What to do for a 50-year-old patient with well-controlled diabetes (on dapagliflozin and metformin), hypertension, and subclinical hypothyroidism, presenting with severe tiredness, lack of motivation, and laziness for two months, with all blood tests being negative, suggesting possible depression?

Management of Severe Fatigue in a Well-Controlled Diabetic Patient with Possible Depression

Screen for depression immediately using a validated tool and initiate treatment within 2 weeks if depression is confirmed, as depression affects 20-25% of people with diabetes and is strongly associated with fatigue symptoms. 1

Initial Diagnostic Considerations

Rule Out Thyroid-Related Causes First

• Verify that "subclinical hypothyroidism" is truly well-controlled by checking current TSH and free T4 levels, as subclinical hypothyroidism significantly increases the risk of depression (56% vs 20% in euthyroid individuals) 2
• If TSH is elevated (even mildly), consider that metformin may actually reduce TSH levels over time, potentially masking worsening hypothyroidism 3, 4
• Check morning cortisol and ACTH levels to exclude adrenal insufficiency, which presents identically with fatigue, lack of motivation, and can coexist with thyroid dysfunction 5

Evaluate Diabetes-Related Factors

• Assess for hypoglycemia patterns through glucose monitoring review, as recurrent hypoglycemia causes fatigue and can occur with dapagliflozin-metformin combination despite "good control" 1
• Review blood glucose variability and nocturnal patterns, as glycemic fluctuations disrupt sleep architecture and worsen daytime fatigue 1
• Screen for diabetic autonomic neuropathy, which causes fatigue independent of glycemic control 1

Depression Screening and Diagnosis

Implement Structured Screening

• Use a validated two-question screen or the Geriatric Depression Scale during the initial evaluation period 1
• Depression screening is particularly critical in diabetes patients, as the bidirectional relationship between diabetes and depression significantly impacts outcomes 1
• Look specifically for: depressed mood, anhedonia (lack of motivation to work), sleep disturbance, concentration difficulties, and feelings of worthlessness 1

Recognize Depression-Fatigue Overlap

• Fatigue is the most common residual symptom in depression and responds poorly to standard antidepressants, often requiring specific intervention 6
• The constellation of "severe tiredness, no mood to do work, laziness" strongly suggests major depressive disorder rather than pure medical causes 1
• Depression in diabetes is associated with poorer self-care, worse glycemic control, and increased cardiovascular mortality 1

Treatment Algorithm

If Depression is Confirmed (Positive Screen)

Initiate or refer for treatment within 2 weeks of positive screening, as delays worsen outcomes 1

First-Line Pharmacological Treatment

• Start sertraline (SSRI) as first-line therapy, beginning at 50 mg daily for depression, with dose adjustments based on response 7
• Sertraline is FDA-approved for major depressive disorder and has established efficacy in patients with medical comorbidities 7
• Evaluate for improvement in target symptoms (specifically fatigue and motivation) within 6 weeks of initiation 1
• If inadequate response at 6 weeks, increase dose or consider augmentation strategies 1

Important Safety Monitoring

• Monitor for suicidal ideation, particularly in the first few weeks of treatment or with dose changes 7
• Watch for serotonin syndrome if patient takes other serotonergic medications (tramadol, triptans) 7
• Check sodium levels, especially given diabetes medications, as SSRIs can cause hyponatremia 7

Concurrent Non-Pharmacological Interventions

Prescribe structured physical activity immediately, as exercise has the strongest evidence for reducing fatigue in patients with medical comorbidities 1

• Recommend 150 minutes of moderate aerobic exercise weekly (brisk walking, cycling, swimming) plus 2-3 strength training sessions 1
• Walking programs are safe for most diabetes patients and can begin without formal exercise testing after physician consultation 1
• Address common barriers: lack of motivation (depression-related), physical limitations, lack of time 1

Consider mind-body interventions as adjunctive therapy:

• Mindfulness-based approaches, yoga, or acupuncture have evidence for fatigue reduction 1
• These may be particularly helpful for diabetes-related distress, which affects 18-45% of patients 1

Collaborative Care Model

• Integrate mental health professional into the diabetes care team for optimal outcomes 1
• Collaborative care approaches improve both depression and glycemic control simultaneously 1
• Schedule follow-up within 2-4 weeks to assess treatment response and medication tolerability 1

Critical Pitfalls to Avoid

Don't Attribute Everything to "Subclinical Hypothyroidism"

• Even with "well-controlled" subclinical hypothyroidism, recheck thyroid function as the clinical picture doesn't match stable disease 1, 5
• Metformin can lower TSH levels, potentially masking progression to overt hypothyroidism 3, 4
• If free T4 is low with normal/low TSH, this suggests central hypothyroidism requiring pituitary evaluation 5

Don't Delay Depression Treatment

• "All blood tests negative" should not delay depression screening and treatment 1
• Depression is a clinical diagnosis; waiting for laboratory confirmation of other causes wastes critical treatment time 1
• Half of patients with depression don't discuss symptoms with their physician—direct screening is essential 1

Don't Ignore Medication Side Effects

• Review all medications for fatigue-inducing effects (beta-blockers for hypertension, if prescribed) 5
• Dapagliflozin can cause volume depletion leading to fatigue—assess orthostatic vital signs 1

Don't Overlook Sleep Disorders

• Screen for sleep apnea, which is highly prevalent in diabetes patients and causes identical symptoms 1, 5
• Assess sleep quality and duration, as sleep disturbances independently worsen glucose control and fatigue 1

When to Refer

Refer to psychiatry or behavioral health if:

• No improvement in target symptoms after 6 weeks of adequate antidepressant therapy 1
• Suicidal ideation or severe functional impairment present 7
• Diagnostic uncertainty between depression, diabetes distress, and medical causes 1

Refer to endocrinology if:

• TSH >10 mIU/L or free T4 is low despite "subclinical" diagnosis 8
• Suspicion of central hypothyroidism (low/normal TSH with low free T4) 5
• Adrenal insufficiency suspected based on morning cortisol testing 5