1. Use of multiple substances
Many patients entering treatment for a specific substance use disorder abuse more than one substance, and co-occurring nicotine dependence is particularly common. For some patients, there is a “drug of choice,” with other substances serving as a substitute when the primary sub- stance is unavailable. Others routinely use multiple substances simultaneously. An individual’s concurrent use of two or more substances may be motivated by his or her wish to modify the effects of the primary drug of choice or to prevent or relieve withdrawal symptoms. In addition, many patients use multiple substances because of their availability. Frequent drug combina- tions include 1) cocaine and alcohol; 2) cocaine and heroin; 3) heroin and benzodiazepines; 4) alcohol, cocaine, and benzodiazepines; 5) nicotine and any other drug; 6) multiple “club
drugs” (e.g., 3,4-methylenedioxymethamphetamine [MDMA], γ-hydroxybutyrate [GHB], ketamine); 7) “club drugs” with prescription medications (e.g., MDMA with sildenafil and/or fluoxetine); and 8) opioids, stimulants, sedatives, steroids, and other substances. The severity of abuse of each substance and the motivation to stop using each substance may vary widely in individuals who abuse multiple substances.
The treatment of patients using multiple substances may be complicated by 1) simultaneous intoxication or withdrawal from two or more drugs, 2) varying time frames for experiencing with- drawal symptoms, 3) the need to detoxify the patient from more than one drug, and 4) potential interactions between an abused substance and medications used to treat a comorbid substance use disorder (e.g., inadvertent precipitation of opioid withdrawal in patients treated with nal- trexone for alcohol dependence).
Although the presence of multiple substance use disorders is the norm, there is limited re- search to guide clinicians on adapting the usual evidence-based clinical interventions to the treatment of individuals using more than one substance, including medication and psychoso- cial treatments. The best recommendation is for the clinician to do a comprehensive assessment of the patient and integrate the evidence-based treatment approaches, including pharmacolog- ical and psychosocial treatments, for each specific substance use disorder (288).
2. Psychiatric factors
The presence of a substance use disorder will have an impact on psychiatric issues, such as the risk of suicide or other self-injurious behaviors and the risk of aggressive behaviors, including homicide. In addition, the presence of co-occurring psychiatric symptoms or disorders affects the patient’s treatment adherence as well as the onset, course, and prognosis of the substance use disorder (170, 288–292). These factors need to be taken into consideration when arriving at a treatment plan for an individual patient.
a) Risk of suicide
The frequency of suicide attempts and death by suicide is substantially higher among patients with a substance use disorder than in the general population. A systematic review of retrospec- tive and prospective cohort studies of substance use disorders and suicide (293) demonstrated that individuals with alcohol use disorder, opioid dependence, or mixed drug use have a substan- tially greater likelihood of suicide compared with the general population, with a 9.8-, 13.5-, and 16.9-fold elevated risk, respectively. This review reported insufficient evidence to compare the suicide risk among patients with other drug use disorders (e.g., cocaine dependence). In terms of lifetime suicide mortality, a review of 83 studies demonstrated a lifetime suicide risk of 7% in individuals with an alcohol use disorder, which is comparable to that of individuals with a mood disorder (6%) or schizophrenia (4%) (294). These rates vary by country and may be slightly lower in the United States (295). In addition, significant rates of substance use disorders are found in psychological autopsy studies of individuals who have died by suicide (296–300), with a recent or impending interpersonal loss being a frequent apparent precipitant (301).
Rates of suicidal ideation and suicidal behaviors, including suicide attempts, are also in- creased in individuals with a substance use disorder. For example, in a recent prospective study, treatment-seeking individuals with alcohol dependence were found to have attempted suicide seven times more frequently than age-matched, non-alcohol-dependent comparison subjects during the 5-year follow-up period after the initial evaluation (302). The alcohol-dependent individuals who attempted suicide (4.5%) were more likely than the other individuals to have made prior attempts; other related factors were earlier onset of the substance disorder, more se- vere substance dependence, dependence on multiple substances, more panic symptoms, being separated or divorced, having had prior treatment, and having been diagnosed with a substance- induced psychiatric disorder (302). In addition, significant high rates of substance use disorders are seen among individuals who have attempted suicide (296, 303–305).
