Targeting self-care adherence for glycaemic control in multimorbid type 2 diabetes mellitus with depression using bupropion: a protocol for cross-over randomised controlled trial

Introduction

Diabetes and depression are severe chronic illnesses with a very high burden. These are among the 10 biggest contributors to the increase in global disease burden over the past three decades (1990–2019).1 The increasing health burden due to these two conditions can be better appreciated in table 1.

Diabetes affects over half a billion people across the world. The associated healthcare expenditure is nearly a trillion USD.2 Alongside, depressive disorders affect over 300 million individuals, corresponding to 4.4% of the population worldwide. It contributes to a disproportionate burden of 7.5% of the total global years lived with disability. Indian figures match global estimates with 4.5% and 7.1%, respectively.3

However, these two disease entities are not independent of each other. Depression is more prevalent in people with diabetes, and a clear pattern can be observed. Depression is 1.8 times more prevalent in previously diagnosed diabetes, 1.27 times more prevalent in undiagnosed diabetes and 1.11 times more prevalent in pre-diabetes.4 A more recent meta-analysis reports that people with type 2 diabetes (T2D) are 1.76 times more likely to have depression than those without diabetes. This finding is significant across all subgroups but is greater in specialist care settings and low-income and middle-income countries.5 Women are more likely to be affected, with 34% of women and 23% of men with T2D also suffering from depression.6

People with diabetes are more likely to have mild depression than full-blown depression.7 However, depression may be more persistent and recurrent in them.8 Depression is a relatively underdiagnosed disease in general. On top of that, it is often not discussed during consultations for diabetes. This could be due to a greater focus on the somatic symptoms of diabetes than the associated psychological symptoms.9 10

Diabetes and depression share a strong bidirectional relationship. Depression and diabetes both increase the risk of development of each other.11 This association is not entirely unexpected. Over three centuries ago, it was hypothesised that prolonged grief could result in diabetes. However, the lack of obviousness meant this idea did not receive the scientific attention it deserved.

Obesity and stress due to the management of diabetes increase the risk of depression in diabetes. The opposite direction of this bidirectional relationship is attributed to a lack of self-care and adverse metabolic effects of antidepressants.12 Depression can result from improper diet, unsuitable lifestyle activities, inadequate sleep and obesity. Conversely, it can also lead to these conditions. Some antidiabetic medications themselves increase the risk of depression. Depression leads to decreased self-care. This then manifests as inadequate lifestyle modifications and lack of adherence to medication and other healthcare advice, ultimately leading to poor glycaemic control.12–19

The pathophysiological mechanisms behind their relationship require further exploration. Both depression and T2D share common pathophysiological processes. Chronic stress, including depression, causes dysregulation of the hypothalamic–pituitary–adrenal axis, overactivity of the sympathetic component of autonomic function, and immune dysregulation. Elevated cortisol and catecholamines lead to insulin resistance and consequent hyperglycaemia. This activates the polyol pathway resulting in oxidative stress and neuronal damage, including hippocampal atrophy. This is followed by the formation of advanced glycation end products associated with depression.11 20 Thus, there is a cycle of pathophysiological changes.

This comorbid condition of depression and diabetes has a synergistic effect, not just an additive one.21 These individuals have a much worse quality of life than those with T2D alone without depression.22 Diabetes with mental health issues get routine biochemical investigations done less frequently, are more likely to develop cardiovascular complications, get hospitalised for complications of diabetes more, have greater mortality (diabetes related, cardiovascular cause related and all cause) and are linked with greater healthcare expenditure.23–29

Since commonly used antidepressants do not differ much in efficacy for depression, the choice of an antidepressant drug revolves around the adverse event profile of the drug and the patient profile.30 The management of this comorbid condition is not a straightforward task. Depression is underdiagnosed and untreated in nearly half of those with diabetes.9 Pharmacological management, mainly with selective serotonin reuptake inhibitors, has provided mixed results.31–33 Instead, the usage of antidepressants in general and specifically SSRIs and TCAs has been implicated with a higher risk of developing T2D. Atypical antipsychotics that have recently grown in popularity are also known to predispose to metabolic adverse events, including T2D and weight gain. There is a growing opinion that instead of incriminating classes of antidepressants in general, we should pay attention to the affinity for H1-receptor seen with specific drugs. Bupropion and fluoxetine are among the antidepressants with the lowest affinity for H1-receptor.34–37 Few trials have reported diverse effects of different antidepressants in diabetes. Thus, they may be better options in the setting of metabolic diseases.

