The effect of methadone on depression among addicts: a systematic review and meta-analysis

Background Opioids addiction and misuse are among the major problems in the world today. There have been several preliminary studies examining the effect of methadone on depression among addicts, however, these studies have reported inconsistent and even contradictory results. Therefore, the aim of the present study was to determine the effect of methadone on depression in addicts in Iran and around the world, using a meta-analysis approach. Methods This study was a systematic review and meta-analysis including articles published in the SID, MagIran, IranMedex, IranDoc, Cochrane, Embase, ScienceDirect, Scopus, PubMed and Web of Science databases were searched systematically to find articles published from 2006 to March 2019. Heterogeneity index was determined using the Cochran's test (Qc) and I2. Considering heterogeneity of studies, the random effects model was used to estimate the standardized difference of mean score for depression. Subsequently, the level of depression reduction in Iran and worldwide in the intervention group before and after the testwas measured. Results A total of 19 articles met the inclusion criteria, and were therefore selected for this systematic review and meta-analysis. The sample size of the intervention group in the selected studies was 1948. According to the meta-analysis results, the mean depression score in the intervention group was 26.4 ± 5.6 and 18.4 ± 2.6 before and after intervention respectively, indicating the reducing effect of methadone on depression, and this difference was statistically significant (P < 0.01). Conclusion The results of the present study show that methadone significantly reduces depression in addicts. Therefore, regular methadone use can be part of a drug treatment plan.


Background
Drug addiction and opioids misuse are among some of the key challenges and concerns of contemporary societies; they are even considered as the fourth major societal challenges after nuclear issues, population increase, and environmental pollution [1]. The addiction phenomenon initially reflects an image of a risky individual problem, while it is a social, economic, health, and security concern in different countries [2]. The prevalence of drug addiction is increasing rapidly in Iran and globally, with youth and adolescents making up a large percentage of drug addicts [3]. For instance, the rate of drug abuse has increased 3 times more than the population growth rate in Iran over the past 20 years [4]. Hence, it is important to control addition to opioid among the general population. Considering 1925 km of common border with Afghanistan and Pakistan, which are the major sources Open Access *Correspondence: n_s_514@yahoo.com 3 Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran Full list of author information is available at the end of the article of poppy cultivation and opium and heroin production in the world, Iran is particularly vulnerable, since it is on the path of transit of opiates from these countries to Europe [1]. Heroin, for instance, is expensive and it is difficult to treat its addiction and break its defective cycle, and hence requires a comprehensive treatment system with different approaches of drug therapy, psychotherapy and rehabilitation. Prevention is logically the preferred option compared to treatments. Nowadays, the addiction problem is not only a family concern, but is also a sociodemographic challenge. It has negative effects on the mental health of the addict and addicts and their families [5]. One of the top priorities in today's societies should be to identify addiction-related problems and plan to control and reduce the number of addicts [1].
Nearly 90% of opioid addicts have some form of mental disorder, among which are depression, antisocial personality disorder, and anxiety [6]. According to the diagnostic and statistical manual of mental disorders (4th edition)text revision (DSM-IV-TR), depression is characterized by sadness, low self-confidence, and a lack of interest in any kind of daily activity and enjoyment. Depression can lead to a significant disorder negatively affecting one's personal and social life, and employment. It also disturbs one's daily performance i.e. eating, sleeping and health [7]. Depression may be a sign of helplessness among addicts; it is considered as a barrier to effective behaviors to combat addiction or to exploit coping resources available to substance abusers [8]. The prevalence of major depressive disorder and minor depression among addicts are approximately 50-60% and 10% respectively [9]. Blanchard (2000) studied 872 methadone-treated patients and examined the presence of axis I and II disorders. He demonstrated that if an opioid addict had one of the first axis disorders, would need the drug addiction therapies, and psychotherapy, combined with methadone maintenance treatment (MMT) [10].
Methadone is used as one of the biological therapies for detoxification and maintenance treatment of heroin addiction and other opioid-like substances. The low cost of methadone, along with its high potency in controlling the physical and psychological conditions of opioid-like addiction, has made it a useful drug in the treatment of addicts [11]. Although MMT is considered a form of physical addiction to this drug, it is not considered equal to addiction, since by the regular use of the drug, the patient gets rid of euphoria, hangover and compulsive drug use. Such deification allows the patients to return to their communities and focus on other areas of life [12]. Previous research works have reported inconsistent results on the effect of MMT on addicts' mental health; for instance, some studies have shown that methadone-treated addicts have a high level of mental health problems compared to the general population and most have experienced mood and emotional disorders such as depression and anxiety [13]. In MMT, the substance is administered to patients in an oral syrup in a controlled manner. Experts believe methadone replacement reduces the prevalence of injection drug addiction and dangerous diseases such as AIDS, and on the other hand, breaks the link between drug addicts with drug dealers and decreases the likelihood of delinquency [1].
There have been several preliminary studies on the effect of methadone on depression in addicts, which yielded contradictory results. One of the applications of meta-analysis studies is to respond to these assumptions and resolve such contradictions. Therefore, the aim of the present study is to determine the effect of methadone on depression in addicts in the world using a meta-analysis approach.

