Edward V. Nunes, MD, Roger D. Weiss, MD, and Carrie A. Davies, BS CHAPTER
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OVERVIEW AND DIAGNOSTIC CRITERIA

Significance

Depressive disorders, major depression, and dysthymia are among the most common psychiatric disorders in the general population. Estimates from community surveys show that over 10% of the general population has experienced a depressive disorder at some point in their lifetime. Major depression is the most common co-occurring psychiatric disorder encountered among patients who present for treatment of substance use disorders, with lifetime prevalence rates ranging from 15% to 50% across samples studied from various treatment settings. In drug- and alcohol-dependent patients, major depression has been associated with worse outcome, including worse substance use outcome, worse psychiatric symptoms, and increased suicide risk. Clinical trials suggest that treatment of depression among substance-dependent patients with medication or behavioral therapy can improve outcome.

Bipolar disorder is rarer in the general population, with estimates of the lifetime prevalence of bipolar I disorder ranging from 1% to 3% and another 1% for bipolar II disorder. Bipolar disorder is less common than is major depression in samples of patients seeking treatment for substance use disorders in routine outpatient settings. However, the strength of the association between bipolar disorders and substance use disorders is greater than for depressive disorders, and the presence of a bipolar disorder increases the likelihood of a substance use disorder by a factor of 4 or more. Hence, among patients with bipolar disorder, the prevalence of substance use disorders is 40% or more. The co-occurrence of bipolar disorder and substance use disorder is associated with worse prognosis, and clinical trials indicate that proper treatment of bipolar disorder improves outcome of the substance use disorder.

Distinguishing Substance-Related Mood Symptoms from Mood Disorders

Mood symptoms (e.g., sadness, apathy, irritability, pessimism, hopelessness, fatigue, appetite changes, anxiety, insomnia or hypersomnia, euphoria, hyperactivity) are extremely common in patients with drug or alcohol use problems. Often, such symptoms are symptoms of substance intoxication or withdrawal and will resolve with abstinence, in which case the substance use problem should be aggressively treated. At other times, the mood symptoms are symptoms of an independent mood disorder that needs to be treated in addition to treating the substance use problems.

Initiation of treatment for the substance use problem and efforts to achieve abstinence should always be a first step in the treatment of a patient with co-occurring mood and substance use disorders.

Despite abstinence or reductions in substance use, some cases of depression will persist. Evidence suggests that a carefully obtained clinical history can help distinguish mood disorders that are independent of substance use and will persist in abstinence from those that will resolve with abstinence. The clinical history should examine the course of mood symptoms in relation to substance use over the patient’s lifetime; clinicians should look for onset of a mood disorder syndrome prior to the onset of substance use problems or the persistence or emergence of a mood disorder during abstinent periods over the lifetime. Patients with primary depression need to receive treatment for their depressive disorder in addition to treatment for substance use.

PREVALENCE AND PROGNOSTIC EFFECTS OF CO-OCCURRING MOOD AND SUBSTANCE USE DISORDERS

General Population

Odds ratios reflecting the strength of association between alcohol or drug dependence and affective or other disorders are at least 2.0 for most combinations of disorders, thereby showing that the presence of alcohol or drug dependence at least doubles the odds of a mood disorder or other disorder being present. For bipolar disorder, the odds ratios are substantially higher than for major depression or dysthymia.

Social phobia, panic disorder with or without agoraphobia, and posttraumatic stress disorder have substantial associations with substance use disorders of at least the same magnitude as major depression or dysthymia. Their cardinal symptoms (fear of social interactions, spontaneous panic attacks and fear of public places, and reexperiencing symptoms triggered by reminders of traumatic events) are distinctive from, and are not attributable to, substance toxicity or withdrawal. Their presence can help rule out substance intoxication or withdrawal as the sole source of mood symptoms, and the presence of one of these anxiety disorders strongly suggests the presence of an independent disorder that warrants specific treatment.

