Comorbid Substance Use Disorder Raises Risk of Treatment-Resistant Depression

Patients with treatment resistant depression (TRD), defined as at least 3 treatment trials within a single depressive episode, were matched with 5 controls with non-treatment–resistant depression.

Current or recent substance use disorder (SUD) may be a risk factor for treatment resistance among patients with depression, according the results of a Swedish nested case-control study published in Addiction.

Philip Brenner, MD, PhD, of the Karolinska Institutet in Stockholm, Sweden, and colleagues used Swedish governmental healthcare registers and data on prescription drugs and diagnoses from specialized healthcare to establish a cohort of subjects initiating antidepressants for depression (N=121,669) from 2006 to 2014. Patients with treatment-resistant depression (TRD), defined as at least 3 treatment trials within a single depressive episode, were matched with 5 controls with non-TRD.

Related Articles

TRD was observed in 13% (n=15,631; mean age, 39.9±15.0; 58% women) of patients. The investigators found that patients with personality disorder and SUD in the year prior had a disproportionately elevated risk for TRD (odd ratio [OR], 21), but because of the limited number of patients with comorbid personality disorder (n=174) these data were excluded from the final analysis.

In analyses adjusted for education level and anxiety, the risk for TRD remained high for patients with SUD during the treatment period (OR, 1.6) and during the 180-day lead-in period (OR, 1.9). Those who had a diagnosis of SUD for 1 year or more before the lead-in period (OR, 0.5) and those with a diagnosis of SUD for 1 to 5 years before the lead-in period (OR, 0.8) had a significantly lower risk of TRD. However, when the data were stratified by SUD subtype, this reduced risk was found only in subjects with alcohol use disorder. Subjects with a sedative (OR, 2.4) or combined SUD (OR, 2.3) were at the highest risk for TRD.

“We found that SUD before start of, or during, treatment increases the risk for subsequent TRD. Findings were similar for alcohol, opioid, cannabinoid, sedative and combined drug SUD. Conversely, risk for TRD was lowered among patients with history of alcohol SUD further back than 180 days before treatment start,” the researchers noted.

However, the study authors cautioned that the relationship between SUD, depression, and TRD is likely complex and multidimensional, as these disorders may not be directly associated with one another but may share underlying sociodemographic and biological risk factors. SUD may cause structural and biochemical changes in the brain, particularly in the dopamine system, which may result in depression and affect antidepressant mechanism substrates at the same time.

Limitations of this study included the use of a definition of TRD that has not yet been verified through clinical data, as well as the inability to assess depression severity level, side effects, clinical effectiveness of treatment, reasons for treatment discontinuation, and patient adherence to antidepressant regimens. The authors called for future research to identify effective interventions for patients with TRD and present or recent comorbid SUD.


Brenner P, Brandt L, Li G, DiBernardo A, Boden R, Reutfors J. Substance use disorders and risk for treatment resistant depression—population based, nested case-control study. Addiction. 2019. doi:10.1002/add.14866.