An Integrative Approach: Case Study of Comorbid Major Depressive Disorder & T1DM
Jaclyn Graham, BSc, ND
The prevalence of depression in type 1 diabetic patients may be 3 times higher than that of non-diabetic patients in the general population, while 40% of patients with type 1 diabetes also have anxiety.1 The consequences of comorbidity are significant: elevated depressive symptoms are associated with higher HbA1c levels, episodes of diabetic ketoacidosis and/or hypoglycemic events, poorer clinical outcomes, and increased suicidality.2 Troublingly, the prevalence of major depressive disorder (MDD) in type 1 diabetic children is 2-3 times higher than in non-diabetic children, which is concerning given the additional challenges youth and their families face managing both conditions during a time of tremendous physical, cognitive, emotional, and social development.3 In addition to reduced self-care, diabetic complications, and a poorer quality of life, MDD increases the risk of all-cause mortality in people with diabetes.4,5
The relationship between major depressive disorder and type 1 diabetes management is still an area of medicine left to be completely elucidated. Does improving depressive symptoms lead to greater glycemic control, and, likewise, what effect does better glycemic control have on mental health? Presumably, the relationship is bidirectional and interdependent; therefore, a multimodal integrative approach to treatment, along with a greater understanding of the underlying pathophysiology, may facilitate optimal patient outcomes.
John was a 31-year-old male when he presented to my clinic with symptoms of low mood and anxiety. He had been experiencing mood disturbances in ebbs and flows since his mid-20s. Correspondingly, in his 20s he was also diagnosed with type 1 diabetes mellitus.
During his first visit, he described persistent low mood, difficulty focusing, irritability, performance anxiety, negative self-image, frequent rumination over daily events, and worry about the future. He communicated considerable stress and anxiety stemming from multiple facets of his daily life. He experienced a lack of pleasure from his typical outdoor physical activities. He complained of decreased motivation at work and recent withdrawal from usual social activities. When asked about suicidality, he reported occasional suicidal thoughts but with no plan and no previous attempts.
John described nighttime anxiety, difficulty falling asleep, and significant sleep-maintenance insomnia. He would wake up 6 times per night during the previous 2 months, with hot sweats and a racing heart, which he self-treated with melatonin and meditation. His daytime energy was consistently low, rated as 4 out of 10.
Relevant past medical history included hereditary motor sensory neuropathy (HMSN), with mild deficits in peripheral motor control, but otherwise stable; his family history was positive for major depressive disorder in a first-degree relative, and negative for diabetes.
A review of systems revealed daily nausea, infrequent heartburn, poor appetite, and 5 lb of weight loss within the previous 2 months. He ate an omnivorous diet consisting of home-prepared, high-fiber, whole foods eaten at regular times throughout the day; however, he enjoyed high-glycemic snacks in the evening before bed. John regularly consumed 1-2 cups of caffeinated coffee as well as 4 cups of fluids each day. He drank 1-4 servings of alcohol per week and was a former smoker, 11 years prior and of 10 years’ duration.
His current supplement regimen consisted of a B-50 complex, vitamin D, and 1 capsule of Hypericum perforatum (St John’s wort) of an unspecified dose. Seven months before our initial appointment, John discontinued taking an antidepressant, the name of which he could not recall.
At the time of the visit, no laboratory access existed for naturopathic doctors in my geographical area, so laboratory measures were limited and dependent on patient report of tests ordered by the co-managing medical provider.
