Why is it important to rule out hypothyroidism (underactive Thyroid (THYROID) Stimulating Hormone (TSH)) in patients with Major Depressive Disorder (MDD)?

Why Hypothyroidism Must Be Ruled Out in MDD

Hypothyroidism must be ruled out in patients with Major Depressive Disorder because subclinical and overt hypothyroidism directly cause depressive symptoms through thyroid-brain interactions, and untreated thyroid dysfunction is a leading cause of treatment-resistant depression. 1, 2

Overlapping Clinical Presentations Make Differentiation Essential

Symptom Overlap Creates Diagnostic Confusion

• Overt hypothyroidism produces symptoms that are nearly identical to major depression, including fatigue, poor concentration, disturbed sleep, and cognitive difficulties 3, 4
• Thyroid hormone receptors are widely expressed throughout the limbic system and brain regions controlling mood regulation, creating a direct physiological pathway for thyroid dysfunction to manifest as depression 5, 6
• The symptom overlap is so significant that distinguishing primary MDD from depression secondary to hypothyroidism based on clinical presentation alone is unreliable 7

Subclinical Hypothyroidism Has High Prevalence in Depression

• Patients with subclinical hypothyroidism have a 63.4% prevalence of depressive symptoms compared to 27.6% in controls without thyroid disease 8
• Women with TSH >10 mIU/ml have a threefold increased risk of depressive symptoms, while those with clinical hypothyroidism have an 8.7-fold increased risk 9
• Even subclinical hypothyroidism demonstrates blunted TSH responses to TRH stimulation, indicating subtle HPT axis dysfunction contributes to mood symptoms even when baseline thyroid levels appear normal 5

Hypothyroidism as a Cause of Treatment-Resistant Depression

Untreated Thyroid Dysfunction Prevents Antidepressant Response

• Hypothyroidism is recognized as one of the leading causes of treatment-resistant depression 1
• Undiagnosed, untreated, or undertreated hypothyroid patients are at significantly increased risk of developing depression that fails to respond to standard antidepressant therapy 1
• Elevated TSH, antithyroglobulin (TgAb), and thyroid peroxidase antibodies (TPOAb) are all independently linked to depression and increased suicide risk 1

Thyroid Replacement Improves Outcomes

• Treating underlying hypothyroidism with levothyroxine significantly improves mood disorders when thyroid dysfunction is the underlying cause 1
• Triiodothyronine (T3) has been successfully used as augmentation therapy in depressed patients resistant to first-line antidepressants 3
• Levothyroxine as adjunctive therapy to antidepressants improves depressive symptoms more rapidly than antidepressants alone 1

Distinct Clinical Features Can Guide Suspicion

Hypothyroid-Associated Depression Has Different Symptom Patterns

• Depressed patients with hypothyroidism present with more severe anxiety symptoms and greater agitation compared to those with primary MDD 7
• In contrast, patients with MDD without hypothyroidism have worse scores on core depressive symptoms including depressed mood, guilt, suicidality, late insomnia, and weight loss 7
• This pattern suggests that when anxiety and agitation predominate over classic vegetative symptoms, hypothyroidism should be strongly suspected 7

Autoimmune Thyroiditis Increases Risk

• Autoimmune thyroiditis is independently associated with increased risk of depression 1
• Thyroid peroxidase antibodies have been positively associated with trait markers of depression, even in the absence of overt thyroid dysfunction 2
• The presence of thyroid antibodies may indicate vulnerability to mood disorders through immune-mediated mechanisms 1

Clinical Algorithm for Thyroid Screening in MDD

When to Screen

• Screen all patients presenting with new-onset depression, particularly those with treatment-resistant symptoms 1, 9
• Screen patients with depression accompanied by prominent anxiety, agitation, or physical symptoms suggestive of thyroid dysfunction 7
• Screen middle-aged and older women with depression, as this population has particularly high rates of comorbid hypothyroidism 9

What to Order

• Obtain TSH as the initial screening test in all depressed patients 9
• If TSH is elevated, measure free T4 and free T3 to distinguish subclinical from overt hypothyroidism 6
• Consider thyroid peroxidase antibodies (TPOAb) and antithyroglobulin antibodies (TgAb) in patients with elevated TSH or treatment-resistant depression 1

Common Pitfalls to Avoid

• Do not assume normal thyroid function based on symptom presentation alone, as the overlap between hypothyroidism and primary depression is too extensive 7
• Do not dismiss subclinical hypothyroidism (elevated TSH with normal free T4) as clinically insignificant in depressed patients, as even subtle thyroid dysfunction significantly increases depression risk 8
• Do not attribute treatment resistance to inadequate antidepressant therapy without first ruling out hypothyroidism, as thyroid dysfunction is a leading reversible cause 1
• Do not overlook the bidirectional relationship: monitor both psychiatric symptoms and thyroid parameters together, as mood symptoms may precede overt thyroid dysfunction 5