The risk of suicidal behaviors and death by suicide is further increased for individuals with a substance use disorder in the context of certain co-occurring psychiatric disorders, such as major depressive disorder, bipolar disorder, and cluster B personality disorders. The presence of major depressive disorder substantially increases impulsive suicidal behaviors and suicide risk (298, 303, 306–308). A recent review of the literature on co-occurring alcohol use disorders and major depressive disorder demonstrated that this comorbidity increases the risk of suicidal ideation, suicidal behaviors, and death by suicide (309). Among patients diagnosed with major depressive disorder and bipolar disorder, cigarette smoking has also been found to be an inde- pendent predictor of future suicidal behavior (310).
Prospective studies of patients with co-occurring bipolar and substance use disorders con- sistently report greater frequency of lifetime suicide attempts and suicidal ideation compared with bipolar disorder patients with no co-occurring substance use disorder (311–313). Bipolar patients with co-occurring anxiety symptoms or cluster B personality disorder features and a substance use disorder may be at the greatest risk for suicidal behaviors (314, 315).
Patients with co-occurring cluster B personality and substance use disorders also have a greater risk of suicidal ideation and death by suicide (316, 317). This population is also at greater risk for accidental death by injection drug overdose (318).
Despite this clear evidence for an increased risk of suicidal behaviors in individuals with a substance use disorder, few controlled studies are available to assist in guiding the treatment of such patients (319). As in the care of any patient with a psychiatric disorder, suicide risk should be assessed regularly and in a systematic manner. Assessment of suicide risk includes determin- ing the presence or absence of current suicidal thoughts, intent, and plan; a history of suicide attempts (e.g., lethality of method, circumstances); a family history of suicide; a history of ag- gression (e.g., weapon use, circumstances); the intensity of current depressive and other mood symptoms; the current treatment regimen and response; recent life stressors (e.g., marital sep- aration, job loss); substance use patterns; psychotic symptoms; and current living situation (e.g., social supports, availability of weapon). In substance-using individuals, suicidal ideation and suicide attempts may occur in the context of a major depressive episode or result from sub- stance-induced sadness or dysphoria combined with increased impulsivity and poor judgment. However, individuals with a substance use disorder can also be at risk for suicide even in the apparent absence of depression. In terms of treatment implications, care should be used when prescribing potentially toxic medications to a suicidal patient. For additional recommendations on the assessment and treatment of suicidal patients with substance use disorders, the reader is referred to APA’s Practice Guideline for the Assessment and Treatment of Patients With Suicidal Behaviors (301).
b) Risk of aggressive behaviors, including homicide
Substance use disorders are associated with an increased risk for aggressive behaviors toward others, including physical assault, sexual aggression, domestic violence, child abuse, and homi- cide (320–322). Substance intoxication and withdrawal states may be associated with anxiety, irritability, agitation, impaired impulse control, disinhibition, decreased pain sensitivity, and impaired reality testing; these effects are hypothesized to account for the increased aggressive behaviors associated with substance use. In particular, intoxication with substances such as al- cohol, cocaine, methamphetamine, PCP, anabolic steroids, and hallucinogens may be associated with aggression (138, 323–327), whereas withdrawal from substances such as alcohol, opioids, sedative-hypnotics, and cannabis can lead to withdrawal syndromes associated with a risk of aggressive behaviors (138, 320, 328). Intoxication with marijuana or hallucinogens may inad- vertently lead individuals to perform aggressive acts because of a faulty perception of reality coupled with high levels of anxiety and paranoia (329–331). Substance use disorders are also indirectly associated with aggressive behaviors engaged in to obtain illicit or expensive sub- stances. Although it is important to assess for and be aware of the potential for aggressive be-
haviors in individuals with a substance use disorder, it is also important to assess for substance use disorders in all individuals who present with a history of agitation or aggression. Because family and partners may be affected by substance-related domestic violence, systematic screen- ing and referral for domestic violence treatment interventions may effectively reduce domestic violence. Some treatments such as abstinent partner therapy (e.g., coping skills training [332]) and couples therapy (e.g., behavioral couples therapy [333]) have been shown to reduce alco- hol-related domestic violence in randomized, controlled trials.
