Introduction

Globally, the use of opiates had affected 16.5 million people, or 0.4% of the population aged between 15 to 64 years old. High prevalence of its use reported in the regions of South-West and Central Asia, Eastern and South-Eastern Europe as well as North America [1]. In Malaysia, the cumulative number of registered substance abusers between 1988 to 2006 was 300,241 and 60.7% of them were opioid users. In the number had increased to 75% [2]. Methadone Maintenance Therapy (MMT) program was introduced in 2005 as part of the National Harm Reduction Program in Malaysia in response to rising numbers of opioid users [3]. Methadone has several adverse effects which include nausea, vomiting, constipation, drowsiness, abdominal pain, QTc prolongation, and sexual dysfunction [4]. Among the commonest side effect of sexual dysfunction is erectile dysfunction. A systemic review and meta-analysis involving 17 studies demonstrated that testosterone level was suppressed in men with chronic and regular opioid use which leads to ED [5]. Earlier studies have reported that higher methadone dosage (80-150 mg/day) was associated with lower plasma testosterone [6]. Studies had been more consistent in reporting no correlation between the duration of methadone treatment and ED [7,8].

Testosterone deficiency symptoms are fatigue, weakness, mood disturbances, and sexual problems such as a decrease in libido and erectile dysfunction [9]. The chronic stimulation of the μ-opioid receptors by methadone also alters the function of the tuberoinfundibular axis and the dopaminergic control of prolactin, with a consequential impact on sexual functioning [10]. Among methadone clients, the worldwide prevalence of ED ranged from 52.8% to 75.7% [11]. In Malaysia, the prevalence of ED in methadone clients was between 67% to 68.5% [12,13]. However, only 3% reported that they had been asked about their sexual relationships by the addiction services [14] and sexual problems were often unexplored and the neglect was more pronounced in Asian populations due to it being regarded as a sensitive subject [15,16].

Major Depressive Disorder (MDD) was the most common mental illness in Malaysia affecting approximately 2.3 million people and the prevalence was estimated to be around 8% and 12% [17]. Globally, the prevalence of MDD ranges between 32.9% to 63.3% among methadone clients [18,19]. In the local setting, MDD was the most prevalent psychiatric disorder in clients on MMT ranging from 10.2% to 44.4% [18,19]. The development of MDD in drug abusers resulted from a familial and social problems as well as biological changes due to prolonged drug use. Studies showed there was significantly smaller grey matter volume (GMV) in multiple cortices, especially in the left inferior frontal gyrus and left cerebellar vermis in the MMT group compared to healthy subjects [20-22]. The smaller GMV in the pre-frontal cortices, left subcallosal, left insula, left post-central gyrus, cingulate gyrus, and right cerebellar declive correlated with higher depression scores. Thus there were significant structural differences in the emotion circuit and cerebellum between heroin-dependent patients on MMT and healthy controls [23,24]

Hallinan et al found that men on MMT had a high prevalence of ED, related to hypogonadism and depression compared to clients on Buprenorphine Maintenance Treatment. In a cross-national study conducted in Brazil, Italy, Japan, and Malaysia, depression was shown to be associated with erectile dysfunction and those with erectile dysfunction were 2.09 times more likely to have depression [25]. Similarly, Shiri et al., found a strong association between depressive symptoms and ED and this relationship was also bidirectional [26]. Also found a strong relationship between psychological distress and ED [27]. However, local studies showed contradicting results whereby it found no association between ED and depression among MMT clients. Hence, to resolve the disparity, this study aimed to determine the prevalence of MDD and its association with ED among MMT clients.

Methods

This was a cross-sectional observational study using a simple random sampling method conducted in Hospital Tengku Ampuan Rahimah (HTAR). Methadone Maintenance Therapy Outpatient clinic in HTAR has been established for about 15 years, led by an addiction psychiatrist, medical officers, nurses, and medical attendants with total registered male clients of 236. The participants of the study were recruited within the period between 1st Jun 2020 to 31st August 2020. The inclusion criteria were clients who were 18 years old and above having a sexual partner (defined as a person engaged in sexual activity with the client) and able to give informed consent and understand Malay or English language. Clients who were experiencing withdrawal, intoxication, active psychosis, irritable or agitated were excluded. Clients with an existing diagnosis of erectile dysfunction were excluded. Clients having chronic and severe medical illnesses such as chronic cardiovascular disease, cerebrovascular disease, respiratory disease, renal disease, urinary tract disease, autoimmune disease, and malignancy were excluded. Ethics approval was obtained from the Ministry of Health Medical Research and Ethics Committee (KKM/NIHSEC/P20-89(8) and Universiti Teknologi MARA Research Ethics Committee (REC/03/2020 FB/46).

The clients attending Methadone outpatient clinic who fulfilled the selection criteria and consented to participate in the study were given the Patient Health Questionnaire-9 (PHQ-9) and the International Index of Erectile Function-5 (IIEF-5) scale meanwhile the socio-demographic and clinical factors questionnaires were filled up by the researcher. The Patient Health Questionnaire-9 (PHQ-9 is a self-administered questionnaire used to screen the presence and the severity of depression [28]. The Malay version of PHQ-9 developed by Sherina et al was used [29]. Those who scored four and above for depressive symptoms were interviewed using MINI Neuropsychiatry Interview (MINI) 6.0 to confirm the diagnosis of MDD.