Method
This study was a systematic review and meta-analysis including articles published in databases of SID, MagIran, IranMedex and IranDoc and Cochrane, Embase, Sci-enceDirect, Scopus, PubMed and Web of Science (WoS) were searched in order to find relevant articles published from 2006 to 2019 in Persian and English language (In order to access quality articles and present more upto-date results, the desired time frame was selected), matching the selected search keywords. These articles were obtained based on PRISMA statement and the initial article search process, removal of duplicate articles, review of articles in terms of relevance, as well as quality evaluation and finally final extraction of articles.

Literature search
The search strategy involved a series of complementary search methods including a comprehensive search of key bibliographic databases and manual search of reference lists or citations follow-up of identified eligible articles and relevant reviews which would not be captured through the bibliographic databases search. Using relevant search terms developed from Medical Subject Headings (MeSH), Search terms to be used included the following: 'Methadone' , 'Depression' , 'Opioid' , 'Drugs' , ' Addicts' , ' Addiction' , 'Drug Addict' , 'Substance Use' and 'Drug Abuse' .
Words "AND" and "OR" were used in combinations to obtain more comprehensive articles, where "OR" was used for different common names of a disorder and "AND" was employed between words.

Selection criteria
Inclusion criteria included studies that examined the effect of methadone on depression among addicts, interventional studies, clinical trials, studies written in English language or with at least an abstract in English, similarly, the exclusion criteria included pre-prints, irrelevant articles (articles that have studied the effects of methadone on addicts but did not have a depression index), research works without sufficient data, duplicate articles, systematic reviews and meta-analysis works, cross sectional studies, case control studies, cohort studies, case reports, case series, letter to the editor.

Quality evaluation
The Newcastle-Ottawa scale was used to assess quality, The Newcastle-Ottawa Scale (NOS) is a quality assessment tool is recommended by the Cochrane Collaboration [14]. The NOS assigns up to a maximum of nine points for the least risk of bias in three domains: (1) selection of study groups; (2) comparability of groups; and (3) ascertainment of exposure and outcomes for case-control and cohort studies, respectively [14], and 11 scores possible. Eventually, articles scoring < 5 points were classified to low quality. In this meta-analysis, all the articles that obtained five or more points were included.

Data extraction
Data from all articles entered into the meta-analysis were extracted using a different pre-prepared checklist. The checklist included article's title, first author's name, year of publication, place of study, sample size, sample size of intervention group, mean sample before and after intervention, and standard deviation of sample before and after intervention. The type of interventions mentioned in each study are reported in Table 1.