Attention deficit hyperactivity disorder (ADHD) has strong associations with alcohol and drug dependence, with odds ratios of 2.8 and 7.9, respectively, as well as with major depression (odds ratio: 2.7), dysthymia (odds ratio: 7.5), and bipolar disorder (odds ratio: 7.4). When evaluating a substance-dependent patient with symptoms of depression, clinicians should look for ADHD in the clinical history and consider specific treatment for ADHD.

Antisocial personality has a strong association with substance use disorders. The presence of antisocial features or antisocial personality disorder does not rule out the presence of a mood or anxiety disorder, and these often co-occur.

Substance Use Disorder Treatment Populations

Lifetime prevalence rates of major depression among patients admitted to alcohol or drug treatment programs range from 20% to 50%, with rates of current major depression in the range of 10% to 20% (substantially exceeding rates found in the general population). Bipolar disorder is less common in these samples, consistent with its low prevalence rate in the general population.

Psychiatric and Primary Care Populations

Among patients presenting in psychiatric and primary care treatment settings for treatment of depression, the prevalence of substance use disorders depends upon the setting and associated severity of the mood disorder. Among outpatients with major depression in community-based psychiatric and primary care clinics, a 13% prevalence rate of concurrent alcohol use disorders and an 8% prevalence rate of drug use disorders have been found. Among psychiatric inpatients, substance use disorders are common in patients with major depression and patients with bipolar disorder, with rates of current substance use disorders of 30% or higher in the latter case.

The majority of individuals with substance use disorders, depression, and other common mental disorders do not present at specialty treatment settings and often present at primary care physicians’ offices—a treatment setting in which substance abuse and depression may go undetected and may be associated with overutilization or underutilization of services and poor outcome.

DIFFERENTIAL DIAGNOSIS

Etiologic Relationships Between Mood and Substance Use Disorders

Not all mood symptoms are caused by toxic and withdrawal effects of substances, nor is all substance abuse a result of underlying psychopathology (as in “self-medication”). It may be difficult to establish for any given patient which of several causal mechanisms may be operating.

DSM-IV Independent Versus Substance-Induced Mood Disorders

Clinicians face the challenge of differentiating mood disorders that are independent of substance use and that likely require antidepressant or mood-stabilizing medications from syndromes that represent toxic or withdrawal effects of substances and that will likely resolve with treatment of the substance use disorder, abstinence, or reduction of substance use.

DSM-IV defines an independent (or “primary”) mood disorder as one that precedes the onset of substance abuse or persists during significant periods of abstinence (1 month or more is suggested as the minimum). The historical data needed to establish these criteria (age at onset, presence of periods of abstinence, and mood syndromes occurring during abstinence periods) can be obtained with good reliability from a clinical history.

The category of substance-induced mood disorder was established to recognize the phenomenon of co-occurring mood syndromes that cannot be established as chronologically independent of substance use, yet the mood symptoms seem to exceed what would be expected from mere intoxication or withdrawal effects from the substance(s) that the patient is taking.

When evaluating patients with co-occurring substance use and mood symptoms, clinicians should explicitly consider the category of “expected effects of substances” in differential diagnosis. DSM-IV specifies that the symptoms of either an independent or a substance-induced mood disorder must exceed the expected effects of intoxication or withdrawal from the substances that the patient is taking. Since, in the course of treatment and as a patient reduces or eliminates substance use, a substance-induced mood disorder may need to be reclassified as an independent mood disorder (substance-induced mood disorder may “convert” to an independent mood disorder), clinicians should conduct a thorough diagnostic assessment and carefully follow the course of a substance-induced mood disorder.

Diagnostic Methods and Predictive Validity of DSM-IV Approach

Some of the DSM-IV criteria are vague, particularly the criteria for substance-induced mood disorder. The Psychiatric Research Interview for Substance and Mental Disorders (PRISM), a semistructured interview that was designed to evaluate mood and other co-occurring psychiatric disorders in patients with substance use disorders, provides more specific criteria for substance-induced mood disorder and its distinction from an independent mood disorder on the one hand or usual effects of substances on the other. For a diagnosis of substance-induced mood disorder to be made, PRISM requires that the patient meet full criteria for a mood disorder and requires that each symptom contributing to the diagnosis exceeds the expected effects of the substances that the patient is taking. The Structured Clinical Interview for DSM-IV, another diagnostic tool, includes a module for substance-induced mood disorder but asks the interviewer to make a clinical judgment based on the criteria.

