Person: Fava, Maurizio
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Fava
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Maurizio
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Fava, Maurizio
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Publication Efficacy of Esketamine Augmentation in Major Depressive Disorder: A Meta-Analysis(Physicians Postgraduate Press, Inc, 2020-05-26) Papakostas, George; Chaaya Salloum, Naji; Hock, Rebecca; Jha, Manish K.; Murrough, James W.; Mathew, Sanjay J.; Iosifescu, Daniel V.; Fava, MaurizioObjective: Esketamine, the s-enantiomer of ketamine, was recently approved as a rapid-acting intranasal therapy for depression and is currently under development for suicidality. The authors sought to determine the efficacy of adjunctive intranasal esketamine in major depressive disorder (MDD). Data Sources: A systematic search of Pubmed/Medline was conducted up to January 2019, in addition to abstracts of major psychiatric meetings held since 2010. Where necessary, authors and/or study sponsors were contacted in order to obtain a copy of the presentation as well as any pertinent study details. Study Selection: 241 study abstracts were initially identified and reviewed. Selected studies were randomized, double-blind clinical trials comparing adjunctive intranasal esketamine to adjunctive placebo for MDD. Data Extration: Data were extracted independently by two of the authors. A random effects model was used to calculate the standardized mean difference (SMD) between esketamine and placebo (intranasal saline) in the MADRS score change from baseline to endpoint, serving as the primary outcome of the study. Results: Five trials with 774 patients were pooled. Adjunctive esketamine was significantly more effective than placebo for MADRS score change, response, and remission (N=774, SMD = 0.36, 95% CI = 0.24 - 0.49, p < .0001; response: RR = 1.40, 95% CI: 1.22 - 1.61, p < .0001; remission: RR = 1.45, 95% CI: 1.20 - 1.75, p < .0001). Results remained statistically significant regardless of differences in the study sample, fixed vs. new/optimized baseline antidepressants, or duration of the study. Conclusions: Adjunctive intranasal esketamine for patients with MDD who are either treatment-resistant or acutely suicidal appears to be an effective treatment strategy.Publication REL-1017 (Esmethadone) as Adjunctive Treatment in Patients With Major Depressive Disorder: A Phase 2a Randomized Double-Blind Trial(American Psychiatric Association Publishing, 2022-02) Fava, Maurizio; Stahl, Stephen; Pani, Luca; De Martin, Sara; Pappagallo, Marco; Guidetti, Clotilde; Alimonti, Andrea; Bettini, Ezio; Mangano, Richard M.; Wessel, Thomas; de Somer, Marc; Caron, Judy; Vitolo, Ottavio V.; DiGuglielmo, Gina R.; Gilbert, Adam; Mehta, Hiren; Kearney, Morgan; Mattarei, Andrea; Gentilucci, Marco; Folli, Franco; Traversa, Sergio; Inturrisi, Charles E.; Manfredi, Paolo L.ABSTRACT Objective: The relationship between the duration of major depressive disorder (MDD) and therapeutic response to standard antidepressant treatment (SAT) is unknown. N-methyl-D- aspartate receptor (NMDAR) uncompetitive antagonists are emerging drugs for MDD. We investigated whether the antidepressant effect of esmethadone (REL-1017) could be related to the duration of depression. Methods: We analyzed data from a Phase 2a study of adjunctive treatment with esmethadone in MDD patients with inadequate response to ongoing SAT (study period May 2018- August 2019). Patients were randomized to treatment with REL-1017 25mg, REL1017 50mg, or placebo for 7 days, followed by an observation period (days 7-14). Duration of depression was derived from time from onset, calculated as the difference in years between age at trial enrollment and age at the onset of the first MDE. First, we compared change from baseline for the Montgomery–Åsberg Depression Rating Scale (MADRS) in patients with time from MDD onset below and above the median value for esmethadone groups versus placebo group with Student's t-test for unpaired data, chi-square or univariate ANOVA. Secondly, bivariate correlations between time from MDD onset and CFB were performed by Spearman’s Rho. Linear mixed model analyses were also conducted. Results: Sixty-two patients participated in the trial. The median absolute values of time from MDD onset for the 62 patients were 11 years (absolute value) and 22 % (percentage of life years). At 25 and 50 mg doses, patients below the median value of time from MDD were significantly