A Historical Overview of the Role of Benzodiazepines including Clonazepam in the Treatment of Adult Restless Legs Syndrome and Periodic Limb Movements in Sleep.

In a recent survey of 16,694 people receiving treatment for Restless Legs Syndrome (RLS), approximately 25% were treated with benzodiazepines either singly or in combination with other RLS treatments. Because of the large number of people receiving benzodiazepines for treatment of RLS, we conducted a historical overview of the therapeutic role of benzodiazepines in RLS and its associated condition Periodic Limb Movements in Sleep (PLMS). We found 17 articles on the use of clonazepam in RLS, PLMS, or both, 3 on triazolam and PLMS, 1 on alprazolam and RLS, 1 on temazepam and PLMS, and 1 on nitrazepam and PLMS. The order of benefit of benzodiazepines from the summarized literature is Sleep>RLS>PLMS and arousals > PLMS. Most of the studies on clonazepam employed dosages of 0.5-2.0 mg. Dosages of 3 or 4 mg caused lethargy, somnolence and confusion. An epidemiological study on the therapy of RLS suggests that treatment of RLS with most types of RLS medications including benzodiazepines in combination with other RLS therapies lowers the future cardiovascular risk associated with RLS. The major effect of benzodiazepines is through potentiation of the effect of GABA on the GABA A receptor. Neuroimaging studies suggest that GABA is altered either positively or negatively in various brain regions in RLS and genetic studies suggest that there are alterations in the GABA receptor in RLS. These results suggest that medications with different GABAergic mechanisms such as tiagabine (Gabitril) or others should be investigated in RLS for their possible therapeutic benefit. Highlights: Benzodiazepines are frequently used as therapy in Restless Legs Syndrome (RLS) and Periodic Limb Movements in Sleep. The order of benefit is Sleep>RLS>PLMS and arousals > PLMS. For clonazepam dosages of 0.5 mg-2.0 mg/day are most frequently employed. Benzodiazepines exert their therapeutic effect through GABA-ergic mechanisms.

Cerebrotendinous xanthomatosis with tremor as the main manifestation: A case report.

INTRODUCTION: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid metabolism disorder. It is caused by a defect in the sterol-27-hydroxylase gene, leading to the deposition of cholesteryl and bile alcohol in large amounts, causing a variety of clinical manifestations; however, tremor as the main manifestation of CTX has not been reported. PATIENTS CONCERNS AND CLINICAL FINDINGS: Herein, we report a 27-year-old woman, who developed head and body tremors at the age of 12 years. Many hospitals misdiagnosed her condition as idiopathic tremor and Parkinson disease, with a poor curative effect. PRIMARY DIAGNOSIS AND INTERVENTION: We diagnosed her with CTX and treated with chenodeoxycholic acid and clonazepam. CONCLUSION: The patient's condition considerably improved. This case could help avoid misdiagnosis and mistreatment in clinical practice.

The effective perospirone augmentation with clonazepam for treatment-resistant burning mouth syndrome: A case report.

Burning mouth syndrome (BMS) is characterized by burning sensations in the oral region without corresponding abnormalities and is often accompanied by uncomfortable sensations. Herein, we present cases of BMS in which the remaining uncomfortable sensations improved with perospirone augmentation with clonazepam. Case 1: A 61-year-old man complained of a burning pain in his tongue, a sensation of dryness and discomfort as if his tongue was sticking to a palatal plate. With the diagnosis of BMS, psychopharmacotherapy was initiated with amitriptyline. At the dose of amitriptyline 50 mg, the pain lessened but uncomfortable sensations persisted. Further attempts to alleviate symptoms by combining aripiprazole with amitriptyline, aripiprazole with mirtazapine, or aripiprazole with clonazepam were limited; however, nearly all symptoms were relieved by a combination of perospirone 8.0 mg with clonazepam 1.5 mg. Case 2: A 51-year-old woman complained of a burning sensation along with oral dryness and crumb-like feeling on her tongue. She was diagnosed with BMS and began treatment with amitriptyline. Her burning sensation improved at the dose of 25 mg, but uncomfortable sensations persisted. Augmentation of amitriptyline with aripiprazole, aripiprazole either with valproate, mirtazapine, or clonazepam failed to produce a significant improvement. However, a regimen of perospirone 6.0 mg and clonazepam 1.5 mg relieved the crumb-like sensation and pain and culminated in a stabilized condition. The reported cases suggested that multiple approaches targeting the dopaminergic circuit in basal ganglia involving the serotoninergic and GABA systems, through the administration of perospirone with clonazepam is an effective adjunctive treatment for the remaining uncomfortable sensations in patients with BMS.

