Available online at Drug and Alcohol Dependence 92 (2008) 79 85

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1 Available online at Drug and Alcohol Dependence 92 (2008) Association between improvement in depression, reduced benzodiazepine (BDZ) abuse, and increased psychotropic medication use in methadone maintenance treatment (MMT) patients Shaul Schreiber a,b,1, Einat Peles a,,1, Miriam Adelson a a Dr. Miriam & Sheldon G. Adelson Clinic for Drug Abuse, Treatment & Research, Tel-Aviv Sourasky Medical Center, 1 Henrietta Szold St., Tel-Aviv 64924, Israel b Department of Psychiatry, Tel-Aviv Sourasky Medical Center & Tel Aviv University Sackler Faculty of Medicine, Tel Aviv, Israel Received 31 January 2007; received in revised form 27 June 2007; accepted 27 June 2007 Available online 13 August 2007 Abstract We had evaluated the depressive symptoms severity of 75 former heroin addicts in methadone maintenance treatment (MMT) using the 21-item Hamilton rating scale for depression (21-HAM-D) and re-assessed 63 of them 1.6 ± 0.3 years later. The second mean 21-HAM-D score was lower than the first (11.8 ± 8.4 versus 17.4 ± 6.2, p < ). Benzodiazepine (BDZ) abuse was lower although not significantly (p = 0.06) during the month preceding the second analysis (32/63, 50.8%) than the month preceding the first one (40/63, 63.5%). Psychotropic medication usage was higher at the second assessment than at the first one (50/63, 79.4% versus 27/63, 42.9%, p < ). 21-HAM-D score reduced significantly over time among 13 no psychotropic medication patients (13.5 ± 6.3 versus 6.8 ± 6.8, p = 0.005) and in 27 who started medication following the first assessment (19.3 ± 3.8 versus 11.0 ± 8.4, p < ), but not in those who were already taking any medication before the first assessment (17.7 ± 7.0 versus 15.0 ± 8.0, p = n.s). 21-HAM-D score reduced in all BDZ groups but scores were still highest in the 32 patients who continued BDZ abuse (19.4 ± 5.6 versus 15.2 ± 7.7) followed by 14 who stopped it (16.8 ± 6.4 versus 9.6 ± 9.1) and were lowest in 17 patients who never abused BDZ (14.2 ± 5.2 versus 7.2 ± 6.4) (repeated measured, time and group effect, each p < ). Predictors for being depressed at follow-up were pre-existing depression only. Stopping BDZ abuse and starting psychotropic treatment was associated with a reduction of depressive symptoms among MMT patients Elsevier Ireland Ltd. All rights reserved. Keywords: Depression; 21-HAM-D; Methadone maintenance treatment; Benzodiazepines; Psychiatric disorders; Follow-up 1. Introduction Depression is highly prevalent among methadone maintenance treatment (MMT) patients, ranging between 19% and 74.3% for lifetime depression and 10 30% for current prevalence (Peles et al., 2007; Havard et al., 2006; Teesson et al., 2005; Brienza et al., 2000; Darke and Ross, 1997; Brooner et al., 1997; Hasin and Nunes, 1988; Rounsaville et al., 1982). The differences are related to the methodology of the study, to whether patients have only recently enrolled in treatment programs or had been in treatment for a prolonged period of time, and to Supplementary information related to this report can be found by accessing the online version of this paper at by entering doi: /j.drugalcdep Corresponding author. Tel.: ; fax: address: einatp@tasmc.health.gov.il (E. Peles). 1 Both authors had contributed equally to the manuscript. the level of opioid and other street drugs-abuse (Peles et al., 2007). The prevalence of depression has been found to be lower in out-of-treatment opioid-addicts than in those who are seeking treatment (Rounsaville and Kleber, 1985), and its presence in MMT and in patients within buprenorphine programs has been associated with worse treatment outcome (retention in treatment) and worse long-term prognosis among opiate addicts (Kosten et al., 1986). Thus, prompt diagnosis and treatment of depression in these patients is indicated, for improvement of both their retention in treatment and overall quality of life. The stability of depressive symptoms is also varied between studies. There are studies reporting that depression in drug users remits regardless of treatment (Nunes and Levin, 2004) or with abstinence (Riehman et al., 2002), while other report that depression is also quite resistant to change (Subramaniam et al., 2004; Hesse, 2006). Hesse (2006) found that patients presented sta /$ see front matter 2007 Elsevier Ireland Ltd. All rights reserved. doi: /j.drugalcdep

