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Effects of Major Depression on Remission and Relapse of Substance Dependence
Deborah Hasin, PhD;
Xinhua Liu, PhD;
Edward Nunes, MD;
Steven McCloud, MS;
Sharon Samet, MSW;
Jean Endicott, PhD
Arch Gen Psychiatry. 2002;59:375-380.
ABSTRACT
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Background The effects of major depressive disorder (MDD) on the course of substance
dependence may differ depending on the temporal relationship of depression
to dependence. We investigated the effects of MDD on the outcome of substance
dependence under 3 circumstances: (1) lifetime onset of MDD prior to lifetime
onset of dependence onset, (2) current MDD occurring during a period of abstinence,
and (3) current MDD during substance use that exceeded the expected effects
of intoxication or withdrawal.
Methods A sample of 250 inpatients with DSM-IV cocaine,
heroin, and/or alcohol dependence were followed up at 6, 12, and 18 months.
The Psychiatric Research Interview for Substance and Mental Disorders (PRISM)
was used to make DSM-IV diagnoses. Using Cox proportional
hazards models, stable remissions (those lasting at least 26 weeks) from DSM-IV cocaine, heroin, and/or alcohol dependence and from
use were studied, as well as subsequent relapses of dependence and use.
Results Patients with current substance-induced MDD were less likely to remit
from dependence (adjusted hazards ratio, 0.11) than patients with no baseline
MDD. A history of MDD prior to lifetime onset of substance dependence also
reduced the likelihood of remission relative to the absence of such a history
(adjusted hazard ratio, 0.49). Major depressive disorder during sustained
abstinence predicted dependence relapse (adjusted hazards ratio, 3.07) and
substance use after hospital discharge compared with those without abstinence
MDD (adjusted hazards ratio, 1.45).
Conclusion The timing of depressive episodes relative to substance dependence served
as an important factor in the remission and relapse of substance dependence
and substance use.
INTRODUCTION
MAJOR DEPRESSIVE disorder (MDD) is common among substance abusers1-5
and associated with considerable psychosocial disability,6-8
suggesting that MDD may impede long-term remission from drug and alcohol dependence.
Diagnostic problems have complicated research in this area, with efforts to
resolve them largely relying on the temporal sequencing of depressive symptoms
relative to substance abuse. In DSM-IV,9
major depression is "primary" if "not due to the physiological effects of
a substance," a causal relationship inferred largely from timing. Primary
MDD is diagnosed when symptoms precede substance use or persist during extended
periods of abstinence. A DSM-IV substance-induced
disorder is diagnosed when clinically significant symptoms co-occur with substance
use but clearly exceed the expected effects of intoxication or withdrawal.
Little prospective research is available on whether these aspects of timing
affect the course of substance dependence or whether primary episodes starting
prior to the lifetime onset of substance use have different effects from primary
episodes occurring during periods of abstinence.
Many studies on MDD among alcoholics or drug addicts investigated lifetime
depression, regardless of its timing. Rounsaville et al10
found that lifetime MDD predicted poor alcoholism outcome among males, while
others11-12 did not. Given the
lack of specificity about timing in these studies, inconsistencies are not
surprising. Prospective studies offer clearer information. Among opiate addicts,
baseline current MDD predicted subsequent heroin13
and cocaine use.14 Among alcoholic subjects,
baseline MDD predicted drinking relapse.15
The lifetime order of onset of 2 disorders is fixed when the second
disorder begins. Thus, a lifetime diagnosis of primary MDD with onset prior
to substance dependence does not necessarily indicate current depression.
However, the remitting and recurring nature of major depression is important
to address in longitudinal research. Time-varying MDD predicted failure to
remit from alcoholism and relapse.16-18
This study did not differentiate primary and substance-induced MDD or separate
prior-onset from abstinence primary depressions. Furthermore, the study did
not include polysubstance abusers, whose switching of substances14
during follow-up can produce an inaccurate impression of remission if only
1 substance is studied.
