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    Clinical Trial Results:
    OxLith: Exploration of the short-term physical and psychological effects of lithium in mood instability.

    Summary
    EudraCT number
    		 2014-002699-98
    Trial protocol
    		 GB  
    Global end of trial date
    15 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Mar 2022
    First version publication date
    16 Mar 2022
    Other versions
    Summary report(s)
    		 OxLith full results and analysis

    Trial information

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    Trial identification
    Sponsor protocol code
    CB001-OL
    Additional study identifiers
    ISRCTN number
    		 ISRCTN91624955
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Warneford Hospital, Oxford, United Kingdom, OX3 7JX
    Public contact
    Professor John Geddes, University of Oxford , +44 (0)1865618202, john.geddes@psych.ox.ac.uk
    Scientific contact
    Professor John Geddes, University of Oxford , +44 (0)1865618202, john.geddes@psych.ox.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
    09 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is the evaluation of the effects of lithium on mood variability measured using weekly self-reports of manic and depressive symptoms. Weekly self-rating is used routinely by many patients as part of ongoing self-management of mood by people with bipolar disorder and daily ratings have been used successfully in a number of research studies. An understanding of the effects of lithium on mood will both inform its use and provide valuable information that will facilitate discovery of more effective and safer treatments.
    Protection of trial subjects
    1. Inclusion of placebo arm. Risks associated with being allocated placebo were minimised by the excluding patients who required active treatment. 2. Lithium toxicity: The trial protocol included frequent checks of lithium levels and participants were fully informed of the potential adverse effects and the circumstances in which they should access immediate medical attention. 3. All staff completing questionnaires that contained potentially sensitive questions with participants were fully trained and instructed to stop if a participant became distressed and, if necessary, seek clinical advice.
    Background therapy
    		 None
    Evidence for comparator
    		 In the absence of an alternative standard therapy for this patient population, a placebo comparator was used for the trial.
    Actual start date of recruitment
    01 Sep 2015
    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: 35
    Worldwide total number of subjects
    35
    EEA total number of subjects
    0
    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)
    35
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started on 15th August 2015 at the Oxford Health NHS Foundation Trust, Oxford UK. The last participant was recruited on 15th January 2018.

    Pre-assignment
    Screening details
    		 41 participants entered the pre-randomisation run-in phase. Patients meeting eligibility criteria were set-up for online reporting of mood on measures used to assess the primary outcome. Participants were people with both bipolar disorder and current mood instability for whom there was uncertainty about the benefits of lithium treatment.

    Pre-assignment period milestones
    Number of subjects started
    		 35
    Number of subjects completed
    		 35

    Period 1
    Period 1 title
    Randomised phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Assessor, Subject
    Blinding implementation details
    Minimisation was achieved using an online program which assigned medication according to allocation. Reporting actual/sham lithium levels to investigators was effected by an unblind staff member not otherwise involved in OxLith. Blood samples for participants on lithium were sent the laboratory. For participants on placebo an approved algorithm based on adherence and current IMP dose was used to select a sham level. The actual/sham level was then reported to the investigator who remained blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lithium
    Arm description
    		 Treatment with Priadel - lithium carbonate.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Priadel
    Investigational medicinal product code
    CAS number 554-13-2
    Other name
    Lithium carbonate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Priadel taken once daily at night. IMP was initiated at 400mg/day and titrated following blood tests at days 4 and 8 post-randomisation to a target serum level of 0.7mmol/L (range 0.4-1.0mmol/L). Additional lithium tests were carried out if required to achieve a stable, tolerable dose. Titration schedule in the absence or clinical reasons to the contrary (e.g. : Lithium level ≤ 0.3mmol/L - dose increased to 800mg/day Lithium level > 0.3mmol/L and < 0.6mmol/L - dose increased to 600 or 800mg/day (clinical judgement) Lithium level 0.6-1.0mmol/L - continue current dose Lithium level ≥ 0.3mmol/L - dose decreased to by 200 or 400mg/day (clinical judgement).

    Arm title
    		 Placebo
    Arm description
    		 Treatment with placebo tablet matched to 400mg tablets of Priadel
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    N/A
    Other name
    Placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    As for active Priadel with titration and final dose based on sham lithium level.

    Number of subjects in period 1
    		Lithium Placebo
    Started
    19
    16
    Completed
    19
    14
    Not completed
    0
    2
         Protocol deviation
    -
    1
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lithium
    Reporting group description
    		 Treatment with Priadel - lithium carbonate.

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment with placebo tablet matched to 400mg tablets of Priadel

