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    Clinical Trial Results:
    Ketamine augmentation of ECT to improve outcomes in depression

    Summary
    EudraCT number
    		 2011-005476-41
    Trial protocol
    		 GB  
    Global end of trial date
    30 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Aug 2020
    First version publication date
    07 Aug 2020
    Other versions
    Summary report(s)
    		 Results summary

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MMHSCT1096
    Additional study identifiers
    ISRCTN number
    		 ISRCTN14689382
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Former Manchester Mental Health and Social Care Trust
    Sponsor organisation address
    Bury New Road, Prestwich, United Kingdom, M25 3BL
    Public contact
    Annya Sekula, Greater Manchester Mental Health Trust, researchoffice@gmmh.nhs.uk
    Scientific contact
    Prof Ian Anderson, University of Manchester, 0044 0161 275 7428, ian.anderson@manchester.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test the effectiveness of adjunctive glutamate antagonist Ketamine in mitigating the adverse effects of electroconvulsive therapy and optimize symptomatic improvement in depression.
    Protection of trial subjects
    Patients excluded if had a history of drug or alcohol abuse, known hypersensitivity or contraindications to ketamine or excipients in the injection, significant cardiovascular disease, uncontrolled hypertension, glaucoma, cirrhosis or abnormal liver function, liver disease, known hypersensitivity or contraindications to concomitant medications used for ECT (propofol, suxamethonium), evidence of organic brain disease, pregnancy or risk of pregnancy.
    Background therapy
    		 Oral psychotropic medication continued by the patient's medical team remained unchanged whee possible for at least the first 4 ECT treatments, and ideally until end of ECT. Anaesthetic for their ECT course.
    Evidence for comparator
    		 Placebo (saline) comparator, no active comparator. Saline used as an adjunct to patient's anaesthetic for their ECT course
    Actual start date of recruitment
    01 Aug 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 79
    Worldwide total number of subjects
    79
    EEA total number of subjects
    79
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    62
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 7 NHS Trusts involved(UK sites only). Recruitment started in December 2012. Last patient assessment was in June 2015.

    Pre-assignment
    Screening details
    		 In total 628 patients received ECT of whom 31% were potentially eligible for the study (47% were ineligible due to detention under the MHA). Of the 196 potentially eligible patients, 79 (40%) were randomised and 70 (36%) formed the final mITT sample (37 in the saline arm, 33 in the Ketamine arm). More: https://pubmed.ncbi.nlm.nih.gov/28359862/

    Pre-assignment period milestones
    Number of subjects started
    		 79
    Number of subjects completed
    		 79

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    The patient, clinical team, ECT psychiatry team and investigator/assessor were blinded to the treatment arm. Only the anaesthetist was not blind. Dispensing was by prescription completed by the anaesthetist on study-approved forms that did not identify whether the drug is ketamine or normal saline and drew up by anaesthetist. ECT Clinic staff drug vials were dispensed boxed in plain packaging and the outer packaging ‘labelled’ as per Annex 13.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ketamine
    Arm description
    		 0.5mg Ketamine per kg, as an adjunct to anaesthetic for ECT.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ketamine hydrochloride
    Investigational medicinal product code
    N01AX03
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.5 mg/kg as an adjunct to anaesthetic for ECT, bolus.

    Arm title
    		 Placebo
    Arm description
    		 Normal Saline bolus
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Saline bolus as an adjunct to ECT anaesthetic.

    Number of subjects in period 1
    		Ketamine Placebo
    Started
    40
    39
    Completed
    33
    37
    Not completed
    7
    2
         organisational reason
    2
    -
         excluded post-randomisation (clinical reasons)
    2
    -
         Medical contrainducation
    -
    1
         Did not start ECT
    3
    1
    Period 2
    Period 2 title
    Started ECT + Study Drug
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ketamine
    Arm description
    		 0.5mg Ketamine per kg, as an adjunct to anaesthetic for ECT.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ketamine hydrochloride
    Investigational medicinal product code
    AS1
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.5 mg/kg as an adjunct to anaesthetic for ECT, bolus.

    Arm title
    		 Placebo
    Arm description
    		 Normal Saline bolus
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Saline bolus as an adjunct to ECT anaesthetic.