To address these issues, we studied the effects of MDD on substance
dependence prospectively. Primary MDD beginning prior to the lifetime onset
of substance dependence was not predicted to affect the outcome of current
substance dependence because primary MDD usually occurs long in the past and
also because of potential memory problems. Proximal abstinence and substance-induced
MDD were predicted to impede remission from substance dependence. Abstinence
MDD was predicted to increase the chance of relapse into substance dependence
when studied in time-varying fashion, since drinking to cope with negative
emotions predicts onset of alcohol dependence.19
SUBJECTS AND METHODS
SUBJECTS
Subjects were inpatients in a dual-diagnosis facility who were not severely
psychotic or medically ill. Of 379 patients invited to participate, 349 (92%)
participated in a baseline evaluation. Of these, 279 patients were of interest
to the present analysis because they had a current diagnosis at baseline of DSM-IV alcohol, cocaine, and/or heroin dependence and never
experienced mania or nonaffective psychosis. Of these patients, 250 (90%)
participated in at least 1 follow-up interview. These are the patients described
herein. Subjects were not required to meet criteria for MDD because we wanted
to compare patients with and without this disorder.
The mean ± SD age of subjects was 36.9 ± 9.2 years, 66%
were male, 57% were white, 15% did not complete high school, and 31% were
married. At baseline, 75% met DSM-IV criteria for
alcohol dependence, 58% for cocaine dependence, and 20% for heroin dependence.
PROCEDURES
Following institutional review board requirements, clinical staff identified
eligible, sequentially admitted patients (who had completed acute withdrawal,
if applicable) and obtained their agreement to meet with research staff, at
which time the study was explained. Consenting subjects participated in a
baseline Psychiatric Research Interview for Substance and Mental Disorders
(PRISM).20-21 In the PRISM, the
drug and alcohol sections are completed before assessment of psychiatric disorders.
A PRISM test-retest study using the version for DSM-IV
substance use disorders and DSM-III-R psychiatric
disorders showed higher reliability than other diagnostic interviews in this
type of sample.20 Lifetime onset of any disorder
was defined as the age when the full disorder was first present. Age at lifetime
onset of MDD was used to create a prior-onset MDD diagnosis, representing
major depression with onset before the lifetime onset of alcohol, cocaine,
or heroin dependence. As a lifetime diagnosis, prior-onset MDD was diagnosed
regardless of current status.
In the PRISM, abstinence MDD either occurred entirely during abstinence,
began at least 2 weeks prior to a period of heavy drinking and/or drug use,
or began during drinking and/or heavy drug use and continued more than 4 weeks
after the substance use ended. Some baseline episodes were diagnosed as abstinence
MDD in subjects currently dependent on alcohol or drugs because the depressive
episodes began before the current substance dependence episodes or continued
into the follow-up at least 4 weeks after cessation of substance use.
Substance-induced disorders in DSM-IV occur
during periods of heavy substance use with symptoms in excess
of (greater than the expected effects of) intoxication or withdrawal
syndromes. PRISM episodes of substance-induced MDD included those occurring
entirely during periods of substance use as well as episodes ending within
a month of abstinence. To systematize this diagnosis, we required the same
duration and number of symptoms as required for DSM-IV
primary MDD. To systematize rating symptoms in excess of expected intoxication
or withdrawal effects, we used the subject's own substance-using but nondepressed
experience as a reference period (most often, a period of substance use immediately
preceding onset of depressed mood). Symptoms during this reference period
represented the subject's expected intoxication or withdrawal effects. Symptoms
that began or became clearly worse only after the onset of depressed mood
were counted toward a diagnosis of substance-induced MDD. Only depressive
symptoms cross-listed as DSM-IV intoxication or withdrawal
symptoms for substances used by the patient were rated this way.
Subjects could report past episodes of both abstinence and substance-induced
MDD. However, we studied MDD current at baseline to provide close, prospective
examination of its relationship to the course of substance dependence.
Follow-up interviews were conducted 6, 12, and 18 months after baseline.
