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Depression outcome in alcohol dependent patients: An evaluation of the role of independent and substance-induced depression and other predictors
Journal of Affective Disorders 174 (2015) 503–510
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Research Report
Depression outcome in alcohol dependent patients: An evaluation of the role of independent and substance-induced depression and other predictors James A. Foulds a,n, J. Douglas Sellman a, Simon J. Adamson a, Joseph M. Boden b, Roger T. Mulder a, Peter R. Joyce a a b
Department of Psychological Medicine, University of Otago, Christchurch, New Zealand Christchurch Health and Development Study, University of Otago, Christchurch, New Zealand
art ic l e i nf o
a b s t r a c t
Article history: Received 3 September 2014 Received in revised form 25 November 2014 Accepted 27 November 2014 Available online 5 December 2014
Background: Depression commonly co-occurs with alcohol use disorders but predictors of depression treatment outcome in patients with both conditions are not well established. Methods: Outpatients with alcohol dependence and major depression (n ¼138) were prescribed naltrexone and randomized to citalopram or placebo for 12 weeks, followed by a 12-week naturalistic outcome phase. General linear mixed models examined predictors of Montgomery Asberg Depression Rating Scale (MADRS) score over 24 weeks. Predictors included whether depression was independent or substance-induced, and demographic, alcohol use, and personality variables (Temperament and Character Inventory subscales). Results: Most improvement in drinking and depression occurred between baseline and week 3. During follow-up, patients with substance-induced depression reduced their drinking more and they had better depression outcomes than those with independent depression. However, greater reduction in drinking was associated with better depression outcomes for both independent and substance-induced groups, while antidepressant therapy had no effect for either group. Baseline demographic and alcohol use variables did not predict depression outcomes. Among personality variables, high self-directedness was a strong predictor of better depression outcomes. Limitations: Subjects were not abstinent at baseline. The influence of naltrexone on depression outcomes could not be tested. Conclusion: Alcohol dependent patients with substance-induced depression have better short term depression outcomes than those with independent depression, but this is largely because they reduce their drinking more during treatment. & 2014 Elsevier B.V. All rights reserved.
Keywords: Alcohol-induced disorder Alcohol-related disorders Depressive disorder Depression Treatment outcome Comorbidity
1. Introduction Patients with alcohol use disorders often have high levels of depressive symptoms when they enter treatment. Depression on average improves substantially in the first six weeks of treatment and more gradually thereafter (Pettinati et al., 2010). However a significant minority of patients experiences enduring depressive symptoms. It would be clinically useful to be able to identify this group prospectively, as this would help treatment allocation and might predict who is at risk of other outcomes such as suicide, (Henriksson et al., 1993) alcohol relapse (Hasin et al., 2002) and n Correspondence to : Department of Psychological Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch 8140 New Zealand. Tel.: þ 64 3 3720 400; fax: þ64 3 3720 407. E-mail address: [email protected] (J.A. Foulds).
http://dx.doi.org/10.1016/j.jad.2014.11.052 0165-0327/& 2014 Elsevier B.V. All rights reserved.
increased healthcare utilization (Parthasarathy and Weisner, 2005). Categorizing depression as independent or substance-induced at baseline is a common way of attempting to predict the course of depression in patients with an alcohol use disorder. Substanceinduced depression (SID) by definition improves when patients stop drinking, and is thought to account for a substantial proportion of major depressive episodes among patients with an alcohol use disorder (Schuckit et al., 2007). Conversely independent depression (ID) should not necessarily remit with abstinence, but is believed to be more responsive to specific depression treatments such as antidepressant medication (Pettinati, 2013). The established method to differentiate between ID and SID is to examine the timing of onset of heavy drinking and depression in the past, and to determine whether depression was ever present during a sustained period of abstinence (Schuckit et al., 2007). This
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approach has been operationalized in instruments such as the Structured Clinical Interview for DSM (SCID) (Spitzer et al., 1992) and the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) (Hasin et al., 1996a). Despite the wide use of this terminology, the size of any difference in depression outcome between ID and SID has not been well characterized (Nunes, 2006). Furthermore patients with SID appear to show a high incidence of ID when followed up over 12 months (Nunes, 2006; Brown et al., 2011) suggesting SID may not be a stable diagnosis. Little is known about more general predictors of depression outcome in patients with co-occurring alcohol dependence and major depression. In patients without an alcohol use disorder, early improvement in depression and some personality characteristics appear to be stronger predictors of 6-month outcome than either demographics or depression characteristics (Mulder et al., 2006). However these findings have not been replicated in comorbid populations. The objective of this study was to investigate whether patients with ID had a different treatment outcome compared to those with SID during 24 weeks of treatment for depression and alcohol dependence. We also examined a range of other candidate variables as predictors of depression outcome, including baseline depression and drinking measures, demographic variables and personality measures.
2. Methods 2.1. Overview of study design Study methods and key results have been previously reported (Adamson et al., in press). In brief, this was a 12-week trial comparing naltrexone plus citalopram to naltrexone plus placebo followed by a 12-week naturalistic continuation phase. The trial was conducted in 8 outpatient alcohol treatment centers in New Zealand from 2007 to 2011. It received approval from local ethics committees at each site and was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12606000413527). 2.2. Participants and measures Screening was conducted on 474 potential subjects, of which 138 were included in the intent-to-treat sample. Eligible participants were outpatients aged 17–65 years seeking treatment for a drinking problem and low mood. They were recruited from addiction treatment centers, psychiatric clinics and via advertising. Participants met current DSM-IV criteria for alcohol dependence and major depressive episode in the past four weeks rated using the Structured Clinical Interview for DSM-IV (SCID), (Spitzer et al., 1992). In addition they had a Montgomery Asberg Depression Rating Scale (MADRS) score of 20 or higher (Montgomery and Asberg, 1979). Abstinence at baseline was encouraged but not enforced. Further baseline characteristics of the sample are shown in Table 1. Using an algorithm adapted from the SCID, the current episode of depression was assumed to be independent if at least one of the following criteria were met: a) First episode of depression occurred before the onset of heavy drinking. b) Past history of depression present for at least one month during a period of abstinence. c) A past history of depressive symptoms substantially in excess of what would be expected given the duration or amount of alcohol use.