    Number of subjects in period 2
    		Ketamine Placebo
    Started
    33
    37
    Completed
    33
    36
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1
    Period 3
    Period 3 title
    Mid-ECT
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ketamine
    Arm description
    		 0.5mg Ketamine per kg, as an adjunct to anaesthetic for ECT.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ketamine hydrochloride
    Investigational medicinal product code
    AS1
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.5 mg/kg as an adjunct to anaesthetic for ECT, bolus.

    Arm title
    		 Placebo
    Arm description
    		 Normal Saline bolus
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Saline bolus as an adjunct to ECT anaesthetic.

    Number of subjects in period 3
    		Ketamine Placebo
    Started
    33
    36
    Completed
    28
    32
    Not completed
    5
    4
         Lost capacity
    1
    -
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    2
    3
         Detained under MHA
    1
    1
    Period 4
    Period 4 title
    End of Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ketamine
    Arm description
    		 0.5mg Ketamine per kg, as an adjunct to anaesthetic for ECT.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ketamine hydrochloride
    Investigational medicinal product code
    AS1
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.5 mg/kg as an adjunct to anaesthetic for ECT, bolus.

    Arm title
    		 Placebo
    Arm description
    		 Normal Saline bolus
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Saline bolus as an adjunct to ECT anaesthetic.

    Number of subjects in period 4
    		Ketamine Placebo
    Started
    28
    32
    Completed
    25
    23
    Not completed
    3
    9
         Consent withdrawn by subject
    2
    2
         Other
    -
    1
         Further ECT
    1
    2
         Lost to follow-up
    -
    4
    Period 5
    Period 5 title
    1 month follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ketamine
    Arm description
    		 0.5mg Ketamine per kg, as an adjunct to anaesthetic for ECT.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ketamine hydrochloride
    Investigational medicinal product code
    AS1
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.5 mg/kg as an adjunct to anaesthetic for ECT, bolus.

    Arm title
    		 Placebo
    Arm description
    		 Normal Saline bolus
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Saline bolus as an adjunct to ECT anaesthetic.

    Number of subjects in period 5
    		Ketamine Placebo
    Started
    25
    23
    Completed
    19
    18
    Not completed
    6
    5
         Consent withdrawn by subject
    -
    1
         Further ECT
    2
    1
         Unavailable
    1
    -
         Lost to follow-up
    3
    2
         Detained under the MHA
    -
    1
    Period 6
    Period 6 title
    4 month follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ketamine
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ketamine hydrochloride
    Investigational medicinal product code
    N01AX03
    Other name
    Pharmaceutical forms
    Injection, Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.5 mg/kg as an adjunct to anaesthetic for ECT, bolus.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection, Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Saline bolus as an adjunct to ECT anaesthetic.

    Number of subjects in period 6
    		Ketamine Placebo
    Started
    19
    18
    Completed
    19
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ketamine
    Reporting group description
    		 0.5mg Ketamine per kg, as an adjunct to anaesthetic for ECT.

    Reporting group title
    Placebo
    Reporting group description
    		 Normal Saline bolus

