Delayed crises following benzodiazepine withdrawal: deficient adaptive mechanisms or simple pharmacokinetics? Detoxification assisted by serum-benzodiazepine elimination tracking

Objective Rapid relapses after successful withdrawal occur even in apparently motivated benzodiazepine (BZD)-dependent patients. Regardless of known personality or biological (re-adaptation) issues, the aim of this open-label, single-arm, seminaturalistic study was to search for any detoxification errors contributing to failures. Methods The data came from 350 inpatients. Based on serum-BZD evolution criteria, the procedure was divided into four stages: substitution, accumulation, elimination and post-elimination observation. After switching the patients to a long-acting substitute (diazepam), to prevent data falsification due to unwanted overaccumulation, the doses were expeditiously reduced under laboratory feedback until accumulation stopped. With the start of effective elimination, the tapering rate slowed and was individually adjusted to the patient’s current clinical state. The tracking of both serum-BZD concentration and the corresponding intensity of withdrawal symptoms was continued throughout the entire elimination phase, also following successful drug withdrawal. Detoxification was concluded only after the patient's post-elimination stabilization. Results Regardless of various initial serum-BZD concentration levels and the customized dose-reduction rate, and despite the novel lab-driven actions preventing initial overaccumulation, elimination was systematically proven to be protracted and varied within the 2- to 95-day range after the final dose. Within this period, withdrawal syndrome culminated several times, with varying combinations of symptoms. The last crisis occurrence (typically 2–3 weeks after withdrawal) correlated with the final serum-BZD elimination. The factors that prolonged elimination and delayed the final crisis were patient age, duration of addiction, adjunct valproate medication and elimination stage start parameters growing with former overaccumulation. Conclusions The low-concentration detoxification stage is critical for patients’ confrontations with recurring withdrawal symptoms. Underestimated elimination time following drug withdrawal and premature conclusions of detoxification expose patients to unassisted withdrawal crises. Concentration tracking defines proper limits for medical assistance, preventing early relapses.

Inhibition of NMDA receptors by agmatine is followed by GABA/glutamate balance in benzodiazepine withdrawal syndrome

Background Drug withdrawal syndrome occurs due to abrupt cessation of an addictive substance. Dependence to diazepam can be manifested by withdrawal syndrome which may include symptoms such as irritability, psychosis, sleep disturbance, seizures, mood disturbance, and anxiety. Studies have described the therapeutic role of agmatine in various neurological disorders such as depressive mood, learning deficits, anxiety, memory impairment, and psychosis. Various studies have also validated agmatine as a putant neuromodulator and revealed its mechanism of action with other neurotransmitters. The study was designed to reveal the potentials of agmatine in benzodiazepine withdrawal syndrome by maintaining GABA/glutamate balance. The study aimed to determine the underlying mechanism of action of agmatine at synaptic level using behavioral and biochemical evaluations. Results Agmatine significantly enhanced locomotion in open filed test and decreased anxiety as observed in elevated plus maze test (p < 0.01). Agmatine also reduced withdrawal symptoms scores along with compulsive behaviors in marble burying test and improved muscular strength by decreasing latency to fall in inverted screen test (p < 0.01). Moreover, agmatine established GABA/glutamate balance by increasing GABA levels and decreased glutamate concentration significantly (p < 0.01). Conclusion The present study reveals the possible mechanism of action of agmatine on NMDA receptor at GABA interneurons and glutamate post synaptic neuron that may lead to GABA/glutamate balance during withdrawal syndrome.

Factors affecting hallucinations in patients with delirium

Delirium develops through a multifactorial process and include multiple subtypes with different pathological factors. To refine the treatment and care for delirium, a more detailed examination of these subtypes is needed. Therefore, this study aimed to explore the factors affecting delirium in cases in which hallucinations are conspicuous. In total, 602 delirium cases referred to the psychiatry department at a general hospital between May 2015 and August 2020 were enrolled. The Delirium Rating Scale-revised-98 was used to assess perceptual disturbances and hallucinations in patients with delirium. Multiple regression analysis was applied to determine whether individual factors were associated with the hallucinations. A total of 156 patients with delirium (25.9%) experienced hallucinations, with visual hallucinations being the most common subtype. Alcohol drinking (p < 0.0005), benzodiazepine withdrawal (p = 0.004), and the use of angiotensin II receptor blockers (p = 0.007) or dopamine receptor agonists (p = 0.014) were found to be significantly associated with hallucinations in patients with delirium. The four factors detected in this study could all be reversible contributing factors derived from the use of or withdrawal from exogenous substances.

Recurrent clonazepam withdrawal delirium in a postoperative neurosurgical patient: a case report

We present a case of benzodiazepine withdrawal delirium in a middle-aged man undergoing spinal surgery. Benzodiazepines were stopped prior to surgery and on postoperative day 4, the patient exhibited significant paranoia, hyperarousal and ideas of reference. Patient’s symptoms resolved after reintroduction of his benzodiazepines. It is important to include benzodiazepine withdrawal in the differential diagnosis for acute delirium even in those patients taking low or moderate doses. Benzodiazepine withdrawal delirium typically responds rapidly to restarting benzodiazepines. In patients with known discontinuation issues, early consultation with consult-liaison psychiatry and preoperative planning for early medication re-initiation is paramount.