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出境医 / 临床实验 / Lithium Effects on Reward Processing and Reappraisal in Healthy Volunteers

Lithium Effects on Reward Processing and Reappraisal in Healthy Volunteers

Study Description
Brief Summary:
Bipolar disorder has been associated with blunted activity in regions associated with emotional processing, such as striatal activity during reward anticipation as well as prefrontal activity during reappraisal. Lithium is the most effective treatment in bipolar disorder. Neurochemical and molecular basis of lithium is well known, but how this translates to mood stabilisation is not understood. This study is designed to address how lithium influences reward and emotion regulation processes in humans.

Condition or disease Intervention/treatment Phase
Healthy Drug: Lithium Other: Placebo - Rayotabs Not Applicable

Detailed Description:

Background:

Bipolar disorder is a relatively common psychiatric disorder for which treatment options are limited. The so-called mood stabiliser, lithium (usually in the form of lithium carbonate) is one of the most commonly used treatments for the disorder, and is effective in treating both acute mania and as a long term maintenance treatment. The investigator's understanding of the pharmacological mechanisms by which lithium exerts its actions is fairly well developed, however there is a lack of understanding of the psychological mechanisms. Within this study the investigators will look at two different types of emotional processing, namely reward anticipation/feedback and emotion regulation, to gain more understanding on how lithium exerts its mood stabilising effects.

Reward processing:

The neural correlates underlying reward anticipation and feedback can be measured with the Monetary Incentive Delay (MID) task, a widely used task for different disorders. Reward anticipation during the MID task has been associated among others, with ventral and dorsal striatum activity. Most critically, bipolar disorder has been associated with blunted reward function of the medial caudate. Reward feedback has been associated with ventral striatum and OFC/vmPFC activity.

Emotion regulation:

One of the most prominent approaches of emotion regulation is reappraisal . Reappraisal has been shown to consistently activate cognitive control regions and to modulate the bilateral amygdala. Insufficient prefrontal control and reduced downregulation of those prefrontal regions of the amygdala while reappraising negative stimuli has been consistently found in bipolar disorder.

Methods:

Using a double-blind, parallel-group design, 37 healthy volunteers (male and female) are randomly allocated to a 11 (+/- 1) day lithium administration or a placebo condition. After the intervention period, all participants undergo fMRI testing with the MID task and the emotional suppression task to assess reward processing and reappraisal of negative stimuli. The participants also complete a visual control task (checkerboard task) and several behavioural tasks and questionnaires. Lithium levels are measured at the end of the intervention period.

Hypothesis:

Based on the literature on bipolar disorder and the mood stabilising effects of Lithium, the investigators expect lithium administration in healthy participants to:

  • Increase caudate activity during reward anticipation
  • Increase activation of prefrontal control regions as well as increase negative connectivity between those regions and the amygdala during reappraisal

Fidelity check: significant increases in lithium levels in the lithium intervention group compared to the placebo group.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 37 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants were randomly assigned to the placebo or lithium group. The two groups were matched in terms of age and gender.
Masking: Double (Participant, Investigator)
Masking Description: The randomisation schedule was drawn up by an experimenter in the lab who is not involved in the study, and all information was kept in a locked cabinet in the Neurosciences building at the Department of Psychiatry, University of Oxford.
Primary Purpose: Basic Science
Official Title: The Effects of Short-term Lithium Administration on Striatal Reward Processing and Prefrontal Control During Reappraisal in Healthy Volunteers
Actual Study Start Date : October 31, 2011
Actual Primary Completion Date : September 4, 2012
Actual Study Completion Date : September 4, 2012
Arms and Interventions
Arm Intervention/treatment
Experimental: Lithium
Increasing amounts of lithium for 11 plus or minus 1 day. Day 1: 400 mg at night Day 2: 600 mg at night Day 3-11: 800 mg at night. The lithium intervention was prepared from 200mg Priadel prolonged release tablets. The intervention was provided in blue and white gelatine capsules to be taken orally.
 Drug: Lithium
Other Names:
  • Priadel
  • Lithium carbonate
Placebo Comparator: Rayotabs
The placebo intervention was 200mg Rayotabs. The intervention was provided in blue and white gelatine capsules to be taken orally - same as the lithium intervention to maintain blinding.
 Other: Placebo - Rayotabs
Outcome Measures
Primary Outcome Measures :
  1. brain response to reward anticipation (MID task, Knutson et al. 2001) [ Time Frame: Completed during the final day of the intervention period (day 11 (+/- 1) of lithium or placebo treatment). ]
    Participants are presented with a cue indicating the option to get a reward when responding correctly, no reward when responding correctly, or a cue indicating not to move, while laying in the MR scanner (fMRI study). Group differences in the brain response while anticipating a reward (after reward cue) will be compared to the brain response while not anticipating a reward (after no reward cue). The tested region of brain activation will be restricted to the caudate nucleus and the nucleus accumbens, based on Yip et al. (2015) and Knutson et al. (2001).

