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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.

Brady D Greene, Adam Fijtman, Nefize Yalin, Mark D Kvarta, Philip R Wang, Mani Yavi, Dede Greenstein, Carlos A. Zarate

Journal of Affective Disorders February 15, 2026 DOI: 10.1016/j.jad.2025.120780 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Secondary exploratory analysis of four randomized, placebo-controlled, double-blind crossover studies Peer reviewed
Sample size 83
Population Inpatients with current major depressive disorder (n=39) or bipolar depression (n=44)
Intervention Ketamine
Dose 0.5 mg/kg
Duration Two-week washout between infusions; outcomes assessed at 230 min and days 1, 2, and 7 post-infusion
Measures Montgomery-Åsberg Depression Rating Scale (MADRS), Snaith-Hamilton Pleasure Scale, Beck Depression Inventory and MADRS suicide items (weighted average for suicidal ideation), thyroid-stimulating hormone (TSH)
Topics Depression Ketamine Esketamine
Keywords Bipolar depression Thyroid-stimulating hormone
Key points In bipolar depression, higher baseline TSH levels were associated with greater decreases in depressive and anhedonia symptom severity after ketamine versus placebo, while TSH was not associated with changes in depression, anhedonia, or suicidal ideation in major depressive disorder. The authors propose TSH as a potential predictive biomarker and suggest a thyroid-glutamate influence in ketamine's mechanism.

Abstract

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. 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. 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. 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.

Comparable studies

Other randomized controlled trials on ketamine for depression, most cited first.

Study Year Design Participants
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode 2013 Randomized controlled trial n = 73
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study Adults with moderate to severe nonpsychotic depression and a history of nonresponse to... 2019 Phase 3, double-blind, active-controlled, multicenter randomized controlled trial n = 227
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression Adults with treatment-resistant depression who achieved stable remission or stable... 2019 Phase 3, multicenter, double-blind, randomized withdrawal study n = 297
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression Adults with DSM-IV-TR diagnosis of major depressive disorder and history of inadequate... 2017 Phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study n = 67
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study Depressed patients at imminent risk for suicide 2018 Randomized controlled trial n = 68

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