Naltrexone and cue exposure with coping and communication skills training for alcoholics: treatment process and 1-year outcomes.

BACKGROUND: Promising treatments for alcoholics include naltrexone (NTX), cue exposure combined with urge-specific coping skills training (CET), and communication skills training (CST). This study investigated the effects of combining these elements as treatment adjuncts. METHODS: A 2 x 2 design investigated the effects of CET combined with CST, as compared with an education and relaxation control treatment, during a 2-week partial hospital program (n = 165) followed by 12 weeks of NTX (50 mg/day) or placebo during aftercare (n = 128). Drinking outcomes were assessed at 3, 6, and 12 months after discharge from the partial hospital. Process measures included urge, self-efficacy (confidence about staying abstinent in risky situations), and self-reported coping skills. Medically eligible alcohol-dependent patients were recruited. RESULTS: Among those compliant with medication on at least 70% of days, those who received NTX had significantly fewer heavy drinking days and fewer drinks on days that they drank than those receiving placebo during the medication phase but not during the subsequent 9 months. CET/CST-condition patients were significantly less likely to report a relapse day and reported fewer heavy drinking days at the 6- and 12-month follow-ups than patients in the control treatment. Interactions of medication with behavioral treatments were not significant. Process measures showed that NTX resulted in lower weekly urge ratings, and those in CET/CST used more of the prescribed coping skills after treatment, reported fewer cue-elicited urges, and reported more self-efficacy in a posttest role-play test. Drinking reductions at 3, 6, and 12 months correlated with more use of coping skills, lower urge, and higher self-efficacy. CONCLUSIONS: The results suggest the probable value of keeping alcoholics on NTX for longer periods of time and the importance of increasing compliance with NTX. They also support the earlier promising effects of CET and CST as adjuncts to treatment programs for alcoholics by maintaining treatment gains over at least a year. The value of the urge-specific and general coping skills and of self-efficacy and urge constructs was demonstrated in their association with drinking outcomes.

A dynamic adaptation of the propensity score adjustment for effectiveness analyses of ordinal doses of treatment.

The propensity score adjustment is a method to reduce bias in observational studies. We propose a strategy that involves a novel combination of three data analytic techniques, which adapts the propensity adjustment for additional perturbations of longitudinal, observational studies. First, ordinal logistic regression examines propensity for ordinal doses of treatment. Second, a mixed-model approach incorporates the multiple treatment trials and multiple episodes that are characteristic of chronically ill subjects. Finally, a mixed-effects grouped-time survival model incorporates the propensity score in treatment effectiveness analyses. The strategy that is applied here to an observational study of affective illness can also be used to evaluate the effectiveness of treatments for other chronic illnesses.

Assessing the risks and benefits of benzodiazepines for anxiety disorders in patients with a history of substance abuse or dependence.

In this article, the authors reevaluate the traditional position that benzodiazepines should be avoided in anxiety disorder patients with a history of substance abuse or dependence. The efficacy of benzodiazepines in each of the anxiety disorders is reviewed, as are their side effects and toxicity. The definitions of benzodiazepine abuse and dependence are discussed, and relevant animal, experimental, and clinical data are reviewed and analyzed. A manual and computerized (MEDLINE) search was performed from 1966 to the present to examine the English-language literature published on benzodiazepines, substance abuse, and each of the anxiety disorders listed in DSM-IV. The authors found that benzodiazepines have demonstrated efficacy in generalized anxiety disorder, panic disorder, and agoraphobia; they are promising agents in the treatment of social phobia and alcohol-induced anxiety disorders. They are generally well tolerated. There is much ambiguity over appropriate definitions for benzodiazepine abuse and dependence: although most benzodiazepine abusers concurrently abuse other substances, there is little evidence to indicate that a history of substance abuse is a major risk factor for future benzodiazepine abuse or dependence. Furthermore, benzodiazepines do not appear to induce relapse of substance abuse in these patients. The authors conclude that the position that benzodiazepines are contraindicated in former substance abusers appears to lack empirical justification. Benzodiazepines may be indicated in certain patients with anxiety disorders and a history of substance abuse or dependence.