Subjects were paid US $35. Subjects not interviewed when due were interviewed
later whenever possible. Median length of follow-up was 91 weeks. Bias from
loss to follow-up was unlikely because of the high follow-up rate and lack
of differences between subjects followed up and not followed up for age (t274 = 0.29, P = .77); sex ( 21 = .004, P = .95); race (21 = .71, P = .40); education (22 = 3.52, P = .17); baseline diagnoses of DSM-IV cocaine (21 = .55, P = .46), heroin (21 = .27, P = .60), and alcohol dependence (21 = .038, P = .85); antisocial personality
disorder (21 = 1.09, P
= .30); prior-onset MDD (21 = .01, P = .94); baseline abstinence-induced MDD (21 = 1.14, P = .29); or baseline substance-induced
MDD (21 = .65, P = .42).
At follow-up, subjects participated in a PRISM-L (longitudinal),21 a version of the PRISM covering the period since
the previous interview. The PRISM-L includes elements of the Longitudinal
Interval Follow-up Evaluation22 and also substance
abuse timeline follow-back methods.23-24
PRISM-L timeline grids allow rating the course of separate conditions (including
substance use, dependence, and depression) by week after study entry. Interviewers
obtain a history since the previous interview and then assess the timing of
alcohol and drug use, dependence and abuse symptoms, and psychiatric syndromes,
referring to the timing of life events as needed. When the relative timing
of substance and psychiatric disorders was unclear, semistructured probes
aided systematic exploration.
Interviewers had clinical experience and received extensive, systematic
training. Two supervisors with several years of research experience conducted
training and supervision. They reviewed each case, conferred occasionally
with members of Columbia's Department of Psychiatry and conducted weekly interviewer
calibration meetings. Supervisors occasionally blindly reviewed each other's
cases to ensure review consistency. After data entry and cleaning, computer
programs produced diagnoses as well as the follow-up onset and offset variables.
OUTCOME MEASURES USED IN THE ANALYSIS
Remission of substance dependence was defined
as 26 or more weeks during follow-up with no symptoms of dependence on heroin,
cocaine, or alcohol, a definition that guarded against substance substitution
and provided periods with stability.16 The
start date of a remission was the first of the 26 or more required weeks. Relapse was defined as 1 or more weeks when patients experienced
symptoms of DSM-IV dependence or abuse for alcohol,
cocaine, or heroin dependence after the 26th week of remission from dependence.
We also investigated 3 outcomes defined by use. The first was remission
for 26 or more weeks in any use of alcohol, cocaine, or heroin. The second
included relapse from such remission, meaning any use of alcohol, cocaine,
or heroin any time after 26 weeks or more of remission. The third was time
from discharge to first use of alcohol, cocaine, or heroin.
STATISTICAL ANALYSIS
Survival analysis was used to investigate these outcomes: weeks from
hospital discharge to remission of dependence and remission of use as defined
already, weeks from establishment of stable remission (ie, the 26th week of
remission) to subsequent relapse into dependence and relapse into use, and
weeks from inpatient discharge to first use of alcohol, cocaine, or heroin
after discharge. The cumulative probabilities of remission and survival curves
of relapse were obtained with Kaplan-Meier estimates. Cox proportional hazard
models were used to examine the effect of time-invariant and time-varying
predictors. Cases were censored if they did not experience an event by the
end of the follow-up, including those lost to death or follow-up. Time-invariant
predictors used in the Cox models included age, sex, race, education, baseline DSM-IV diagnoses of alcohol, cocaine, and heroin dependence,
antisocial personality disorder with symptoms in the year prior to the interview,
and prior-onset MDD. Note that prior-onset MDD was tested independently of
current MDD status. Thus, it characterized an unchanging aspect of lifetime
history, regardless of current status. The models compared the effects of
prior-onset MDD to the absence of such a history.
Time-varying predictors indicated the effects of change in MDD on subsequent
outcome of dependence. The 2 time-varying predictors were the status of substance-induced
MDD (present or absent) and the status of abstinence MDD (present or absent).
These 2 types of depression were mutually exclusive at any point in time and
were examined separately to determine their unique effects on remission. The
basis of comparison for each type of depression was the absence of depression.
Only abstinence MDD was tested in relation to relapse, since substance-induced
MDD could not start during remission. Tests were 2-tailed with  = .05.
Because time in a restrained environment is not remission, the follow-up period
for the 138 patients hospitalized longer than a week after their baseline
interview began the week of discharge.
