Major Depressive Disorder (MDD) is the most prevalent mental health condition, i.e., associated with a severe decline in function, disability, and a 15% risk of suicide. Allopurinol is a potent inhibitor of the enzyme xanthine oxidase and is primarily used to treat hyperuricemia and gout. This drug can increase tryptophan levels in the body by inhibiting xanthine oxidase. Therefore, it can be hypothesized that increasing the level of tryptophan, i.e., a precursor of serotonin can improve the symptoms of depression. Therefore, this study aimed to investigate the impact of allopurinol on MDD.

In this double-blind clinical trial, patients with MDD were randomly divided into two equal groups. Initially, their demographic information, blood uric acid level, liver tests (AST, ALT), and Hamilton Depression Rating Scale (HDRS) were measured. Both study groups received 40 mg of citalopram daily for 6 weeks. In addition to citalopram, the intervention group received 300 mg of allopurinol daily and the control group received a placebo. At the end of the third and sixth weeks, the research patients were re-tested by the HDRS. Furthermore, liver tests were repeated after 2-4 weeks to receive hepatic complications. The HDRS is a clinical assessment scale for measuring depression. Finally, the obtained data were analyzed by SPSS 21, t-test, Chi-squared test, and repeated-measures Analysis of Variance (ANOVA).
 Ethical considerations: This study was registered with the code IR.ARAKMU.REC1394.68 in the Ethics Committee of Arak University of Medical Sciences and with the code IRCT201508277373n6 in the Iranian Clinical Trial Registration Center.

The Mean±SD age of the study subjects was 40.28±9.88 in the control group and 41.93±12.5 in the intervention group. According to the obtained P-value, the study groups were age-matched (P=0.238).



 The Mean±SD score of HDRS in the citalopram group with placebo before treatment was equal to 32.28±2.8 and in the citalopram + allopurinol group, it was calculated as 33.22±3.2. According to the obtained P-value, there was no statistically significant difference respecting depression in both groups. However, 3 weeks after conducting the treatment, the mean HDRS scores in the citalopram and placebo groups were measured as 28.42±3.1, and in the citalopram + allopurinol group, the Mean±SD was obtained as 23.02±3.4. According to the obtained P-value, a significant difference was observed respecting depression in both groups; thus, the citalopram + allopurinol group achieved a lower mean depression score, compared to the citalopram group with placebo. Moreover, 6 weeks after the treatment, the Mean±SD depression score in the citalopram and placebo groups was equal to 23.28±4.1. In the citalopram + allopurinol group, the Mean±SD score of depression was 20.4±1.2. According to the obtained P-value, a statistically significant difference was observed between the research groups; therefore, the intervention group had a lower mean score of depression in HDRS, compared to the controls.

The current research results revealed that the allopurinol plus citalopram group indicated a significantly higher efficacy than the group that received citalopram alone. Caution must also be considered in interpreting the results regarding allopurinol tolerance; it has been evaluated in studies in the acute treatment phase (with a maximum follow-up of 8 weeks). However, its long-term safety in individuals with MDD remains unknown. Although a biological reason for using allopurinol in clinical practice can be found in elevated uric acid levels in subjects with MDD, further research is required to elucidate the role of purine dysfunction in the pathophysiology of MDD. Tryptophan is a cyclic amino acid and a precursor to 5-hydroxytryptamine (serotonin). Tryptophan is metabolized by the enzyme tryptophan pyrolase; this enzyme is also activated by xanthine oxidase. The activity of these enzymes increases the degradation of tryptophan and decreases its level in the body. Besides, tryptophan deficiency has been manifested to cause depressive symptoms in several studies. Allopurinol can increase the level of tryptophan, i.e., a precursor of serotonin, by inhibiting xanthine oxidase. In our study, allopurinol fostered the same mechanism to improve depressive symptoms. According to the present study data, allopurinol adjunct to citalopram provided better therapeutic effects than citalopram plus placebo. Additionally, mental health disorders associated with depression in patients with allopurinol treatment regimens were significantly improved, compared to citalopram and placebo. Moreover, allopurinol can improve depressive symptoms by increasing the level of tryptophan, i.e., a precursor of serotonin. It can also be used as an effective adjunct in treating MDD.

This study was approved by the Ethics Committee of the Arak University of Medical Sciences (Code: IR.ARAKMU.REC.1394.68). Also, it was approved by the Iranian Registry of Clinical Trials (Code: IRCT201508277373n6).

This study was extracted from PhD. dissertation of the first author at the Department of Psychiatry, Faculty of Medicine, Arak University of Medical Sciences, Arak.

All authors have participated in preparing and editing this article.

The authors declared no conflicts of interest

 

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