Predictors of compliance with naltrexone among alcoholics.

OBJECTIVE: Naltrexone has been found to be an effective adjunct to treatment to reduce the rate of drinking among alcoholics. However, adherence to the medication has been of considerable concern; the high rates of noncompliance with the medication limits the benefits that could potentially be realized from this pharmacotherapy. Knowledge of predictors of noncompliance could result in interventions targeted at these variables. METHOD: Participants were 128 alcohol-dependent patients who participated in a clinical placebo-controlled trial of naltrexone. Upon discharge from a 1- to 2-week partial hospital program, patients were randomly placed into 12 weeks of naltrexone (50 mg/day) or placebo (n = 64 per condition). Patients met with a physician and a research assistant weekly for 4 weeks then biweekly for 8 weeks. RESULTS: Compliance (number of days taking medication) was not predicted by demographic or pretreatment alcohol use variables. Number and severity of side effects in the first week, particularly nausea and fatigue, predicted early termination. Compliance was not predicted by commitment to abstinence or self-efficacy about abstinence, but was greater among patients who believed more strongly that the medication would help them stay sober. Compliance was not predicted by general level of urge to drink during the first week on medication but compliance was greater among those with a higher urge to drink in response to alcohol stimuli in the laboratory. CONCLUSIONS: Implications for approaches to increase compliance include reducing side effects and increasing patients' beliefs in the efficacy of naltrexone.

Psychosocial disability during the long-term course of unipolar major depressive disorder.

BACKGROUND: The goal of this study was to investigate psychosocial disability in relation to depressive symptom severity during the long-term course of unipolar major depressive disorder (MDD). METHODS: Monthly ratings of impairment in major life functions and social relationships were obtained during an average of 10 years' systematic follow-up of 371 patients with unipolar MDD in the National Institute of Mental Health Collaborative Depression Study. Random regression models were used to examine variations in psychosocial functioning associated with 3 levels of depressive symptom severity and the asymptomatic status. RESULTS: A progressive gradient of psychosocial impairment was associated with a parallel gradient in the level of depressive symptom severity, which ranges from asymptomatic to subthreshold depressive symptoms to symptoms at the minor depression/dysthymia level to symptoms at the MDD level. Significant increases in disability occurred with each stepwise increment in depressive symptom severity. CONCLUSIONS: During the long-term course, disability is pervasive and chronic but disappears when patients become asymptomatic. Depressive symptoms at levels of subthreshold depressive symptoms, minor depression/ dysthymia, and MDD represent a continuum of depressive symptom severity in unipolar MDD, each level of which is associated with a significant stepwise increment in psychosocial disability.

Multiple recurrences of major depressive disorder.

OBJECTIVE: The authors of this study examined multiple recurrences of unipolar major depressive disorder. METHOD: A total of 318 subjects with unipolar major depressive disorder were prospectively followed for 10 years within a multicenter naturalistic study. Survival analytic techniques were used to examine the probability of recurrence after recovery from the index episode. RESULTS: The mean number of episodes of major depression per year of follow-up was 0. 21, and nearly two-thirds of the subjects suffered at least one recurrence. The number of lifetime episodes of major depression was significantly associated with the probability of recurrence, such that the risk of recurrence increased by 16% with each successive recurrence. The risk of recurrence progressively decreased as the duration of recovery increased. Within subjects, there was very little consistency in the time to recurrence. CONCLUSIONS: Major depressive disorder is a highly recurrent illness. The risk of the recurrence of major depressive disorder progressively increases with each successive episode and decreases as the duration of recovery increases.

A brief assessment of psychosocial functioning of subjects with bipolar I disorder: the LIFE-RIFT. Longitudinal Interval Follow-up Evaluation-Range Impaired Functioning Tool.