  2. Brain response during reappraisal task (Phan et al. 2005) [ Time Frame: Completed during the final day of the intervention period (day 11 (+/- 1) of lithium or placebo treatment). ]
    Participants will perform a reappraisal task (Phan et al. 2005). Trials in which they were asked to either down-regulate negative affect evoked by highly arousing and aversive pictures (e.g., experience naturally) using cognitive reappraisal will be compared to trials where negative affect if maintained. Group differences in brain activation changes during this comparison will be assessed with a specific focus on the prefrontal cortex, as well as on connectivity changes between prefrontal cortex and amygdala during this contrast.


Secondary Outcome Measures :
  1. brain activation in response to reward feedback (MID task) [ Time Frame: Completed during the final day of the intervention period (day 11 (+/- 1) of lithium or placebo treatment). ]
    Participants are presented with a cue indicating the option to get a reward when responding correctly, no reward when responding correctly, or a cue indicating not to move, while laying in the MR scanner (fMRI study). After an inter-trial-interfval of 2000-2500ms, a target is presented during which participants need to press a button on reward and no reward trials. If they respond on time it is a hit, otherwise a loss. Group differences in the brain response while receiving feedback on a hit during reward trials will be compared to the brain response while receiving feedback on a loss during reward trials. The tested region of brain activation will be restricted to the caudate nucleus and the nucleus accumbens, based on Yip et al. (2015) and Knutson et al. (2001).


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subject is willing and able to give informed consent for participation in the study.
  • Subject is between 18 and 55 years of age
  • Subject has a body mass index (BMI) in the range of 19-30
  • Subjects will be physically fit, as assessed by a physical examination by a medical doctor.
  • if female and of child bearing age must have a negative pregnancy test for inclusion and must be using two forms of effective contraception.
  • Subjects will be fluent English speakers
  • Thyroid stimulating hormone and creatinine will be assessed pre-treatment to ensure that these are within healthy range
  • non or light smoker < 5 cigarettes per day
  • right handed

Exclusion Criteria:

  • taking psychotropic medication
  • any past or current axis 1 psychiatric disorder on DSM-IV
  • Any medical contra-indication (for example, conditions that might alter absorption of lithium or which could impact on the safety of the druk for the volunteer, for example impaired renal function as assessed by creatinine levels or impaired thyroid function as assessed by thyroid stimulating hormone levels)
  • Current pregnancy or breastfeeding
  • Current or past history of drug or alcohol dependency
  • Participant in a psychological or medical study involving the medication within the last 3 months
  • Smoker > 5 cigarettes per day
  • Dyslexia
  • Any contra-indication to MRI scanning, for example chance of metal in the body
  • Left-handed
Contacts and Locations

Sponsors and Collaborators
University of Oxford
Investigators
Layout table for investigator information
Principal Investigator: Catherine Harmer University of Oxford
Tracking Information
First Submitted Date  ICMJE April 26, 2019
First Posted Date  ICMJE May 28, 2019
Last Update Posted Date May 28, 2019
Actual Study Start Date  ICMJE October 31, 2011
Actual Primary Completion Date September 4, 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 24, 2019)
  • brain response to reward anticipation (MID task, Knutson et al. 2001) [ Time Frame: Completed during the final day of the intervention period (day 11 (+/- 1) of lithium or placebo treatment). ]
    Participants are presented with a cue indicating the option to get a reward when responding correctly, no reward when responding correctly, or a cue indicating not to move, while laying in the MR scanner (fMRI study). Group differences in the brain response while anticipating a reward (after reward cue) will be compared to the brain response while not anticipating a reward (after no reward cue). The tested region of brain activation will be restricted to the caudate nucleus and the nucleus accumbens, based on Yip et al. (2015) and Knutson et al. (2001).
  • Brain response during reappraisal task (Phan et al. 2005) [ Time Frame: Completed during the final day of the intervention period (day 11 (+/- 1) of lithium or placebo treatment). ]
    Participants will perform a reappraisal task (Phan et al. 2005). Trials in which they were asked to either down-regulate negative affect evoked by highly arousing and aversive pictures (e.g., experience naturally) using cognitive reappraisal will be compared to trials where negative affect if maintained. Group differences in brain activation changes during this comparison will be assessed with a specific focus on the prefrontal cortex, as well as on connectivity changes between prefrontal cortex and amygdala during this contrast.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: May 24, 2019) 		brain activation in response to reward feedback (MID task) [ Time Frame: Completed during the final day of the intervention period (day 11 (+/- 1) of lithium or placebo treatment). ]
Participants are presented with a cue indicating the option to get a reward when responding correctly, no reward when responding correctly, or a cue indicating not to move, while laying in the MR scanner (fMRI study). After an inter-trial-interfval of 2000-2500ms, a target is presented during which participants need to press a button on reward and no reward trials. If they respond on time it is a hit, otherwise a loss. Group differences in the brain response while receiving feedback on a hit during reward trials will be compared to the brain response while receiving feedback on a loss during reward trials. The tested region of brain activation will be restricted to the caudate nucleus and the nucleus accumbens, based on Yip et al. (2015) and Knutson et al. (2001).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Lithium Effects on Reward Processing and Reappraisal in Healthy Volunteers
Official Title  ICMJE The Effects of Short-term Lithium Administration on Striatal Reward Processing and Prefrontal Control During Reappraisal in Healthy Volunteers
Brief Summary Bipolar disorder has been associated with blunted activity in regions associated with emotional processing, such as striatal activity during reward anticipation as well as prefrontal activity during reappraisal. Lithium is the most effective treatment in bipolar disorder. Neurochemical and molecular basis of lithium is well known, but how this translates to mood stabilisation is not understood. This study is designed to address how lithium influences reward and emotion regulation processes in humans.
Detailed Description

