Jonathan G. Leung

Melatonin therapy for REM sleep behavior disorder: a critical review of evidence

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia associated with dream enactment often involving violent or potentially injurious behaviors during REM sleep that is strongly associated with synucleinopathy neurodegeneration. Clonazepam has long been suggested as the first-line treatment option for RBD. However, evidence supporting melatonin therapy is expanding. Melatonin appears to be beneficial for the management of RBD with reductions in clinical behavioral outcomes and decrease in muscle tonicity during REM sleep. Melatonin also has a favorable safety and tolerability profile over clonazepam with limited potential for drug-drug interactions, an important consideration especially in elderly individuals with RBD receiving polypharmacy. Prospective clinical trials are necessary to establish the evidence basis for melatonin and clonazepam as RBD therapies.

Influence of dexmedetomidine therapy on the management of severe alcohol withdrawal syndrome in critically ill patients

PURPOSE Although benzodiazepines are first-line drugs for alcohol withdrawal syndrome (AWS), rapidly escalating doses may offer little additional benefit and increase complications. The purpose of this study was to evaluate dexmedetomidines impact on benzodiazepine requirements and hemodynamics in AWS. MATERIALS AND METHODS This retrospective case series evaluated 33 critically ill adults with a primary diagnosis of AWS from 2006 to 2012 at an academic medical center. RESULTS Dexmedetomidine began a median (interquartile range) of 11 (2, 32) hours into intensive care unit admission and was titrated to an infusion rate of 0.7 (0.4, 0.7) μg kg(-1) h(-1) to achieve the desired depth of sedation. In the 12 hours after dexmedetomidine began, patients experienced a 20-mg reduction in median cumulative benzodiazepine dose used (P < .001), a 14-mm Hg lower mean arterial pressure (P = .03), and a 17-beats/min reduction in median heart rate (P < .001). Four (12%) patients experienced hypotension (systolic blood pressure <80 mm Hg) during therapy, and there were no cases of bradycardia (heart rate <40 beats/min). CONCLUSION Dexmedetomidine decreased benzodiazepine requirements and improved the overall hemodynamic profile of patients with severe AWS. These results provide promising evidence about the potential benefit of dexmedetomidine for AWS.

Clinical effectiveness of baclofen for the treatment of alcohol dependence: a review

Baclofen, an agonist at the B subunit of gaba-aminobutyric acid receptor, possesses pharmacologic properties that may confer utility for the treatment of alcohol dependence. Research suggests that not only can it be useful in promoting maintenance of alcohol abstinence but also it may play a key role in decreasing alcohol cravings and anxiety often associated with alcohol dependence. To assess the benefit of baclofen for alcohol dependence, a review of the literature was conducted to identify published data investigating this off-label treatment. Four randomized controlled trials to date have been published and were included in this review. Although primary outcomes differ between studies, patients randomized to baclofen experience higher rates of abstinence from alcohol than those taking placebo in two of the trials. Secondary analyses indicate that baclofen is safe in patients with alcohol dependence, including those with moderate to severe liver cirrhosis, and may provide beneficial anxiolytic effects. Despite some positive data, the largest available randomized controlled trial failed to find any differences between baclofen and placebo. In all studies, individuals with severe medical comorbidities, seizure disorders, and psychiatric disorders were excluded from trials, which may limit external validity. In summary, there may be beneficial effects from using baclofen for the treatment of alcohol dependence; however, limited conclusions can be drawn from the small number of studies currently available for review. Larger well-designed trials are needed to further define baclofen’s role for the treatment of alcohol dependence.

KETAMINE FOR TREATMENT‐RESISTANT UNIPOLAR AND BIPOLAR MAJOR DEPRESSION: CRITICAL REVIEW AND IMPLICATIONS FOR CLINICAL PRACTICE

There is an urgent need for more rapidly effective pharmacotherapies for major depressive disorder and bipolar disorder (BP) that are efficacious and tolerable for depressed patients who respond poorly to conventional treatments. Multiple controlled trials have now demonstrated a rapid, nonsustained antidepressive response to a single intravenous infusion of ketamine. Early controlled studies of intranasal or serial infusion therapy appear promising. The effective dose for depression is lower than the typical anesthetic doses, and side‐effects are generally mild and transient. The data investigating the adjunctive use of concurrent ketamine in the course of electroconvulsive therapy (ECT) for depression do not suggest efficacy or tolerability. The therapeutic potential of ketamine has stimulated considerable excitement among clinicians, patients, and industry, and has led to the increasing use of ketamine as an off‐label substitute for ECT and other antidepressive treatments. This clinical review of ketamine will assess the evidence‐based use of ketamine and initial clinical implications of further development of a potentially novel treatment for rapid reduction of symptoms in depressed patients.

