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Nature and Science of Sleep 2023Restless Legs Syndrome (RLS) is a sensorimotor disorder associated with an unpleasant urge to move the limbs, relieved with movement, occurring in the evenings and with...
PURPOSE
Restless Legs Syndrome (RLS) is a sensorimotor disorder associated with an unpleasant urge to move the limbs, relieved with movement, occurring in the evenings and with prolonged rest/inactivity. Treatment with dopamine agonists is effective for up to 60-90% of affected individuals. However, augmentation, ie, the paradoxical worsening of RLS symptoms after prolonged RLS treatment, is frequently reported, typically after 3-10 years of treatment. Here, we present 4 patients with RLS who were successfully treated with dopamine agonists but later developed augmentation. A trial of aripiprazole, a dopamine receptor partial agonist (DRPA), was initiated for treatment of augmentation symptoms.
PATIENTS AND METHODS
Four patients treated for RLS with dopamine agonists developed augmentation. In each instance, augmentation symptoms did not respond adequately to a variety of medications including α2δ drugs, opioids or other agents. A trial of aripiprazole was initiated for each patient, and effects were evaluated.
RESULTS
All four patients with severe RLS and augmentation with dopamine agonists achieved symptom control with aripiprazole. Patients endorsed 90-100% efficacy with aripiprazole by subjective self-report after failures with other agents. Further evaluation with the International Restless Legs Syndrome Study Group RLS Rating Scale (IRLS-SGRS) showed that benefits (from moderate to very severe, to mild to moderate severity) were largely maintained for 1-2 years. Aripiprazole doses to control augmentation symptoms were low (1-4 mg). No significant side effects were reported.
CONCLUSION
Aripiprazole may have utility for augmentation in RLS. We speculate that the partial agonist and antagonist properties of aripiprazole may limit potential for dopamine hyposensitization to progress to cause augmentation. Further research is needed to see if aripiprazole and/or other DRPAs are a viable long-term treatment option for patients experiencing augmentation and/or severe RLS with dopamine agonist therapy.
PubMed: 37818170
DOI: 10.2147/NSS.S421189 -
Schizophrenia (Heidelberg, Germany) Jan 2024Autonomic adverse effects of antipsychotic drugs (APs) cause clinical challenges, but few studies have investigated sex differences and their underlying biological...
Autonomic adverse effects of antipsychotic drugs (APs) cause clinical challenges, but few studies have investigated sex differences and their underlying biological pathways. Sex-specific regulation of relevant hormones could be involved. We investigated sex differences in autonomic adverse effects related to olanzapine, quetiapine, risperidone, and aripiprazole, and the role of hormones related to APs. Patients with severe mental disorders (N = 1318) were included and grouped based on AP monotherapy: olanzapine (N = 364), quetiapine (N = 211), risperidone (N = 102), aripiprazole (N = 138), and no AP (N = 503). Autonomic symptoms from the Udvalg for Kliniske Undersøgelser (UKU) side effect scale was analyzed with logistic regression, adjusting for age, diagnosis, and polypharmacy. Further, we analyzed associations between autonomic symptoms and hormones related to APs. We found associations between autonomic adverse effects and APs, with sex-specific risk for palpitations/tachycardia associated with hormonal changes related to APs. Results showed increased salivation associated with aripiprazole, reduced salivation with quetiapine, and nausea/vomiting and palpitations/tachycardia with olanzapine, and higher risk of nausea/vomiting, diarrhea, constipation, polyuria/polydipsia, and palpitations/tachycardia in females. Significant sex x AP interaction was found for palpitations/tachycardia, with higher risk in risperidone-treated males, which was associated with different hormone profiles of prolactin, cortisol, and insulin. Our findings implicate a role of several hormones in the sex-specific autonomic adverse effects related to APs.