Polysomnographic features associated with clonazepam and melatonin treatment in isolated REM sleep behavior disorder: Time for new therapeutic approaches?

AIMS: Although clonazepam (CLO) and melatonin (MLT) are the most frequently used treatments for REM sleep behavior disorder, the polysomnographic features associated with their use are little known. The aim of this study was to evaluate polysomnographic and clinical parameters of patients with idiopathic/isolated REM sleep behavior disorder (iRBD) treated chronically with CLO, sustained-release MLT, alone or in combination, and in a group of drug-free iRBD patients. METHODS: A total of 96 patients were enrolled: 43 drug-free, 21 with CLO (0.5-2 mg), 20 with sustained-release MLT (1-4 mg), and 12 taking a combination of them (same doses). Clinical variables and polysomnography were collected. RESULTS: Although clinical improvement was reported in all groups, MLT impacted sleep architecture more than the other treatments, with significant and large increase in N3 stage, moderate reduction in N2 and REM sleep, and moderate increase in REM latency. CLO moderately increased the percentage of both REM sleep and especially N2, while reducing N1 and wakefulness. Patients treated with both CLO and MLT did not show major changes in sleep architecture. CONCLUSION: These results suggest that the administration of MLT or CLO impacts (positively) on sleep parameters of iRBD patients. However, there is a need to better stratify patients, in order to treat them in a targeted manner, depending on the patient's individual sleep architecture and expected differential effects of these agents.

Seizure control and complications in patients switching from clobazam to clonazepam due to drug shortage.

BACKGROUND: Antiseizure medication (ASM) shortages are a global problem that have a negative impact on outcomes such as seizure control in patients with epilepsy (PWE). In the case of clobazam (CLB) shortage, there is no study regarding the management strategy. This study aims to investigate the alteration in seizure frequency and the occurrence of side effects in PWE undergoing an abrupt switch from clobazam (CLB) to clonazepam (CLZ), during CLB shortage. MATERIAL AND METHODS: A retrospective study was conducted from electronic health records at our neurology outpatient clinic from January to July 2022. Change in seizure frequency and percentage of CLZ-associated side effects were determined as primary and secondary outcomes, respectively. Potential drug-drug interactions (Level C and above) were evaluated by using Lexicomp Drug Interaction Checker. RESULTS: The analysis included a total of 29 adult patients (15F, median age: 29). The switching ratio was 10 mg CLB for every 1 mg CLZ (10:1). Seizure frequency was higher during the CLZ period compared to the CLB period (p < 0.05), but no status epilepticus cases were observed. All patients exhibited potential drug-drug interactions, leading to reduced CLZ levels in 12 cases. A total of 36 CLZ-associated side effects were identified, with fatigue (19.4 %), drowsiness (16.6 %), and somnolence (13.8 %) being the most prevalent. A positive and strong correlation was found between CLZ dose and the number of side effects (r: 0.556; p: 0.002). CONCLUSION: The abrupt switch from CLB to CLZ was observed to increase seizure frequency without leading to status epilepticus in PWE. CLZ-associated side effects were found to be tolerable despite the abrupt switch. Future studies may explore the effect of alternative switching ratios.