The MINI is a short, structured diagnostic interview tool for psychiatric disorders in Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) and International Classification of Diseases-Tenth Edition (ICD 10) which was developed by Sheehan and colleagues in 1998 [30,31]. The translated MINI Malay version is acceptable and clinically relevant in making a diagnosis of major depressive disorder [32]. The International Index of Erectile Function-5 (IIEF-5) was given to assess for erectile dysfunction. It was developed by Raymond C. Rosen in 1996. The erectile function was explored using an abridged five-item version of the International Index of Erectile Function (IIEF-5), a self-administered questionnaire that explores the quality of erectile function and sexual intercourse confidence and satisfaction for the past six months [33]. The validated in Malay version developed by was used.

The data were analyzed using the Statistical Package for Social Sciences (SPSS) version 25.0 (IBM). Variables were described as mean ± standard deviation (±SD) for continuous data and number (n) and percentage for dichotomous or nominal data. The factors associated with MDD were analyzed using simple logistic regression (SLogR) followed by the hierarchical method of multiple logistic regression (MLogR). The socio-demographic factors, clinical factors, and presence of ED being the independent variables were entered into the SLogR. Variables with a p-value of less than 0.25 from the SLogR were subsequently included in the MLogR analysis. Model fitness was checked using the Hosmer-Lemeshow goodness of fit test. Confounders were adjusted; interactions, multicollinearity, and assumptions were also checked. The p-value of less than 0.05 with a confidence interval of 95% was taken as statistically significant.

Results

Prevalence of MDD and ED

74 participants had mild to severe depressive symptoms on the PHQ-9 and among them 30.6% (n=49) (95% CI: 23.5–37.7) were diagnosed to have major depressive disorder. The prevalence of ED in this study was 72.5% (n=116) (95% CI: 65.6–79.4). There were 40 % of the participants (95% CI: 27–52.0) who had a mild degree of erectile dysfunction and 22.5 % (95% CI: 16.0–30.0) of them had mild to moderate level of erectile dysfunction. While 8.1% (95% CI: 2.0–14.0) of them had moderate erectile dysfunction and 1.9% (95% CI: 2.3–3.5%) had severe erectile dysfunction.

Sociodemographic and Clinical Characteristic

A total of 160 participants were involved in this study with the age ranging from 25 to 76 years old. The sociodemographic characteristics and clinical features are shown in Table 1. About two-thirds of the participants were more than 40 years old with a mean age of 44.81 ± 10.2 years. More than two-thirds of the participants were Malay (70%) and 71.2% were employed. 65% of the articipants received a secondary education and 3% received tertiary education. Employment profiling revealed that 114 (71.2%) were employed and 46 (28.8%) were unemployed.

Table 1. Background characteristics of the patients (N=160)

The duration of methadone use was between one month to 15 years and the mean duration of usage was 4.83 (±3.71) years. The methadone dose prescribed was between 2 to 130 mg and the mean methadone dose is 54.22 (±26.93) mg. More than three-quarters of the clients were smokers (133; 83.1%) and 44.4% of clients were concomitantly using other illicit substances. 42.2% of clients took heroin, followed by alcohol (27%), stimulant (22.5%), benzodiazepine (7%), and cannabis (1%). There were 40% (64 clients) of the clients have existing comorbid medical illnesses with the highest recorded comorbidity was hepatitis C (56.2%) followed by hypertension (36%), HIV (29.6%), hepatitis B (9%), Diabetes mellitus (6%) and dyslipidaemia (4%). The results of bivariate analysis between sociodemographic factors with MDD. In the socio-demographic characteristics, there were three significant factors have been found. These were age (OR: 2.2 (95% CI: 1.03-4.63), p: 0.04), employment status (OR: 0.26 (95%CI: 0.12-0.53), p <0.001) and income (OR: 0.37 (95% CI: 0.18-0.76), p: 0.006). The other factors were not statistically significant (Table 2).

Table 2. Association between sociodemographic characteristics and major depressive disorder (N=160)

Factors Associated With MDD in MMT Clients

The results of bivariate analysis between clinical factors with MDD. There were seven significant factors have been found. There were: smoking status (OR: 0.4 95% (CI: 0.17-0.93), p: 0.03), stimulant usage (OR: 3.34 (95% CI: 1.17-9.58), p: 0.019), heroin usage (OR: 3.36 (95% CI: 1.48-7.61), p: 0.003), benzodiazepines usage (OR: 9.78 (95%CI: 1.06, 89.90), p=0.03), Hepatitis C status (OR: 2.2 (95% CI: 1.02-4.75), p=0.041), HIV status (OR: 8.48 (95%CI: 2.85- 25.23), p:<0.001) and ED (OR: 14.30 (95% CI: 2.3.30, 61.97), p:<0.001) (Table 3).

Table 3: Association between clinical factors and major depressive disorder (N=160)

The bivariate analysis had identified variables as potential covariates for the multivariate analysis at an alpha level of 0.25. In multiple logistic regression analysis, adding the erectile dysfunction to the first model explained 19.9% (Nagelkerke R2) of variance in major depressive disorder. In this model, erectile dysfunction was noted to be a factor contributing to MDD. Adding the sociodemographic characteristics to the second model explained 29.6% (Nagelkerke R2) of variance in major depressive disorder. In this model, the significant predictors were identified to be erectile dysfunction and employment status. In the third model, adding the substance usages explained 41.2% (Nagelkerke R2) of variance in major depressive disorder. In this model, the significant predictors were identified to be erectile dysfunction, smoking, and heroin usage. While adding the medical comorbidities in the fourth model (final model) explained 43.7% (Nagelkerke R2) of variance in the major depressive disorder. The final model indicated that smoking and erectile dysfunction are the factors contributing to major depressive disorder in this study. The summary of the final model is shown in (Table 4).