Increased indolamine 2,3-dioxygenase activity in people with type 2 diabetes and comorbid depression

INTRODUCTION

Diabetes is a major non-communicable disease (NCD) affecting more than 62 million people in India.¹ It is likely to affect nearly 80 million Indians by 2030, turning into a major public health challenge.² Depression is a psychiatric disorder with a lifetime prevalence of 5.2% and is recognized as a common comorbid condition among people with diabetes.^3,4 A meta-analysis concluded that type 2 diabetes mellitus (T2DM) doubles the odds of comorbid depression.⁵ Another meta-analysis showed that people with T2DM had a 24% greater risk of developing depression in comparison with healthy controls.⁶ Depression was also seen to be a common comorbid condition among Indians with diabetes in various studies done in northern India (41%)^7,8 and southern India (49%).⁹

The relationship between diabetes and depression is complex, and a meta-analysis of cohort studies suggested a bidirectional relationship of moderate effect size.¹⁰ The Montreal Evaluation of Diabetes Treatment study, included a cohort of more than 1600 people with T2DM, and suggested a cyclic relationship with depression worsening diabetes and vice-versa.^6,11

However, the exact mechanism of the development of depression in DM is not clearly elucidated. Neurotransmitter imbalance and chronic inflammation are commonly postulated mechanisms. The monoamine hypothesis of depression proposes that depression is related to a deficiency in the amount or function of cortical and limbic neurotransmitters, particularly serotonin (5-HT).¹² 5-HT is derived from tryptophan (TRP) through a complex biochemical pathway. Indolamine-2,3-dioxygenase (IDO) is the rate-limiting enzyme of the kynurenine pathway, the main TRP metabolic pathway that shares TRP with the 5-HT pathway. The enzyme IDO is widely distributed in various tissues, including the brain, lung, heart, kidney, and intestine. It converts TRP to Nformyl-kynurenine, resulting in decreased availability of TRP for central 5-HT synthesis.¹³

Cytokines, such as IFN- α, IFN- β , TNF- α , and IFN- γ , upregulate IDO expression.^14–17 Overstimulation of IDO leads to depletion of plasma concentrations of TRP and, therefore, reduced synthesis of 5-HT in the brain, which may cause the development of depressive symptoms. Thus, inflammation may mediate the development of depression in chronic illnesses.¹⁸ Alteration of TRP metabolism due to the inflammatory response system (IRS) results in decreased synthesis of 5-HT, which may relate to the monoamine hypothesis of depression.

Clinical evidence also links inflammation and depression in the development of comorbid depression in patients receiving cytokine immunotherapy treatment.¹⁹ Further, there are several studies on depression in immune-mediated disorders, chronic diseases like coronary artery disease, chronic renal failure, and chronic infections like tuberculosis and Toxoplasma gondii.^19,20 Patients with chronic inflammatory diseases and major depression have reduced circulating TRP levels and a concomitant increase in IDO metabolites like kynurenine.^21–24 Further, up-regulated IDO expression and activation of the kynurenine pathway lead to the production of a variety of neuroactive metabolites. These kynurenine metabolites may themselves be causative, because the kynurenine to TRP ratio (K/T) is positively associated with depression and anxiety scores.^25,26

Inflammatory processes have also been implicated in the development of diabetes and its complications.^27,28 Various studies have demonstrated significantly high levels of circulating pro-inflammatory cytokines like IL-3, IFN- α , and TNF- α in people with T2DM.^29–31 These cytokines may upregulate IDO expression, which may divert TRP towards the kynurenine pathway and reduce its availability for 5-HT synthesis in the brain, leading to depressive symptoms. This study was therefore designed to evaluate the role of impaired TRP metabolism via altered IDO enzymatic activity to understand the pathophysiological mechanisms of comorbid depression in T2DM.

METHODS

This prospective study was conducted over 2 years, from January 2020 to June 2022. Purposive sampling was followed, and the sample size was determined based on the prevalence of depression in people with diabetes from recent Indian studies.^7–9 Assuming the percentage of depression in people with diabetes at 48%, an absolute error of 10%, and a non-response rate of 10%, a sample of 106 people with diabetes was estimated to screen for depressive symptoms. The patient evaluation was done by the psychiatrist from Dr Ram Manohar Lohia Hospital, New Delhi, and the sample processing was done in the laboratory at the Maulana Azad Medical College, New Delhi.

Study participants were recruited from primary healthcare facilities, which closely mimic community-based parameters compared to tertiary care settings. Patients attending the wellness centres of Delhi Jal Board in Gokalpuri, Delhi, and the Central Government Health Scheme in Timarpur, Delhi, were evaluated for eligibility, and those providing written informed consent were recruited. The study protocol was approved by the ethics committee of Dr Ram Manohar Lohia Hospital, New Delhi, and Maulana Azad Medical College, New Delhi.