Statistical analysis
Frequency, percentage and standard deviation indices were used to combine the reported results of all of the selected studies. To evaluate the heterogeneity of the research works, the I 2 index test was used. Due to heterogeneity of the studies, the random effects model was used to amalgamate the reported results and conduct the meta-analysis. Low, moderate, and high heterogeneity were indicated by I 2 < 25%, 25% < I 2 < 75%, and I 2 > 75%, respectively. P < 0.05 was considered as the significance level. The Egger's test and corresponding Funnel plots were used to assess the publication bias.

Results
In this work, studies were reviewed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Initially, 1182 articles were identified, and following different PRISMA phases, a number of articles were excluded. Finally, 19 studies were selected for meta-analysis (Fig. 1).
The total amalgamated sample size was 1948. The details of the systematically reviewed studies are provided in Table 1. All studies were clinical trials; Nine articles were written in English and 10 in Persian (Table 1).
Considering the available data, the standardized mean difference indices were used to determine the outcome of the effects of the studies. The standardized mean difference index was used in the meta-analysis of studies where results were reported using standard deviation of mean ± SD. The results of meta-analysis showed that there was heterogeneity between studies and pre-and post-intervention heterogeneity values were I 2 = 99.9 and I 2 = 99.9 respectively; thus, the random effects method was used to amalgamated the reported results of the selected studies and determine an overall outcome.
According to the results of the meta-analysis, the preand post-intervention standardized mean difference in the intervention group was estimated to be 26.5 ± 4.6 and 18.2 ± 4.6, respectively, indicating that methadone reduces depression. The accumulation diagrams (Figs. 2 and 3) show the standardized mean difference index and 95% confidence interval in each study as well as the final estimation of the index obtained from the combination of all results. The diagram demonstrates the weight of each study in the final combined value, and the size of each square is proportional to the weight of each study in the meta-analysis. The horizontal line of each square also denotes a 95% confidence interval. The Egger's test was used to investigate the publication bias in the articles, and the results showed no publication bias in the pre-and post-intervention studies (P = 0.184, P = 0.052, respectively) (Figs. 4 and 5).

Sub-group analysis
According to many studies conducted in Iran, subgroup analysis was performed for studies in Iran and other countries. according to the results of the meta-analysis in Iran, the pre-and post-intervention standardized mean difference in the intervention group was estimated to be 23.9 ± 4.6 and 15.5 ± 3.2 and according to the results of the meta-analysis in other countries, the pre-and post-intervention standardized mean difference in the intervention group was estimated to be 27.8 ± 3.8 and 18.4 ± 4.8, respectively (Table 2).
In order to investigate the effect of heterogeneity factors, meta-regression test was used to determine which factor has the greatest impact on the values of meta-analysis. The two factors of 'sample size' and 'year of publication' were considered in the meta-regression. Results showed that with increasing sample size, mean depression scores increased, whilst mean depression decreased with increasing year of study before intervention (Figs. 6 and 7). Moreover, the mean depression scores increased with increasing sample size, and the mean depression score decreased with increasing years of study after the intervention (Figs. 8 and 9).