    Reporting group values
    		 Lithium Placebo Total
    Number of subjects
    		 19 16 35
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 19 16 35
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28.9 ± 9.8 35.2 ± 13.8 -
    Gender categorical
    Units: Subjects
        Female
    		 11 9 20
        Male
    		 8 7 15
    Ethnic Group
    Units: Subjects
        White British
    		 13 9 22
        White other
    		 1 1 2
        Mixed
    		 1 1 2
        Asian
    		 0 1 1
        Black American
    		 1 0 1
        Other
    		 3 4 7
    Bipolar Diagnosis
    Units: Subjects
        BD I
    		 3 4 7
        BD II
    		 16 11 27
        BD
    		 0 1 1
    QIDS
    Quick inventory of depressive symptomology
    Units: Score
        arithmetic mean (standard deviation)
    		 10.6 ± 6.6 11.6 ± 5.4 -
    Altman
    Altman self rating scale for mania
    Units: score
        arithmetic mean (standard deviation)
    		 2.3 ± 3.7 3.6 ± 3.9 -
    PANAS +
    Positive and negative affect scale, positive subscale
    Units: Score
        arithmetic mean (standard deviation)
    		 6.8 ± 4.7 7.1 ± 5.2 -
    PANAS -
    Positive and negative affect scale, negative subscale
    Units: Score
        arithmetic mean (standard deviation)
    		 5.0 ± 4.5 5.5 ± 5.9 -
    CGI Mania
    Clinical Global Impression, Mania
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 1 (1 to 2) 1 (1 to 2) -
    CGI Depression
    Clinical Global Impression, Depression
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 2 (1 to 4) 3 (2 to 3) -
    CGI Bipolar
    Clinical Global Impression, Bipolar
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 2 (2 to 4) 2 (2 to 3) -
    IL6
    Interleukin 6 - blood test
    Units: pg/mL
        arithmetic mean (standard deviation)
    		 1.4 ± 0.6 1.4 ± 0.6 -
    NGAL
    Neutrophil gelatinase-associated lipocalin - blood test
    Units: ng/ml
        arithmetic mean (standard deviation)
    		 0.13 ± 0.03 0.13 ± 0.03 -
    T4
    Thyroxine - blood test
    Units: pmol/L
        arithmetic mean (standard deviation)
    		 12.9 ± 1.5 13.1 ± 0.8 -
    T3
    Triiodothyronine - blood test
    Units: pmol/L
        arithmetic mean (standard deviation)
    		 4.6 ± 0.6 4.3 ± 0.4 -
    TSH
    Thyroid stimulating hormone - blood test
    Units: mU/L
        arithmetic mean (standard deviation)
    		 1.3 ± 0.6 1.3 ± 0.7 -
    Calcium
    Calcium - blood test
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 2.4 ± 0.1 2.4 ± 0.1 -
    PTH
    Parathyroid hormone - blood test
    Units: pmol/L
        arithmetic mean (standard deviation)
    		 5.3 ± 1.5 5.4 ± 2.9 -
    VItamin D
    Vitamin D - blood test
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 45.9 ± 18.6 53.7 ± 35.7 -
    Creatinine
    Creatinine - blood test
    Units: umol/L
        arithmetic mean (standard deviation)
    		 68.1 ± 14.1 67.3 ± 13.1 -
    Cystatin C
    Cystatin C - blood test
    Units: mg/L
        arithmetic mean (standard deviation)
    		 0.90 ± 0.13 0.87 ± 0.12 -
    CRP
    C-reactive protein - blood test
    Units: mg/L
        arithmetic mean (standard deviation)
    		 1.9 ± 3.1 2.5 ± 3.4 -

    End points

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    End points reporting groups
    Reporting group title
    Lithium
    Reporting group description
    		 Treatment with Priadel - lithium carbonate.

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment with placebo tablet matched to 400mg tablets of Priadel

    Primary: Change in QIDS score from baseline to 6 weeks

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    End point title
    		 Change in QIDS score from baseline to 6 weeks
    End point description
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    18
    13
    Units: Score
        arithmetic mean (standard deviation)
    -1.94 ± 7.01
    -1.92 ± 5.81
    Statistical analysis title
    		 QIDS, change from baseline to 6 weeks
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8357
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.96
         upper limit
    		 3.66

    Primary: Change in ALTMAN score from baseline to 6 weeks

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    End point title
    		 Change in ALTMAN score from baseline to 6 weeks
    End point description
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    18
    13
    Units: Score
        arithmetic mean (standard deviation)
    0.94 ± 3.57
    -0.46 ± 3.28
    Statistical analysis title
    		 ALTMAN, change from baseline to 6 weeks
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant.
    Comparison groups
    Placebo v Lithium
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9294
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.54
         upper limit
    		 2.32

    Primary: Change in PANAS + score from baseline to 6 weeks

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    End point title
    		 Change in PANAS + score from baseline to 6 weeks
    End point description
    Change in PANAS positive affect ratings between baseline and 6 weeks
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    16
    12
    Units: Score
        arithmetic mean (standard deviation)
    -2.44 ± 4.83
    0.50 ± 3.66
    Statistical analysis title
    		 PANAS +, change from baseline to 6 weeks
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0129
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.77
         upper limit
    		 -0.8

    Primary: Change in PANAS - score from baseline to 6 weeks

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    End point title
    		 Change in PANAS - score from baseline to 6 weeks
    End point description
    Change in PANAS negative affect ratings between baseline and 6 weeks
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    16
    12
    Units: score
        arithmetic mean (standard deviation)
    -1.19 ± 5.90
    -1.75 ± 4.61
    Statistical analysis title
    		 PANAS -, change from baseline to 6 weeks
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4482
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.84
         upper limit
    		 4.16

    Primary: Change in CGI Mania from baseline to 6 weeks

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    End point title
    		 Change in CGI Mania from baseline to 6 weeks
    End point description
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    14
    10
    Units: Score
        median (inter-quartile range (Q1-Q3))
    4 (4 to 4)
    4 (4 to 4)
    Statistical analysis title
    		 CGI Mania, change from baseline to 6 weeks
    Statistical analysis description
    Wilcoxon signed rank test
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4453
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in CGI Depression from baseline to 6 weeks

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    End point title
    		 Change in CGI Depression from baseline to 6 weeks
    End point description
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    14
    10
    Units: Score
        median (inter-quartile range (Q1-Q3))
    3.5 (2 to 4)
    3 (2 to 4)
    Statistical analysis title
    		 CGI Depression, change from baseline to 6 weeks
    Statistical analysis description
    Wilcoxon signed rank test
    Comparison groups
    Placebo v Lithium
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9047
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in CGI Bipolar from baseline to 6 weeks

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    End point title
    		 Change in CGI Bipolar from baseline to 6 weeks
    End point description
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    14
    10
    Units: Score
        median (inter-quartile range (Q1-Q3))
    3 (2 to 4)
    3 (2 to 4)
    Statistical analysis title
    		 CGI Bipolar, change from baseline to 6 weeks
    Statistical analysis description
    Wilcoxon signed rank test
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.741
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in QIDS score from baseline to 8 days

