An Integrative Approach: Example of Comorbid Major Despression symptoms & T1DM

The prevalence of depression in type 1
diabetics may be Three times higher than those 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
despression symptoms in type 1 diabetic children is 2-3 times higher than
in non-diabetic children, which is concerning because of the additional challenges
youth and their families face managing both conditions during a duration 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 chance of all-cause mortality in individuals with diabetes.4,5

The relationship between major depressive
disorder and type 1 diabetes management is still an area of drugs left to become
completely elucidated. Does improving depressive symptoms result in 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, plus a greater
understanding of the underlying pathophysiology, may facilitate optimal patient

Case Study

John would be a 31-year-old male as 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 your body mellitus.

During his first visit, he described
persistent low mood, difficulty focusing, irritability, performance anxiety,
negative self-image, frequent rumination over daily events, and be worried about the
future. He communicated considerable anxiety and stress stemming from multiple
facets of his everyday life. He experienced deficiencies in pleasure from his typical
outdoor physical activities. He reported decreased motivation at the office and
recent withdrawal from usual social activities. When asked about suicidality,
he reported occasional thoughts of suicide however with no plan and no previous

John described nighttime anxiety, difficulty
falling asleep, and significant sleep-maintenance insomnia. He would awaken 6 times
every 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 health background included
hereditary motor sensory neuropathy , with mild deficits in peripheral
motor control, but otherwise stable; his genealogy was positive for major
depressive disorder inside 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
8 weeks. He ate an omnivorous diet consisting of home-prepared, high-fiber,
whole foods eaten at regular times during the day; however, he enjoyed high-glycemic
snacks in the evening before bed. John regularly consumed 1-2 glasses of
caffeinated coffee as well as 4 glasses of fluids each day. He drank 1-4 servings
of alcohol per week and would be a former smoker, 11 years prior as well as 10 years'

His current supplement regimen contained a
B-50 complex, vitamin D, and 1 capsule of Hypericum
of an unspecified dose. Seven months before our
initial appointment, John discontinued taking an antidepressant, the name of which
he couldn't recall.

At the time of the visit, no laboratory access
existed for naturopathic doctors in my geographical area, so laboratory
measures were limited and determined by patient report of tests ordered through the
co-managing medical professional.

John reported the results of his newest
blood act 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

Treatment goals included the

  1. Minimize feelings of overwhelm,
    anxiety, and depression
  2. Improve mood and pleasure of
    previously enjoyed activities
  3. Improve feelings of
    self-efficacy and self-esteem
  4. Address sleep disturbances
  5. Increase overall energy
  6. Improve glycemic control
  7. Modify physiological and
    behavioral response to current life stressors

Treatment Plan

Initial treatment began with the
introduction of nutrition and lifestyle counseling. John was asked to
continue a well-balanced diet, to increase fluids, and to replace his high-glycemic
bedtime snack having a high-protein/lower-glycemic option in order to stabilize
blood sugar levels throughout the night. Other recommendations included spending time
with positive social supports, structured journaling before bed, and
co-management having a local counselor. His prescribed herbal and supplement
regimen are outlined below:

  • Omega-3 Omega-3 fatty acids

To modulate inflammation and oxidative stress. High-dose EPA supplementation
has been discovered to provide clinical help to patients with depressive symptoms6

  • Methylated B-complex

To aid the nervous and adrenal systems to enhance energy, control
peripheral neuropathy, and reduce depressive and anxious symptoms. Adequate
levels of vitamins B6, B12, and folate are essential for normal homocysteine
metabolism, disturbances which are likely involved in mental health, type 1
diabetes, and associated cardiovascular risk.7-9

  • Vitamin D3

To modulate immune-inflammatory pathways, such as the balance of Th1-type and
Th-2 type cytokines10

  • Vitamin C

To enhance antioxidant status and supply adrenal support in combination with
the B-complex during chronic stress, which can contribute to fatigue and mood

  • B12-methylcobalamin, IM post-deltoid

Purpose: Essential for methylation and homocysteine
metabolism. Interestingly, patients with increased vitamin B12 serum levels are
also more prone to respond to antidepressant therapy.8

  • Hypericum perforatum, Valeriana officinalis, and
    Passiflora incarnata herbal

To treat both depression and anxiety via anti-inflammatory effects, increased
serotonin production, and GABA system modulation12

  • L-glycine

To enhance sleep and lessen nighttime anxiety. The protein may blunt the
results of norepinephrine during acute anxiety.13 Interestingly, de novo synthesis of glycine may
decrease up to 33% among type 1 diabetics inside a hyperglycemic state.14

One-Month Follow-up

During our appointment 1 month later,
John described a worsening of symptoms, with feelings of sadness, lack of
motivation at work, sleep-maintenance insomnia, home loan business appetite,
sluggish digestion, reduced intake of high-protein foods, and an increased
consumption of high-sugar foods. He denied any worsening of suicidal ideation, and
he was succeeding to keep up with his weekly psychological counseling.

