Examining Lithium's Mechanism in Bipolar Disorder

Official title

Investigating the Acute Effect of Lithium on Visual and Non-visual Responses to Light in Healthy Individuals

Overview

The primary objective of the current study is to examine the acute effect of lithium on the visual and non-visual responses to light in a sample of healthy participants. Our experiments will investigate the effects of lithium on light sensitivity at the level of the retina as well as central visual and non-visual pathways. Our primary hypothesis is that the administration of lithium to healthy volunteers will reduce the magnitude of a range of non-visual responses to light including melatonin suppression, alertness, performance, mood and electrophysiology in a manner that is dependent of the amount of lithium in the brain. To better understand the postulated effects of lithium on light sensitivity and to examine its relationship at the level of the retina, we will assess the visual and non-visual responses to light, as well as the distribution of lithium in the brain using a non-invasive imaging technique. In addition to that, we also aim to examine the impact of both lithium and light on a molecular level through whole blood transcriptome sequencing.

Interventions

• Drug Lithium carbonate (Priadel)
  Oral lithium carbonate 600 mg daily for 7 days prior to the second laboratory assessment (and for both days while in the laboratory)
• Other Controlled light exposure
  Participants undergo 90-minute dim light (\<1 lux) and light exposure (100-850 lux) conditions during laboratory assessments to evaluate visual and non-visual responses to light.

Primary outcome measures

• Plasma melatonin change in response to light stimulation [Time frame: Measured during the 90-minute light exposure session after 7 days of lithium treatment and after 7 days in the no-lithium condition (days 9-11 and 19-21).]
• Brain lithium signal intensity measured by 7Li-MRI [Time frame: Measured once following 9 days of lithium carbonate administration (Day 21)]

Secondary outcome measures (10)

• Difference in colour vision post-light exposure between lithium and no-lithium conditions [Time frame: Measured immediately following the 90-minute light exposure session after 7 days in the lithium condition and after 7 days in the no-lithium condition (days 9-11 and 19-21)]
• Waking EEG Measures [Time frame: EEG recordings will occur pre, post and throughout the 90-minute light exposure during days 9-11 and 19-21. EEG recordings will be conducted hourly when the participant is awake in the laboratory.]
• Pittsburgh Sleep Quality Index [Time frame: Measured at screening and following 7 days of lithium administration (screening stage 2 and day 19)]
• Munich Chronotype Questionnaire [Time frame: Measured at screening and following 7 days of lithium administration (screening Stage 2 and Day 19)]
• General Health Questionnaire - 12 [Time frame: Measured at screening and following 7 days of lithium administration (screening stage 2 and day 19).]
• Karolinska Sleepiness Scale [Time frame: Measured during and immediately following the 90-minute light exposure session after 7 days in the no-lithium condition and after 7 days of lithium administration (days 9-11 and 19-21).]
• Psychomotor Vigilance Test [Time frame: Measured immediately following the 90-minute light exposure session after 7 days in the no-lithium condition and after 7 days of lithium administration. (And hourly while awake in the laboratory) (Days 9-11 and 19-21)]
• Morningness-Eveningness Questionnaire [Time frame: Measured at screening and following 7 days of lithium administration (screening stage 2 and day 19).]
• Reading the Mind in the Eyes [Time frame: This task will be implemented during the laboratory segment of the lithium and no-lithium condition. The task will be implemented hourly when the participant is awake in the laboratory. (Days 9-11 and Days 19-21)]
• Karolinska Drowsiness Test [Time frame: Days 9-11 and 19-21, hourly while awake and before/after the light exposure segments.]

Eligibility criteria

Inclusion criteria

• Aged between 18 and 40 years old
• Fluent in English (both spoken and written)
• Sleep duration between 6.5 and 9 hours daily
• Have a regular normal sleep schedule with bedtime (weekdays) between 21:30 and 01:00.
• BMI between 18 and 28kg/m2
• Currently enrolled and registered with a general practitioner
• Female participants only: should use effective contraception or refrain from engaging in sexual activity that could result in pregnancy during participation in the study.

