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

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 (drug*TSH, p < 0.0007) and anhedonia (drug*TSH, 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.