If none of the above criteria were met, the depression was labeled as substance-induced. The categorization as independent or substance-induced is, for convenience, referred to hereafter as depression type. Participants were not explicitly informed whether they were categorized as having ID or SID, but their belief about the causal relationship between their drinking and depression was recorded at baseline. Study exclusion criteria were: past or current intravenous drug use; current opioid use; psychosis; mania or hypomania; suicidality or homicidality; psychiatric hospitalization required; unstable medical illness; recent disulfiram, naltrexone, antidepressant or mood stabilizing medication; significantly elevated transaminases or raised bilirubin; pregnancy, breastfeeding or inadequate contraception; and current or pending imprisonment. 2.3. Interventions The citalopram/placebo dose started at one capsule (20 mg) daily and it could be increased to three capsules during the trial if depression persisted. The naltrexone dose was 25 mg daily for one week, then 50 mg daily as tolerated. The dose could be further increased to 75 or 100 mg after 6 weeks. Citalopram/placebo and naltrexone were given for 12 weeks, after which both medications were scheduled to be withdrawn. However weeks 12–24 were designed as a naturalistic follow-up phase and any medications for mood or drinking could be freely prescribed following discussion between the patient and their treating clinicians. All participants received manualised clinical case management throughout the 24 weeks. This comprised: enhancing motivation and commitment to change drinking behavior; co-ordinating care; involving family and significant others; encouraging the development of coping strategies; promoting adherence; providing education about depression and alcohol dependence; and promoting involvement in self-help groups. There were 19 research clinicians involved in the overall TEAM study, of which demographic data were available for 18. Clinicians were aged 34–61 (mean 48), 10/18 were female and 14/18 were of New Zealand European ethnicity. Clinicians had worked in the addiction field for between 9 and 30 years and had trained in psychiatry, psychiatric nursing, social work, clinical psychology or counseling. 2.4. Main outcome The primary outcome was the MADRS score at 3-weekly intervals from week 3 to week 24. 2.5. Predictors Alcohol measures were percentage of days abstinent (PDA) and drinks per drinking day (DDD) obtained using the timeline follow back procedure (Sobell, 1986), for the 12 weeks prior to baseline and then 3-weekly until 24 weeks. Personality characteristics were assessed using the 144-item Temperament and Character Inventory (TCI) (Cloninger et al., 1993). This self-report instrument measures personality on four temperament dimensions: novelty seeking (NS), harm avoidance (HA), reward dependence (RD) and persistence (PS); and three character dimensions: cooperativeness (C), self-directedness (SD) and self-transcendence (ST). Stage of change was assessed with the Readiness to Change Questionnaire (Rollnick et al., 1992). Alcohol addiction severity was measured with the Leeds Dependence Questionnaire (Raistrick et al., 1994). Therapeutic alliance was assessed with the Working Alliance Inventory (Horvath and Greenberg 1989) client and therapist versions, measured between weeks 3 and 6. This is a self-report
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Table 1 Baseline characteristics of sample for 24-week completers and dropouts. Range
Value or % (sd) Whole sample (n¼138)
Study completers to 24 weeks (n¼ 106)
Dropouts before 24 weeks (n¼ 32)
t or χ2; p
59.4% 43.6 (5.1)
60.4% 43.9 (9.3)
56.3% 42.5 (8.3)
χ2 ¼ 0.17, p ¼ 0.68 t ¼0.77, p ¼ 0.44
34.1% 21.0% 44.9%
34.9% 22.6% 42.5%
31.3% 15.6% 53.1%
χ2 ¼ 1.30, p ¼0.52
31.9% 46.4% 21.7% 13.5 (3.1)
28.3% 48.1% 23.6% 13.6 (3.1)
43.8% 40.6% 15.6% 13.4 (3.2)
χ2 ¼ 2.85, p¼ 0.24
t ¼0.24, p ¼0.81
20–48 0.3–3.8
31.0 (5.8) 2.0 (0.7) 70.3% 52.9%
31.1 (5.8) 2.0 (0.7) 67.0% 50.9%
30.6 (5.9) 2.0 (0.8) 81.3% 56.3%
t ¼0.46, p ¼ 0.65 t ¼ 0.04, p ¼ 0.97 χ2 ¼ 2.4, p¼ 0.12 χ2 ¼ 0.28, p¼ 0.60
0–96% 3.0–52.5 0–24
25.8% (27.4) 14.3 (8.0) 16.0 (5.5)
25.2% (27.6) 13.9 (7.3) 15.7 (5.4)
27.9% (27.1) 15.7 (9.9) 16.8 (5.5)
t ¼ 0.48, p ¼ 0.63 t ¼ 1.13, p ¼ 0.26 t ¼ 1.02, p ¼ 0.31
Comorbidity Current tobacco smoker Current cannabis disorder Current anxiety disorder Lifetime antisocial personality disorder
57.2% 15.9% 47.8% 6.5%
53.8% 13.2% 42.5% 5.7%
68.8% 25.0% 65.6% 9.4%
χ2 ¼ 2.25, χ2 ¼ 2.55, χ2 ¼ 5.29, χ2 ¼ 0.56,
Temperament and character inventory subscales Novelty seeking 2–20 Harm avoidance 2–19 Reward dependence 3–20 Persistence 0–20 Self directedness 1–20 Cooperativeness 5–20 Self transcendence 0–20
10.7 (3.7) 11.4 (4.6) 11.7 (3.9) 10.9 (4.9) 10.1 (4.6) 16.2 (3.2) 6.2 (5.2)
10.7 (3.7) 11.6 (4.6) 11.7 (3.9) 10.9 (4.7) 10.2 (4.3) 16.5 (3.1) 6.1 (5.2)
10.9 (3.6) 10.6 (4.8) 11.9 (4.0) 11.2 (5.9) 9.7 (5.8) 15.3 (3.5) 6.6 (5.2)
t ¼ 0.27, p ¼0.79 t ¼0.75, p ¼ 0.45 t ¼0.01, p ¼0.93 t ¼ 0.23, p ¼0.82 t ¼0.93, p ¼ 0.36 t ¼1.9, p ¼ 0.06 t ¼ 0.45, p ¼0.66
Demographics Female Age Employment Full-time Part-time Unemployed Relationship status Single Married/de facto Divorced/widowed Years of education Depression variables MADRS score SCL-90 depression score Independent depression Assigned to citalopram Alcohol variables Percent days abstinenta Drinks per drinking daya Readiness to change questionnaire
a
20–64
p¼ 0.13 p¼ 0.11 p¼ 0.02 p¼ 0.46
Average in 12 weeks before treatment commenced.
instrument that assesses the quality of the relationship between therapist and client in relation to bond, tasks and goals. An independent research clinician administered the instruments. Clinicians and patients were blind to each other's responses. 2.6. Power calculation The study was powered to be able to detect a clinically significant difference (effect size 0.5) in change in depression score from baseline to 12 weeks between citalopram and placebo. The study was also designed to detect a difference in citalopram effect according to depression type, but as the ratio of independent to substance-induced depression was not known a priori, a power calculation was not possible. The approximately 2.5–1 ratio of independent to substance-induced depression that eventuated provided less power for this subgroup effect (relative to the power for a main citalopram effect) because of unbalanced group sizes but this loss of power was mitigated through the use of repeated measures analyses for the present study (Gueorguieva and Krystal, 2004). 2.7. Statistical methods Analyses were conducted with general linear mixed models using PROC MIXED in SAS version 9.3 (SAS Institute Inc., Cary, NC). These methods have advantages over the last observation carried
forward method in alcohol studies, as they allow more realistic handling of missing data (Hallgren and Witkiewitz, 2013). Point estimates are least squares means from linear mixed models, expressed with 95% confidence intervals, unless otherwise stated. There were three series of models fitted to the data: the first series comprised univariate analyses of baseline predictors; the second comprised multivariate analyses on baseline predictors identified as relevant from the first series; and the third investigated potential mediators of depression outcome during treatment. All models were repeated measures analyses using the MADRS scores in follow up (weeks 3, 6, 9, 12, 15, 18, 21 and 24) as the dependent variable and the baseline MADRS score, predictor(s) and predictor time interaction term(s) as independent variables. The time variable was treated as continuous, and was centered due to the multilevel structure of models and the presence of interaction terms. There was no evidence of higher-order polynomial trends therefore these terms were omitted from models. An autoregressive covariance structure was specified and Kenward-Roger adjustment of degrees of freedom was applied for estimates of fixed effects. Model assumptions were checked using diagnostic plots and models were formulated on the assumption that data were missing at random. Model fit was assessed using the Bayesian Information Criterion. In the first series of models, the effect of individual baseline predictors was separately examined in univariate models. The baseline predictors were grouped into demographic, depression, alcohol, comorbidity and personality (TCI) variables.
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In the second series of models, baseline predictors that were significant at the 0.10 level in the first series were investigated by combining them in multivariate models. The first model in this series included TCI variables alone; the second added depression type and the final model dropped variables that were not significant at the 0.10 level in the previous models. In the third series of models, dynamic mediators of outcome during treatment were investigated. These were: Working Alliance Inventory therapist and patient scores (WAI-T and WAI-P respectively, measured between weeks 3 and 6); adherence (number of treatment sessions attended); and drinking measures (PDA and DDD), modeled as time-varying covariates in linear mixed models. Finally baseline and mediator variables were combined in a full model. The purpose of this final model was to determine whether there was evidence the potential mediator variables lay on a causal pathway between selected baseline predictors (SDI and depression type) and depression outcome.
3. Results 3.1. Subject characteristics Follow up data were available at 24 weeks for 106 subjects (77%). Baseline characteristics of the sample are shown in Table 1, broken into 24-week completers and non-completers. As shown in Table 1, non-completers had a significantly higher prevalence of comorbid anxiety disorders but did not differ from completers on other baseline measures. 3.2. Overall depression outcomes The mean MADRS score was 31.0 (sd 5.8, range 20–48) at baseline. Estimates of the mean MADRS score were 16.1 (14.4, 17.8) at week 3, 10.9 (9.1, 12.7) at week 12 and 9.3 (7.5, 11.1) at week 24. At week 24, 15/106 subjects (14.2%) who were still in follow up had a MADRS score of more than 19, indicating at least moderate depression (Snaith et al., 1986). There was no evidence of significant heterogeneity in depression response across treatment venues. As previously reported, there was no evidence that citalopram had an effect on depression outcome (Adamson et al., in press). 3.3. Drinking outcomes As shown in Table 1, at baseline subjects were abstinent for a mean of 25.8% of days (sd 27.4) and their mean daily alcohol consumption was 14.3 drinks (sd 8.0). The correlation between PDA and DDD was 0.20 at baseline and the correlation at each time point ranged from 0.27 to 0.43 in weeks 3–24. Change in drinking occurred early in treatment: the mean PDA was 63.8% (sd 33.6) at week 3 and there was little change in this figure from week 3 to week 24. The pattern was similar for DDD: the mean DDD was 6.4 (sd 7.0) at week 3 and it remained close to this level between week 3 and week 24.
