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Dichtel, Laura

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Dichtel

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Laura

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Dichtel, Laura

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2017 - 20202

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Author's Publications: search.filters.isAuthorOfPublication.716f397d-4d15-4555-adca-c6837a148101

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    Effects of Open-Label, Adjunctive Ganaxolone on Persistent Depression Despite Adequate Antidepressant Treatment in Postmenopausal Women
    (Physicians Postgraduate Press, Inc, 2020-06-09) Dichtel, Laura; Nyer, Maren; Dording, Christina; Fisher, Lauren; Cusin, Cristina; Shapero, Benjamin; Pedrelli, Paola; Kimball, Allison; Rao, Elizabeth; Mischoulon, David; Fava, Maurizio; Miller, Karen K.
    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.
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    The Association Between IGF-1 Levels and the Histologic Severity of Nonalcoholic Fatty Liver Disease
    (Nature Publishing Group, 2017) Dichtel, Laura; Corey, Kathleen; Misdraji, Joseph; Bredella, Miriam; Schorr, Melanie; Osganian, Stephanie A; Young, Brian J; Sung, Joshua C; Miller, Karen
    Objectives: The mechanisms responsible for the development of nonalcoholic fatty liver disease (NAFLD) and progression to nonalcoholic steatohepatitis (NASH) are incompletely understood. Growing evidence suggests that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) may have roles in the development and progression of NAFLD. We hypothesized that lower serum IGF-1 levels would be associated with increased liver fat accumulation, inflammation, and fibrosis in a group of meticulously phenotyped obese subjects with liver biopsies. Methods: A retrospective, cross-sectional study was performed at Massachusetts General Hospital, Boston, MA, USA and St. Mary's Hospital, Richmond, VA, USA. Liver biopsies were performed in 142 subjects during NAFLD work-up or bariatric surgery and were graded by a single, blinded pathologist. Main outcome measures included liver histology and serum IGF-1. Results: Mean age was 52±10 years and body mass index (BMI) was 43±9 kg/m2. Mean serum IGF-1 was lower in subjects with lobular inflammation (112±47 vs. 136±57 ng/ml, P=0.01), hepatocyte ballooning (115±48 vs. 135±57 ng/ml, P=0.05), higher fibrosis stage (stage 2–4 vs. 0–1; 96±40 vs. 125±51 ng/ml, P=0.005), and NASH (109±45 vs. 136±57 ng/ml, P=0.002). All results remained significant after controlling for age, BMI, and a diagnosis of diabetes, and all but hepatocyte ballooning (trend, P=0.06) remained significant after excluding individuals with cirrhosis. Steatosis was not significantly associated with mean serum IGF-1 levels. Conclusions: Low serum IGF-1 levels are associated with increased histologic severity of NAFLD when rigorously controlled for age, BMI, the presence of diabetes, and after the exclusion of subjects with cirrhosis. Further investigation is warranted to determine the differential effects of GH and IGF-1 on the development and progression of NAFLD, which could further elucidate pathophysiology and identify therapeutic targets.