Luận văn Thạc sĩ Antidepressant Treatment Of Major Depressive Disorder In Patients With Comorbid Alcohol Use Disorder

Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine January 2020 Antidepressant Treatment Of Major Depressive Disorder In Patients With Comorbid Alcohol Use Disorder: Two MetaAnalyses Of Randomized Placebo-Controlled Trials Isaac Nathan Smullin Johnson Follow this and additional works at: https://elischolar.library.yale.edu/ymtdl Recommended Citation Johnson, Isaac Nathan Smullin, "Antidepressant Treatment Of Major Depressive Disorder In Patients With Comorbid Alcohol Use Disorder: Two Meta-Analyses Of Randomized Placebo-Controlled Trials" (2020) Yale Medicine Thesis Digital Library 3917 https://elischolar.library.yale.edu/ymtdl/3917 This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale For more information, please contact elischolar@yale.edu Antidepressant Treatment of Major Depressive Disorder in Patients with Comorbid Alcohol Use Disorder: Two Meta-analyses of Randomized Placebo-controlled Trials A Thesis Submitted to the Yale University School of Medicine in Partial Fulfillment of the Requirements for the Degree of Doctor of Medicine by Isaac Nathan Smullin Johnson Yale School of Medicine Class of 2020 Table of Contents Dedication and Acknowledgements………………………………………………………….3 Abstract……………………………………………………………………………………….4 Introduction………………………………………………………………………………… Methods for Aim 1………………………………………………………………………… 11 Results for Aim 1…………………………………………………………………………….13 Methods for Aim 2………………………………………………………………………… 19 Results for Aim 2…………………………………………………………………………….22 Discussion……………………………………………………………………………………27 Tables and Figures for Aim 1……………………………………………………………… 32 Tables and Figures for Aim 2……………………………………………………………… 44 References……………………………………………………………………………………56 Dedication and Acknowledgements: I am thankful for the loving support that I have received from my mother Leslie Bourne, my father Mark Johnson, and my brother Jacob Johnson In loving memory of my grandparents Samuel Smullin, Frances Smullin, Paul Johnson, and Ruth Johnson I could not have asked for better mentorship than I have received throughout medical school I am tremendously grateful for the mentorship and guidance I have received in life and in research from my thesis advisor Dr Michael Bloch and his wife Dr Angeli Landeros-Weisenberger They have been an everpresent source of inspiration, support, advice, and humor over the course of my years in medical school I am also grateful for the mentorship I have received from Dr Robert Rohrbaugh, Dr Andrés Martin, Dr James Leckman, Dr Zheala Qayyum, Dr Brian Fuehrlein, Dr Linda Mayes, Dr Kirsten Wilkins, Dr Karen Jubanyik, Dr Euripedes Miguel, Dr Marcelo Hoexter, Dr Yukiko Kano, Dr Yu Hamamoto, Dr Emeric Bojarski, Dr Eunice Yuen, Dr João Paulo De Aquino and numerous additional residents, fellows, and faculty who have inspired me with their kindness and generosity My work is built upon the sacrifice of my family and my mentors Thesis advisor: Dr Michael H Bloch, Yale Child Study Center Authors who contributed to this thesis: Aim 1: Isaac N.S Johnson, Bridget J Shovestul, Mark J Niciu, Fenghua Li, and Michael H Bloch Aim 2: Jason I Dailey, Bachaar Arnaout, Isaac N.S Johnson, Jessica A Johnson, Megan McNivens, and Michael H Bloch Research reported in this publication was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Number T35AA023760 The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health This publication was also made possible by the Yale School of Medicine Medical Student Research Fellowship Abstract Objective: Aim 1: To examine the efficacy of antidepressant agents compared with placebo in reducing depressive symptoms in subjects with comorbid Alcohol Use Disorders (AUD) Aim 2: To examine the efficacy of antidepressant agents compared with placebo on measures of alcohol consumption Data Sources: Aim 1: PubMed was searched for randomized, placebo-controlled trials that examined the efficacy of antidepressant medications for treating depression symptoms with comorbid AUD Aim 2: Ovid MEDLINE (1946 to September 23, 2016) and CENTRAL (Issue 8, August 2016) were searched with no language limits for randomized placebo-controlled trials that examined the effects of antidepressant medications on alcohol consumption Study Selection: Aim 1: Trials were included if they: 1) were randomized, placebo-controlled clinical trials, 2) examined the effects of an antidepressant medication for comorbid MDD and AUD, and 3) reported depression outcomes Aim 2: Trials were included if they: 1) were randomized, placebo-controlled clinical trials, 2) examined the effects of an antidepressant medication for comorbid MDD and AUD, and 3) reported alcohol consumption outcomes Data Extraction: Aim 1: Random effects meta-analysis was utilized to examine standardized mean difference (SMD) in improvement of depressive symptoms and risk ratio for treatment response Stratified subgroup analysis was used to examine the moderating effects of type of antidepressant medication and other trial characteristics Aim 2: We examined the effect of antidepressant treatment on four alcohol consumption outcomes: (1) drinking days, (2) drinks per day, (3) hazardous drinking days, and (4) abstinence rates Our primary outcome was standardized mean difference for continuous measures and risk ratio for dichotomous outcomes using random effects meta-analysis We also used stratified subgroup analysis to examine the moderating effects of type of antidepressant medication and diagnostic indication Results: Aim 1: Eighteen distinct trial arms involving 1,318 participants were included in this systematic review and meta-analysis In subjects with AUD, antidepressant medications significantly decreased depression severity compared with placebo (SMD=0.33±0.10 (95% Confidence Interval (CI): 0.14-0.51, k=18, z=3.4, p=0.001) Type of antidepressant medication did not significantly affect the magnitude of depressive symptom improvement compared with placebo (Test for subgroup differences χ2=2.15, df=2, p=0.34) TCAs (SMD=0.51±0.19 (95% CI: 0.15-0.88, k=3, z=2.7, p=0.006) and SSRIs (SMD=0.22±0.12 (95% CI: -0.01-0.46, k=10, z=1.9, p=0.06) suggested similar benefits for depressive symptoms in subjects with comorbid AUD The use of concomitant psychotherapy (for either depression or alcohol use) (Test for subgroup differences χ2=9.9, df=1, p=0.002) or concomitant pharmacotherapy for AUD (Test for subgroup differences χ2=4.7, df=1, p=0.03) was associated with a significantly smaller measured treatment benefit of antidepressant agents Aim 2: Twenty-six trials involving 2,771 participants were included in this systematic review and meta-analysis Overall, antidepressant use was not associated with significant changes in drinking outcomes (drinking days, drinks per day, abstinence rates, and hazardous drinking days) When antidepressants were utilized to treat comorbid depression symptoms, antidepressant treatment was associated with improved drinking outcomes on some (drinking days and drinks per day) but not all measures (abstinence rates and hazardous drinking days) When antidepressants were utilized primarily to treat symptoms of other disorders, antidepressant treatment was associated with worsened drinking outcomes on some (drinking days and drinks per day) but not all measures (abstinence rates and hazardous drinking days) Class of antidepressant treatment did not significantly affect any drinking-related outcomes Conclusion: Aim 1: Our meta-analysis suggests that antidepressant medications significantly decrease depressive symptoms in participants with comorbid AUD The magnitude of depressive symptom improvement in subjects with comorbid AUD appears similar to that achieved in MDD trials without comorbid substance use Aim 2: Antidepressant therapy results in improvement in some drinking outcomes when used for comorbid depression, though it may worsen these outcomes in the absence of comorbid depression More research is needed on the impact of antidepressants on drinking outcomes, including the potential moderating effects of age, genotype, and depression and anxiety symptoms Introduction Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD) are among the most prevalent