The Role of Gabapentin in the Management of Alcohol Withdrawal and Dependence

Objective: To review the literature evaluating gabapentin for alcohol withdrawal and dependence. Data Sources: A literature search of MEDLINE (1966 to end of March 2015) and PubMed was performed using the terms alcohol, gabapentin, withdrawal, and dependence. Additional references were identified from a review of literature citations. Study Selection and Data Extraction: English-language prospective studies evaluating gabapentin for alcohol withdrawal and dependence were evaluated. Data Synthesis: A total of 10 publications utilizing gabapentin in alcohol withdrawal (n = 5) and alcohol dependence (n = 5) were included in this review. Limited data suggest that gabapentin can provide benefit in managing mild alcohol withdrawal syndrome. There were 5 reported or suspected seizures in the withdrawal studies, suggesting that additional safety data are necessary before gabapentin monotherapy can be routinely considered. Sleep and mood/anxiety-related outcomes were positively influenced by gabapentin, which may result in long-term benefits if continued beyond the withdrawal period for the treatment of alcohol dependence. Studies evaluating gabapentin for alcohol dependence demonstrated dose-dependent benefits for complete abstinence, rates of no heavy drinking, and cravings. Gabapentin used to treat alcohol dependence was well tolerated with no severe adverse reactions reported in the extant literature. Conclusion: Gabapentin may have a role in the treatment of mild alcohol withdrawal, but future studies should focus on adequate dosing strategies. Gabapentin should be considered for the treatment of alcohol dependence when barriers prevent the use of traditional agents. Additional studies should be conducted to further validate findings from the research conducted to date, but the current literature is promising for gabapentin in the treatment of alcohol dependence.

The Role of Diazepam Loading for the Treatment of Alcohol Withdrawal Syndrome in Hospitalized Patients

BACKGROUND Alcohol withdrawal accounts for a significant amount of hospital admissions and can quickly progress to the development of delirium tremens (DTs), seizures, and death. Rapid identification and management of alcohol withdrawal syndrome (AWS) is vital and can be managed with a number of different treatment strategies. Diazepam loading is a treatment strategy that utilizes the pharmacokinetics of this agent to achieve a rapid reduction in symptoms followed by sustained benefit over a period of days. OBJECTIVE The purpose of this review is to evaluate the role of diazepam loading for AWS. METHODS A literature search of four databases-Pubmed, PsychInfo, Biosis, and Embase-was conducted to identify publications between 1960 and August 2011 that described the use of diazepam loading for the treatment of AWS. Eight trials, both open-label and controlled trials were identified. Only four randomized controlled-trials (RCTs) have been published and they are reviewed in this paper. RESULTS Included trials of hospitalized inpatients found that diazepam loading provided rapid symptom relief as well as reduced the incidence of seizures and duration of DTs. In patients diagnosed with severe DTs, rapidly administered doses of diazepam produced a quick calming effect. While no adverse events resulting from diazepam loading were noted, no formal assessment tool was used to evaluate its safety. Larger randomized controlled-trials are needed to better evaluate safety outcomes. CONCLUSIONS Diazepam loading is an effective treatment option for hospitalized patients experiencing AWS. Diazepam loading uses the concept of symptom-triggered therapy, a mainstay of current AWS treatment, while exploiting its prolonged elimination half-life and eliminating the need for additional pharmacologic therapy. Studies reviewed found diazepam loading significantly improved a number of important outcomes in AWS, including time in DTs, compared to traditional treatment strategies.

Potential Risks of Poorly Monitored Ketamine Use in Depression Treatment.

At the time of his initial presentation to a tertiary medical center in 2012, “Mr. A” was a 52-year-old divorced man with a 30-year history of recurrent major depressive disorder, persistent depressive disorder, and a remote history of outpatient treatment for alcohol use disorder as a young adult. His first episode of major depression occurred at age 22 in association with a suicide attempt (he jumped off a four-story building) and subsequent hospitalization. Mr. A’s medical history was significant for corrected hypothyroidism. The prospective course of illness encompassed four subsequent psychiatric admissions at our medical center, annually from 2012 to 2014, illustrating clear treatment-resistant depression and a reemerging pattern of substance misuse (alcohol, benzodiazepines, and ketamine). Mr. A’s admission in the summer of 2012 focused on consultation for depression and consideration of ECT. Prior medication trials of optimal dose and duration included trazodone, escitalopram, bupropion, and mirtazapine with lamotrigine and aripiprazole augmentation strategies. Mr. A reported negligible alcohol consumption (a single drink on rare occasions). He received seven bilateral ECT treatments, and his symptoms improved; his score on the Hamilton Depression Rating Scale declined from 37 on admission to 8 at discharge. He was discharged after 18 days on mirtazapine monotherapy with recommendations to maximize his dosing of mirtazapine and to add lithium for augmentation following his ECT course. HereceivedthreeadditionalECTtreatmentspriortoself