PubMed: 38182592
DOI: 10.1038/s41537-023-00430-4 -
Medicina (Kaunas, Lithuania) Dec 2023: Aripiprazole (APZ), an atypical antipsychotic, is mainly prescribed for conditions such as schizophrenia and bipolar disorder, while ongoing research indicates...
: Aripiprazole (APZ), an atypical antipsychotic, is mainly prescribed for conditions such as schizophrenia and bipolar disorder, while ongoing research indicates promising neuroprotective qualities. APZ's mechanism of action, involving the regulation of neurotransmitter levels, appears to contribute to its potential to shield neural tissues from specific forms of harm and degeneration. : To investigate its neuroprotective mechanisms, groups of rats were orally administered APZ at 1 or 2 mg/kg once daily for a 30-day period. In addition, neuronal toxicity was induced through intraperitoneal injection of four doses of lipopolysaccharide (LPS) at a concentration of 1 mg/kg. To evaluate cognitive function, particularly, short-term recognition memory, the procedure implemented the novel object recognition (NOR) task. Subsequently, brain tissues were gathered to examine markers linked with neuroinflammation, oxidative stress, and apoptosis. : The administration of LPS led to a decline in memory performance during the NOR tasks. Simultaneously, this LPS treatment raised inflammatory markers like cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, and nuclear factor kappa B (NF-κB), increased oxidative markers such as malondialdehyde (MDA), and triggered apoptosis markers like Caspase-3 and Bcl2 associated X protein (Bax) within the brain. Furthermore, it decreased levels of antioxidants like reduced glutathione (GSH) and catalase, as well as the anti-apoptotic marker B-cell lymphoma (Bcl)-2 in brain tissue. The use of APZ resulted in enhanced recognition memory performance, as indicated by improved exploration and discrimination abilities of the objects in the NOR task. Moreover, APZ lowered the markers associated with neuronal vulnerability, such as COX-2, NF-κB, MDA, Caspase-3, and Bax. Additionally, it increased the levels of protective markers, including GSH, catalase, and Bcl-2 in LPS-challenged brains. : In summary, the findings suggest that APZ exhibits protective properties against neuronal inflammation, oxidative stress, and apoptosis markers in the context of inflammatory-related neurodegeneration. Additional in-depth investigations are needed to further explore potential applications.
Topics: Animals; Rats; Aripiprazole; Lipopolysaccharides; bcl-2-Associated X Protein; Caspase 3; Catalase; NF-kappa B; Cognitive Dysfunction; Oxidative Stress; Inflammation; Apoptosis; Cyclooxygenase 2
PubMed: 38256307
DOI: 10.3390/medicina60010046 -
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 -
Child and Adolescent Psychiatry and... Jun 2024Global antipsychotic usage, including off-label prescriptions, has increased in recent decades. However, trends in China, particularly for children and adolescents,...
BACKGROUND
Global antipsychotic usage, including off-label prescriptions, has increased in recent decades. However, trends in China, particularly for children and adolescents, remain unclear. This study explored these trends from 2016 to 2021 and identified factors associated with off-label prescriptions.
METHODS
In this retrospective study, we analyzed on-label and off-label prescriptions based on drug information approved by the China National Medical Products Administration. To identify factors associated with off-label prescriptions, we conducted multivariate logistic regression analysis.
RESULTS
Our study included 48,258 antipsychotic prescriptions, 52.4% (25,295) of which were prescriptions for males. Of these, 61.7% (29,813) were off-label. Over time, the number of antipsychotics and the percentage of off-label prescriptions for children and adolescents overall increased from 2016 to 2021. The use of atypical antipsychotics increased, whereas that of typical antipsychotics decreased. For off-label usage, all of the factors in our study were associated with off-label usage, including age, sex, year, region, department, reimbursement, antipsychotic type, drug expense, number of polypharmacy and diagnoses. Additionally, tiapride (15.8%) and aripiprazole (18.6%) were the most common typical and atypical antipsychotics, respectively. For pediatric diseases, common diagnoses included mood or affective disorders (31.7%) and behavioral and emotional disorders, with onset usually occurring in childhood and adolescence (29.1%). Furthermore, a depressive state was the most common diagnosis for which antipsychotic polypharmacy was used for treatment.