Background:

Bipolar disorder is a relatively common psychiatric disorder for which treatment options are limited. The so-called mood stabiliser, lithium (usually in the form of lithium carbonate) is one of the most commonly used treatments for the disorder, and is effective in treating both acute mania and as a long term maintenance treatment. The investigator's understanding of the pharmacological mechanisms by which lithium exerts its actions is fairly well developed, however there is a lack of understanding of the psychological mechanisms. Within this study the investigators will look at two different types of emotional processing, namely reward anticipation/feedback and emotion regulation, to gain more understanding on how lithium exerts its mood stabilising effects.

Reward processing:

The neural correlates underlying reward anticipation and feedback can be measured with the Monetary Incentive Delay (MID) task, a widely used task for different disorders. Reward anticipation during the MID task has been associated among others, with ventral and dorsal striatum activity. Most critically, bipolar disorder has been associated with blunted reward function of the medial caudate. Reward feedback has been associated with ventral striatum and OFC/vmPFC activity.

Emotion regulation:

One of the most prominent approaches of emotion regulation is reappraisal . Reappraisal has been shown to consistently activate cognitive control regions and to modulate the bilateral amygdala. Insufficient prefrontal control and reduced downregulation of those prefrontal regions of the amygdala while reappraising negative stimuli has been consistently found in bipolar disorder.

Methods:

Using a double-blind, parallel-group design, 37 healthy volunteers (male and female) are randomly allocated to a 11 (+/- 1) day lithium administration or a placebo condition. After the intervention period, all participants undergo fMRI testing with the MID task and the emotional suppression task to assess reward processing and reappraisal of negative stimuli. The participants also complete a visual control task (checkerboard task) and several behavioural tasks and questionnaires. Lithium levels are measured at the end of the intervention period.

Hypothesis:

Based on the literature on bipolar disorder and the mood stabilising effects of Lithium, the investigators expect lithium administration in healthy participants to:

  • Increase caudate activity during reward anticipation
  • Increase activation of prefrontal control regions as well as increase negative connectivity between those regions and the amygdala during reappraisal