    Reporting group values
    		 Ketamine Placebo Total
    Number of subjects
    		 40 39 79
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.5 ± 11.9 56.4 ± 12.4 -
    Gender categorical
    Units: Subjects
        Female
    		 22 22 44
        Male
    		 18 17 35
    Ethnicity
    Units: Subjects
        White
    		 31 35 66
        Other
    		 9 4 13
    Marital status
    Units: Subjects
        Married or current partner
    		 13 19 32
        Other
    		 27 20 47
    Illness Characteristics
    Units: Subjects
        Inpatient
    		 11 21 32
        Other
    		 29 18 47
    Illness Characteristics: Diagnosis
    Units: Subjects
        Bipolar disorder
    		 4 7 11
        Other
    		 36 32 68
    Illness characteristics: Previous ECT?
    Units: Subjects
        Yes
    		 18 16 34
        No
    		 22 23 45
    Illness characteristics: Family history of depression?
    Units: Subjects
        Yes
    		 23 18 41
        No
    		 17 21 38
    Illness characteristics: Family history of bipolar disorder
    Units: Subjects
        Yes
    		 2 10 12
        No
    		 38 29 67
    Current depressive episode: Melancholia no psychosis
    Units: Subjects
        Yes
    		 26 25 51
        No
    		 14 14 28
    Current depressive episode: Psychosis, with or without melancholia
    Units: Subjects
        Yes
    		 3 8 11
        No
    		 37 31 68
    Comorbidity: Anxiety disorder or secondary OCD
    Units: Subjects
        Yes
    		 16 18 34
        No
    		 24 21 45
    Comorbidity: Other psychiatric disorder
    Units: Subjects
        Yes
    		 1 0 1
        No
    		 39 39 78
    Comorbidity: Medical Illness
    Units: Subjects
        Yes
    		 12 9 21
        No
    		 28 30 58
    Psychotropic medication: SSRI
    Units: Subjects
        Yes
    		 10 10 20
        No
    		 30 29 59
    Psychotropic medication: SNRI
    Units: Subjects
        Yes
    		 17 16 33
        No
    		 23 23 46
    Psychotropic medication: TCA
    Units: Subjects
        Yes
    		 4 7 11
        No
    		 36 32 68
    Psychotropic medication: MAOI
    Units: Subjects
        Yes
    		 0 1 1
        No
    		 40 38 78
    Psychotropic medication: Other antidepressant
    Units: Subjects
        Yes
    		 13 9 22
        No
    		 27 30 57
    Psychotropic medication: Antipsychotic
    Units: Subjects
        Yes
    		 21 25 46
        No
    		 19 14 33
    Psychotropic medication: Lithium
    Units: Subjects
        Yes
    		 10 5 15
        No
    		 30 34 64
    Psychotropic medication: Antiepileptic mood stabiliser
    Units: Subjects
        Yes
    		 5 6 11
        No
    		 35 33 68
    Psychotropic medication: Hypnotic/anxiolytic
    Units: Subjects
        Yes
    		 18 24 42
        No
    		 22 15 37
    Mean years in full time education
    Units: Years
        arithmetic mean (standard deviation)
    		 13.7 ± 4.0 13.5 ± 3.2 -
    IQ
    Units: IQ score
        arithmetic mean (standard deviation)
    		 105.1 ± 11.3 109.9 ± 11 -
    MMSE
    Units: MMSE Score
        median (standard deviation)
    		 28.8 ± 2.0 29.0 ± 1.2 -
    Illness Characteristic: Age of onset
    Units: Years
        arithmetic mean (standard deviation)
    		 29.6 ± 14.0 32.2 ± 17.0 -
    Illness Characteristics: Number of Depressive episodes (lifetime)
    Units: Number
        median (standard deviation)
    		 4.9 ± 4.4 5.3 ± 5.2 -
    Illness Characteristics: number of hypomanic/manic episodes
    Units: Number
        median (standard deviation)
    		 0.3 ± 1.0 0.5 ± 1.8 -
    Current depressive episode: MADRS score
    Units: numeric score
        arithmetic mean (standard deviation)
    		 31.8 ± 7.4 35.2 ± 8.4 -
    Current depressive episode: Median duartion
    Units: Months
        median (inter-quartile range (Q1-Q3))
    		 14 (7 to 38) 8 (3.5 to 20.5) -
    Current depressive episode: MGHS score
    Units: Numeric score:
        median (standard deviation)
    		 4.8 ± 2.6 4.0 ± 3.4 -
    Physical signs: Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 82.2 ± 17.1 77.2 ± 17.7 -
    Physical signs: BMI
    Units: Kg/m2
        arithmetic mean (standard deviation)
    		 29.3 ± 5.8 28.8 ± 6.7 -
    Physical signs: Systolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 132.9 ± 18.0 126.1 ± 17.2 -

    End points

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    End points reporting groups
    Reporting group title
    Ketamine
    Reporting group description
    		 0.5mg Ketamine per kg, as an adjunct to anaesthetic for ECT.

    Reporting group title
    Placebo
    Reporting group description
    		 Normal Saline bolus
    Reporting group title
    Ketamine
    Reporting group description
    		 0.5mg Ketamine per kg, as an adjunct to anaesthetic for ECT.