mental health conditions in adult populations AUD is overrepresented in adults with MDD compared with the general population, and depression is overrepresented in patients with AUD.1 Recent genetic analysis supports a strong genetic overlap between MDD and AUD.2 Patients with MDD and comorbid AUD tend to experience greater depression severity, depressive symptoms at an earlier age of onset, increased suicidality and functional impairment, higher rates of relapse and decreased likelihood of recovery from depressive symptoms.3-7 In patients with AUD, comorbid depressive symptoms are associated with an increased likelihood of treatment dropout and relapse.8-10 Pharmacotherapy with antidepressant medications is a first-line treatment for MDD In meta-analysis, antidepressant agents demonstrate a significant benefit compared with placebo for the treatment of major depression with effect sizes of 0.3011 and 0.3712 reported in the literature and a NNT of 6.13 Despite the high rate of comorbidity between AUD and MDD, subjects who meet criteria for current or recent alcohol or other substance use disorders are typically excluded from these pivotal randomized, placebo-controlled trials of antidepressant medications Thus, it is uncertain how well the results of positive antidepressant trials in non-alcohol dependent patients will generalize to clinical MDD populations, where patients often have comorbid AUD.14-20 Previous meta-analyses have found mixed results regarding the efficacy of antidepressants in treating comorbid MDD and AUD A 2004 meta-analysis found that antidepressants have a “modest beneficial effect” in reducing depressive symptoms in patients with a comorbid substance use disorder (not limited to AUD).21 A subsequent metaanalysis suggested a similar effect when meta-analysis was confined to just trials involving subjects with comorbid AUD and MDD This meta-analysis further reported that Selective Serotonin Reuptake Inhibitors (SSRIs), as a class, were not associated with an increased likelihood of response in terms of depressive symptoms, compared to placebo.22 A more recent meta-analysis published in 2011 that similarly examined only treatment response, demonstrated that antidepressant agents overall were more effective than placebo at reducing depressive symptoms in patients with comorbid AUD However, this meta-analysis was not able to demonstrate that SSRIs, as a class, were effective in this population and further suggested that they were less effective than other antidepressants.13 These previous meta-analyses examined only treatment response and not continuous outcomes Also, there are additional recent trials with second generation antidepressants that have been published subsequent to these previous reviews Alcohol use disorder has a lifetime prevalence of 30.3% in the United States according to results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).23 Comorbid alcohol dependence and depression result in 44% more healthcare costs compared to treating depression alone.24 It has been suggested that alcohol use disorder may be causally linked to increased rates of depression,25 though genetic variations in serotonin transporter (SERT) function have also been implicated in both disorders.26 While second- and third-generation antidepressant medications remain the mainstay for treating depression,27 they can also be used in many other psychiatric conditions that are often comorbid with alcohol use disorder For example, Americans with alcohol dependence are three times more likely to have an anxiety disorder and more than five times more likely to have nicotine dependence.23 Moreover, antidepressants were at one time the most commonly prescribed medication for alcohol use disorder,28 though several reviews and meta-analyses have questioned their efficacy for this indication.22, 29, 30 Unfortunately, there has been some case report31 and clinical trial32-35 evidence that the SSRI antidepressants may actually increase alcohol consumption in a subset of the population This would suggest that providers should consider a different class of antidepressants for