CONCLUSION
In this retrospective study, off-label antipsychotic prescriptions were common, with trends generally increasing among children and adolescents from 2016 to 2021. However, there is a lack of evidence supporting off-label usage, thus emphasizing the need for studies on the efficacy and safety of these treatments.
PubMed: 38907356
DOI: 10.1186/s13034-024-00766-4 -
ELife Apr 2024Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic...
Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic drugs are a class of small molecules with relatively broad binding affinity for a variety of neuromodulator receptors that, in humans, can prevent or ameliorate psychosis. How these drugs influence the function of cortical circuits, and in particular their ability to distinguish between externally and self-generated activity patterns, is still largely unclear. To have experimental control over self-generated sensory feedback, we used a virtual reality environment in which the coupling between movement and visual feedback can be altered. We then used widefield calcium imaging to determine the cell type-specific functional effects of antipsychotic drugs in mouse dorsal cortex under different conditions of visuomotor coupling. By comparing cell type-specific activation patterns between locomotion onsets that were experimentally coupled to self-generated visual feedback and locomotion onsets that were not coupled, we show that deep cortical layers were differentially activated in these two conditions. We then show that the antipsychotic drug clozapine disrupted visuomotor integration at locomotion onsets also primarily in deep cortical layers. Given that one of the key components of visuomotor integration in cortex is long-range cortico-cortical connections, we tested whether the effect of clozapine was detectable in the correlation structure of activity patterns across dorsal cortex. We found that clozapine as well as two other antipsychotic drugs, aripiprazole and haloperidol, resulted in a strong reduction in correlations of layer 5 activity between cortical areas and impaired the spread of visuomotor prediction errors generated in visual cortex. Our results are consistent with the interpretation that a major functional effect of antipsychotic drugs is a selective alteration of long-range layer 5-mediated communication.
Topics: Humans; Animals; Mice; Antipsychotic Agents; Clozapine; Haloperidol; Brain; Aripiprazole
PubMed: 38578678
DOI: 10.7554/eLife.86805 -
Cureus Nov 2023Oculogyric crisis (OGC) is a rare type of acute dystonia characterized by spasmodic upward deviation of the eyes lasting for a few minutes to several hours. It is...
Oculogyric crisis (OGC) is a rare type of acute dystonia characterized by spasmodic upward deviation of the eyes lasting for a few minutes to several hours. It is commonly seen with the administration of first-generation antipsychotics and rarely reported in patients taking second-generation antipsychotics. Although aripiprazole, a second-generation antipsychotic, is known for its low potential for extrapyramidal side effects (EPS), there are multiple case reports of it resulting in acute dystonia, especially OGC. In this paper, we report a case of aripiprazole-induced OGC in a 16-year-old female patient after a suicide attempt by taking 40 mg of aripiprazole and 5 g of acetaminophen. The necessary investigations were ordered, and the patient's dystonic symptoms resolved completely after administering parenteral diazepam and benztropine.
PubMed: 38054149
DOI: 10.7759/cureus.48267 -
JMIR Formative Research Dec 2023Wearable sensors in digital health may pose a risk for skin irritation through the use of wearable patches. Little is known about how patient- and product-related...
BACKGROUND
Wearable sensors in digital health may pose a risk for skin irritation through the use of wearable patches. Little is known about how patient- and product-related factors impact the risk of skin irritation. Aripiprazole tablets with sensor (AS, Abilify MyCite; Otsuka America Pharmaceutical, Inc) is a digital medicine system indicated for the treatment of patients with schizophrenia, bipolar I disorder, and major depressive disorder. AS includes aripiprazole tablets with an embedded ingestible event marker, a wearable sensor attached to the skin through a wearable patch, a smartphone app, and a web-based portal. To continuously improve the final product, successive iterations of wearable patches were developed, including raisin patch version 4 (RP4), followed by disposable wearable sensor version 5 (DW5), and then reusable wearable sensor version 2 (RW2).