2 80 S. Schreiber et al. / Drug and Alcohol Dependence 92 (2008) bility from baseline and following 18 months in opiate agonist maintenance treatment, except a minority of very severe drug users at baseline. We recently reported that 50% of 90 former heroin addicts who were current MMT clinic patients (a convenience sample with no exclusion) were diagnosed with concurrent depression. The main risk factors for depression in our group were already being in an MMT program (compared to newly admitted patients), female gender, any concurrent DSM-IV Axis I psychiatric diagnosis, being already on any psychotropic medication treatment, using or abusing BDZ (Ananth and Ghadirian, 1980; Patten et al., 1996), and treatment with methadone dosages >120 mg/day (Peles et al., 2007). In order to assess the stability of the diagnosis of depression in terms of whether or not it is a chronic or a transient feature during treatment in the MMT setting, and to evaluate possible effects of the measures taken following the previous evaluation (referral to psychiatric treatment; vigorous efforts to help patients discontinue BDZ abuse) we re-evaluated all available patients 1.6 ± 0.3 years (range 6 months to 2.1 years) later. We examined changes in depression over time and factors that were associated with these changes. 2. Methods 2.1. Study population During the study period, The Adelson Clinic was treating 300 patients who met criteria similar to those of the U.S. Federal Regulations for entering methadone treatment (i.e., DSM-IV criteria of dependence on multi-selfadministrations of heroin for 1 year or more) and who were admitted to the MMT Clinic in Tel Aviv, Israel, between July 1993 and August Since the beginning of 2004, the use of psychiatric rating scales has been added to the patients general charts review, to accompany the clinical psychiatric assessment (and treatment) of each patient referred to the clinic s psychiatrist (all newly admitted patients and by decision of therapists for those already in treatment). Ninety patients were studied between January 21, 2004 and August 29, 2005 (first assessment). After a mean duration of 1.6 ± 0.3 years (range , between January10, 2006 and March 9, 2006) since the first assessment, we re-assessed the 78 available patients of the original group of 90. For the current analyses we excluded 15 patients who differed from the other 63 by having their first evaluation of depression prior to treatment entry. The study was approved by the local IRB at TASMC (No ). The 12 missing patients were no longer in treatment: 2 decided to undergo detoxification and leave treatment, 3 passed away, 2 were in prison (convicted for felonies performed prior to entering the MMT clinic), 2 were expelled for extremely aggressive behavior (associated with massive abuse of cocaine), 2 dropped out and one had a massive stroke and was transferred to a community rehabilitation institute elsewhere. The characteristics of the current 78-patient cohort (those who completed the 2 questionnaires), as well as of the 63 in analyses patients, did not differ significantly from the 12 patients who left and did not complete the study with respect to demographic characteristics, psychiatric diagnoses, psychotropic medication, and drug abuse on admission, except for their higher rate of hepatitis C positive (61% of the 78, and 65.1% of the 63) compared with 25% only in those who left (p = 0.03 and p = 0.02, respectively). All the data collected in their charts throughout the interval since the first evaluation were reviewed and added to the data that had already been studied for the first evaluation (for details see Peles et al., 2007) Questionnaire and clinical assessment The 63 study patients were evaluated for depression clinically and the severity of symptoms was assessed by means of the 21-item Hamilton rating scale for depression (21-HAM-D) (Hamilton, 1960). The 21-HAM-D questionnaire evaluates the severity of symptoms associated with depression (e.g., changes in appetite and weight, changes in sleep and activity, lack of energy, feelings of guilt, problems in thinking and in making decisions, and recurring thoughts of death and suicide). Scoring of answers is based on 21 questions: 10 are scored on a Likert scale from 0 to 4, 9 are scored from 0 to 2 and 2 are scored from 0 to 3. The 21-HAM-D score ranges from 0 to 64: a global sum of 18 is indicative of a depressive state. The 21-HAM-D internal reliability of the 21 questions in our 78 patients was Cronbach s alpha = Drugs in urine Each patient s urine tests (taken randomly and observed once weekly) were