    Reporting group title
    Placebo
    Reporting group description
    		 Normal Saline bolus
    Reporting group title
    Ketamine
    Reporting group description
    		 0.5mg Ketamine per kg, as an adjunct to anaesthetic for ECT.

    Reporting group title
    Placebo
    Reporting group description
    		 Normal Saline bolus
    Reporting group title
    Ketamine
    Reporting group description
    		 0.5mg Ketamine per kg, as an adjunct to anaesthetic for ECT.

    Reporting group title
    Placebo
    Reporting group description
    		 Normal Saline bolus
    Reporting group title
    Ketamine
    Reporting group description
    		 0.5mg Ketamine per kg, as an adjunct to anaesthetic for ECT.

    Reporting group title
    Placebo
    Reporting group description
    		 Normal Saline bolus
    Reporting group title
    Ketamine
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: HVLT-R:Delayed Recall

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    End point title
    		 HVLT-R:Delayed Recall
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 4 month follow-up
    End point values
    		 Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo
    Number of subjects analysed
    33
    37
    29
    35
    26
    32
    23
    23
    19
    18
    Units: Score
        median (standard deviation)
    6.12 ± 2.69
    5.86 ± 3.63
    5.17 ± 2.92
    5.54 ± 3.42
    5.69 ± 2.80
    5.44 ± 3.18
    6.70 ± 2.67
    7.26 ± 2.63
    6.63 ± 3.17
    8.11 ± 2.83
    Statistical analysis title
    		 Repeated measures analysis: Mid-ECT
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.73
         upper limit
    		 0.87
    Statistical analysis title
    		 Repeated measures model analysis: end of treatment
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.22
         upper limit
    		 1.13
    Statistical analysis title
    		 Repeated measures analysis: 1 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.66
         upper limit
    		 0.6
    Statistical analysis title
    		 Repeated measures analysis: 4 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.91
         upper limit
    		 0.12

    Primary: HVLT-R: Total learning

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    End point title
    		 HVLT-R: Total learning
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 4 month follow-up
    End point values
    		 Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo
    Number of subjects analysed
    33
    37
    29
    36
    26
    32
    23
    23
    19
    18
    Units: HVLT-R Score
        arithmetic mean (standard deviation)
    20.0 ± 4.1
    20.8 ± 6.7
    20.2 ± 5.8
    21.0 ± 5.4
    19.8 ± 4.9
    21.2 ± 5.6
    22.3 ± 4.7
    23.5 ± 5.6
    21.6 ± 5.0
    24.1 ± 6.1
    Statistical analysis title
    		 Repeated measures analysis: Mid-ECT
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.91
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.04
         upper limit
    		 1.81
    Statistical analysis title
    		 Repeated measures analysis: End of treatment
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.97
         upper limit
    		 1.06
    Statistical analysis title
    		 Repeated measures analysis: 1 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.63
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.54
         upper limit
    		 1.54
    Statistical analysis title
    		 Repeated measures analysis: 4 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.39
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.68
         upper limit
    		 1.44

    Primary: HVLT-R: Retention

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    End point title
    		 HVLT-R: Retention
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 4 month follow-up
    End point values
    		 Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo
    Number of subjects analysed
    33
    37
    29
    35
    26
    32
    23
    23
    19
    18
    Units: HVLT-R Score
        arithmetic mean (standard deviation)
    73.3 ± 27.8
    65.2 ± 32.9
    58.6 ± 25.0
    62.4 ± 31.8
    69.4 ± 26.6
    58.7 ± 26.4
    73.3 ± 24.0
    77.1 ± 16.1
    74.72 ± 23.3
    85.5 ± 18.7
    Statistical analysis title
    		 Repeated measures analysis: Mid-ECT
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18
         upper limit
    		 7.8
    Statistical analysis title
    		 Repeated measures analysis: End of treatment
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.88
         upper limit
    		 18.8
    Statistical analysis title
    		 Repeated measures analysis: 1 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.53
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.3
         upper limit
    		 6.9
    Statistical analysis title
    		 Repeated measures analysis: 4 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.052
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -11.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24
         upper limit
    		 0.1

