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 ( ).

Clinical presentation

Differentiating SIMD from MDD involves examining the timing of onset of AUD and depressive symptoms to determine if depressive episodes were established during a period of sustained abstinence ( ).

Diagnosis is particularly challenging because of overlapping symptoms such as insomnia and psychomotor agitation/depression, poor concentration, and feelings of guilt/worthlessness ( ; ).

Studies showed that patients with SIMD have better short-term reduction in symptoms after treatment, as compared to patients with major depression and cooccurring AUD ( ). However, SIMD may not be a stable diagnosis as evidenced by the finding that a high percentage of patients with SIMD also have major depression after sustained sobriety is achieved ( ; ; ).

Alcohol-induced depression disorder is defined by remission of depression during periods of abstinence; however, studies show that alcohol-induced depression is associated with risk for onset of a later MDD. A minimum of 4 weeks of abstinence may be necessary to distinguish alcohol-induced depression from primary depressive disorder in the absence of reliable symptom history ( ).

Treatment

Clinicians treating patients with AUD may be reluctant to initiate antidepressant medications for depressive symptoms for a number of reasons, including concerns about distinguishing from SIMD versus MDD ( ; ). The chronology of symptom onset, symptom severity, and duration should be considered when determining potential treatment interventions ( ). Temporary alcohol-induced depressive symptoms may result from the effects of intoxication or withdrawal, and tends to resolve within 1 month of abstinence from alcohol ( ; ). As such, antidepressant treatment may not be required in this scenario, and it may be prudent to focus on treatment of AUD in cases of mild depression. However, when the cooccurring disorders are of significant duration or severity pharmacologic treatment of both disorders may be required, particularly patients with significant risk of suicidality ( ). Studies showed that antidepressants may reduce the severity of depression in patients with cooccurring AUD, and increase the rate of abstinence and decrease severity of alcohol consumption (the number of drinks per drinking days) ( ). Additionally, the magnitude of benefit of antidepressants for patients with AUD and depression is similar to that of those with depression alone ( ; ).

Concurrent MDD and AUD present specific safety concerns that should be assessed prior to determining appropriate treatment setting and modality. Cooccurring alcohol and depression increase the risk of self-harm, suicide, and unintended harm to self or others such as workplace injuries and as such, hospitalization should be considered given this elevated risk. For nonsuicidal patients with cooccurring depression and AUD, outpatient management may be appropriate and motivational interviewing techniques may be useful in assessing the patient’s readiness for change.

When deciding on specific medications for the treatment of depression in the context of AUD, bupropion should be used with caution in patients with severe AUD, and avoided in those with a history of alcohol-withdrawal seizure or other complicated alcohol withdrawal. Sedating antidepressants, such as sedating TCAs and mirtazapine should be used cautiously due to the risk of increased sedating effects with alcohol ( ). Earlier literature suggested that less sedating tricyclic antidepressants, such as nortriptyline may be more effective in reducing depressive symptoms in people with cooccurring depression and AUD as compared to selective serotonin reuptake inhibitors (SSRIs) ( ).

Recently, combinations of medications for both depression and AUD, such as sertraline with naltrexone, and acamprosate with escitalopram have shown promise for reducing depressive symptoms and maintaining abstinence in patients with cooccurring disorders ( ; ). A study aimed at evaluating efficacy of combining approved medications for depression and alcohol dependence, found that depressed, alcohol-dependent patients treated with the combination of sertraline and naltrexone had delayed relapse to heavy drinking and fewer adverse events as compared to a group taking single-medication treatment ( ). One randomized control trial evaluated a group of adults with cooccurring major depression and alcohol dependence who were randomized to citalopram or placebo plus naltrexone. Both the citalopram and placebo groups showed substantial improvements in mood and drinking outcomes in this 12-week study. The combination of naltrexone and citalopram was well tolerated overall as evidenced by the similar reporting of adverse events between the two groups in this study ( ). Animal studies have looked at the combined effects of acamprosate and escitalopram on ethanol consumption in mice, and one human study found this combination of medications to be well tolerated ( ). These findings support the use of combination pharmacotherapies to address cooccurring major depression and alcohol dependence.