analyzed for opiates, methadone, cocaine metabolite (benzoylecgonine), benzodiazepines, cannabis (THC), amphetamines and methadone metabolite using enzyme immunoassay systems (DRI and CEDIA for the two latter substances) (Hawks, 1986). Drug abuse was evaluated before the first and second assessments. Positive urine results for drugs during the month prior to filling in each of the questionnaires were recorded. Drug abuse was defined by at least one positive urine test result Methadone dose The maintenance methadone dosage for each study patient was recorded on the day the two questionnaires were completed Data analyses Statistic analyses were done using the SPSS-12 package. We studied the depression severity score as a continuous variable and as a categorical variable (21-HAM-D 18 was defined as depression). The matched pair t-test and repeated measure multivariate analyses were used for changes in the scores (continuous variable) between the two evaluations. The McNemar test (nonparametric for related samples) was used for changes in the categorical variables. Correlations between depression scores and other variables were done using the Pearson correlation. A logistic regression model (multivariate analyses) for the presence of depression was used and included all the variables that were found to be significantly (p < 0.05) associated with depression in the univariate analyses. The adequacy of the model was determined by means of the Hosmer and Lemeshow goodness-of-fit test (chi-square = 3.2, p = 0.8) (Hosmer and Lemeshow, 1980). 3. Results 3.1. Characteristics of study group Characteristics of the 63 patients for whom there were both baseline and follow-up data and comprise the current study cohort are described in Table Drug abuse During the month prior to the first assessment, 40 (63.5%) patients were positive for BDZ compared to 32 (50.8%) patients who were positive for BDZ before the second assessment (McNemar test: exact p two-tailed p = 0.1, one-tailed, p = 0.06). Specifically, 26 (41.3%) continued abusing BDZ, 6 (9.5%) started abusing, 14 (22.2%) stopped abusing, and 17 (27.0%) never abused BDZ. There were no changes in the use of other drugs: 11 (17.5%) were positive for opiates, during the month before the first assessment compared to 7 (11.1%) before the second assessment

3 S. Schreiber et al. / Drug and Alcohol Dependence 92 (2008) Table 1 Characterization of the study group (N = 63) N (%) Gender Male 34 (54.0) Female 29 (46.0) Age at admission (years) 37.3 ± 8.0 a Age at 1st assessment (years) 41.4 ± 8.4 a Place of birth Israel 38 (60.3) Former USSR 21 (33.3) Others 4 (6.3) Being a parent Yes 41 (65.1) No 22 (34.9) Ever drug injectors Yes 49 (77.7) No 14 (22.3) Positive Hepatitis C antibody b Yes 41 (65.1) No 22 (34.9) Positive Hepatitis B antigen Yes 4 (6.3) No 59 (93.7) Positive HIV antibody Yes 3 (4.8) No 57 (90.5) Unknown 3 (4.8) Methadone dose at 1st evaluation mg/day 19 (30.2) >120 mg/day 44 (69.8) Duration of opiate abuse a 20 years 19 (30.6) <20 years 43 (69.4) Psychiatric diagnosis No-DSM-IV Axis I&II 6(9.5) No-DSM-IV Axis I 17 (27.0) Schizophrenia/paranoid disorder 7 (11.1) Affective disorders 10 (15.9) Adjustment disorders 12 (19.0) Anxiety disorders 9 (14.3) Organic disorders 2 (3.2) a Mean ± S.D. b Duration of opiate abuse was unknown in one patient. MMT, methadone maintenance treatment. (McNemar test exact p(two-tailed) = 0.5, p(one-tailed) = 0.2). Two patients (3.2%) were positive for amphetamines during the month before the first assessment compared to none before the second assessment (McNemar test Exact p(twotailed) = 0.5, p(one-tailed) = 0.3). Seven patients (11.1%) were positive for cocaine during the month before the first as well as the second assessment, and 5 (7.9%) patients were positive for cannabis during the month before the first and to the second assessment Prescribed psychotropic medications Twenty-seven (42.9%) of the 63 patients were on any psychotropic medication before the first assessment, while 50 (79.4%) patients were on active psychotropic medication treatment before the second one (McNemar test p < ). Specifically, 13 (20.6%) had never used any psychotropic medication, 27 used it before the first assessment (six had used at least one type and 21 added additional medications, mostly antidepressants, following the first assessment and preceding the second), and 23 (36.5%) used at least one type of psychotropic medication following the first assessment (for details see supplementary material 1 ). The breakdown in