Although there is considerable epidemiological and neurobiological evidence linking alcohol use and depression, the exact nature of this relationship has yet to be elucidated and may vary between patients. In their review of the substance abuse and depression literature, Swendsen and Merikangas (11) proposed that multiple causal factors and mechanisms probably underlie the association of alcoholism and depression. Neurobiological similarities have been postulated as one of these mechanisms. For example, monoamine, cholinergic, and other neurotransmitter systems have been implicated in both disorders (12,13).
The relationship between depression and both acute alcohol-related states (such as intoxication and withdrawal) and chronic use problems (such as abuse, protracted withdrawal, and chemical dependence) has been studied. All of these alcohol-related conditions have been shown to be associated with dysphoric mood states, but the mechanism of mood depression is not well understood and may differ among various alcohol-related conditions. In addition, the length of time alcohol has been abused, amount of use, predisposing genetic factors, gender, and multiple other variables may influence the mechanism of comorbidity with depression. Likewise, the different depressive states may be caused by different underlying neurochemical mechanisms, and thus could be associated with alcoholism by different processes. Current informa tion must therefore be considered only a beginning in our understanding of this complex problem.
Alcohol is a CNS depressant, and so it is not surprising that acute alcohol intoxication can produce a dysphoric state (14). The dysphoria appears to be related to the amount of use. Alcohol intoxication increases impulsivity and thus raises the risk of self-injury and suicidal behavior. For example, a study by Cornelius et al. (15) found an approximately 40% prevalence of suicide attempts in the week prior to hospitalization, with most involving impulsiveness and heavy drinking. They suggested that heavy alcohol use increased impulsivity rather than induced suicidal ideation.
The association between depression and chronic alcohol use has been another area of interest. Some studies suggest that alcohol and affective disorders occur together at higher rates than would be expected by chance (16,17). In a community sample of over 500 subjects, using the Schedule for Affective Disorders and Schizophrenia (SADS) and Research Diagnostic Criteria (RDC), Weissman and Myers (18) found a 44% lifetime prevalence of major depression in alcoholics and a 15% lifetime prevalence of minor depression. Negative life events, a family history of depression, and neuroticism have been identified as risk factors for depression in alcoholics (19,20).
A family study suggested that a lifetime history of depression and a family history of alcoholism were associated with comorbid alcohol dependence (21). Others, however, reported that depression and alcoholism segregated independently in families (22).
The comorbidity of alcoholism and depression can be clinically very important. In most cases, alcohol and depression negatively influence the comorbid disorder, causing more severe problems than either alone (23). As with intoxication, concurrent chronic alcohol abuse and depressive disorders have been associated with an increased risk for suicide (24-28). In addition, certain areas of performance may be greatly affected by the co-morbidity (29,30). Cortical operations known to be affected by both alcohol and depression include learning, memory, and motor function (31). For example, alcohol consumption, depression, and neuropsychological performance have been linked (29,30). In some reports the comorbidity appeared to be less important. For example, Hirschfeld et al. (32) found no differences in either time to recovery from major depression or time to relapse to another episode of depression in two samples, with and without concurrent alcoholism, although the course of the former was worse in terms of social functioning.
Treatment options may also be influenced by detection of comorbidity. Thus, it is generally considered important to treat an alcohol-related disorder if significant progress is to be made with depression. That is, if alcohol abuse or dependence goes undetected or untreated, depressive symptoms may be more resistant to medications and other forms of treatment. Data suggest that remission in alcoholism increased the odds of remission in depression (33).
Similar relationships between depressed mood and alcohol abuse have been reported in adolescents. In a prospective study of over 1000 adolescents, those with depressive symptoms and heavy drinking were more likely to have low levels of functioning, high levels of childhood externalizing problems and stressful life events, low levels of family social support, and high levels of delinquency (34). Alpert et al. (35) found that childhood and adolescent onsets of depression were risk factors in the development of alcohol dependence and abuse in adulthood. King et al. (36) noted that depressed male adolescents had increased risk of later alcohol and drug abuse.
Several studies suggest that the relationship between alcohol and depression is different for men and women. Depressed women alcoholics appear to be more severely depressed than their male counterparts, and that depressive symptoms were predictive for alcoholism in women but that the reverse was true for men (36-39). In a study of 3755 twin pairs, Prescott et al. (40) found major depression to be more common in women and alcoholism in men. About 68% of women with both depression and alcoholism identified depression as preceding alcoholism, whereas the opposite was reported in 61% of the men (39). These results suggested that possible causal relationships may be gender-influenced processes.
Substantial evidence exists that mood changes induced by alcohol diminish with abstinence (41-49). For example, Brown and Schuckit (44) reported that 42% of their 191 alcoholic inpatients had Hamilton Depression Rating Scale (HDRS) scores in the moderately to severely depressed range, but that by the fourth week of abstinence this number had declined to 6%. Furthermore, 3 months after discharge, there was no recurrence of depressive symptoms except in those who relapsed. In a similar study they found that the rate of remission of depressive symptoms consistently followed the course of the primary illness (i.e., either depression or alcohol dependence), and a minimum of 3 weeks of abstinence was necessary to differentiate between the two groups (50). Other data also suggest that relapses are accompanied by the return of previously remitted depressive symptoms (51).