    Primary: HVLT-R: Recognition discrimination

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    End point title
    		 HVLT-R: Recognition discrimination
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 4 month follow-up
    End point values
    		 Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo
    Number of subjects analysed
    33
    37
    29
    35
    26
    32
    23
    23
    19
    18
    Units: HVLT-R score
        arithmetic mean (standard deviation)
    9.45 ± 2.05
    8.16 ± 3.48
    8.48 ± 2.81
    8.54 ± 2.84
    8.58 ± 2.90
    9.66 ± 2.10
    9.52 ± 2.33
    9.52 ± 2.33
    10.42 ± 1.43
    9.56 ± 2.97
    Statistical analysis title
    		 Repeated measures analysis: Mid-ECT
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.74
         upper limit
    		 0.44
    Statistical analysis title
    		 Repeated measures analysis: End of treatment
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.76
         upper limit
    		 -0.42
    Statistical analysis title
    		 Repeated measures analysis: 1 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.61
         upper limit
    		 0.43
    Statistical analysis title
    		 Repeated measures analysis: 4 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.78
         upper limit
    		 1.8

    Primary: COWAT: Letter Fluency

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    End point title
    		 COWAT: Letter Fluency
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 4 month follow-up
    End point values
    		 Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo
    Number of subjects analysed
    33
    37
    29
    36
    26
    32
    23
    23
    19
    18
    Units: COWAT Score
        arithmetic mean (standard deviation)
    33.8 ± 13.1
    36.1 ± 14.3
    31.5 ± 2.91
    36.1 ± 13.2
    33.0 ± 13.4
    34.2 ± 13.5
    35.6 ± 13.4
    39.5 ± 14.1
    37.6 ± 13.2
    38.6 ± 10.7
    Statistical analysis title
    		 Repeated measures analysis: Mid-ECT
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.86
         upper limit
    		 2.23
    Statistical analysis title
    		 Repeated measures analysis: End of treatment
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.57
         upper limit
    		 3.54
    Statistical analysis title
    		 Repeated measures analysis: 1 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.74
         upper limit
    		 2.7
    Statistical analysis title
    		 Repeated measures analysis: 4 moth follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.17
         upper limit
    		 4.8

    Primary: COWAT: Category Fluency

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    End point title
    		 COWAT: Category Fluency
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to follow-up
    End point values
    		 Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo
    Number of subjects analysed
    33
    37
    29
    36
    26
    32
    23
    23
    19
    18
    Units: COWAT Score
        arithmetic mean (standard deviation)
    15.8 ± 5.5
    16.8 ± 5.3
    15.9 ± 5.3
    16.4 ± 4.2
    14.3 ± 5.1
    15.8 ± 4.2
    16.5 ± 5.6
    17.1 ± 4.1
    17.8 ± 4.6
    18.1 ± 5.3
    Statistical analysis title
    		 Repeated measures analysis: Mid-ECT
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.73
         upper limit
    		 1.78
    Statistical analysis title
    		 Repeated measures analysis: End of treatment
    Comparison groups
    Placebo v Ketamine
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.15
         upper limit
    		 0.57
    Statistical analysis title
    		 Repeated measures analysis: 1 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.84
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.43
         upper limit
    		 1.96
    Statistical analysis title
    		 Repeated measures analysis: 4 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 2.21

    Primary: AMI-SF

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    End point title
    		 AMI-SF
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 4 month follow-up
    End point values
    		 Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo
    Number of subjects analysed
    33
    37
    29
    36
    25
    32
    23
    23
    19
    16
    Units: AMI-SF score
        arithmetic mean (standard deviation)
    45.5 ± 9.2
    44.2 ± 10.3
    39.3 ± 9.0
    38.0 ± 10.0
    34.7 ± 9.8
    34.8 ± 10.5
    35.1 ± 10.0
    35.4 ± 10.4
    37.4 ± 10.1
    38.9 ± 8.4
    Statistical analysis title
    		 Repeated measures analysis: Mid-ECT
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.16
         upper limit
    		 1.81
    Statistical analysis title
    		 Repeated measures analysis: End of treatment
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.95
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.63
         upper limit
    		 3.41
    Statistical analysis title
    		 Repeated measures analysis: 1 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.91
         upper limit
    		 3
    Statistical analysis title
    		 Repeated measures analysis: 4 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.67
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.93
         upper limit
    		 2.54

