Can Levothyroxine Cause Increased Anxiety and Depression?
Yes, levothyroxine can cause anxiety and depression through both overdosage and hypersensitivity reactions to inactive ingredients, and changing formulations may improve symptoms in select cases.
Levothyroxine-Associated Anxiety and Depression
Direct Adverse Effects from Levothyroxine
The FDA label explicitly lists anxiety, nervousness, irritability, emotional lability, and insomnia as adverse reactions associated with levothyroxine therapy, primarily due to therapeutic overdosage causing iatrogenic hyperthyroidism 1. These central nervous system effects occur when levothyroxine doses exceed what is needed to maintain euthyroid status 1.
Persistent Mood Symptoms Despite Treatment
Even when adequately treated with levothyroxine, hypothyroid patients experience significantly higher rates of anxiety and depression compared to those without thyroid disease. A 2019 case-control study found that levothyroxine-treated hypothyroid women had nearly double the risk of anxiety (OR = 2.08) and triple the risk of depression (OR = 3.13) compared to women without hypothyroidism, despite receiving appropriate thyroid replacement 2. This suggests levothyroxine monotherapy may be insufficient to fully resolve mood disturbances in some patients 2.
Hypersensitivity to Formulation Ingredients
Hypersensitivity reactions to inactive ingredients in thyroid hormone products can occur and may manifest with various symptoms including gastrointestinal disturbances, which could indirectly affect mood 1. Notably, some levothyroxine formulations contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions in susceptible individuals, particularly those with aspirin hypersensitivity 1.
When to Consider Formulation Change
Clinical Algorithm for Formulation Assessment
Change levothyroxine formulation when:
- TSH levels are suppressed (undetectable) indicating overdosage, which directly causes anxiety symptoms through excessive thyroid hormone 3, 1
- Anxiety/depression symptoms temporally correlate with levothyroxine initiation or dose changes 1
- Symptoms of hypersensitivity are present (urticaria, pruritus, gastrointestinal symptoms, flushing) suggesting reaction to inactive ingredients 1
- Patients have known tartrazine or aspirin sensitivity and are taking formulations containing FD&C Yellow No. 5 1
Monitoring Parameters
Monitor both psychiatric symptoms and thyroid parameters together, as mood symptoms may reflect subtle HPT axis dysfunction even when baseline thyroid levels appear normal 4. The physiological basis for this connection is that thyroid hormone receptors are widely expressed throughout the limbic system and brain regions controlling mood regulation 5, 4.
Treatment Approach Beyond Formulation Change
Optimize Levothyroxine Dosing First
Approximately one-quarter of patients receiving levothyroxine are inadvertently maintained on doses high enough to make TSH levels undetectable, which increases risk for anxiety and other adverse effects 3. Administer the minimum dose of levothyroxine that achieves the desired clinical and biochemical response 1.
Consider Adjunctive Therapy
If anxiety and depression persist despite euthyroid status on appropriate levothyroxine dosing, triiodothyronine (T3) has been successfully used as augmentation therapy in depressed patients resistant to first-line antidepressants 5. Measure free T4 and free T3 when TSH is elevated to distinguish subclinical from overt hypothyroidism 5.
Drug Interactions That Worsen Mood
Concurrent use of tricyclic or tetracyclic antidepressants with levothyroxine may increase toxic effects of both drugs, including increased risk of cardiac arrhythmias and central nervous system stimulation 1. Conversely, sertraline may increase levothyroxine requirements in stabilized patients 1.
Critical Pitfalls to Avoid
Do not assume all mood symptoms are due to hypothyroidism itself - levothyroxine overdosage is a common iatrogenic cause of anxiety that is easily corrected by dose reduction 3, 1. Women with known hypothyroidism report significantly worse self-rated health even when treated, suggesting the need for comprehensive mood assessment beyond thyroid replacement alone 3.