more responsive to esmethadone than placebo compared to patients above the median value. Duration of depression was statistically significant correlated with MADRS CFB on day 14 (r=0.398; p=0.02), even when controlling for the effect of current depression severity (r=0.395; p=0.023). We further used linear mixed model to test the effect of treatment, duration of depression, baseline depression severity and their interaction on MADRS CFB at day 7 and day 14. The interaction term between treatment group and duration of depression was statistically significant (B=0.382, p=0.037 for 25 mg group; B=0.344, 1p=0.036 for 50 mg group). Conclusion: Esmethadone 25 and 50 mg was more effective in reducing MADRS scores in the subpopulation with shorter time from MDD onset. ClinicalTrials.gov Identifier: NCT03051256Publication Effect of Adjunctive Pimavanserin on Sleep/Wakefulness in Patients With Major Depressive Disorder(Physicians Postgraduate Press, Inc, 2020-12-01) Jha, Manish; Fava, Maurizio; Freeman, Marlene; Thase, Michael; Papakostas, George; Shelton, Richard; Trivedi, Madhukar; Birks, Bryan; Liu, Keith; Stankovic, SrdjanABSTRACT Objective: This was an analysis of pimavanserin, a 5-hydroxytryptamine 2A antagonist/inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response. Methods: For this analysis of CLARITY, a Phase 2 study of adjunctive pimavanserin, sleep/wakefulness disturbances were measured with the sum of Hamilton Depression Rating Scale (HAMD) insomnia items (Items 4, 5, and 6) and the Karolinska Sleepiness Scale (KSS). Outcomes included change from baseline for HAMD insomnia score >3, correlation between the HAMD insomnia score and KSS, and change from baseline for the Sheehan Disability Scale (SDS) and Unproductive Days subscore in patients with a baseline KSS >6. Results: The study was conducted between December 2016 and October 2018. At baseline, HAMD insomnia factor score >3 occurred in 76% with placebo and 85% with pimavanserin. The overall LS mean (standard error) weighted difference was -0.5 (0.32) with a 95% confidence interval (CI) -1.2 to, 0.1 (p=0.088) at Week 5. Improvement was observed with pimavanserin vs. placebo at Weeks 2, 3, and 4, with effect sizes of 0.370 to 0.524 (p<0.05). For KSS, the LS mean difference at Week 5 was -1.1 (0.30), 95% CI -1.7 to, -0.5 (p=0.0003; effect size: 0.627) for pimavanserin vs. placebo. Among those with a KSS >6 at baseline (n=120 placebo and n=42 pimavanserin), the LS mean difference in the SDS mean score at Week 5 was -1.1 (0.46), 95% CI -2.0 to, -0.2 (p=0.019; effect size: 0.442) for pimavanserin vs. placebo. Conclusions: Adjunctive pimavanserin significantly improved sleep/wakefulness sleep disturbance during treatment of MDD, which was associated with greater improvement in function. This study was registered at clinicaltrials.gov: NCT03018340. Key Words: insomnia, major depressive disorder, pimavanserin, sleepPublication 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.Publication Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder(Physicians Postgraduate Press, Inc, 2022-05-30) Iosifescu, Dan V.; Jones, Amanda; O’Gorman, Cedric; Streicher, Caroline; Feliz, Samantha; Fava, Maurizio; Tabuteau, HerriotAbstract Objective: Altered glutamatergic neurotransmission has been implicated in the pathogenesis of depression. This trial evaluated the efficacy and safety of AXS-05 (dextromethorphan-bupropion), an oral NMDA receptor antagonist and σ1 receptor agonist, in the treatment of major depressive disorder (MDD). Methods: This double-blind, Phase 3 trial, was conducted between June 2019 and December 2019. Patients with a DSM-5 diagnosis of MDD were randomized in a 1:1 ratio to receive dextromethorphan-bupropion (45 mg-105 mg tablet) or placebo, orally (once daily for days 1-3, twice daily thereafter) for 6 weeks. The primary endpoint was the change from baseline to week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Other efficacy endpoints and variables included MADRS changes from baseline at week 1 and 2, clinical remission (MADRS score ≤ 10), clinical response (≥ 50% reduction in MADRS score from baseline), clinician- and patient-rated global assessments, Quick Inventory of Depressive Symptomology-Self-Rated, Sheehan Disability Scale, and quality of life measures. Results: A total of 327 patients were randomized: 163 patients to dextromethorphan-bupropion and 164 patients to placebo. Mean baseline MADRS total scores were 33.6 and 33.2 in the dextromethorphan-bupropion and