Those afflicted with bipolar disorder often suffer from substantial functional impairment both when in episode and when in remission. This study examined the psychometric properties of a brief assessment of psychosocial functioning, the Range of Impaired Functioning Tool (LIFE-RIFT), among subjects with bipolar I disorder. The study sample consisted of 163 subjects who presented with bipolar I disorder at intake into the NIMH Collaborative Depression Study (CDS). All LIFE-RIFT items come from the Longitudinal Interval Follow-up Evaluation (LIFE). Follow-up data that were used to examine the reliability and validity of the scale come from assessments of psychosocial functioning that were conducted 6, 12, 18, and 24 months after intake into the CDS. The results of factor analyses indicate that the scale items are measures of one construct, psychosocial functioning. The interrater agreement on the scale score was very good with an intraclass correlation coefficient was 0.94. The internal consistency reliability among the scale items was uniformly satisfactory over the four assessment periods, with coefficient alpha ranging from 0.78 to 0.84. Mixed-effect regression analyses showed that during mood episodes subjects were significantly more impaired than those in recovery. In conclusion, the psychometric properties of the LIFE-RIFT were examined in subjects with bipolar I disorder. The analyses from this longitudinal, observational study provide empirical support for the reliability and validity of the scale. The LIFE-RIFT provides a brief, inexpensive alternative to scales currently used to assess psychosocial functioning and can be easily added to semistructured assessments that are used in clinical and treatment outcome studies.

Naltrexone's effect on cue-elicited craving among alcoholics in treatment.

BACKGROUND: Advancing knowledge of biobehavioral effects of interventions can result in improved treatments. Thus, a standardized laboratory cue reactivity assessment has been developed and validated to assess the cognitive and psychophysiological responses to a simulated high-risk situation: alcohol cues. The present study investigates the effects of a pharmacotherapy (naltrexone) on a laboratory-based, cue-elicited urge to drink among abstinent alcoholics in treatment. METHODS: Alcohol-dependent subjects were randomized to 12 weeks of naltrexone or placebo after completing a partial hospital program. After approximately 1 week on medication, all received cue reactivity assessment. RESULTS: Significantly fewer patients taking naltrexone reported any urge to drink during alcohol exposure than did those on placebo. Those with any urges reported no decrement in level of the urges. Mean arterial pressure decreased significantly for those on placebo, but not for those on naltrexone, whereas cue-elicited decreases in heart rate were not affected by the medication. CONCLUSIONS: The results have implications for models of relapse and naltrexone's effects. Cue reactivity methodology has utility for investigating hypothesized mediators of therapeutic effects of pharmacotherapies as well as behavioral treatments.

The Range of Impaired Functioning Tool (LIFE-RIFT): a brief measure of functional impairment.

BACKGROUND: The literature documents that functional impairment is associated with affective disorders. Nevertheless, the choice among thorough, yet brief, well-validated assessments of functional impairment is limited. The objective of this study was to evaluate the psychometric properties of a brief scale of functional impairment, the Range of Impaired Functioning Tool (LIFE-RIFT). METHOD: The study sample included subjects who presented with major depressive disorder at intake into the NIMH Collaborative Depression Study (CDS). The LIFE-RIFT is composed of items that are included in the Longitudinal Interval Follow-up Evaluation (LIFE). The reliability and validity were examined using data from LIFE-RIFT assessments conducted at four points in time: 6, 12, 18 and 24 months after intake into the CDS. RESULTS: Cross-sectional one factor models accounted for the covariance structure among the four scale items. A longitudinal factor model, with an invariant factor structure over time, also fitted the data well and indicated that the scale items are measures of one construct, namely functional impairment. The internal consistency reliability of the scale was supported with alpha coefficients ranging from 0.81 to 0.83. The inter-rater reliability intraclass correlation coefficient (ICC) was 0.94. Mixed-effect linear regression models showed that those in episode were significantly more impaired than those in recovery. Furthermore, in analyses of predictive validity, impairment was positively associated with subsequent recurrence and negatively associated with subsequent recovery. CONCLUSIONS: This psychometric evaluation provides empirical support for the reliability and validity of the LIFE-RIFT, a brief measure of functional impairment.