OBJECTIVE
This analysis pooled safety data from clinical studies in adult participants using the RP4, DW5, and RW2 wearable patches of AS and evaluated adverse events related to the use of wearable patches.
METHODS
Safety data from 12 studies in adults aged 18-65 years from May 2010 to August 2020 were analyzed. All studies evaluated safety, with studies less than 2 weeks also specifically examining human factors associated with the use of the components of AS. Healthy volunteers or patients with schizophrenia, bipolar I disorder, or major depressive disorder were enrolled; those who were exposed to at least 1 wearable patch were included in the safety analysis. Adverse events related to the use of a wearable patch were evaluated. Abrasions, blisters, dermatitis, discoloration, erythema, irritation, pain, pruritus, rash, and skin reactions were grouped as skin irritation events (SIEs). All statistical analyses were descriptive.
RESULTS
The analysis included 763 participants (mean [SD] age 42.6 [12.9] years; White: n=359, 47.1%; and male: n=420, 55%). Participants were healthy volunteers (n=269, 35.3%) or patients with schizophrenia (n=402, 52.7%), bipolar I disorder (n=57, 7.5%), or major depressive disorder (n=35, 4.6%). Overall, 13.6% (104/763) of the participants reported at least 1 SIE, all of which were localized to the wearable patch site. Incidence of ≥1 patch-related SIEs was seen in 18.1% (28/155), 14.2% (55/387), and 9.2% (28/306) of participants who used RP4, DW5, and RW2, respectively. Incidence of SIE-related treatment discontinuation was low, which is reported by 1.9% (3/155), 3.1% (12/387), and 1.3% (4/306) of participants who used RP4, DW5, and RW2, respectively.
CONCLUSIONS
The incidence rates of SIEs reported as the wearable patch versions evolved from RP4 through RW2 suggest that information derived from reported adverse events may have informed product design and development, which could have improved both tolerability and wearability of successive products.
TRIAL REGISTRATION
Clinicaltrials.gov NCT02091882, https://clinicaltrials.gov/study/NCT02091882; Clinicaltrials.gov NCT02404532, https://clinicaltrials.gov/study/NCT02404532; Clinicaltrials.gov NCT02722967, https://clinicaltrials.gov/study/NCT02722967; Clinicaltrials.gov NCT02219009, https://clinicaltrials.gov/study/NCT02219009; Clinicaltrials.gov NCT03568500, https://clinicaltrials.gov/study/NCT03568500; Clinicaltrials.gov NCT03892889, https://clinicaltrials.gov/study/NCT03892889.
PubMed: 38085556
DOI: 10.2196/44768 -
The Lancet. Child & Adolescent Health Jul 2024The degree of physiological responses to individual antipsychotic drugs is unclear in children and adolescents. With network meta-analysis, we aimed to investigate the... (Meta-Analysis)
Meta-Analysis Comparative Study
BACKGROUND
The degree of physiological responses to individual antipsychotic drugs is unclear in children and adolescents. With network meta-analysis, we aimed to investigate the effects of various antipsychotic medications on physiological variables in children and adolescents with neuropsychiatric and neurodevelopmental conditions.