c) Sleep disturbances
Individuals with substance use disorders frequently report sleep disturbances, particularly after being detoxified. For some patients, managing sleep disturbances will be an important compo- nent of the treatment plan. Indeed, some studies have demonstrated that among detoxified al- cohol-dependent individuals, insomnia is a strong predictor of relapse (334–336). Despite the recognition that sleep disturbances are a problem among individuals with substance use disor- ders, only a handful of studies have examined the treatment of sleep disturbances in these in- dividuals, and these studies have focused only on individuals with alcohol dependence. For example, one small double-blind study found that trazodone was superior to placebo in im- proving sleep in alcohol-dependent individuals with insomnia (337). In an open-label study comparing trazodone and gabapentin for the treatment of insomnia in alcohol-dependent individuals, both medications were found to improve insomnia, but the gabapentin group showed greater improvements than the trazodone group (338). Given the open-label nature of this study, more research is needed to determine if gabapentin is an effective treatment for sleep disturbances related to alcohol dependence. In addition, more research is needed to determine if trazodone and gabapentin, as well as other sedating psychotropic medications, can effectively treat sleep disturbances not only in individuals with alcohol dependence but also in those with other substance use disorders.
In addition to the studies of pharmacological agents, there has been one randomized, con- trolled study that showed that CBT strategies helped improve sleep disturbances in alcohol- dependent individuals in recovery (339). As with the pharmacological treatments for sleep dis- turbances, more research is needed to determine if these strategies will help improve insomnia in individuals with other substance use disorders as well.
d) Co-occurring psychiatric and substance use disorders
(1) General principles
Co-occurring psychiatric and substance use disorders are common in all treatment settings (e.g., centers for the treatment of substance use disorders, mental health clinics, primary care settings, emergency departments) and in the general community. In fact, only a few differences (e.g., higher prevalence of schizophrenia and primary psychotic disorders in mental health care settings, more severe patterns of substance use in substance use treatment settings) are observ- able between patients with co-occurring psychiatric disorders receiving treatment in substance abuse treatment centers and patients with co-occurring substance use disorders receiving treat- ment in mental health treatment centers (340). In community population samples studied in the National Comorbidity Survey (341), individuals with alcohol dependence had high rates of clinically significant depression during their lifetime (men: 24% depression and 11% dys- thymia; women: 49% depression and 21% dysthymia). Individuals with bipolar disorder had high rates of alcohol (61%) and other substance (41%) dependence (342). Treatment-seeking individuals have even higher rates of co-occurring disorders (343–345). For example, Penick et al. (346) studied a U.S. Department of Veterans Affairs (VA) hospital outpatient population with alcohol dependence or abuse and found that 56% reported co-occurring psychiatric dis- orders. In substance use disorder treatment settings, depression, anxiety, and personality disor- ders frequently occur. However, posttraumatic stress disorder (PTSD), adult ADHD, learning
disabilities, social anxiety disorder, eating disorders, and pathological gambling are also com- mon and are often underrecognized and undertreated (121, 288).
Individuals with nicotine dependence are more likely to have co-occurring psychiatric dis- orders than the general U.S. population (347). Furthermore, in mental health and substance use disorder treatment settings, nicotine dependence continues to be the most common co- occurring substance use disorder, with approximately 60%–95% of patients being nicotine dependent, although this varies by the type of psychiatric disorder and the treatment setting (348). One analysis of nicotine use as reported in the National Comorbidity Survey found that individuals with psychiatric disorders were about twice as likely to smoke as the general popu- lation and that about 44% of the cigarettes smoked in the United States were smoked by indi- viduals with a psychiatric disorder (349).
Use of multiple substances and co-occurring psychiatric and substance use disorders are now so common in treatment settings that these combinations should be expected. Thus, all pa- tients with a substance use disorder should be carefully assessed for the presence of co-occurring psychiatric disorders, including additional substance use disorders. Conversely, patients with identified psychiatric disorders should be routinely assessed for the presence of a co-occurring substance use disorder (350, 351).
Treating individuals with co-occurring psychiatric and substance use disorders in traditional inpatient and outpatient programs is challenging. Patients’ motivation to change may vary ac- cording to the type of substance(s) they use and the severity of their psychiatric issues, and this needs to be taken into consideration in treatment planning. Recent research and consensus opinions by experts in the field support the notion that the integration of substance abuse and mental health treatment strategies, including integrated systems, programs, and clinical treat- ment, improves patient outcome (80, 121, 352, 353). There is growing evidence that patients in psychiatric or substance abuse treatment settings have better outcomes if they receive inte- grated treatment for their coexisting psychiatric and substance use disorders (121, 288, 354– 356). Integrated treatment usually requires incorporating and modifying traditional psychiat- ric and substance abuse treatment methods so that the co-occurring disorders receive simulta- neous treatment.
a. Integrated treatment
Recent research and clinical experience (80, 288) has also shed light on the question of treatment timing (e.g., if co-occurring disorders should be treated together in an integrated manner or in what circumstances one problem should be addressed before another). In general, the length of the observation period for a psychiatric or substance use disorder will be determined by balanc- ing the following considerations: the degree of diagnostic certainty, the severity of the patient’s condition, and the anticipated benefits and risks of the proposed treatment (288, 353).
