Person:

Cusin, Cristina

We tested the hypothesis that etomidate and ketamine produce residual effects that modify functional mobility (measured by the balance beam test) and adrenal function (adrenocorticotropic hormone (ACTH) stimulation) immediately following recovery from loss of righting reflex in rats. Intravenous etomidate or ketamine was administered in a randomized, crossover fashion (2 or 4 mg/kg and 20 or 40 mg/kg, respectively) on eight consecutive days. Following recovery of righting reflex, animals were assessed for residual effects on functional mobility on the balance beam, motor behavior in the open field and adrenal function through ACTH stimulation. We evaluated the consequences of the effects of the anesthetic agent-induced motor behavior on functional mobility. On the balance beam, etomidate-treated rats maintained their grip longer than ketamine-treated rats, indicating greater balance abilities (mean ± SD, 21.5 ± 25.1 s vs. 3.0 ± 4.3 s respectively, p < 0.021). In the open field test, both dosages of etomidate and ketamine had opposite effects on travel behavior, showing ketamine-induced hyperlocomotion and etomidate-induced hypolocomotion. There was a significant interaction between anesthetic agent and motor behavior effects for functional mobility effects (p < 0.001). Corticosterone levels were lower after both 40 mg/kg ketamine and 4 mg/kg etomidate anesthesia compared to placebo, an effect stronger with etomidate than ketamine (p < 0.001). Following recovery from anesthesia, etomidate and ketamine have substantial side effects. Ketamine-induced hyperlocomotion with 20 and 40 mg/kg has stronger effects on functional mobility than etomidate-induced hypolocomotion with 2 and 4 mg/kg. Etomidate (4 mg/kg) has stronger adrenal suppression effects than ketamine (40 mg/kg).

Objective: We compared the impact of three eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms. Methods: We randomized 61 unmedicated adults (75% female; 45.5 ± 13.8 years) with DSM-5 major depressive disorder (MDD), body mass index (BMI) >25 kg/m2, and plasma high-sensitivity C-Reactive Protein (hs-CRP) ≥3.0 mg/L to EPA 1 g/day, 2 g/day, 4 g/day or placebo for 12 weeks. Prespecified endpoints were a ≥.40 effect size decrease in plasma interleukin (IL)-6, peripheral blood mononuclear cell (PBMC) cytokines, and lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) production. Response was defined as a ≥50% decrease of Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scores. We compared outcomes for the three EPA doses versus placebo. Results: In 45 completers, only median PBMC TNF decreased at 2 g/day EPA. No EPA dose produced a ≥.35 ES reduction in plasma IL-6 or mitogen-stimulated TNF. Response rates for EPA 4 g/day were 64%, versus 40% for placebo (odds ratio [OR]= 2.63; Cohen d = 0.53), 38% for EPA 1 g/day and 36% for EPA 2 g/day (all P>0.05). EPA 4 g/day showed a significant correlation between percent decrease in plasma hs-CRP and IDS-C30 symptom reduction at 12 weeks (Spearman rho=0.691, p=0.019).
Conclusion: EPA 4 g/day demonstrated a medium effect size for response rates versus placebo. This dose may alleviate MDD in overweight individuals with elevated inflammatory markers, and hs-CRP may be correlated with clinical response.

Abstract Objective: The neuroactive steroid metabolite of progesterone, allopregnanolone, is a positive allosteric modulator of GABAA receptors and a putative treatment for mood disorders. We performed a pilot study to determine whether an oral allopregnanolone analog (ganaxolone) may be effective for treatment-resistant depression in postmenopausal women.

Methods: Ten post-menopausal women (age 62.8±6.3 years, range 53-69) with treatment-resistant depression [current DSM-IV major depressive episode per the Structured Clinical Interview for DSM-IV (SCID), Montgomery-Asberg Depression Rating Scale (MADRS) 16, and treated with an adequately dosed antidepressant for ≥6 weeks] were studied from 12/2016 to 4/2018. Open-label ganaxolone (225 mg BID, increased to 450 mg BID if tolerated) was administered for 8 weeks, followed by a 2-week taper.

Results: Mean total MADRS score (primary endpoint) decreased by 8 weeks [24.4±1.6 (SEM) to 12.8±2.9, p=0.015] and persisted over the two-week taper (p=0.019); 44% of subjects experienced response (score decrease ≥50%) and remission (final score <10), which persisted in 100% and 50% of subjects at 10 weeks, respectively. Secondary endpoints showed significant improvement, including the Inventory of Depressive Symptomatology-Self-Report (IDS-SR; p=0.003), MADRS Reduced Sleep subscale (p<0.001), Symptoms of Depression Questionnaire (SDQ) total score (p=0.012), and SDQ subscales for disruptions in sleep quality (p=0.003) and changes in appetite and weight (p=0.009) over 8 weeks. No significant effects were observed on quality-of-life or sexual function. All subjects experienced sleepiness and fatigue; 60% experienced dizziness.

Conclusion: In this open-label, uncontrolled pilot study, ganaxolone appears to exert antidepressant effects but produces sedation with twice-daily dosing. Ganaxolone may also improve sleep, which may be useful in patients with depression and insomnia.