Discussion
The lifetime prevalence of substance abuse is about 20% [34]. Nowadays, since drug abuse is one of the most important health problems in societies, health promotion practitioners are still in search of solutions to combat addiction and the associated problems. The aim of this study was thus to determine the effect of methadone on depression in addicts in Iran and around the world using a meta-analysis approach.
The results of this study show that the prevalence of depression among addicts is high, which indicates the impacts of addiction on all aspects of addicts' lives. Therefore, it is necessary to intervene in lifestyle changes, offer regular control of depression in people to prevent the disorder, and reduce its complications. In addition, since depression is primarily preventable and can be controlled and treated in the event of a complication, it is necessary to provide people with complete education about depression and how to prevent its complications, as well as early and timely diagnosis of the complications. Due to the high prevalence of depression among addicts, it is recommended that physicians pay more attention to the symptoms of this disorder among drug abuse patients; education should also be offered through various suitable media with the aim of raising awareness, and to reduce delays in the diagnosis.
The results also show a significant difference between the mean scores of depression severity in the intervention group before and after intervention. The results of the present study reported a mean depression severity of 26.4 ± 5.6 in the patients of the intervention group in the pretest phase, while it was significantly reduced to 18.2 ± 4.6 in the posttest phase.
The most comprehensive study in terms of sample size was the work of Yin et al. [27] in China, which reported the mean severity of depression in the pretest phase as 50.52 ± 10.99 and 48.22 ± 10.06 in the posttest. Furthermore, one of the most high-quality research works (according to the CONOSRT checklist) was conducted by El Hage et al. in Canada [33] which reported the mean severity of depression in the pre-test 34.3 ± 1.5 and the post-test 17.3 ± 2.3; the results are consistent with the overall results of our work.
Depression is characterized by symptoms such as helplessness and hinders the cessation of addiction and the use of available coping resources. However, the results of some studies suggest that treatment of addiction-related 1 Beck depression inventory 2 Goldberg health questionnaire 3 Symptom check list-90-revised 4 Self-rating depression scale 5 Montgomery-asberg depression rating scale  2 Accumulation diagram of studies included in the meta-analysis, using the standardized mean difference index before intervention  their body enzymes can therefore be redirected to more efficient pathways [36].
There have been very few studies comparing the efficacy of methadone maintenance therapy and other common treatments, including non-pharmacological   treatments, on the psychiatric disorders of the population of drug abusers. Evidences from reviewed experimental studies suggest the efficacy of opioid dependence and agonist maintenance therapies, especially methadone maintenance therapy, as a common treatment in most countries [37].
One of the characteristics that makes methadone suitable for the addiction treatment is the efficacy of this drug in eliminating the withdrawal symptoms, that are occurring due to suspension of drugs intake for 24 h or longer. Methadone is a long-acting pure agonist that resides on μ receptors and removes withdrawal symptoms [38]. Broers et al. referred to the role of methadone as a protective factor in reducing injections and common syringe use [39]; similarly, Beoers et al. highlighted the role of methadone treatment in significantly reducing AIDS and hepatitis B and C among addicts [40]. Dolan et al. also reported that methadone therapy (over 60 mg/day) is effective in reducing injections in addicts [41].  In a study comparing two groups of methadone-treated addicts (n = 62), Lollis et al. concluded that methadonetreated groups had less risky sexual partners and were more likely to use safe sex, and there was a significant difference between the two groups in this regard [42]; their findings are consistent with the results of the research work conducted by Gossop et al. [43].
To investigate the effect of factors affecting heterogeneity, the meta-regression test was used for the two factors of 'sample size' and 'year of the study' . The results show that before and after the intervention, with increasing sample size, the average depression scores increase. Moreover, before and after the intervention, with increasing year of study, the average scores of depression decrease, which may be due to the development of treatment and diagnostic methods for depression in recent years.
Methadone use clearly reduces risky behaviors such as injections, tattoos, self-harm, unsafe sexual behaviors, and imprisonment. Given the prevalence of addiction in communities and the detrimental consequences of such high-risk behaviors, particularly transmission of infections such as AIDS, hepatitis B and C, and the associated costs, the development of addiction treatment centers, encouragement of addicts to use therapies offered at these centers, and provision of related facilities are recommended.

Limitations
One of the limitations in some of the articles was the inability to protect the anonymity of patients and therapists, which was not possible due to the nature of oral methadone treatment.
Another limitation of the study was that some samples were not randomly selected. Moreover, among the limitations, the non-uniform reporting of articles, inconsistent implementation methods, and the unavailability of the full text of the papers that has been presented at conferences can be mentioned.

Conclusion
The results of the present study show that methadone significantly reduces depression among substance abusers. It is recommended to treat addicts using methadone under the supervision of a psychiatrist and along with counseling in addiction treatment centers.