Diagnosing Bipolar Disorder in the Setting of Substance Abuse

Persistence of symptoms over time, severity of impairment, and occurrence of the symptoms during periods of abstinence are key markers in establishing a diagnosis of mania. Symptoms of cocaine or stimulant intoxication may resemble symptoms of mania (i.e., irritability, grandiosity, hyperactivity, talkativeness, impulsivity, insomnia, and paranoia). Impulsivity of patients with alcohol or sedative intoxication may sometimes resemble the impulsivity of patients with mania. However, full-blown mania must last for at least a week, during which time the symptoms should be persistent; in contrast, symptoms of intoxication are usually intermittent. The marked impairment or psychosis required for a diagnosis of mania is usually in excess of what would be produced by intoxication.

Hypomania, which includes the same core symptoms as mania but which may be briefer (at least 4 days) with less impairment in functioning, may be more difficult to distinguish from substance intoxication or withdrawal effects. The same is true of cyclothymia, which may be difficult to distinguish from symptoms present during alternating periods of intoxication and withdrawal, which mimic hypomanic and depressive symptoms, respectively.

Rapid cycling bipolar disorder is diagnosed when patients have experienced over the past 12 months at least four mood episodes that have been punctuated either by periods of remission or by switches in polarity (e.g., from mania to depression). Twenty percent of cases of bipolar disorder are rapid cycling, and the pattern is associated with greater impairment and poorer response to treatment. Some evidence suggests that the rapid cycling subtype is associated with increased prevalence of substance use disorders.

Substance intoxication is likely to exacerbate the disinhibition and poor judgment associated with mania and is associated with poor medication adherence, which promotes relapse.

For most patients with bipolar disorder, particularly for those who have had the disorder for an extended time, the clinical course predominantly consists of depression, with occasional episodes of mania or hypomania. Clinicians should carefully review the past history of depressed patients with substance abuse problems in search of episodes of mania or hypomania, which would indicate a diagnosis of bipolar disorder. Identification of clear-cut episodes of mania or hypomania (which are distinctive from the usual effects of substances) helps to establish the presence of an independent mood disorder in patients with chronic substance abuse.

MANAGEMENT OF CO-OCCURRING MOOD AND SUBSTANCE USE DISORDERS

Depressive Disorders

Antidepressant Medications

Antidepressant medication is the most thoroughly studied treatment modality for co-occurring mood and substance use disorders. There are numerous placebo-controlled trials in the literature. Two meta-analyses reached a similar conclusion: Antidepressant medication is more effective than placebo in improving outcome among alcohol-dependent patients with depressive disorders; evidence was less clear for cocaine- or opioid-dependent patients.

Meta-analyses suggest that treatment of depression with antidepressant medication is helpful in reducing substance abuse when the depression improves, but it is not a stand-alone treatment and cannot be expected to resolve substance use problems when used alone; concurrent treatment for the substance use disorder (counseling or medication) is also important.

Data from clinical trials suggest that depression and substance use outcome are at least in part causally related, with improvement in mood resulting in improvement in substance use for some patients. However, causality may run in both directions (improvement in substance use may drive improvement in mood).

Research on moderators of medication effect (i.e., features of clinical trials that predict greater or lesser effect of medication in comparison to placebo) can aid development of guidelines for treatment for co-occurring depression and substance abuse.

