Alcohol use disorder (AUD) is a common condition with a lifetime prevalence of approximately 30% in the general population (1) and highly prevalent in veterans (2). Among adults with AUD, 30–59% also meet criteria for post-traumatic stress disorder (PTSD) (3), and up to 50% meet criteria for major depressive disorder (MDD) (4). Among veterans with AUD, there are also high rates of comorbid psychiatric conditions, including MDD and PTSD (5, 6). Comorbidity between MDD and PTSD is also common; one recent study reported that 36.8% of veterans with co-occurring PTSD and AUD also screened positive for MDD (7).

Alcohol use disorder and co-occurring MDD or PTSD is associated with more severe symptoms and worse alcohol-related outcomes, functional impairment, and increased risk of suicide (7–10). However, to date, very few studies have examined the effectiveness of pharmacologic treatments when there are multiple psychiatric diagnoses, such as co-occurring MDD and/or PTSD in those with AUD. When comorbid conditions occur, clinically it is often unclear whether treatments which have been developed in individuals without the comorbid condition are effective in “real world” clinical settings where comorbid conditions are often the rule rather than the exception (11).

Selective serotonin reuptake inhibitors (SSRIs), including paroxetine, are first-line evidence-based pharmacotherapies for both PTSD and depression (12, 13). The literature evaluating the effectiveness of SSRIs when used in individuals with comorbid AUD is mixed. Studies mostly support the use of SSRIs in reduction of PTSD and depressive symptoms in patients who have AUD with co-occurring PTSD (14, 15) and MDD (16, 17), respectively. However, most studies do not support the role of SSRIs in improving alcohol use outcomes in patients with co-occurring PTSD and AUD (15, 18–22) and MDD and AUD (20, 23).

Tricyclic antidepressants with noradrenergic reuptake inhibition (NRI) properties were one of the first medications for PTSD supported by double-blind, placebo-controlled clinical trials (24). Desipramine is an oral tricyclic antidepressant, and has both noradrenergic and serotonergic reuptake inhibiting properties (25). Noradrenergic mechanisms are implicated in the pathophysiology of PTSD (26) and depression (27). While noradrenergic antidepressants are approved for treatment of depression (28), they have not been rigorously tested in PTSD (14). Few studies have directly compared them to SSRIs (29) and their role in comorbidity is not well-known. Our work comparing the noradrenergic antidepressant desipramine to the SSRI paroxetine in 88 individuals with co-occurring PTSD and AUD found that desipramine and paroxetine were equivalent in decreasing symptoms of PTSD, but desipramine was superior to paroxetine in reducing alcohol consumption, with significantly reduced heavy drinking days and number of drinks per week compared to paroxetine (14). Depressive symptoms significantly decreased over time with no difference between treatment arms. Of note, adding naltrexone did not demonstrate any additional advantage on drinking outcomes although did significantly improve craving for alcohol. All in all, extant literature suggests that co-occurring psychiatric disorders in patients with AUD complicate treatment and deserves further investigation to guide clinical decision making. Further, while some studies have evaluated the effectiveness of treatment of AUD when it co-occurs with either PTSD or MDD, the comorbidity of all three disorders has not yet been examined.

In this study, 128 subjects who had alcohol dependence [using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)] who also had co-occurring PTSD and/or MDD were recruited to participate in a study comparing the effects of desipramine vs. paroxetine with or without naltrexone vs. placebo on alcohol use craving, mood, and PTSD symptoms. As noted above, we have previously published the results of those with PTSD with and without MDD (14). In a further effort to investigate the differences in treatment outcomes by comorbidity, we first compared the effects of desipramine vs. paroxetine and naltrexone vs. placebo regardless of diagnostic group in the full sample. Then we examined separately the groups with (1) current MDD alone (MDD group), (2) current PTSD alone (PTSD group), and (3) both MDD and PTSD (comorbid group), and compared alcohol use craving, as well as depressive symptoms by medication. The aim of the current study was to elucidate the role of comorbid diagnoses in treatment outcomes that may offer guidance in clinical settings.

In this randomized clinical trial of 128 veterans with AUD and co-occurring MDD and/or PTSD, we found different responses to antidepressant medication in drinking outcomes by comorbidity; paroxetine demonstrated better drinking results than desipramine for those with co-occurring MDD, whereas desipramine showed better drinking results relative to paroxetine for individuals with PTSD, even in the case of concurrent major depression (MD). With regards to craving, naltrexone showed greater superiority over placebo, and this difference was driven by the response in the PTSD group. For depressive symptoms overall, paroxetine was statistically superior to desipramine in reducing depressive symptoms in the full sample. There was no clinical advantage of adding naltrexone compared to placebo.