Alcohol withdrawal is a condition that has repeatedly been shown to be associated with dysphoria, but the extent to which this occurs is variable (14,41). Some estimates of withdrawal-related dysphoria are as high as 98% (41). Because of the relationship between depression and alcohol withdrawal, some earlier prevalence studies should be considered in this light (52). For example, Ross et al. (53) reported a lifetime prevalence of about 23% for major depression and approximately 13% for dysthymia in alcoholics; however, 66% of the sample had been drinking within 7 days of the interview. Forty-three percent claimed onset of depressive symptoms before alcohol use and 40% after the onset of alcohol use. Other studies (54,55) estimated secondary depression at 28-70%, depending on the assessment method. Herz et al. (56) found a 16% current prevalence for depression and an 11% current prevalence for dysthymia in 74 patients.
Regarding possible markers for depression in alcoholics, Dackis et al. (57) found thyroid-releasing hormone (TRH) abnormalities in 53% of patients in alcohol withdrawal. Twenty-five percent had a blunted response to the thyroid-stimulating hormone (TSH) test after 3 weeks of sobriety, suggesting that the TRH test is not specific for depression in alcoholics. They also examined the dexamethasone suppression test (DST) and found abnormal results in three of 15 subjects in withdrawal but no abnormalities in 32 subjects after 4 weeks of sobriety, concluding that the DST may have more diagnostic utility as an adjunct in diagnosing depression in alcoholics with some sobriety. One caveat in the use of the DST, however, arose from the work of Nelson et al. (58), who found that advanced age (over 45 years) may confound the results by making patients nonsuppressors.
A major area of interest has been the distinguishing of alcohol-induced transient secondary depression from primary depression with a comorbid alcoholism. Schuckit (59) and others (60) have investigated a primary-secondary depression dichotomy, with secondary depressions being directly attributable to alcohol use and resolving with abstinence (59,61). Schuckit cautioned that prevalence of depressive symptoms in alcoholics must be considered in light of the sample, criteria, timeframe, and duration (14,62). He suggested that about one-third of alcoholics will have lifetime major depression, which will improve with abstinence and supportive treatment, that only about 5% of men and 10% of women will have a current coexisting major depression, and that these patients typically have depressive episodes independent of drinking (59). Schuckit defined primary depression as occurring prior to the onset of first major life problem from alcoholism or after 3 months of abstinence. Secondary depression often disappeared within 1 week of abstinence but may mimic a course similar to that of primary depression (63). Weissman et al. (64) found similar depressive symptoms that were less severe in patients with secondary depression.
In a study of 231 men and 90 women, Hesselbrock et al. (65) identified gender differences as being important in the dichotomy. As in the studies reviewed above (36-40), major depression was most common among females and more often preceded alcohol use compared to males. Hesselbrock and colleagues noted that patients with primary depression reported more "affective disturbances" than did secondary depressives. Powell et al. (66) reported trends suggesting that primary depressives had more psychiatric hospitaliza-
tions, more ECT treatments, longer duration of depression, and shorter duration of alcoholism. Raimo and Schuckit (67) postulated that there was no relationship between primary unipolar depression and alcoholism. From a sample of 2945 alcoholic subjects, Schuckit and coworkers also concluded that primary and secondary depressions could be differentiated by demographic and other factors (68). In contrast, Greenfield et al. (69) reported that concurrent major depression, either primary or secondary, was predictive of relapse in their sample of over 100 patients (60 men and 41 women).
Some studies have not found significant correlations between alcoholism and depression. For example, Hodgins et al. (70) reported no direct causal relationship between depression and drinking outcomes in their 84 treatment subjects. Similar results were reported by Davidson and Blackburn (71).
The neurochemical mechanism(s) involved in alcoholism and depression continue to be investigated. The effects of alcohol on the brain are widespread, involving most systems and structures. Mechanisms may differ according to the specific alcohol-related problem of a particular patient (i.e., intoxication, withdrawal, abuse, or dependence). Serotonergic and glutamatergic systems are particularly affected by alcohol, which in turn affects most neurotransmitter systems.
Withdrawal has been associated with various neuropathological alterations (72). Identified abnormalities include decreased serotonin transmission (73-75) that becomes normal on acute alcohol administration (73). Serotonin deficiency may be an important component of alcohol-related disorders and depression. Branchey et al. (76) found significantly elevated tyrosine and phenylalanine levels and decreased tryptophan levels and tryptophan ratios in eight depressed alcoholic patients compared to 26 alcoholics without a history of depression. Badawy's work (77) supports this hypothesis, linking serotonin deficiency to higher liver tryptophan pyrrolase activity and implicating the tryptophan metabolite quinolinate in the development of depressive symptoms. In a study of 58 alcoholic subjects, Swann et al. (78) found a positive correlation among plasma tryptophan, large neutral amino acids (a marker of 5-HT function), symptoms of dysphoria, and later onset of alcoholism.
Heinz et al. (79) compared Beck Depression Inventory (BDI) and HDRS scores with various neurotransmitter metabolite levels in 21 abstinent alcoholics and 11 controls. They found correlations between cerebral spinal fluid (CSF) 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations and depressive symptoms, implicating noradrenergic abnormalities as well as serotonergic function in the onset of depressive symptoms. Serotonin deficiency was implicated in the higher suicide rate found among alcoholics with depression (80,81), in mem ory impairment (82), and in blackouts (83) frequently seen in alcoholics. Other studies suggested that low serotonin levels are associated with increased alcohol preference and consumption (84,85). Some reports suggest no relationship between depression and either postsynaptic alpha2-adrenoceptor function (86) or reduced sensitivity of dopamine receptors (87).
Overall, it appears that primary depression and alcoholism may occur independently, that secondary depression frequently exists in relation to alcohol use and withdrawal, that there are gender differences in the expression of these two disorders, and that serotonin and its precursors as well as other neurochemical systems are implicated in the development of depressive symptoms. Greater understanding of the association between alcoholism and depression may lead to improved methods of prevention and treatment of these important, and common, comorbid disorders.
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