RESULTS
DEPRESSION DIAGNOSES
Of the 250 patients, 37 (15%) received a lifetime diagnosis of prior-onset
MDD. At baseline, 18 (49%) of 37 patients with prior-onset MDD had current
abstinence MDD, while 12 (32%) of 37 had current substance-induced MDD. Thus,
most patients with prior-onset MDD had a current diagnosis of MDD. The average
age at onset of prior-onset MDD was 16.7 years. Since the average age of the
37 patients with prior-onset MDD was 36.0 years, MDD first occurred on average
19.3 years previously.
Of the 213 patients with no lifetime diagnosis of prior-onset MDD, 60
(28%) had baseline diagnoses of abstinence MDD and 50 (24%) had current substance-induced
MDD. Subjects with prior-onset MDD were more likely to have any current diagnosis
of MDD at baseline than those without prior-onset MDD (21 = 4.41, P = .04) and also were more likely
to have baseline abstinence MDD (21 = 6.16, P = .01). Those with and without prior-onset MDD did not
differ on substance-induced MDD (21 = 1.36, P = .24). The Cox proportional hazards models (below) allowed
us to study the effects of current depression controlling for
prior-onset MDD.
REMISSION FROM DEPENDENCE
Among the 250 patients, 133 (53%) had a remission of all dependence
symptoms lasting at least 26 weeks. Figure
1 shows the Kaplan-Meier estimates of cumulative probabilities of
remission from dependence. The cumulative probability curve reached its plateau
of 57.1% at week 100. Prior-onset MDD decreased the likelihood of stable remission
from substance dependence compared with patients without such a history (Table 1). Time-varying substance-induced
MDD decreased the likelihood of stable remission from substance dependence
compared with subjects with no current MDD. Abstinence MDD was not related
to remission of dependence.
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Figure 1. Time to remission, cumulative
probabilities.
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Association of Major Depression With Time to Outcome of Substance Dependence
or Use for 250 Patients*
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REMISSION FROM USE
Among the 250 patients, 117 (47%) remitted from alcohol, cocaine, and/or
heroin use for at least 26 consecutive weeks. Figure 1 shows the Kaplan-Meier estimates of cumulative probabilities
of remission from use. The MDD diagnoses were not associated with time to
remission in substance use (Table 1).
RELAPSE INTO DEPENDENCE
Among the 133 patients who remitted from dependence, 45 relapsed during
the follow-up, leaving only 88 (35%) of the 250 patients with dependence remission
from all 3 substances throughout the follow-up. Figure 2 shows the Kaplan-Meier estimates of survival probabilities
of relapse into dependence. As shown in Table 1, abstinence MDD increased the risk of relapse into dependence
by a factor of about 3, thus constituting an important risk factor for dependence
relapse.
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Figure 2. Relapse after stable remission,
survival curves.
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RELAPSE INTO USE
Among the 250 patients, 205 (82%) reported substance use after discharge.
Of the 117 with remission of use lasting 26 weeks or more, 52 relapsed into
use of alcohol, cocaine, and/or heroin, leaving only 65 (26%) of the 250 patients
with stable remission from use lasting 26 weeks or more. Figure 2 shows the Kaplan-Meier estimates of cumulative probabilities
of relapse into use. As shown in Table 1, neither prior-onset MDD nor abstinence MDD was associated with
relapse into use. However, abstinence MDD was related to risk of use after
hospital discharge. Figure 3 shows
the Kaplan-Meier estimates of survival probabilities of substance use after
hospital discharge.
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Figure 3. Time from discharge to substance
use, survival curve.
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COMMENT
Under all 3 temporal circumstances studied, major depression was related
to the course of substance dependence, including lifetime onset prior to substance
dependence, during periods of abstinence and periods of substance use when
symptoms clearly exceeded the effects of intoxication and/or withdrawal. However,
the effects of MDD were not uniform across the outcomes and circumstances.
Prior-onset MDD was associated with reduced likelihood of remission of substance
dependence, as was substance-induced MDD current at baseline. No depression
variable was associated with stable remission in use. Abstinence MDD was associated
with substance use after hospital discharge and relapse into dependence after
a stable remission. Prior-onset MDD was not related to relapse.
