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. 2021 Sep 12;9(9):CD011612.
doi: 10.1002/14651858.CD011612.pub3.

Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder

Rebecca L Dean  1 , Claudia Hurducas  1 , Keith Hawton  2 , Styliani Spyridi  3 , Philip J Cowen  4 , Sarah Hollingsworth  1 , Tahnee Marquardt  1 , Annabelle Barnes  1 , Rebecca Smith  1 , Rupert McShane  1   4 , Erick H Turner  5   6 , Andrea Cipriani  1   4
Affiliations

Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder

Rebecca L Dean et al. Cochrane Database Syst Rev. .

Abstract

Background: Many studies have recently been conducted to assess the antidepressant efficacy of glutamate modification in mood disorders. This is an update of a review first published in 2015 focusing on the use of glutamate receptor modulators in unipolar depression.

Objectives: To assess the effects - and review the acceptability and tolerability - of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with unipolar major depressive disorder.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase and PsycINFO all years to July 2020. We did not apply any restrictions to date, language or publication status.

Selection criteria: Double- or single-blinded randomised controlled trials (RCTs) comparing ketamine, memantine, esketamine or other glutamate receptor modulators with placebo (pill or saline infusion), other active psychotropic drugs, or electroconvulsive therapy (ECT) in adults with unipolar major depression.

Data collection and analysis: Three review authors independently identified studies, assessed trial quality and extracted data. The primary outcomes were response rate (50% reduction on a standardised rating scale) and adverse events. We decided a priori to measure the efficacy outcomes at different time points and run sensitivity/subgroup analyses. Risk of bias was assessed using the Cochrane tool, and certainty of the evidence was assessed using GRADE.

Main results: Thirty-one new studies were identified for inclusion in this updated review. Overall, we included 64 studies (5299 participants) on ketamine (31 trials), esketamine (9), memantine (5), lanicemine (4), D-cycloserine (2), Org26576 (2), riluzole (2), atomoxetine (1), basimglurant (1), citicoline (1), CP-101,606 (1), decoglurant (1), MK-0657 (1), N-acetylcysteine (1), rapastinel (1), and sarcosine (1). Forty-eight studies were placebo-controlled, and 48 were two-arm studies. The majority of trials defined an inclusion criterion for the severity of depressive symptoms at baseline: 29 at least moderate depression; 17 severe depression; and five mild-to-moderate depression. Nineteen studies recruited only patients with treatment-resistant depression, defined as inadequate response to at least two antidepressants. The majority of studies investigating ketamine administered as a single dose, whilst all of the included esketamine studies used a multiple dose regimen (most frequently twice a week for four weeks). Most studies looking at ketamine used intravenous administration, whilst the majority of esketamine trials used intranasal routes. The evidence suggests that ketamine may result in an increase in response and remission compared with placebo at 24 hours odds ratio (OR) 3.94, 95% confidence interval (CI) 1.54 to 10.10; n = 185, studies = 7, very low-certainty evidence). Ketamine may reduce depression rating scale scores over placebo at 24 hours, but the evidence is very uncertain (standardised mean difference (SMD) -0.87, 95% CI -1.26 to -0.48; n = 231, studies = 8, very low-certainty evidence). There was no difference in the number of participants assigned to ketamine or placebo who dropped out for any reason (OR 1.25, 95% CI 0.19 to 8.28; n = 201, studies = 6, very low-certainty evidence). When compared with midazolam, the evidence showed that ketamine increases remission rates at 24 hours (OR 2.21, 95% CI 0.67 to 7.32; n = 122,studies = 2, low-certainty evidence). The evidence is very uncertain about the response efficacy of ketamine at 24 hours in comparison with midazolam, and its ability to reduce depression rating scale scores at the same time point (OR 2.48, 95% CI 1.00 to 6.18; n = 296, studies = 4,very low-certainty evidence). There was no difference in the number of participants who dropped out of studies for any reason between ketamine and placebo (OR 0.33, 95% CI 0.05 to 2.09; n = 72, studies = 1, low-certainty evidence). Esketamine treatment likely results in a large increase in participants achieving remission at 24 hours compared with placebo (OR 2.74, 95% CI 1.71 to 4.40; n = 894, studies = 5, moderate-certainty evidence). Esketamine probably results in decreases in depression rating scale scores at 24 hours compared with placebo (SMD -0.31, 95% CI -0.45 to -0.17; n = 824, studies = 4, moderate-certainty evidence). Our findings show that esketamine increased response rates, although this evidence is uncertain (OR 2.11, 95% CI 1.20 to 3.68; n = 1071, studies = 5, low-certainty evidence). There was no evidence that participants assigned to esketamine treatment dropped out of trials more frequently than those assigned to placebo for any reason (OR 1.58, 95% CI 0.92 to 2.73; n = 773, studies = 4,moderate-certainty evidence). We found very little evidence for the remaining glutamate receptor modulators. We rated the risk of bias as low or unclear for most domains, though lack of detail regarding masking of treatment in the studies reduced our certainty in the effect for all outcomes.

Authors' conclusions: Our findings show that ketamine and esketamine may be more efficacious than placebo at 24 hours. How these findings translate into clinical practice, however, is not entirely clear. The evidence for use of the remaining glutamate receptor modulators is limited as very few trials were included in the meta-analyses for each comparison and the majority of comparisons included only one study. Long term non-inferiority RCTs comparing repeated ketamine and esketamine, and rigorous real-world monitoring are needed to establish comprehensive data on safety and efficacy.

Trial registration: ClinicalTrials.gov NCT02417064 NCT03039192 NCT00408031 NCT00977353 NCT03097133 NCT01304147 NCT00680433 NCT00610649 NCT02418585 NCT00491686 NCT00781742 NCT00344682 NCT01457677 NCT00986479 NCT03965871 NCT04019704 NCT04210804.

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Conflict of interest statement

Rebecca Dean: none known.

Claudia Hurducas: none known.

Sarah Hollingsworth: none known.

Tahnee Marquardt: none known.

Stella Spyridi: none known.

Phil Cowen: PJC has a patent with the University of Oxford on the use of ebselen in treatment‐resistant depression

Keith Hawton: none known.

Rupert McShane: Rupert McShane runs NHS and self‐pay ketamine clinics for Oxford Health NHS Foundation Trust. Rupert has undertaken educational and scientific advisory board work for Janssen Pharmaceuticals to support educational and research activity, no funds are received personally. Janssen supported Rupert's attendance at the APA conference in New York in 2018. Rupert has undertaken scientific advisory board work for Sage pharmaceuticals, no funds are directly received.

Erick Turner: Erick Turner has no financial interest in esketamine, ketamine or competing treatments. Erick previously worked as a Medical Officer for the US Food and Drug Administration (FDA), charged with reviewing applications submitted by pharmaceutical companies and determining whether the evidence on drug efficacy and safety met the FDA’s criteria for US marketing approval. Erick is a former member of the Psychopharmacologic Drugs Advisory Committee which, together with the Drug Safety and Risk Management Advisory Committee, convened in Feb 2019, to advise the FDA on whether to approve esketamine, although Erick did not take part in that particular meeting due to matters related to the government shutdown.