In a meta-analysis, low placebo response rate was the strongest moderator of medication effect, accounting for approximately 70% of the variance in effect sizes across studies. Studies with low placebo response rates (20% to 30%) showed large medication versus placebo differences. About half of the studies in the meta-analysis had high placebo response rates in the range of 40% to 60%, and this group of studies showed no benefit of medication over and above placebo. Placebo response in studies of antidepressant treatment of depressed substance abusers suggests that some patients respond to accompanying treatment that they received (a form of substance abuse treatment in most trials). Thus, the treatment of a substance use disorder in patients with co-occurring depression and substance abuse should be clinicians’ first priority in treatment and may result in improvement of both depression and substance use.

In a meta-analysis, greater evidence for the efficacy of antidepressant medications was found in depressed alcoholics than in depressed drug-dependent patients. Among studies of treatment of depression in cocaine- or opioid-dependent patients, some studies demonstrated benefits of antidepressants in depressed cocaine- or opioid-dependent patients and other studies showed little or no effect (substantial heterogeneity of effect across trials). Studies of antidepressant medications for treatment of cocaine dependence (without regard to depression) have yielded primarily negative results, but several recent trials have indicated that antidepressant medications are effective in reducing cocaine use when combined with voucher incentive therapy. In a recent trial with intravenous opioid addicts not engaged in any treatment, the proportion of participants who achieved remission from depression was higher in those who received a combination of cognitive–behavioral therapy (CBT) and the antidepressant citalopram than in the assessment-only control condition (in addition, remission was associated with adherence).

Studies suggest that clinicians should help patients to initiate abstinence and should closely watch depression symptoms during early stages of abstinence before initiating treatment with antidepressant medication. Depression that persists during an initial period of abstinence could be diagnosed as independent major depression. More severe depression may need to be treated with antidepressant medication from the outset.

Studies suggest that serotonin reuptake inhibitors (SRIs) are generally well tolerated and have less potential for sedation or other adverse effects. Thus, SRIs are recommended as first-line treatment, followed by a non-SRI antidepressant (e.g., venlafaxine, duloxetine, mirtazapine, bupropion, tricyclic antidepressant) if the SRI trial fails (patients with early-onset substance use and prominent externalizing symptoms or antisocial personality features, for whom studies suggest caution in the use of selective serotonin reuptake inhibitors, are an exception). Tricyclic antidepressants carry risks of sedation, overdose, and seizures.

A meta-analysis found high placebo response rates and lesser medication effects in placebo-controlled medication trials that provided an accompanying manual-guided psychosocial intervention to all participants—a finding that indicates that the manual-guided psychosocial interventions may have inherent antidepressant effects and may result in reduced substance use, which in turn improves mood. This finding emphasizes the importance of initiating treatment for a substance use disorder as the first step in treatment of a patient with co-occurring substance use disorder and depression.

Behavioral Treatments for Depression and Substance Abuse

Studies (small and preliminary, in some cases) support the effectiveness of behavioral therapies for depressed substance-dependent patients and suggest that an appropriate behavioral intervention, particularly cognitive–behavioral approaches that target depressive symptoms and promote behaviors that may improve depression, should be initiated with depressed substance-dependent patients from the outset. Cognitive–behavioral approaches focused on depression and approaches developed for treating substance dependence (e.g., Community Reinforcement Approach) have shown promise in studies. Twelve-Step groups (e.g., Alcoholics Anonymous) contain elements (e.g., social support) that likely help depression and substance use disorders among individuals who are engaged in the groups.

Medication Treatments for Substance Use Disorders

Although medication treatments for substance use disorders have received less attention and study in terms of their effects among patients with co-occurring depression and substance use disorders, evidence is favorable. Naltrexone and disulfiram have been shown to be safe and effective among alcohol-dependent patients with co-occurring psychiatric disorders, including major depression. Depressive symptoms decrease substantially during the first 1 to 2 weeks of methadone maintenance treatment for opioid dependence, and approximately half of major depressive syndromes in patients presenting for methadone maintenance can be expected to resolve during initial weeks of treatment. The effect of these treatments is likely attributable to reduction in substance use (which, in turn, reduces substance-induced depressive symptoms), reduction in stress, and improvement in functioning, which may occur as effective treatment for a substance use problem takes effect. These medications also may have direct effects on mood. Clinicians should monitor patients for failure to improve, worsening symptoms, and side effects.