The data support the DSM-IV primary and substance-induced
distinctions as well as distinction between prior-onset and abstinence depressions
because different types of depression were related to different aspects of
outcome. While we did not predict the association of prior-onset MDD with
remission from substance dependence because of its distal nature, prior-onset
MDD reduced the likelihood of dependence remission even with current MDD in
the model. As noted, prior-onset MDD began at about age 16 years. This early
MDD may cause distinct psychosocial disability, contributing to difficulties
in achieving remission from substance dependence. The time-varying course
of substance-induced MDD also decreased the likelihood of dependence remission.
Substance-induced MDD may place an additional proximal burden on individuals
trying to recover from dependence that may interfere with activities or efforts
needed to achieve sustained remission.
The effects of abstinence MDD on relapse might occur several ways. It
may reduce energy needed to refrain from drug and/or alcohol use. Feeling
worse during abstinence than when using substances due to depression may reduce
motivation to continue abstinence efforts. Depression may lead to self-medication.25-26 Aspects of MDD may become conditioned
cues for drug use, continuing to prompt drug cravings during abstinence.27 Abstinence MDD may also reflect preexisting negative
thinking that presents a common risk for depression and relapse. Consistent
with this, antidepressants for depression during treatment for alcoholism28-32
or drug addiction29, 33 improve
depression and modestly improve substance abuse.
We analyzed abstinence and substance-induced MDD as separate variables,
finding distinct effects. Combining them would have attenuated the ability
to show an effect. This supports the utility of the DSM-IV primary vs substance-induced distinction. Our approach also supported
differentiation between lifetime primary-onset and abstinence MDD. If these
types of depression are truly different, combining them limits the ability
to understand each one. Note that effects were found controlling for baseline
dependence on all 3 substances, using an outcome defined by remission from
all 3 substances. This eliminated questions about substance switching.
Several methodological limitations warrant comment. Our results were
based on naturalistic findings in treated inpatients. To generalize the results,
untreated subjects and different types of patients need to be studied. Also,
this study did not include urine samples or informant reports. However, in
the absence of sanctions, reports of drug use tend to be accurate.34 Only a few patients reported sustained remission
from alcohol and/or drug use without relapse, so the scope of disclosure suggests
relatively accurate reporting. Finally, we analyzed remissions lasting at
least 26 weeks because we wanted periods with stability. Analyzing longer
remissions would require longer follow-ups.
Investigators differ on the best outcome indicators in substance abuse
research. We separated remission from relapse to study whether their predictors
differed. We also analyzed dependence and use separately. Individuals can
stop manifesting dependence symptoms while decreasing but not ceasing use,
as indicated by the proportion of untreated drinkers with past-only alcohol
dependence.35 However, in the clinical sphere,
many think that a harm reduction strategy leaves patients vulnerable for relapse.
Therefore, investigating predictors of sustained abstinence is important.
Difficulty diagnosing MDD in alcohol and drug patients has led to inconsistencies
in the relationship of depression to substance outcome. This study presented
evidence of differential effects of major depression occurring under different
temporal relationships to substance dependence. Research on the reasons for
differences in the effects (for example, effects of different levels or types
of disability) may yield clinically useful information. We suggest that future
studies on these issues be conducted.
AUTHOR INFORMATION
Accepted for publication August 13, 2001.
The study was supported by grant R01 DA 08409 from the National Institute
on Drug Abuse, Bethesda, Md, grant AA K02 AA00151 from the National Institute
on Alcohol Abuse and Alcoholism, Bethesda, and by the New York State Psychiatric
Institute.
Corresponding author and reprints: Deborah Hasin, PhD, Columbia University/New
York State Psychiatric Institute, 1051 Riverside Dr, Box 123, New York, NY
10032 (e-mail: dsh2{at}columbia.edu).
From the Mailman School of Public Health, Divisions of Epidemiology
(Dr Hasin) and Biostatistics (Drs Hasin, Liu, and Endicott); College of Physicians
and Surgeons, Department of Psychiatry (Drs Hasin and Nunes), Columbia University;
and New York State Psychiatric Institute (Dr Hasin, Liu, Nunes, and Endicott
and Mr McCloud and Ms Samet), New York, New York.
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