Mitochondrial sodium/calcium exchanger (NCLX) regulates basal and starvation-induced autophagy through calcium signaling.

Mitochondria shape intracellular Ca2+ signaling through the concerted activity of Ca2+ uptake via mitochondrial calcium uniporters and efflux by Na+ /Ca2+ exchangers (NCLX). Here, we describe a novel relationship among NCLX, intracellular Ca2+ , and autophagic activity. Conditions that stimulate autophagy in vivo and in vitro, such as caloric restriction and nutrient deprivation, upregulate NCLX expression in hepatic tissue and cells. Conversely, knockdown of NCLX impairs basal and starvation-induced autophagy. Similarly, acute inhibition of NCLX activity by CGP 37157 affects bulk and endoplasmic reticulum autophagy (ER-phagy) without significant impacts on mitophagy. Mechanistically, CGP 37157 inhibited the formation of FIP200 puncta and downstream autophagosome biogenesis. Inhibition of NCLX caused decreased cytosolic Ca2+ levels, and intracellular Ca2+ chelation similarly suppressed autophagy. Furthermore, chelation did not exhibit an additive effect on NCLX inhibition of autophagy, demonstrating that mitochondrial Ca2+ efflux regulates autophagy through the modulation of Ca2+ signaling. Collectively, our results show that the mitochondrial Ca2+ extrusion pathway through NCLX is an important regulatory node linking nutrient restriction and autophagy regulation.

Rapid Eye Movement Sleep Behavior Disorder: Management and Prognostic Counseling.

Management of rapid eye movement sleep behavior disorder (RBD) includes reducing injurious dream-enactment behaviors, risk of injury to self and bedpartner, and vivid or disruptive dreams and improving sleep quality and bedpartner sleep disruption. Safety precautions should be reviewed at each visit. Medications to reduce RBD symptoms such as melatonin, clonazepam, pramipexole, and rivastigmine should be considered for most patients. Isolated RBD confers a high lifetime risk of neurodegenerative diseases with a latency often spanning many years. A patient-centered shared decision-making approach to risk disclosure is recommended. Knowledge of the risk allows for life planning and participation in research.

The teratogenesis risk associated with antiseizure medication duotherapy in women with epilepsy.

PURPOSE: To investigate rates of occurrence of pregnancies associated with a foetal malformation (FM pregnancy rates) following simultaneous intrauterine exposure to two antiseizure medications in 524 pregnancies in women with epilepsy from the Australian Pregnancy Register who were treated simultaneously with various combinations and dosages of two antiseizure medications (duotherapy). RESULTS: FM pregnancy rates tended to be higher in those exposed simultaneously to two antiseizure medications, each of which was a statistically significant teratogen (valproate, topiramate, or carbamazepine), than when there was exposure to only one such teratogen. When there was exposure to only one such teratogen together with clonazepam or levetiracetam, for neither of which there was statistically significant evidence of heightened teratogenicity, the FM pregnancy rates also tended to be higher, but less so. When lamotrigine was the other component of the duotherapy with an established teratogen, FM pregnancy rates tended to be lower than that for the teratogen used as monotherapy. CONCLUSION: Leaving aside issues in relation to seizure control, our data suggest that it would be best to avoid using established teratogenic antiseizure medications (carbamazepine, valproate and topiramate) in combination with each other due to the increased FM risks. When combining an established teratogenic medication with a less teratogenic one, i.e. lamotrigine, levetiracetam or clonazepam, lamotrigine appears to be the safer option.

Treatment of high dose of intravenous midazolam abuse: a case report.

