Lupine Publishers | Scholarly Journal Of Psychology And Behavioral Sciences
Abstract
Introduction: Varenicline is an effective drug approved for
smoking cessation. This study was conducted to evaluate the effect of
Varenicline on depression in smokers treated with methadone.
Methods: The present study was a double-blind randomized
clinical trial that was performed on 60 smokers aged 18-60 years old who were
referred to addiction treatment clinics who had a primary diagnosis of major
depression based on the DSM-5 criteria. Both groups were treated with
Citalopram tablets 20 mg daily for the treatment of depression. For the group
of varenicline for 6 weeks, the first three days 0.5mg, followed by 1mg daily
and the control group was given the same placebo. Both groups were evaluated
using BDI-II by a psychiatrist before the intervention, 3 and 6 weeks after treatment.
Results: The mean and standard deviation of the
depression scores in the Varenicline group and the control after intervention
were 19.74±6.36 and 21.39±6.4 respectively, and the estimated effect size was
0.259, that according to the Cohen table was lower than the mean. There was no
significant difference between the mean depressions scores in the Varenicline
group before intervention 29.85 and in the control group were 30.32. At 3 and 6
weeks after treatment, the depression score in the Varenicline group was lower
than that of the other drug effects; however, this difference was not
statistically significant.
Conclusion: Varenicline is a relatively effective drug for
smokers with depression who are treated with methadone.
Keywords: Depression; Methadone; Varenicline; Nicotine;
Smoking cessation
Introduction
Major depressive disorder is a common,
chronic, and severe disease and community-related research has shown that
between 3-11% of the world’s population suffers from these disorders every year.
It is expected that this disorder will be the second-largest disorder in the
world by 2020 [1]. Depression is a serious and prevalent affective disorder
that surpassed only the consumption of substances and phobias. According to the
World Health Organization, around 121 million people worldwide suffer from this
disorder, and this disorder is one of the major disabling factors around the
world. The risk of life-long depression for women is estimated at 10-25% and
for men 5-12%. Forecasts suggest that, by 2020, depression will be the second
cause of global health damage [2]. Many patients with depression have failed to
receive adequate treatment and many patients despite appropriate treatment, up
to one-third did not improve. Pre-clinical studies show the antidepressive
effects of drugs that target nicotine acetylcholine receptors, which observe
the most consistent results with the regulators of alpha 4 beta 2 nicotinic
receptors such as varenicline and non-specific antagonists such as
Mecamylamine. The regulators of nicotine acetylcholine receptors affect
neurological processes, including the behavioral effects of antidepressants,
such as cell proliferation in the hippocampus. Clinical and pre-clinical
evidence suggests that drugs that target nicotinic acetylcholine receptors may
be an important approach to treating depression [3].
Varenicline is an effective drug for the
nicotinic acetylcholine receptor, which is an alpha 4 beta 2 partial agonist,
and a complete alpha-7 agonist approved for smoking cessation. In tests,
varenicline decreases the symptoms of nicotine withdrawal, including
depression, anxiety, irritability, and sleep disorder [4, 5]. Varenicline in
smoking cessation is effective and safe in treating patients with methadone
[6]. Several pharmacological properties of varenicline are consistent with
potentially potent antidepressants. Varenicline is a structure associated with
plant alkaloid, which antidepressant effects have been found in animal models
[7]. Through the activity of alpha 4 beta 2 nicotinic receptors in the nucleus
accumbens, varenicline was able to modulate the neurotransmitter of dopamine
[8, 9] and anhedonia caused by depression [10, 11]. According to other
evidence, the Nicotine cholinergic system is involved in moderating mood in
depression [12, 13]. These findings have suggested that varenicline has an
independent anti-depressant effect. But evaluations of such effects are not
systematically carried out. Therefore, with regard to the above, this study was
conducted as a randomized clinical trial with the aim of evaluating the effect
of varenicline on major depressive disorder in smokers undergoing methadone
treatment.