Ketamine for treatment-resistant unipolar and bipolar major depression

There is an urgent need for more rapidly effective pharmacotherapies for major depressive disorder and bipolar disorder (BP) that are efficacious and tolerable for depressed patients who respond poorly to conventional treatments. Multiple controlled trials have now demonstrated a rapid, nonsustained antidepressive response to a single intravenous infusion of ketamine. Early controlled studies of intranasal or serial infusion therapy appear promising. The effective dose for depression is lower than the typical anesthetic doses, and side‐effects are generally mild and transient. The data investigating the adjunctive use of concurrent ketamine in the course of electroconvulsive therapy (ECT) for depression do not suggest efficacy or tolerability. The therapeutic potential of ketamine has stimulated considerable excitement among clinicians, patients, and industry, and has led to the increasing use of ketamine as an off‐label substitute for ECT and other antidepressive treatments. This clinical review of ketamine will assess the evidence‐based use of ketamine and initial clinical implications of further development of a potentially novel treatment for rapid reduction of symptoms in depressed patients.

Infection and Inflammation Leading to Clozapine Toxicity and Intensive Care A Case Series

Objective: To describe 3 cases of clozapine toxicity associated with infectious and/or inflammatory processes. Case Summaries: Three patients stable on clozapine therapy prior to a medical hospital admission developed clozapine toxicity. It was suspected that an acute infectious and/or inflammatory process in each patient was related to abrupt mental status changes, onset of sialorrhea, myoclonus, and/or need for ventilatory support. Investigations of altered mental status did not reveal alternative causes and presentations were not consistent with neuroleptic malignant syndrome, other acute neurologic complications, or psychiatric decompensation. All patients improved after clozapine dose reductions allowing for transfer from intensive care units. Using the Naranjo ADR Probability Scale for each case, a probable relation between clozapine toxicity and the infectious and/or inflammatory process was determined. Discussion: Clozapine toxicity may manifest with multiple symptoms, including sedation, sialorrhea, and hypotension. In addition to overdose and drug interactions; infection and/or inflammation may precipitate clozapine toxicity. This may be related to cytokine-mediated inhibition of cytochrome P450 1A2. The likelihood of toxicity via this mechanism has not been well characterized, thus careful monitoring is required for medically ill patients receiving clozapine. Clozapine is extensively bound to the acute phase reactant, α-1 acid glycoprotein, which may unpredictably protect against clinical toxicity. C-reactive protein has also been investigated to relate clozapine toxicity to infection and/or inflammation. Conclusion: Clozapine toxicity developed in 3 patients admitted to a medical setting suspected to be related to infection and/or inflammation. Clinicians should be aware of this potential adverse drug event with clozapine.

Torsades De Pointes after Administration of Low-Dose Aripiprazole

OBJECTIVE: To describe a case of torsades de pointes (TdP) in a patient treated with aripiprazole. CASE SUMMARY: A 42-year-old white male with schizophrenia, diabetes, hypertension, and a history of stroke was admitted to the intensive care unit following 2 days of fever, diarrhea, and altered mental status. Following the resolution of his acute illness, previous therapy with quetiapine 400 mg orally at bedtime was resumed for schizophrenia and presumed delirium. Quetiapine was discontinued after 1 dose because of QTc interval prolongation. Twenty-three days later, with a baseline Q Tc interval of 414 milliseconds, aripiprazole 2.5 mg orally once daily was initiated. Following 5 days of aripiprazole therapy, the patient had a cardiac arrest due to TdP. Normal sinus rhythm was restored after 30 seconds of cardiopulmonary resuscitation, 1 shock of 200 Joules, and 4 g of intravenous magnesium sulfate. Serial electrocardiographs obtained after aripiprazole discontinuation revealed resolution of QTc interval prolongation. DISCUSSION: Aripiprazole is a second-generation antipsychotic that may be selected for patients with prolonged QTc intervals and at risk for TdP. Data from trials indicate that aripiprazole has minimal effects on the QTc interval. However, in this case, aripiprazole was associated with TdP in a patient with minimal risk factors. The Naranjo probability scale was used to determine a probable association between aripiprazole and the development of TdP. To our knowledge, this is the first reported case of TdP associated with the use of aripiprazole. CONCLUSIONS: Five days of low-dose aripiprazole therapy was associated with the development of TdP in a man with minimal risk factors. Clinicians should be aware of this potential adverse drug event with aripiprazole.