the antecedent of mixed depression or personality disorder. Conclusion The literature review and KAP responses emphasize the importance of early identification for personalized care strategies with SGAs for DTD. Large-scale real-world evidence needs to evolve with due recognition of different phenotypes as TRD or DTD with partial or functional impairment to understand the impact of appropriate treatment pathways with SGAs.
PubMed: 38406088
DOI: 10.7759/cureus.52878