the number of patients taking prescribed medications were: 22 used none, 15 used 1 type (e.g., antidepressants or tranquilizers), 14 used 2 different types, 10 used 3 (e.g., antidepressants and antipsychotics and mood stabilizers), 2 used 4 different types of medications HAM-D The mean 21-HAM-D score in the first assessment was 17.4 ± 6.2 (range 0 28). After a mean interval of 1.6 years, it was 11.8 ± 8.4, representing a highly significant reduction of severity of depressive symptoms with time (repeated measures F = 28.4, p < ). At the time of the first assessment, 35 (55.6%) patients were clinically diagnosed as having major depression (and 21-HAM-D score 18), while only 19 (30.2%) patients had clinical major depression at the time of the second one (McNemar test exact p(two-tailed) = (one-tailed) = 0.001). There were several factors that were significantly related to these differences. First, reduction in the 21-HAM-D score between the two evaluations was significant for the 34 males (17.0 ± 5.8 versus 11.9 ± 7.7, paired t = 3.7, p = 0.001) and for 9 pregnant females (19.8 ± 4.5 versus 7.7 ± 7.4, paired t = 4.6, p = 0.002), but not for the 20 non-pregnant females (17.1 ± 7.3 versus 13.5 ± 9.7, paired t = 2, p = 0.06). Second, there was a significant interaction between the time effect and these three groups, but not between groups. When the psychiatric subgroups were evaluated separately, the groups that achieved significant reduction in the 21-HAM-D score over time were the 10 patients with affective disorders (18.3 ± 7.2 versus 13.4 ± 9.5, paired t = 2.8, p = 0.02), the 9 patients diagnosed as having anxiety (19.6 ± 4.0 versus 7.6 ± 5.1, paired t = 4.9, p = 0.001) and the 17 non-axis I psychiatric diagnosis patients (15.1 ± 6.4 versus 11.4 ± 7.1, paired t = 2.5, p = 0.02). Reduction in the 21-HAM-D score was significant over time in the 13 patients with no medication (13.5 ± 6.3 versus 6.8 ± 6.8, paired t = 3.4, p = 0.005), and in those 27 patients who started medication after 1st assessment (19.3 ± 3.8 versus 1 An appendix showing types of medications can be found by accessing the online version of this paper at by entering doi: /j.drugalcdep

4 82 S. Schreiber et al. / Drug and Alcohol Dependence 92 (2008) Table 2a Hamilton score during 1st and 2nd evaluations by variables (repeated measures) N (%) Hamilton score Time effect Group effect 1st questionnaire Follow-up questionnaire F P-value F P-value BDZ groups 63(100) 30.0 < < Never used 17 (27.0) 14.2 ± ± 6.4 Stopped 14 (22.2) 16.8 ± ± 9.1 Current, always/started 32 (50.8) 19.4 ± ± 7.7 Psychiatric diagnosis 63(100) 25.7 < No-DSM-IV Axis I&II 6(9.5) 13.8 ± ± 4.4 No-DSM-IV Axis I 17 (27.0) 15.1 ± ± 7.1 Schizophrenia/paranoid disorder 7 (11.1) 17.1 ± ± 6.7 Affective disorders 10 (15.9) 18.3 ± ± 9.5 Adjustment disorders 12 (19.0) 19.3 ± ± 11.2 Anxiety disorders 9 (14.3) 19.6 ± ± 5.1 Organic disorders 2 (3.2) 23.5 ± ± 12.0 Psychotropic medication use 63 (100) 31 < None 13 (20.6) 13.5 ± ± 6.8 Stated before 1st assessment 27 (42.9) 17.7 ± ± 8.0 Started after 1st assessment 23 (36.5) 19.3 ± ± 8.4 Gender 63 (100) 35.5 < Male 34 (54.0) 17.0 ± ± 7.7 Female 20 (31.7) 17.1 ± ± 9.7 Pregnant female 9 (14.3) 19.8 ± ± 7.4 Methadone dose change 63 (100) 31.9 < Tapered up 13 (20.6) 18.5 ± ± 7.7 Tapered down 25 (39.7) 16.8 ± ± 8.1 No change 25 (39.7) 17.5 ± ± 9.1 Opiate abuse groups 63 (100) 22.3 < Never 46 (73.0) 17.2 ± ± 8.5 Continued 7 (11.1) 21.4 ± ± 8.8 Stopped 10 (15.9) 15.4 ± ± 8.5 Methadone dose at 1st evaluation 63 (100) 27.6 < mg/day 19 (30.2) 15.7 ± ± 7.6 >120 mg/day 44 (69.8) 18.2 ± ± 8.4 BDZ, benzodiazepines; MMT, methadone maintenance treatment ± 8.4, paired t = 4.9, p < ), but with no change over time in those who have already been on psychotropic medication before 1st assessment. There was a significant interaction between the time effect and these three groups, and between groups in repeated measures (Table 2a). Reduction over time in the 21-HAM-D score was significant in the 17 patients who had never abused BDZ, in the 14 patients who succeeded in stopping BDZ abuse, and among the 32 patients who continued BDZ abuse. However, the scores of patients in the BDZ group who always abused BDZ were significantly higher than those who never abused BDZ and from those who stopped abusing BDZ, with no significant differences between the last two. Having a BDZ prescription (versus abusing street-acquired BDZ) was not related to BDZ effect on depressive symptoms (see Table 2b). Reduction in the 21-HAM-D score was significant in 