Andrea Cipriani: Andrea Cipriani has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation and Angelini Pharma.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 Ketamine versus Placebo, outcome: 1.1 Response rate.
5
5
Forest plot of comparison: 2 Ketamine versus Midazolam, outcome: 2.1 Response rate.
6
6
Forest plot of comparison: 9 Esketamine versus placebo, outcome: 9.1 Response rate.
1.1
1.1. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 1: Response rate
1.2
1.2. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 2: AE Abdominal Pain
1.3
1.3. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 3: AE Agitation/anxiety
1.4
1.4. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 4: AE Blurred vision
1.5
1.5. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 5: AE Change in blood pressure
1.6
1.6. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 6: AE Confusion
1.7
1.7. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 7: AE Dissociative symptoms
1.8
1.8. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 8: AE Dizziness
1.9
1.9. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 9: AE Emotional blunting
1.10
1.10. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 10: AE Euphoria
1.11
1.11. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 11: AE Hallucinations
1.12
1.12. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 12: AE Headache
1.13
1.13. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 13: AE Infections and Infestations
1.14
1.14. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 14: AE Loss of Appetite
1.15
1.15. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 15: AE Mania/hypomania
1.16
1.16. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 16: AE Musculoskeletal and connective tissue disorders
1.17
1.17. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 17: AE Nausea/vomiting
1.18
1.18. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 18: AE Nervousness
1.19
1.19. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 19: AE Nervous system disorders
1.20
1.20. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 20: AE Palpitations
1.21
1.21. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 21: AE Psychiatric disorders
1.22
1.22. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 22: AE Restlessness
1.23
1.23. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 23: AE Skin and subcutaneous tissue disorders
1.24
1.24. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 24: AE Suicidal Ideas
1.25
1.25. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 25: AE Tremor
1.26
1.26. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 26: Remission rate
1.27
1.27. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 27: Depression rating scale score
1.28
1.28. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 28: Suicidal ideation composite
1.29
1.29. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 29: Cognition scores
1.30
1.30. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 30: Quality of Life
1.31
1.31. Analysis
Comparison 1: Ketamine versus Placebo, Outcome 31: Acceptability
2.1
2.1. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 1: Response rate
2.2
2.2. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 2: AE Abnormal dreams
2.3
2.3. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 3: AE Agitation/anxiety
2.4
2.4. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 4: AE Back pain
2.5
2.5. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 5: AE Blurred vision
2.6
2.6. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 6: AE Chest pain
2.7
2.7. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 7: AE Chills
2.8
2.8. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 8: AE Constipation
2.9
2.9. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 9: AE Decreased energy
2.10
2.10. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 10: AE Decreased libido
2.11
2.11. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 11: AE Depression
2.12
2.12. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 12: AE Diarrhea
2.13
2.13. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 13: AE Difficulty swallowing
2.14
2.14. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 14: AE Dizziness
2.15
2.15. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 15: AE Dry mouth
2.16
2.16. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 16: AE Dry skin
2.17
2.17. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 17: AE Fatigue
2.18
2.18. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 18: AE General malaise
2.19
2.19. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 19: AE Insomnia
2.20
2.20. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 20: AE Headache
2.21
2.21. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 21: AE Increased blood pressure or heart rate
2.22
2.22. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 22: AE Increase in systolic blood pressure and heart rate
2.23
2.23. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 23: AE Increased perspiration
2.24
2.24. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 24: AE Indigestion
2.25
2.25. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 25: AE Insomnia
2.26
2.26. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 26: AE Irritability
2.27
2.27. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 27: AE Itching
2.28
2.28. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 28: AE Loss of consciousness
2.29
2.29. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 29: AE Memory problems
2.30
2.30. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 30: AE Muscle/bone/joint pain
2.31
2.31. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 31: AE Nasal congestion
2.32
2.32. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 32: AE Nausea/vomiting
2.33
2.33. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 33: AE Numbness
2.34
2.34. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 34: AE Pain in extremities
2.35
2.35. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 35: AE Palpitations
2.36
2.36. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 36: AE Poor concentration
2.37
2.37. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 37: AE Poor co‐ordination
2.38
2.38. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 38: AE Poor quality sleep
2.39
2.39. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 39: AE Rash
2.40
2.40. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 40: AE Reduced duration of sleep
2.41
2.41. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 41: AE Restlessness
2.42
2.42. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 42: AE Sensory disturbance
2.43
2.43. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 43: AE Sexual dysfunction
2.44
2.44. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 44: AE Sleepiness/drowsiness
2.45
2.45. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 45: AE Stomach or abdominal discomfort
2.46
2.46. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 46: AE Suicide attempt
2.47
2.47. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 47: AE Suicidal ideas
2.48
2.48. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 48: AE Tachycardia
2.49
2.49. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 49: AE Tinnitus
2.50
2.50. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 50: AE Tooth Abscess
2.51
2.51. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 51: AE Tremor
2.52
2.52. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 52: AE Urination issues
2.53
2.53. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 53: Remission rate
2.54
2.54. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 54: Depression rating scale score
2.55
2.55. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 55: Suicidal ideation composite
2.56
2.56. Analysis
Comparison 2: Ketamine versus Midazolam, Outcome 56: Acceptability
3.1
3.1. Analysis
Comparison 3: Ketamine versus Thiopental, Outcome 1: Response rate
3.2
3.2. Analysis
Comparison 3: Ketamine versus Thiopental, Outcome 2: AE Blood Pressure Rise
3.3
3.3. Analysis
Comparison 3: Ketamine versus Thiopental, Outcome 3: AE Delirium
3.4
3.4. Analysis
Comparison 3: Ketamine versus Thiopental, Outcome 4: AE Emergence reactions
3.5
3.5. Analysis
Comparison 3: Ketamine versus Thiopental, Outcome 5: AE Headache
3.6
3.6. Analysis
Comparison 3: Ketamine versus Thiopental, Outcome 6: AE Heart Rate Rise
3.7
3.7. Analysis
Comparison 3: Ketamine versus Thiopental, Outcome 7: AE Increased secretions
3.8
3.8. Analysis
Comparison 3: Ketamine versus Thiopental, Outcome 8: AE Nausea/vomiting
3.9
3.9. Analysis
Comparison 3: Ketamine versus Thiopental, Outcome 9: Depression rating scale score
3.10
3.10. Analysis
Comparison 3: Ketamine versus Thiopental, Outcome 10: Acceptability
4.1
4.1. Analysis
Comparison 4: Ketamine versus Methohexital, Outcome 1: Depression rating scale score
5.1
5.1. Analysis
Comparison 5: Ketamine versus Propofol, Outcome 1: Depression rating scale score
6.1
6.1. Analysis
Comparison 6: Ketamine versus Remifentanil hydrochloride, Outcome 1: Depression rating scale score
7.1
7.1. Analysis
Comparison 7: Ketamine versus Esketamine, Outcome 1: Response Rate
7.2
7.2. Analysis
Comparison 7: Ketamine versus Esketamine, Outcome 2: Cognition
8.1
8.1. Analysis
Comparison 8: Ketamine versus ECT, Outcome 1: Response rate
8.2
8.2. Analysis
Comparison 8: Ketamine versus ECT, Outcome 2: AE Increase in systolic blood pressure and heart rate
8.3
8.3. Analysis
Comparison 8: Ketamine versus ECT, Outcome 3: Remission rate
8.4
8.4. Analysis
Comparison 8: Ketamine versus ECT, Outcome 4: Depression rating scale score
9.1
9.1. Analysis
Comparison 9: Esketamine versus placebo, Outcome 1: Response rate
9.2
9.2. Analysis
Comparison 9: Esketamine versus placebo, Outcome 2: AE Aggression
9.3
9.3. Analysis
Comparison 9: Esketamine versus placebo, Outcome 3: AE Agitation/anxiety
9.4
9.4. Analysis
Comparison 9: Esketamine versus placebo, Outcome 4: AE Arrhythmia
9.5
9.5. Analysis
Comparison 9: Esketamine versus placebo, Outcome 5: AE Change in blood pressure
9.6
9.6. Analysis
Comparison 9: Esketamine versus placebo, Outcome 6: AE Constipation
9.7
9.7. Analysis
Comparison 9: Esketamine versus placebo, Outcome 7: AE Depersonalisation/derealization
9.8
9.8. Analysis
Comparison 9: Esketamine versus placebo, Outcome 8: AE Depression
9.9
9.9. Analysis
Comparison 9: Esketamine versus placebo, Outcome 9: AE Diabetic ketoacidosis
9.10
9.10. Analysis
Comparison 9: Esketamine versus placebo, Outcome 10: AE Diarrhoea
9.11
9.11. Analysis
Comparison 9: Esketamine versus placebo, Outcome 11: AE Dissociative symptoms
9.12
9.12. Analysis
Comparison 9: Esketamine versus placebo, Outcome 12: AE Dizziness
9.13
9.13. Analysis
Comparison 9: Esketamine versus placebo, Outcome 13: AE Dizziness postural
9.14
9.14. Analysis