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    End point title
    		 Change in QIDS score from baseline to 8 days
    End point description
    End point type
    Secondary
    End point timeframe
    8 days
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: Score
        arithmetic mean (standard deviation)
    -0.95 ± 4.29
    0.40 ± 4.82
    Statistical analysis title
    		 Change in QIDS score from baseline to 8 days
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3869
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.49
         upper limit
    		 1.74

    Secondary: Change in QIDS score from baseline to 4 weeks

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    End point title
    		 Change in QIDS score from baseline to 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    14
    Units: Score
        arithmetic mean (standard deviation)
    -3.16 ± 5.59
    -0.21 ± 5.18
    Statistical analysis title
    		 QIDS, change from baseline to 4 weeks
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0578
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.26
         upper limit
    		 0.1

    Secondary: Change in ALTMAN score from baseline to 8 days

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    End point title
    		 Change in ALTMAN score from baseline to 8 days
    End point description
    End point type
    Secondary
    End point timeframe
    8 days
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: Score
        arithmetic mean (standard deviation)
    0.53 ± 3.50
    -1.40 ± 5.37
    Statistical analysis title
    		 ALTMAN, change from baseline to 8 days
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3977
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.29
         upper limit
    		 3.24
    Variability estimate
    Standard deviation

    Secondary: Change in ALTMAN score from baseline to 4 weeks

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    End point title
    		 Change in ALTMAN score from baseline to 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    14
    Units: Score
        arithmetic mean (standard deviation)
    1.05 ± 5.56
    -0.64 ± 2.68
    Statistical analysis title
    		 Change in ALTMAN score, baseline to 4 weeks
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4903
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 3.12

    Secondary: Change in PANAS + score from baseline to 8 days

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    End point title
    		 Change in PANAS + score from baseline to 8 days
    End point description
    Change in PANAS positive affect ratings between baseline and 8 days
    End point type
    Secondary
    End point timeframe
    8 days
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: Score
        arithmetic mean (standard deviation)
    -0.21 ± 5.24
    -2.67 ± 6.65
    Statistical analysis title
    		 Change in PANAS + score, baseline to 8 days
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2526
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.15
         upper limit
    		 4.37

    Secondary: Change in PANAS + score from baseline to 4 weeks

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    End point title
    		 Change in PANAS + score from baseline to 4 weeks
    End point description
    Change in PANAS positive affect ratings between baseline and 4 weeks
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    17
    14
    Units: Score
        arithmetic mean (standard deviation)
    -1.24 ± 5.71
    -1.00 ± 5.01
    Statistical analysis title
    		 Change in PANAS + score, baseline to 4 weeks
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3171
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.34
         upper limit
    		 1.41

    Secondary: Change in PANAS - score from baseline to 8 days

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    End point title
    		 Change in PANAS - score from baseline to 8 days
    End point description
    Change in PANAS negative affect ratings between baseline and 8 days
    End point type
    Secondary
    End point timeframe
    8 days
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: Score
        arithmetic mean (standard deviation)
    -0.89 ± 4.81
    1.53 ± 5.33
    Statistical analysis title
    		 PANAS -, change from baseline to 8 days
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2965
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.34
         upper limit
    		 1.32

    Secondary: Change in PANAS - score from baseline to 4 weeks

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    End point title
    		 Change in PANAS - score from baseline to 4 weeks
    End point description
    Change in PANAS negative affect ratings between baseline and 4 weeks
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    17
    14
    Units: Score
        arithmetic mean (standard deviation)
    -2.41 ± 5.15
    0.07 ± 5.50
    Statistical analysis title
    		 PANAS -, change from baseline to 4 weeks
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3918
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.19
         upper limit
    		 1.64

    Secondary: Change in CGI Mania from baseline to 4 weeks

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    End point title
    		 Change in CGI Mania from baseline to 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    15
    10
    Units: Score
        median (inter-quartile range (Q1-Q3))
    4 (4 to 4)
    4 (4 to 4)
    Statistical analysis title
    		 CGI Mania, change from baseline to 4 weeks
    Statistical analysis description
    Wilcoxon signed rank test
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in CGI Depression from baseline to 4 weeks

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    End point title
    		 Change in CGI Depression from baseline to 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    15
    10
    Units: Score
        median (inter-quartile range (Q1-Q3))
    4 (3 to 4)
    3.5 (3 to 4)
    Statistical analysis title
    		 CGI Depression, change from baseline to 4 weeks
    Statistical analysis description
    Wilcoxon signed rank test
    Comparison groups
    Placebo v Lithium
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4233
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in CGI Bipolar from baseline to 4 weeks

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    End point title
    		 Change in CGI Bipolar from baseline to 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    15
    10
    Units: Score
        median (inter-quartile range (Q1-Q3))
    4 (4 to 5)
    3.5 (3 to 4)
    Statistical analysis title
    		 CGI Bipolar, change from baseline to 4 weeks
    Statistical analysis description
    Wilcoxon signed rank test
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1739
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: PANAS + score at 8 days

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    End point title
    		 PANAS + score at 8 days
    End point description
    PANAS positive affect ratings score at 8 days
    End point type
    Secondary
    End point timeframe
    8 days
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: Score
        arithmetic mean (confidence interval 95%)
    5.5 (4.1 to 6.9)
    5.3 (3.8 to 6.9)
    Statistical analysis title
    		 PANAS + score, 8 days
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, continuous time, randomised group (Lithium or placebo), pre or post randomisation period, and the interaction between time and randomised group, between time and pre or post randomisation period and between pre or post randomisation period and randomised group, and the three way interaction between pre or post randomisation period, time and randomised group, and with a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8734
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.95
         upper limit
    		 2.3