23 no psychotropic medication patients (9.2 ± 7.2 versus 5.9 ± 6.2 paired t = 2.1 p = 0.05) and in 24 patients who started any psychotropic medication following the first evaluation (18.5 ± 5.3 versus 11 ± 8.2 paired t = 4.0 p < ), but the scores did not change over time among those who had not been taking any medication before the first evaluation (20 patients were prescribed psychotropic medications after the first evaluation while 11 did not take them at any time) (16.7 ± 7.5 versus 15.1 ± 7.6 paired t =1p = 0.3). Looking at the 63 patients who already were in MMT, patients with a high methadone dose (>120 mg/day) at the time of the first questionnaire had significantly higher 21-HAM-D scores than patients with a low methadone dose ( 120 mg/day), although the 21-HAM-D scores were reduced significantly for both dose groups. In terms of their opiate abuse status and 21-HAM-D scores, there was a reduction in scores for patients who always abused, never abused or who succeeded in stopping opiates abuse, with no differences between these three groups. The 15 pre-mmt-treatment patients who were all (by definition) opiate abusers, were excluded from these analyses since they were already found to form a different group with respect to depression.

5 S. Schreiber et al. / Drug and Alcohol Dependence 92 (2008) Table 2b Hamilton score during 1st and 2nd evaluations by variables (repeated measures) by BDZ in urine groups and BDZ prescribed/nonprescribed N Hamilton score Time effect Group effect 1st questionnaire Follow-up questionnaire F P-value F P-value BDZ groups Never used ± ± 6.4 Prescribed Non prescribed ± ± 6.6 Stopped ± ± 9.1 Prescribed Non prescribed ± ± 9.3 Current, always/started ± ± 7.2 Prescribed ± ± 8.9 Nonprescribed ± ± Predictors for depression in the follow-up (logistic regression) Predictors for existing depression in the follow-up was only the presence of depression at the time of first evaluation (OR = %CI ). This held true in a model that also included using any psychotropic medication at the time of the first evaluation, BDZ abuse at first evaluation, and any DSM-IV Axis I or II psychiatric diagnosis. 4. Discussion The overall proportion of depressed patients in our MMT clinic is high (55.6%), as in other studies (Peles et al., 2007; Havard et al., 2006; Teesson et al., 2005; Brienza et al., 2000; Darke and Ross, 1997; Brooner et al., 1997; Hasin and Nunes, 1988; Rounsaville et al., 1982). This rate decreased significantly, however, after a mean of 1.6 years in the program (to 30.2%) as expressed by the changes in baseline and follow-up 21-HAM-D scores. The improvement was accompanied with (and may be attributed to) a reduction of BDZ abuse and a significant increase in the proportion of patients who started using psychotropic medications (mostly prescription antidepressants). Importantly, 23 patients (36.5%) were started on psychotropic medication treatment following their first depression assessment. Their depression scores dropped significantly (from 19.3 ± 3.8 at the first evaluation to 11.0 ± 8.4 at the second one), indicating that they represented a group of undiagnosed and untreated depressed patients who benefited from the assessment process and the referral that followed (diagnosis and appropriate antidepressant treatment). The severity of depression of the group of patients who were already taking some kind of antidepressant medication at the time of the first evaluation did not change at the time of the second evaluation. This may raise questions regarding compliance/adherence with the prescribed treatment vis-à-vis the possibility of resistant depression, or the adequacy of the pre-1st evaluation antidepressant drug choice (made by a general practitioner or a specialized psychiatrist, and if so, whether by an addiction-oriented psychiatrist versus a regular one), but these issues are far beyond the scope of the current study. Furthermore, the numbers of patients within the various groups were too small to allow a valid characterization of treatment-resistant patients. Although it would be interesting to investigate what types of antidepressant medications did succeed in helping most of our patients, the small number of patients and medication types as well as the nature of the study design (an observational follow-up and not a randomized controlled trial) again precluded our arriving at any reliable conclusions. Recent recommendations suggest concurrent substance abuse should not be a barrier to treating depression (Whooley and Simon, 2000). Nunes