Comparison 9: Esketamine versus placebo, Outcome 14: AE Double vision
9.15
9.15. Analysis
Comparison 9: Esketamine versus placebo, Outcome 15: AE Euphoria
9.16
9.16. Analysis
Comparison 9: Esketamine versus placebo, Outcome 16: AE Fatigue
9.17
9.17. Analysis
Comparison 9: Esketamine versus placebo, Outcome 17: AE Feeling drunk
9.18
9.18. Analysis
Comparison 9: Esketamine versus placebo, Outcome 18: AE Headache
9.19
9.19. Analysis
Comparison 9: Esketamine versus placebo, Outcome 19: AE Hypertransaminasemia
9.20
9.20. Analysis
Comparison 9: Esketamine versus placebo, Outcome 20: AE Increased sweating
9.21
9.21. Analysis
Comparison 9: Esketamine versus placebo, Outcome 21: AE Infections and Infestations
9.22
9.22. Analysis
Comparison 9: Esketamine versus placebo, Outcome 22: AE Insomnia
9.23
9.23. Analysis
Comparison 9: Esketamine versus placebo, Outcome 23: AE Lethargy
9.24
9.24. Analysis
Comparison 9: Esketamine versus placebo, Outcome 24: AE Mental impairment
9.25
9.25. Analysis
Comparison 9: Esketamine versus placebo, Outcome 25: AE Nasal discomfort
9.26
9.26. Analysis
Comparison 9: Esketamine versus placebo, Outcome 26: AE Nausea/vomiting
9.27
9.27. Analysis
Comparison 9: Esketamine versus placebo, Outcome 27: AE Paresthesia/neuropathy exacerbation
9.28
9.28. Analysis
Comparison 9: Esketamine versus placebo, Outcome 28: AE Pericardial effusion
9.29
9.29. Analysis
Comparison 9: Esketamine versus placebo, Outcome 29: AE Pneumothorax
9.30
9.30. Analysis
Comparison 9: Esketamine versus placebo, Outcome 30: AE Sensory disturbance
9.31
9.31. Analysis
Comparison 9: Esketamine versus placebo, Outcome 31: AE Sedation
9.32
9.32. Analysis
Comparison 9: Esketamine versus placebo, Outcome 32: AE Sleepiness/drowsiness
9.33
9.33. Analysis
Comparison 9: Esketamine versus placebo, Outcome 33: AE Sore throat
9.34
9.34. Analysis
Comparison 9: Esketamine versus placebo, Outcome 34: AE Suicide attempt
9.35
9.35. Analysis
Comparison 9: Esketamine versus placebo, Outcome 35: AE Suicidal ideas
9.36
9.36. Analysis
Comparison 9: Esketamine versus placebo, Outcome 36: AE Taste perversion
9.37
9.37. Analysis
Comparison 9: Esketamine versus placebo, Outcome 37: AE Tremor
9.38
9.38. Analysis
Comparison 9: Esketamine versus placebo, Outcome 38: AE Urination issues
9.39
9.39. Analysis
Comparison 9: Esketamine versus placebo, Outcome 39: AE Vertigo
9.40
9.40. Analysis
Comparison 9: Esketamine versus placebo, Outcome 40: AE Vision blurred
9.41
9.41. Analysis
Comparison 9: Esketamine versus placebo, Outcome 41: Remission rate
9.42
9.42. Analysis
Comparison 9: Esketamine versus placebo, Outcome 42: Depression rating scale score
9.43
9.43. Analysis
Comparison 9: Esketamine versus placebo, Outcome 43: Suicidal ideation composite
9.44
9.44. Analysis
Comparison 9: Esketamine versus placebo, Outcome 44: Acceptability
10.1
10.1. Analysis
Comparison 10: Memantine versus Placebo, Outcome 1: Response rate
10.2
10.2. Analysis
Comparison 10: Memantine versus Placebo, Outcome 2: AE Abdominal Pain
10.3
10.3. Analysis
Comparison 10: Memantine versus Placebo, Outcome 3: AE Active suicidal ideation
10.4
10.4. Analysis
Comparison 10: Memantine versus Placebo, Outcome 4: AE Agitation/anxiety
10.5
10.5. Analysis
Comparison 10: Memantine versus Placebo, Outcome 5: AE Appetite increase
10.6
10.6. Analysis
Comparison 10: Memantine versus Placebo, Outcome 6: AE Back pain
10.7
10.7. Analysis
Comparison 10: Memantine versus Placebo, Outcome 7: AE Balance or gait problems
10.8
10.8. Analysis
Comparison 10: Memantine versus Placebo, Outcome 8: AE Carbohydrate craving
10.9
10.9. Analysis
Comparison 10: Memantine versus Placebo, Outcome 9: AE Chest pain
10.10
10.10. Analysis
Comparison 10: Memantine versus Placebo, Outcome 10: AE Chills
10.11
10.11. Analysis
Comparison 10: Memantine versus Placebo, Outcome 11: AE Clammy hands
10.12
10.12. Analysis
Comparison 10: Memantine versus Placebo, Outcome 12: AE Confusion/decreased mental clarity
10.13
10.13. Analysis
Comparison 10: Memantine versus Placebo, Outcome 13: AE Conjunctival swelling
10.14
10.14. Analysis
Comparison 10: Memantine versus Placebo, Outcome 14: AE Constipation
10.15
10.15. Analysis
Comparison 10: Memantine versus Placebo, Outcome 15: AE Decreased appetite
10.16
10.16. Analysis
Comparison 10: Memantine versus Placebo, Outcome 16: AE Delusions
10.17
10.17. Analysis
Comparison 10: Memantine versus Placebo, Outcome 17: AE Diaphoresis
10.18
10.18. Analysis
Comparison 10: Memantine versus Placebo, Outcome 18: AE Difficulty breathing
10.19
10.19. Analysis
Comparison 10: Memantine versus Placebo, Outcome 19: AE Dissociative symptoms
10.20
10.20. Analysis
Comparison 10: Memantine versus Placebo, Outcome 20: AE Dizziness
10.21
10.21. Analysis
Comparison 10: Memantine versus Placebo, Outcome 21: AE Dry mouth
10.22
10.22. Analysis
Comparison 10: Memantine versus Placebo, Outcome 22: AE Dyskinesia
10.23
10.23. Analysis
Comparison 10: Memantine versus Placebo, Outcome 23: AE Dyspepsia
10.24
10.24. Analysis
Comparison 10: Memantine versus Placebo, Outcome 24: AE Ear pain/jaw pain
10.25
10.25. Analysis
Comparison 10: Memantine versus Placebo, Outcome 25: AE Emotional lability
10.26
10.26. Analysis
Comparison 10: Memantine versus Placebo, Outcome 26: AE Eye photosensitivity
10.27
10.27. Analysis
Comparison 10: Memantine versus Placebo, Outcome 27: AE Facial twitching
10.28
10.28. Analysis
Comparison 10: Memantine versus Placebo, Outcome 28: AE Falls
10.29
10.29. Analysis
Comparison 10: Memantine versus Placebo, Outcome 29: AE Fatigue
10.30
10.30. Analysis
Comparison 10: Memantine versus Placebo, Outcome 30: AE Feeling flushed/hot
10.31
10.31. Analysis
Comparison 10: Memantine versus Placebo, Outcome 31: AE Generalised aches
10.32
10.32. Analysis
Comparison 10: Memantine versus Placebo, Outcome 32: AE Head pressure/ear pressure
10.33
10.33. Analysis
Comparison 10: Memantine versus Placebo, Outcome 33: AE Headache
10.34
10.34. Analysis
Comparison 10: Memantine versus Placebo, Outcome 34: AE Heart palpitations
10.35
10.35. Analysis
Comparison 10: Memantine versus Placebo, Outcome 35: AE Hypomania/mania
10.36
10.36. Analysis
Comparison 10: Memantine versus Placebo, Outcome 36: AE Increased menstrual pain
10.37
10.37. Analysis
Comparison 10: Memantine versus Placebo, Outcome 37: AE Insomnia
10.38
10.38. Analysis
Comparison 10: Memantine versus Placebo, Outcome 38: AE Internal sensation of speed or rapid thoughts
10.39
10.39. Analysis
Comparison 10: Memantine versus Placebo, Outcome 39: AE Irritability
10.40
10.40. Analysis
Comparison 10: Memantine versus Placebo, Outcome 40: AE Leg weakness
10.41
10.41. Analysis
Comparison 10: Memantine versus Placebo, Outcome 41: AE Nausea
10.42
10.42. Analysis
Comparison 10: Memantine versus Placebo, Outcome 42: AE Nightmares
10.43
10.43. Analysis
Comparison 10: Memantine versus Placebo, Outcome 43: AE Paresthesia/neuropathy exacerbation
10.44
10.44. Analysis
Comparison 10: Memantine versus Placebo, Outcome 44: AE Passive suicidal ideation
10.45
10.45. Analysis
Comparison 10: Memantine versus Placebo, Outcome 45: AE Perceived weight gain
10.46
10.46. Analysis
Comparison 10: Memantine versus Placebo, Outcome 46: AE Perceived weight loss
10.47
10.47. Analysis
Comparison 10: Memantine versus Placebo, Outcome 47: AE Pruritus
10.48
10.48. Analysis
Comparison 10: Memantine versus Placebo, Outcome 48: AE Rash
10.49
10.49. Analysis
Comparison 10: Memantine versus Placebo, Outcome 49: AE Sedation
10.50
10.50. Analysis
Comparison 10: Memantine versus Placebo, Outcome 50: AE Skin lesion
10.51
10.51. Analysis
Comparison 10: Memantine versus Placebo, Outcome 51: AE Sleepiness/drowsiness
10.52
10.52. Analysis
Comparison 10: Memantine versus Placebo, Outcome 52: AE Sleepwalking
10.53
10.53. Analysis
Comparison 10: Memantine versus Placebo, Outcome 53: AE Sore throat
10.54
10.54. Analysis
Comparison 10: Memantine versus Placebo, Outcome 54: AE Taste perversion
10.55
10.55. Analysis
Comparison 10: Memantine versus Placebo, Outcome 55: AE Tinnitus
10.56
10.56. Analysis
Comparison 10: Memantine versus Placebo, Outcome 56: AE Upper respiratory infection symptoms
10.57
10.57. Analysis
Comparison 10: Memantine versus Placebo, Outcome 57: AE Vomiting
10.58
10.58. Analysis
Comparison 10: Memantine versus Placebo, Outcome 58: AE Worsened acne
10.59
10.59. Analysis
Comparison 10: Memantine versus Placebo, Outcome 59: AE Worsened sleep apnoea
10.60
10.60. Analysis
Comparison 10: Memantine versus Placebo, Outcome 60: Remission rate
10.61
10.61. Analysis
Comparison 10: Memantine versus Placebo, Outcome 61: Depression scale rating score
10.62
10.62. Analysis
Comparison 10: Memantine versus Placebo, Outcome 62: Quality of life
10.63
10.63. Analysis
Comparison 10: Memantine versus Placebo, Outcome 63: Acceptability
10.64
10.64. Analysis
Comparison 10: Memantine versus Placebo, Outcome 64: Acceptability ‐ adverse events
11.1
11.1. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 1: Response rate
11.2
11.2. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 2: AE Agitation/anxiety
11.3
11.3. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 3: AE Back pain
11.4
11.4. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 4: AE Blood Pressure Rise
11.5
11.5. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 5: AE Dissociative symptoms
11.6
11.6. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 6: AE Dizziness
11.7
11.7. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 7: AE Dry mouth
11.8
11.8. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 8: AE Feeling drunk
11.9
11.9. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 9: AE Insomnia
11.10
11.10. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 10: AE Muscle/bone/joint pain
11.11
11.11. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 11: AE Nausea
11.12
11.12. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 12: AE Rash
11.13
11.13. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 13: AE Sedation
11.14
11.14. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 14: AE Upper respiratory infection symptoms
11.15
11.15. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 15: AE Vomiting
11.16
11.16. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 16: AE Weight gain
11.17
11.17. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 17: Remission rate
11.18
11.18. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 18: Depression rating scale score
11.19
11.19. Analysis
Comparison 11: Lanicemine (AZD6765) versus Placebo, Outcome 19: Acceptability
12.1
12.1. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 1: Response rate
12.2
12.2. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 2: AE Abnormal dreams
12.3
12.3. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 3: AE Back pain
12.4
12.4. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 4: AE Disturbance in attention
12.5
12.5. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 5: AE Dizziness
12.6
12.6. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 6: AE Fatigue