John reported the results of his most recent blood work as follows:
- Postprandial glucose: 11 mmol/L
- HbA1c: 7.6%
- Serum cobalamin: 350 pmol/L
- Height: 5’9”; weight: 175 lb; BMI: 25.8
Treatment goals included the following:
- Minimize feelings of overwhelm, anxiety, and depression
- Improve mood and enjoyment of previously enjoyed activities
- Improve feelings of self-efficacy and self-esteem
- Address sleep disturbances
- Increase overall energy
- Improve glycemic control
- Modify physiological and behavioral response to current life stressors
Initial treatment began with the introduction of nutrition and lifestyle counseling. John was encouraged to continue a well-balanced diet, to increase fluids, and to replace his high-glycemic bedtime snack with a high-protein/lower-glycemic option so as to stabilize blood sugar throughout the night. Other recommendations included spending time with positive social supports, structured journaling before bed, and co-management with a local counselor. His prescribed herbal and supplement regimen are outlined below:
- Omega-3 Fish Oil (3:1 EPA:DHA – 3000 mg total per day)
Purpose: To modulate inflammation and oxidative stress. High-dose EPA supplementation has been found to provide clinical benefit to patients with depressive symptoms6
- Methylated B-complex (including 100 mg B6/1000 µg B12/1000 µg folate per day)
Purpose: To support the nervous and adrenal systems to improve energy, protect against peripheral neuropathy, and decrease depressive and anxious symptoms. Adequate levels of vitamins B6, B12, and folate are needed for normal homocysteine metabolism, disturbances of which may play a role in mental health, type 1 diabetes, and associated cardiovascular risk.7-9
- Vitamin D3 (4000 IU per day)
Purpose: To modulate immune-inflammatory pathways, such as the balance of Th1-type and Th-2 type cytokines10
- Vitamin C (2000 mg per day, to bowel tolerance)
Purpose: To improve antioxidant status and provide adrenal support in combination with the B-complex during chronic stress, which can contribute to fatigue and mood changes11
- B12-methylcobalamin, IM post-deltoid (1000 µg 1x/week for 6 weeks)
Purpose: Important for methylation and homocysteine metabolism. Interestingly, patients with increased vitamin B12 serum levels are also more likely to respond to antidepressant therapy.8
- Hypericum perforatum, Valeriana officinalis, and Passiflora incarnata herbal combination (2 tabs twice daily, providing a total daily dose of 240 mg St John’s wort, 112 mg valerian, and 128 mg passion flower)
Purpose: To treat both depression and anxiety via anti-inflammatory effects, increased serotonin production, and GABA system modulation12
- L-glycine (15 g as needed before bed in cases of acute anxiety)
Purpose: To improve sleep and lessen nighttime anxiety. The amino acid may blunt the effects of norepinephrine during acute anxiety.13 Interestingly, de novo synthesis of glycine may decrease by as much as 33% among type 1 diabetics in a hyperglycemic state.14
During our appointment 1 month later, John described a worsening of symptoms, with feelings of sadness, lack of motivation at work, sleep-maintenance insomnia, a decrease in appetite, sluggish digestion, reduced intake of high-protein foods, and an increased intake of high-sugar foods. He denied any worsening of suicidal ideation, and he was doing well to keep up with his weekly psychological counseling.
During this visit, we discussed ways to increase physical exercise, I encouraged protein intake at each meal, and I introduced a trial gluten-free diet (GFD). Although we did not have access to laboratory testing to rule in/out celiac disease, it is well recognized in the literature that type 1 diabetic patients and their relatives have a higher prevalence of undiagnosed celiac disease.15 Extra care to guide patients with diabetes through a gluten-free diet – with close monitoring of blood sugar levels – must be provided, since diabetic patients with symptomatic or silent celiac disease may experience acute hyperglycemia and an increase in HbA1c on a GFD. This is possibly due to intestinal healing and greater absorption of macronutrients, or due to an increased intake of high-glycemic index foods, such as corn, rice, or potato-based gluten-free products.16
I also prescribed an herbal tincture containing digestive bitters, to be taken before meals to help increase appetite and encourage regular bowel movements.
At our 3-month follow-up, John decided to discontinue current herbal therapies and commence pharmaceutical treatment for his depression. He continued to have insomnia and anxiety. During this visit, John became more expressive of specific life circumstances that he had been unhappy with for several months and unable to control. He was encouraged to recognize that his thoughts and feelings regarding life circumstances were authentic and valid, and that by expressing his concerns openly with his partner, he could begin to make meaningful changes.
