Propofol for treatment resistant depression: A randomized controlled trial.

Background: Anesthetic agents including ketamine and nitrous oxide have shown antidepressant properties when appropriately dosed. Our recent open-label trial of propofol, an intravenous anesthetic known to elicit transient positive mood effects, suggested that it may also produce robust and durable antidepressant effects when administered at a high dose that elicits an electroencephalographic (EEG) burst-suppression state. Here we report findings from a randomized controlled trial ( NCT03684447 ) that compared two doses of propofol. We hypothesized greater improvement with a high dose that evoked burst suppression versus a low dose that did not. Methods: Participants with moderate-to-severe, treatment-resistant depression were randomized to a series of 6 treatments at low versus high dose (n=12 per group). Propofol infusions were guided by real-time processed frontal EEG to achieve predetermined pharmacodynamic criteria. The primary and secondary depression outcome measures were the 24-item Hamilton Depression Rating Scale (HDRS-24) and the Patient Health Questionnaire (PHQ-9), respectively. Secondary scales measured suicidal ideation, anxiety, functional impairment, and quality of life. Results: Treatments were well tolerated and blinding procedures were effective. The mean [95%-CI] change in HDRS-24 score was -5.3 [-10.3, -0.2] for the low-dose group and -9.3 [-12.9, -5.6] for the high-dose group (17% versus 33% reduction). The between-group effect size (standardized mean difference) was -0.56 [-1.39, 0.28]. The group difference was not statistically significant (p=0.24, linear model). The mean change in PHQ-9 score was -2.0 [-3.9, -0.1] for the low dose and -4.8 [-7.7, -2.0] for the high dose. The between-group effect size was -0.73 [-1.59, 0.14] (p=0.09). Secondary outcomes favored the high dose (effect sizes magnitudes 0.1 - 0.9) but did not generally reach statistical significance (p>0.05). Conclusions: The medium-sized effects observed between doses in this small, controlled, clinical trial suggest that propofol may have dose-dependent antidepressant effects. The findings also provide guidance for subsequent trials. A larger sample size and additional treatments in series are likely to enhance the ability to detect dose-dependent effects. Future work is warranted to investigate potential antidepressant mechanisms and dose optimization.

Outcomes of Youth Treated With Electroconvulsive Therapy: A Retrospective Cohort Study.

BACKGROUND: The use of electroconvulsive therapy (ECT) in children and adolescents is based on a limited evidence base in the medical literature. We report outcomes of a cohort of youth treated with ECT at a single US academic medical center. METHODS: We conducted a retrospective chart review and analysis of all patients aged 18 years and younger who received ECT at the University of Utah from 1985 through 2016. For each patient record, 3 short-term clinical outcomes were assessed: response on the Clinical Global Impressions-Improvement scale, number of treatments administered, and reported side effects. Baseline characteristics were tested as predictors of clinical outcomes. RESULTS: One hundred seven youth (aged 10-18 years, 46% female) received ECT for a mood disorder, psychotic disorder, catatonia, or neuroleptic malignant syndrome. The most common diagnoses (DSM-IV-TR or DSM-5) were major depressive disorder (76 patients) and bipolar disorder (23 patients). The rate of response (much improved or very much improved) for the entire cohort was 77%. The mean number of treatments administered was 10.5. The most commonly reported side effects were headache (75%) and memory problems (65%). One patient experienced tardive seizures. There were no deaths or serious injuries. Clinical response was not predicted by age, sex, or clinical features (all P > .05). CONCLUSIONS: These data suggest that ECT is a safe and effective treatment for children and adolescents with certain severe psychiatric illnesses. ECT outcomes and side effects were similar to those reported in adults, particularly for patients aged 15-18 years, for whom there are the most data.

Propofol for Treatment-Resistant Depression: A Pilot Study.

Background: We hypothesized that propofol, a unique general anesthetic that engages N-methyl-D-aspartate and gamma-aminobutyric acid receptors, has antidepressant properties. This open-label trial was designed to collect preliminary data regarding the feasibility, tolerability, and efficacy of deep propofol anesthesia for treatment-resistant depression. Methods: Ten participants with moderate-to-severe medication-resistant depression (age 18-45 years and otherwise healthy) each received a series of 10 propofol infusions. Propofol was dosed to strongly suppress electroencephalographic activity for 15 minutes. The primary depression outcome was the 24-item Hamilton Depression Rating Scale. Self-rated depression scores were compared with a group of 20 patients who received electroconvulsive therapy. Results: Propofol treatments were well tolerated by all subjects. No serious adverse events occurred. Montreal Cognitive Assessment scores remained stable. Hamilton scores decreased by a mean of 20 points (range 0-45 points), corresponding to a mean 58% improvement from baseline (range 0-100%). Six of the 10 subjects met the criteria for response (>50% improvement). Self-rated depression improved similarly in the propofol group and electroconvulsive therapy group. Five of the 6 propofol responders remained well for at least 3 months. In posthoc analyses, electroencephalographic measures predicted clinical response to propofol. Conclusions: These findings demonstrate that high-dose propofol treatment is feasible and well tolerated by individuals with treatment-resistant depression who are otherwise healthy. Propofol may trigger rapid, durable antidepressant effects similar to electroconvulsive therapy but with fewer side effects. Controlled studies are warranted to further evaluate propofol's antidepressant efficacy and mechanisms of action. ClinicalTrials.gov: NCT02935647.

Topiramate-induced confusion following a single ingestion of 400 mg.

BACKGROUND: Topiramate is an anticonvulsant medication commonly used for a variety of neurological disorders including migraine prophylaxis. Broadened use of topiramate has brought an increased awareness of toxicity from this medication, particularly central nervous system side effects and metabolic acidosis. OBJECTIVE: We describe a case of topiramate toxicity occurring in a 22-year-old female following the ingestion of two 200 mg tablets, which she was prescribed for the treatment of migraines. RESULTS: During her outpatient cardiology evaluation for suspected postural orthostatic tachycardia syndrome (POTS), the patient experienced flushing and anxiety. Upon transfer to our hospital she was tachycardic, hypertensive, and confused. Her autonomic symptoms were consistent with her prior episodes of autonomic instability, while the confusion was new. Admission laboratory values revealed a metabolic acidosis with a mildly elevated anion gap. A blood topiramate level returned a value of 8.4 mg/L 15 h after the ingestion. Her symptoms cleared within 24 h following admission. CONCLUSION: Clinicians should consider topiramate toxicity in their differential diagnosis for patients with neurological diseases presenting with acute-onset confusion and metabolic acidosis.