Utilization of psychotherapy is often understudied in patients with cooccurring depression and AUD despite evidence to support its effectiveness in both AUD and depression ( ; ). Additionally, recent evidence suggests that behavioral activation therapy may also be useful for treating cooccurring depression and AUD ( ).

Integral to the treatment of comorbid AUD and MDD is directing efforts specifically toward the AUD. Positive trial data exist for multiple medications as well as psychotherapies.

Among all medications for AUD, naltrexone or acamprosate should be offered to patients with moderate-to-severe AUD who intend to reduce alcohol consumption or achieve abstinence, especially those who prefer pharmacotherapy or have failed nonpharmacological treatments alone. Disulfiram, an old medication that is still in use, is often recommended to patients who have a goal of achieving abstinence. For disulfiram, supervision is important in maximizing the benefits. Additionally, topiramate or gabapentin can also be offered; however, clinicians need to know that they are used as off-label ( ; ). Motivational interview, contingency management, cognitive behavioral therapy, mindfulness-based interventions, and family/couples therapy for AUD all have positive trial data for achieving abstinence, reducing number of drinking days, and reducing harms associated with drinking alcohol ( ).

Conclusion

Distinguishing mood symptoms that are substance-related from independent mood disorders is a pivotal part of the clinical assessment and may impact treatment decisions. Evaluating mood symptoms during periods of sustained abstinence, 4 weeks per DMS5 guidelines, is ideal. Seeking collateral information from family, friends, and other healthcare providers regarding the timeline of symptoms may also be useful. Toxicology screens and laboratory tests such as CDT, GGT, or blood alcohol concentration or alcohol metabolites may also be helpful in clarifying the history of substance use. During the diagnostic assessment, clinicians should also keep in mind alcohol intoxication symptoms, such as mood lability and agitation, that may mimic major depression or mania. Alcohol withdrawal symptoms, such as sleep disturbance and dysphoria may mimic major depression as well. If an AUD is established, then a goal of abstinence or reduction in alcohol use should be implemented prior to diagnosis and treatment of depression.

In people with cooccurring AUD and depression, antidepressants may be useful for the treatment of depression, AUD, or both ( ). Early intervention is supported by the finding that patients receiving comprehensive integrated treatment for AUD and depression have the most significant reduction in symptoms within the first 3 weeks of beginning treatment ( ). Treatment with antidepressants should be considered for severe or persistent depressive symptoms. SSRIs should be considered as first line due to their good tolerability and safety characteristics in the setting of AUD. Clinicians may consider switching to a non-SSRI antidepressant if SSRI trials fail. Antidepressant side effect profiles should be considered when selecting a medication, for example, avoiding antidepressants that are more sedating, have high overdose risk or lower the seizure threshold. Substance use treatment should be initiated concurrently with addressing depressive symptoms ( ).

Limitations in the available evidence include the large number of studies showing high or unclear risk of bias ( ). Other limiting factors include the uncertainty of diagnosis of depression in people affected by AUD, inadequacy of reporting psychosocial interventions, and timeframe concerns related to the antidepressants reaching full effect. Additionally, there are limited studies that compare one antidepressant to another antidepressant or other medication. Two metaanalyses concluded that antidepressant medication is more effective than placebo in improving outcomes among patients with cooccurring alcohol and depressive disorders ( ; ).

Epidemiology

Of the estimated 44,965 suicides in the United States in 2016, about 15% were related to drug overdose according to the CDC ( ). According to the same survey, the proportion of suicides that were opioid overdoses rose from 2.2% to 4.3% between 1999 and 2001. Evidence from clinical studies support the association between prescription opioid analgesic use and risk of new-depression episodes ( ). One study suggests that new depressive episodes related to chronic opioid dependence are at least as severe, if not more severe, than new depressive episodes unrelated to chronic opioid use ( ). In comparison to individuals with one disorder alone, individuals with comorbid disorders often demonstrate a more severe course of illness, including increased social and occupational impairment, disability, and economic burden ( ). Comorbidity has also been shown to be associated with poorer treatment outcome, higher rates of relapse, and rehospitalization ( ). Of note, both MDD and SIMD are risk factors for future depressive episodes ( ).