    Secondary: PANAS + score at 4 weeks

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    End point title
    		 PANAS + score at 4 weeks
    End point description
    PANAS positive affect rating score at 4 weeks
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: Score
        arithmetic mean (confidence interval 95%)
    5.0 (3.6 to 6.4)
    6.9 (5.4 to 8.5)
    Statistical analysis title
    		 PANAS + score, 4 weeks
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, continuous time, randomised group (Lithium or placebo), pre or post randomisation period, and the interaction between time and randomised group, between time and pre or post randomisation period and between pre or post randomisation period and randomised group, and the three way interaction between pre or post randomisation period, time and randomised group, and with a random effect for participant.
    Comparison groups
    Placebo v Lithium
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0734
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.04
         upper limit
    		 0.18

    Secondary: PANAS + score, 6 weeks

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    End point title
    		 PANAS + score, 6 weeks
    End point description
    PANAS positive affect rating score, 6 weeks
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: Score
        arithmetic mean (confidence interval 95%)
    4.7 (3.2 to 6.1)
    8.1 (6.4 to 9.7)
    Statistical analysis title
    		 PANAS + score, 6 weeks
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, continuous time, randomised group (Lithium or placebo), pre or post randomisation period, and the interaction between time and randomised group, between time and pre or post randomisation period and between pre or post randomisation period and randomised group, and the three way interaction between pre or post randomisation period, time and randomised group, and with a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0028
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.63
         upper limit
    		 -1.17

    Secondary: PANAS - score, 8 days

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    End point title
    		 PANAS - score, 8 days
    End point description
    PANAS negative affect rating score, 8 days
    End point type
    Secondary
    End point timeframe
    8 days
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: Score
        arithmetic mean (confidence interval 95%)
    3.3 (1.8 to 4.8)
    5.4 (3.7 to 7.0)
    Statistical analysis title
    		 PANAS - score, 8 days
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, continuous time, randomised group (Lithium or placebo), pre or post randomisation period, and the interaction between time and randomised group, between time and pre or post randomisation period and between pre or post randomisation period and randomised group, and the three way interaction between pre or post randomisation period, time and randomised group, and with a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0795
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.34
         upper limit
    		 0.24

    Secondary: PANAS - score at 4 weeks

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    End point title
    		 PANAS - score at 4 weeks
    End point description
    PANAS negative affect rating score, 4 weeks
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: Score
        arithmetic mean (confidence interval 95%)
    3.6 (2.1 to 5.1)
    4.3 (2.6 to 5.9)
    Statistical analysis title
    		 PANAS - score, 4 weeks
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, continuous time, randomised group (Lithium or placebo), pre or post randomisation period, and the interaction between time and randomised group, between time and pre or post randomisation period and between pre or post randomisation period and randomised group, and the three way interaction between pre or post randomisation period, time and randomised group, and with a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5487
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.97
         upper limit
    		 1.58

    Secondary: PANAS - score at 6 weeks

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    End point title
    		 PANAS - score at 6 weeks
    End point description
    PANAS negative affect rating score, 6 weeks
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: Score
        arithmetic mean (confidence interval 95%)
    3.7 (2.2 to 5.3)
    3.5 (1.7 to 5.2)
    Statistical analysis title
    		 PANAS - score, 6 weeks
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, continuous time, randomised group (Lithium or placebo), pre or post randomisation period, and the interaction between time and randomised group, between time and pre or post randomisation period and between pre or post randomisation period and randomised group, and the three way interaction between pre or post randomisation period, time and randomised group, and with a random effect for participant.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8363
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.12
         upper limit
    		 2.62

    Secondary: Change in PANAS+ SD, baseline to 6 weeks

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    End point title
    		 Change in PANAS+ SD, baseline to 6 weeks
    End point description
    Change from baseline to 6 weeks in the standard deviation of the PANAS positive affect scale.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    17
    13
    Units: N/A
        arithmetic mean (standard deviation)
    -0.73 ± 1.67
    -0.67 ± 1.87
    Statistical analysis title
    		 PANAS + SD, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo).
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7689
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.21
         upper limit
    		 0.9

    Secondary: Change in PANAS- SD, baseline to 6 weeks

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    End point title
    		 Change in PANAS- SD, baseline to 6 weeks
    End point description
    Change from baseline to 6 weeks in the standard deviation of the PANAS negative affect scale
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    17
    13
    Units: N/A
        arithmetic mean (standard deviation)
    -0.56 ± 1.68
    -1.31 ± 1.55
    Statistical analysis title
    		 PANAS - SD, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo).
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2609
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 1.74

    Secondary: Change in PANAS+ rmssd,baseline to 6 weeks

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    End point title
    		 Change in PANAS+ rmssd,baseline to 6 weeks
    End point description
    Change from baseline to 6 weeks in the root mean square of successive differences (rmssd) of the PANAS positive affect scale
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    17
    13
    Units: N/A
        arithmetic mean (standard deviation)
    -0.53 ± 2.08
    -0.94 ± 2.06
    Statistical analysis title
    		 PANAS + rmssd, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo).
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7824
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.18
         upper limit
    		 1.56

    Secondary: Change in PANAS- rmssd,baseline to 6 weeks

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    End point title
    		 Change in PANAS- rmssd,baseline to 6 weeks
    End point description
    Change from baseline to 6 weeks in the root mean square of successive differences (rmssd) of the PANAS negative affect scale
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    17
    13
    Units: N/A
        arithmetic mean (standard deviation)
    -0.75 ± 2.51
    -1.59 ± 1.81
    Statistical analysis title
    		 PANAS - rmssd, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo).
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3685
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.75
         upper limit
    		 1.96