    Primary: MCGCFT: Copy

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    End point title
    		 MCGCFT: Copy
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 4 month follow-up
    End point values
    		 Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo
    Number of subjects analysed
    33
    37
    29
    36
    26
    32
    23
    23
    19
    18
    Units: MCGCFT Score
        arithmetic mean (standard deviation)
    34.6 ± 2.4
    33.4 ± 4.3
    33.9 ± 4.0
    34.1 ± 3.2
    34.6 ± 2.0
    34.4 ± 2.4
    35.3 ± 1.2
    34.4 ± 3.0
    35.2 ± 1.1
    35.0 ± 1.1
    Statistical analysis title
    		 Repeated measures analysis: Mid-ECT
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.27
         upper limit
    		 0.96
    Statistical analysis title
    		 Repeated measures analysis: End of treatment
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.66
         upper limit
    		 0.57
    Statistical analysis title
    		 Repeated measures analysis: 1 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.61
         upper limit
    		 0.78
    Statistical analysis title
    		 Repeated measures analysis: 4 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.32
         upper limit
    		 0.34

    Primary: MCGCFT: Immediate recall

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    End point title
    		 MCGCFT: Immediate recall
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 4 month follow-up
    End point values
    		 Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo
    Number of subjects analysed
    33
    37
    29
    36
    26
    32
    23
    23
    19
    18
    Units: MCGCFT Score
        arithmetic mean (standard deviation)
    19.0 ± 8.8
    17.9 ± 7.6
    18.6 ± 8.6
    18.4 ± 7.2
    19.0 ± 7.4
    16.6 ± 6.2
    19.5 ± 6.0
    19.7 ± 6.7
    23.8 ± 8.1
    21.5 ± 6.4
    Statistical analysis title
    		 Repeated measures analysis: Mid-ECT
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.09
         upper limit
    		 2.39
    Statistical analysis title
    		 Repeated measures analysis: End of Treatment
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.61
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.77
         upper limit
    		 3
    Statistical analysis title
    		 Repeated measures analysis: 1 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.43
         upper limit
    		 0.5
    Statistical analysis title
    		 Repeated measures analysis: 4 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.88
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.05
         upper limit
    		 3.58

    Primary: MCGCFT: Delayed recall

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    End point title
    		 MCGCFT: Delayed recall
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 4 month follow-up
    End point values
    		 Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo
    Number of subjects analysed
    33
    36
    29
    35
    25
    32
    22
    23
    19
    18
    Units: MCGCFT Score
        arithmetic mean (standard deviation)
    18.9 ± 7.7
    17.6 ± 6.9
    17.7 ± 8.2
    17.7 ± 7.5
    17.6 ± 5.9
    15.3 ± 5.3
    18.9 ± 6.4
    19.0 ± 6.5
    22.9 ± 9.7
    20.8 ± 6.8
    Statistical analysis title
    		 Repeated measures analysis: Mid-ECT
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.64
         upper limit
    		 2.1
    Statistical analysis title
    		 Repeated measures analysis: End of treatment
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.85
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.94
         upper limit
    		 2.36
    Statistical analysis title
    		 Repeated measures analysis: 1 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 0.37
    Statistical analysis title
    		 Repeated measures analysis: 4 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.89
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.79
         upper limit
    		 4.36

    Primary: Digit span: Forward

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    End point title
    		 Digit span: Forward
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to follow-up
    End point values
    		 Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo
    Number of subjects analysed
    33
    37
    29
    36
    26
    32
    23
    23
    19
    18
    Units: Digits
        arithmetic mean (standard deviation)
    5.70 ± 1.07
    5.84 ± 1.07
    5.48 ± 0.95
    6.0 ± 1.04
    5.88 ± 1.34
    5.84 ± 1.02
    5.91 ± 1.04
    5.83 ± 1.11
    5.68 ± 1.20
    5.72 ± 0.89
    Statistical analysis title
    		 Repeated measures analysis: Mid-ECT
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 -0.11
    Statistical analysis title
    		 Repeated measures analysis: End of treatment
    Comparison groups
    Placebo v Ketamine
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 0.5
    Statistical analysis title
    		 Repeated measures analysis: 1 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 0.46
    Statistical analysis title
    		 Repeated measures analysis: 4 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.43
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.64
         upper limit
    		 0.27

