Managing treatment-resistant depression with comorbid substance use disorders

Overview: Double-trouble

Substance use disorders (SUDs) and depressive disorders, including major depressive disorder (MDD), dysthymia, and substance induced mood (depressive) disorder (SIMD) are among the most prevalent psychiatric disorders in the world ( ; ). Not only are both independently common in the general population, they frequently cooccur in patients leading to challenges in assessment, differential diagnosis, treatment, and clinical management. Therefore, this chapter will focus on this area of clinical importance with a specific focus on the comorbidity between depression and alcohol use disorder (AUD), opioid use disorder (OUD), and stimulant (cocaine and methamphetamine) use disorder.

Throughout this chapter, the terms of drug dependence, drug addiction, alcohol and drug abuse will be used as most research conducted in the field used these terms, based on previous versions of the DSM systems (such as DSM-IV). However, it should be noted that these terms are no longer used in DSM-5 terminology and criteria, and a distinction will be made where relevant.

SUDs are common in the general population with the most recent data showing the prevalence of 12-month and lifetime AUD (DSM-IV) were 13.9% and 29.1%, respectively ( ). The same survey also revealed prevalence rates of 12-month and lifetime substance use disorders (amphetamine, cannabis, club drug, cocaine, hallucinogen, heroin, nonheroin opioid, sedative/tranquilizer, and/or solvent/inhalant use disorders) were 3.9% and 9.9%, respectively.

SUDs are common among individuals with depressive disorders. One early study, the Epidemiologic Catchment Area Study ( ) found that, among individuals with mood disorders, nearly one-third (32%) had a cooccurring SUD. Among those with lifetime major depression, 16.5% met the diagnosis of an AUD and 18% met the diagnosis of a substance use disorder. The National Comorbidity Survey found that, compared with individuals with no mood disorders, those with depression were approximately twice as likely to have a SUD ( ).

On the other hand, depressive disorders are also common among individuals with SUDs. One study ( ) found that people with alcohol dependence (DSM-IV) are 3.7 times more likely to also have MDD, and 2.8 times more likely to have dysthymia, in the previous year. Among people in treatment for DSM-IV AUD, almost 33% met criteria for MDD in the past year, and 11% met criteria for dysthymia. In another analysis of 6050 former drinkers ( ), the authors found that the risk of major depression during the past year was 4.2 times greater among respondents with a history of alcohol dependence than among those without such a history. Importantly, this relationship was not attenuated after controlling confounding factors. Additionally, current major depression has been associated with worse clinical outcome among substance-dependent patients ( ).

SUDs and depressive disorders tend to impact each other in several ways. Individuals with both SUDs and depression often present with a more severe clinical course and worse outcomes than individuals who have only one or the other ( ; ). They tend to be more difficult to manage and are more likely to be treatment-resistant ( ; ). Outcomes and prognosis of patients with both SUDs and depression tend to be worse than either disorder alone ( ; ). Some found that patients with comorbid depression and SUD had a higher risk of suicidal behavior ( ; ).

Hypotheses and mechanisms of comorbidity

When considering the temporal relationship between SUDs and depressive disorders, there are the following possibilities: (1) the depressive disorder preceded the SUDs, (2) the SUDs preceded the depressive disorder, and (3) the depressive disorder and SUDs occurred nearly in the same time. After treatment, there are the following possibilities: (1) the depressive disorder symptoms improve or remit before that of the SUDs, (2) the SUDs improve or remit before the symptoms of the depressive disorder, and (3) both disorders improve or remit in the same time frame.

The mere correlation or coexistence between SUDs and depressive disorders does not imply a casual relationship in either direction, although some have proposed that it is possible that the pathological effects of a depressive disorder or SUD may actually increase risk for the other (disorder fostering disorder hypothesis) ( ). With regard the possible mechanisms underlying their cooccurrence, several possibilities have been suggested: (1) Common risk factors contribute to both depressive disorders and SUDs, such as genetic, neurobiological and environmental risk factors ( ). Environmental factors, such as childhood adverse experience and chronic stress may cause alterations in the hypothalamic–pituitary–adrenal (HPA) axis and those changes may affect limbic brain circuits that are involved in important functions such as motivation, learning, and adaptation. These functions are known to be impaired in individuals with both SUDs and depressive disorders ( ; ). Additionally, the association between childhood adversities and mental disorders (including SUDs) is often nonspecific ( ). (2) Depressive disorders may contribute to drug use and substance use disorders ( ; ). Some mental health conditions have been identified as risk factors for developing a substance use disorder ( ), and some even propose that people with mental illnesses may use drugs or alcohol as a form of self-medication ( ; ). (3) Substance use and SUDs contribute to the development of depressive disorder. Substance use may change the brain in ways that make a person more likely to develop a mental illness ( ). Additionally, substance use often cause or worsen psychosocial stressors, including financial difficulty, relationship problems, unemployment, unstable housing and legal issues, all of which may increase the risk of depression ( ).