Clinical presentation

The following symptoms of opioid intoxication resemble major depression or dysthymia: apathy, dysphoria, and psychomotor agitation. Opioid withdrawal symptoms that resemble depressive disorders include irritability, dysphoria, insomnia, and fatigue. Clinicians should also keep in mind the time of last opioid use and typical time course of intoxication and withdrawal syndromes, which is of variable length of time depending on the half-life of the opioid. For patients with chronic opioid exposure, their acute withdrawal symptoms may be followed by more chronic signs of a protracted abstinence syndrome, which may last for weeks even months ( ).

Chronic depression, even if more mild symptoms, should be taken seriously among patients with opioid and other substance use disorders due to the association with worse clinical outcome in patients with dual diagnoses ( ).

Assessment of depression in patients with cooccurring opioid dependence is difficult by confounding issues such as state at the time of evaluation ( ). Patients who are acutely intoxicated may not accurately relay the extent of depressive symptoms, while those who are experiencing withdrawal symptoms may exaggerate the depressive symptoms over the preceding weeks ( ).

Studies of patients with OUD and cooccurring depression show that elevated scores on depression symptoms scales improve substantially after initiation of abstinence ( ). Efforts to address withdrawal symptoms and begin treatment to achieve abstinence should always be a first step in the treatment of patients with both OUD and depression. Clinicians should also keep in mind that some cases of depression may persist despite abstinence of reductions in opioid use. A careful clinical history as well as a period of abstinence may be helpful in distinguishing which patients may have a primary depressive disorder that should be addressed while patient is receiving substance use treatment ( ). The DSM-5 suggests an abstinence period of 4 weeks; however, clinical judgment should be used.

Treatment

For treatment of severe and/or obviously independent depressive symptoms in patients with active opioid use disorder (OUD), antidepressants may be considered. SSRIs are considered first line of treatment in these patients in part due to their low level of sedation as compared to other antidepressants and overall lower risk of adverse interactions with substances of abuse ( ). Other antidepressants can be considered as well if patients do not respond to SSRIs. In clinical studies, use of TCAs in patients with a cooccurring SUDs shows evidence of substantial improvement of depressive symptoms; however, TCAs are associated with more side effects and toxicity than other new generation antidepressants ( ). Several recent studies demonstrated that, at low doses, buprenorphine is an efficacious, well-tolerated, and safe option in reducing depressive symptoms, serious suicidal ideation, and nonsuicidal self-injury, even in patients with treatment-resistant depression ( ). Placebo-controlled trials that offered a manual-guided psychosocial intervention for all participants tend to have high placebo depression response rates ( ). This finding emphasizes the importance of considering behavioral interventions as part of the treatment plan for cooccurring disorders. Cognitive behavioral interventions and 12-step facilitation were utilized in the aforementioned placebo-controlled trials. These substance use disorder interventions have components that focus on managing mood symptoms in addition to helping reduce substance use ( ).

Integral to the treatment of comorbid OUD and MDD is directing efforts specifically toward the OUD as pursuing abstinence without treatment has relapse rates above 90%. The following medications have positive trial data: methadone, buprenorphine/naloxone, sublingual buprenorphine, buprenorphine implants, intramuscular long-acting buprenorphine, and intramuscular long-acting naltrexone. Methadone maintenance requires referral to a federally certified opioid use treatment center, whereas buprenorphine requires special certification in the treatment of opioid disorder and X-waiver from on the prescriber’s DEA license. Intramuscular naltrexone is an effective medication; however, drop off rates tend to be high. Behavioral therapy may be effective for relapse prevention in those who decline medication; however, medication-assisted treatment (MAT) is noted to be twice as effective ( ).

Conclusion

Comprehensive treatment is recommended for patient with both OUD and MDD, and it includes evidence-based behavioral interventions ( ) and medications. Antidepressants used concurrently with other treatment modalities for OUD can be helpful for managing cooccurring mood symptoms and support recovery in some patients ( ).

