Treatment Recommendations for Major Depressive Disorder in Medical Illness

A disabled man in a wheelchair
A disabled man in a wheelchair

Major depressive disorder (MDD) is commonly observed in medical settings, with a prevalence of up to 14% compared with 2% to 4% in the general population.1 Various studies have found rates of 12% to 18% in patients with diabetes, 15% to 23% in those with coronary heart disease, 23% to 54% in patients with multiple sclerosis (MS), and 18% to 85% in patients with chronic pain.1,2 Some findings suggest that depression may result from the pathophysiology of medical illness (such as inflammatory cytokines involved in chronic pain) or from medications such as corticosteroids.

In many cases, the link between MDD and medical illness appears to be bidirectional, as with diabetes. Studies have demonstrated that the relative risk of developing diabetes is 2.23 among patients with MDD, and the risk of developing MDD is twice as high among patients with vs without diabetes.3,4

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A similar relationship has been observed between MS and depression.5 It is known that “MS causes depression and depression worsens MS, and depression is one of the various risk factors that must align  in order to develop MS,” Adam Kaplin, MD, PhD, assistant professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine, told Psychiatry Advisor. “Treating the depression improves MS, and treating the MS — specifically blocking inflammation from gaining access to the [central nervous system] — has antidepressant effects on people with MS who are depressed.”

It can be challenging to distinguish depressive symptoms from a “normal” emotional response to medical illness. However, it is important to not dismiss these symptoms, as depression may increase mortality and worsen health outcomes, while treating depression may improve the prognosis of the medical illness and the patient’s adherence with treatment. The same first-line treatment strategies for depression that are used in the general psychiatric population — second-generation antidepressants and psychotherapeutic approaches including cognitive behavioral therapy — are also typically indicated for patients with medical illness, although consideration must be made for those with impaired renal or hepatic function or other special circumstances.  

Additional research is needed to further elucidate the association between depression and medical illness and to improve treatment for co-occurring depression and medical disease. “Ultimately, when we are able to identify biomarkers that can help us distinguish psychiatric syndromes from the psychological and emotional response to medical illnesses, we will be able to make greater strides in achieving diagnostic and therapeutic accuracy and efficacy,” according to Dr Kaplin. “In the meantime, research into understanding how the cross- talk between the brain and body can lead to bidirectional impacts, such as through the hypothalamic-pituitary-adrenal axis and the immune system — will help us unravel the close connections between the somatic and psychological symptoms that manifest so often in the context of medical illnesses and psychiatric sequelae.”

Dr Kaplin offers recommendations to clinicians regarding the diagnosis and treatment of depression in patients with medical illness. First and foremost, do not dismiss symptoms of depression merely because the patient has a comorbid medical illness. Not only are medical illnesses breeding grounds for neuropsychiatric sequelae — making depression more common rather than less common in this setting — but nothing about having a medical illness is somehow protective against depression. Although that makes common sense, the most common reaction of patients and clinicians to finding symptoms consistent with depression in the context of a comorbid medical illness is often, “Well, gee, anyone would be depressed if they had this illness.” This can prove to be poor diagnostic reasoning and can result in tragedy, since depression is a potentially lethal illness.

It is often difficult to distinguish depression in the context of comorbid medical illnesses because of overlapping symptoms between the 2 conditions, such as poor sleep, pain, and decreased appetite. Among the more specific symptoms suggestive of depression is diurnal variation. It is common for patients with a mood disorder to show cycling of their mood over the course of a day, often worse in the morning and better in the evening. Since a patient’s medical illness may be just as bad at both times of day, a varying mood course is suggestive of a mood disorder.

The best approach is to start by casting a wider net and not exclude symptoms from the diagnosis of depression just because they could be caused by the comorbid medical illness. This is reasonable because the attribution of a symptom to the medical illness is often wrong, or the patient’s preoccupation with the severity of the symptom is drastically heightened by their depression. You will also be less likely to miss depression with this approach.

In the end, sometimes the patient needs to be told that whether they have depression or merely an overlap of symptoms with their medical illness in conjunction with, for example, demoralization, a diagnosis cannot be made unambiguously. In this case, the severity of the depression will often guide whether treatment should be instituted — for example, if the patient is suicidal or not eating, then desperate times call for desperate measures — but in other situations, the medical illness may need to be treated in hopes that when it improves, the psychiatric symptoms will abate if they are not due to depression.

Alternatively, in the case of MS, I often tell my patients that I cannot tell them ahead of time how much of their fatigue or cognitive impairment is due to their depression or MS, but I can tell them that their depression is far easier to manage and hopefully treat to remission than the contribution of their MS to these symptoms. And when their mood is back to baseline and their depression in remission, however much fatigue or cognitive impairment that is left will then be attributable to MS.

The one fly in the ointment for many medical providers is delirium — delirium trumps depression diagnostically. That is, patients with delirium can have dysphoric presentations that simulate depression [Editor’s note: Delirium has been identified in up to 40% of hospitalized patients initially referred for psychiatric evaluation of depressive symptoms1], just as delirium can present with psychotic symptoms that appear to be caused by  a psychiatric disorder, but when the delirium clears, so do the psychiatric symptoms. So, the first issue is usually making sure the patient does not have a waxing and waning inattentiveness consistent with delirium.


1. Thom R, Silbersweig DA, Boland RJ. Major depressive disorder in medical illness: a review of assessment, prevalence, and treatment options. Psychosom Med. 2019;81(3):246-255.

2. Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain comorbidity: a literature review. Arch Intern Med. 2003;163(20):2433-2445.

3. Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care. 2008;31(12):2383-2390.

4. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care. 2001;24 (6):1069-1078.

5. Feinstein A. Multiple sclerosis and depression. Mult Scler. 2011;17(11):1276-1281.