Insomnia and anxiety exhibit distinct short-term associations following ketamine in treatment-resistant depression
Nadia S. Hejazi, Mina Kheirkhah, Robin Chholak, Brady A. Riedner, Hamidreza Jamalabadi, Martin Walter, Stefan G Hofmann, Wallace C. Duncan, David Goldman, Carlos A. Zarate
Translational Psychiatry October 6, 2026 DOI: 10.1038/s41398-026-04443-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational pre-post study Peer reviewed |
|---|---|
| Sample size | 71 |
| Population | Patients with treatment-resistant depression |
| Intervention | Ketamine |
| Dose | 0.5 mg/kg |
| Duration | 24 hours post-ketamine |
| Measures | Montgomery–Åsberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), insomnia items from the Hamilton Depression Rating Scale (HAM-D) |
| Topics | Anxiety Depression Esketamine Ketamine |
| Registration | NCT00088699 |
| Key findings | A single 0.5 mg/kg intravenous ketamine infusion reduced depression (MADRS β = –11.72), anxiety (HAM-A β = –7.87), and insomnia (HAM-D insomnia items β = –0.89) 24 hours later. Changes in anxiety were strongly associated with changes in depression (Spearman ρ = 0.61), but changes in insomnia were not significantly associated with changes in either domain. Greater baseline insomnia severity was associated with larger absolute insomnia reductions. |
Abstract
Insomnia and anxiety frequently co-occur with treatment-resistant depression (TRD). This study examined short-term changes in depression, anxiety, and insomnia symptoms post-ketamine in TRD and their inter-relationships. Seventy-one patients with TRD were assessed at baseline and 24 h after intravenous ketamine (0.5 mg/kg). Depression, anxiety, and insomnia were measured using the Montgomery–Åsberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HAM-A), and insomnia items from the Hamilton Depression Rating Scale (HAM-D), respectively. Linear mixed-effects models tested pre–post changes, while Spearman, Pearson, and simple linear regression examined associations between symptom domains. As an exploratory analysis, linear discriminant analysis (LDA) and logistic regression were used to classify insomnia improvement. All symptom domains decreased significantly post-ketamine treatment, including depression (MADRS; β = –11.72, P < 0.001), anxiety (HAM-A; β = –7.87, P < 0.001), and insomnia ( β = –0.89, P < 0.001). At baseline, insomnia was moderately correlated with anxiety (Spearman ρ = 0.36), and anxiety was correlated with depression (Pearson r = 0.39); similar associations were observed post-ketamine (Spearman ρ = 0.36; Pearson r = 0.57). Changes in anxiety were strongly associated with changes in depression (Spearman ρ = 0.61), whereas changes in insomnia were not significantly associated with changes in either domain. Greater baseline insomnia severity was associated with larger absolute insomnia reductions. Exploratory polysomnography analyses suggested short-term increases in total sleep time, slow-wave sleep, and sleep efficiency, and reduced sleep latency. In conclusion, although all symptom domains decreased post-ketamine, short-term changes in HAM-D insomnia symptoms were not significantly associated with changes in depression or anxiety in TRD. Clinical Trial Identifier : www.clinicaltrials.gov (NCT00088699)
Comparable studies
Other non-randomized and open-label trials on ketamine for anxiety, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Rapid Resolution of Suicidal Ideation After a Single Infusion of anN-Methyl-D-Aspartate Antagonist in Patients With Treatment-Resistant Major Depressive Disorder Subjects with DSM-IV-diagnosed treatment-resistant major depressive disorder | 2010 | Open-label trial | n = 33 |
| Brain-Derived Neurotrophic Factor and Initial Antidepressant Response to anN-Methyl-D-Aspartate Antagonist Adults aged 18 to 65 years with DSM-IV major depressive disorder (treatment resistant) | 2009 | Open-label trial | n = 23 |
| Effect of Baseline Anxious Depression on Initial and Sustained Antidepressant Response to Ketamine Inpatients with treatment-resistant major depressive disorder | 2014 | Post hoc analysis of a single-arm open-label trial | n = 26 |
| A single infusion of ketamine improves depression scores in patients with anxious bipolar depression Patients with anxious (n=21) and non-anxious (n=15) treatment-resistant bipolar... | 2014 | Post-hoc analysis of a clinical trial | n = 36 |
| Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study Patients with treatment-resistant depression/anxiety who had previously demonstrated... | 2020 | Open-label flexible dose uncontrolled study | n = 7 |