Recurrence after recovery from major depressive disorder during 15 years of observational follow-up.

OBJECTIVE: The recurrence of an affective disorder in people who initially recover from major depressive disorder was characterized by using the unique longitudinal prospective follow-up data from the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression-Clinical Studies. METHOD: Up to 15 years of prospective follow-up data on the course of major depressive disorder were available for 380 subjects who recovered from an index episode of major depressive disorder and for 105 subjects who subsequently remained well for at least 5 years after recovery. Baseline demographic and clinical characteristics were examined as predictors of recurrence of an affective disorder. The authors also examined naturalistically applied antidepressant therapy. RESULTS: A cumulative proportion of 85% (Kaplan-Meier estimate) of the 380 recovered subjects experienced a recurrence, as did 58% (Kaplan-Meier estimate) of those who remained well for at least 5 years. Female sex, a longer depressive episode before intake, more prior episodes, and never marrying were significant predictors of a recurrence. None of these or any other characteristic persisted as a predictor of recurrence in subjects who recovered and were subsequently well for at least 5 years. Subjects reported receiving low levels of antidepressant treatment during the index episode, which further decreased in amount and extent during the well interval. CONCLUSIONS: Few baseline demographic or clinical characteristics predict who will or will not experience a recurrence of an affective disorder after recovery from an index episode of major depressive disorder, even in persons with lengthy well intervals. Naturalistically applied levels of antidepressant treatment are well below those shown effective in maintenance pharmacotherapy studies.

Prospective study of fluoxetine treatment and suicidal behavior in affectively ill subjects.

OBJECTIVE: There has been speculation in the literature about a link between fluoxetine use and suicidal behavior. The authors of this study hypothesized that there is no elevation in risk of suicidal behavior associated with use of fluoxetine. METHOD: The data come from the National Institute of Mental Health Collaborative Depression Study, a prospective, naturalistic follow-up of persons who presented for treatment of affective disorders. The analyses included data on 643 subjects who were followed up after fluoxetine was approved by the Food and Drug Administration in December 1987 for the treatment of depression. RESULTS: Nearly 30% (N = 185) of the study group was treated with fluoxetine at some point during the follow-up period. Relative to the other subjects, those who were subsequently treated with fluoxetine had onset of affective illness at a younger age and, after intake into the study and before 1988, had elevated rates of suicide attempts before fluoxetine treatment. A mixed-effects survival analysis that incorporated treatment exposure time, multiple treatment trials, and multiple suicide attempts per subject showed that relative to no treatment, use of fluoxetine and use of other somatic antidepressants were associated with nonsignificant reductions in the likelihood of suicide attempts or completions. Severity of psychopathology was strongly associated with elevated risk, and each suicide attempt after intake into the Collaborative Depression Study was associated with a marginally significant increase in risk of suicidal behavior. CONCLUSIONS: The results do not support the speculation that fluoxetine increases the risk of suicide. Rather, there was a nonsignificant reduction in risk of suicidal behavior among patients treated with fluoxetine, even though those subjects were more severely ill before treatment with fluoxetine.

Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse.

BACKGROUND: The study tested whether level of recovery from major depressive episodes (MDEs) predicts duration of recovery in unipolar major depressive disorder (MDD) patients. METHODS: MDD patients seeking treatment at five academic centers were followed naturalistically for 10 years or longer. Patients were divided on the basis of intake MDE recovery into residual depressive symptoms (SSD; N=82) and asymptomatic (N=155) recovery groups. They were compared on time to first episode relapse/recurrence, antidepressant medication, and comorbid mental disorders. Recovery level was also compared to prior history of recurrent MDEs ( > 4 lifetime episodes) as a predictor of relapse/recurrence. RESULTS: Residual SSD compared to asymptomatic recovery patients relapsed to their next MDE > 3 times faster (median=68 vs. 23 weeks) and to any depressive episode > 5 times faster (median=33 vs. 184 weeks). Residual SSD recovery status was significantly associated with early episode relapse (OR=3.65) and was stronger than history of recurrent MDEs (OR=1.64). Rapid relapse in the SSD group could not be attributed to higher comorbidity or lower antidepressant treatment. LIMITATIONS: Although inter-rater agreement on weekly depressive symptom ratings was very high (ICC > 0.88), some error may exist in assigning recovery levels. Antidepressant treatments were recorded, but were not controlled. CONCLUSIONS: MDE recovery is a powerful predictor of time to episode relapse/recurrence. Residual SSD recovery is associated with very rapid episode relapse which supports the idea that SSD is an active state of illness. Asymptomatic recovery is associated with prolonged delay in episode recurrence. These findings of this present study have important implications for the goals of treatment of MDD and for defining true MDE recovery.