and Levin (2004) published a meta analysis that included four MMT controlled clinical trial studies: Nunes et al. (1998) and Kleber et al. (1983) on imipramine, Carpenter et al. (2004) on sertraline, and Petrakis et al. (1998) on fluoxetine, but only imipramine (Nunes et al., 1998) produced a significant effect compared to placebo. While the latter study (Nunes et al., 1998) showed a low (8%) placebo effect, the other three had a high one (range 29 52%), suggesting that other variables were influencing the outcome. In their meta analysis, Nunes and Levin (2004) explained that high placebo response likely results either from selection of patients with transient depressions that improve without specific treatment or a concurrent psychosocial intervention that exerts substantial antidepressant effects, obscuring effects of medication. While our study was not designed to evaluate any specific antidepressant medication or other treatment modality effect, our results also found general improvement over time. As expected, our group of patients who were not affected by depression and had not taken any medications before the first assessment had only some mild depressive symptoms (with low 21-HAM-D scores) that even decreased (improved) significantly at the time of the second evaluation. This may be attributed to a general improvement in the lifestyle of the patients during MMT, such as discontinuation of illicit BDZ or any other drug of abuse and the improvement in quality of life that accompanies it. Benzodiazepine use/abuse is highly prevalent among drug abusers in general (Kurtz et al., 2005), and is highly prevalent among former heroin addicts currently in MMT programs (Peles et al., 20067; Havard et al., 2006; Teesson et al., 2005; Brienza

6 84 S. Schreiber et al. / Drug and Alcohol Dependence 92 (2008) et al., 2000; Darke and Ross, 1997; Brooner et al., 1997; Hasin and Nunes, 1988; Rounsaville et al., 1982). The mere initiation of BDZ abuse in this population may be attributed to various reasons, and whether it is for self-medication/self-treatment (of anxiety, depression, sleep problems) or in the search of a sensation of euphoria (methadone, unlike heroin, does not induce euphoria) or for both reasons, the abuse of BDZ almost always causes further deterioration of their condition, as we could see from our findings. However, it seems that already having a BDZ prescription was not related to BDZ clinical effects, suggesting a possibly better manipulative ability to obtain prescriptions without clinical indication, rather than a well-diagnosed mental condition for which BDZ are indicated. Indeed, although an improvement in the depression scores were found in all BDZ groups, those who used BDZ during the two evaluations or only at the time of the second one had the highest scores in each time point. While those who never used BDZ had the best 21-HAM-D scores (i.e., not depressed) and, most importantly, patients who abused BDZ at the time of the 1st evaluation but had managed to stop it by the time of the 2nd one showed a significant decrease in their 21-HAM-D scores, achieving figures close to the patients who had never abused BDZ. The significance of these findings is that BDZ abuse not only does not improve depression but also may even induce or aggravate existing depression. Evaluation of the improvement of 21-HAM-D scores according to subgroups of psychiatric illness revealed that the depressive symptoms of the no DSM-IV Axis I psychiatric diagnosis group, anxiety group, and the affective disorders group, had the most significant improvement, while the other groups (i.e., schizophrenic/paranoidal, and non-dsm-iv Axis I and II diagnosis) did not achieve a level of significance (might be because of the small sample size). The pregnant female patients who were admitted to our MMT program suffered from a worse depressive state than the nonpregnant females (Peles et al., 2007). Importantly, depression scores in the follow-up evaluation improved significantly among this group, a finding in concordance with the rates of high retention and discontinuation of illicit drug abuse that were already reported in this group (Peles and Adelson, 2006). In the current study, this group had low rates of BDZ abuse (i.e., 55.6% of the pregnant patients never abused BDZ compared to 30% of the non-pregnant females and 17.6% of the males). While depression scores also improved in males, they did not get better among the non-pregnant females. In terms of gender differences, 76.5% of males