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.

Increased Pneumonia Risk Associated with Concomitant Use of Inhaled Corticosteroids and Benzodiazepines: A Pharmacovigilance Analysis.

BACKGROUND: Inhaled corticosteroids (ICS) are effective in managing asthma and chronic obstructive pulmonary disease (COPD) but increase the risk of pneumonia. Benzodiazepines (BZD), commonly prescribed for comorbid psychiatric disorders in asthma or COPD patients, are also associated with pneumonia. This study investigates the risk of pneumonia associated with the concomitant use of ICS and BZD. METHODS: Data from the FDA Adverse Event Reporting System from Q4 2013 to Q3 2023 were extracted. Reports involving asthma or COPD patients were included. Disproportionality analysis and logistic regression analysis were performed to assess the risk of pneumonia associated with the combined use of ICS and BZD. Additive and multiplicative models were used to further confirm the results. Additionally, subgroup analyses were conducted based on gender, age, and disease type. RESULTS: A total of 238,411 reports were included. The combined use of ICS and BZD was associated with a higher reporting of pneumonia (ROR: 2.41, 95% CI 2.25-2.58). Using additive and multiplicative methods, the results remained significant. The strongest risk signals were observed in specific drug combinations, such as mometasone with clonazepam, budesonide with temazepam, and mometasone with zopiclone. Subgroup analyses showed higher pneumonia risks in females, patients over 60 years old, and those with asthma. CONCLUSION: Our findings identified a significantly elevated pneumonia risk with the combined use of ICS and BZD. These results highlighted the necessity for cautious co-prescription of ICS and BZD and suggested the need for more comprehensive clinical studies to assess this interaction.

Clonazepam monotherapy for treating people with newly diagnosed epilepsy.

BACKGROUND: Epilepsy is one of the most common neurological disorders worldwide, with an age-adjusted prevalence of 4 to 8 per 1000 population and an age-adjusted incidence of 44 per 100,000 person-years in developed countries. Monotherapy represents the best therapeutic option in people with newly diagnosed epilepsy. This is an updated version of the original Cochrane Review published in 2019, Issue 11. OBJECTIVES: To assess the efficacy and tolerability of oral clonazepam used as monotherapy for newly diagnosed epilepsy, compared with placebo or a different anti-seizure medication. SEARCH METHODS: For the latest update of this review we searched the following databases on 14 September 2021: the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid) (1946 to 13 September 2021). CRS Web includes randomized controlled trials (RCTs) or quasi-RCTs from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups, including Epilepsy. SELECTION CRITERIA: We included RCTs or quasi-RCTs comparing oral clonazepam used as monotherapy treatment versus placebo or a different anti-seizure medication (active comparator) in people of any age with newly diagnosed epilepsy, defined according to the clinical practical definition proposed by the International League Against Epilepsy (ILAE). DATA COLLECTION AND ANALYSIS: The following outcomes were considered: proportion of participants seizure-free at one, three, six, 12, and 24 months after randomization; proportion of responders (those with at least a 50% reduction in seizure frequency from baseline to end of treatment); proportion of participants with treatment-emergent adverse events (TEAEs) during the treatment period or leading to discontinuation during the treatment period; proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons; and improvement in quality of life, as assessed by validated and reliable rating scales. Two review authors independently screened all titles and abstracts to assess the eligibility of publications identified by the searches. We independently extracted data from trial reports and cross-checked them for accuracy. Any disagreements between the two authors regarding data extraction were resolved by discussion and consensus. We scrutinized trials and evaluated the methodological quality of all included studies. We used GRADE assessment criteria to evaluate the certainty of the evidence. MAIN RESULTS: Two randomized controlled trials had already been included in the previous version of the review, with a total of 115 participants. One study compared clonazepam to carbamazepine as monotherapy for participants with newly diagnosed psychomotor epilepsy (a condition corresponding to what is now termed mesial temporal lobe epilepsy). One study (published as an abstract) compared clonazepam to ethosuximide as monotherapy for children with absence seizures. Based on the available data and the details on methodology provided, we judged both studies as being at unclear or high risk of bias for the domains assessed (apart from the selective reporting (reporting bias) domain - we judged one study as being at low risk of bias and the other study at high risk of bias). In the study comparing clonazepam to carbamazepine, no difference was found between the groups regarding the proportion of participants who were seizure-free at one month after randomization (risk ratio (RR) 1.97, 95% confidence interval (CI) 0.99 to 3.94; 30 participants; very low-certainty evidence), three months after randomization (RR 1.19, 95% CI 0.62 to 2.29; 26 participants; very low-certainty evidence), and six months after randomization (RR 0.50, 95% CI 0.09 to 2.73; 9 participants; very low-certainty evidence). No statistical difference was found between clonazepam and carbamazepine in terms of proportion of participants with TEAEs leading to discontinuation (RR 2.61, 95% CI 0.80 to 8.52; 36 participants; very low-certainty evidence) and in terms of dropouts/withdrawals due to side effects, lack of efficacy or other reasons (RR 1.56, 95% CI 0.61 to 4.02; 36 participants; very low-certainty evidence). The study did not provide any information on our other prespecified outcomes of interest. The study comparing clonazepam to ethosuximide did not provide any data on efficacy. The proportion of dropouts/withdrawal was higher in the group receiving clonazepam compared to the group receiving ethosuximide (RR 3.63, 95% CI 1.12 to 11.74; 79 participants; very low-certainty evidence). No information on other outcomes of interest was provided in this study. AUTHORS' CONCLUSIONS: We did not find any new studies since the last version of this review. There is only limited and very low-certainty evidence from randomized controlled trials on the efficacy and tolerability of clonazepam used in monotherapy for the treatment of epilepsy. No difference in efficacy and tolerability was found in a small trial comparing clonazepam to carbamazepine for the treatment of mesial temporal lobe epilepsy. Clonazepam was less well tolerated than ethosuximide in a trial of children with absence seizures, however no comparative data on efficacy were provided. There is currently insufficient evidence to support the use of clonazepam as monotherapy treatment for epilepsy.