Methods
The present study was a randomized,
double-blind clinical trial with the aim of determining the therapeutic effect
of varenicline on the major depressive disorder in smokers undergoing methadone
treatment. In this study, 60 smokers aged 18-60 who referred to Yazd addiction
treatment clinics, primarily diagnosed with depression based on DSM-5 criteria,
were randomly divided into two groups of varenicline and placebo. After a
preliminary assessment and ensuring that the criteria for entry into the study
were approved by the psychiatric assistant, both groups were treated with 20mg
citalopram daily for a period of 6 weeks. On the first three days 0.5mg
Varenicline was administrated (Kosar Pharmaceutical Company), followed by 1mg
of Varenicline daily. The control group was given the same placebo. By fellow
pharmacists, varenicline and placebo (starch) were prepared in similar capsule
form, divided into two groups (A and B) by a pharmacist. Therefore, the
psychiatrist resident, statistics consultant, and patients were not informed
about drugs until the end of the study. Data were collected using the Beck Depression
Inventory-II (BDI-II). It consists of 21 multiple choice questions ranging from
0-3, taking 5-10 minutes to complete. Wahhab and Parto confirmed the diagnostic
value of the questionnaire in Iran in 1973 and 1974. Both groups were evaluated
by the Beck Depression Inventory (BDI-II) by assistant psychiatrists in the
third and sixth weeks. Of course, evaluation of depression score before the
start of treatment was also performed for both groups. At the end of the sixth
week, the drug complications questionnaire was completed by the patient. SPSS
software version 21 was used to analyze data by appropriate statistical methods
including chi-square, t-test, and paired t-test). The significance level was
set at 0.05.
Results
At first 60 patients were enrolled in the
study, 5 of whom were excluded from the study due to discontinuation of the
drug. The results of this study showed that the mean age of patients in the
varenicline group was 37.33±8.52 years and in the control group was 38.18±8.1
years. Also, in the group of varenicline, 26 (96.3%) were male and 1 female
(3.7%) and all controls were male. There were no significant differences
between the two groups regarding age and sex (p <0.05), and the two groups
were similar in age and sex (Table 1). The mean number of years of smoking in
the varenicline group was 18.22 and in the control group was 17.93, and this
case was not significantly different between the two groups (p= 0.91). In the
Varenicline group, 21 (77.8%) were married and 6 (22.2%) were single while 21
(75%) were married, 6 (1.21%) were single and 1 (3.6%) was divorced in the
control group. The marital status did not differ between the two groups (p=
0.61). There is also no significant difference in the level of education
between groups.
Table 1: Patient’s
characteristics: comparison of the control and varenicline group.
The most common complication in the
varenicline group was nausea (44.4%) and dry mouth (33.3%), and in the control
group was nausea (25%) and dry mouth (21.4%). There was no significant
difference between the groups in terms of complications (p>0.05). The mean
and standard deviation of the depression scores in the varenicline group and
the control after intervention were 19.74±6.36 and 21.39±6.4 respectively, and
the estimated effect size was 0.259, the effect size according to the Cohen
table was lower than the mean. The mean score of depression before the
intervention was 29.85 and in the control group, it was 30.32 with no
significant difference. At 3 and 6 weeks after treatment, although the
depression score in the varenicline group was lower than the control group and
the effect of the drug was better than the control group, this difference was
not statistically significant (Table 2). The mean of depression scores in the
varenicline group was 29.85 before the intervention, 23.67 after 3 weeks and
19.74 after 6 weeks. The difference was significant in the varenicline group
using the paired t-test (p= 0.001), and the depression scores of patients were
significant with Varenicline treatment was reduced. In the control group, the
difference was significant before the intervention and after 3 and 6 weeks,
probably due to the treatment of all patients with citalopram, but the decrease
in depression scores in the varenicline group was higher.
Table 2: The
mean Beck Depression test score between the two groups.