The most notable finding of our study is the difference in response of drinking outcomes to desipramine vs. paroxetine by comorbidity profile. The findings extend the results from our previous study (14). Consistent with that study, there was superiority of desipramine over paroxetine in alcohol use outcomes among those with PTSD. However, when there is MDD without co-occurring PTSD diagnosis, paroxetine reduced alcohol use compared to desipramine. Desipramine has been tested previously in MDD with co-occurring AUD in a placebo-controlled RCT of 71 patients with AUD (18). Desipramine reduced alcohol relapse compared to placebo in patients with co-occurring depression and AUD, but not in those without depression (18). Since the present study did not have a placebo antidepressant, it is unknown whether desipramine would fare better than placebo and whether there the difference between desipramine and paroxetine is clinically meaningful. There is interest in using noradrenergic agents, such as prazosin (39, 40) and doxazosin (41, 42) to treat AUD alone and as it co-occurs with PTSD (14, 43). However, there are no studies to our knowledge on whether these agents are also effective with co-occurring MDD. Although noradrenergic mechanisms are implicated in both MDD and PTSD (26, 27), this study suggests that effectiveness of some medications used for AUD may yield different responses among those with co-occurring MDD when it occurs without PTSD. This would be an important area of further study, given how commonly MDD occurs in AUD.

Adding naltrexone to an antidepressant did not demonstrate statistical significance in reduction of drinking outcomes over placebo. One possible explanation of this finding is that a “floor effect” may have affected the results of this study (44). Further, the effect of naltrexone may not have been detected due to lack of power. However, naltrexone significantly decreased cravings compared to placebo in the PTSD group which is consistent with the primary paper (14), however, this did not demonstrate differences in the comorbid and MDD groups.

Future studies investigating the role of comorbidity in response to antidepressants should also consider the differences in responses by clinical subtypes of AUD. For example, age of onset has been found to influence outcomes with serotonergic agents in terms of depression (45, 46) and similarly, presence of comorbidity also has been shown to be important (20). Consistent with this, in a study of PTSD and AUD, late onset AUD and early onset PTSD was associated with better outcomes while those with more severe AUD and later-onset PTSD who were treated with sertraline showed poorer drinking outcomes relative to placebo (21).

The finding that paroxetine was superior to desipramine in reducing depressive symptoms regardless of diagnostic group has several caveats. Further examination suggests this finding was driven primarily by the subsample of those with MDD alone; our previous study in those with PTSD, showed no difference in paroxetine or desipramine in reducing symptoms of PTSD or depressive symptoms. Second, it should be noted that these differences were small and may not have been clinically significant. Baseline depression scores were in the mild range and there may have been a floor effect (44). There was no placebo comparison, so it is unknown whether this was a true medication effect. It is also plausible that reduction of alcohol use may have partially mediated the reduction of depressive symptoms. The comparative effectiveness between serotonergic and noradrenergic antidepressants in reducing depressive symptoms has been studied in numerous trials in the depression literature (47). In a meta-analysis of 15 head-to-head RCTs comparing SSRIs and SNRIs showed that SNRIs had statistical significance over SSRIs in treating MDD (47); these studies did not include participants with AUD. In the AUD literature, a recent network meta-analysis of 68 RCTs consisting of 5,890 patients with AUD comparing different classes of antidepressants including SSRIs (e.g., paroxetine, citalopram, escitalopram, fluoxetine, and sertraline), NRIs (e.g., venlafaxine and viloxazine), and tricyclic antidepressants (e.g., desipramine, imipramine, amitriptyline) showed that NRIs demonstrated the best efficacy and were superior to SSRIs in reducing scores of depression scales (48). However, in that study, desipramine was categorized as a tricyclic antidepressant, which did not show any statistically significant difference in both depression and AUD outcomes when compared to SSRIs (including paroxetine) (48).

This study has several limitations. First, given the nature of the parent trial, the overall HAM-D scores were low on average, even though all participants met criteria for MDD. Second, we were not able to look into the clinical subtypes of AUD, which have been suggested to impact treatment response of alcohol use outcomes to antidepressants in previous trials of co-occurring AUD and PTSD (21). Third, there were large drop outs in both groups (54% for desipramine vs. 47% for paroxetine). An attrition analysis was not conducted given that the attrition rates were similar in both groups. Lastly, the study sample was predominantly male which limits its generalizability to women.

Notwithstanding these limitations, this study provides preliminary evidence on how different comorbidities may influence clinical practices in individuals with AUD and co-occurring psychiatric disorders. Clinical implications of these findings are that when a patient presents with AUD and MDD, paroxetine may have an advantage in addressing both depressive symptoms and alcohol use outcomes. In addition to the findings of the primary study showing that for patients with co-occurring AUD and PTSD, desipramine may have an advantage in alcohol use outcomes, it further suggests that when individuals with co-occurring AUD and PTSD also meet criteria for MDD, desipramine may have even larger benefits over paroxetine.

The raw data supporting the conclusions of this article may be made available by the authors, upon request.

The studies involving human participants were reviewed and approved by VA Connecticut HSS and Yale IRB. The patients/participants provided their written informed consent to participate in this study.

IP: supervised all aspects of study conduct, acted as senior author of the manuscript, and contributed to the writing of the manuscript. ER: conducted data analysis, contributed to the writing of the manuscript, and supervised the recruitment and study conduct. PN: contributed to the drafting, writing, and editing processes for the manuscript. OJ and AW: contributed to literature review and editing of the manuscript. All authors contributed to the article and approved the submitted version.

This study was funded by the New England Mental Illness Research Education and Clinical Center (MIRECC) and the National Center for PTSD (NC-PTSD).

IP has served as a consultant for Alkermes and BioXcel Therapeutics and has received in-kind medication from Alkermes and BioXcel for grant-funded studies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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