This study reports a rare case of high-dose midazolam abuse and Munchausen Syndrome. A 48-year-old female physician was referred by a psychiatrist to the Toxicology Department of Imam Reza Hospital for abstaining from 300 mg/day of parenteral midazolam. She had mimicked the symptoms of Crohn's disease; therefore, she had undergone 15 colonoscopies and 40 times MRI or CT scan, all of which were normal. Six months earlier, she had switched oral methadone to 30 mg/day of intravenous midazolam. She also had several skin lesions on injection sites that she considered pyoderma gangrenosum. When the total daily dose of intravenous midazolam was switched to oral bioequivalence of clonazepam, she could not tolerate withdrawal (Clinical Institute Withdrawal Assessment Scale-Benzodiazepines = 68). Therefore, she received midazolam again as a continuous intravenous infusion. Within 7 days, the whole dose was replaced by the bioequivalence oral dose of clonazepam. She was also treated with carbamazepine and cognitive behavior therapy. Afterward, she was transferred to the psychiatric ward for further psychiatric treatment. Dependency on a high dose of midazolam could be treated by tapering off the long-acting benzodiazepine.

The anthelmintic meclonazepam activates a schistosome transient receptor potential channel.

Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago. New drugs are urgently needed, as while PZQ is broadly effective it suffers from several limitations including poor efficacy against juvenile worms, which may prevent it from being completely curative. An old compound that retains efficacy against juvenile worms is the benzodiazepine meclonazepam (MCLZ). However, host side effects caused by benzodiazepines preclude development of MCLZ as a drug and MCLZ lacks an identified parasite target to catalyze rational drug design for engineering out human host activity. Here, we identify a transient receptor potential ion channel of the melastatin subfamily, named TRPMMCLZ, as a parasite target of MCLZ. MCLZ potently activates Schistosoma mansoni TRPMMCLZ through engagement of a binding pocket within the voltage-sensor-like domain of the ion channel to cause worm paralysis, tissue depolarization, and surface damage. TRPMMCLZ reproduces all known features of MCLZ action on schistosomes, including a lower activity versus Schistosoma japonicum, which is explained by a polymorphism within this voltage-sensor-like domain-binding pocket. TRPMMCLZ is distinct from the TRP channel targeted by PZQ (TRPMPZQ), with both anthelmintic chemotypes targeting unique parasite TRPM paralogs. This advances TRPMMCLZ as a novel druggable target that could circumvent any target-based resistance emerging in response to current mass drug administration campaigns centered on PZQ.

A case of prazosin in treatment of rapid eye movement sleep behavior disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dream-enactment behaviors that emerge during a loss of REM sleep atonia. Untreated RBD carries risks for physical injury from falls or other traumatic events during dream enactment as well as risk of injury to the bed partner. Currently, melatonin and clonazepam are the mainstay pharmacological therapies for RBD. However, therapeutic response to these medications is variable. While older adults are most vulnerable to RBD, they are also particularly vulnerable to the adverse effects of benzodiazepines, including increased risk of falls, cognitive impairment, and increased risk of Alzheimer disease. Prazosin is a centrally active alpha-1 adrenergic receptor antagonist often prescribed for trauma nightmares characterized by REM sleep without atonia in patients with posttraumatic stress disorder. We report a case of successful RBD management with prazosin in a patient in whom high-dose melatonin was ineffective. Although there was no observable reduction in dream-enactment behaviors with high-dose melatonin, the possibility of a synergistic effect of prazosin combined with melatonin cannot be ruled out. This case report supports further evaluation of prazosin as a potential therapeutic for RBD. CITATION: Cho Y, Iliff JJ, Lim MM, Raskind M, Peskind E. A case of prazosin in treatment of rapid eye movement sleep behavior disorder. J Clin Sleep Med. 2024;20(2):319-321.

A Strategy for Rescuing a Child From Clonazepam Poisoning: A Case Study.

BACKGROUND: This report describes the successful rescue of a 12-year-old girl who ingested large quantities of clonazepam tablets. METHODS: The patient was promptly treated with flumazenil and hemoperfusion to alleviate the symptoms of central depression. Therapeutic drug monitoring was used to evaluate detoxification efficacy. The authors analyzed the rescue protocol for clonazepam poisoning based on the pathophysiology, clinical manifestations, and pharmacokinetics of clonazepam overdose. RESULTS: The patient responded well to the treatment and was discharged from the hospital without adverse events. CONCLUSIONS: This case study demonstrated the effectiveness and safety of combining flumazenil with hemoperfusion as a treatment for clonazepam poisoning. This study aimed to provide insights into more effective methods for treating clonazepam overdose and contribute to the ongoing issue of managing this condition.