12.7
12.7. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 7: AE Feeling drunk
12.8
12.8. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 8: AE Headache
12.9
12.9. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 9: AE Insomnia
12.10
12.10. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 10: AE Irritability
12.11
12.11. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 11: AE Muscle twitching
12.12
12.12. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 12: AE Nasal congestion
12.13
12.13. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 13: AE Nausea
12.14
12.14. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 14: AE Palpitations
12.15
12.15. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 15: AE Post‐lumbar puncture syndrome
12.16
12.16. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 16: AE Rash
12.17
12.17. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 17: AE Sedation
12.18
12.18. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 18: AE Sensory disturbance
12.19
12.19. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 19: AE Sleepiness/drowsiness
12.20
12.20. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 20: AE Total
12.21
12.21. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 21: Remission rate
12.22
12.22. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 22: Depression rating scale score
12.23
12.23. Analysis
Comparison 12: Org 26576 versus Placebo, Outcome 23: Acceptability ‐ adverse events
13.1
13.1. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 1: Response rate
13.2
13.2. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 2: AE Abdominal Pain
13.3
13.3. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 3: AE Appetite decrease
13.4
13.4. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 4: AE Appetite increase
13.5
13.5. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 5: AE Agitation/anxiety
13.6
13.6. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 6: AE Blurred vision
13.7
13.7. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 7: AE Chest pain
13.8
13.8. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 8: AE Concentration difficulty
13.9
13.9. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 9: AE Confusion
13.10
13.10. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 10: AE Constipation
13.11
13.11. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 11: AE Coughing
13.12
13.12. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 12: AE Cramps
13.13
13.13. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 13: AE Decreased appetite
13.14
13.14. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 14: AE Decreased motor activity
13.15
13.15. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 15: AE Decreased libido
13.16
13.16. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 16: AE Dental problems
13.17
13.17. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 17: AE Depression
13.18
13.18. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 18: AE Dermatologic/skin irritation/lesions
13.19
13.19. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 19: AE Diarrhoea
13.20
13.20. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 20: AE Dizziness
13.21
13.21. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 21: AE Dry mouth
13.22
13.22. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 22: AE Eye irritation
13.23
13.23. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 23: AE Flatulence
13.24
13.24. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 24: AE Flu/upper respiratory infection
13.25
13.25. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 25: AE Genital discomfort
13.26
13.26. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 26: AE Gum problems
13.27
13.27. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 27: AE Headache
13.28
13.28. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 28: AE Increased libido
13.29
13.29. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 29: AE Increased thirst
13.30
13.30. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 30: AE Insomnia
13.31
13.31. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 31: AE Irritability
13.32
13.32. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 32: AE Memory problems
13.33
13.33. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 33: AE Mouth ulcer
13.34
13.34. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 34: AE Muscle/bone/joint pain
13.35
13.35. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 35: AE Nasal congestion
13.36
13.36. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 36: AE Nausea
13.37
13.37. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 37: AE Oedema
13.38
13.38. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 38: AE Sexual dysfunction
13.39
13.39. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 39: AE Shortness of breath
13.40
13.40. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 40: AE Sleepiness/drowsiness
13.41
13.41. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 41: AE Sore throat
13.42
13.42. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 42: AE Sore tongue
13.43
13.43. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 43: AE Stomach or abdominal discomfort
13.44
13.44. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 44: AE Suicidal ideas
13.45
13.45. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 45: AE Sweating
13.46
13.46. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 46: AE Tachycardia
13.47
13.47. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 47: AE Tinnitus
13.48
13.48. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 48: AE Tiredness/fatigue
13.49
13.49. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 49: AE Urination problems
13.50
13.50. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 50: AE Weight gain
13.51
13.51. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 51: AE Weight loss
13.52
13.52. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 52: Remission rate
13.53
13.53. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 53: Depression rating scale score
13.54
13.54. Analysis
Comparison 13: Riluzole versus Placebo, Outcome 54: Acceptability
14.1
14.1. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 1: Response rate
14.2
14.2. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 2: AE Agitation/anxiety
14.3
14.3. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 3: AE Constipation
14.4
14.4. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 4: AE Depressed mood
14.5
14.5. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 5: AE Diarrhea
14.6
14.6. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 6: AE Dizziness
14.7
14.7. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 7: AE Dry mouth
14.8
14.8. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 8: AE Fatigue
14.9
14.9. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 9: AE Flatulence
14.10
14.10. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 10: AE Headache
14.11
14.11. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 11: AE Increased sweating
14.12
14.12. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 12: AE Insomnia
14.13
14.13. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 13: AE Nasopharyngitis
14.14
14.14. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 14: AE Nausea
14.15
14.15. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 15: AE Tremor
14.16
14.16. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 16: Remission rate
14.17
14.17. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 17: Depression rating scale score
14.18
14.18. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 18: Acceptability
14.19
14.19. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 19: Acceptability ‐ adverse events
14.20
14.20. Analysis
Comparison 14: Atomoxetine versus Placebo, Outcome 20: Acceptability ‐ lack of efficacy
15.1
15.1. Analysis
Comparison 15: Basimglurant versus Placebo, Outcome 1: Response rate
15.2
15.2. Analysis
Comparison 15: Basimglurant versus Placebo, Outcome 2: AE Dizziness
15.3
15.3. Analysis
Comparison 15: Basimglurant versus Placebo, Outcome 3: AE Dry mouth
15.4
15.4. Analysis
Comparison 15: Basimglurant versus Placebo, Outcome 4: AE Fatigue
15.5
15.5. Analysis
Comparison 15: Basimglurant versus Placebo, Outcome 5: AE Headache
15.6
15.6. Analysis
Comparison 15: Basimglurant versus Placebo, Outcome 6: AE Insomnia
15.7
15.7. Analysis
Comparison 15: Basimglurant versus Placebo, Outcome 7: AE Nasopharyngitis
15.8
15.8. Analysis
Comparison 15: Basimglurant versus Placebo, Outcome 8: AE Nausea
15.9
15.9. Analysis
Comparison 15: Basimglurant versus Placebo, Outcome 9: Remission rate
15.10
15.10. Analysis
Comparison 15: Basimglurant versus Placebo, Outcome 10: Depression rating scale score
16.1
16.1. Analysis
Comparison 16: Citicoline versus Placebo, Outcome 1: Response rate
16.2
16.2. Analysis
Comparison 16: Citicoline versus Placebo, Outcome 2: AE Abdominal Pain
16.3
16.3. Analysis
Comparison 16: Citicoline versus Placebo, Outcome 3: AE Appetite decrease
16.4
16.4. Analysis
Comparison 16: Citicoline versus Placebo, Outcome 4: AE Appetite increase
16.5
16.5. Analysis
Comparison 16: Citicoline versus Placebo, Outcome 5: AE Dizziness
16.6
16.6. Analysis
Comparison 16: Citicoline versus Placebo, Outcome 6: AE Diarrhoea
16.7
16.7. Analysis
Comparison 16: Citicoline versus Placebo, Outcome 7: AE Headache
16.8
16.8. Analysis
Comparison 16: Citicoline versus Placebo, Outcome 8: AE Insomnia
16.9
16.9. Analysis
Comparison 16: Citicoline versus Placebo, Outcome 9: AE Nausea
16.10
16.10. Analysis
Comparison 16: Citicoline versus Placebo, Outcome 10: AE Sedation
16.11
16.11. Analysis
Comparison 16: Citicoline versus Placebo, Outcome 11: Remission rate
17.1
17.1. Analysis
Comparison 17: CP‐101,606 versus Placebo, Outcome 1: AE Change in blood pressure
17.2
17.2. Analysis
Comparison 17: CP‐101,606 versus Placebo, Outcome 2: AE Dissociative reaction
17.3
17.3. Analysis
Comparison 17: CP‐101,606 versus Placebo, Outcome 3: Depression rating scale score
17.4
17.4. Analysis
Comparison 17: CP‐101,606 versus Placebo, Outcome 4: Acceptability
18.1
18.1. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 1: Response rate
18.2
18.2. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 2: AE Agitation/anxiety
18.3
18.3. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 3: AE Concentration difficulties
18.4
18.4. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 4: AE Constipation
18.5
18.5. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 5: AE Failing memory
18.6
18.6. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 6: AE Headache
18.7
18.7. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 7: AE Increased dream activity
18.8
18.8. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 8: AE Increased duration of sleep
