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Substance Use Disorders: Sex Differences and Psychiatric Comorbidities
Psychiatric Comorbidity as Predictor of Treatment Outcome
Even though extensive literature documents the high prevalence of depression in substance use disorders, particularly in women, only a few studies address the impact of this comorbidity on outcome. Several studies from the 1970s and 1980s observe that treatment outcome for alcoholism is worse for men with comorbid depression and alcoholism, compared with the outcome for men without comorbidity, while the opposite is true for women (16,58–60). This differential outcome seems to be associated with a lifetime diagnosis of depression and shorter follow-ups. With longer follow-ups, the sex difference in treatment outcome tends to disappear, with overall better outcomes at a 3-year follow-up for both women and men with lifetime comorbid depression than for those without comorbidity (61). Again, no sex difference in the effect of depression on drinking outcome was found at a 1-year follow-up when current, rather than lifetime, depression was taken into account, but the drinking outcome was worse when depression was present. In the same study, however, the prescription of antidepressants for subjects with comorbidity was associated with longer time to relapse (62). Similarly, in a 5-year follow-up study, improved depression symptoms in subjects with comorbidity was significantly related to better treatment outcome for alcohol use, with no sex differences (63). Further, the temporal relation of depression and substance use disorders likely affects substance use treatment outcomes (64). (The results of this study were not reported by sex.) Finally, Hodgins and others found that women with alcohol dependency and a diagnosis of major depression at some time within their lifetime were significantly more likely to have primary depression, compared with their male counterparts (69% vs 35% respectively) (65). Men, however, were more likely to suffer from current depression than were women (29% vs 10%). This 3-year follow-up study did not identify any sex differences in the effect of depression on alcohol drinking outcome. Given the inconsistency of the results, it is clear that a better understanding of the impact of sex on the comorbidity of substance use disorders and depression and the relation of sex to treatment outcome is still much needed. Key variables need to be further defined so that findings can be compared. They include the nature of depression diagnosed (lifetime or current and primary or secondary), whether and how depression was addressed, and time of follow-up (short- or long-term).
The impact of other comorbid psychiatric disorders on the treatment outcome for substance use disorders has been less studied, and the role of sex needs further investigation. For example, although the comorbidity between cocaine dependence and depression has been studied for its treatment impact, and depression in subjects who abuse cocaine has been associated with both better (66) and worse (67) retention and abstinence outcomes, sex differences were not analyzed.
Summary. Not all studies identify sex differences in the treatment outcome of individuals with comorbid alcohol use disorders and depression. However, some evidence suggests that lifetime diagnosis of depression is associated with better short-term prognosis for the alcohol disorder in women, as opposed to men. Further, current depression per se is associated with poorer prognosis for the alcohol disorder, regardless of sex. However, antidepressant treatment may be associated with better outcome for problem drinking.
Treatment of Women With Comorbid Substance Use Disorders
Sex differences in the response to several medications have been reported, attributable at least in part to differing pharmacokinetics between the sexes. For example, women with depression seem to respond better to selective serotonin reuptake inhibitors (SSRIs), while men with depression seem to respond better to tricyclic antidepressants (TCAs) (68). Variability by sex has been reported in regard to the potential of some SSRIs to reduce alcohol consumption (69). However, most efficacy studies investigating pharmacotherapy treatment of individuals with alcohol use disorders have failed to analyze data by sex. For instance, Naranjo and others observed that, among individuals with alcohol dependence but without depression, men benefited more than women from citalopram treatment, reinforcing the importance of considering sex in the analysis (70). Other authors have provided preliminary evidence regarding the efficacy of fluoxetine in the treatment of patients with comorbid alcohol dependence and severe major depression, but sex differences were not investigated (71).
There is some evidence showing that, among individuals with alcoholism, a negative mood (not necessarily major depression) influences craving for alcohol in distinct ways according to sex, being associated with increased alcohol craving in women but not in men (72). This finding suggests that mood may be an important determinant in relapse for women with alcohol use disorders and underscores the need to develop specific relapse-prevention strategies focusing on coping skills for depression.