    Secondary: Change in PANAS+ entropy,baseline to 6 weeks

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    End point title
    		 Change in PANAS+ entropy,baseline to 6 weeks
    End point description
    Change from baseline to 6 weeks in the entropy of the PANAS positive affect scale
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    14
    12
    Units: N/A
        arithmetic mean (standard deviation)
    -0.33 ± 0.69
    0.05 ± 0.65
    Statistical analysis title
    		 PANAS + entropy, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo).
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0619
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.08
         upper limit
    		 0.03

    Secondary: Change in PANAS- entropy,baseline to 6 weeks

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    End point title
    		 Change in PANAS- entropy,baseline to 6 weeks
    End point description
    Change from baseline to 6 weeks in the entropy of the PANAS negative affect scale
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    16
    10
    Units: N/A
        arithmetic mean (standard deviation)
    -0.22 ± 0.92
    -0.22 ± 0.83
    Statistical analysis title
    		 PANAS - entropy, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo).
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.266
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.27
         upper limit
    		 0.37

    Secondary: Change in PANAS+ TKEO, baseline to 6 weeks

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    End point title
    		 Change in PANAS+ TKEO, baseline to 6 weeks
    End point description
    Change from baseline to 6 weeks in the Teager Kaiser Energy Operator (TKEO) of the PANAS positive affect scale
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    16
    13
    Units: N/A
        arithmetic mean (standard deviation)
    -4.60 ± 12.5
    -4.95 ± 11.4
    Statistical analysis title
    		 Change in PANAS+ TKEO, baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-value obtained using bootstrapping with 10000 simulations.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7162
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.18
         upper limit
    		 3.17

    Secondary: Change in PANAS- TKEO, baseline to 6 weeks

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    End point title
    		 Change in PANAS- TKEO, baseline to 6 weeks
    End point description
    Change from baseline to 6 weeks in the Teager Kaiser Energy Operator (TKEO) of the PANAS negative affect scale
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    16
    13
    Units: N/A
        arithmetic mean (standard deviation)
    -4.3 ± 14.8
    -4.8 ± 7.3
    Statistical analysis title
    		 PANAS - TKEO, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-value obtained using bootstrapping with 10000 simulations.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5791
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.09
         upper limit
    		 5.54

    Secondary: Change in SCI, baseline to 6 weeks

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    End point title
    		 Change in SCI, baseline to 6 weeks
    End point description
    Change in sleep pattern (SCI) from baseline to 6 weeks
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    14
    10
    Units: N/A
        arithmetic mean (standard deviation)
    -0.07 ± 5.21
    2.70 ± 7.59
    Statistical analysis title
    		 SCI, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-values were obtained by bootstrapping with 10000 reps due to skewness in the data.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9264
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.3
         upper limit
    		 5.73

    Secondary: Change in IL6, baseline to 6 weeks

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    End point title
    		 Change in IL6, baseline to 6 weeks
    End point description
    Change in interleukin 6 from baseline to 6 weeks
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    18
    14
    Units: pg/mL
        arithmetic mean (standard deviation)
    0.34 ± 1.18
    0.01 ± 0.38
    Statistical analysis title
    		 IL6, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-values were obtained by bootstrapping with 10000 reps due to skewness in the data.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3351
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 0.84

    Secondary: Change in NGAL, baseline to 6 weeks

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    End point title
    		 Change in NGAL, baseline to 6 weeks
    End point description
    Change in neutrophil gelatinase-associated lipocalin (NGAL) from baseline to 6 weeks
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: ng/ml
        arithmetic mean (standard deviation)
    0.02 ± 0.02
    0.00 ± 0.03
    Statistical analysis title
    		 NGAL, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-values were obtained by bootstrapping with 10000 reps due to skewness in the data.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0334
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.05

    Secondary: Change in T4 , baseline to 6 weeks

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    End point title
    		 Change in T4 , baseline to 6 weeks
    End point description
    Change in Thyroxine (T4) from baseline to 6 weeks
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    14
    Units: pmol/L
        arithmetic mean (standard deviation)
    -0.81 ± 1.38
    -0.41 ± 0.76
    Statistical analysis title
    		 T4 thyroxine, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-values were obtained by bootstrapping with 10000 reps due to skewness in the data.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5405
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.34
         upper limit
    		 0.7

    Secondary: Change in T3, baseline to 6 weeks

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    End point title
    		 Change in T3, baseline to 6 weeks
    End point description
    Change in Triiodothyronine (T3) from baseline to 6 weeks
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    18
    11
    Units: pmol/L
        arithmetic mean (standard deviation)
    -0.14 ± 0.78
    0.10 ± 0.49
    Statistical analysis title
    		 Triiodothyronine, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-values were obtained by bootstrapping with 10000 reps due to skewness in the data.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 0.34

    Secondary: Change in TSH, baseline to 6 weeks

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    End point title
    		 Change in TSH, baseline to 6 weeks
    End point description
    Change in thyroid stimulating hormone (TSH) from baseline to 6 weeks.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    16
    Units: mU/L
        arithmetic mean (standard deviation)
    1.03 ± 1.04
    0.13 ± 0.56
    Statistical analysis title
    		 TSH, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-values were obtained by bootstrapping with 10000 reps due to skewness in the data.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0499
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 1.26

    Secondary: Change in calcium, baseline to 6 weeks

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    End point title
    		 Change in calcium, baseline to 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    17
    13
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.01 ± 0.08
    0.00 ± 0.09
    Statistical analysis title
    		 Calcium, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-values were obtained by bootstrapping with 10000 reps due to skewness in the data.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.809
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.05