3.5. Depression type: independent and substance-induced depression The percentage of patients who had ID was 70.3%, and the remaining 29.7% had SID. There was no significant difference in mean MADRS score at baseline, which was 31.3 (sd 5.8, range 20–48) for ID subjects and 30.2 (sd 5.6, range 20–45) for SID subjects (t ¼0.90 p ¼0.31). Compared to subjects with SID, those with ID had higher self-directedness (t¼ 2.63, p¼ 0.01), their current episode of depression was longer (t¼2.03, p¼ 0.04) and they had more years of education (t¼2.35 p¼ 0.02). The two groups were comparable on all other baseline measures. At baseline patients with SID (16/39; 41.0%) were more likely than those with ID (9/95; 9.5%) to believe drinking caused their depression while more patients with ID (66/95; 69.4%) than SID (17/39; 35.9%) believed drinking did not cause, but worsened their depression (χ2 ¼ 20.2, p o0.001). At week 24, ID study completers had a mean MADRS score of 10.3 (sd 9.4, range 0–43) and for SID completers the mean score was 7.0 (sd 7.9, range 0–29). As shown in Table 2, there was an overall difference in depression outcome between the two groups but no evidence of a group time interaction effect, indicating the difference between the two groups was already apparent by week 3, and the groups followed a parallel path thereafter. This pattern is also shown in Fig. 1. The estimate for the mean difference in MADRS score between ID and SID during follow up was 3.9 (1.3, 6.5), a standardized mean difference of 0.68. Subjects with SID had significantly higher PDA during follow up compared to ID subjects, after adjusting for baseline PDA (75.6% compared to 62.7%; p¼ 0.007), but there was no difference in DDD between the two groups (p ¼0.10). The difference in PDA between the groups was already present at week 3, and persisted throughout the 24 weeks of follow up. There was a significant correlation between change in PDA and change in depression from baseline to week 3 for both ID subjects (r ¼0.285, p¼ 0.005) and SID subjects (r ¼0.442, p ¼0.004).
3.6. Temperament and character measures TCI data were missing for 11 subjects. TCI subscales were not significantly correlated with baseline depression or drinking measures, with two exceptions: SD was negatively correlated with baseline PDA (r¼ 0.226) while HA was negatively correlated with baseline DDD (r¼ 0.224). TCI subscales were not correlated with change in drinking during the study, with the exception of SD and change in DDD (r¼0.232) and C and change in DDD (r¼0.182). For the temperament and character variables, low HA, high SD, and high C were univariate predictors of better depression outcome. The effect of SD is shown in Fig. 2, which illustrates that the difference in outcome was most noticeable for subjects in the highest SD quartile, with the other 3 groups having a similar trajectory. The overall difference in MADRS score between the highest and lowest SD quartiles was 6.9 (3.5, 10.19; standardized mean difference 1.17) across all follow-up time-points.
3.4. Predictors of depression outcome 3.7. Multivariate models of baseline predictors Table 2 shows the results of univariate analyses of predictors of MADRS score at weeks 3–24, adjusted for baseline MADRS. In these models, baseline demographic, drinking and depression variables did not have a main effect on depression outcome, with the exception of depression type. No predictor time interactions were significant, indicating the rate of change in depression in weeks 3–24 was not altered by any of the predictors.
Table 3 shows the results of the next step of the analyses, which was a series of multivariate models of baseline predictors that were significant at the 0.10 level in univariate models. In the final model, SD (p o0.001) and depression type (po 0.05) remained significant predictors of depression score. Time interaction effects were not significant for either variable.
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Table 2 Univariate predictors of depression score during treatmenta. b Treatment variables Antidepressant assignment Citalopram
SE
p
0.35
1.23
0.78
0.43 0.06
1.25 0.07
0.73 0.36
1.54 1.24 0
1.39 1.68
0.53
0.40 2.20 0 0.28
1.67 1.54
0.13
0.20
0.17
0.45 1.99 3.74
0.11 1.51 1.29
o 0.001 0.19 0.004
2.60 0.40 0.08 0
1.99 1.48 1.80
0.60
0.63 1.22 0
1.40 1.73
0.58
Alcohol variables Baseline percent days abstinent Baseline drinks per drinking day Leeds dependence questionnaire score Readiness to change questionnaire score
3.24 0.01 0.06 0.02
2.22 0.08 0.10 0.11
0.15 0.88 0.58 0.85
Comorbidity variables Current tobacco smoker Current cannabis disorder Current anxiety disorder Lifetime antisocial personality disorder
0.77 1.55 1.17 2.14
1.23 1.70 1.24 2.63
0.53 0.36 0.35 0.42
0.05 0.39 0.09 0.13 0.44 0.61 0.04
0.11 0.13 0.16 0.13 0.20 0.13 0.12
0.76 0.005 0.58 0.32 0.03 o 0.001 0.71
Demographic variables Gender Male Age Current employment category Unemployed Part time Full time (reference group) Relationship status Single Married or de facto Widowed, separated or divorced (reference group) Years of education Depression variables Baseline MADRS score Melancholic depression Depression type (independent vs substance-induced) Number of previous episodes Fewer than 3 3–5 5 or more Too many or too indistinct to count (reference group) Duration of current episode 6 months or less 6–12 months More than 12 months (reference group)
Temperament and character subscales Novelty seeking Harm avoidance Reward dependence Persistence Cooperativeness Self-directedness Self-transcendence
a Results from linear mixed models of predictors of MADRS scores at 3-weekly intervals from week 3 to week 24, adjusted for baseline MADRS. Models included predictor time interaction terms, however no significant interaction effects were found therefore these results have been omitted. For predictors with two categories (eg gender), only the results for the non-reference group category are shown.
3.8. Effect of mediator variables on change in depression The effect of change in drinking on depression outcomes was initially explored by dividing drinkers into four categories according to the global change in PDA from baseline to week 24. The mean MADRS score at week 24 was 16.4 (11.4, 21.5) for subjects who did not increase their PDA during the study; 9.4 (5.6, 13.1) for subjects who increased their PDA but were still drinking 450% of days; 7.5 (4.7, 10.2) for those who increased their PDA and were still drinking but on o50% of days; and 8.3 (4.8, 11.9) for subjects who were abstinent at week 24. When depression type was added to this model, there was no evidence of an interaction effect of change in PDA depression type. Illustrating this point, for patients with ID, the mean MADRS score at week 24 was 16.1 (10.4, 21.7) for those with no improvement in PDA and 9.9 (5.4, 14.4) for those who were abstinent. The corresponding figures for the SID group were 17.2
(6.7, 27.7) and 5.9 (0.1, 11.7) respectively, however these figures need to be viewed with caution as the standard errors are inflated due to small numbers in each cell. These findings were further elucidated with models treating PDA and DDD as time-varying predictors. The results of these analyses are shown in Table 4, along with results for therapeutic alliance and treatment adherence. In univariate models, DDD and PDA at weeks 3– 24 (adjusted for their respective baseline values) and the therapist rating of therapeutic alliance (WAI-T) were significant predictors of depression outcome. In a model combining the two drinking measures and WAI-T, the drinking variables remained significant at the.001 level while therapeutic alliance was not significant (p¼0.06). A final model added two baseline predictors- depression type and self-directednessto the three mediators DDD, PDA and WAI-T. In this model depression type was no longer significant (p¼0.25) suggesting differences in drinking patterns may have mediated the relationship between
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Course of independent and substanceinduced depression 35
Independent 30
Substance-induced
MADRS score
25 20 15 10 5 0
0
3
6
9
12
15
18
21
24
Week number Fig. 1. MADRS score from baseline to week 24, for subjects with independent and substance-induced depression; p value¼ 0.004 for the overall difference between groups in repeated measures analysis. Estimates of MADRS score at timepoints from week 3 to week 24 are least squares means from linear mixed models including time as a categorical predictor. Standardised mean difference 0.68 for group difference across all timepoints (excluding baseline) and 0.54 for group difference at week 24.