Combining Medications for Depression and Substance Use Disorder

Studies suggest the potential utility of combining medications for depression with medications for substance dependence in the treatment of depressed substance-dependent patients.

Adolescents and Treatment of Co-Occurring Depression and Substance Abuse

Onset of substance use disorders and mood disorders often occurs in adolescence, and the co-occurrence of these disorders is associated with risk factors such as abuse and with worse clinical outcome. Effective intervention early in the course of these disorders can improve functioning during adolescence and prevent progression to chronic mood and substance use problems during adulthood. Treatment research on mood and substance use disorders in adolescents lags behind research in adults, partly due to greater difficulties in conducting research in adolescents than in adults. Controlled trials of antidepressant medication treatments in depressed adolescents (not selected for substance use disorders) and in adolescents with co-occurring depression and substance use disorders have produced mixed results and have yielded high placebo response rates. Some studies suggest that manual-guided psychosocial treatments (e.g., CBT) alone may be effective for many depressed, substance-abusing adolescents.

Late Life and Treatment of Co-Occurring Depression and Substance Abuse

Substance dependence may be an underrecognized problem in the elderly. Patterns of substance abuse differ in the elderly from youth (elderly experience more alcohol and prescription drug problems). Effective treatment of depression may improve sleep, pain tolerance, and general functioning, thereby possibly reducing need for other prescription medications. Clinicians should note risk factors for substance use problems, warn patients of risks and signs of addiction, and monitor elderly patients for the development of signs of addiction. As substance-dependent patients age, diseases of aging, depression, and other psychiatric disorders become more prevalent and complicate clinical management. Research on treatment of substance use disorders and co-occurring substance use and depression in the elderly is limited, but results to date are encouraging and suggest that treatment strategies for young and middle-aged adults can be cautiously applied to the elderly.

Suicidal Behavior and Co-Occurring Depression/Substance Abuse

Depression and substance abuse are important risk factors for suicide. The potential for suicide must be carefully assessed in any patient with co-occurring depression and substance abuse. Recent evidence suggests that independent depression and substance-induced depression are both associated with increased suicidal thinking and behavior in drug- and alcohol-dependent patients. Other common risk factors for suicide include family history of suicide, history of trauma, history of irritability or violence, current support systems, and physical illness. Although antidepressants may exacerbate suicidal thinking or behavior, the general consensus (based on recent data) is that the benefits of antidepressant treatment (improved symptoms) outweigh the risks. Patients should be informed of risks and carefully monitored during the course of treatment.

Interventions at the Level of Service Delivery and Primary Care

Most patients with depression, substance use problems, or both depression and substance use problems present to primary care physicians or to treatment providers in emergency rooms or primary care clinics (rather than to specialty practitioners or treatment providers in specialty clinics). Studies suggest that increasing screening for and treatment of co-occurring depression and substance use disorders in primary care settings would have favorable effects. Whether treatment of psychiatric disorders and substance use disorders is best delivered through an integrated model (i.e., both disorders are treated at one program) or through referral to specialty clinics (i.e., disorders are treated at separate programs) depends on availability of integrated services and severity of the disorders.

Depression and the Treatment of Nicotine Dependence

The prevalence of nicotine dependence is higher among patients with mood disorders and is very high among patients with substance use disorders. Evidence suggests that patients in treatment for substance use disorders are interested in attempting to quit smoking and that treatment with nicotine patch and counseling is modestly effective. Depressed patients with or without concurrent substance use disorders should be assessed for nicotine dependence, encouraged to quit smoking, and assisted in attempting to quit with pharmacotherapy and counseling. Clinicians should address lack of motivation to quit and should concurrently treat depression and other substance use disorders. Clinicians should carefully monitor patients for the emergence of depression or worsening of depression symptoms while patients attempt to quit smoking and particularly if patients succeed in quitting.

Summary of Treatment Recommendations for Co-Occurring Depression and Substance Use Disorders

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