Safety and efficacy of melatonin, clonazepam, and trazodone in patients with Parkinson's disease and sleep disorders: a randomized, double-blind trial.

BACKGROUND: Sleep disturbances are common non-motor symptoms of Parkinson's disease (PD). We aimed to compare the safety and efficacy of trazodone with melatonin and clonazepam in patients with PD and sleep complaints. METHODS: This single-center, double-blind, randomized clinical trial was conducted on PD patients with subjective sleep complaints. Eligible patients were randomized 1:1:1 to receive melatonin 3 mg/day, clonazepam 1 mg/day, or trazodone 50 mg/day for 4 weeks. The primary outcome measure was the changes in Pittsburgh Sleep Quality Index (PSQI) scores. The mean change in Epworth Sleepiness Scale (ESS) and RBD screening questionnaire (RBDSQ) was considered as the secondary outcome measures. RESULTS: A total of 112 eligible patients were randomized and 93 participants, melatonin (n = 31), trazodone (n = 31), and clonazepam (n = 31), completed the study. There was a significant decrease in PSQI scores after 4 weeks of treatment in all groups. The mean changes of PSQI from baseline were similar among the treatment arms (P = 0.325). Mean changes of RBDSQ and ESS from baseline were significantly different between study arms (P < 0.05). Melatonin intake was associated with a higher decrease in RBDSQ score compared to trazodone (P = 0.011) and clonazepam (P = 0.004). Trazodone intake was associated with a higher decrease in ESS score compared to clonazepam (P = 0.010). Mild adverse events were reported in three patients in the clonazepam, two patients in the trazodone group, and none in the melatonin group. CONCLUSIONS: Trazodone 50 mg/day, clonazepam 1 mg/day, and melatonin 3 mg/day were all tolerable and effective in improving sleep quality in patients with PD. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (registration number; IRCT20170821035819N2).

Clinical efficacy of clonazepam in the treatment of status epilepticus.

To explore the clinical efficacy of clonazepam in the treatment of status epilepticus. Totally 60 patients with status epilepticus were identified as research subjects and assigned (1:1) via the randomized double-blind method to receive either diazepam (Valium) comparison group) or clonazepam (observation group). After treatment and follow-up visits, the treatment efficacy, incidence of adverse reactions, quality of life, and recurrence were evaluated and compared between the two groups. The total effective rate of the observation group was 93.33%, which was higher than that of 66.67% in the comparison group (P<0.05). A longer mean duration of drug effect was observed in the observation group than in the comparison group (P<0.05). The observation group outperformed the comparison group in terms of quality of life (P<0.05). The observation group had a lower incidence of adverse reactions than the comparison group (P<0.05). The overall recurrence rate in the comparison group was 23.33%, which was significantly higher than that of 6.67% in the observation group (P<0.05). Clonazepam yields a promising efficacy in the treatment of patients with status epilepticus.