Depression score by self-directedness quartile 35
MADRS score
30
quartile 1
quartile 2
quartile 3
quartile 4
25 20 15 10 5 0 0
3
6
9
12
15
18
21
24
Week number Fig. 2. MADRS score from baseline to week 24 according to self-directedness quartile; p valueo 0.001 for overall group difference. Estimates of MADRS score at timepoints from week 3 to week 24 are least squares means from linear mixed models including time as a categorical predictor. Standardised mean difference 1.17 between quartile 1 (low self-directedness) and quartile 4 (high self-directedness) across all timepoints (excluding baseline) and 0.69 for difference between quartile 1 and quartile 4 at week 24.
depression type and depression outcomes. SDI remained significant (po0.001) suggesting it had an independent effect on depression outcome beyond any effect mediated via drinking.
4. Discussion In this 24-week study of patients receiving comprehensive integrated treatment for alcohol dependence and depression, most of the change in depression and drinking occurred in the first three weeks of treatment. This pattern is consistent with other
literature suggesting much of the reduction in symptom burden in comorbid patients occurs early in treatment, with as much as a third of the improvement even occurring before the first treatment session (Baker et al., 2014). In the first three weeks, patients with substance-induced depression (SID) experienced more improvement in both depression and percentage of days abstinent than those with independent depression (ID). After that, the depression and drinking patterns of both groups followed approximately parallel paths from weeks 3 to 24, with alcohol outcomes remaining static and depression showing a small improvement over this period. The difference in depression outcomes between patients with ID and those with SID (an effect size of about 0.7) appeared to arise mainly because SID patients reduced their drinking more, rather than because they derived greater benefit from any reduction in drinking. The greater increase in abstinent days among SID patients was an unexpected finding, as all patients regardless of depression type were encouraged to reduce their drinking. However, the assessment process did encourage patients to consider the relationship between their drinking and mood, and this may have provided a greater incentive for SID patients to address their drinking. Although SID patients altered their drinking more, change in drinking was also associated with change in depression in ID patients; this runs counter to what would be expected if depression is truly “independent” of drinking in this group. For both groups of patients, a poor depression response was much more prevalent among subjects who did not improve their drinking at all or drank more; surprisingly, patients who achieved even modest improvement in drinking had similar depression outcomes to those who were abstinent at the end of the study. The importance of categorizing depression as independent or substance-induced in patients with a concurrent substance disorder has been repeatedly emphasized (Schuckit, 1995; Schuckit et al., 1997; Grant et al., 2004; Samet et al., 2013). In spite of this, few studies have prospectively compared the outcome of depression treatment between these groups (Nunes, 2006) therefore little is known about the magnitude of any difference in outcome. The apparently high incidence of ID among patients originally diagnosed with SID (Brown et al., 2011; Nunes, 2006) has raised further concerns about the face validity and predictive value of the concept as it is currently defined. It is currently suggested that patients with ID benefit more from antidepressants and patients with SID benefit more from reduced drinking (Schuckit, 2006). We found no evidence ID patients respond better to antidepressant medication, and limited support for the belief that reduced drinking benefits patients with SID more. In fact it seems likely reduced drinking benefits both groups. The limited antidepressant response among depressed, alcohol dependent patients coupled with evidence that the course of alcoholism affects the course of depression (Hasin et al., 1996b) suggests reduced drinking should be the primary treatment strategy for depression regardless of whether depression is believed to be independent or substance-induced. We found baseline demographic and alcohol consumption variables, and depression variables other than depression type, did not predict the course of depression over 24 weeks. This is consistent with results from a study of depressed subjects without an alcohol disorder (Mulder et al., 2006). In that study, Mulder et al. reported baseline demographic variables and depression characteristics did not generally predict depression outcome, while early depression response and personality variables did. We identified three personality variables – high self-directedness, low harm avoidance and high cooperativeness – which were associated with better depression outcome in univariate models. Of these, only self-directedness remained significant in multivariate models. The effect of self-directedness was
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Table 3 Multivariate models of baseline predictors of depression score during treatmenta.
Harm avoidance Cooperativeness Self directedness Depression typec
Model 1: Temperament and character variables Model 2: Temperament and character variables plus only BICb ¼5460.3 depression type BICb ¼5454.6
Model 3: Best multivariate model BICb ¼ 5423.4
b
SE
p
b
SE
p
b
SE
p
0.49 0.17 0.49 Not in model
0.15 0.20 0.15
0.15 0.38 0.001
0.22 0.18 0.41 2.62
0.14 0.20 0.15 1.32
0.10 0.36 0.01 0.05
Not in model Not in model 0.53 2.47
0.19 1.26
o 0.001 0.05
a Results from linear mixed models of predictors of MADRS scores at 3 weekly intervals from week 3 to week 24, adjusted for baseline MADRS. Models included predictor time interactions, however no significant interaction effects were found therefore these results have been omitted. b Model fit, assessed using Bayesian Information Criterion. c Independent or substance-induced depression.
Table 4 The role of mediator variables as predictors of MADRS score during follow upa. Univariate models of intermediate outcomes
Multivariate model of intermediate outcomes. BICb ¼4436.9
Combined model: baseline and intermediate predictors. BICb ¼4303.3
b
p
b
p
b
SE
p
o 0.001 o 0.001 0.33 0.03 0.78
0.31 0.06 6.56 1.34 Not in models 2.12 1.12 Not in models
o 0.001 o 0.001
0.29 6.35
0.06 1.37
o 0.001 o 0.001
0.06
1.50
1.10
0.18
0.53 1.60
0.14 1.37
o 0.001 0.25
SE
Drinks per drinking day at weeks 3–24 0.40 0.10 Percent days abstinent at weeks 3–24 8.37 1.25 Therapeutic alliance: patient rating 1.28 1.32 Therapeutic alliance: clinician rating 2.49 1.15 Treatment adherence: number of sessions attended 0.01 0.08 Self directedness Not in models Depression typec Not in models
SE
a Results from linear mixed models of predictors of MADRS scores during weeks 3–24 (repeated measures), adjusted for baseline MADRS. No significant predictor time interactions were found in univariate models therefore interaction terms were dropped from multivariate models. b Model fit, assessed using Bayesian Information Criterion. c Independent or substance-induced depression.
already apparent by week 3, after which group differences were maintained but did not increase. The findings for selfdirectedness are consistent with previous research in other populations. Low self-directedness is associated with poorer outcomes in non-comorbid depression populations (Sato et al., 1999, Joyce et al., 2007) and worse 5-year outcome in women with bulimia nervosa (Rowe et al., 2011). Self-directedness relates to an individual's ability to regulate and adapt their behavior to the environment (Cloninger et al., 1993) and it appears to be a non-specific marker for personality disorders (Cloninger, 2000). It also shares similarities with Bandura's concept self-efficacy (Bandura, 1977), which features prominently in the alcohol literature (Adamson et al., 2009). There are mixed views on whether personality disorders adversely influence treatment outcome in non-comorbid major depression (Newton-Howes et al., 2006; Mulder, 2002). However the results from the present study suggest that personality variables are relevant to depression outcome in patients with an alcohol use disorder. This area has previously received little attention and warrants further study. This study's strengths include its relatively high retention rate of 77% at 24 weeks, and its inclusion of several measures that have not been extensively reported in this population, particularly temperament and character. A potential limitation is that subjects were not required to be abstinent at baseline. However this reflects real-life outpatient practice whereby not all patients are able to immediately stop drinking. Recruitment for the study stopped before reaching the target sample size, reducing power for the main study outcomes. However in the present analyses we were able to mitigate the loss of power issue by using repeated measures analyses on up to nine time-points per subject. Lastly the potential influence of naltrexone on both drinking and depression outcomes in this study was not known, although it is
now suggested naltrexone has little effect on depressive symptoms (Petrakis et al., 2007). In conclusion, alcohol dependent patients whose depression is categorized as substance-induced show greater improvement in depression during treatment compared to those with independent depression. However this appears to be mainly because they reduce their drinking more, possibly because of greater recognition of the benefit this will provide for their depression. Furthermore although patients with independent depression should not theoretically experience much, if any, improvement in depressive symptoms as a direct result of curtailing their drinking, this appears not to be the case. Our view is that regardless of whether depression is believed to be independent or substance-induced, alcohol reduction should be prioritized as the first step in treating depression in all actively drinking, alcohol dependent patients.
Role of funding source The Health Research Council of New Zealand providing funding for the conduct of the clinical trial on which this research is based.
Conflict of interest The authors have no potential conflicts of interest to declare.
