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Comorbidities in MDD

CME

Comorbidity Considerations in Major Depressive Disorder and Treatment Augmentation

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: April 13, 2020

Expiration: April 12, 2021

CME/CE Information

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In your practice, when managing patients with MDD, how likely are you to address smoking cessation and substance use disorder?
MDD and Comorbid Substance Use Disorder

Another important comorbidity in patients with MDD includes substance use disorders. Approximately 1 in 3 patients with MDD has a comorbid substance use disorder, most commonly alcohol use disorder.42 Rates of comorbid cannabis use disorders among patients with MDD have ranged between 12% and 30%, whereas stimulant abuse has been relatively low, at 5%.43

Recent or current substance use disorders are associated with treatment‑resistant depression.42 However, the relationship is complex and potentially bidirectional.

It could be that the treatment resistance leads to drug abuse in an attempt to self‑medicate and briefly feel better, which unfortunately promotes worsening of depression in the long run.

Alternatively, the substance abuse could be part of the etiology of depression, being associated with cravings, psychosocial adversity, and stress, which may promote MDD.

In general, people with substance use disorders have a higher risk of social and personal impairment, increased comorbid psychiatric conditions, as well as suicidality.44 

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SAMHSA: Past-Year Substance Abuse Among Adults With and Without Major Depressive Episode

In a review by the US Department of Health and Human Services’ Substance Abuse and Mental Health Services Administration, there was a clear preponderance of substance use in people with a major depressive episode of MDD in the previous year.45

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MDD and Comorbid Substance Use Disorder: Mechanistic Commonalities

Why is there an association between MDD and comorbid substance use disorders? This relationship may result from dysregulation of reward pathways and anhedonia, which are at the core of MDD.

Individuals with MDD have a dysfunction of their reward circuitry involving the ventromedial prefrontal cortex, subgenual cortex, and nucleus accumbens.46 These dysfunctions lead to a low hedonic tone and mood disorders, whereas the acute effect of most substances is an increase in dopamine and reward. However, over time, the reward system becomes exhausted and patients are likely to become more depressed than without the substance use disorder.

Anhedonia is also a core component of both MDD and substance use disorder; both conditions lead to altered activation patterns within brain regions that are involved in reward processing and monoamine signaling.46 Moreover, patients who are receiving SSRI antidepressants may experience adverse events such as emotional blunting or indifference that can contribute to anhedonia. In addition, antipsychotic‑induced strong dopamine blockade can both dampen reward circuitry functioning as well as induce anhedonia or dysphoria.

Therefore, dosages of second‑generation antipsychotics used for treatment augmentation in MDD are generally far lower than those used and needed for the treatment of psychosis or mania, where dopamine blockade is central.

As mentioned previously, second‑generation antipsychotics given as augmentation with antidepressants have an effect on depression via nondopaminergic mechanisms that are engaged at lower dose levels. The use of partial dopamine agonists, such as aripiprazole and brexpiprazole, also relates to effective treatment without complete or too much dopamine blockade.

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MDD and Treatment of Comorbid Substance Use Disorder

How would we treat comorbid substance use disorders in people with MDD? Since both conditions are relevant and interact with each other, both should be treated simultaneously.47 This approach generally involves a combination of psychosocial interventions.48

For depression, cognitive behavioral therapy has the best evidence; for substance use disorders, treatments and psychosocial interventions that promote abstinence or at least a reduction in substance intake tend to be most effective. These efforts are generally combined with self‑help/support groups (eg, Alcoholics Anonymous, Narcotics Anonymous). If needed, pharmacotherapy can be implemented for the treatment of depression and/or substance abuse. For substance use disorders, approved treatments include buprenorphine and methadone for opioid addiction, naltrexone for opioid and alcohol addiction, and acamprosate for alcohol addiction.

It is my clinical impression that effective MDD treatment can lead to an improvement in substance use behavior, particularly in patients who are believed to be self‑medicating because of inappropriate antidepressant efficacy. Current data are not particularly strong in this area, but more research is warranted. Antidepressants may improve depression in patients with alcohol use disorder; it is unclear whether the same therapies may alleviate depression in patients who abuse cocaine or opioids.47 Neither antidepressants nor antipsychotics have been shown to improve outcomes in alcohol, cocaine, or opioid use disorders, suggesting again that a combined pharmacologic and psychosocial intervention may be most useful. Additional clinical studies are needed in this area.

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Treatment Choices for MDD With Comorbid Substance Use Disorder

Norepinephrine reuptake inhibitors and dopamine stimulants directly elevate extracellular dopamine in the nucleus accumbens and may be more effective than SSRIs in patients with MDD and comorbid substance use disorder.46 Psychostimulants have the risk of being abused themselves, so in this case, the selective dopamine‑enhancing antidepressant bupropion may be preferable.

Tricyclic antidepressants, mirtazapine, venlafaxine, and duloxetine all elevate norepinephrine and have shown more consistent efficacy than SSRIs in patients with MDD and comorbid substance use disorder.46

Second‑generation antipsychotics generally block both serotonin and dopamine receptors.49 Theoretically, partial D2 agonists such as aripiprazole and brexpiprazole may stabilize the dopamine system, and they have the potential to modulate depression and craving and thereby potentially improve treatment adherence and reduce substance use behaviors. However, more data are needed in this area.

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