METHODS
For this network meta-analysis, we searched Medline, EMBASE, PsycINFO, Web of Science, and Scopus from database inception until Dec 22, 2023, and included randomised controlled trials comparing antipsychotics with placebo in children or adolescents younger than 18 years with any neuropsychiatric and neurodevelopmental condition. Primary outcomes were mean change from baseline to end of acute treatment in bodyweight, BMI, fasting glucose, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, prolactin, heart rate, systolic blood pressure (SBP), and QT interval corrected for heart rate (QTc) for patients receiving either active treatment or placebo. For multigroup trials reporting several doses, we calculated a summary value for each physiological variable for all doses. After transitivity assessment, we fitted frequentist random-effects network meta-analyses for all comparisons in the network. A Kilim plot was used to summarise the results for all treatments and outcomes, providing information regarding the strength of the statistical evidence of treatment effects, using p values. Network heterogeneity was assessed with τ, risk of bias of individual trials was assessed with the Cochrane Collaboration's Tool for Assessing Risk of Bias, and the credibility of findings from each network meta-analysis was assessed with the Confidence in Network Meta-Analysis (CINEMA) app. This study is registered on PROSPERO (CRD42021274393).
FINDINGS
Of 6676 studies screened, 47 randomised controlled trials were included, which included 6500 children (mean age 13·29 years, SD 2·14) who received treatment for a median of 7 weeks (IQR 6-8) with either placebo (n=2134) or one of aripiprazole, asenapine, blonanserin, clozapine, haloperidol, lurasidone, molindone, olanzapine, paliperidone, pimozide, quetiapine, risperidone, or ziprasidone (n=4366). Mean differences for bodyweight change gain compared with placebo ranged from -2·00 kg (95% CI -3·61 to -0·39) with molindone to 5·60 kg (0·27 to 10·94) with haloperidol; BMI -0·70 kg/m (-1·21 to -0·19) with molindone to 2·03 kg/m (0·51 to 3·55) with quetiapine; total cholesterol -0·04 mmol/L (-0·39 to 0·31) with blonanserin to 0·35 mmol/L (0·17 to 0·53) with quetiapine; LDL cholesterol -0·12 mmol/L (-0·31 to 0·07) with risperidone or paliperidone to 0·17 mmol/L (-0·06 to 0·40) with olanzapine; HDL cholesterol 0·05 mmol/L (-0·19 to 0·30) with quetiapine to 0·48 mmol/L (0·18 to 0·78) with risperidone or paliperidone; triglycerides -0·03 mmol/L (-0·12 to 0·06) with lurasidone to 0·29 mmol/L (0·14 to 0·44) with olanzapine; fasting glucose from -0·09 mmol/L (-1·45 to 1·28) with blonanserin to 0·74 mmol/L (0·04 to 1·43) with quetiapine; prolactin from -2·83 ng/mL (-8·42 to 2·75) with aripiprazole to 26·40 ng/mL (21·13 to 31·67) with risperidone or paliperidone; heart rate from -0·20 bpm (-8·11 to 7·71) with ziprasidone to 12·42 bpm (3·83 to 21·01) with quetiapine; SBP from -3·40 mm Hg (-6·25 to -0·55) with ziprasidone to 10·04 mm Hg (5·56 to 14·51) with quetiapine; QTc from -0·61 ms (-1·47 to 0·26) with pimozide to 0·30 ms (-0·05 to 0·65) with ziprasidone.
INTERPRETATION
Children and adolescents show varied but clinically significant physiological responses to individual antipsychotic drugs. Treatment guidelines for children and adolescents with a range of neuropsychiatric and neurodevelopmental conditions should be updated to reflect each antipsychotic drug's distinct profile for associated metabolic changes, alterations in prolactin, and haemodynamic alterations.
FUNDING
UK Academy of Medical Sciences, Brain and Behaviour Research Foundation, UK National Institute of Health Research, Maudsley Charity, the Wellcome Trust, Medical Research Council, National Institute of Health and Care Research Biomedical Centre at King's College London and South London and Maudsley NHS Foundation Trust, the Italian Ministry of University and Research, the Italian National Recovery and Resilience Plan, and Swiss National Science Foundation.
Topics: Humans; Antipsychotic Agents; Child; Adolescent; Network Meta-Analysis; Randomized Controlled Trials as Topic; Mental Disorders; Heart Rate; Blood Pressure
PubMed: 38897716
DOI: 10.1016/S2352-4642(24)00098-1 -
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