Acknowledgments This study has been funded by Grants from the New Zealand Ministry of Health and New Zealand Health Research Council (Grant HRC 07/138).
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Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research Report
Depression outcome in alcohol dependent patients: An evaluation of the role of independent and substance-induced depression and other predictors James A. Foulds a,n, J. Douglas Sellman a, Simon J. Adamson a, Joseph M. Boden b, Roger T. Mulder a, Peter R. Joyce a a b
Department of Psychological Medicine, University of Otago, Christchurch, New Zealand Christchurch Health and Development Study, University of Otago, Christchurch, New Zealand
art ic l e i nf o
a b s t r a c t
Article history: Received 3 September 2014 Received in revised form 25 November 2014 Accepted 27 November 2014 Available online 5 December 2014
Background: Depression commonly co-occurs with alcohol use disorders but predictors of depression treatment outcome in patients with both conditions are not well established. Methods: Outpatients with alcohol dependence and major depression (n ¼138) were prescribed naltrexone and randomized to citalopram or placebo for 12 weeks, followed by a 12-week naturalistic outcome phase. General linear mixed models examined predictors of Montgomery Asberg Depression Rating Scale (MADRS) score over 24 weeks. Predictors included whether depression was independent or substance-induced, and demographic, alcohol use, and personality variables (Temperament and Character Inventory subscales). Results: Most improvement in drinking and depression occurred between baseline and week 3. During follow-up, patients with substance-induced depression reduced their drinking more and they had better depression outcomes than those with independent depression. However, greater reduction in drinking was associated with better depression outcomes for both independent and substance-induced groups, while antidepressant therapy had no effect for either group. Baseline demographic and alcohol use variables did not predict depression outcomes. Among personality variables, high self-directedness was a strong predictor of better depression outcomes. Limitations: Subjects were not abstinent at baseline. The influence of naltrexone on depression outcomes could not be tested. Conclusion: Alcohol dependent patients with substance-induced depression have better short term depression outcomes than those with independent depression, but this is largely because they reduce their drinking more during treatment. & 2014 Elsevier B.V. All rights reserved.
Keywords: Alcohol-induced disorder Alcohol-related disorders Depressive disorder Depression Treatment outcome Comorbidity
1. Introduction Patients with alcohol use disorders often have high levels of depressive symptoms when they enter treatment. Depression on average improves substantially in the first six weeks of treatment and more gradually thereafter (Pettinati et al., 2010). However a significant minority of patients experiences enduring depressive symptoms. It would be clinically useful to be able to identify this group prospectively, as this would help treatment allocation and might predict who is at risk of other outcomes such as suicide, (Henriksson et al., 1993) alcohol relapse (Hasin et al., 2002) and n Correspondence to : Department of Psychological Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch 8140 New Zealand. Tel.: þ 64 3 3720 400; fax: þ64 3 3720 407. E-mail address: [email protected] (J.A. Foulds).
http://dx.doi.org/10.1016/j.jad.2014.11.052 0165-0327/& 2014 Elsevier B.V. All rights reserved.
increased healthcare utilization (Parthasarathy and Weisner, 2005). Categorizing depression as independent or substance-induced at baseline is a common way of attempting to predict the course of depression in patients with an alcohol use disorder. Substanceinduced depression (SID) by definition improves when patients stop drinking, and is thought to account for a substantial proportion of major depressive episodes among patients with an alcohol use disorder (Schuckit et al., 2007). Conversely independent depression (ID) should not necessarily remit with abstinence, but is believed to be more responsive to specific depression treatments such as antidepressant medication (Pettinati, 2013). The established method to differentiate between ID and SID is to examine the timing of onset of heavy drinking and depression in the past, and to determine whether depression was ever present during a sustained period of abstinence (Schuckit et al., 2007). This
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approach has been operationalized in instruments such as the Structured Clinical Interview for DSM (SCID) (Spitzer et al., 1992) and the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) (Hasin et al., 1996a). Despite the wide use of this terminology, the size of any difference in depression outcome between ID and SID has not been well characterized (Nunes, 2006). Furthermore patients with SID appear to show a high incidence of ID when followed up over 12 months (Nunes, 2006; Brown et al., 2011) suggesting SID may not be a stable diagnosis. Little is known about more general predictors of depression outcome in patients with co-occurring alcohol dependence and major depression. In patients without an alcohol use disorder, early improvement in depression and some personality characteristics appear to be stronger predictors of 6-month outcome than either demographics or depression characteristics (Mulder et al., 2006). However these findings have not been replicated in comorbid populations. The objective of this study was to investigate whether patients with ID had a different treatment outcome compared to those with SID during 24 weeks of treatment for depression and alcohol dependence. We also examined a range of other candidate variables as predictors of depression outcome, including baseline depression and drinking measures, demographic variables and personality measures.
2. Methods 2.1. Overview of study design Study methods and key results have been previously reported (Adamson et al., in press). In brief, this was a 12-week trial comparing naltrexone plus citalopram to naltrexone plus placebo followed by a 12-week naturalistic continuation phase. The trial was conducted in 8 outpatient alcohol treatment centers in New Zealand from 2007 to 2011. It received approval from local ethics committees at each site and was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12606000413527). 2.2. Participants and measures Screening was conducted on 474 potential subjects, of which 138 were included in the intent-to-treat sample. Eligible participants were outpatients aged 17–65 years seeking treatment for a drinking problem and low mood. They were recruited from addiction treatment centers, psychiatric clinics and via advertising. Participants met current DSM-IV criteria for alcohol dependence and major depressive episode in the past four weeks rated using the Structured Clinical Interview for DSM-IV (SCID), (Spitzer et al., 1992). In addition they had a Montgomery Asberg Depression Rating Scale (MADRS) score of 20 or higher (Montgomery and Asberg, 1979). Abstinence at baseline was encouraged but not enforced. Further baseline characteristics of the sample are shown in Table 1. Using an algorithm adapted from the SCID, the current episode of depression was assumed to be independent if at least one of the following criteria were met: a) First episode of depression occurred before the onset of heavy drinking. b) Past history of depression present for at least one month during a period of abstinence. c) A past history of depressive symptoms substantially in excess of what would be expected given the duration or amount of alcohol use.