Psychotherapeutic trials analyzing sex differences are also needed. A large, 8-year clinical trial designed to investigate whether individuals with alcohol use disorders responded differently to specific psychotherapeutic approaches reported that, compared with men, women generally presented better outcomes following hospitalization; however, no sex effect in treatment matching was found (73). Specific treatments for individuals with psychiatric comorbidities were not investigated.
Recurrent depressive episodes and suicidal ideation in women with substance use disorders are often part of a broader picture compatible with a diagnosis of borderline personality disorder (BPD). Dialectical behaviour therapy is a specific type of time-limited, cognitive-behavioural approach that combines individual psychotherapy with skills training focusing on emotion-regulation and acceptance strategies. It was developed to treat chronically suicidal women with BPD. Preliminary data for women with comorbid substance dependence and BPD suggest that, compared with traditional treatments in the community, this approach is associated with greater reductions in substance use and improved overall functioning, as well as with increased treatment retention (74,75). It has been further suggested that women with substance use disorders and a history of trauma may benefit from psychodrama strategies, but specific research is still lacking (76).
Summary. There is some preliminary evidence that sex differences may exist in the pharmacologic treatment response of individuals with alcohol use disorders. To our knowledge, however, no studies have investigated differential responses to pharmacotherapy in individuals with comorbid conditions. Further, the importance of a depressive mood in relapse for women with alcohol use disorders has been recognized, and some preliminary data point out the efficacy of specific psychotherapeutic interventions for women with comorbid conditions, but additional research efforts are clearly needed.
Discussion
Generally, more recent cohorts confirm earlier study results indicating sex differences in the prevalence rates of psychiatric comorbidity among individuals with substance use disorders. In most studies, overall rates are consistently higher for women than for men. One possible explanation is that, because substance use is less normative for women than for men (that is, less socially acceptable for women), those women who develop a substance use disorder may represent a more severely afflicted population at higher risk for psychiatric comorbidity. An alternate explanation is that women with psychiatric disorders are more likely than men to use substances to self-medicate and are therefore at higher risk for developing secondary substance use disorders. Further research is needed to confirm or refute these hypotheses. Sex differences in the rates of specific disorders were also consistently observed: in particular, higher rates of depressive and anxiety disorders were observed in women, and higher rates of substance use disorders and APD were observed in men. This distribution does not simply reflect the general population pattern: these estimates are also based on ORs or prevalence ratios (that is, the risk and prevalence rates of a psychiatric disorder in individuals with a substance use disorder relative to the rates of a psychiatric disorder in individuals without a substance use disorder). Thus, these rates indicate that individuals with substance use disorders display relative increases in specific psychiatric disorders, compared with the general population. The use of odds or prevalence ratios may also explain the NCS findings: in that study, the sex difference for psychiatric comorbidity among individuals with alcohol use disorders was significant only for alcohol abuse but not for alcohol dependence. For instance, although 48.5% of women with a lifetime diagnosis of alcohol dependence also fulfilled criteria for depression, compared with only 24.3% of men with the same diagnosis, the sex difference in the OR is nonsignificant. These differential results regarding alcohol abuse and alcohol dependence suggest that the sex difference in psychiatric comorbidity may be more subtle at higher levels of alcohol use severity (alcohol dependence) than at lower levels (alcohol abuse). Care must be exercised when analyzing prevalence rates, since large differences emerge when one considers treatment, as opposed to epidemiological, samples and inpatient, as opposed to outpatient, samples, as well as lifetime, as opposed to current, diagnosis. The attempt to generalize results derived from treatment samples is complicated by the fact that their subjects often represent the more severe end of the spectrum of substance use disorders. Some studies looking at Axis I comorbidity rates in subjects dependent on other drugs include alcohol use disorders, and others do not. Other common comorbid conditions, such as pathological gambling, eating disorders, ADHD, and personality disorders other than APD are usually not included. Selectively including some diagnoses but not others may bias the results. Particularly for personality disorders, including only the antisocial subtype in most surveys usually yields higher rates of personality disorders for men. Including other personality disorders may reveal important sex differences in Axis II comorbidity. These differences in diagnostic inclusion and definition may at least partly explain discrepancies among prevalence studies.