Clonazepam-induced lichenoid drug eruption: a case report.

BACKGROUND: Lichenoid drug eruption is rare and can mimic idiopathic lichen planus and other dermatoses. Clonazepam, a commonly used drug for the treatment of anxiety-related disorders and seizures, is known to be an unlikely cause of cutaneous adverse effects. Only one case report of LDE due to clonazepam has been reported. CASE PRESENTATION: A 81-year-old male patient with Alzheimer's disease developed a lichenoid eruption after taking clonazepam. He developed a violaceous scaly patch on his lower extremities, from both buttocks to the feet. The cutaneous eruption resolved 2 months after cessation of clonazepam and with initiation of corticosteroid therapy. CONCLUSION: A skin eruption that develops after clonazepam administration can be a lichenoid drug eruption, which is less likely to resolve spontaneously and requires discontinuation of clonazepam administration.

Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with anticonvulsants in a Japanese population: Matched case-control and cohort studies.

BACKGROUND: Evidence for the risk and incidence of anticonvulsant-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Japan is scarce. METHODS: We conducted a matched case-control study using a large-scale Japanese claims database. SJS/TEN cases were identified using a claims-based algorithm developed in a previous study (sensitivity 76.9%, specificity 99.0%). Conditional logistic regression with Firth's bias correction to address an issue of rare events was used to estimate odds ratios (ORs) for SJS/TEN for each anticonvulsant use (90 days before the index date) versus non-use. 90-day cumulative incidence of SJS/TEN per 100,000 new users was calculated for 33 anticonvulsants. Causality between anticonvulsant use and SJS/TEN in each exposed case was assessed using the algorithm of drug causality for epidermal necrolysis (ALDEN) score. RESULTS: From 5,114,492 subjects, we selected 71 SJS/TEN cases and 284 controls. We observed significantly increased ORs for SJS/TEN among new users of carbamazepine (OR 68.00) and lamotrigine (OR 36.00) with ALDEN scores of "probable" or higher. Cumulative incidence of SJS/TEN was 93.83 for carbamazepine and 84.33 for lamotrigine. One case newly exposed to phenytoin which developed SJS/TEN was rated "unlikely" in ALDEN causality, resulting in cumulative incidence of 66.27. Cumulative incidence of SJS/TEN was 25.23 for levetiracetam, 7.52 for clonazepam, and 1.23 for diazepam, but their ALDEN scores were "very unlikely". CONCLUSIONS: This study is the first to document the differential risk of SJS/TEN for anticonvulsants in a real-world setting in Japan. Exposure to carbamazepine and lamotrigine was associated with an increased risk of SJS/TEN.

Antiepileptic combination therapy with Stevens-Johnson syndrome and toxic epidermal necrolysis: Analysis of a Japanese pharmacovigilance database.

OBJECTIVE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are immune-mediated diseases characterized by an extensive loss of the epidermal skin layer, often resulting in death. SJS and TEN are often triggered by certain drugs, including antiepileptic drugs (AEDs). Epilepsy is very difficult to treat and often involves the combination of two or more AEDs. In this study, we quantified not only the risk of SJS or TEN associated with single-AED therapy but also the risk related to concomitant AED treatment using reporting-derived signals. METHODS: An analysis of the Japanese Adverse Drug Event Report (JADER) database was performed from the first quarter of 2004 to the fourth quarter of 2018. The single-AED signals were evaluated using the proportional reporting ratio (PRR), and the combination therapy signals were evaluated using Ω shrinkage measure and combination risk ratio (CRR). RESULTS: SJS signals were associated with 11 AEDs, and TEN signals were related to 12 AEDs. Moreover, the following AED combinations were associated with SJS signals: carbamazepine-lorazepam (Ω025 : 0.33, CRR: 2.18) and fosphenytoin-lorazepam (Ω025 : 0.99, CRR: 39.20). The TEN signals were related to the following combinations: clobazam-gabapentin (Ω025 : 0.35, CRR: 3.14), phenytoin-gabapentin (Ω025 : 0.03, CRR: 2.18), valproic acid-gabapentin (Ω025 : 0.15, CRR: 2.25), clobazam-clonazepam (Ω025 : 0.03, CRR: 2.93), clobazam-valproic acid (Ω025 : 0.29, CRR: 1.55), fosphenytoin-lamotrigine (Ω025 : 0.05, CRR: 7.37), and lacosamide-levetiracetam (Ω025 : 0.74, CRR: 1.85). SIGNIFICANCE: This study identified two AED combinations that increased the SJS signals and seven combinations that increased the TEN signals. Although AED monotherapies require attention for SJS and TEN, some AED combinations require extra caution.