When considering antidepressant medications for patients with both OUD and depression, clinicians should consider factors such as past history of independent depression, family history, or past positive response to antidepressant medication. Current evidence supports the use of SSRIs as first line for patients with dual diagnosis due to their safety profiles and overall tolerability. Additionally, evidence-based psychosocial interventions have also been shown to improve mood symptoms ( ).

Epidemiology

According to the 2018 National Survey on Drug Use and Health, in the demographic over 18 years of age, cocaine use was estimated at 6.25 million uses in the last year with 0.97 million meeting criteria for cocaine use disorder (0.4% of the population) ( ). Methamphetamine (MA) use was estimated at 1.87 million users in the last year with 1.03 million meeting criteria for methamphetamine use disorder (0.4% of the population) ( ).

Cocaine use disorder is highly associated with SIMD as opposed to independent MDD. However, female sex, age of onset < 18, and comorbid psychiatric diagnoses are associated with independent depression ( ).

Up to 74% of active methamphetamine users have experienced independent MDD or dysthymia with disproportionate levels of females meeting criteria for independent MDD ( ). Lifetime diagnosis of MDD, a Beck’s Depression Inventory (BDI) score above the moderate range at time of active use, having received treatment for AUD, intravenous methamphetamine use, female sex, and history of suicide attempt are associated with the persistence of MDD at longitudinal follow-up, despite abstinence ( ).

Clinical presentation

Accurate diagnosis is challenging given the overlap in symptomatology and time consideration of cocaine and methamphetamine-induced depressive disorder (encompassing cocaine and methamphetamine use and withdrawal) and MDD. Cocaine and methamphetamine use and withdrawal can be associated with severe dysphoria, irritability, anxiety, fatigue, poor concentration, hypersomnia, hyperphagia, and suicidal ideation ( ). DSM-5 criteria suggest the cutoff of 4 weeks postabstinence to diagnose independent MDD.

In addition to common presentations described above, cocaine use has been found to be associated with several other medical conditions, such as cardiovascular disease, kidney disease, movement disorders, and dystonic reactions with antipsychotic medications ( ; ; ). In addition to neurovegetative symptoms, MA use is associated with psychosis, violence, anxiety, suicidality, and various health consequences including higher all-cause mortality ( ), cardiovascular disease ( ), stroke ( ), and high-risk sexual behavior ( ).

A detailed history of presubstance use depressive episodes as well as obtaining collateral information may reveal that depression preceded the onset of cocaine use, in which event, it is essential to direct treatment toward both the substance use disorder as well as the likely MDD, as untreated MDD is associated with higher cocaine use and risk of relapse ( ). Of note, the presence and severity of comorbid depressive symptoms does not affect ability of those with cocaine use disorder to engage in substance use disorder treatment or achieve remission ( ). Regular urine drug screening is also recommended with the detection of cocaine typically being positive up to 3 days from last use as concurrent cocaine use complicates the treatment of depression. When assessing individuals with cocaine use disorder, severity of the illness may additionally direct treatment recommendations. Specifically when assessing individuals with methamphetamine use disorder, severity of the illness and route of administration may direct treatment and are associated with different prognoses, with IV/IM use being associated with the worst outcomes ( ).

Treatment

Conclusion

There are no FDA-approved medications or psychological interventions effective for the treatment of comorbid independent depression and cocaine or methamphetamine use disorder, though various approaches have demonstrated reduction in substance use, which has demonstrated a reduction in depressive symptoms via abstinence.

Where positive trial data exist for the treatment of depression in the context of ongoing cocaine use, results are limited by small sample size, high dropout rate, and/or lack of generalizability; therefore, no strong recommendations can be currently made.

It is in this context that no medication or psychotherapy can be strongly recommended at this time for the treatment of depression with concomitant cocaine or methamphetamine use. Of note, sertraline and aripiprazole should be avoided when the patient is using methamphetamine as they may worsen cravings and/or potentiate the effect of methamphetamine use. However, it is recommended that patients be referred for cocaine use disorder—specific psychotherapy and/or inpatient substance use rehabilitation based on severity of cocaine use disorder.