It is clinically significant that individuals presenting for treatment with a comorbid substance dependence and psychiatric disorder show significant sex differences in the severity of both conditions, as well as in overall functioning. In particular, clinicians need to deal with the substantially higher risk of suicide attempts that women with comorbid diagnoses display, compared with men. Close monitoring is relevant, especially when one considers that women with substance use disorders are more likely to have a partner suffering from addiction than are men; consequently, they have less spousal support to encourage treatment and follow-up. As well, communication among health professionals is essential, because women with comorbid conditions may have more severe physical conditions than men and are more likely to be prescribed potentially addictive medications, such as tranquilizers, sleeping pills, and analgesics. This puts them at greater risk for iatrogenic dependencies and doctor-shopping behaviour. Women with primary or independent mood or anxiety disorders in addition to substance disorders may need long-term follow up. Further, they should be taught to monitor potential symptoms of recurrence, so that they may recognize them early and forestall a subsequent relapse of their substance use disorder.
It is also clear that the literature focusing on alcohol use is somewhat more developed than is research on other drugs. Some of the sex differences in psychiatric comorbidity described for individuals with alcohol use disorders may also apply to individuals with other drug use disorders. Further studies are needed to confirm this trend.
The distinction between primary and secondary depression is particularly helpful for women with substance use disorders; they will more frequently display a primary or independent disorder potentially requiring specific antidepressant treatment. Some authors recommend that, ideally, clinicians wait until the patient has had 3 to 4 weeks of abstinence before establishing an independent diagnosis of depression (36). However, a careful history may reveal the presence of a clearly primary depressive disorder, favouring more immediate treatment. The intensity of depressive symptoms may seriously impair a patient’s ability to achieve abstinence. In these circumstances, treating depression with antidepressants needs to be considered even when complete abstinence has not been reached, because treatment is often associated with subsequently reduced quantity and frequency of drinking. Anti- depressants may also be indicated for patients with comorbidity who have a chronic course, with depressive symptoms persisting during past attempts at abstinence, or who have a family history of mood disorders (77). To avoid cycling secondary to antidepressants, it is also important to determine whether a depressive disorder is unipolar or bipolar. Several medications are metabolized by the liver, and monitoring liver function is essential, because women with alcohol dependency develop alcohol-related liver impairment faster than men, with less total alcohol consumed (6). Because a depressive episode represents a risk factor for later development of alcohol use disorders in women, and because women have a higher risk for progressing to a chronic course, we recommend early screening for, and vigorous treatment of, depression in women.
The extent to which these principles should apply to other psychiatric diagnoses in comorbidity with substance use disorders is uncertain, but it is likely, for example, that the same rationale could be considered for anxiety disorders. For disorders such as pathological gambling, schizophrenia, and eating disorders, concurrent treatment is indicated whether or not the disorder is primary. More research is needed to clarify and develop this aspect of comorbid treatment and to establish monitoring and safety guidelines. Likewise, studies to develop related specific psychotherapeutic and relapse prevention interventions are much needed.
Because psychiatric disorders, particularly depression and PTSD, are associated in women with increased risk for developing substance use disorders, careful psychiatric assessment and treatment of these conditions may prevent the occurrence of substance use disorders.
Finally, psychiatric comorbidity affects treatment outcome in distinct ways according to sex. At least for the comorbidity between depression and alcohol use disorders, the prognosis for women with comorbidity is better than that for their counterparts without comorbidity, while the opposite seems to be true for men. Again, further studies are needed to clarify the nature of this relation; the difference was found in the short-term follow up but disappeared in the longer term. Last, it is not totally clear how lifetime and current diagnoses influence treatment outcome, but evidence confirms that the adequate management of comorbid depression improves treatment outcome for substance use disorders, particularly among women.
Funding and Support
In preparing this review, Dr Zilberman and Dr Tavares were supported in part by the National Council on Research and Development (CNPq), Brazil.
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Author(s)
Manuscript received and accepted November 2002.
1. Fellow, Addiction Centre, University of Calgary, Calgary, Alberta.
2. Clinical Professor of Psychiatry, State University of New York, Stony Brook, New York.
3. Professor and Head, Substance Abuse Division, University of Calgary, Calgary, Alberta.
Address for correspondence: Dr M Zilberman, Addiction Centre, Foothills Medical Centre, University of Calgary, 1403–29th Street NW, Calgary, AB T2N 2T9
e-mail: monica.zilberman@calgaryhealthregion.ca
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