All herbal formulas were discontinued, and John was advised to continue his B-complex, vitamin D, omega-3s, and to try GABA, 600-700 mg before bed, for 2-3 weeks.
At our 4-month follow-up appointment, John had just discontinued a 4-week trial of the serotonin-norepinephrine reuptake inhibitor (SNRI), venlafaxine, due to adverse effects (nausea, dizziness, and headaches). He returned to this visit with a more positive outlook on life, and despite having low energy (5 out of 10), he expressed feeling happy for the first time in a while. Notably, he had a recent change of job and was now spending more time outside during the day. His reported HbA1c had also improved to 7.2%.
John continued to feel mild-to-moderate anxiety, so I recommended 5-hydroxytryptophan (5-HTP), 300 mg per day in divided dosages, and to continue his B-complex, vitamin D, omega-3s, and vitamin C regimen.
At our last follow-up visit, John reported that he had continued to experience improved mood and better blood sugar control; he only complained of fatigue due to overwork. I prescribed a tincture of Withania somnifera (ashwagandha), 2.5 mL 3 times daily; we also discussed strategies to manage a demanding life. After this visit, the patient was lost to follow-up, as my practice was relocated.
A 2019 longitudinal study demonstrated the association between symptoms of depression and glycemia: of the 2744 participants, a total of 15% experienced depressive symptoms at some point during the 4-year study, and these depressive subjects were statistically more likely to experience diabetic ketoacidosis.17 The authors concluded that treatment of depression may assist in better glycemic control in type 1 diabetes patients.
A 12-month prospective trial followed 181 diabetic participants receiving either cognitive-behavioral therapy (CBT) or a standard group-based diabetes education program. Regardless of which treatment they received, a reduction of depressive symptoms was associated with improved glycemic control and a greater likelihood of reaching in-target HbA1c.4,18,19
A 2011 literature review on the pathophysiology of comorbid major depressive disorder and type 1 diabetes mellitus describes several possible mechanisms linking the 2 conditions.3 Two major categories are discussed:
- Immuno-inflammatory factors
- Endocrinological factors
The autoimmune destruction of insulin-producing beta cells of the islets of Langerhans in the pancreas coincides with elevated circulating cytokines. In addition, first-degree relatives who are both positive for anti-islet antibodies and have an imbalanced Th1/Th2 cytokine profile have been found to be at greater risk of eventual progression to overt type 1 diabetes.20 The increased circulating cytokines is further augmented by continued beta-cell destruction and resultant hyperglycemia, which in turn leads to greater oxidative stress.
In animal studies, pancreatic cells have been found to exhibit low activity of antioxidant enzymes compared to other tissues, thus may be especially vulnerable to the effects of oxidative stress.21 Furthermore, a 2007 study revealed decreased glutathione peroxidase activity and increased lipid peroxidation in youth with type 1 diabetes.22 Several studies have linked increased inflammation and oxidative stress to depressive symptoms, including fatigue, insomnia, decreased appetite, and lack of self-care.23 Among the proposed mechanisms are oxidative stress-induced mitochondrial dysfunction and hypercortisolism, which can be potential outcomes as well as perpetuating factors in both mood disorders and type 1 diabetes.3
A rat study suggested that a lack of insulin may disrupt amino acid metabolism and lead to deficits in the production of serotonin, since it is contingent on the presence of its precursor, tryptophan.24 Reinforcing this concept, type 1 diabetic patients have been found to have decreased brain serotonergic neurotransmission.25 Excess insulin and hypoglycemic episodes have been associated with depressive symptoms and may also increase risk of cognitive impairment.3
An additional endocrinological factor appears to link mood disorders and type 1 diabetes: hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Both conditions may be associated with increased cortisol secretion and increased 24-hour urinary free cortisol, which decreases cerebral and hippocampal uptake of glucose and may inhibit hippocampal 5-HT1A receptors, a subtype of serotonin receptor.3 Moreover, HPA axis hyperactivity appears to increase the risk of diabetic complications.26 Relief of depressive symptoms following successful treatment of HPA hyperactivity has been documented, offering a potential opportunity for naturopathic therapies.27,28
The Importance of Addressing Stress
Diabetes-related distress appears to be an important modifiable risk factor for mood disturbances in diabetics. The Diabetes Distress Scale is a well-validated instrument to assess for the presence of diabetes-related distress in both type 1 and type 2 diabetes.29 Simplified dietary modifications, patient education, and effective biomedical and naturopathic therapies all play a role in lessening the overwhelm experienced by so many depressed/anxious and diabetic patients alike. Co-managing patients with a mental health practitioner is important when therapeutic methods fall outside of the scope of naturopathic medicine.
