Concerns regarding the recommendation against prescribing selective serotonin reuptake inhibitors in the Canadian guideline for the clinical management of high-risk drinking and alcohol use disorder
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* Anees Bahji
* Marlon Danilewitz
* Matthew Sloan
* Victor Tang
* David Crockford

The Canadian guideline by Wood and colleagues1 on the management of high-risk drinking and alcohol use disorder (AUD) highlights an under-recognized issue. Most of the recommendations are well supported, but recommendation 13’s caution against the use of selective serotonin reuptake inhibitors (SSRIs) for people with AUD and non-substance-induced major depressive disorder (MDD) or anxiety warrants further consideration given potential unexplored issues.

In support of this recommendation, the guideline cites studies by Charney and colleagues2 and Friedmann and colleagues,3 along with a systematic review by Stokes and colleagues;4 however, these studies have limitations. For example, the study by Charney and colleagues2 primarily focused on AUD treatment, not depression, making it challenging to draw conclusions on use of SSRIs for AUD with comorbid depression. The study by Friedmann and colleagues3 used low-dose trazodone, not an SSRI, and did not effectively distinguish between substance-induced and primary depression or anxiety disorders. In essence, these studies were not designed to assess SSRIs’ efficacy for AUD with primary MDD or anxiety disorders, so using them to recommend against SSRIs in these cases is inappropriate.

Unlike studies using antidepressant monotherapy in patients with AUD, combining SSRIs with AUD treatment in those with both AUD and MDD has shown important benefits. For instance, Pettinati and colleagues5 found improved outcomes with sertraline and naltrexone combination therapy. Similarly, Moak and colleagues6 reported that patients took fewer daily drinks with sertraline and cognitive behavioural therapy (CBT), compared with placebo plus CBT. Integrated care models for substance use and mental health treatment have also shown promise, improving both depressive symptoms and alcohol use outcomes.5,7

Cochrane reviews suggest that SSRIs may help treat MDD, anxiety, AUD, or cooccurring AUD and MDD or anxiety with minimal adverse effects compared with placebo.8,9 Long-term studies by Cornelius and colleagues10–13 show fluoxetine’s persistent efficacy in reducing depressive symptoms and alcohol consumption in patients with MDD and AUD. Pragmatic trials have not found a significant difference in the antidepressant effects of SSRIs for the treatment of MDD alone compared with MDD and comorbid AUD.14–16

Untreated MDD in AUD has consequences; Samet and colleagues17 found that substance-induced depression predicted post-discharge substance use, while independent MDD worsened alcohol and cocaine use disorders.

The guideline’s recommendation advises against prescribing SSRIs for comorbid anxiety disorders and AUD despite limited evidence. However, some evidence suggests SSRIs may help, and strongly discouraging SSRIs is not justified, considering patients may still have debilitating symptoms after trying other treatments like psychotherapy.

In conclusion, the recommendation against use of SSRIs in patients with AUD and comorbid MDD or anxiety is not justified. Although polypharmacy should be minimized whenever possible, there is evidence that SSRIs can be effective for those with AUD and well-diagnosed comorbid MDD or anxiety disorders.

## Footnotes

*   Competing interests: Anees Bahji is supported by the Canadian Institutes of Health Research (CIHR), the University of Calgary, and the Calgary Health Trust. He also reports consulting fees from the City of Calgary, honoraria from TED-Ed, and travel grants from the Canadian Psychiatric Association (CPA), the Canadian Society of Addiction Medicine, the American Psychiatric Association, and the American Society of Addiction Medicine. He is an associate editor with the *Canadian Journal of Addiction*, board member with the International Society of Addiction Journal Editors, and co-chair of the Section of Addiction Psychiatry with the CPA. Marlon Danilewitz reports personal fees for advisory board participation, speaker fees, consulting fees, or education grants from Eisai, Otsuka, Janssen, Lundbeck, Winterlight Labs, Rapids Health, Pearls for Primary Care, the BC Psychiatric Association, and the Ontario Brain Institute. He receives a stipend from the CPA for administrative work and has received support for academic meeting attendance and presentations from Ontario Shores Centre for Mental Health Sciences, the Canadian Academy of Addiction Psychiatry, and the CPA. Matthew Sloan receives funding from the CIHR, the Ontario Ministry of Health and Long-Term Care, Health Canada, the Centre for Addiction and Mental Health Discovery Fund, and the Department of Psychiatry, University of Toronto. He reports honoraria from McGill University Health Centre and travel awards from the Society of Biological Psychiatry and the International Society for Central Nervous System Clinical Trials and Methodology. No other competing interests were declared.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: [https://creativecommons.org/licenses/by-nc-nd/4.0/](https://creativecommons.org/licenses/by-nc-nd/4.0/)

## References

1.  Wood E, Bright J, Hsu K, et al.; Canadian Alcohol Use Disorder Guideline Committee. Canadian guideline for the clinical management of high-risk drinking and alcohol use disorder. CMAJ 2023;195:E1364–79.
    
    [Abstract/FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY21haiI7czo1OiJyZXNpZCI7czoxMjoiMTk1LzQwL0UxMzY0IjtzOjQ6ImF0b20iO3M6MjI6Ii9jbWFqLzE5Ni8xMC9FMzQ2LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

2.  Charney DA, Heath LM, Zikos E, et al. Poorer drinking outcomes with citalopram treatment for alcohol dependence: a randomized, double-blind, placebo-controlled Trial. Alcohol Clin Exp Res 2015;39:1756–65.
    