    Secondary: Change in PTH, baseline to 6 weeks

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    End point title
    		 Change in PTH, baseline to 6 weeks
    End point description
    Change in parathyroid hormone (PTH) from baseline to 6 weeks
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    16
    13
    Units: pmol/L
        arithmetic mean (standard deviation)
    -0.21 ± 1.71
    -0.57 ± 1.46
    Statistical analysis title
    		 PTH, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-values were obtained by bootstrapping with 10000 reps due to skewness in the data.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3326
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 1.49

    Secondary: Change in vitamin D, baseline to 6 weeks

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    End point title
    		 Change in vitamin D, baseline to 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    16
    Units: nmol/L
        arithmetic mean (standard deviation)
    1.67 ± 22.83
    -0.15 ± 18.74
    Statistical analysis title
    		 Vitamin D, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-values were obtained by bootstrapping with 10000 reps due to skewness in the data.
    Comparison groups
    Placebo v Lithium
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2513
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    7.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.2
         upper limit
    		 19.9

    Secondary: Change in creatinine, baseline to 6 weeks

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    End point title
    		 Change in creatinine, baseline to 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    16
    Units: umol/L
        arithmetic mean (standard deviation)
    6.24 ± 4.78
    2.38 ± 6.41
    Statistical analysis title
    		 Creatinine, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-values were obtained by bootstrapping with 10000 reps due to skewness in the data.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0501
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 9.2

    Secondary: Change in cystatin, baseline to 6 weeks

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    End point title
    		 Change in cystatin, baseline to 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    14
    12
    Units: mg/L
        arithmetic mean (standard deviation)
    0.05 ± 0.11
    0.00 ± 0.05
    Statistical analysis title
    		 Cystatin C, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-values were obtained by bootstrapping with 10000 reps due to skewness in the data.
    Comparison groups
    Placebo v Lithium
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1226
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.13

    Secondary: Change in CRP, baseline to 6 weeks

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    End point title
    		 Change in CRP, baseline to 6 weeks
    End point description
    Change in C-reactive protein (CRP) from baseline to 6 weeks
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    13
    10
    Units: mg/L
        arithmetic mean (standard deviation)
    4.01 ± 10.5
    0.28 ± 5.02
    Statistical analysis title
    		 CRP, change from baseline to 6 weeks
    Statistical analysis description
    Linear regression model with covariates for baseline measurement, gender, age, and randomised group (Lithium or placebo). Confidence intervals and p-values were obtained by bootstrapping with 10000 reps due to skewness in the data.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7857
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 8.2

    Other pre-specified: Medication compliance, 4 days

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    End point title
    		 Medication compliance, 4 days
    End point description
    Compliance to study medication regime, reported at 4 days
    End point type
    Other pre-specified
    End point timeframe
    4 days
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    16
    Units: People
        More than 65%
    19
    15
        Between 50 and 65%
    0
    1
        Missing
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Medication compliance, 8 days

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    End point title
    		 Medication compliance, 8 days
    End point description
    Compliance to study medication regime, reported at 8 days
    End point type
    Other pre-specified
    End point timeframe
    8 days
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    16
    Units: People
        More than 65%
    19
    15
        Between 50 and 65%
    0
    0
        Missing
    0
    1
    No statistical analyses for this end point

    Other pre-specified: Medication compliance, 4 weeks

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    End point title
    		 Medication compliance, 4 weeks
    End point description
    Compliance to study medication regime, reported at 4 weeks
    End point type
    Other pre-specified
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    16
    Units: People
        More than 65%
    19
    14
        Between 50 and 65%
    0
    0
        Missing
    0
    2
    No statistical analyses for this end point

    Other pre-specified: Medication compliance, 6 weeks

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    End point title
    		 Medication compliance, 6 weeks
    End point description
    Compliance to study medication regime, reported at 6 weeks
    End point type
    Other pre-specified
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    16
    Units: People
        More than 65%
    18
    14
        Between 50 and 65%
    0
    0
        Missing
    1
    2
    No statistical analyses for this end point

    Other pre-specified: Change in QIDS, baseline to 8 days, ITT

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    End point title
    		 Change in QIDS, baseline to 8 days, ITT
    End point description
    Change in QIDS-SR16 (Quick Inventory of Depressive Symptomatology) score from baseline to 8 days, using the intention to treat population.
    End point type
    Other pre-specified
    End point timeframe
    8 days
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: Score
        arithmetic mean (standard deviation)
    -0.9 ± 4.3
    0.4 ± 4.8
    Statistical analysis title
    		 QIDS, change from baseline to 8 days, ITT
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant. Analysis carried out on the ITT population.
    Comparison groups
    Placebo v Lithium
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3841
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 1.7

    Other pre-specified: Change in QIDS, baseline to 4 weeks, ITT

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    End point title
    		 Change in QIDS, baseline to 4 weeks, ITT
    End point description
    Change in QIDS-SR16 (Quick Inventory of Depressive Symptomatology) score from baseline to 4 weeks, using the intention to treat population.
    End point type
    Other pre-specified
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: Score
        arithmetic mean (standard deviation)
    -3.2 ± 5.6
    -0.07 ± 5.0
    Statistical analysis title
    		 QIDS, change from baseline to 4 weeks, ITT
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant. Analysis carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0473
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 -0.04

    Other pre-specified: Change in QIDS, baseline to 6 weeks, ITT

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    End point title
    		 Change in QIDS, baseline to 6 weeks, ITT
    End point description
    Change in QIDS-SR16 (Quick Inventory of Depressive Symptomatology) score from baseline to 6 weeks, using the intention to treat population.
    End point type
    Other pre-specified
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    14
    Units: Score
        arithmetic mean (standard deviation)
    -1.7 ± 6.9
    -1.9 ± 5.6
    Statistical analysis title
    		 QIDS, change from baseline to 6 weeks, ITT
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant. Analysis carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7577
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 3.6

