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    Clinical Trial Results:
    Downstream targets of SSRI effect in treatment of Major Depressive Disorder

    Summary
    EudraCT number
    		 2019-002232-82
    Trial protocol
    		 SE  
    Global end of trial date
    30 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jan 2025
    First version publication date
    05 Jan 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KIH18001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Karolinska Institutet
    Sponsor organisation address
    Nobels väg 6, Solna, Sweden,
    Public contact
    Mikael Tiger, Karolinska Institutet PET centre, mikael.tiger@ki.se
    Scientific contact
    Mikael Tiger, Karolinska Institutet PET centre, mikael.tiger@ki.se
    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
    25 Feb 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a clinical study of the downstream mechanism of action of SSRI treatment for MDD. Primary research questions (outcomes): • Does SSRI for MDD reduce serotonin 1B (5-HT1B) receptor binding in the raphe nuclei and increase 5-HT1B receptor binding in serotonin projection areas? • Is this putative change in 5-HT1B receptor binding related to change in MDD symptom rating scores or side effects?
    Protection of trial subjects
    All participants provided oral and written consent before initiation of any study-related event. The study was approved by the Swedish Ethical Review Authority in Stockholm and the Swedish Medical Products Agency in Uppsala.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Oct 2019
    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
    Sweden: 8
    Worldwide total number of subjects
    8
    EEA total number of subjects
    8
    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)
    8
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Study participants were recruited either via Gustavsberg University Primary Care Center or through online advertising. The diagnosis of MDD was confirmed by a psychiatrist (M.G.or M.T.) at a face-to-face visit using the Mini-International Neuropsychiatric Interview

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Escitalopram
    Arm description
    		 Escitalopram
    Arm type
    		 Experimental

    Investigational medicinal product name
    Escitalopram
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Escitalopram 10 mg daily the day after their first PET examination (PET 1).

    Number of subjects in period 1
    		Escitalopram
    Started
    8
    Completed
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 8 8
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 8 8
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.4 ( 7.58 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 4 4
    PET 1: Anterior cingulate cortex
    Units: Score
        arithmetic mean (standard deviation)
    		 1.16 ( 0.18 ) -
    PET 1: Orbitofrontal cortex
    Units: Score
        arithmetic mean (standard deviation)
    		 1.17 ( 0.19 ) -
    PET 1: Hippocampus
    Units: Score
        arithmetic mean (standard deviation)
    		 0.38 ( 0.14 ) -
    PET 1: Dorsal brainstem
    Units: Score
        arithmetic mean (standard deviation)
    		 0.71 ( 0.37 ) -
    PET 1: MADRS
    Units: Score
        arithmetic mean (standard deviation)
    		 25.5 ( 2.28 ) -

    End points

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    End points reporting groups
    Reporting group title
    Escitalopram
    Reporting group description
    		 Escitalopram

    Subject analysis set title
    PET 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    PET 1 is the first PET examination before the patients with moderate to severe major depressive disorder (MDD) underwent treatment with the SSRI escitalopram 10 mg daily for 3 to 4 weeks.

    Primary: PET 2: Anterior cingulate cortex

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    End point title
    		 PET 2: Anterior cingulate cortex
    End point description
    End point type
    Primary
    End point timeframe
    PET 2 was performed after 3 to 4 weeks (mean ± SD = 3.5 ± 0.5) of daily treatment with the SSRI escitalopram 10 mg.
    End point values
    		 Escitalopram PET 1
    Number of subjects analysed
    8
    8
    Units: Score
        arithmetic mean (standard deviation)
    1.19 ( 0.29 )
    1.16 ( 0.18 )
    Statistical analysis title
    		 Change in Anterior cingulate cortex
    Statistical analysis description
    Change in 5-HT1B receptor binding potential, Anterior cingulate cortex between PET 1 and PET 2.
    Comparison groups
    Escitalopram v PET 1
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.391
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [1] - 5-HT1B receptor change after escitalopram treatment.

