Clonazepam

We conducted an exploratory qualitative study among adult patients meeting criteria for (high-dose) BZD-dependence according to the 10th revision of the International Classification of Diseases (ICD-10)[34 ]. To the authors’ knowledge there is no universally accepted definition of high-dose benzodiazepine dependence. In previous studies on detoxification for high dose benzodiazepine dependence, patients with a dose of 40 to 500 mg diazepam equivalents (Median 150mg) were included [35 (link)]. Quaglio et al included in their study on “High dose benzodiazepine dependence: Description of 29 patients treated with flumazenil infusion and stabilized with clonazepam” patients that received a daily dose (converted to diazepam equivalents) that ranged from 38 to 1800 mg per day (median 333 mg/day)[36 (link)]. In a previous publication [30 (link)] we were reluctant to describe ‘high-dose’ users as a well-defined group (e.g. by a certain amount of diazepam equivalents) as, in our opinion, this does not reflect clinical reality and may provoke unnecessary dose–range discussions. We chose to use the following definition for that study, which also formed the basis for the present manuscript:
Patients who typically have a high-dose, long-term and/or otherwise problematic use of benzodiazepines, such as mixing benzodiazepines (e.g. midazolam, flunitrazepam, lorazepam, oxazepam), escalating their dosage repeatedly, using benzodiazepines to enhance the effects of other substances, obtaining their BZDs by illegal means and those who experience negative social consequences. These included high-dose users as defined by the use of 40 mg diazepam equivalents per day over an extended period of time and/or otherwise problematic use of benzodiazepines, such as mixing, repeated dose escalation, euphoric effect enhancement, or illegal acquisition strategies.
The participants in this study were recruited from patients who presented to the Psychiatric University Hospital, Zurich, between 03/2011 and 11/2012, using a combination method of purposeful- and saturation sampling principles. To achieve greater variation of themes and motives, we recruited subjects from general treatment settings as well as from specialized units for the treatment of substance-use disorders. Patients that were recruited from the outpatient units of the Psychiatric University Hospital were seen on an “as needed” basis by their physicians. Treatment duration (weeks to years) and form of intervention varied amongst participants, ranging from an abstinence oriented benzodiazepine discontinuation approach to the more permanent prescription of slow-onset, long-acting BZDs. Furthermore, the sample was chosen to incorporate diversity with regards to: (a) past clinical experience and comorbidity, (b) duration of high-dose benzodiazepine use, (c) gender, (d) age and (e) occupational status. Exclusion criteria were insufficient language skills and acute intoxication.
The research team contacted sixty potential participants in person, previously identified by treating physicians as those patients who had a problematic (high-dose) use of benzodiazepines, but not for those fulfilling only ICD-10 criteria for BZD dependence. Potential participants were verbally informed of the reasons for the present research and received an opt-in letter (384 words). Nineteen declined to participate. Barriers to participation were directly addressed in a few instances. Two potential participants declined inclusion in this study, because they felt the amount of honorarium (a 5 Swiss Franc gift card for inpatients and a 5 Swiss Franc cash payment for outpatients) was insufficient. More commonly, potential participants left the impression of being too ashamed to discuss the subject (14). In three cases, potential participants initially agreed to be interviewed, but then withdrew their consent for participation during the interview–citing a lack of interest in the research topic. In total, 41 subjects provided their written, informed consent and completed the interview. The full chart of each patient, including their complete biographical and psychiatric history and their diagnosis according to ICD-10, was provided by the clinic.

Serum from five patients (Pat1-5) with anti-GlyR autoantibodies was used for the experiments. Clinical data of two patients (Pat1 with SPS, Pat5 with PERM) were described previously (Rauschenberger et al., 2020 (link)). Serum from five healthy individuals served as negative control (HC), a serum from a patient with multiple sclerosis was used as disease control (DC).
Patients 2 and 3 did not have a history of cancer, SPS or PERM but another neurological disorder. Their serum and CSF samples did not exhibit antibodies directed against other neuronal surface antigens (NMDAR, AMPAR, LGI1, CASPR2, GABA_AR, GABA_BR) but autoantibodies against the GlyR assessed by appropriate cell-based assays (Ekizoglu et al., 2014 (link)). Sera of patients 2 and 3 were included in the present study to examine general molecular mechanisms for autoantibody binding and detection.
Patient 2 was a 33-year old woman with a 16-year history of focal epilepsy of unknown cause, characterized with focal temporal seizures evolving to bilateral convulsive seizures and loss of consciousness. Her CSF and MRI examinations were normal. She favorably responded to antiepileptic medications (oxcarbazepine and topiramate) and thus immunotherapy was not considered.
Patient 3 was a 14-year old girl with a 6-year history of unclassified epileptic encephalopathy characterized with generalized tonic–clonic seizures and atypical absences. She showed mildly progressive cognitive decline with normal metabolic screening, normal CSF findings and mild cerebral atrophy on MRI. EEG showed generalized discharges and focal spikes over the right frontotemporal region. She favorable responded to IVIG treatment and anti-epileptic medications (carbamazepine and valproate).
Patient 4, a 71-year old male at blood withdrawal, developed symptoms of SPS (PERM) at age 65. He suffered from stiffness and spasms of the right arm, falls with bone fractures and a pronounced startle reaction, and was finally wheelchair bound. Extensive search for a malignoma and for other autoantibodies than GlyR antibodies was negative. Under i.v. steroid pulse therapy every 4 months and oral clonazepam at a dose of 0.25 mg in the morning and 0.375 mg in the evening he recovered the ability to walk, and his condition remained mostly stable.