Burden of comorbid disorders
The high frequency of comorbid mental disorders in individuals with a high intake of psychoactive substances has been well documented in clinical and epidemiological studies. Such dual disorders are a matter of great concern because of their serious consequences for the patients, their families, health services, and society. Compared with patients diagnosed with a single mental disorder or substance use disorder (SUD), patients with comorbid disorders run a higher risk of delayed diagnosis , more severe psychopathological symptoms , less compliance with treatment , poorer effects of treatment , more impairment of social functioning , increased admissions to emergency departments , higher prevalence of physical comorbidity , and suicidal ideation . They are also more often unemployed , homeless , and involved in violent episodes  or criminal behavior . The poor outcomes of these patients call for more research within this field.
Necessity of diagnosing comorbid disorders
Traditionally, SUDs and psychiatric disorders have been treated as separate conditions. However, in the last few decades, the close connection between the two has been increasingly acknowledged . Attention has focused on the fact that many psychiatric patients have undiagnosed comorbid SUDs, which go untreated, and therefore jeopardize the treatment of their mental disorder. The majority of SUD patients also have mental disorders, and often do not receive the appropriate treatment.
Many patients receive treatment from both mental and addiction services, but these are uncoordinated and are given at different times. Patients are sometimes rejected in one kind of clinic and sent to another, based on the disorder that is considered to be their major problem. Comorbid disorders may be treated sequentially, simultaneously, or in an integrated way, depending on the type and severity of the two disorders. Integrated treatments are now commonly recommended for more severe disorders [14–16]. Some treatment modalities may be the treatment of choice for both the mental and substance-related disorders; e.g., cognitive behavioral therapy or medication.
The reliable assessment of comorbid disorders is usually achieved in non-SUD psychiatric patients with one or more comorbid psychiatric disorders, in patients with a mental disorder and a previous but not ongoing SUD, and in patients with only an SUD diagnosis. It is much more complicated to assess the mental disorders of patients with ongoing SUD . A successful diagnosis is essential for well-adapted and high-quality treatment. Therefore, it is extremely important that all the disorders of a patient are diagnosed.
Earlier studies have shown variations in the prevalence of comorbid substance use and mental disorders. This is attributable to a lack of consensus regarding the definition of the term "comorbidity", problems in distinguishing induced and independent disorders, problems in separating psychiatric disorders from the symptoms of intoxication or withdrawal, the choice of diagnostic instruments, the skills of the interviewers, and differences in the study samples. In most studies, patients are recruited from general populations or selected from clinical treatment units. As far as we know, no previous study has included all possible subjects from a single catchment area within a specific time period.
Classification of disorders related to the use of psychoactive substances
When patients are heavy users of psychoactive substances, it is challenging to assess their psychiatric symptoms, which may be independent of their substance use, caused by intoxication or withdrawal, or an expected effect of the substance used. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) of the American Psychiatric Association distinguishes "Substance use disorders" (SUDs), i.e., dependence on or abuse of a psychoactive substance, and "Substance-induced disorders" (SIDs), which are mental disorders caused by substance use, i.e., occurring during a period of heavy use or during the first four weeks of withdrawal. To diagnose an SID, the substance must be known to cause the type of symptoms observed, and the symptoms must be in excess of the expected effect of the substance. Such symptoms should not be diagnosed as symptoms of a primary psychiatric disorder, even if the symptoms of the two conditions are identical. The symptoms of an SID must be sufficiently severe to warrant independent clinical attention. An SID does not always need to fulfill all the diagnostic criteria of the related primary psychiatric disorder. The diagnoses of dependence, abuse, intoxication, and withdrawal for each substance are described in the chapter entitled "Substance-Related Disorders" in DSM-IV. Other substance-induced disorders, such as delirium, psychotic disorder, mood disorder, and anxiety disorder, are described in the chapters concerning the respective mental disorders. DSM-IV does not include substance-induced personality disorders.
Relationship between mental disorders and substance use
There are several types of relationships between mental disorders and SUDs. The causes of comorbidity may include coincidence, common genetic vulnerability, common neural substrate, underlying shared origins, self-medication, environment, and lifestyle.
The terms "primary" and "secondary" are frequently applied to disorders in the literature. "Primary" refers to the first condition to develop. This is a chronologically based term only, and does not necessarily represent causality. More meaningfully, it should be recognized that some disorders are independent and some are induced by other disorders [18, 19]. Most patients with SUD report that their symptoms of a mental disorder preceded their SUD. In some cases, this may mean that their mental symptoms caused their SUD (e.g., the self-medication hypothesis) . In other cases, it may indicate that the age of onset of some mental disorders is lower than the age of onset of an SUD . Some symptoms of mental disorders are temporary, caused by substance intoxication or withdrawal [22, 23]. For instance, the high incidence of depression in SUD patients may represent such a phenomenon, and this is sometimes called the "substance-related artifact hypothesis" . However, depressive symptoms in addicted patients may reflect neuroadaptations in the dopamine system caused by chronic drug administration [25, 26]. Drug-induced changes in neurotransmitter systems alter the function of the reward circuitry  and motivational and behavioral systems in the brain [28, 29]. This causes symptoms such as dysthymia, anhedonia, irritability, and motivational and emotional changes during drug withdrawal.
