Thyroid-stimulating hormone is associated with differential antidepressant and anti-anhedonic response to ketamine in bipolar depression but not major depressive disorder

Nov 27, 2025Journal of affective disorders

Thyroid-stimulating hormone levels relate to ketamine’s antidepressant and pleasure-improving effects in bipolar depression but not in major depression

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Abstract

Higher baseline thyroid-stimulating hormone (TSH) levels were associated with greater decreases in depressive and anhedonia symptoms in bipolar disorder after ketamine treatment.

In bipolar disorder, elevated baseline TSH levels correlated with significant reductions in depressive symptoms post-ketamine.
A strong association was found between higher baseline TSH levels and decreased anhedonia symptoms after ketamine administration.
No significant relationship was observed between baseline TSH levels and treatment outcomes for depression, anhedonia, or suicidal ideation in major depressive disorder.
The results may indicate that TSH could potentially serve as a biomarker for predicting ketamine response in bipolar disorder.

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BACKGROUND: No clinically useful biomarkers currently predict antidepressant response to ketamine in treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD). This study investigated whether baseline thyroid-stimulating hormone (TSH) levels are associated with ketamine's antidepressant, anti-anhedonic, and anti-suicidal effects.

METHODS: This was a secondary exploratory analysis of data drawn from four NIH-sponsored, randomized, placebo-controlled, double-blind crossover studies of ketamine in inpatients with current MDD (n = 39) or bipolar depression (n = 44). Baseline TSH levels were measured before the first intravenous saline or ketamine infusion (0.5 mg/kg). A two-week washout preceded the second infusion. Depression and anhedonia were measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale, respectively. Suicidal ideation (SI) was measured as a weighted average of the Beck Depression Inventory and the MADRS suicide items. Linear mixed models were used to evaluate baseline TSH levels as a moderator of response to ketamine (versus placebo), controlling for thyroid disease, lithium use, and depression severity at 230 min and days 1, 2, and 7 post-infusion.

RESULTS: In individuals with BD, higher baseline TSH levels were associated with greater decreases in the severity of depressive (drugTSH, p < 0.0007) and anhedonia (drugTSH, p < 0.0001) symptoms post-ketamine. TSH levels were not associated with changes in depression, anhedonia, or SI severity in MDD post-ketamine.

CONCLUSION: Baseline TSH levels were associated with ketamine's antidepressant and anti-anhedonic effects in BD but not MDD. These findings suggest that TSH may serve as a predictive biomarker of response and highlight a potential thyroid-glutamate influence in ketamine's mechanism of action.

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Thyroid-stimulating hormone is associated with differential antidepressant and anti-anhedonic response to ketamine in bipolar depression but not major depressive disorder

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