The integrated treatment of co-occurring psychiatric and substance use disorders can in- clude psychosocial and/or pharmacological interventions. Initial treatment efforts should in- clude engaging the patient in treatment and assessing and managing the most severe symptoms of both types of disorders. This may include addressing symptoms of intoxication or with- drawal. Sometimes severe psychiatric symptoms (e.g., psychosis, suicidal ideation) can be man- aged while a patient is intoxicated or experiencing withdrawal; such patients may require immediate treatment in an emergency department or an inpatient psychiatric unit. Once a pa- tient’s acute psychiatric symptoms and intoxication or withdrawal states have been stabilized, the patient can be evaluated for treatment in an ongoing rehabilitative treatment program. When patients are being treated in a substance abuse treatment setting, their psychiatric symp- toms should be monitored and addressed clinically through psychiatric medications, when ap- propriate, as well as through integrated psychosocial strategies (e.g., teaching patients mood management as part of relapse prevention therapy) and integrated treatment approaches for psychiatric disorders and substance use disorders (357).
In a psychiatric treatment setting, it would be incorrect to assume that successful treatment of a psychiatric disorder will resolve the substance use disorder. The substance use disorder will require specific treatment even when it arises in the context of another psychiatric disorder, a situation that is quite common and that presents an opportunity for the prevention of a sec- ondary disorder (358).
Certain psychosocial and pharmacological treatments have been studied for specific com- binations of psychiatric and substance use disorders (e.g., major depression and alcohol de- pendence, schizophrenia and cocaine dependence) (288, 353); the literature about these treatments is presented in the specific substance use disorder sections of this practice guideline. The reader is also advised to review other APA practice guidelines for the treatment of patients with specific psychiatric disorders for additional information.
b. Pharmacological management of psychiatric disorders
In most patients, the same medications are recommended for the treatment of a specific psy- chiatric disorder whether that disorder co-occurs with a substance use disorder or not. Clinical issues such as medication tolerability, safety, and abuse potential are important considerations in choosing a medication and will influence traditional psychopharmacological treatment al- gorithms. There is no evidence to suggest that the duration of pharmacotherapy for a psychi- atric disorder in conjunction with a co-occurring substance use disorder would differ from that needed to treat the psychiatric condition alone, and there are no data to suggest that decisions about continuation and maintenance treatment should differ (288). An important clinical question in treating a co-occurring psychiatric disorder in a substance use disorder treatment setting is whether the prescribing clinician should initiate psychiatric medications during the acute treatment of the substance use disorder. For some psychiatric disorders (especially depres- sion, generalized anxiety disorder [GAD], social anxiety disorder, and PTSD), there have been widely differing opinions about the amount of time a patient should be abstinent from a sub- stance before a definitive diagnosis of a co-occurring psychiatric disorder versus a substance- induced psychiatric disorder can be made. If there is little overlap between the symptoms ob- served and the expected abstinence syndrome (such as bulimia nervosa in an opioid-dependent patient), then the psychiatric diagnosis can be immediately established. In circumstances when prominent mood or anxiety symptoms could be equally attributable to early abstinence or an independent co-occurring psychiatric disorder, a clinician may consider whether similar symp- toms occurred before the substance use or during previous abstinence periods or whether the individual’s family history suggests a vulnerability to a co-occurring mood or anxiety disorder. A common recommendation is to consider the severity of an individual’s functional impair- ment when deciding whether or not to initiate pharmacotherapy, continue ongoing monitor- ing of symptoms, and initiate psychosocial treatment strategies for the management of anxiety and depression (288).
Medication nonadherence is common among individuals with co-occurring psychiatric and substance use disorders (359, 360). Nonadherence can be due to many factors, including cog- nitive impairment, the patient’s fear of the interaction between prescribed medication and