    Secondary: Digit Span: Backwards

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    End point title
    		 Digit Span: Backwards
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to follow-up
    End point values
    		 Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo Ketamine Placebo
    Number of subjects analysed
    33
    37
    29
    36
    26
    32
    23
    23
    19
    18
    Units: Digits
        arithmetic mean (standard deviation)
    3.64 ± 1.17
    3.95 ± 1.10
    3.86 ± 1.38
    3.94 ± 1.01
    3.88 ± 1.21
    3.97 ± 0.97
    3.87 ± 1.25
    4.13 ± 1.29
    3.89 ± 1.05
    4.06 ± 1.06
    Statistical analysis title
    		 Repeated measures analysis: Mid-ECT
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0.59
    Statistical analysis title
    		 Repeated measures analysis: End of treatment
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.87
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0.42
    Statistical analysis title
    		 Repeated measures analysis: 1 month follow-up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.63
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.43
    Statistical analysis title
    		 Repeated measures analysis: 4 month follow up
    Comparison groups
    Ketamine v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8
    Method
    		 Repeated measures model analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 0.5

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to 4 month follow-up. Time frame for ARs during administration of IMP
    Adverse event reporting additional description
    Safety was monitored by standard clinical procedures during ECT treatments, degree of re-orientation 30min after ECT, and adverse event recording.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Ketamine
    Reporting group description
    		 Ketamine 0.5mg/kg as an adjunct to anaesthetic for ECT.

    Reporting group title
    Placebo
    Reporting group description
    		 Normal saline bolus

    Serious adverse events
    		 Ketamine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 33 (6.06%)
    5 / 37 (13.51%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Overdose
    Additional description: Placebo-overdose requiring treatment in accident and emergency department Ketamine- overdose requiring treatment in accident and emergency department
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Chest pain
    Additional description: chest pain requiring admission to hospital overnight
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizures
    Additional description: spontaneous seizure and status epilepticus between ETC treatments
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
    Additional description: Suicide attempt requiring general hospital admission.
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt with intervention
    Additional description: Suicide attempt on in patient ward requiring intervention
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    psychiatric deterioration
    Additional description: clinical deterioration with suicidal ideation requiring admission to hospital
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ketamine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 33 (66.67%)
    10 / 37 (27.03%)
    Vascular disorders
    Vascular disorders
    Additional description: Vascular disorders
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
    Additional description: Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 37 (2.70%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Psychiatric disorders
    Additional description: Psychiatric disorders
         subjects affected / exposed
    7 / 33 (21.21%)
    6 / 37 (16.22%)
         occurrences all number
    7
    6
    Cardiac disorders
    Cardiac disorders
    Additional description: Cardiac disorders
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    Nervous system disorders
    Nervous system disorder
    Additional description: Nervous system disorder
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 37 (2.70%)
         occurrences all number
    4
    1
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
    Additional description: Blood and lymphatic system disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    Eye disorders
    Eye disorders
    Additional description: Eye disorders
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Gastrointestinal disorders
    Additional description: Gastrointestinal disorders
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatobiliary disorders
    Additional description: Hepatobiliary disorders
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorder
    Additional description: Skin and subcutaneous tissue disorder
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Renal and urinary disorders
    Additional description: Renal and urinary disorders
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
    Additional description: Musculoskeletal and connective tissue disorder
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Infections and infestations
    Additional description: Infections and infestations
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jul 2012
    Protocol changed to implement: -Change of timing of primary outcome and MR imaging -Definition clarified of timing of primary outcome (after 4th ECT subject to SOP defined variation) and end of ECT -Modification/addition of some assessments -Change of timing of ketamine administration to before the anaesthetic induction agent which has now been limited to propofol only -Addition of sample for DNA

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Recruitment under 50%. In the fNIRS sub-study the effect of ketamine could not be assessed and the other findings must be viewed as preliminary. Included patients were younger, with limited cognitive impairment with ECT which limits generalisation.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28359862
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