18.9
18.9. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 9: AE Increased sexual desire
18.10
18.10. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 10: AE Increased tendency to sweat
18.11
18.11. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 11: AE Nausea/vomiting
18.12
18.12. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 12: AE Palpitation/tachycardia
18.13
18.13. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 13: AE Sleepiness/drowsiness
18.14
18.14. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 14: AE Urination issues
18.15
18.15. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 15: Remission rate
18.16
18.16. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 16: Depression rating scale score
18.17
18.17. Analysis
Comparison 18: D‐cycloserine versus Placebo, Outcome 17: Acceptability
19.1
19.1. Analysis
Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 1: Response Rate
19.2
19.2. Analysis
Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 2: AE Diarrhea
19.3
19.3. Analysis
Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 3: AE Dizziness
19.4
19.4. Analysis
Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 4: AE Headache
19.5
19.5. Analysis
Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 5: AE Nausea
19.6
19.6. Analysis
Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 6: AE Sleepiness/drowsiness
19.7
19.7. Analysis
Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 7: AE Vomiting
19.8
19.8. Analysis
Comparison 19: Decoglurant (mGlu2/3) versus placebo, Outcome 8: Remission rate
20.1
20.1. Analysis
Comparison 20: MK‐0657 versus Placebo, Outcome 1: Depression rating scale score
21.1
21.1. Analysis
Comparison 21: N‐acetylcysteine versus Placebo, Outcome 1: Response rate
21.2
21.2. Analysis
Comparison 21: N‐acetylcysteine versus Placebo, Outcome 2: AE Back pain
21.3
21.3. Analysis
Comparison 21: N‐acetylcysteine versus Placebo, Outcome 3: AE Gastrointestinal problems
21.4
21.4. Analysis
Comparison 21: N‐acetylcysteine versus Placebo, Outcome 4: AE Joint pain
21.5
21.5. Analysis
Comparison 21: N‐acetylcysteine versus Placebo, Outcome 5: AE Muscle spasms
21.6
21.6. Analysis
Comparison 21: N‐acetylcysteine versus Placebo, Outcome 6: Remission rate
21.7
21.7. Analysis
Comparison 21: N‐acetylcysteine versus Placebo, Outcome 7: Depression rating scale score
21.8
21.8. Analysis
Comparison 21: N‐acetylcysteine versus Placebo, Outcome 8: Quality of life
21.9
21.9. Analysis
Comparison 21: N‐acetylcysteine versus Placebo, Outcome 9: Acceptability
21.10
21.10. Analysis
Comparison 21: N‐acetylcysteine versus Placebo, Outcome 10: Acceptability ‐ adverse events
22.1
22.1. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 1: Response rate
22.2
22.2. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 2: AE Total
22.3
22.3. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 3: AE Agitation/anxiety
22.4
22.4. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 4: AE Asthenia/increased fatigability
22.5
22.5. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 5: AE Constipation
22.6
22.6. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 6: AE Concentration difficulties
22.7
22.7. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 7: AE Depression
22.8
22.8. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 8: AE Dizziness
22.9
22.9. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 9: AE Dystonia
22.10
22.10. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 10: AE Headache/migraine
22.11
22.11. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 11: AE Increased dream activity
22.12
22.12. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 12: AE Increased duration of sleep
22.13
22.13. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 13: AE Nausea/vomiting
22.14
22.14. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 14: AE Palpitations/tachycardia
22.15
22.15. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 15: AE Reduced duration of sleep
22.16
22.16. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 16: AE Sleepiness/drowsiness
22.17
22.17. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 17: AE Tremor
22.18
22.18. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 18: AE Weight gain
22.19
22.19. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 19: AE Weight loss
22.20
22.20. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 20: Remission rate
22.21
22.21. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 21: Depression rating scale score
22.22
22.22. Analysis
Comparison 22: Sarcosine versus Citalopram, Outcome 22: Acceptability
23.1
23.1. Analysis
Comparison 23: Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 1: Response rate
23.2
23.2. Analysis
Comparison 23: Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 2: Remission rate
23.3
23.3. Analysis
Comparison 23: Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 3: Depression rating scale score
23.4
23.4. Analysis
Comparison 23: Ketamine versus Placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 4: Suicidal ideation composite
24.1
24.1. Analysis
Comparison 24: Ketamine versus Placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 1: Response rate
24.2
24.2. Analysis
Comparison 24: Ketamine versus Placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 2: Remission rate
24.3
24.3. Analysis
Comparison 24: Ketamine versus Placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 3: Depression rating scale score
25.1
25.1. Analysis
Comparison 25: Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 1: Response rate
25.2
25.2. Analysis
Comparison 25: Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 2: Remission rate
25.3
25.3. Analysis
Comparison 25: Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 3: Depression rating scale score
25.4
25.4. Analysis
Comparison 25: Esketamine versus placebo (pre‐planned subgroup analysis: outpatient treatment setting), Outcome 4: Suicidal ideation composite
26.1
26.1. Analysis
Comparison 26: Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 1: Response rate
26.2
26.2. Analysis
Comparison 26: Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 2: Remission rate
26.3
26.3. Analysis
Comparison 26: Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 3: Depression rating scale score
26.4
26.4. Analysis
Comparison 26: Esketamine versus placebo (pre‐planned subgroup analysis: inpatient treatment setting), Outcome 4: Suicidal ideation composite
27.1
27.1. Analysis
Comparison 27: Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years), Outcome 1: Response rate
27.2
27.2. Analysis
Comparison 27: Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years), Outcome 2: Remission rate
27.3
27.3. Analysis
Comparison 27: Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years), Outcome 3: Depression rating scale score
27.4
27.4. Analysis
Comparison 27: Esketamine versus placebo (pre‐planned subgroup analysis: excluding elderly populations >65 years), Outcome 4: Suicidal ideation composite
28.1
28.1. Analysis
Comparison 28: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 1: Response rate
28.2
28.2. Analysis
Comparison 28: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 2: Remission rate
28.3
28.3. Analysis
Comparison 28: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 3: Depression rating scale score
28.4
28.4. Analysis
Comparison 28: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 4: Suicidal ideation composite
29.1
29.1. Analysis
Comparison 29: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 1: Response rate
29.2
29.2. Analysis
Comparison 29: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 2: Remission rate
29.3
29.3. Analysis
Comparison 29: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 3: Depression rating scale score
30.1
30.1. Analysis
Comparison 30: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 1: Response rate
30.2
30.2. Analysis
Comparison 30: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 2: Remission rate
30.3
30.3. Analysis
Comparison 30: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 3: Depression rating scale score
30.4
30.4. Analysis
Comparison 30: Ketamine versus Placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 4: Suicidal ideation composite
31.1
31.1. Analysis
Comparison 31: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses), Outcome 1: Response rate
31.2
31.2. Analysis
Comparison 31: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses), Outcome 2: Remission rate
31.3
31.3. Analysis
Comparison 31: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses), Outcome 3: Depression rating scale score
31.4
31.4. Analysis
Comparison 31: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding multiple doses), Outcome 4: Suicidal ideation composite
32.1
32.1. Analysis
Comparison 32: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies), Outcome 1: Response rate
32.2
32.2. Analysis
Comparison 32: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies), Outcome 2: Remission rate
32.3
32.3. Analysis
Comparison 32: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies), Outcome 3: Depression rating scale score
32.4
32.4. Analysis
Comparison 32: Ketamine versus Placebo (post‐hoc sensitivity analysis: excluding add‐on ECT studies), Outcome 4: Suicidal ideation composite
33.1
33.1. Analysis
Comparison 33: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 1: Response rate
33.2
33.2. Analysis
Comparison 33: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 2: Remission rate
33.3
33.3. Analysis
Comparison 33: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 3: Depression rating scale score
33.4
33.4. Analysis
Comparison 33: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding studies that included participants with bipolar disorder or psychotic features), Outcome 4: Suicidal ideation composite
34.1
34.1. Analysis
Comparison 34: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 1: Response rate
34.2
34.2. Analysis
Comparison 34: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 2: Remission rate
34.3
34.3. Analysis
Comparison 34: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 3: Depression rating scale score
34.4
34.4. Analysis
Comparison 34: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding TRD populations), Outcome 4: Suicidal ideation composite
35.1
35.1. Analysis
Comparison 35: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 1: Response rate
35.2
35.2. Analysis
Comparison 35: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 2: Remission rate
35.3
35.3. Analysis
Comparison 35: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 3: Depression rating scale score
35.4
35.4. Analysis
Comparison 35: Esketamine versus placebo (pre‐planned sensitivity analysis: excluding trials with a dropout rate greater than 20%, Outcome 4: Suicidal ideation composite
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References