    Other pre-specified: Change in ALTMAN, baseline to 8 days, ITT

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    End point title
    		 Change in ALTMAN, baseline to 8 days, ITT
    End point description
    Change in ALTMAN mania score from baseline to 8 days, using the intention to treat population.
    End point type
    Other pre-specified
    End point timeframe
    8 days
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: score
        arithmetic mean (standard deviation)
    0.5 ± 3.5
    -1.4 ± 5.4
    Statistical analysis title
    		 ALTMAN, change from baseline to 8 days, ITT
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant. Analysis carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4389
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 3.2

    Other pre-specified: Change in ALTMAN, baseline to 4 weeks, ITT

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    End point title
    		 Change in ALTMAN, baseline to 4 weeks, ITT
    End point description
    Change in ALTMAN mania score from baseline to 4 weeks, using the intention to treat population.
    End point type
    Other pre-specified
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: Score
        arithmetic mean (standard deviation)
    1.1 ± 5.6
    -0.9 ± 2.8
    Statistical analysis title
    		 ALTMAN, change from baseline to 4 weeks, ITT
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant. Analysis carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4091
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 3.2

    Other pre-specified: Change in ALTMAN, baseline to 6 weeks, ITT

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    End point title
    		 Change in ALTMAN, baseline to 6 weeks, ITT
    End point description
    Change in ALTMAN mania score from baseline to 6 weeks, using the intention to treat population.
    End point type
    Other pre-specified
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    14
    Units: Score
        arithmetic mean (standard deviation)
    0.3 ± 4.6
    -0.8 ± 3.4
    Statistical analysis title
    		 ALTMAN, change from baseline to 6 weeks, ITT
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant. Analysis carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8594
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 2.1

    Other pre-specified: Change in PANAS + , baseline to 8 days, ITT

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    End point title
    		 Change in PANAS + , baseline to 8 days, ITT
    End point description
    Change in PANAS positive affect ratings between baseline and 8 days, using the intention to treat population.
    End point type
    Other pre-specified
    End point timeframe
    8 days
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: score
        arithmetic mean (standard deviation)
    -0.2 ± 5.2
    -2.7 ± 6.7
    Statistical analysis title
    		 PANAS +, change from baseline to 8 days, ITT
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant. Analysis carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.247
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 4.4

    Other pre-specified: Change in PANAS + , baseline to 4 weeks, ITT

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    End point title
    		 Change in PANAS + , baseline to 4 weeks, ITT
    End point description
    Change in PANAS positive affect ratings between baseline and 4 weeks, using the intention to treat population.
    End point type
    Other pre-specified
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    17
    15
    Units: Score
        arithmetic mean (standard deviation)
    -1.2 ± 5.7
    -1.0 ± 4.8
    Statistical analysis title
    		 PANAS + , change from baseline to 4 weeks, ITT
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant. Analysis carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4542
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 1.8

    Other pre-specified: Change in PANAS + , baseline to 6 weeks, ITT

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    End point title
    		 Change in PANAS + , baseline to 6 weeks, ITT
    End point description
    Change in PANAS positive affect ratings between baseline and 6 weeks, using the intention to treat population.
    End point type
    Other pre-specified
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    16
    12
    Units: Score
        arithmetic mean (standard deviation)
    -2.4 ± 4.8
    0.5 ± 3.7
    Statistical analysis title
    		 PANAS + , change from baseline to 6 weeks, ITT
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant. Analysis carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0177
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 -0.6

    Other pre-specified: Change in PANAS - , baseline to 8 days, ITT

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    End point title
    		 Change in PANAS - , baseline to 8 days, ITT
    End point description
    Change in PANAS negative affect ratings between baseline and 8 days, using the intention to treat population.
    End point type
    Other pre-specified
    End point timeframe
    8 days
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    19
    15
    Units: score
        arithmetic mean (standard deviation)
    -0.9 ± 4.8
    1.5 ± 5.3
    Statistical analysis title
    		 PANAS - , change from baseline to 8 days, ITT
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant. Analysis carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2891
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 1.3

    Other pre-specified: Change in PANAS - , baseline to 4 weeks, ITT

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    End point title
    		 Change in PANAS - , baseline to 4 weeks, ITT
    End point description
    Change in PANAS negative affect ratings between baseline and 4 weeks, using the intention to treat population.
    End point type
    Other pre-specified
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    17
    15
    Units: Score
        arithmetic mean (standard deviation)
    -2.4 ± 5.1
    0.4 ± 5.4
    Statistical analysis title
    		 PANAS - , change from baseline to 4 weeks, ITT
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant. Analysis carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2965
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 1.3

    Other pre-specified: Change in PANAS - , baseline to 6 weeks, ITT

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    End point title
    		 Change in PANAS - , baseline to 6 weeks, ITT
    End point description
    Change in PANAS negative affect ratings between baseline and 6 weeks, using the intention to treat population.
    End point type
    Other pre-specified
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    16
    12
    Units: Score
        arithmetic mean (standard deviation)
    -1.2 ± 5.9
    -1.8 ± 4.6
    Statistical analysis title
    		 PANAS - , change from baseline to 6 weeks, ITT
    Statistical analysis description
    Linear mixed effects model with fixed effects for baseline total score, gender, age, assessment point (8 days, 4 weeks or 6 weeks), randomised group (Lithium or placebo) and interaction between assessment point and randomised group, and a random effect for participant. Analysis carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4931
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 4

    Other pre-specified: Change in CGI Mania from baseline to 4 weeks, ITT

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    End point title
    		 Change in CGI Mania from baseline to 4 weeks, ITT
    End point description
    Change in CGI mania scale between baseline and 4 weeks, using the intention to treat population
    End point type
    Other pre-specified
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    15
    10
    Units: Score
        median (inter-quartile range (Q1-Q3))
    4 (4 to 4)
    4 (4 to 4)
    Statistical analysis title
    		 CGI Mania, change from baseline to 4 weeks, ITT
    Statistical analysis description
    Wilcoxon signed rank test, carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Other pre-specified: Change in CGI Mania from baseline to 6 weeks, ITT