in our study used any psychotropic medications compared to 85% of the non-pregnant females and 77.8% of the pregnant ones. Also, 35.3% of the males, 20% of the nonpregnant females and 11.1% of the pregnant patients had no DSM-IV Axis I psychiatric diagnosis. One of the factors that were significantly associated with the level of depression was high methadone dosage. Thus, the follow-up findings showed that there was no significant change in the methadone treatment dosages: 21-HAM-D scores independently improved in all of them, even in those whose methadone dosages were tapered up or down (for clinical reasons) or did not change. We can conclude with a high level of confidence that methadone dosage is not the cause of, nor is it a treatment for depression, and that the association between high methadone doses and depression is rather related to the finding that high methadone doses may serve as a marker of multiple problems (i.e., chronic pain, sleep complaints, etc.) and not as an inducer (Peles et al., 2005, 2006, 2007). Metzger et al. (1991) reported on more patients engaging in needle-sharing behaviors program, to be depressed than other psychiatric problem group. In contrast, we did not find any differences in depression severity between ever and never drug injectors, or yes and no hepatitis C antibody. We did, however, find a clear correlation between BDZ abuse and the presence of depression, and improvement of the depression associated with BDZ discontinuation. We conclude that depression is highly prevalent among former heroin addicts who are current MMT program patients. Assessment of depression in this population should be part of the basic workup, and prompt antidepressant pharmacological intervention should be considered in parallel with discontinuation of BDZ abuse. 5. Limitation Our study has several limitations that would hamper the possibility of generalizing our findings to other MMT patients. The inclusion of subjects with varying lengths of stay in an MMT program is a serious methodological limitation because one does not know what effect previous time in MMT (a treatment which includes ongoing psychosocial treatment) has on depression scores. Also, varying lengths of time between the first and second assessment of depression is a limitation since length of time between assessments may partially account for changes in severity of depressive symptoms. Since clinical psychiatric evaluation is needed in order to diagnose depression, but quantification of the severity of depressive symptoms is done using various rating scales, results may vary between studies depend on the instruments used for evaluation. Our choice of the rating scales might have biased findings, however, since we used the same tool at both ends, this is minimal. Another caveat of the present study is that although we used the same questionnaire at both evaluations, the interviewer might not have been the same person at both occasions. However, since we had shown a high inter-rater reliability in previous studies (Peles et al., 2007) and the same personnel performed the tests in the present one, we believe that it did not alter results. Conflict of interest All authors declare no conflict of interest that could have had any influence on this work. Acknowledgements We would like to extend thanks to Dr. Y Naumovsky, Dr. V Rados, Dr. V Schmidt, Dr. Z Gitman, Z Balas, D Potik, A Sason, Y Abramsohn, N Caspi, I Cohen, Z Mayzlish, H Israel, and A Mesulam who carry out the clinical work. Last, but not least, Esther Eshkol is thanked for editorial assistance.

7 S. Schreiber et al. / Drug and Alcohol Dependence 92 (2008) This study accompanied our routine clinical work and was carried out without any external funding or financial support. Contributors: S.S. designed the study, wrote the protocol, carried out the clinical study and drafted the manuscript. E.P. designed the study, wrote the protocol, undertook the statistical analysis and drafted the manuscript. M.A. participated in the design of the study and drafted the manuscript. All authors contributed to, have read and approved the final manuscript. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi: /j.drugalcdep References Ananth, J., Ghadirian, A.M., Drug-induced mood disorders. Int. Pharmacopsychiatry 15, Brienza, R.S., Stein, M.D., Chen, M., Gogineni, A., Sobota, M., Maksad, J., Hu, P., Clarke, J., Depression among needle exchange program and methadone maintenance clients. J. Subst. 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