A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders.

BACKGROUND: Investigations of unipolar major depressive disorder (MDD) have focused primarily on major depressive episode remission/recovery and relapse/recurrence. This is the first prospective, naturalistic, long-term study of the weekly symptomatic course of MDD. METHODS: The weekly depressive symptoms of 431 patients with MDD seeking treatment at 5 academic centers were divided into 4 levels of severity: (1) depressive symptoms at the threshold for MDD; (2) depressive symptoms at the threshold for minor depressive or dysthymic disorder (MinD); (3) subsyndromal or subthreshold depressive symptoms (SSDs), below the thresholds for MinD and MDD; and (4) no depressive symptoms. The percentage of weeks at each level, number of changes in symptom level, and medication status were analyzed overall and for 3 subgroups defined by mood disorder history. RESULTS: Patients were symptomatically ill in 59% of weeks. Symptom levels changed frequently (1.8/y), and 9 of 10 patients spent weeks at 3 or 4 different levels during follow-up. The MinD (27%) and SSD (17%) symptom levels were more common than the MDD (15%) symptom level. Patients with double depression and recurrent depression had more chronic symptoms than patients with their first lifetime major depressive episode (72% and 65%, respectively, vs 46% of follow-up weeks). CONCLUSION: The long-term weekly course of unipolar MDD is dominated by prolonged symptomatic chronicity. Combined MinD and SSD level symptoms were about 3 times more common (43%) than MDD level symptoms (15%). The symptomatic course is dynamic and changeable, and MDD, MinD, and SSD symptom levels commonly alternate over time in the same patients as a symptomatic continuum of illness activity of a single clinical disease.

Recovery from major depression. A 10-year prospective follow-up across multiple episodes.

BACKGROUND: Major depressive disorder is often marked by repeated episodes of depression. We describe recovery from major depression across multiple mood episodes in patients with unipolar major depression at intake and examine the association of sociodemographic and clinical variables with duration of illness. METHODS: A cohort of 258 subjects treated for unipolar major depressive disorder was followed up prospectively for 10 years as part of the Collaborative Depression Study, a multicenter naturalistic study of the mood disorders. Diagnoses were made according to the Research Diagnostic Criteria, and the course of illness was assessed with the Longitudinal Interval Follow-up Evaluation. Survival analyses were used to calculate the duration of illness for the first 5 recurrent mood episodes after recovery from the index episode. RESULTS: Diagnosis remained unipolar major depressive disorder for 235 subjects (91%). The median duration of illness was 22 weeks for the first recurrent mood episode, 20 weeks for the second, 21 weeks for the third, and 19 weeks for the fourth and fifth recurrent mood episodes; the 95% confidence intervals were highly consistent. From one episode to the next, the proportion of subjects who recovered by any one time point was similar. For subjects with 2 or more recoveries, the consistency of duration of illness from one recovery to the next was low to moderate. None of the sociodemographic or clinical variables consistently predicted duration of illness. CONCLUSION: In this sample of patients treated at tertiary care centers for major depressive disorder, the duration of recurrent mood episodes was relatively uniform and averaged approximately 20 weeks.

Cognitive-behavioral treatment for depression in alcoholism.