Focusing lifestyle counseling on our patients’ unique sources of stress, along with building healthy coping skills, is one of the most important aspects of therapy. This case is no exception. One might conclude that the greatest shift came from John allowing himself to express his feelings, validating them, and then realizing a sense of personal control over life stressors. Certainly, a lack of self-directedness, self-disclosure, and an exaggerated feeling of external locus of control can together play a significant role in exacerbating mental-emotional distress, and can contribute to poorer treatment outcomes.30 We mustn’t forget, John’s shift occurred in concert with a holistic approach that was set out over several months and which emphasized self-care as well as biology. This ultimately benefited his mental health as well as glycemic control. And so, as naturopathic doctors continue to provide integrative care for type 1 diabetic patients experiencing mental health concerns, cultivating a sense of self-efficacy while addressing underlying pathophysiology is essential.
- Băcescu SV, Tătaru C, Kobylinksa L, et al. The association between Diabetes mellitus and Depression. J Med Life. 2016;9(2):120-125.
- Trief PM, Xing D, Foster NC, et al. T1D Exchange Clinic Network. Depression in adults in the T1D Exchange Clinic Registry. Diabetes Care. 2014;37(6):1563-1572.
- Korczak DJ, Pereira S, Koulajian K, et al. Type 1 diabetes mellitus and major depressive disorder: evidence for a biological link. Diabetologia. 2011;54:2483-2493.
- Reimer A, Schmitt A, Ehrmann D, et al. Reduction of diabetes-related distress predicts improved depressive symptoms: A secondary analysis of the DIAMOS study. PLoS One. 2017;12(7):e0181218.
- Lin EH, Heckbert SR, Rutter CM, et al. Depression and increased mortality in diabetes: unexpected causes of death. Ann Fam Med. 2009;7(5):414-421.
- Hallahan B, Ryan T, Hibbeln JR, et al. Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. Br J Psychiatry. 2016;209(3):192-201.
- Bjelland I, Tell GS, Vollset SE, et al. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: The Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003;60(6):618-626.
- Maier H, Helm S, Toto S, et al. S100B, Homocysteine, Vitamin B12, Folic Acid and Procalcitonin Serum Levels in Remitters to Electroconvulsive Therapy: A Pilot Study. Dis Markers. 2018;2018:2358451.
- Dinleyici EC, Kirel B, Alatas O, et al. Plasma total homocysteine levels in children with type 1 diabetes: relationship with vitamin status, methylene tetrahydrofolate reductase genotype, disease parameters and coronary risk factors. J Trop Pediatr. 2006;52(4):260-266.
- Komisarenko YI, Bobryk MI. Vitamin D Deficiency and Immune Disorders in Combined Endocrine Pathology. Front Endocrinol (Lausanne). 2018;9:600.
- Brody S, Preut R, Schommer K, Schürmeyer TH. A randomized controlled trial of high dose ascorbic acid for reduction of blood pressure, cortisol, and subjective responses to psychological stress. Psychopharmacology (Berl). 2002;159(3):319-324.
- Ernst E. Herbal remedies for depression. Adv Psychiatr Treat. 2007;13(4):312-316.
- Mitchell WA Jr. Foundations of Natural Therapeutics: Biochemical Apologetics of Naturopathic Medicine. Tempe, AZ: Southwest College Press. 1997: 105-108.