As mentioned above, some mental disorders are coincidentally concurrent with substance abuse. Both disorders may then run their different courses, or they might exacerbate the prognosis of the other. The high frequency of comorbidity reflects the overlapping environmental, genetic, and neurobiological factors that negatively influence both types of disorders. Early life stress or chronic stress results in long-term changes in stress responses, which may alter the sensitivity of the dopamine system. Low dopamine activity makes the individual susceptible to the self-administration of drugs. The chronic stress model suggests why the substance abuse of some susceptible patients increases their risk of mental disorders and vice versa .
Substance abuse or dependence develops in the course of repeated substance use. The amount of substance necessary varies with age, genetics, and other risk factors. In adolescents, the brain regions involved in the process of executive control and motivation are still incompletely developed. Therefore, repeated drug use in adolescents leads to long-lasting brain changes, which undermine voluntary control, hinder brain maturation, and make the brain susceptible to the development of further SUDs. Early drug use is associated with, and predicts, later mental disorders [31, 32].
To distinguish between independent and substance-induced disorders, the following questions should be answered. 1) Are the symptoms in excess of those expected given the type and amount of substance used and the duration of use? 2) Have the symptoms occurred in periods of abstinence? 3) Did the onset of the symptoms precede the onset of the substance use by a sufficient time period? 4) Have the symptoms persisted for at least a month after the cessation of substance use? 5) Does any close relative of the patient have the same or a related disorder? 6) Can the symptoms be explained by a medical condition or the treatment of such a condition? 7) Can the symptoms be explained by exposure to other noxious agents?
Diagnostic challenges in epidemiological studies
In epidemiological studies of comorbid mental disorders and SUDs, there is a risk of exaggerating both the number of SUD diagnoses and the number of primary mental diagnoses. In such studies, patients with symptoms that do not meet all the criteria for the diagnostic categories may be included. Moreover, symptoms related to drug abuse (e.g., nervousness, tension, agitation, depressed mood, loss of motivation) may at the same time be symptoms included in the diagnostic criteria for mental disorders (e.g., generalized anxiety disorder, depressive disorder). In epidemiological studies, persons with SUDs are in different stages of their disorder: intoxicated, abstinent, or experiencing withdrawal symptoms. Moreover, the most severely ill patients are probably unable to participate in the surveys.
Research instruments are also often insufficiently sensitive to discriminate between independent and substance-induced symptoms in patients with ongoing substance abuse, intoxication, or withdrawal symptoms. The traditional use of trained but nonprofessional interviewers may be a problem when clinical judgments are required. Caution is needed in interpreting the results of many studies, because the diagnoses were made by nonclinicians and the symptoms were reported retrospectively.
Studies within this field have methodological problems related to the differentiation of alcohol/drug abuse and other mental disorders. In some studies, diagnoses are based only on screening instruments; in others, the diagnostic interviews used have not been validated for both SUDs and mental disorders. Diagnoses drawn from different diagnostic interviews give different results, to varying extents [33–35], and even the same diagnostic interview, used in different groups, can poorly differentiate psychiatric symptoms from symptoms of intoxication or withdrawal . Structured instruments have been shown to increase the diagnostic validity of SUD diagnoses compared with clinical judgments, but psychiatric comorbid diagnoses show poor validity, regardless of the method used [37, 38].
Prevalence of comorbidity in epidemiological studies
Epidemiological studies from different countries have shown a high prevalence of comorbid alcohol or other drug disorders and mental disorders. In the Epidemiologic Catchment Area Program in the USA undertaken in the early 1980s, the estimated prevalence of mental disorders was 22.5%, and the lifetime incidence was 32%. Among subjects with an alcohol disorder, 37% had a comorbid mental disorder, and among drug-abusing subjects, 53% had a mental disorder. In the general population, 16% of individuals had an SUD, whereas 29% of people with a mental disorder had a comorbid SUD .
The US National Comorbidity Study (NCS) undertaken in the late 1980s found that almost 50% of the participants met the criteria for at least one lifetime mental disorder, and almost 30% had suffered at least one mental illness in the preceding year. The most common disorders were severe depression, compulsive drinking, and social and simple phobias. Among male alcoholics, 78% had a comorbid mental disorder or SUD, as did 86% of female alcoholics [40, 41]. The overall results from the NCS are very similar to those obtained with a Norwegian epidemiological study in Oslo , except for a lower prevalence of illegal drug abuse in Norway. A similar study performed in a rural area in western Norway showed a lower prevalence of all disorders, but the same basic pattern was observed .
The European Study of the Epidemiology of Mental Disorders was a population study performed in six European countries between 2001 and 2003 . Among all the subjects, 14% reported a lifetime history of a mood disorder, 13.6% an anxiety disorder, and 5.2% an alcohol disorder. Mental disorders were more frequent in younger people and in female, unemployed, unmarried, or disabled people.