References to studies included in this review

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Fava 2018 {published and unpublished data}
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Fernie 2017 {published data only}
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Gálvez 2018 {published data only}
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Grunebaum 2018 {published data only}
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Ibrahim 2012a {published and unpublished data}
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Nations 2012 (part II) {published and unpublished data}
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Ochs‐Ross 2020 {published data only}
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Popova 2019 {published and unpublished data}
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Preskorn 2008 {published and unpublished data}
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Quiroz 2016 {published data only}
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Roohi‐Azizi 2017 {published data only}
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Salardini 2016 {published data only}
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Salehi 2015 {published data only}
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Sanacora 2014 (a) {published and unpublished data}
    1. Sanacora G, Smith MA, Pathak S, Su HL, Boeijinga PH, McCarthy DJ, et al. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Molecular Psychiatry 2014;19(9):978-85. - PMC - PubMed
Sanacora 2014 (b) {published and unpublished data}
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Sanacora 2017 {published data only}
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Shams Alizadeh 2015 {published data only}
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Shiroma 2020 {published and unpublished data}
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Singh 2016 a {published data only}
    1. Singh JB, Fedgchin M, Dally EJ, De Boer P, Cooper K, Lim P, et al. A Double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. American Journal of Psychiatry August 2016;173(8):816-26. [DOI: 10.1176/appi.ajp.2016.16010037] - DOI - PubMed
Singh 2016 b {published data only}
    1. Singh JB, Fedgchin M, Daly E, Xi L, Melman C, De Bruecker G, Tadic A, Sienaert P, Wiegand F, Manji H, Drevets WC, Van Nueten L. Intravenous esketamine in adult treatment-resistant depression: A double-blind, double-randomization, placebo-controlled study. Biological Psychiatry September 2016;80:424-431. [DOI: 10.1016/j.biopsych.2015.10.018] - DOI - PubMed
Smith 2013 {published and unpublished data}
    1. Smith EG, Deligiannidis KM, Ulbricht CM, Landolin CS, Patel JK, Rothschild AJ. Antidepressant augmentation using the N-methyl-D-aspartate antagonist memantine: A randomized, double-blind, placebo-controlled trial. Journal of Clinical Psychiatry Diseases of the Nervous System 2013;74:966-73. - PMC - PubMed
Sos 2013 {published and unpublished data}
    1. Sos P, Klirova M, Novak T, Kohutova B, Horacek J, Palenicek T. Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinology Letters 2013;34(4):287-93. - PubMed
Su 2017 {published data only}
    1. Chen MH, Lin WC, Tu PC, Li CT, Bai YM, Tsai SJ, et al. Antidepressant and antisuicidal effects of ketamine on the functional connectivity of prefrontal cortex-related circuits in treatment-resistant depression: a double-blind, placebo-controlled, randomized, longitudinal resting fMRI study. Journal of Affected Disorders 2019;259:15-20. [CLINICAL TRIAL REGISTRATION: R000019001- UMIN000016985] [DOI: ] - PubMed
    1. Su T-P, Chen M-H, Li C-T, Lin W-C, Hong C-J, Gueorguieva R, et al. Dose-related effects of adjunctive ketamine in Taiwanese patients with treatment-resistant depression. Neuropsychopharmacology 2017;42(13):2482-92. - PMC - PubMed
Sumner 2020 {published and unpublished data}
    1. Sumner RL, McMillian R, Spriggs MJ, Campbell D, Malpas G, Maxwell E, Deng C, Hay J, Ponton R, Kirk IJ, Sundram F, Muthukumaraswamy SD. Ketamine Enhances Visual Sensory Evoked Potential Long-term Potentiation in Patients With Major Depressive Disorder. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging 2020;5(1):45-55. [DOI: 10.1016/j.bpsc.2019.07.002] - DOI - PubMed
Tiger 2020 {published and unpublished data}
    1. Tiger M, Veldman ER, Ekman C-J, Halldin C, Svenningsson P, Lundberg J. A randomized placebo-controlled PET study of ketamine's effect on serotonin1B receptor binding in patients with SSRI-resistant depression. Translational Psychiatry 2020;10(1):159. [DOI: ] - PMC - PubMed
Umbricht 2020 {published data only (unpublished sought but not used)}
    1. Umbricht D, Niggli M, Sanwald-Ducray P, Deptula D, Moore R, Grunbauer W, et al. Randomised, double-blind, placebo-controlled trial of the mglu2/3 negative allosteric modulator decoglurant in partially refractory major depressive disorder. Journal of Clinical Psychiatry 2020;81(4):18m12470. [DOI: 10.4088/JCP.18m12470] - DOI - PubMed
Yoosefi 2014 {published and unpublished data}
    1. Yoosefi A, Sepehri AS, Kargar M, Akhondzadeh S, Sadeghi M, Rafei A, et al. Comparing effects of ketamine and thiopental administration during electroconvulsive therapy in patients with major depressive disorder: a randomized, double-blind study. Journal of ECT 2014;30:15-21. - PubMed
Zarate 2006a {published and unpublished data}
    1. Zarate C, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry 2006;63:856-64. - PubMed
Zarate 2006b {published and unpublished data}
    1. Zarate C, Singh JB, Quiroz JA, De JG, Denicoff KK, Luckenbaugh DA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. American Journal of Psychiatry 2006;163:153-5. - PubMed
Zarate 2013 {published and unpublished data}
    1. Zarate C, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, et al. A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biological Psychiatry 2013;74:257-64. - PMC - PubMed