Challenges in diagnosis and assessments

The diagnosis and assessment of patients with both depressive disorders and substance use disorders often pose clinical challenges ( ; ). Several factors may contribute to the complexity and difficult in assessing and diagnosing these patients: (1) Patients often have multiple comorbid diagnoses, including other substance use disorder, anxiety disorders, personality disorders, and depressive disorders. Polysubstance use often makes it hard to establish a clear timeline of different symptoms and describe their symptoms clearly; (2) Cooccurring disorders often obscure the presentations of one another, making it difficult to make appropriate diagnoses ( ). Chronic use of central nervous system depressants, such as alcohol, benzodiazepines, and opioids, may lead to anhedonia, depressed mood, and sleep disorders (such as insomnia) ( ); cocaine and other stimulants may also cause presentations similar to mania or hypomania or psychotic symptoms. (3) Patients may be poor historians or no family members are available to provide collateral information; (4) Some patients may have cognitive impairments related to their substance use that may or may not improve once abstinent for a sufficient period of time ( ).

To clarify whether a patient’s presentation is part of a primary psychiatric disorder or a psychiatric disorder that is a consequence of substance use (SUDs), a detailed history is essential, including the timeline of the onset and changes of different symptoms and substance use. If possible, clinicians should obtain the history of symptoms and function during past periods of sobriety. Collateral information from family members and other significant others can also be very helpful. Even with a careful history, it may be necessary to employ the use of structured interview instruments such as the Structured Clinical Interview for DSM-5 (SCID-5) or the Diagnostic Interview Schedule (DIS). When there is no clear separation in the timeline or onset of the two disorders, sometimes the only way to clarify the diagnosis is to reassess the symptoms after patients are abstinent for a suggested period of 4 weeks according to the DSM-5. However, some patients may need earlier assessment and intervention sooner due to the severity of the symptoms and other factors. Clinicians need to use their own clinical judgment.

Treatment considerations and sequence of treatment implementations

Several significant barriers exist for patients with comorbid disorders. Overall, they have poor treatment adherence ( ; ) and higher rates of treatment dropout ( ; ), which negatively affects outcomes, including treatment response and functions ( ; ; ).

Despite these challenges, research in the past few decades shows significant progress on treating patients with comorbid depression and SUDs ( ; ; ; ).

Evidence-based treatments exist for both depression and SUDs. However, when treating patients with dual diagnosis, it is important to apply these methods in a way that produces the best outcomes for both disorders.

With respect to the implementation of treatments for the comorbid disorders, three common models have been adopted: the sequential, parallel, and integrated models.

The sequential approach : This approach suggests treating one disorder prior to addressing the other disorder. The sequential approach often prioritizes treating active substance use first, as it is believed that patients with active substance use are less likely to benefit from treatment of depression. It may also help with differential diagnosis by reassessing depressive symptoms and their severity after sobriety is achieved. Sometimes, treating depression first may also reduce patient’s substance use and make them more motivated to change their behavior. It may also be a pragmatic treatment strategy, at least in the early stage, for patients with dual diagnosis who may only have interest or expectation in treating one of the disorders.

The parallel approach : This approach requires that specific treatments for both disorders are provided simultaneously, although not necessarily by the same provider or even in the same facility. This approach may be sensible and realistic from a practical standpoint, given that in the current treatment culture, addiction and mental health settings generally are separated and efforts to unify and integrate treatment services have been slow. However, several limitations need to be mentioned. One common challenge is coordination and communication among providers. Second, as the patients need to be engaged in treatments for both disorders, they can easily feel overburdened and the approach generally may be inefficient.

The Integrated Approach : The integrated approaches are similar to the parallel approach, but with two additional features: both disorders are treated by a single provider (or a team) and treatment addresses the functional interrelationship of the comorbid disorders. The integrated approach has been found to be consistently superior compared with separate treatment of each diagnosis ( ; ; ; ; ). The integrated approach often involves using cognitive behavioral therapy strategies to boost interpersonal and coping skills and other approaches that support motivation and functional recovery ( ). Based on the range of potential advantages associated with integrated therapy, expert opinion strongly suggests adopting this approach to treating depression and SUDs. However, many changes need to be made, including changing the current organization of care, updating guidelines, revising insurance reimbursement policies, and training current providers and change their practice models.

Epidemiology

A recent comprehensive literature review on the relationship between alcohol use disorder (AUD) and MDD confirmed a previously reported association between AUD and MDD. That is, that the presence of either disorder doubled the risks of the second disorder. Further data analysis suggests that the association between AUD and MDD cannot be fully accounted for by common factors, and there seems to be a causal relationship. Specifically, the data suggest that AUD contributes to the risk of MDD, rather than vice versa ( ).

MDD and alcohol dependence (DSM-IV) are among the most prevalent mental disorders worldwide and commonly cooccurring ( ; ). The 12-month prevalence of depression in adults is 5.3% and lifetime prevalence is 13.3% ( ) and the 12-month prevalence of alcohol dependence is 13.9% ( ). The prevalence of depression is higher in people with alcohol dependence and each of these disorders is associated with a significant risk of developing the other ( ). Treatment of both cooccurring disorders is imperative as past year AUD remission has been associated with a threefold-reduced risk of depression ( ).