Depression is a leading cause of disability, with potentially disastrous outcomes such as suicide.1 Major depressive disorder (MDD) is a highly prevalent, debilitating disease that is often recurrent, resulting in significant loss of function, excess healthcare costs, and premature death. By 2030, the WHO predicts that MDD will be a leading cause of global disease burden.2 The economic impacts are high – in 2016, for example, decreased workplace productivity and impaired occupational functioning associated with MDD resulted in losses of more than $200 billion in the United States.3

When Depression Treatment Fails: Risk Factors & Approaches

Studies have shown that up to 50% of patients with MDD do not respond adequately after two antidepressant treatment trials. Such failure to achieve an adequate response is the most common definition of treatment-resistant depression (TRD).

Risk factors for TRD include:

  • symptom severity
  • comorbid anxiety disorders
  • psychotic symptoms
  • elevated risk of suicide
  • a higher number of lifetime depressive episodes
  • longer episode duration4

Common treatment strategies for TRD include:

See also, the growth of rapidly acting antidepressants.

Depression and Risks of Substance Use Disorder

Substance use disorders (SUDs) are a major contributor to and risk factor for the development of MDD.6 Among patients with depression, the lifetime prevalence of any SUD, but especially alcohol use disorder (AUD), is as high as 40%.7

A temporal association between depression and SUD exists, but it is complex. Depression and other mental disorders often precede the presentation of SUDs, but the relationship may be bidirectional and it may vary for different types of drug use and during different stages in life. It’s a classic chicken-or-egg question. Adding to the mix is that the effect of antidepressants is decreased when a comorbid SUD is present.8

In a recent study of 121,699 patients with major depressive disorder who were identified in governmental health registries in Sweden, Philip Brenner, MD, PhD, and colleagues at the Karolinska Institute in Stockholm sought to determine whether the 13% of patients considered to have TRD had a higher risk for subsequent SUD compared with those with MDD, and whether that risk was dependent on having had a previously known SUD. They found that patients with TRD, both with and without previous SUD, had an elevated risk for subsequent SUD compared with other patients with MDD.8

Dr. Brenner’s team further investigated the reverse relationship – that is, whether having a diagnosed SUD increases an individual’s risk for developing TRD.9 In that study, Dr. Brenner’s team found that those who had any SUD during or up to 180 days before the start of treatment had almost double the risk for TRD (OR = 1.86, CI = 1.7 – 2.05). These findings were similar for alcohol, opioid, cannabinoid, sedative, and combined drug SUD. However, patients with a history of alcohol SUD more than 180 days before treatment initiation had a lower risk for TRD.9

Substance Use Disorders and Treatment-Resistant Depression

Substance use disorder, depression, and treatment-resistant depression may not only be directly associated with each other, according to Dr. Brenner and team, but they share underlying socio-demographic and biological risk factors.

SUD, for instance, may cause structural and biochemical changes in the brain, especially in the dopamine system, that induce a depression-like state and affect substrates for antidepressant medication.9

In addition, under the “self-medication hypothesis,” patients with undiagnosed depression may be more prone to developing a SUD when they use substances to cope with difficult symptoms.10 Underlying genetic factors may also be at play, increasing an individual’s susceptibility to both SUD and depression.

Anxiety and personality disorders are known risk factors for depression, TRD, and SUD alike. These connections are supported in Dr. Brenner’s study by the increased risk for TRD among patients with comorbid SUD and personality disorders.10

Clinical Implications: The Need to Co-Treat Depression and Substance Use Disorder

Overall, the data provide clear and persuasive evidence that mood and anxiety disorders must be addressed by alcohol and drug treatment specialists and that SUDs must be addressed by primary care physicians and mental health treatment specialists.7 The risk of suicide is elevated among patients with TRD, and substance abuse is a strong independent risk factor for attempted suicide (OR 2.6, CI = 2.2-3.1).

Suicide attempts, especially recent ones, are strong risk factors for completed suicide among patients with TRD.11 In fact, a recently released report on rising midlife mortality rates found that drug- and alcohol-related deaths made up 8% of all deaths among working-age adults from 1990 to 2017 and contributed to the 2020 decrease in life expectancy.12

Because healthcare providers have multiple contacts with patients with TRD, they have opportunities for clinical evaluation and suicide risk assessment. Close follow-up after a suicide attempt may have a protective effect against completed suicide. Clinicians should inquire about current or prior SUD in any patient who presents with depression. Inquiring about self-medication with drugs or alcohol and providing alternate coping strategies for mental distress may forestall the development of SUD and comorbid TRD.10

When an SUD is identified, current guidelines state that both conditions should be treated simultaneously, targeting both the depression and the SUD. If treatment resistance emerges in a patient with depression, add-on medication or electroconvulsive therapy or transcranial magnetic stimulation (ECT/rTMS) should be considered.9

See our primer on treating alcohol use disorder and opioid use disorder. Plus, how race and stigma can affect SUD treatment outcomes.

On the Horizon: Emerging Approaches for Treatment-Resistant Depression

More novel treatments for TRD are also under consideration but need more research. According to Dr. Brenner, “Emerging, potentially effective treatment strategies for TRD, such as [ketamine and other] NMDA receptor agonists, as well as hallucinogens, may have a known potential for illicit use but have also shown potential for treatment of SUD. Their role in the treatment of patients with combined TRD and SUD is yet to be determined.”9

See also, tailored antidepressant therapy.


Last Updated: Oct 1, 2021