Effectiveness of High-dose Clonazepam Versus Low-Dose Clonazepam With Cognitive Behavioral Therapy in Older Adults With Moderately Severe Insomnia: A Prospective Cohort Study.

PURPOSE: To evaluate the effectiveness of high-dose clonazepam (1 mg) versus low-dose clonazepam (0.5 mg) with cognitive behavioral therapy for insomnia (CBT-i) in older adults with moderately severe insomnia. METHODS: A prospective cohort study was conducted in patients who did not respond to low-dose clonazepam for insomnia secondary to chronic medical conditions. After starting with 0.25 mg of clonazepam, their dose was increased to 0.5 mg, then to 1 mg (Group A), or to the same dose with additional CBT-i (Group B). They were followed for 24 weeks, and scores of the insomnia severity index (ISI) and subjective units of distress scale (SUDS) were recorded. Patient adverse drug reactions (ADRs) were documented and assessed for their causality. ISI and SUDS scores were considered primary outcome measures. FINDINGS: Between-group analysis revealed a significant decline in the mean score of ISI at week 16 (P < 0.05) and for SUDS at week 20 (P < 0.05) in group B compared to group A. Similarly, within-group analysis also revealed a statistically significant reduction of the mean score in ISI and SUDS scores at week 4 and 8 (P < 0.05) in both groups. ADRs occurred more frequently in group A (14%) than in group B (5%). Assessments of causality showed that the majority of cases were possible. IMPLICATIONS: For individuals who were resistant to 0.5 mg of clonazepam, adding CBT-i with low-dose clonazepam is a viable alternative to increasing the dose to 1 mg.

A rare case of tongue biting during sleep in childhood.

Bleeding tongue-biting episodes during sleep are a rare and alarming situation that can negatively impact the child's and parents' sleep, affecting their quality of life. Although highly suggestive of epilepsy, a differential diagnosis should be made with sleep-related movement disorders such as bruxism, hypnic myoclonus, facio-mandibular myoclonus, and geniospasm when this hypothesis is excluded. The clinical history, electroencephalogram, and video-polysomnography are essential for diagnostic assessment. Treatment with clonazepam can be necessary in the presence of frequent tongue biting that causes severe injuries and sleep disturbance. This study reports the challenging case of managing and diagnosing a 2-year-old boy with recurrent tongue biting during sleep since he was 12 months old, causing bleeding lacerations, frequent awakenings, and significant sleep impairment with daytime consequences for him and his family. CITATION: Cascais I, Ashworth J, Ribeiro L, Freitas J, Rios M. A rare case of tongue biting during sleep in childhood. J Clin Sleep Med. 2024;20(4):653-656.

Implicaciones de iniciar fármacos antiepilépticos previo a la realización de EEG en primeras crisis epilépticas / Implications of initiating antiseizure drugs prior to the performance of EEG in first epileptic seizures