    Primary: PET 2: Orbitofrontal cortex

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    End point title
    		 PET 2: Orbitofrontal cortex
    End point description
    End point type
    Primary
    End point timeframe
    PET 2 was performed after 3 to 4 weeks (mean ± SD = 3.5 ± 0.5) of daily treatment with the SSRI escitalopram 10 mg.
    End point values
    		 Escitalopram PET 1
    Number of subjects analysed
    8
    8
    Units: Score
        arithmetic mean (standard deviation)
    1.20 ( 0.26 )
    1.17 ( 0.19 )
    Statistical analysis title
    		 Change in Orbitofrontal cortex
    Statistical analysis description
    Change in 5-HT1B receptor binding potential, Orbitofrontal cortex between PET 1 and PET 2.
    Comparison groups
    Escitalopram v PET 1
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.362
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [2] - 5-HT1B receptor change after escitalopram treatment.

    Primary: PET 2: Hippocampus

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    End point title
    		 PET 2: Hippocampus
    End point description
    End point type
    Primary
    End point timeframe
    PET 2 was performed after 3 to 4 weeks (mean ± SD = 3.5 ± 0.5) of daily treatment with the SSRI escitalopram 10 mg.
    End point values
    		 Escitalopram PET 1
    Number of subjects analysed
    8
    8
    Units: Score
        arithmetic mean (standard deviation)
    0.36 ( 0.18 )
    0.38 ( 0.14 )
    Statistical analysis title
    		 Change in Hippocampus
    Statistical analysis description
    Change in 5-HT1B receptor binding potential, Hippocampus between PET 1 and PET 2.
    Comparison groups
    Escitalopram v PET 1
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.738
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [3] - 5-HT1B receptor change after escitalopram treatment.

    Primary: PET 2: Dorsal brainstem

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    End point title
    		 PET 2: Dorsal brainstem
    End point description
    End point type
    Primary
    End point timeframe
    PET 2 was performed after 3 to 4 weeks (mean ± SD = 3.5 ± 0.5) of daily treatment with the SSRI escitalopram 10 mg.
    End point values
    		 Escitalopram PET 1
    Number of subjects analysed
    8
    8
    Units: Score
        arithmetic mean (standard deviation)
    0.57 ( 0.33 )
    0.71 ( 0.37 )
    Statistical analysis title
    		 Change in Dorsal brainstem
    Statistical analysis description
    Change in 5-HT1B receptor binding potential, Dorsal brainstem between PET 1 and PET 2.
    Comparison groups
    Escitalopram v PET 1
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.036
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [4] - 5-HT1B receptor change after escitalopram treatment.

    Primary: PET 2: MADRS

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    End point title
    		 PET 2: MADRS
    End point description
    End point type
    Primary
    End point timeframe
    PET 2 was performed after 3 to 4 weeks (mean ± SD = 3.5 ± 0.5) of daily treatment with the SSRI escitalopram 10 mg.
    End point values
    		 Escitalopram PET 1
    Number of subjects analysed
    8
    8
    Units: Score
        arithmetic mean (standard deviation)
    14.00 ( 9.24 )
    25.5 ( 2.28 )
    Statistical analysis title
    		 MADRS change
    Statistical analysis description
    MADRS change after escitalopram treatment.
    Comparison groups
    Escitalopram v PET 1
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.009
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [5] - Change in MADRS between PET 1 and PET 2.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    07 Oct 2020 - 30 Apr 2022.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 UKU
    Dictionary version
    NA
    Reporting groups
    Reporting group title
    Overall group
    Reporting group description
    		 -

    Serious adverse events
    		 Overall group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Overall group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 8 (50.00%)
    Reproductive system and breast disorders
    Sexual dysfunction
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    3
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    13 Mar 2020
    COVID-19 restrictions
    17 Aug 2020

    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/38695786
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