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    End point title
    		 Change in CGI Mania from baseline to 6 weeks, ITT
    End point description
    Change in CGI mania scale between baseline and 6 weeks, using the intention to treat population
    End point type
    Other pre-specified
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    13
    10
    Units: Score
        median (inter-quartile range (Q1-Q3))
    4 (4 to 4)
    4 (4 to 4)
    Statistical analysis title
    		 CGI Mania, change from baseline to 6 weeks, ITT
    Statistical analysis description
    Wilcoxon signed rank test, carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4453
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Other pre-specified: Change in CGI Depression from baseline to 4 weeks, ITT

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    End point title
    		 Change in CGI Depression from baseline to 4 weeks, ITT
    End point description
    Change in CGI depression scale between baseline and 4 weeks, using the intention to treat population
    End point type
    Other pre-specified
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    15
    10
    Units: Score
        median (inter-quartile range (Q1-Q3))
    4 (3 to 4)
    3.5 (3 to 4)
    Statistical analysis title
    		 CGI Depression,change from baseline to 4 weeks,ITT
    Statistical analysis description
    Wilcoxon signed rank test, carried out on the ITT population.
    Comparison groups
    Placebo v Lithium
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4233
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Other pre-specified: Change in CGI Depression from baseline to 6 weeks, ITT

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    End point title
    		 Change in CGI Depression from baseline to 6 weeks, ITT
    End point description
    Change in CGI depression scale between baseline and 6 weeks, using the intention to treat population
    End point type
    Other pre-specified
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    14
    10
    Units: Score
        median (inter-quartile range (Q1-Q3))
    3.5 (2 to 4)
    3 (2 to 4)
    Statistical analysis title
    		 CGI Depression,change from baseline to 6 weeks,ITT
    Statistical analysis description
    Wilcoxon signed rank test, carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9047
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Other pre-specified: Change in CGI Bipolar from baseline to 4 weeks, ITT

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    End point title
    		 Change in CGI Bipolar from baseline to 4 weeks, ITT
    End point description
    Change in CGI bipolar scale between baseline and 4 weeks, using the intention to treat population
    End point type
    Other pre-specified
    End point timeframe
    4 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    15
    10
    Units: Score
        median (inter-quartile range (Q1-Q3))
    4 (4 to 5)
    3.5 (3 to 4)
    Statistical analysis title
    		 CGI Bipolar, change from baseline to 4 weeks, ITT
    Statistical analysis description
    Wilcoxon signed rank test, carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1739
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Other pre-specified: Change in CGI Bipolar from baseline to 6 weeks, ITT

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    End point title
    		 Change in CGI Bipolar from baseline to 6 weeks, ITT
    End point description
    Change in CGI bipolar scale between baseline and 6 weeks, using the intention to treat population
    End point type
    Other pre-specified
    End point timeframe
    6 weeks
    End point values
    		 Lithium Placebo
    Number of subjects analysed
    14
    10
    Units: Score
        median (inter-quartile range (Q1-Q3))
    3 (2 to 4)
    3 (2 to 4)
    Statistical analysis title
    		 CGI Bipolar, change from baseline to 6 weeks, ITT
    Statistical analysis description
    Wilcoxon signed rank test, carried out on the ITT population.
    Comparison groups
    Lithium v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.741
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Expedited reporting of commonly occurring SAEs (psychiatry admission for mood symptoms and/or suicidal behaviour) was not required. Reporting within 24 hours of the Investigator becoming aware of the event was required for all other SAEs/SUSARs.
    Adverse event reporting additional description
    Reporting of non-serious adverse events was only required if they were judged to be reactions to lithium and were not consistent with the Reference Safety Information used for the trial.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Frequency threshold for reporting non-serious adverse events: 1%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Previously described

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Apr 2015
    OxLith SA02: New assessments introduced to measure: 1) Heart rate variability [using ePatches]. 2) Clinician rating of mood [Clinical Global Impression scales]. 3) Sleep patterns (Sleep Condition Indicator]. Plus minor changes to procedures to facilitate the conduct of the trial.
    01 Jun 2015
    OxLith SA01-nd: Approval for a booklet to be given to participants providing information about visits and tasks.
    28 Jun 2016
    OxLith SA03: Introduction of an Information Leaflet to be placed in Oxford Health NHS Foundation Trust clinic areas.
    13 Jul 2016
    OxLith NSA04: Non-substantial amendment notifying REC of change of laboratory performing assays for lithium and calcium levels.
    10 Aug 2016
    OxLith SA05: Withdrawal of unused out-of-hours phone contact number for trial participants.
    07 Sep 2016
    OxLith SA07: Change of Principal Investigator for Oxford Health NHS Foundation Trust.
    03 Nov 2016
    OxLith SA06: Approval for trial information to be made available online.
    22 Dec 2016
    OxLith SA08: Update of Summary of Product Characteristics for Priadel which form the Research Safety Information provided to Trial Investigators.
    23 Feb 2017
    OxLith SA10: Changes to procedures: 1. Change of procedure for making payments to participants. 2. Recommendation to have scans on separate days. 3. Revision to time required to complete scans.
    28 Feb 2017
    OxLith SA09: Non-substantial notification to REC of extension to trial period from 04/01/2017 to 01/04/2018.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Feb 2017
    Recruitment was stopped because the supply of one IMP ran out. None of the 4 participants in the randomised phase when the problem occurred were left without treatment and only one had to be withdrawn from trial treatment prematurely to return to routine clinical care.
    20 Mar 2017

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26936776
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