Factors associated with depression in people with epilepsy: a retrospective case-control analysis.

PURPOSE: This study investigated factors associated with depression in people with epilepsy. METHODS: All adult patients attending our epilepsy clinic in 2018 were screened for inclusion in this study. Eligible patients were divided into case and control groups, depending on the presence of co-morbid depression. Depressive disorders were diagnosed by a psychiatrist. Demographics and clinical characteristics, including epilepsy features and antiepileptic drug use, were compared between groups. The factors contributing to onset of depression after diagnosis of epilepsy were further analysed by binomial logistic regression. Statistical significance was set at P<0.05. RESULTS: Forty four patients with epilepsy who had depression and 514 patients with epilepsy who did not have depression were included in this study (occurrence rate=7.9%). Female sex (P=0.005), older age (P<0.001), temporal lobe epilepsy (P=0.01), and higher number of antiepileptic drugs used (P=0.003) were associated with depression in patients with epilepsy. No differences were observed in other epilepsy-related factors including aetiology, seizure type, and laterality of epileptic focus. Binomial logistic regression showed that female sex (P=0.01; odds ratio [OR]=3.56), drug-resistant epilepsy (P<0.001; OR=4.79), and clonazepam use (P<0.001; OR=14.41) were significantly positively associated with risk of depression after epilepsy diagnosis, whereas valproate use (P=0.03; OR=0.37) was significantly negatively associated with risk of depression. CONCLUSION: Female sex, refractoriness, and clonazepam use may be risk factors for depression after epilepsy diagnosis. Valproate may protect against depression in people with epilepsy. Better understanding of clinical features may aid in medical management or research studies regarding co-morbid depression in people with epilepsy.

A randomized, single-dose, two-sequence, two-period, crossover study to assess the bioequivalence between two formulations of clonazepam tablet in healthy subjects.

Clonazepam is a benzodiazepine commonly prescribed to treat panic disorder, epilepsy, anxiety, depression and certain types of seizures. This study aimed to evaluate the bioequivalence between two formulations of clonazepam tablets in order to meet regulatory requirements for marketing in Colombia and other countries in Latin America. An open-label, randomized, single-dose, two-period, two-sequence, two-treatment crossover study was conducted in 36 healthy subjects of both genders. Subjects received a single dose of clonazepam 2 mg test tablet (Sanofi-Aventis de Colombia S.A.) and reference product (Rivotril®, Produtos Roche Químicos e Farmacêuticos S.A.) under fasting conditions according to a randomly assigned order with a 21-day washout period. Serial blood samples were collected up to 96 h post-dose. Plasma concentrations of clonazepam were obtained by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated using non-compartmental methods. A total of 36 healthy subjects were enrolled and 31 of them completed the study. Twenty-nine adverse events were reported (11 events with test product versus 18 events with reference product). There were no serious adverse events during the study. Geometric mean ratios (90% confidence intervals) for Cmax and AUC0-96h were 103.28% (98.10-108.64) and 102.50% (99.87-105.19), respectively. The test formulation of clonazepam 2 mg tablet manufactured by Sanofi-Aventis de Colombia S.A. was considered bioequivalent to reference product Rivotril® (Produtos Roche Químicos e Farmacêuticos S.A.) according to regulatory requirements. Both formulations were safe and well-tolerated during the study.

Investigations on clonazepam-loaded polymeric micelle-like nanoparticles for safe drug administration during pregnancy.