In a Canadian study, the 12-month prevalence of major depressive disorder (MDD) was almost three times higher in people with substance dependence than in the general population. The risk of MDD and suicidal thoughts increased with more severe substance use . Significant comorbidity between mental disorders and SUDs has been observed in several countries, including the Netherlands [46, 47], England , Finland , Taiwan , and Russia .
Diagnostic challenges in clinical samples
In many studies of samples of SUD inpatients, the duration of abstinence before the mental disorder is diagnosed has not been described, or the studies vary in the duration of abstinence examined. Some authors have found that most substance-induced depression and anxiety symptoms decline rapidly with abstinence [52, 53]. In most situations, DSM-IV recommends four weeks abstinence before the diagnosis of a mental disorder, to avoid confounding symptoms of intoxication or withdrawal. However, many dependent patients experience a protracted abstinence syndrome, which can last for several months or more. The duration of abstinence required for the symptoms of intoxication or withdrawal to decline varies with the type of substance, the duration of substance use, and the type of symptoms in question [22, 54]. In clinical situations with short hospitalizations or nonhospitalized patients, it is often impossible to achieve four weeks of abstinence.
Few studies have been undertaken in outpatient settings with SUD patients, probably because the patients often drop out and are seldom consistently abstinent during the assessment period. It would be very interesting to investigate the possibility of diagnosing nonabstinent individuals in an outpatient clinical setting, because this is the everyday challenge of many clinicians.
Different diagnostic interviews have advantages and limitations when used to assess comorbid SUDs and mental disorders [18, 55]. The Psychiatric Research Interview for Substance and Mental Disorders (PRISM) was designed to correct the lack of diagnostic interviews suitable for such assessments .
Prevalence of SUDs in patients with mental disorders
Many studies have demonstrated a high prevalence of SUDs in patients with mental disorders, e.g., in general patient samples [57, 58], and in patients with psychoses or schizophrenia [59, 60], bipolar disorder , depression or anxiety , personality disorders , and eating disorders .
Several studies from acute psychiatric wards in Norway found that about 45% of patients had substance-related problems. Among patients with first-episode nonaffective psychosis in Norway and Denmark, 23% had abused drugs and 15% had abused alcohol during the preceding six months . In another study of psychotic inpatients, 54% had abused substances within the 30 days preceding their admission . It is estimated that between 40% and 50% of patients with psychotic disorders in Western countries also have substance-related disorder. Up to 69% of patients with bipolar disorders have a lifetime history of substance abuse or dependence .
In a nationwide Norwegian study, the substance disorder diagnoses of psychiatric inpatients (November 2003) and psychiatric outpatients (September 2004) were registered . Of the patients in psychiatric wards, 10% were diagnosed with dual disorders. The real number is probably higher, because therapists often do not perform exact substance-use assessments.
Prevalence of mental disorders in SUD patients
A high level of comorbidity between substance abuse and psychiatric disorders in clinical samples has been reported in several countries, including the USA [68–70], Germany , Iceland , the United Kingdom , and New Zealand . The most common psychiatric disorders in SUD patients are anxiety disorders, mood disorders, and personality disorders. Many also have more than one SUD. Much research has been undertaken in this field.
The estimated prevalence of panic disorder and agoraphobia in patients with alcohol use disorders ranges from 5% to 42% . The prevalence of panic disorder varies with the substance used, and only 1.7% of cocaine-dependent patients experienced panic disorder in a large study . Some symptoms of generalized anxiety disorder (GAD) largely overlap those of acute intoxication with stimulants or withdrawal from alcohol, sedative/hypnotics, or opiates. Therefore, it is not surprising that the prevalence of GAD in different studies varies between 8% and 53% in alcohol-dependent individuals. The same variance has been observed in comorbid alcoholism and social phobia . In cocaine-dependent individuals, social phobia has a lifetime prevalence of 14% . Substance users have a high prevalence of posttraumatic stress disorder of 36%-50% . MDD has been found in 16.5% of patients with alcohol use disorder and in 18% of patients with drug use disorder. Depressive disorder in treatment-seeking alcoholic individuals ranges from 15% to 67% . The prevalence of affective disorders ranges from 33% to 53% in cocaine-dependent individuals and from 16% to 75% in opiate-dependent individuals. In studies of treated addicts, 45% to 80% of the patients had personality disorders . In a study of 370 SUD patients in the USA, 57% had one or more personality disorders, most often in cluster B (45.7%) .
In a clinical sample of SUD patients in Norway, 90% had at least one lifetime substance-independent mental disorder, most often an axis I disorder . Furthermore, 79% of polysubstance abusers and 66% of alcohol abusers had one or more axis II disorders.
In a nationwide study in Norway , only 25% of patients undergoing treatment for SUD were assessed for a psychiatric disorder, and 65% of the patients presenting with psychiatric problems were not diagnosed. Of the diagnosed patients, 47% had a nonsubstance-related psychiatric disorder, most often an anxiety disorder (34%), mood disorder (25%), or personality disorder (22%).
The wide range of results within diagnostic groups probably does not reflect real differences in prevalence but demonstrates the complexity of reliable assessment.