References to studies excluded from this review

Aftanas 2019 {published data only}
    1. Aftanas LI, Bazanova OM, Khabarov AN, Pustovoit SM, Brack IV. Placebo-controlled study of xenon effect on the emotions and frequency of the EEG alpha-oscillations [Russian]. Vestnik Rossiiskoi Akademii Meditsinskikh Nauk 2019;74(5):342-50.
Barzman 2005 {published data only}
    1. Barzman DH, DelBello MP, Kowatch RA, Gernert B, Fleck DE, Pathak S, et al. The effectiveness and tolerability of aripiprazole for pediatric bipolar disorders: A retrospective chart review. Journal of Child and Adolescent Psychopharmacology 2005;14:593-600. - PubMed
Bondolfi 2000 {published data only}
    1. Bondolfi G, Lissner C, Kosel M, Eap CB, Baumann P. Fluoxetine augmentation in citalopram non-responders: Pharmacokinetic and clinical consequences. International Journal of Neuropsychopharmacology 2000;3:55-60. - PubMed
Burger 2016 {published data only}
    1. Burger J, Capobianco M, Lovern R, Boche B, Ross E, Darracq MA, et al. A double-blinded, randomized, placebo-controlled sub-dissociative dose ketamine pilot study in the treatment of acute depression and suicidality in a military emergency department setting. Military Medicine 2016;181(10):1195-9. - PubMed
Chen 2020 {published data only}
    1. Chen MH, Lin WC, Wu HJ, Bai YM, Li CT, Tsai SJ, et al. Efficacy of low-dose ketamine infusion in anxious vs nonanxious depression: revisiting the adjunctive ketamine study of Taiwanese patients with treatment-resistant depression. CNS Spectrums 2020;26(4):1-6. [DOI: 10.1017/S1092852920001194] - DOI - PubMed
Erdil 2015 {published data only}
    1. Erdil F, Begeç Z, Kayhan GE, Yoloğlu S, Ersoy MÖ, Durmuş M. Effects of sevoflurane or ketamine on the QTc interval during electroconvulsive therapy. Journal of Anasthesia 2015;29(2):180-5. - PubMed
Giese 2014 {published data only}
    1. Giese M, Beck J, Brand S, Muheim F, Hemmeter U, Hatzinger M, et al. Fast BDNF serum level increase and diurnal BDNF oscillations are associated with therapeutic response after partial sleep deprivation. Journal of Psychiatric Research 2014;59:1-7. - PubMed
Huey 2005 {published data only}
    1. Huey ED, Dustin IH, Overman GP, Mirza N, Sunderland T. Development of subtle psychotic symptoms with memantine: A case report 4 [letter]. Journal of Clinical Psychiatry 2005;66:658-9. - PubMed
Irwin 2010 {published data only}
    1. Irwin SA, Iglewicz A. Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. Journal of Palliative Medicine 2010;13:903-8. - PMC - PubMed
Liebrenz 2009 {published data only}
    1. Liebrenz M, Stohler R, Borgeat A. Repeated intravenous ketamine therapy in a patient with treatment-resistant major depression. World Journal of Biological Psychiatry 2009;10:640-3. - PubMed
O'Gorman 2019 {published data only}
    1. O'Gorman C, Anderson A, Jacobson M, Jones A, Tabuteau H. P. 601 AXS-05 (dextromethorphan/bupropion), a novel, oral, investigational agent for major depressive disorder: Results of a randomized, double-blind, active-controlled, multi-center trial (ASCEND).. European Neuropsychopharmacology 2019;29:S410.
Park 2020 {published data only}
    1. Park LT, uckenbaugh SJ, Pennybaker MA, Hopkins ID, Denter MS, Lener B, et al. The effects of ketamine on typical and atypical depressive symptoms. Acta Psychiatrica Scandinavica 2020;142(5):394-401. - PMC - PubMed
Rasmussen 2014 {published data only}
    1. Rasmussen KG, Kung S, Lapid MI, Oesterle TS, Geske JR, Nuttall GA, et al. A randomized comparison of ketamine versus methohexital anesthesia in electroconvulsive therapy. Psychiatry Research 2014;215:362-5. - PubMed
Rosenblat 2019 {published data only}
    1. Rosenblat, JD. Potential differences in antidepressant effects of oral ketamine liquid suspension versus compounded capsules. British Journal of Psychiatry 2019;215(1):434. - PubMed
Sharma 2020 {published data only}
    1. Sharma, R K. Antidepressant effects of ketamine and ECT: a pilot comparison. Journal of Affective Disorders 2020;276:260-6. - PubMed
Shiroma 2020 {published data only}
    1. Shiroma PR. A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression. Translational Psychiatry 2020;10(1):206. - PMC - PubMed
Zhang 2018 {published data only}
    1. Zhang M, Rosenheck R, Lin X, Li Q, Zhou Y, Xiao, et al. A randomized clinical trial of adjunctive ketamine anesthesia in electro-convulsive therapy for depression. Journal of Affective Disorders 2018;227:372-8. - PubMed
Zhong 2016 {published data only}
    1. Zhong X, He H, Zhang C, Wang Z, Jiang M, Li Q, et al. Mood and neuropsychological effects of different doses of ketamine in electroconvulsive therapy for treatment-resistant depression. Journal of Affective Disorders 2016;201:124-30. - PubMed

References to studies awaiting assessment

IRCT201104092266N2 {published data only}
    1. IRCT201104092266N2. Comparison of the effect of electroconvulsive therapy and intravenous infusion of ketamine on control and relapse of depressive symptoms in depressive cases who are candidates of electro convulsive therapy. http://www.irct.ir/searchresult.php?id=2266&number=2 (August 28th 2015).
ISRCTN87057460 {published data only}
    1. ISRCTN87057460. Effectiveness of the dual serotonin norepinephrine reuptake inhibitor venlafaxine in depressed patients. http://www.isrctn.com/ISRCTN87057460 (August 28th 2015).
NCT01046630 {published data only}
    1. NCT01046630. A Phase I, multi-centre, double-blind, placebo-controlled parallel group study to assess the pharmacoMRI effects of AZD6765 in male and female subjects fulfilling the criteria for major depressive disorder. http://clinicaltrials.gov/show/NCT01046630 (August 28th 2015).
NCT01482221 {published data only}
    1. NCT01482221. A multicenter, randomized, double-blind, parallel group, placebo-controlled, phase IIb efficacy and safety study of adjunctive AZD6765 in patients with major depressive disorder (MDD) and a history of inadequate response to antidepressants study D6702C00031. http://clinicaltrials.gov/show/NCT01482221 (August 28th 2015).
NCT01627782 {published data only}
    1. NCT01627782. A double-blind, randomized, placebo-controlled, parallel group, dose frequency study of ketamine in subjects with treatment-resistant depression. http://clinicaltrials.gov/show/NCT01627782 (August 28th 2015).