placebo groups, respectively. The least-squares mean change from baseline to week 6 in MADRS total score was -15.9 points in the dextromethorphan-bupropion group and -12.0 points in the placebo group (least-squares mean difference, -3.87; 95% confidence interval [CI], -1.39 to -6.36; P<0.001). Dextromethorphan-bupropion was superior to placebo for MADRS improvement at all timepoints including week 1 (P=0.007) and week 2 (P<0.001). Remission was achieved by 39.5% of patients with dextromethorphan-bupropion versus 17.3% with placebo (least-squares mean difference, 22.2; 95% CI, 11.7 to 32.7; P<0.001), and clinical response by 54.0% versus 34.0%, respectively (least-squares mean difference, 20.0%; 95% CI, 8.4%, 31.6%; P<0.001), at week 6. Results for most secondary endpoints were significantly better with dextromethorphan-bupropion than with placebo at almost all timepoints (eg, CGI-S least-squares mean difference at week 6, -0.48; 95% CI, -0.48 to -0.79; P=0.002). The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction. Conclusions: In this Phase 3 trial in patients with MDD, treatment with dextromethorphan-bupropion (AXS-05) resulted in significant improvements in depressive symptoms compared to placebo starting one week after treatment initiation, and was generally well tolerated. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT04019704Publication Agoraphobia and Follicle-Stimulating Hormone Levels between Tamoxifen and Goserelin versus Tamoxifen Alone in Premenopausal Hormone Receptor-Positive Breast Cancer: A 12-Month Prospective Randomized Study(Korean Neuropsychiatric Association, 2017) Heo, Jung-Yoon; Yoon, Sechang; Yi, Hawoo; Fava, Maurizio; Mischoulon, David; Kim, Kiwon; Jeon, Hong Jin; Lee, Jeong EonObjective: Tamoxifen is an estrogen receptor antagonist used to prevent recurrence of breast cancer, which may provoke depression and anxiety and increase follicle-stimulating hormone (FSH) to patients. We compared anxiety and depression symptoms and FSH levels who received conventional tamoxifen alone and combination treatment of goserelin, a gonadotropin-releasing hormone (GnRH) analogue, with tamoxifen. Methods: Sixty-four premenopausal women with hormone receptor-positive early-stage breast cancer were included and were assigned randomly to receive either tamoxifen and goserelin combination or tamoxifen alone for 12 months. The participants were evaluated blindly using the Hamilton Depression and Anxiety Rating Scale, the Beck Depression Rating Scale, and the Albany Panic and Phobia Questionnaire (APPQ). Blood FSH levels were assessed at baseline, 6 and 12 months. Results: A significant time×group difference was detected in the agoraphobia trends subscale of the APPQ and in FSH levels. The combination group showed significantly less increases in agoraphobia subscale of APPQ and greater decreases in FSH level than those in the tamoxifen-alone group from baseline to 12 months of treatment. No significant differences for age, tumor grade, body mass index, or family history were found at baseline between the two groups. Conclusion: Our results suggest that the combination treatment of tamoxifen and goserelin resulted in less agoraphobia than tamoxifen alone in premenopausal women with breast cancer, which may associated with FSH suppression of goserelin.Publication Anterior insula activation during inhibition to smoking cues is associated with ability to maintain tobacco abstinence(Elsevier, 2018) Gilman, Jodi; Radoman, Milena; Schuster, Randi; Pachas, Gladys; Azzouz, Nour; Fava, Maurizio; Evins, A. EdenRelapse to smoking after initial abstinence is a major clinical challenge with significant public health consequences. At the brain and behavioral level, those who relapse to tobacco smoking have both greater cue-reactivity and lower inhibitory control than those who remain abstinent. Little is known about neural activation during inhibitory control tasks in the presence of drug-related cues. In the current study, tobacco smokers (SMK; n = 22) and non-smoking controls (CON; n = 19) completed a Go/NoGo task involving smoking cues during a functional magnetic resonance imaging (fMRI) scan. Following the scan session, smokers were required to quit smoking, and maintenance of abstinence was evaluated as part of a 12-week smoking cessation trial. We evaluated pre-cessation brain activity during NoGo trials in smokers who were versus were not able to quit smoking. We then compared fMRI and inhibitory control measures between smokers and