    

3.  Friedmann PD, Rose JS, Swift R, et al. Trazodone for sleep disturbance after alcohol detoxification: a double-blind, placebo-controlled trial. Alcohol Clin Exp Res 2008;32:1652–60.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1111/j.1530-0277.2008.00742.x&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=18616688&link_type=MED&atom=%2Fcmaj%2F196%2F10%2FE346.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000258726700016&link_type=ISI) 

4.  Stokes PRA, Jokinen T, Amawi S, et al. Pharmacological treatment of mood disorders and comorbid addictions: a systematic review and meta-analysis. Can J Psychiatry 2020;65:749–69.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1177/0706743720915420&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=32302221&link_type=MED&atom=%2Fcmaj%2F196%2F10%2FE346.atom) 

5.  Pettinati HM, Volpicelli JR, Kranzler HR, et al. Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype. Alcohol Clin Exp Res 2000;24:1041–9.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1111/j.1530-0277.2000.tb04648.x&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=10924008&link_type=MED&atom=%2Fcmaj%2F196%2F10%2FE346.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000088212400015&link_type=ISI) 

6.  Moak DH, Anton RF, Latham PK, et al. Sertraline and cognitive behavioral therapy for depressed alcoholics: results of a placebo-controlled trial. J Clin Psychopharmacol 2003;23:553–62.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1097/01.jcp.0000095346.32154.41&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=14624185&link_type=MED&atom=%2Fcmaj%2F196%2F10%2FE346.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000186613500005&link_type=ISI) 

7.  Samokhvalov AV. Theory and practice of treatment of concurrent major depressive and alcohol use disorders: 7 lessons from clinical practice and research. Can J Addict 2021;12:39–46.
    
    

8.  Agabio R, Trogu E, Pani PP. Antidepressants for the treatment of people with co-occurring depression and alcohol dependence. Cochrane Database Syst Rev 2018;4:CD008581. doi: 10.1002/14651858.CD008581.pub2.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1002/14651858.CD008581.pub2&link_type=DOI) 

9.  Ipser JC, Wilson D, Akindipe TO, et al. Pharmacotherapy for anxiety and comorbid alcohol use disorders. Cochrane Database Syst Rev 2015; 1:CD007505. doi: 10.1002/14651858.CD007505.pub2.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1002/14651858.CD007505.pub2&link_type=DOI) 

10. Cornelius JR, Bukstein OG, Birmaher B, et al. Fluoxetine in adolescents with major depression and an alcohol use disorder: an open-label trial. Addict Behav 2001;26:735–9.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1016/S0306-4603(00)00152-0&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=11676382&link_type=MED&atom=%2Fcmaj%2F196%2F10%2FE346.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000171105700009&link_type=ISI) 

11. Cornelius JR, Salloum IM, Haskett RF, et al. Fluoxetine versus placebo in depressed alcoholics: a 1-year follow-up study. Addict Behav 2000; 25:307–10.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1016/S0306-4603(99)00065-9&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=10795957&link_type=MED&atom=%2Fcmaj%2F196%2F10%2FE346.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000085833900015&link_type=ISI) 

12. Cornelius JR, Bukstein OG, Wood DS, et al. Double-blind placebo-controlled trial of fluoxetine in adolescents with comorbid major depression and an alcohol use disorder. Addict Behav 2009;34:905–9.
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=19321268&link_type=MED&atom=%2Fcmaj%2F196%2F10%2FE346.atom) 

13. Cornelius JR, Clark DB, Bukstein OG, et al. Fluoxetine in adolescents with comorbid major depression and an alcohol use disorder: a 3-year follow-up study. Addict Behav 2005;30:807–14.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1016/j.addbeh.2004.08.025&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=15833583&link_type=MED&atom=%2Fcmaj%2F196%2F10%2FE346.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000228757100015&link_type=ISI) 

14. Tang VM, Yu D, Weissman CR, et al. Treatment outcomes in major depressive disorder in patients with comorbid alcohol use disorder: a STAR*D analysis. J Affect Disord 2023;339:691–7.
    
    

15. Davis LL, Wisniewski SR, Howland RH, et al. Does comorbid substance use disorder impair recovery from major depression with SSRI treatment? An analysis of the STAR*D level one treatment outcomes. Drug Alcohol Depend 2010;107:161–70.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1016/j.drugalcdep.2009.10.003&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=19945804&link_type=MED&atom=%2Fcmaj%2F196%2F10%2FE346.atom) 

16. Davis LL, Pilkinton P, Wisniewski SR, et al. The effect of concurrent substance use disorder on the effectiveness of single and combination antidepressant medications for the treatment of major depression: an exploratory analysis of a single-blind randomized trial. Depress Anxiety 2012;29:111–22.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1002/da.20918&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=22495941&link_type=MED&atom=%2Fcmaj%2F196%2F10%2FE346.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000302618400005&link_type=ISI) 

17. Samet S, Fenton MC, Nunes E, et al. Effects of independent and substance-induced major depressive disorder on remission and relapse of alcohol, cocaine and heroin dependence. Addiction 2013;108:115–23.