Introducción: Determinar si la administración de fármacos antiepilépticos (FAE) puede alterar la probabilidad de encontrar anomalías epileptiformes en EEG realizados de forma precoz tras una primera crisis epiléptica (CE). Método: Estudio observacional retrospectivo en el que se incluyó a los pacientes atendidos en urgencias de nuestro centro por una primera CE entre julio del 2014 y noviembre del 2019. Se recogieron los datos clínicos, las características técnicas de adquisición e interpretación de los EEG efectuados durante las primeras 72 h tras la CE y los factores relacionados con la recurrencia. Resultados: Se recogieron 155 pacientes; edad media 48,6 ±22,5 años; 61,3% hombres. El 51% presentó crisis tónico-clónicas de inicio desconocido y el 12% focales con progresión a tónico-clónica bilateral. El 25,2% (39/155) recibió tratamiento con FAE antes de la realización del EEG; en 33 pacientes se administró un FAE no benzodiacepínico y en 6 una benzodiacepina. Se observaron anomalías epileptiformes en 29,7% de los pacientes. La administración previa de FAE no se asoció de forma significativa ni con la probabilidad de detectar anomalías epileptiformes (p = 0,25) ni con el riesgo de recurrencia a los 6 meses (p = 0,63). Conclusiones: La administración de un FAE previo a la realización del EEG precoz tras una primera CE no disminuye la probabilidad de detectar anomalías epileptiformes. Estos hallazgos sugieren que iniciar un FAE de forma inmediata en aquellos pacientes con alto riesgo de recurrencia precoz no implica un menor rendimiento diagnóstico de dicha prueba.(AU)

Introduction: This study aimed to determine whether the administration of antiepileptic drugs (AED) alters the likelihood of detecting epileptiform abnormalities in electroencephalographies (EEG) performed early after a first epileptic seizure. Method: We performed a retrospective, observational study including patients with a first seizure attended at our centre's emergency department between July 2014 and November 2019. We collected clinical data, as well as technical data on the acquisition and interpretation of the EEG performed within the first 72 hours after the seizure, and the factors related with seizure recurrence. Results: We recruited 155 patients with a mean (SD) age of 48.6 (22.5) years; 61.3% were men. Regarding seizure type, 51% presented tonic-clonic seizures of unknown onset and 12% presented focal to bilateral tonic-clonic seizures. Thirty-nine patients (25.2%) received AED treatment before the EEG was performed: 33 received a non-benzodiazepine AED and 6 received a benzodiazepine. Epileptiform abnormalities were observed in 29.7% of patients. Previous administration of AEDs was not significantly associated with the probability of detecting interictal epileptiform abnormalities (P=.25) or with the risk of recurrence within 6 months (P=.63). Conclusions: Administration of AEDs before an early EEG following a first seizure does not decrease the likelihood of detecting epileptiform abnormalities. These findings suggest that starting AED treatment immediately in patients with a high risk of early recurrence does not imply a reduction in the diagnostic accuracy of the test.(AU)

Pharmacological treatments in panic disorder in adults: a network meta-analysis.

BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines. OBJECTIVES: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses. MAIN RESULTS: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low. AUTHORS' CONCLUSIONS: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.

Treatment of severe tardive dyskinesia with concurrent administration of olanzapine, clonazepam, baclofen, and gabapentin: a case report.

BACKGROUND: Long-term use of antipsychotics or other dopamine antagonists can result in the extrapyramidal side effect of tardive dyskinesia (TD).Case presentation: An 18-year-old female patient experienced abnormal speech and behavior and because of an equivocal diagnosis, she was given daily doses of 300 mg of quetiapine and 60 mg of ziprasidone. She had used these medications for 2 years before the appearance of involuntary abnormal movements. These movements, which were classified as TD, steadily worsened and markedly interfered with her daily life. Following a trial-and-error course of therapy with vitamin E, vitamin B6, amantadine, valproic acid sodium, lorazepam, and diazepam, the drugs were gradually reduced and stopped, yet the aberrant movements persisted. Finally, the patient was given olanzapine, clonazepam, baclofen, and gabapentin. The Abnormal Involuntary Movement Scale was used to assess changes in the patient's condition. Her TD was efficiently managed through co-administration of olanzapine, clonazepam, baclofen, and gabapentin. CONCLUSIONS: The possibility of TD inducing by antipsychotic use is a clinical concern, even though atypical antipsychotics decrease the incidence of extrapyramidal side effects, and it cannot be entirely excluded. This report provides useful insights into the management of TD and will help clinicians manage similar cases.