Fidelity check: significant increases in lithium levels in the lithium intervention group compared to the placebo group.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Participants were randomly assigned to the placebo or lithium group. The two groups were matched in terms of age and gender.
Masking: Double (Participant, Investigator)
Masking Description:
The randomisation schedule was drawn up by an experimenter in the lab who is not involved in the study, and all information was kept in a locked cabinet in the Neurosciences building at the Department of Psychiatry, University of Oxford.
Primary Purpose: Basic Science
Condition  ICMJE Healthy
Intervention  ICMJE
  • Drug: Lithium
    Other Names:
    • Priadel
    • Lithium carbonate
  • Other: Placebo - Rayotabs
Study Arms  ICMJE
  • Experimental: Lithium
    Increasing amounts of lithium for 11 plus or minus 1 day. Day 1: 400 mg at night Day 2: 600 mg at night Day 3-11: 800 mg at night. The lithium intervention was prepared from 200mg Priadel prolonged release tablets. The intervention was provided in blue and white gelatine capsules to be taken orally.
    Intervention: Drug: Lithium
  • Placebo Comparator: Rayotabs
    The placebo intervention was 200mg Rayotabs. The intervention was provided in blue and white gelatine capsules to be taken orally - same as the lithium intervention to maintain blinding.
    Intervention: Other: Placebo - Rayotabs
Publications *
  • Yip SW, Worhunsky PD, Rogers RD, Goodwin GM. Hypoactivation of the ventral and dorsal striatum during reward and loss anticipation in antipsychotic and mood stabilizer-naive bipolar disorder. Neuropsychopharmacology. 2015 Feb;40(3):658-66. doi: 10.1038/npp.2014.215. Epub 2014 Aug 13.
  • Lähteenvuo M, Tanskanen A, Taipale H, Hoti F, Vattulainen P, Vieta E, Tiihonen J. Real-world Effectiveness of Pharmacologic Treatments for the Prevention of Rehospitalization in a Finnish Nationwide Cohort of Patients With Bipolar Disorder. JAMA Psychiatry. 2018 Apr 1;75(4):347-355. doi: 10.1001/jamapsychiatry.2017.4711.
  • Knutson B, Fong GW, Adams CM, Varner JL, Hommer D. Dissociation of reward anticipation and outcome with event-related fMRI. Neuroreport. 2001 Dec 4;12(17):3683-7.
  • Oldham S, Murawski C, Fornito A, Youssef G, Yücel M, Lorenzetti V. The anticipation and outcome phases of reward and loss processing: A neuroimaging meta-analysis of the monetary incentive delay task. Hum Brain Mapp. 2018 Aug;39(8):3398-3418. doi: 10.1002/hbm.24184. Epub 2018 Apr 25.
  • Buhle JT, Silvers JA, Wager TD, Lopez R, Onyemekwu C, Kober H, Weber J, Ochsner KN. Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. Cereb Cortex. 2014 Nov;24(11):2981-90. doi: 10.1093/cercor/bht154. Epub 2013 Jun 13.
  • Townsend JD, Torrisi SJ, Lieberman MD, Sugar CA, Bookheimer SY, Altshuler LL. Frontal-amygdala connectivity alterations during emotion downregulation in bipolar I disorder. Biol Psychiatry. 2013 Jan 15;73(2):127-35. doi: 10.1016/j.biopsych.2012.06.030. Epub 2012 Aug 1.
  • Kanske P, Schönfelder S, Forneck J, Wessa M. Impaired regulation of emotion: neural correlates of reappraisal and distraction in bipolar disorder and unaffected relatives. Transl Psychiatry. 2015 Jan 20;5:e497. doi: 10.1038/tp.2014.137.
  • Zhang L, Opmeer EM, van der Meer L, Aleman A, Ćurčić-Blake B, Ruhé HG. Altered frontal-amygdala effective connectivity during effortful emotion regulation in bipolar disorder. Bipolar Disord. 2018 Jun;20(4):349-358. doi: 10.1111/bdi.12611. Epub 2018 Feb 11.
  • Hirschowitz J, Kolevzon A, Garakani A. The pharmacological treatment of bipolar disorder: the question of modern advances. Harv Rev Psychiatry. 2010 Sep-Oct;18(5):266-78. doi: 10.3109/10673229.2010.507042. Review.
  • Phan KL, Fitzgerald DA, Nathan PJ, Moore GJ, Uhde TW, Tancer ME. Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study. Biol Psychiatry. 2005 Feb 1;57(3):210-9.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 24, 2019) 		37
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE September 4, 2012
Actual Primary Completion Date September 4, 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Subject is willing and able to give informed consent for participation in the study.
  • Subject is between 18 and 55 years of age
  • Subject has a body mass index (BMI) in the range of 19-30
  • Subjects will be physically fit, as assessed by a physical examination by a medical doctor.
  • if female and of child bearing age must have a negative pregnancy test for inclusion and must be using two forms of effective contraception.
  • Subjects will be fluent English speakers
  • Thyroid stimulating hormone and creatinine will be assessed pre-treatment to ensure that these are within healthy range
  • non or light smoker < 5 cigarettes per day
  • right handed

Exclusion Criteria:

  • taking psychotropic medication
  • any past or current axis 1 psychiatric disorder on DSM-IV
  • Any medical contra-indication (for example, conditions that might alter absorption of lithium or which could impact on the safety of the druk for the volunteer, for example impaired renal function as assessed by creatinine levels or impaired thyroid function as assessed by thyroid stimulating hormone levels)
  • Current pregnancy or breastfeeding
  • Current or past history of drug or alcohol dependency
  • Participant in a psychological or medical study involving the medication within the last 3 months
  • Smoker > 5 cigarettes per day
  • Dyslexia
  • Any contra-indication to MRI scanning, for example chance of metal in the body
  • Left-handed
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03965247
Other Study ID Numbers  ICMJE REC 10/H0605/71
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: When data was collected, no approval was acquired to share individual participant data. The investigators will make the summary statistics and analyses scripts available.
Responsible Party CatherineHarmer, University of Oxford
Study Sponsor  ICMJE University of Oxford
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Catherine Harmer University of Oxford
PRS Account University of Oxford
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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