If none of the above criteria were met, the depression was labeled as substance-induced. The categorization as independent or substance-induced is, for convenience, referred to hereafter as depression type. Participants were not explicitly informed whether they were categorized as having ID or SID, but their belief about the causal relationship between their drinking and depression was recorded at baseline. Study exclusion criteria were: past or current intravenous drug use; current opioid use; psychosis; mania or hypomania; suicidality or homicidality; psychiatric hospitalization required; unstable medical illness; recent disulfiram, naltrexone, antidepressant or mood stabilizing medication; significantly elevated transaminases or raised bilirubin; pregnancy, breastfeeding or inadequate contraception; and current or pending imprisonment. 2.3. Interventions The citalopram/placebo dose started at one capsule (20 mg) daily and it could be increased to three capsules during the trial if depression persisted. The naltrexone dose was 25 mg daily for one week, then 50 mg daily as tolerated. The dose could be further increased to 75 or 100 mg after 6 weeks. Citalopram/placebo and naltrexone were given for 12 weeks, after which both medications were scheduled to be withdrawn. However weeks 12–24 were designed as a naturalistic follow-up phase and any medications for mood or drinking could be freely prescribed following discussion between the patient and their treating clinicians. All participants received manualised clinical case management throughout the 24 weeks. This comprised: enhancing motivation and commitment to change drinking behavior; co-ordinating care; involving family and significant others; encouraging the development of coping strategies; promoting adherence; providing education about depression and alcohol dependence; and promoting involvement in self-help groups. There were 19 research clinicians involved in the overall TEAM study, of which demographic data were available for 18. Clinicians were aged 34–61 (mean 48), 10/18 were female and 14/18 were of New Zealand European ethnicity. Clinicians had worked in the addiction field for between 9 and 30 years and had trained in psychiatry, psychiatric nursing, social work, clinical psychology or counseling. 2.4. Main outcome The primary outcome was the MADRS score at 3-weekly intervals from week 3 to week 24. 2.5. Predictors Alcohol measures were percentage of days abstinent (PDA) and drinks per drinking day (DDD) obtained using the timeline follow back procedure (Sobell, 1986), for the 12 weeks prior to baseline and then 3-weekly until 24 weeks. Personality characteristics were assessed using the 144-item Temperament and Character Inventory (TCI) (Cloninger et al., 1993). This self-report instrument measures personality on four temperament dimensions: novelty seeking (NS), harm avoidance (HA), reward dependence (RD) and persistence (PS); and three character dimensions: cooperativeness (C), self-directedness (SD) and self-transcendence (ST). Stage of change was assessed with the Readiness to Change Questionnaire (Rollnick et al., 1992). Alcohol addiction severity was measured with the Leeds Dependence Questionnaire (Raistrick et al., 1994). Therapeutic alliance was assessed with the Working Alliance Inventory (Horvath and Greenberg 1989) client and therapist versions, measured between weeks 3 and 6. This is a self-report
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505
Table 1 Baseline characteristics of sample for 24-week completers and dropouts. Range
Value or % (sd) Whole sample (n¼138)
Study completers to 24 weeks (n¼ 106)
Dropouts before 24 weeks (n¼ 32)
t or χ2; p
59.4% 43.6 (5.1)
60.4% 43.9 (9.3)
56.3% 42.5 (8.3)
χ2 ¼ 0.17, p ¼ 0.68 t ¼0.77, p ¼ 0.44
34.1% 21.0% 44.9%
34.9% 22.6% 42.5%
31.3% 15.6% 53.1%
χ2 ¼ 1.30, p ¼0.52
31.9% 46.4% 21.7% 13.5 (3.1)
28.3% 48.1% 23.6% 13.6 (3.1)
43.8% 40.6% 15.6% 13.4 (3.2)
χ2 ¼ 2.85, p¼ 0.24
t ¼0.24, p ¼0.81
20–48 0.3–3.8
31.0 (5.8) 2.0 (0.7) 70.3% 52.9%
31.1 (5.8) 2.0 (0.7) 67.0% 50.9%
30.6 (5.9) 2.0 (0.8) 81.3% 56.3%
t ¼0.46, p ¼ 0.65 t ¼ 0.04, p ¼ 0.97 χ2 ¼ 2.4, p¼ 0.12 χ2 ¼ 0.28, p¼ 0.60
0–96% 3.0–52.5 0–24
25.8% (27.4) 14.3 (8.0) 16.0 (5.5)
25.2% (27.6) 13.9 (7.3) 15.7 (5.4)
27.9% (27.1) 15.7 (9.9) 16.8 (5.5)
t ¼ 0.48, p ¼ 0.63 t ¼ 1.13, p ¼ 0.26 t ¼ 1.02, p ¼ 0.31
Comorbidity Current tobacco smoker Current cannabis disorder Current anxiety disorder Lifetime antisocial personality disorder
57.2% 15.9% 47.8% 6.5%
53.8% 13.2% 42.5% 5.7%
68.8% 25.0% 65.6% 9.4%
χ2 ¼ 2.25, χ2 ¼ 2.55, χ2 ¼ 5.29, χ2 ¼ 0.56,
Temperament and character inventory subscales Novelty seeking 2–20 Harm avoidance 2–19 Reward dependence 3–20 Persistence 0–20 Self directedness 1–20 Cooperativeness 5–20 Self transcendence 0–20
10.7 (3.7) 11.4 (4.6) 11.7 (3.9) 10.9 (4.9) 10.1 (4.6) 16.2 (3.2) 6.2 (5.2)
10.7 (3.7) 11.6 (4.6) 11.7 (3.9) 10.9 (4.7) 10.2 (4.3) 16.5 (3.1) 6.1 (5.2)
10.9 (3.6) 10.6 (4.8) 11.9 (4.0) 11.2 (5.9) 9.7 (5.8) 15.3 (3.5) 6.6 (5.2)
t ¼ 0.27, p ¼0.79 t ¼0.75, p ¼ 0.45 t ¼0.01, p ¼0.93 t ¼ 0.23, p ¼0.82 t ¼0.93, p ¼ 0.36 t ¼1.9, p ¼ 0.06 t ¼ 0.45, p ¼0.66
Demographics Female Age Employment Full-time Part-time Unemployed Relationship status Single Married/de facto Divorced/widowed Years of education Depression variables MADRS score SCL-90 depression score Independent depression Assigned to citalopram Alcohol variables Percent days abstinenta Drinks per drinking daya Readiness to change questionnaire
a
20–64
p¼ 0.13 p¼ 0.11 p¼ 0.02 p¼ 0.46
Average in 12 weeks before treatment commenced.
instrument that assesses the quality of the relationship between therapist and client in relation to bond, tasks and goals. An independent research clinician administered the instruments. Clinicians and patients were blind to each other's responses. 2.6. Power calculation The study was powered to be able to detect a clinically significant difference (effect size 0.5) in change in depression score from baseline to 12 weeks between citalopram and placebo. The study was also designed to detect a difference in citalopram effect according to depression type, but as the ratio of independent to substance-induced depression was not known a priori, a power calculation was not possible. The approximately 2.5–1 ratio of independent to substance-induced depression that eventuated provided less power for this subgroup effect (relative to the power for a main citalopram effect) because of unbalanced group sizes but this loss of power was mitigated through the use of repeated measures analyses for the present study (Gueorguieva and Krystal, 2004). 2.7. Statistical methods Analyses were conducted with general linear mixed models using PROC MIXED in SAS version 9.3 (SAS Institute Inc., Cary, NC). These methods have advantages over the last observation carried
forward method in alcohol studies, as they allow more realistic handling of missing data (Hallgren and Witkiewitz, 2013). Point estimates are least squares means from linear mixed models, expressed with 95% confidence intervals, unless otherwise stated. There were three series of models fitted to the data: the first series comprised univariate analyses of baseline predictors; the second comprised multivariate analyses on baseline predictors identified as relevant from the first series; and the third investigated potential mediators of depression outcome during treatment. All models were repeated measures analyses using the MADRS scores in follow up (weeks 3, 6, 9, 12, 15, 18, 21 and 24) as the dependent variable and the baseline MADRS score, predictor(s) and predictor time interaction term(s) as independent variables. The time variable was treated as continuous, and was centered due to the multilevel structure of models and the presence of interaction terms. There was no evidence of higher-order polynomial trends therefore these terms were omitted from models. An autoregressive covariance structure was specified and Kenward-Roger adjustment of degrees of freedom was applied for estimates of fixed effects. Model assumptions were checked using diagnostic plots and models were formulated on the assumption that data were missing at random. Model fit was assessed using the Bayesian Information Criterion. In the first series of models, the effect of individual baseline predictors was separately examined in univariate models. The baseline predictors were grouped into demographic, depression, alcohol, comorbidity and personality (TCI) variables.
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In the second series of models, baseline predictors that were significant at the 0.10 level in the first series were investigated by combining them in multivariate models. The first model in this series included TCI variables alone; the second added depression type and the final model dropped variables that were not significant at the 0.10 level in the previous models. In the third series of models, dynamic mediators of outcome during treatment were investigated. These were: Working Alliance Inventory therapist and patient scores (WAI-T and WAI-P respectively, measured between weeks 3 and 6); adherence (number of treatment sessions attended); and drinking measures (PDA and DDD), modeled as time-varying covariates in linear mixed models. Finally baseline and mediator variables were combined in a full model. The purpose of this final model was to determine whether there was evidence the potential mediator variables lay on a causal pathway between selected baseline predictors (SDI and depression type) and depression outcome.
3. Results 3.1. Subject characteristics Follow up data were available at 24 weeks for 106 subjects (77%). Baseline characteristics of the sample are shown in Table 1, broken into 24-week completers and non-completers. As shown in Table 1, non-completers had a significantly higher prevalence of comorbid anxiety disorders but did not differ from completers on other baseline measures. 3.2. Overall depression outcomes The mean MADRS score was 31.0 (sd 5.8, range 20–48) at baseline. Estimates of the mean MADRS score were 16.1 (14.4, 17.8) at week 3, 10.9 (9.1, 12.7) at week 12 and 9.3 (7.5, 11.1) at week 24. At week 24, 15/106 subjects (14.2%) who were still in follow up had a MADRS score of more than 19, indicating at least moderate depression (Snaith et al., 1986). There was no evidence of significant heterogeneity in depression response across treatment venues. As previously reported, there was no evidence that citalopram had an effect on depression outcome (Adamson et al., in press). 3.3. Drinking outcomes As shown in Table 1, at baseline subjects were abstinent for a mean of 25.8% of days (sd 27.4) and their mean daily alcohol consumption was 14.3 drinks (sd 8.0). The correlation between PDA and DDD was 0.20 at baseline and the correlation at each time point ranged from 0.27 to 0.43 in weeks 3–24. Change in drinking occurred early in treatment: the mean PDA was 63.8% (sd 33.6) at week 3 and there was little change in this figure from week 3 to week 24. The pattern was similar for DDD: the mean DDD was 6.4 (sd 7.0) at week 3 and it remained close to this level between week 3 and week 24.