Systematic review of drug therapy for chorea in NXK2-1-related disorders: Efficacy and safety evidence from case studies and series.

BACKGROUND: The NKX2-1-related disorders (NKX2-1-RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in NKX2-1-RD, aiming to provide clinical recommendations for its management. METHODS: A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and NKX2-1-RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO. RESULTS: Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low. CONCLUSIONS: The management of chorea in individuals with NKX2-1-RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations.

REM behavior disorder: When Parkinson's disease meets Morpheus.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the absence of normal muscle atonia during REM sleep, resulting in excessive motor activity while dreaming. RBD can be classified as isolated which is the strongest clinical marker of prodromal synucleinopathy, or secondary, associated with other neurological diseases, mainly Parkinson's disease (PD) and dementia with Lewy bodies. The diagnosis of RBD must be systematically documented by a video polysomnography in the case of isolated RBD. PD associated with RBD may represent a distinct phenotype compared to PD without RBD, indicating a more severe and widespread synucleinopathy. Clinically, it is associated with poorer motor and cognitive performance, more severe non-motor symptoms, and faster disease progression. Imaging studies have revealed broader brain damage and significant alterations in cerebral metabolism and neurotransmission in PD patients with RBD. The management of RBD involves safety precautions and pharmacotherapy. Safety measures aim to minimize the risk of injury during RBD episodes and include creating a safe sleeping environment and separating the patient from their bed partner if necessary. Pharmacotherapy options include clonazepam and melatonin. Clonazepam must be cautiously prescribed in older patients due to potential side effects.

Utilization of Antiseizure Medications in Women of Childbearing Age With Epilepsy and Nonepilepsy Indications: A Retrospective Cohort Study.

BACKGROUND AND OBJECTIVES: Antiseizure medications (ASMs) are among the most commonly prescribed teratogenic drugs in women of childbearing age. Limited data exist on utilization patterns across different indications for therapy and for the newer-generation ASMs in this population. Thus, we assessed the pattern of ASM use in women of childbearing age with epilepsy and nonepilepsy indications (pain and psychiatric disorders). METHODS: We conducted a retrospective analysis of deidentified administrative data submitted to the Optum Clinformatics database. Eligible participants included women aged 12-50 years who filled ASMs between year 2011 and 2017. Participants were followed from date of index prescription filled to study end or insurance disenrollment, whichever came first. For the overall cohort and potential therapy indications, we assessed the type and frequency of ASMs filled; proportion of participants on monotherapy, polytherapy, or treatment switching; and duration of continuous use. Trends were characterized using annual percent change from study start to study end. RESULTS: Our analysis included 465,131 participants who filled 603,916 distinct ASM prescriptions. At baseline, most of the participants had chronic pain (51.0%) and psychiatric disorders (32.7%), with epilepsy the least common (0.9%). The most frequently dispensed were diazepam (24.3%), lorazepam (20.1%), gabapentin (17.4%), clonazepam (12.7%), topiramate (11.3%), and lamotrigine (4.6%). Significant linear increase in trends were observed with gabapentin (annual percent change [95% CI]: 8.4 [7.3-9.4]; p < 0.001) and levetiracetam (3.4 [0.7-6.2]; p = 0.022) and decreasing trends for diazepam (-3.5 [-2.4 to 4.5]; p < 0.001) and clonazepam (-3.4 [-2.3 to 4.5]; p = 0.001). No significant change in trend was observed with valproate (-0.4 [-2.7 to 1.9]; p = 0.651), while nonlinear changes in trends were observed with lorazepam, topiramate, lamotrigine, and pregabalin. DISCUSSION: Decreasing trends were observed with older ASMs in the overall cohort and across the potential indications for therapy. Conversely, increasing trends were seen with the newer ASMs. Considering the risk of teratogenicity associated with the newer medications largely unknown, counseling and education in addition to a careful consideration of the benefits vs potential risks should remain pivotal when prescribing ASMs for women of childbearing age.