During this visit, we discussed methods to
increase physical exercise, I encouraged protein intake at each meal, and that i
introduced an effort gluten-free diet . Although we did not have use of
laboratory testing to rule in/out celiac disease, it's well known within the
literature that type 1 diabetics and their relatives have a higher
prevalence of undiagnosed celiac disease.15 Special care to guide
patients with diabetes through a gluten-free diet – with close monitoring of
blood sugar levels – should be provided, since diabetics with symptomatic
or silent celiac disease may experience acute hyperglycemia and an increase in
HbA1c on the GFD. This is possibly because of intestinal healing and greater
absorption of macronutrients, or due to a heightened intake of high-glycemic
index foods, such as corn, rice, or potato-based gluten-free products.16

I also prescribed a natural tincture
containing digestive bitters, to be taken before meals to help increase
appetite and encourage regular bowel movements.

Three-Month Follow-up

At our 3-month follow-up, John decided
to discontinue current herbal therapies and initiate pharmaceutical treatment
for his depression. He continued to possess insomnia and anxiety. During this
visit, John became more expressive of specific life circumstances he had
been unhappy with for several months and not able to control. He was encouraged
to acknowledge that his feelings and thoughts regarding life circumstances were
authentic and valid, which 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 carry on his B-complex, vitamin D, omega-3s, and also to try
GABA, 600-700 mg before bed, for 2-3 weeks.

Four-Month Follow-up

At our 4-month follow-up appointment,
John had just discontinued a 4-week trial from the serotonin-norepinephrine
reuptake inhibitor , venlafaxine, due to adverse effects . He returned for this visit having a more positive
lifestyle, and even with low energy , he expressed
feeling happy the very first time shortly. Notably, he had a current change of
job and was now spending additional time outside throughout the day. His reported HbA1c had
also improved to 7.2%.

John continued to feel mild-to-moderate
anxiety, and so i recommended 5-hydroxytryptophan , 300 mg each day in
divided dosages, and to continue his B-complex, vitamin D, omega-3s, and vitamin
C regimen.

Five-Month Follow-up

At our last follow-up visit, John
reported he had continued to see improved mood and blood
sugar control; he only complained of fatigue because of overwork. I prescribed a
tincture of Withania somnifera ,
2.5 mL 3 times daily; we discussed strategies to manage a demanding life.
After this visit, the patient was lost to follow-up, as my practice was


A 2023 longitudinal study demonstrated
the association between symptoms of depression and glycemia: from the 2744 participants,
a total of 15% experienced depressive symptoms sooner or later during the 4-year
study, which depressive subjects were statistically more prone to
experience diabetic ketoacidosis.17 The authors concluded that
management of depression may assist in better glycemic control in type 1

A 12-month prospective trial followed 181
diabetic participants receiving either cognitive-behavioral therapy 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 probability 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:

  1. Immuno-inflammatory factors
  2. Endocrinological factors

Immuno-inflammatory Factors

The autoimmune destruction of
insulin-producing beta cells of the islets of Langerhans within 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 become at greater risk of eventual
progression to overt type 1 diabetes.20 The elevated circulating
cytokines is further augmented by continued beta-cell destruction and resultant
hyperglycemia, which in turn results in greater oxidative stress.

In animal studies, pancreatic cells have been
found to exhibit low activity of antioxidant enzymes when compared with other tissues,
thus may be especially susceptible to the effects of oxidative stress.21
Furthermore, a 2007 study revealed decreased glutathione peroxidase activity
and increased lipid peroxidation in youth with your body.22
Several research has 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 may be
potential outcomes in addition to perpetuating factors both in mood disorders and
your body.3

Endocrinological Factors

A rat study suggested that the insufficient
insulin may disrupt amino acid metabolic process and lead to deficits in the
manufacture of serotonin, since it is contingent on the existence of its
precursor, tryptophan.24 Reinforcing this concept, type 1 diabetic
patients have been discovered to have decreased brain serotonergic
neurotransmission.25 Excess insulin and hypoglycemic episodes have
been related to 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 axis. Both conditions may be associated
with an increase of cortisol secretion and increased 24-hour urinary free cortisol,
which decreases cerebral and hippocampal uptake of glucose and could inhibit
hippocampal 5-HT1A receptors, a subtype of serotonin receptor.3
Moreover, HPA axis hyperactivity appears to increase the chance of diabetic
complications.26 Relief of depressive symptoms following successful
treatment of HPA hyperactivity continues to be documented, offering a possible
opportunity for naturopathic therapies.27,28

The Importance of Addressing Stress

Diabetes-related distress seems to
be an important modifiable risk factor for mood disturbances in diabetics. The
Diabetes Distress Scale is a well-validated instrument to evaluate for that
presence of diabetes-related distress both in type 1 and kind 2 diabetes.29
Simplified dietary modifications, patient education, and efficient biomedical
and naturopathic therapies all lead to lessening the overwhelm
felt by a lot of depressed/anxious and diabetic patients alike.
Co-managing patients having a mental physician is important when
therapeutic methods fall outside the scope of naturopathic medicine.


Focusing lifestyle counseling on our
patients' unique sources of stress, along with building healthy coping skills,
is among the most significant aspects of therapy. This example is no exception. One
might conclude 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, as well as an exaggerated feeling of external locus of control can
together play a significant role in exacerbating mental-emotional distress, and
can bring about poorer treatment outcomes.30 We mustn't forget,
John's shift took place concert with a holistic approach that was set out over
many months and which emphasized self-care as well as biology. This ultimately
benefited his mental health in addition to glycemic control. And so, as naturopathic
doctors continue to provide integrative care for type 1 diabetics
experiencing mental health concerns, cultivating a sense of self-efficacy while
addressing underlying pathophysiology is important.