Discussion
Varenicline is an effective drug for the
nicotinic acetylcholine receptor, which is an alpha 4 beta 2 partial agonist,
and a full alpha-7 agonist approved for smoking cessation. In tests,
Varenicline decreases the symptoms of nicotine withdrawal, including
depression, anxiety, irritability, and sleep disorder [9,13]. Therefore, the
present study was a double-blind randomized clinical trial with a therapeutic
approach aimed at determining the therapeutic effect of Varenicline on the
major depressive disorder in smokers treated with methadone. The results of
this study showed that the mean depression scores in the varenicline group before
intervention, 3 weeks later and 6 weeks later, despite the fact that depression
score in the Varenicline group was lower than the control group and the effect
of the drug was better than the control group, but this difference was not
significant. But in each group, the mean depression score was significantly
reduced during 3 weeks and 6 weeks after treatment, which was probably due to
the effect of citalopram administration in all patients, but the decrease in
the varenicline group was more than that in the control group. Also, there was
no significant difference in side effects between the two groups in the
evaluation of possible side effects. The most common complication in both
groups was nausea and dry mouth.
The study of Philip et al. was conducted
to investigate the effect of anti-depressant varenicline on depressed
nicotine-dependent patients in 18 patients. In addition to routine treatment,
patients were treated with Varenicline. Varenicline was initially started with
a dose of 0.5mg daily and then titrated to 1 mg twice a day for one week and
lasted for up to 8 weeks if patients were tolerated. Four patients were
excluded from the study due to adverse events, including gastrointestinal
disorders, and worsening mood and irritability. Patients showed a significant
improvement in the final outcome of depression. 44% of the patients responded
to complete treatment and 33% were in the recovery phase, which was categorized
according to the Depression Detection Questionnaire (QIDS-SR). Their study
showed that symptom improvement has been observed since the second week of the
follow-up. One of the differences between the present study and the Philip
study was the sample size, the way depression was assessed in patients, the
duration of the follow-up, and the lack of control group in their study [14].
Unlike the present study, the most common side effects in their study were
sleep disorders. 44% of patients reported insomnia. While in previous studies,
approximately 19% of patients had insomnia and this probably reflects an
interaction between psychotropic drugs and varenicline, which requires
extensive studies.
In another study by Patterson et al.,
prescribing Varenicline in smokers in a double-blind clinical trial, the
Varenicline group showed lower negative affective symptoms compared with the
control group which is in line with the side effects such as dry mouth, nausea
and sleep disorder we found in the patients in this study. However, in their
study, dry mouth, nausea, constipation, and sleep disorders were significantly
higher in the varenicline group [15]. The findings of Avery et al. (2013) on
152 menopausal women showed that patients treated with varenicline had a lower
CESD score (depression scale at the Center for Epidemiological Studies), which
ultimately resulted in the effects of varenicline antidepressants, patient
selection, use of relaxation or unknown cause [16]. Kausch’s study showed that
the administration of varenicline can improve depression and discontinue it in
a smoker can cause recurrence of depressive periods. Their case study was from
a 47-year-old man with chronic depression who was treated with varenicline
because of cessation of smoking and significantly improved his symptoms [17].
In the study conducted by Antennule et al. on 525 adult smokers diagnosed with
depression to evaluate the effect of varenicline on smoking cessation. There
was no significant difference between the two groups in terms of thought or
suicidal behavior, worsening of depression and anxiety. According to the present
study, the most common side effect was nausea [18]. The results of this study
and other studies, together with the evidence for the relative anti-depressant
effect of the α4β2 partial agonist [8], and the evidence of the potential
benefits of nicotinic receptor antagonist for major depression [19], suggest
that varenicline may be effective as a treatment for mood disorders. According
to this study, varenicline can be considered as a relatively effective drug for
smokers treated with methadone with depression. According to the survey, this
study was the first clinical trial to investigate the effect of varenicline on
the treatment of depression in Iran. Considering its positive effect and
decreasing depression score in patients, wider studies with larger sample sizes
in both groups of smokers and non-smokers are recommended for a better
understanding of the potential for anti-depressant effects of varenicline.
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