The inclusion criteria were people with T2DM of both sexes between the age range of 20 to 60 years, on stable dosages of oral hypoglycaemic agents (OHA) for the past 3 months, with major depression. The exclusion criteria were anti-depressant use for any indication in the past 3 months, major complications of T2DM like retinopathy, nephropathy, uncontrolled hypertension, major psychiatric disorders (such as schizophrenia, bipolar disorder) or substance abuse disorders, pregnancy, depressed subjects having suicidal ideation or gestures or psychotic symptoms or severe agitation, head injury, cerebrovascular disorders, dementia, seizure disorders, mental retardation, and recent myocardial infarction in the past 3 months.

Assessment of depression

Depression was first screened using the Patient Health Questionnaire-2,³² and syndromal depression was confirmed using the ICD-10-DCR, along with a score ≥8 on the HAMD 17-item version.³³ Based on the Hamilton Depression Rating Scale (HAM-D 17 items) rating, depression was further categorised as mild (score 8–13), moderate (score 14–18), and severe depression (score ≥19). These patients were categorised as depressed diabetics, and their details were collected in a predesigned form.

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FIG 1.

Proposed scientific model for depression in type-2 diabetes mellitus through inflammatory pathways. IDO indolamine-2,3-dioxygenase LTRP L-tryptophan

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The subjects were given standard pharmacotherapy (fluoxetine 20 to 40 mg/day) and evaluated again after 16 weeks for a change in HAM-D scores. The quantum of improvement of depressive symptoms as measured by the difference in HAM-D scores between baseline and at 16 weeks was correlated with serum kynurenine and TRP, and their ratio as a marker for IDO activity.

RESULTS

A total of 106 people with diabetes were screened for depressive symptoms, of which 52 (49.05%) were diagnosed with syndromal depression and recruited for the study. The mean (SD) age of the participants was 52.35 (5.12) years, with an equal number of male and female participants (Table 1). On HAM-D rating, 12 participants had mild depression (score 8–13), 29 had moderate depression (score 14–18), and 11 had severe depression (score >19). There was no significant difference between age, sex, marital status, religion, and background between the groups, except for education qualifications between those with mild and severe depression. (p<0.01; Table 1).

The mean (SD) concentration of serum kynurenine and TRP was 372.32 (96.09) ng/ml and 233.98 (161.59) ng/ml, respectively. There was no significant difference in the serum kynurenine and TRP levels among the three groups. The mean K/T ratio was 1.46 (0.83). There was a significantly higher K/T ratio among patients with severe depression (1.75 [1.01]) as compared to those with mild depression (0.97 [0.53]; p<0.05; Table 2). The correlation between the improvement in HAM-D scores at 16 weeks and baseline was statistically significant for serum kynurenine, but not for serum TRP or the K/T ratio (Table 3).

DISCUSSION

Depression is a common comorbid condition among people with T2DM. The relationship between diabetes and depression is complex, and an inflammatory response could be a common underlying pathophysiological mechanism. Our study was designed to evaluate the IDO activity among people with T2DM and comorbid depression. The serum levels of TRP and kynurenine were measured, and their ratio (K/T ratio) was taken as a surrogate marker for measuring IDO activity.

We diagnosed depression among 52 people with T2DM (49%). This finding was comparable with the previous studies from India, which report the prevalence of depression among people with T2DM to range between 41% and 49%.^7–9 Most (55.7%) of these depressed people with T2DM had moderate depression, while 12 (23%) had mild depression, and 11 (21%) had severe depression. A similar study by Chaudhary R et al. from northern India assessed psychiatric manifestations among people with diabetes and reported depression in 42% using HAM-D scores.³⁶

A significantly higher K/T ratio in people with diabetes and severe depression, as compared to those with mild to moderate depression, indicates that higher IDO activity is associated with the severity of depression in people with diabetes. This suggests that the K/T ratio may be a severity marker for depression in T2DM. Previous studies also report high IDO activity among people with T2DM as compared to healthy controls, and it is positively correlated with the severity of diabetic nephropathy.³⁷ Abedi et al. also reported increased IDO activity, as measured by the serum K/T ratio, in people with T2DM who had poor glycaemic control.³⁸ Zaho et al. studied the effect of gestational diabetes on postpartum depression-like behaviour in rats and found a significant increase in expression of IDO and an increase in K/T ratio in the serum and prefrontal cortex of rats showing depression like behaviour.³⁹

To the best of our knowledge, this is the first report demonstrating an association between IDO activity and comorbid depression in people with T2DM, and its findings suggest that depression in people with T2DM may be mediated by the induction of the enzyme IDO, especially in those patients who develop moderate to severe depressive symptoms. The increased IDO activity, as observed with increased K/T ratio, results in activation of the kynurenine pathway of TRP degradation and results in decreased central synthesis of 5-HT, which explains the emergence of depressive symptoms.

The correlation between the improvement of HAM-D scores at 16 weeks and baseline serum kynurenine, TRP, and their ratio was not statistically significant. This suggests that the K/T ratio may not be a predictive marker for improvement for depression in T2DM.

The major limitation of our study was purposive sampling, which is prone to researcher bias. Also, a larger sample size could not be taken as this study was conducted during the Covid-19 pandemic, and as diabetes was a high-risk group for Covid-19 infection, several patients did not consent to participate in the study. Despite this, the initial results of the K/T ratio, as a marker for IDO activity in depressed people with diabetes, are promising.