non-smokers. We did not find differences between SMK and CON in performance or activation to smoking or neutral cues. However, compared to SMK who relapsed, SMK who attained biochemically-validated abstinence at the end of the smoking cessation trial had greater neural activation in the anterior insula during NoGo trials specifically with smoking-related cues. Results indicate that within SMK, decreased inhibitory control activation during direct exposure to drug-related stimuli may be a marker of difficulty quitting and relapse vulnerability.Publication Greater Extracellular Free Water in First-Episode Psychosis Predicts Better Neurocognitive Functioning(2017) Lyall, Amanda; Pasternak, Ofer; Robinson, Delbert G.; Newell, Dominick; Trampush, Joey W.; Gallego, Juan A.; Fava, Maurizio; Malhotra, Anil K.; Karlsgodt, Katherine H.; Kubicki, Marek; Szeszko, Philip R.Free Water Imaging is a novel diffusion magnetic reasonance imaging (MRI) method that is able to separate changes affecting the extracellular space from those that reflect changes in neuronal cells and processes. A previous Free Water Imaging study in schizophrenia identified significantly greater extracellular water volume in the early stages of the disorder; however, it’s clinical and functional sequelae have not yet been investigated. Here, we applied Free Water Imaging to a larger cohort of 63 first-episode patients with psychosis and 70 healthy matched controls to better understand the functional significance of greater extracellular water. We used diffusion MRI data and the Tract-Based Spatial Statistics analytic pipeline to first analyze fractional anisotropy (FA), the most commonly employed metric for assessing white matter. This comparison was then followed by Free Water Imaging analysis, where two parameters, the fractional volume of extracellular free-water (FW) and cellular tissue FA (FA-t), were estimated and compared across the entire white matter skeleton between groups, and correlated with cognitive measures at baseline and following 12 weeks of antipsychotic treatment. Our results indicated lower FA across the whole brain in patients compared to healthy controls that overlap with significant increases in FW, with only limited decreases in FA-t. In addition, higher FW correlated with better neurocognitive functioning following 12 weeks of antipsychotic treatment. This is the first study to suggest that an extracellular water increase during the first-episode of psychosis, which may be indicative of an acute neuroinflammatory process, and/or cerebral edema may predict better functional outcome.Publication Using the Electronic Medical Record to Examine Racial and Ethnic Differences in Depression Diagnosis and Treatment in a Primary Care Population(2011) Trinh, Nhi-Ha; LaRocca, Rachel; Regan, Susan; Chang, Trina; Gilman, Stephen Edward; Fava, Maurizio; Yeung, AlbertObjective: We assessed racial and ethnic differences in depression diagnosis and treatment in a primary care population. Methods: A sample of primary care outpatients in 2007 was generated using the electronic medical record (EMR). Patients were considered depressed if their providers billed for depression-related codes; they were considered prescribed antidepressants if any antidepressants were on their medication list. Rates of diagnosis and medication prescription were estimated using a generalized linear model with a Poisson distribution, adjusting for covariates. Results: In the resulting sample (n=85,790), all minority groups were less likely to be diagnosed with depression as compared to Whites (p<0.05); 11.36% of Whites had a depression diagnosis, as compared to 6.44% of Asian Americans, 7.55% of African Americans, and 10.18% of Latino Americans. Among those with a depression diagnosis (n=11,096), 54.07% of African Americans were prescribed antidepressant medications, as compared to 63.19% Whites (p<0.05); Asian Americans and Latino Americans showed a trend of being less likely to be prescribed antidepressant medications. Conclusions: Our study illustrates differences in diagnosis and treatment for minority primary care patients, and is innovative in using the EMR to probe these differences. Further research is needed to understand the underlying reasons for these observed differences.Publication Epidemiologic Evidence Concerning the Bereavement Exclusion in Major Depression(American Medical Association (AMA), 2012) Gilman, Stephen Edward; Breslau, Joshua; Trinh, Nhi-Ha; Fava, Maurizio; Murphy, Jane; Smoller, Jordan