patients prone to alcohol use disorder Of course, this assumes that classes of antidepressants other than SSRIs have superior outcomes Two recent meta-analyses demonstrated the efficacy of antidepressants for treating depressive disorders in patients with comorbid alcohol use disorder, but either did not report36 or reported only very limited data13 on alcohol consumption outcomes Notably, a 2004 metaanalysis21 studied antidepressant effects on both depression and substance use outcomes in the treatment of depressive disorders with comorbid dependence on alcohol or illicit drugs, and demonstrated improvement in substance use outcomes in the subset of studies in which depressive symptoms improved Similarly, a 2005 meta-analysis22 examined alcohol and illicit drug outcomes in both studies of comorbid depression and studies without comorbid depression, but only found a statistically significant effect on substance use outcomes for first-generation antidepressants, in the treatment of comorbid depression and alcohol use disorder Statement of Purpose The goals of the current meta-analyses are to update previous meta-analyses, as well as, to examine several unanswered questions regarding the use of antidepressant agents in subjects with MDD and comorbid AUD In Aim 1, we specifically sought to determine: (1) What is the measured effect size and relative risk of response for subjects with MDD and AUD treated with antidepressant agents compared with placebo?; (2) Do different medication classes (TCA vs SSRI) have the same measured benefit compared with placebo for subjects with MDD and AUD?; (3) Does the use of concomitant psychotherapy, targeting either depression or alcohol use, or concomitant pharmacotherapy for AUD moderate the benefits of antidepressant agents in the treatment of MDD with comorbid AUD?; and (4) Does the 46 Figure 1: PRISMA Flow Diagram44 Records identified through database searching (n = 446) (n = ) Additional records identified through other sources (n = 3) Records after duplicates removed (n = 354) Records screened (n = 354) Records excluded (n = 260) Full-text articles assessed for eligibility (n = 94) Full-text articles excluded (n = 68): • • Studies included in qualitative synthesis (n = 26) • • Studies included in quantitative synthesis (meta-analysis) (n = 26) • • Duplicate studies (n = 18) Not randomized, placebo-controlled trials (n=21) Did not evaluate antidepressants of interest (n=7) Did not report on alcohol consumption outcomes (n=16) Did not examine adult subjects (n=2) 47 Figure 2a Forest Plot-SMD in Drinking Days Stratified by Medication Type 48 Figure 3a Forest Plot-SMD in Drinking Days Stratified by Diagnostic Indication 49 Figure 2b Forest Plot-SMD in Drinks per Day Stratified by Medication Type 50 Figure 3b Forest Plot-SMD in Drinks per Day Stratified by Diagnostic Indication 51 Figure 2c Forest Plot-SMD in Hazardous Drinking Days Stratified by Medication Type SSRI Brady KT 0.63 (0.21, 1.04) Cornelius JR 1997 -0.81 (-1.39, -0.24) Hien DA Kranzler HR 2011-LL EO Kranzler HR 2011 - S EO Kranzler HR 2011 - LL LO Kranzler HR 2011 - S LO 0.33 (-1.39, -0.24) 2.38 (0.95, 3.80) 0.13 (-0.56, 0.82) -0.91 (-1.79, -0.03) 0.41 (-0.08, 0.90) Thomas SE -0.02 (-0.62, 0.59) Fixed 0.18 (-0.03, 0.39) Random 0.16 (-0.31, 0.64) SNRI Ciraulo DA-relaxation 0.13 (-0.46, 0.72) Ciraulo DA-CBT 0.38 (-0.29, 1.06) Fixed 0.24 (-0.21, 0.68) Random 0.24 (-0.21, 0.68) Other -4 Cornelius JR 2016 0.65 (-0.42, 1.73) Hernandez-Avila CA -1.06 (-1.71, -0.40) Kranzler HR 2000 0.17 (-0.19, 0.52) Wetzel H - Supportive -0.03 (-0.43, 0.37) Fixed Fixed Random Random -3 -2 -1 Decreased Hazardous Drinking Days with Antidepressants Increased Hazardous Drinking Days with Antidepressants Standardized Mean Difference in Hazardous Drinking Days 52 Figure 3c Forest Plot-SMD in Hazardous Drinking Days Stratified by Diagnostic Indication 53 Figure 2d Forest Plot-Risk Ratio of Response-Abstinence Stratified by Medication Type 54 Figure 3d Forest Plot-Risk Ratio of Response-Abstinence Stratified by Diagnostic Indication 55 Figure Legends for Aim 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