Medication during pregnancy is often a necessity for women to treat their acute or chronic diseases. The goal of this study is to evaluate the potential of micelle-like nanoparticles (MNP) for providing safe drug usage in pregnancy and protect both foetus and mother from medication side effects. Clonazepam-loaded MNP were prepared from copolymers [polystyrene-poly(acrylic acid) (PS-PAA), poly(ethylene glycol)-b-poly(lactic acid) (PEG-PLA) and distearyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-poly(ethylene glycol) (PEG-DSPE)] with varying monomer ratios and their drug-loading efficiency, drug release ratio, particle size, surface charge and morphology were characterised. The cellular transport and cytotoxicity experiments were conducted on clonazepam and MNP formulations using placenta-choriocarcinoma-BeWo and brain-endothelial-bEnd3 cells. Clonazepam-loaded PEG5000-PLA4500 MNP reduced the drug transport through BeWo cells demonstrating that MNP may lower foetal drug exposure, thus reduce the drug side effects. However, lipofectamine modified MNP improved the transport of clonazepam and found to be promising for brain and in-utero-specific drug treatment.

New benzodiazepine and Z-hypnotic users and disability pension: an eight-year nationwide observational follow-up study.

OBJECTIVE: To compare how newly initiated treatment with benzodiazepines, Z-hypnotics or both associates with the reception of disability pension among 40,661 individuals of a working age. DESIGN: Prescription register study. SETTING: Norwegian nationwide prescriptions socio-economic and disability status data. METHODS: Cox regression analyses. SUBJECTS: New benzodiazepine or Z-hypnotic users. MAIN OUTCOME MEASURE: Time to receive disability pension given benzodiazepine or Z-hypnotic use or both. Additional analyses focused on the benzodiazepine first redeemed. RESULTS: Among new users 8.65% of Z-hypnotic users, 12.29% of benzodiazepines users and 13.96% of combined Z-hypnotic and benzodiazepine users became disability pensioners. Z-hypnotic users were weaker associated with becoming disability pensioners (HR = 0.78, CI: 0.73-0.84) and combined users were stronger associated (HR = 1.09, CI: 1.01-1.17), than benzodiazepine users. Women had higher risk than men for becoming disability pensioners. Higher age, lower education, previous drug use and psychiatrist as first prescriber were risk factors. Comparing first benzodiazepine redeemed; clonazepam initiators were stronger associated with becoming disability pensioners than diazepam initiators were (HR = 2.22, CI: 1.81-2.71). No differences between other benzodiazepine users were found. CONCLUSIONS: Adjusting for known risk factors gave lower risk for Z-hypnotic users compared to benzodiazepine users for receiving disability pension. Combined use increased the risk further. Clonazepam initiators are especially at risk. These findings may be helpful in prescribing situations to identify and guide individuals at risk for becoming disability pensioners.

Optimization of Clonazepam Therapy Adjusted to Patient's CYP3A Status and NAT2 Genotype.

BACKGROUND: The shortcomings of clonazepam therapy include tolerance, withdrawal symptoms, and adverse effects such as drowsiness, dizziness, and confusion leading to increased risk of falls. Inter-individual variability in the incidence of adverse events in patients partly originates from the differences in clonazepam metabolism due to genetic and nongenetic factors. METHODS: Since the prominent role in clonazepam nitro-reduction and acetylation of 7-amino-clonazepam is assigned to CYP3A and N-acetyl transferase 2 enzymes, respectively, the association between the patients' CYP3A status (CYP3A5 genotype, CYP3A4 expression) or N-acetyl transferase 2 acetylator phenotype and clonazepam metabolism (plasma concentrations of clonazepam and 7-amino-clonazepam) was evaluated in 98 psychiatric patients suffering from schizophrenia or bipolar disorders. RESULTS: The patients' CYP3A4 expression was found to be the major determinant of clonazepam plasma concentrations normalized by the dose and bodyweight (1263.5±482.9 and 558.5±202.4ng/mL per mg/kg bodyweight in low and normal expressers, respectively, P<.0001). Consequently, the dose requirement for the therapeutic concentration of clonazepam was substantially lower in low-CYP3A4 expresser patients than in normal expressers (0.029±0.011 vs 0.058±0.024mg/kg bodyweight, P<.0001). Furthermore, significantly higher (about 2-fold) plasma concentration ratio of 7-amino-clonazepam and clonazepam was observed in the patients displaying normal CYP3A4 expression and slower N-acetylation than all the others. CONCLUSION: Prospective assaying of CYP3A4 expression and N-acetyl transferase 2 acetylator phenotype can better identify the patients with higher risk of adverse reactions and can facilitate the improvement of personalized clonazepam therapy and withdrawal regimen.