- Robert JJ, Beaufrere B, Koziet J, et al. Whole body de novo amino acid synthesis in type I (insulin-dependent) diabetes studied with stable isotope-labeled leucine, alanine, and glycine. Diabetes. 1985;34(1):67-73.
- Not T, Tommasini A, Tonini G, et al. Undiagnosed coeliac disease and risk of autoimmune disorders in subjects with Type 1 diabetes mellitus. Diabetologia. 2001;44(2):151-155.
- Pietzak MM. Follow-up of patients with celiac disease: achieving compliance with treatment. Gastroenterology. 2005;128(4 Suppl 1):S135-S141.
- Trief PM, Foster NC, Chaytor N, et al. Longitudinal Changes in Depression Symptoms and Glycemia in Adults with Type 1 Diabetes. Diabetes Care. 2019;42(7):1194-1201.
- Schmitt A, Reimer A, Ehrmann D, et al. Reduction of depressive symptoms predicts improved glycaemic control: Secondary results from the DIAMOS study. J Diabetes Complications. 2017:31(11):1608-1613.
- Hermanns N, Schmitt A, Gahr A, et al. The Effect of a Diabetes-Specific Cognitive Behavioral Treatment Program (DIAMOS) for Patients with Diabetes and Subclinical Depression: Results of a Randomized Controlled Trial. Diabetes Care. 2015;38(4):551-560.
- Rapoport MJ, Bistritzer T, Aharoni D et al. TH1/TH2 cytokine secretion of first degree relatives of T1DM patients. Cytokine. 2005;30(5):219-227.
- Tiedge M, Lortz S, Drinkgern J, Lenzen S. Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes. 1997;46(11):1733-1742.
- Martin-Gallan P, Carrascosa A, Gussinye M, Dominguez C. Oxidative stress in childhood type 1 diabetes: results from a study covering the first 20 years of evolution. Free Radic Res. 2007;41(8):919-928.
- Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27(1):24-31.
- Crandall EA, Gillis MA, Fernstrom JD. Reduction in brain serotonin synthesis rate in streptozotocin-diabetic rats. Endocrinology. 1981;109(1):310-312.
- Manjarrez G, Herrera R, Leon M, Hernandez RJ. A low brain serotonergic neurotransmission in children with type 1 diabetes detected through the intensity dependence of auditory- evoked potentials. Diabetes Care. 2006;29(1):73-77.
- Chiodini I, Adda G, Scillitani A, et al. Cortisol Secretion in Patients with Type 2 Diabetes: Relationship With Chronic Complications. Diabetes Care. 2007;30(1):83-88.
- Ribeiro SC, Tandon R, Grunhaus L, Greden JF. The DST as a predictor of outcome in depression: a meta-analysis. Am J Psychiatry. 1993;150(11):1618-1629.
- Wolkowitz OM, Reus VI. Treatment of Depression with Antiglucocorticoid Drugs. Psychosom Med. 1999;61(5):698-711.
- Polonsky WH, Fisher L, Earles J, et al. Assessing Psychosocial Distress in Diabetes: Development of the Diabetes Distress Scale. Diabetes Care. 2005;28(3):626-631.
- Langan-Fox J, Sankey MJ, Canty JM. Incongruence between implicit and self-attributed achievement motives and psychological well-being: The moderating role of self-directedness, self-disclosure and locus of control. Pers Individ Dif. 2009;47(2):99-104.
Jaclyn Graham, BSc, ND, graduated with honours from the University of Waterloo with a degree in Biomedical Sciences; she went on to obtain her Doctor of Naturopathic Medicine from the Canadian College of Naturopathic Medicine in 2011. Dr Graham’s particular foci include mental health, stress reduction, women’s and children’s specific health concerns, fertility, post-partum care, and digestive disorders. In addition to seeing patients in her practice in St Catharines and the Niagara Region, Dr Graham provides consultation services, researching and writing high-quality educational content on a variety of topics.