Lithium Effects on Reward Processing and Reappraisal in Healthy Volunteers

NCT03965247 | Completed

• 1 other identifier: REC 10/H0605/71
• Study Type: interventional
• Target: 37
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Healthy

Keywords

Lithium; Reward; Caudate; Reappraisal; Prefrontal cortex; Amygdala

Outcome Measures

Primary Outcomes (2)

• brain response to reward anticipation (MID task, Knutson et al. 2001)

  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).

  Completed during the final day of the intervention period (day 11 (+/- 1) of lithium or placebo treatment).

• Brain response during reappraisal task (Phan et al. 2005)

  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.

  Completed during the final day of the intervention period (day 11 (+/- 1) of lithium or placebo treatment).

Secondary Outcomes (1)

• brain activation in response to reward feedback (MID task)

  Completed during the final day of the intervention period (day 11 (+/- 1) of lithium or placebo treatment).

Study Arms (2)

Lithium

EXPERIMENTAL

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

Rayotabs

PLACEBO COMPARATOR

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

Interventions

Lithium DRUG

Also known as: Priadel, Lithium carbonate

Lithium

Placebo - Rayotabs OTHER

Rayotabs

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Oxford: lead

Related Publications (10)

• 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.

  PMID: 25139065 BACKGROUND

• Lahteenvuo 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.

  PMID: 29490359 BACKGROUND

• 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. doi: 10.1097/00001756-200112040-00016.

  PMID: 11726774 BACKGROUND

• Oldham S, Murawski C, Fornito A, Youssef G, Yucel 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.

  PMID: 29696725 BACKGROUND

• 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.

  PMID: 23765157 BACKGROUND

• 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.

  PMID: 22858151 BACKGROUND

• Kanske P, Schonfelder 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(1):e497. doi: 10.1038/tp.2014.137.

  PMID: 25603413 BACKGROUND

• Zhang L, Opmeer EM, van der Meer L, Aleman A, Curcic-Blake B, Ruhe 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.

  PMID: 29430790 BACKGROUND

• 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.

  PMID: 20825264 BACKGROUND

• 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. doi: 10.1016/j.biopsych.2004.10.030.

  PMID: 15691521 BACKGROUND

MeSH Terms

Interventions

Lithium; Lithium Carbonate

Intervention Hierarchy (Ancestors)

Metals, Alkali; Elements; Inorganic Chemicals; Metals, Light; Metals; Carbonates; Alkalies; Carbonic Acid; Carbon Compounds, Inorganic; Lithium Compounds

Study Officials

• Catherine Harmer

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: 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.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Participants were randomly assigned to the placebo or lithium group. The two groups were matched in terms of age and gender.

Study Record Dates

• First Submitted: April 26, 2019
• First Posted: May 28, 2019
• Study Start: October 31, 2011
• Primary Completion: September 4, 2012
• Study Completion: September 4, 2012
• Last Updated: May 28, 2019

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will not share