3.5. Depression type: independent and substance-induced depression The percentage of patients who had ID was 70.3%, and the remaining 29.7% had SID. There was no significant difference in mean MADRS score at baseline, which was 31.3 (sd 5.8, range 20–48) for ID subjects and 30.2 (sd 5.6, range 20–45) for SID subjects (t ¼0.90 p ¼0.31). Compared to subjects with SID, those with ID had higher self-directedness (t¼ 2.63, p¼ 0.01), their current episode of depression was longer (t¼2.03, p¼ 0.04) and they had more years of education (t¼2.35 p¼ 0.02). The two groups were comparable on all other baseline measures. At baseline patients with SID (16/39; 41.0%) were more likely than those with ID (9/95; 9.5%) to believe drinking caused their depression while more patients with ID (66/95; 69.4%) than SID (17/39; 35.9%) believed drinking did not cause, but worsened their depression (χ2 ¼ 20.2, p o0.001). At week 24, ID study completers had a mean MADRS score of 10.3 (sd 9.4, range 0–43) and for SID completers the mean score was 7.0 (sd 7.9, range 0–29). As shown in Table 2, there was an overall difference in depression outcome between the two groups but no evidence of a group time interaction effect, indicating the difference between the two groups was already apparent by week 3, and the groups followed a parallel path thereafter. This pattern is also shown in Fig. 1. The estimate for the mean difference in MADRS score between ID and SID during follow up was 3.9 (1.3, 6.5), a standardized mean difference of 0.68. Subjects with SID had significantly higher PDA during follow up compared to ID subjects, after adjusting for baseline PDA (75.6% compared to 62.7%; p¼ 0.007), but there was no difference in DDD between the two groups (p ¼0.10). The difference in PDA between the groups was already present at week 3, and persisted throughout the 24 weeks of follow up. There was a significant correlation between change in PDA and change in depression from baseline to week 3 for both ID subjects (r ¼0.285, p¼ 0.005) and SID subjects (r ¼0.442, p ¼0.004).
3.6. Temperament and character measures TCI data were missing for 11 subjects. TCI subscales were not significantly correlated with baseline depression or drinking measures, with two exceptions: SD was negatively correlated with baseline PDA (r¼ 0.226) while HA was negatively correlated with baseline DDD (r¼ 0.224). TCI subscales were not correlated with change in drinking during the study, with the exception of SD and change in DDD (r¼0.232) and C and change in DDD (r¼0.182). For the temperament and character variables, low HA, high SD, and high C were univariate predictors of better depression outcome. The effect of SD is shown in Fig. 2, which illustrates that the difference in outcome was most noticeable for subjects in the highest SD quartile, with the other 3 groups having a similar trajectory. The overall difference in MADRS score between the highest and lowest SD quartiles was 6.9 (3.5, 10.19; standardized mean difference 1.17) across all follow-up time-points.
3.4. Predictors of depression outcome 3.7. Multivariate models of baseline predictors Table 2 shows the results of univariate analyses of predictors of MADRS score at weeks 3–24, adjusted for baseline MADRS. In these models, baseline demographic, drinking and depression variables did not have a main effect on depression outcome, with the exception of depression type. No predictor time interactions were significant, indicating the rate of change in depression in weeks 3–24 was not altered by any of the predictors.
Table 3 shows the results of the next step of the analyses, which was a series of multivariate models of baseline predictors that were significant at the 0.10 level in univariate models. In the final model, SD (p o0.001) and depression type (po 0.05) remained significant predictors of depression score. Time interaction effects were not significant for either variable.
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507
Table 2 Univariate predictors of depression score during treatmenta. b Treatment variables Antidepressant assignment Citalopram
SE
p
0.35
1.23
0.78
0.43 0.06
1.25 0.07
0.73 0.36
1.54 1.24 0
1.39 1.68
0.53
0.40 2.20 0 0.28
1.67 1.54
0.13
0.20
0.17
0.45 1.99 3.74
0.11 1.51 1.29
o 0.001 0.19 0.004
2.60 0.40 0.08 0
1.99 1.48 1.80
0.60
0.63 1.22 0
1.40 1.73
0.58
Alcohol variables Baseline percent days abstinent Baseline drinks per drinking day Leeds dependence questionnaire score Readiness to change questionnaire score
3.24 0.01 0.06 0.02
2.22 0.08 0.10 0.11
0.15 0.88 0.58 0.85
Comorbidity variables Current tobacco smoker Current cannabis disorder Current anxiety disorder Lifetime antisocial personality disorder
0.77 1.55 1.17 2.14
1.23 1.70 1.24 2.63
0.53 0.36 0.35 0.42
0.05 0.39 0.09 0.13 0.44 0.61 0.04
0.11 0.13 0.16 0.13 0.20 0.13 0.12
0.76 0.005 0.58 0.32 0.03 o 0.001 0.71
Demographic variables Gender Male Age Current employment category Unemployed Part time Full time (reference group) Relationship status Single Married or de facto Widowed, separated or divorced (reference group) Years of education Depression variables Baseline MADRS score Melancholic depression Depression type (independent vs substance-induced) Number of previous episodes Fewer than 3 3–5 5 or more Too many or too indistinct to count (reference group) Duration of current episode 6 months or less 6–12 months More than 12 months (reference group)
Temperament and character subscales Novelty seeking Harm avoidance Reward dependence Persistence Cooperativeness Self-directedness Self-transcendence
a Results from linear mixed models of predictors of MADRS scores at 3-weekly intervals from week 3 to week 24, adjusted for baseline MADRS. Models included predictor time interaction terms, however no significant interaction effects were found therefore these results have been omitted. For predictors with two categories (eg gender), only the results for the non-reference group category are shown.
3.8. Effect of mediator variables on change in depression The effect of change in drinking on depression outcomes was initially explored by dividing drinkers into four categories according to the global change in PDA from baseline to week 24. The mean MADRS score at week 24 was 16.4 (11.4, 21.5) for subjects who did not increase their PDA during the study; 9.4 (5.6, 13.1) for subjects who increased their PDA but were still drinking 450% of days; 7.5 (4.7, 10.2) for those who increased their PDA and were still drinking but on o50% of days; and 8.3 (4.8, 11.9) for subjects who were abstinent at week 24. When depression type was added to this model, there was no evidence of an interaction effect of change in PDA depression type. Illustrating this point, for patients with ID, the mean MADRS score at week 24 was 16.1 (10.4, 21.7) for those with no improvement in PDA and 9.9 (5.4, 14.4) for those who were abstinent. The corresponding figures for the SID group were 17.2
(6.7, 27.7) and 5.9 (0.1, 11.7) respectively, however these figures need to be viewed with caution as the standard errors are inflated due to small numbers in each cell. These findings were further elucidated with models treating PDA and DDD as time-varying predictors. The results of these analyses are shown in Table 4, along with results for therapeutic alliance and treatment adherence. In univariate models, DDD and PDA at weeks 3– 24 (adjusted for their respective baseline values) and the therapist rating of therapeutic alliance (WAI-T) were significant predictors of depression outcome. In a model combining the two drinking measures and WAI-T, the drinking variables remained significant at the.001 level while therapeutic alliance was not significant (p¼0.06). A final model added two baseline predictors- depression type and self-directednessto the three mediators DDD, PDA and WAI-T. In this model depression type was no longer significant (p¼0.25) suggesting differences in drinking patterns may have mediated the relationship between
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Course of independent and substanceinduced depression 35
Independent 30
Substance-induced
MADRS score
25 20 15 10 5 0
0
3
6
9
12
15
18
21
24
Week number Fig. 1. MADRS score from baseline to week 24, for subjects with independent and substance-induced depression; p value¼ 0.004 for the overall difference between groups in repeated measures analysis. Estimates of MADRS score at timepoints from week 3 to week 24 are least squares means from linear mixed models including time as a categorical predictor. Standardised mean difference 0.68 for group difference across all timepoints (excluding baseline) and 0.54 for group difference at week 24.