Alcohol and Sedative-Hypnotic Withdrawal Catatonia: Two Case Reports, Systematic Literature Review, and Suggestion of a Potential Relationship With Alcohol Withdrawal Delirium.

BACKGROUND: Withdrawal from alcohol and sedative-hypnotics can be complicated by seizures, hallucinations, or delirium. Withdrawal catatonia is another, less commonly discussed complication that clinicians should appreciate. METHODS: We present a case of alcohol withdrawal catatonia and a case of benzodiazepine withdrawal catatonia and offer a systematic review of previous cases of alcohol or sedative-hypnotic withdrawal catatonia. We outline clinical features that suggest a potential link between withdrawal catatonia and withdrawal delirium. RESULTS: We identified 26 cases of withdrawal catatonia in the literature-all principally with catatonic stupor-with an average age of 56 years (range: 27-92) and balanced prevalence between sexes. Withdrawal catatonia tends to occur only after chronic use of alcohol or sedative-hypnotic agents with a typical onset of 3-7 days after discontinuation and duration of 3-10 days. Withdrawal catatonia is responsive to benzodiazepines or electroconvulsive therapy. Features that suggest a parallel between withdrawal catatonia and withdrawal delirium include time course, neurobiologic convergence, efficacy of benzodiazepines and electroconvulsive therapy, typical absence of abnormal electroencephalographic findings, and phenotypic classification suggested by a recent literature in sleep medicine. CONCLUSION: Alcohol and sedative-hypnotic withdrawal may present with catatonia or catatonic features. The clinical and neurobiologic convergence between withdrawal catatonia and withdrawal delirium deserves further attention. In view of these similarities, we propose that withdrawal delirium may represent excited catatonia: these new viewpoints may serve as a substrate for a better understanding of the delirium-catatonia spectrum.

[Addiction to benzodiazepines - analysis of patients of Independent Public Hospital for Mental Diseases Patients in Miedzyrzecz].

Benzodiazepines (BZD) are substances with proven anxiolytic, sedative, hypnotic, muscle relaxant, and anticonvulsant effect whose activity targets a macromolecular complex comprising GABAA receptors, benzodiazepine receptors and chloride channels. Broad spectrum of action of benzodiazepines affects their more and more frequent consumption by the patients, despite the reports on their addictive potential. The aim of the study was to analyze patients addicted to benzodiazepines, taking into account factors that may increase the risk of addiction. Material and Methods: The study was based on medical records of 52 patients (27 women, 25 men) of Independent Public Hospital for Mental Diseases Patients in Miedzyrzecz from January 2013 to June 2015. The initial diagnosis of admitted patients included psychiatric and behavioral disorders due to taking hypnotics and sedatives (substance withdrawal). We analyzed the amount and time of use of benzodiazepines, alcohol consumption, as well as previous therapies due to alcohol abuse or alcohol dependence. Results: Among the 52 patients (27 women, 25 men aged 26 to 68 years), the majority of city dwellers was working with secondary education Average time of benzodiazepine use was 16 years, 60% of the patients were addicted to 1 benzodiazepine, 20% to two, 10% to three, and nearly 10% to 4. Clonazepam, alprazolam and diazepam were among the most frequently abused benzodiazepines. Conclusions: More and more often observed too long term treatment with benzodiazepines poses the risk of dependence on this group of drugs.

Mixed myoclonic-absence status epilepticus in juvenile myoclonic epilepsy.

Myoclonic status epilepticus or mixed absence-myoclonic status is uncommon in juvenile myoclonic epilepsy (JME), often precipitated by sleep deprivation, withdrawal of medication, or inadequate antiepileptic drugs (Thomas et al., 2006; Crespel et al., 2013). Such episodes respond well to benzodiazepines or valproate (Crespel et al., 2013). We present the video-EEG of a 24-year-old woman with JME and bipolar disorder. She had a confusional state five days after withdrawal of clonazepam (14 mg/d) and introduction of oxazepam (200 mg/d), followed by catatonic stupor with subtle myoclonus of the face and the arms. The EEG showed absence status (figures 1, 2), which stopped after IV injection of clonazepam (1 mg) (figure 3). Consciousness returned to normal [Published with video sequence and figures (1)].

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.

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.