Alcoholics with depressive symptoms score > or = 10 on the Beck Depression Inventory (A.T. Beck, C. H. Ward, M. Mendelson, J. Mock, & J. Erbaugh, 1961) received 8 individual sessions of cognitive-behavioral treatment for depression (CBT-D, n = 19) or a relaxation training control (RTC; n = 16) plus standard alcohol treatment. CBT-D patients had greater reductions in somatic depressive symptoms and depressed and anxious mood than RTC patients during treatment. Patients receiving CBT-D had a greater percentage of days abstinent but not greater overall abstinence or fewer drinks per day during the first 3-month follow-up. However, between the 3- and 6-month follow-ups, CBT-D patients had significantly better alcohol use outcomes on total abstinence (47% vs. 13%), percent days abstinent (90.5% vs. 68.3%), and drinks per day (0.46 vs. 5.71). Theoretical and clinical implications of using CBT-D in alcohol treatment are discussed.

A double-blind, placebo-controlled pilot study of carbamazepine for the treatment of alcohol dependence.

Carbamazepine, chemically related to the tricyclic antidepressants, has multiple clinical actions. It is a potent anticonvulsant, mild sedative, and mood stabilizer. It is nonaddictive and has little toxicity when clinical and laboratory monitoring is performed. It has proven efficacy in the treatment of acute alcohol withdrawal. Kindling and protracted withdrawal are the theoretical rationale for the mechanism of its action in the treatment of alcohol dependence. This 12-month double-blind placebo-controlled pilot study of 29 subjects evaluated the efficacy of carbamazepine for the treatment of alcohol dependence. Subjects were randomly assigned to either placebo or carbamazepine. A baseline assessment and bimonthly follow-up for 12 months assessed demographic variables, mood and functioning, treatment compliance, drinking behaviors, biological markers of drinking, and medication toxicity. Despite the small sample size, compliance difficulties after 4 months and a sizable drop-out rate, there were treatment effects favoring carbamazepine. Univariate analyses showed a decrease in drinks per drinking day and maximum number of heavy drinking days in a row at 2 and 4 months of follow-up. Survival analysis revealed a significant delay in time to first episode of heavy drinking, and close to a trend level of significance for time to first drink. There were significant time, but not time by treatment group, effects on multiple measures of mood. These pilot results are encouraging and support carbamazepine as a possible pharmacologic tool in the treatment of alcohol dependence.

Does major depression result in lasting personality change?

OBJECTIVE: Individuals with a history of depression are characterized by high levels of certain personality traits, particularly neuroticism, introversion, and interpersonal dependency. The authors examined the "scar hypothesis," i.e., the possibility that episodes of major depression result in lasting personality changes that persist beyond recovery from the depression. METHOD: A large sample of first-degree relatives, spouses, and comparison subjects ascertained in connection with the proband sample from the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression were assessed at two points in time separated by an interval of 6 years. Subjects with a prospectively observed first episode of major depression during the interval were compared with subjects remaining well in terms of change from time 1 to time 2 in self-reported personality traits. All subjects studied were well (had no mental disorders) at the time of both assessments. RESULTS: There was no evidence of negative change from premorbid to postmorbid assessment in any of the personality traits for subjects with a prospectively observed first episode of major depression during the interval. The results suggested a possible association of number and length of episodes with increased levels of emotional reliance and introversion, respectively. CONCLUSIONS: The findings suggest that self-reported personality traits do not change after a typical episode of major depression. Future studies are needed to determine whether such change occurs following more severe, chronic, or recurrent episodes of depression.

Five-year course of major depression: effects of comorbid alcoholism.

Some patients enter psychiatric treatment with clear cases of both major depression and alcoholism. While assumptions are often made about the relationships of these two conditions, little empirical evidence exists on the effects of sustained remissions in alcoholism on sustained remissions in depression. 127 patients with both disorders at treatment entry were studied over a 5-year period. Survival analyses with time-dependent covariates indicating alcoholism status were used to investigate remissions and relapses in major depression. Remission in alcoholism strongly and significantly increased the chances of remission in depression and were also related to reduced chances of depression relapse, although at a weaker level.