Depression score by self-directedness quartile 35
MADRS score
30
quartile 1
quartile 2
quartile 3
quartile 4
25 20 15 10 5 0 0
3
6
9
12
15
18
21
24
Week number Fig. 2. MADRS score from baseline to week 24 according to self-directedness quartile; p valueo 0.001 for overall group difference. Estimates of MADRS score at timepoints from week 3 to week 24 are least squares means from linear mixed models including time as a categorical predictor. Standardised mean difference 1.17 between quartile 1 (low self-directedness) and quartile 4 (high self-directedness) across all timepoints (excluding baseline) and 0.69 for difference between quartile 1 and quartile 4 at week 24.
depression type and depression outcomes. SDI remained significant (po0.001) suggesting it had an independent effect on depression outcome beyond any effect mediated via drinking.
4. Discussion In this 24-week study of patients receiving comprehensive integrated treatment for alcohol dependence and depression, most of the change in depression and drinking occurred in the first three weeks of treatment. This pattern is consistent with other
literature suggesting much of the reduction in symptom burden in comorbid patients occurs early in treatment, with as much as a third of the improvement even occurring before the first treatment session (Baker et al., 2014). In the first three weeks, patients with substance-induced depression (SID) experienced more improvement in both depression and percentage of days abstinent than those with independent depression (ID). After that, the depression and drinking patterns of both groups followed approximately parallel paths from weeks 3 to 24, with alcohol outcomes remaining static and depression showing a small improvement over this period. The difference in depression outcomes between patients with ID and those with SID (an effect size of about 0.7) appeared to arise mainly because SID patients reduced their drinking more, rather than because they derived greater benefit from any reduction in drinking. The greater increase in abstinent days among SID patients was an unexpected finding, as all patients regardless of depression type were encouraged to reduce their drinking. However, the assessment process did encourage patients to consider the relationship between their drinking and mood, and this may have provided a greater incentive for SID patients to address their drinking. Although SID patients altered their drinking more, change in drinking was also associated with change in depression in ID patients; this runs counter to what would be expected if depression is truly “independent” of drinking in this group. For both groups of patients, a poor depression response was much more prevalent among subjects who did not improve their drinking at all or drank more; surprisingly, patients who achieved even modest improvement in drinking had similar depression outcomes to those who were abstinent at the end of the study. The importance of categorizing depression as independent or substance-induced in patients with a concurrent substance disorder has been repeatedly emphasized (Schuckit, 1995; Schuckit et al., 1997; Grant et al., 2004; Samet et al., 2013). In spite of this, few studies have prospectively compared the outcome of depression treatment between these groups (Nunes, 2006) therefore little is known about the magnitude of any difference in outcome. The apparently high incidence of ID among patients originally diagnosed with SID (Brown et al., 2011; Nunes, 2006) has raised further concerns about the face validity and predictive value of the concept as it is currently defined. It is currently suggested that patients with ID benefit more from antidepressants and patients with SID benefit more from reduced drinking (Schuckit, 2006). We found no evidence ID patients respond better to antidepressant medication, and limited support for the belief that reduced drinking benefits patients with SID more. In fact it seems likely reduced drinking benefits both groups. The limited antidepressant response among depressed, alcohol dependent patients coupled with evidence that the course of alcoholism affects the course of depression (Hasin et al., 1996b) suggests reduced drinking should be the primary treatment strategy for depression regardless of whether depression is believed to be independent or substance-induced. We found baseline demographic and alcohol consumption variables, and depression variables other than depression type, did not predict the course of depression over 24 weeks. This is consistent with results from a study of depressed subjects without an alcohol disorder (Mulder et al., 2006). In that study, Mulder et al. reported baseline demographic variables and depression characteristics did not generally predict depression outcome, while early depression response and personality variables did. We identified three personality variables – high self-directedness, low harm avoidance and high cooperativeness – which were associated with better depression outcome in univariate models. Of these, only self-directedness remained significant in multivariate models. The effect of self-directedness was
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509
Table 3 Multivariate models of baseline predictors of depression score during treatmenta.
Harm avoidance Cooperativeness Self directedness Depression typec
Model 1: Temperament and character variables Model 2: Temperament and character variables plus only BICb ¼5460.3 depression type BICb ¼5454.6
Model 3: Best multivariate model BICb ¼ 5423.4
b
SE
p
b
SE
p
b
SE
p
0.49 0.17 0.49 Not in model
0.15 0.20 0.15
0.15 0.38 0.001
0.22 0.18 0.41 2.62
0.14 0.20 0.15 1.32
0.10 0.36 0.01 0.05
Not in model Not in model 0.53 2.47
0.19 1.26
o 0.001 0.05
a Results from linear mixed models of predictors of MADRS scores at 3 weekly intervals from week 3 to week 24, adjusted for baseline MADRS. Models included predictor time interactions, however no significant interaction effects were found therefore these results have been omitted. b Model fit, assessed using Bayesian Information Criterion. c Independent or substance-induced depression.
Table 4 The role of mediator variables as predictors of MADRS score during follow upa. Univariate models of intermediate outcomes
Multivariate model of intermediate outcomes. BICb ¼4436.9
Combined model: baseline and intermediate predictors. BICb ¼4303.3
b
p
b
p
b
SE
p
o 0.001 o 0.001 0.33 0.03 0.78
0.31 0.06 6.56 1.34 Not in models 2.12 1.12 Not in models
o 0.001 o 0.001
0.29 6.35
0.06 1.37
o 0.001 o 0.001
0.06
1.50
1.10
0.18
0.53 1.60
0.14 1.37
o 0.001 0.25
SE
Drinks per drinking day at weeks 3–24 0.40 0.10 Percent days abstinent at weeks 3–24 8.37 1.25 Therapeutic alliance: patient rating 1.28 1.32 Therapeutic alliance: clinician rating 2.49 1.15 Treatment adherence: number of sessions attended 0.01 0.08 Self directedness Not in models Depression typec Not in models
SE
a Results from linear mixed models of predictors of MADRS scores during weeks 3–24 (repeated measures), adjusted for baseline MADRS. No significant predictor time interactions were found in univariate models therefore interaction terms were dropped from multivariate models. b Model fit, assessed using Bayesian Information Criterion. c Independent or substance-induced depression.
already apparent by week 3, after which group differences were maintained but did not increase. The findings for selfdirectedness are consistent with previous research in other populations. Low self-directedness is associated with poorer outcomes in non-comorbid depression populations (Sato et al., 1999, Joyce et al., 2007) and worse 5-year outcome in women with bulimia nervosa (Rowe et al., 2011). Self-directedness relates to an individual's ability to regulate and adapt their behavior to the environment (Cloninger et al., 1993) and it appears to be a non-specific marker for personality disorders (Cloninger, 2000). It also shares similarities with Bandura's concept self-efficacy (Bandura, 1977), which features prominently in the alcohol literature (Adamson et al., 2009). There are mixed views on whether personality disorders adversely influence treatment outcome in non-comorbid major depression (Newton-Howes et al., 2006; Mulder, 2002). However the results from the present study suggest that personality variables are relevant to depression outcome in patients with an alcohol use disorder. This area has previously received little attention and warrants further study. This study's strengths include its relatively high retention rate of 77% at 24 weeks, and its inclusion of several measures that have not been extensively reported in this population, particularly temperament and character. A potential limitation is that subjects were not required to be abstinent at baseline. However this reflects real-life outpatient practice whereby not all patients are able to immediately stop drinking. Recruitment for the study stopped before reaching the target sample size, reducing power for the main study outcomes. However in the present analyses we were able to mitigate the loss of power issue by using repeated measures analyses on up to nine time-points per subject. Lastly the potential influence of naltrexone on both drinking and depression outcomes in this study was not known, although it is
now suggested naltrexone has little effect on depressive symptoms (Petrakis et al., 2007). In conclusion, alcohol dependent patients whose depression is categorized as substance-induced show greater improvement in depression during treatment compared to those with independent depression. However this appears to be mainly because they reduce their drinking more, possibly because of greater recognition of the benefit this will provide for their depression. Furthermore although patients with independent depression should not theoretically experience much, if any, improvement in depressive symptoms as a direct result of curtailing their drinking, this appears not to be the case. Our view is that regardless of whether depression is believed to be independent or substance-induced, alcohol reduction should be prioritized as the first step in treating depression in all actively drinking, alcohol dependent patients.
Role of funding source The Health Research Council of New Zealand providing funding for the conduct of the clinical trial on which this research is based.
Conflict of interest The authors have no potential conflicts of interest to declare.
Acknowledgments This study has been funded by Grants from the New Zealand Ministry of Health and New Zealand Health Research Council (Grant HRC 07/138).
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