In a systematic review and meta-analysis (SRMA) of 116 studies, antidepressants had varied effects on weight gain. Some increased weight, some were weight-neutral and some decreased. Bupropion was the only antidepressant associated with persistent weight loss and is not limited to the acute phase of treatment.38 This corroborates using bupropion with naltrexone for weight loss in individuals with weight-related multimorbidities like T2D.36 39

Sexual dysfunction often occurs in people with diabetes and is multifactorial in origin.40 41 To add to our concerns regarding the comorbid population suffering from T2D and depression, antidepressants commonly cause sexual dysfunction. This then leads to premature treatment discontinuation and a worse quality of life. One of the key takeaways from an SRMA investigating sexual dysfunction using antidepressants was that bupropion had a lower risk of sexual dysfunction.42 A newer review article also lists bupropion as one of the antidepressants with the least risk of sexual dysfunction.43 Bupropion is even recommended for antidepressant-related sexual dysfunction and is used for it off-label.44 45 Instead, bupropion effectively treats females with low sexual dysfunction in a dose-dependent manner, as reported in a recent SRMA.46 It improves sexual dysfunction in men, too.47 Moreover, a cost–utility analysis in a specific circumstance found benefits with Bupropion as opposed to other antidepressants like venlafaxine or sertraline.48

Bupropion has shown promising results in a single-arm observational study of patients with T2D and depression.49 50 Inadequate management of depression in diabetes results in poor glycaemic control and consequent diabetic complications.8

People with diabetes with depression need increased attention during management. It is crucial that the bidirectional linkage between these two diseases is appreciated and that the vicious cycle is targeted appropriately. We should not consider the two diseases as separate entities requiring separate management. Instead, a holistic model of care involving a multipronged strategy should be employed to control these individuals’ unique healthcare needs better.

There is a lack of consensus on managing this public health burden of multimorbidity of diabetes and depression.51 Moreover, though there is a lack of data on the usage of bupropion in this condition, many factors, including the safety profile of this drug, beg for a study to explore further. Hence, we are planning a crossover randomised controlled trial to assess the efficacy and safety of add-on bupropion in T2D with mild depression. We are evaluating various outcomes, including glycaemic control, self-care adherence, sexual satisfaction, autonomic function, lipid profile, urine albumin-to-creatinine ratio, quality of life and adverse events.

Research design and methods

Study design

This is a cross-over open-labelled randomised controlled trial. We are comparing the efficacy and safety of add-on bupropion against standard care in individuals with T2D and mild depression. The study will be performed from October 2022 to June 2024. The study will occur at the All India Institute of Medical Sciences (AIIMS), Jodhpur.

We will screen patients with T2D at the department of endocrinology and metabolism. The following criteria will be used:

Inclusion criteria

• Age of 30–70 years.

• Diagnosis of T2DM as per International Diabetes Federation criteria.

• Duration of T2D for 5 years or more.

• HbA1c between 6.5% and 12%.

• Having a score of 5–9 (mild depression) on the Patient Health Questionnaire-9.

Exclusion criteria

• T1DM.

• History of traumatic brain injury.

• Patients had any comorbid psychiatric disorder other than mild depression or a history of psychiatric illness.

• Treatment with antipsychotic or antidepressant medications, benzodiazepines, dopaminergic medications, monoamine oxidase inhibitors or amantadine within the last 4 weeks before study participation.

• Pregnant and lactating women.

• History of allergy/intolerance to bupropion.

• Patients with any significant neurological disorders or any significant medical or surgical condition.

Eligible patients will be recruited after obtaining informed consent. Participants will be allocated to the two arms using stratified block randomisation. A variable block size of 4 or 6 will be used. According to the computer-generated randomisation sequence, they will be allocated to either add-on bupropion or standard care for 3 months. This allocation will be done using sequentially numbered opaque sealed envelopes. The individuals in the intervention arm will receive 150 mg of extended-release bupropion.

They will then be referred to the department of psychiatry. The intervention arm will be prescribed the study drug. Both groups will receive supportive care. The participants will also submit their serum and urine samples at an appropriate time for the investigations discussed under objectives. They will be sent to the physiology department for autonomic function assessment. Autonomic function testing consists of Ewing’s battery of tests as deemed feasible.

Standard care consists of treatment for diabetes and mild depression as deemed fit by the treating physicians. Only the intervention of add-on bupropion will undergo randomisation.

Participants will be contacted fortnightly telephonically. Compliance with the study drug and adverse events will be recorded. Participants will be provided support to promote trial retention. They will also be advised to contact the research team at any time throughout the study period if they need to do so. Participants are asked to report any side effects. No further data are collected if a participant decides to quit the trial. After 3 months, participants will be followed up, and all investigations will be repeated. Following a washout period of 1 month, all the investigations will be repeated. Then, the two study arms will be swapped, and investigations will be repeated after 3 months, as depicted in figure 1.

Figure 1

Flow chart explaining study design.