References to ongoing studies

EUCTR2011‐001520‐37‐SE {published data only}
    1. EUCTR2011-001520-37-SE. Ketamine as an alternative to electroconvulsive therapy for treatment of major depressive disorder. https://www.clinicaltrialsregister.eu/ctr-search/search?query=Vestibular... (August 28th 2015).
EUCTR2011‐005476‐41‐GB {published data only}
    1. EUCTR2011-005476-41-GB. Ketamine augmentation of ECT to improve outcomes in depression - Ketamine-ECT study. https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-005476-41/GB (August 28th 2015). - PMC - PubMed
IRCT201307181556N54 {published data only}
    1. IRCT201307181556N54. Riluzole as adjuvant therapy in the treatment of moderate to severe major depression: a double - blind placebo-controlled trial. http://www.irct.ir/searchresult.php?keyword=&id=1556&number=54&a... (August 28th 2015).
NCT00988663 {published data only}
    1. NCT00988663. Memantine augmentation of electroconvulsive therapy in patients with major depression. http://clinicaltrials.gov/show/NCT00988663 (August 28th 2015).
NCT01179009 {published data only}
    1. NCT01179009. A safe ketamine-based therapy for treatment resistant depression. http://clinicaltrials.gov/show/NCT01179009 (August 28th 2015).
NCT01204918 {published data only}
    1. NCT01204918. Efficacy and tolerability of riluzole in treatment resistant depression. http://clinicaltrials.gov/show/NCT01204918 (August 28th 2015).
NCT01260649 {published data only}
    1. NCT01260649. N-methyl-D-aspartate antagonist (ketamine) augmentation of electroconvulsive treatment for severe major depression. http://clinicaltrials.gov/show/NCT01260649 (August 28th 2015).
NCT01441505 {published data only}
    1. NCT01441505. A study of ketamine as an antidepressant. http://clinicaltrials.gov/show/NCT01441505 (August 28th 2015).
NCT01557712 {published data only}
    1. NCT01557712. Estimate the efficiency of the association of an injection of ketamine and the venlafaxine in the severe major depressive disorder for six weeks (KETADEP). http://clinicaltrials.gov/show/NCT01557712 (August 28th 2015).
NCT01558063 {published data only}
    1. NCT01558063. The antidepressant action of ketamine: brain chemistry. http://clinicaltrials.gov/show/NCT01558063 (August 28th 2015).
NCT01613820 {published data only}
    1. NCT01613820. Combination of anticholinergic and glutamatergic effects in treatment-resistant major depressive disorder. A pilot study. http://clinicaltrials.gov/show/NCT01613820 (August 28th 2015).
NCT01667926 {published data only}
    1. NCT01667926. Randomized, double-blind ketamine augmentation in chronically suicidal, treatment-resistant major depression. http://clinicaltrials.gov/show/NCT01667926 (August 28th 2015).
NCT01684163 {published data only}
    1. NCT01684163. Phase 2, double-blind, placebo controlled, randomized withdrawal, parallel efficacy and safety study of GLYX-13 in subjects with inadequate/partial response to antidepressants during the current episode of major depressive disorder. http://clinicaltrials.gov/show/NCT01684163 (August 28th 2015).
NCT01700829 {published data only}
    1. NCT01700829. Ketamine vs. midazolam: testing rapid relief of suicide risk in depression. http://clinicaltrials.gov/show/NCT01700829 (August 28th 2015).
NCT01703039 {published data only}
    1. NCT01703039. Riluzole augmentation pilot in depression (RAPID) trial. http://clinicaltrials.gov/show/NCT01703039 (August 28th 2015).
NCT01868802 {published data only}
    1. NCT01868802. Ketamine for treatment-resistant depression: a multicentric clinical trial in Mexican population. http://clinicaltrials.gov/show/NCT01868802 (August 28th 2015).
NCT01880593 {published data only}
    1. NCT01880593. Ketamine plus lithium as a novel pharmacotherapeutic strategy in treatment-resistant depression. http://clinicaltrials.gov/show/NCT01880593 (August 28th 2015).
NCT01881763 {published data only}
    1. NCT01881763. Comparing therapeutic efficacy and cognitive side effects of electroconvulsive therapy (ECT) using ketamine versus methohexital anesthesia. http://clinicaltrials.gov/show/NCT01881763 (August 28th 2015).
NCT01882829 {published data only}
    1. NCT01882829. Targeting the NMDA glutamate receptor as novel antidepressant strategy: a pilot clinical trial of nuedexta in treatment-resistant major depression. http://clinicaltrials.gov/show/NCT01882829 (August 28th 2015).
NCT01887990 {published data only}
    1. NCT01887990. Treatment of suicidal ideation with intravenous ketamine infusion. http://clinicaltrials.gov/show/NCT01887990 (August 28th 2015).
NCT01902004 {published data only}
    1. NCT01902004. Treatment of geriatric depression with mild cognitive impairment: a double-blind placebo-controlled trial of namenda (memantine) augmentation of lexapro (escitalopram) in depressed patients at least 60 years of age. http://clinicaltrials.gov/show/NCT01902004 (August 28th 2015).
NCT01920555 {published data only}
    1. NCT01920555. Double-blind, placebo-controlled trial of ketamine therapy in treatment-resistant depression (TRD). http://clinicaltrials.gov/show/NCT01920555 (August 28th 2015).
NCT01935115 {published data only}
    1. NCT01935115. A prospective randomized double blinded control trial using ketamine or propofol anesthesia for electroconvulsive therapy: improving treatment-resistant depression. http://clinicaltrials.gov/show/NCT01935115 (August 28th 2015).
NCT01944293 {published data only}
    1. NCT01944293. Ketamine vs. midazolam in bipolar depression. http://clinicaltrials.gov/show/NCT01944293 (August 28th 2015).
NCT01945047 {published data only}
    1. NCT01945047. Phase 2 optimization of the antidepressant action of ketamine in treatment-resistant depression and investigations on its mechanism of action. http://clinicaltrials.gov/show/NCT01945047 (August 28th 2015).
NCT01957410 {published data only}
    1. NCT01957410. An open-label and double-blind study to investigate evoked potentials as markers of ketamine-induced cortical plasticity in subjects with major depressive disorder. http://clinicaltrials.gov/show/NCT01957410 (August 28th 2015).
NCT02012335 {published data only}
    1. NCT02012335. Ketamine use in electroconvulsive therapy: clinical, cognitives and neurotrophic outcomes. http://clinicaltrials.gov/show/NCT02012335 (August 28th 2015).
NCT02014363 {published data only}
    1. NCT02014363. Double blind, non-inferiority study to evaluate the antidepressant activity of ETS6103 compared with amitriptyline in the treatment of major depressive disorder (MDD) in patients who have an unsatisfactory response to selective serotonin re-uptake Inhibitors (SSRIs). http://clinicaltrials.gov/show/NCT02014363 (August 28th 2015).
NCT02037503 {published data only}
    1. NCT02037503. Effect of oral ketamine treatment on suicidal ideation and drug resistant major depression, a clinical and fMRI study. http://clinicaltrials.gov/show/NCT02037503 (August 28th 2015).
NCT02067793 {published data only}
    1. NCT02067793. Phase 2, randomized, double-blind, multiple-dose level, placebo controlled, single intravenous dose, parallel efficacy and safety study of NRX-1074 in subjects with major depressive disorder. http://clinicaltrials.gov/show/NCT02067793 (August 28th 2015).
NCT02106325 {published data only}
    1. NCT02106325. A randomized, double-blinded controlled trial of an N-methyl D-aspartate antagonist as a rapidly-acting antidepressant in depressed emergency department patients. http://clinicaltrials.gov/show/NCT02106325 (August 28th 2015).
NCT02139540 {published data only}
    1. NCT02139540. Nitrous oxide as treatment for major depression - a pilot study. http://clinicaltrials.gov/show/NCT02139540 (August 28th 2015).
NCT02153502 {published data only}
    1. NCT02153502. A phase 2, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy, safety, and tolerability of AVP-786 (deuterium modified dextromethorphan hydrobromide/quinidine sulfate) as an adjunctive therapy in patients with Major depressive disorder with an inadequate response to antidepressant treatment. http://clinicaltrials.gov/show/NCT02153502 (August 28th 2015).
NCT02267980 {published data only}
    1. NCT02267980. Effect of the addition of ketamine to sevoflurane anesthesia in electroconvulsive therapy. http://clinicaltrials.gov/show/NCT02267980 (August 28th 2015). - PubMed
NCT02295787 {published data only}
    1. NCT02295787. Intranasal ketamine for late-life depression and suicidal ideation. http://clinicaltrials.gov/show/NCT02295787 (August 28th 2015).
NCT02299440 {published data only}
    1. NCT02299440. Evaluation of the effects of ketamine in the acute phase of suicidal ideation: a multicenter randomized double-blind trial. http://clinicaltrials.gov/show/NCT02299440 (August 28th 2015).
NCT02305394 {published data only}
    1. NCT02305394. Effect of subanesthetic dose of ketamine combined with propofol on cognitive function in depressive patients undergoing electroconvulsive therapy - a randomized control double-blind clinical trial. http://clinicaltrials.gov/show/NCT02305394 (August 28th 2015).
NCT04082858 {published data only}
    1. NCT04082858. Ketamine interleaved with electroconvulsive therapy for depression. https://clinicaltrials.gov/show/NCT04082858. 2019.
NCT04116528 {published data only}
    1. Opiate Suicide Study in Patients With Major Depression (AFSP). Ongoing study. August 1, 2020. Contact author for more information.
NCT04234776 {published data only}
    1. NCT04234776. Intramuscular ketamine versus aripiprazole and escitalopram in the treatment of resistant depression. https://clinicaltrials.gov/show/NCT04234776. 2019.
NCT04399070 {published data only}
    1. NCT04399070. The Effect of S-ketamine for patients undergoing electroconvulsive therapy (ECT. https://clinicaltrials.gov/show/NCT04399070. 2020.
NTR3753 {published data only}
    1. NTR3753. ECT and Memantine. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3753 (August 28th 2015).
Phillips 2020 {published data only}
    1. Phillips. A randomized, crossover comparison of ketamine and electroconvulsive therapy for treatment of major depressive episodes: a Canadian biomarker integration network in depression (CAN-BIND) study protocol. BMC Psychiatry 2020;20(1):268. - PMC - PubMed

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