Exclusion criteria

• History of psychiatric or neurological disorders
• First-degree family history of psychosis or severe mood disorder
• Current or past suicidal ideation or self-harm
• Current, chronic infections or diseases.
• Life-threatening allergies, specifically a nut allergy.
• Known visual disorders e.g., colour blindness, glaucoma, cataracts, diabetic retinopathy.
• Known medical conditions that could affect the conduct of the study including

• sleep disorders
• cancer
• diabetes
• anaemia
• epilepsy
• psoriasis
• thyroid disorders
• kidney disease
• severe eczema
• anemia
• migraines
• Taking any long-term or regular medications other than oral contraceptives (e.g., antidepressants, diuretics (water-tablets), pain killers or anti-inflammatory drugs (such as ibuprofen) or medications for high blood pressure).
• Have donated blood in the past 1 month
• Regular or recent recreational drug use
• Chronic alcohol addiction/misuse
• Known contraindication to magnetic resonance imaging such as pacemaker or metal implants, recent surgery, severe claustrophobia and/or recent head or neck tattoos.
• A current smoker (including use of cigarettes, vapes, and/or cigars).
• Planning to travel across time zones at any point in time during the conduct of the study or have travelled across time zones within 1 month prior to enrolment.
• Currently work night shifts
• Been a shift worker in the past 3 months.
• Current enrolment in any other interventional studies
• Enrolment in any other interventional studies in the 1 month prior to the start of participation in this study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Basic science

Study locations

United Kingdom · 1 center

• Northumbria University — Newcastle upon Tyne

Publications

• Zeitzer JM, Dijk DJ, Kronauer R, Brown E, Czeisler C; New Collective Author. Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression. J Physiol. 2000 Aug 1;526 Pt 3(Pt 3):695-702. doi: 10.1111/j.1469-7793.2000.00695.x. PMID 10922269
• Merikangas KR, Swendsen J, Hickie IB, Cui L, Shou H, Merikangas AK, Zhang J, Lamers F, Crainiceanu C, Volkow ND, Zipunnikov V. Real-time Mobile Monitoring of the Dynamic Associations Among Motor Activity, Energy, Mood, and Sleep in Adults With Bipolar Disorder. JAMA Psychiatry. 2019 Feb 1;76(2):190-198. doi: 10.1001/jamapsychiatry.2018.3546. PMID 30540352
• Zisapel N. Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting. Cell Mol Neurobiol. 2001 Dec;21(6):605-16. doi: 10.1023/a:1015187601628. PMID 12043836
• Freedman MS, Lucas RJ, Soni B, von Schantz M, Munoz M, David-Gray Z, Foster R. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science. 1999 Apr 16;284(5413):502-4. doi: 10.1126/science.284.5413.502. PMID 10205061
• Czeisler CA, Shanahan TL, Klerman EB, Martens H, Brotman DJ, Emens JS, Klein T, Rizzo JF 3rd. Suppression of melatonin secretion in some blind patients by exposure to bright light. N Engl J Med. 1995 Jan 5;332(1):6-11. doi: 10.1056/NEJM199501053320102. PMID 7990870
• Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Rosenthal NE. Manic-depressive patients may be supersensitive to light. Lancet. 1981 Feb 14;1(8216):383-4. doi: 10.1016/s0140-6736(81)91697-4. No abstract available. PMID 6110011
• Ritter P, Soltmann B, Sauer C, Yakac A, Boekstaegers L, Reichard M, Koenitz K, Bauer M, Guldner H, Neumann S, Wieland F, Skene DJ. Supersensitivity of Patients With Bipolar I Disorder to Light-Induced Phase Delay by Narrow Bandwidth Blue Light. Biol Psychiatry Glob Open Sci. 2021 Jun 19;2(1):28-35. doi: 10.1016/j.bpsgos.2021.06.004. eCollection 2022 Jan. PMID 36324599
• Malhi GS, Tanious M, Das P, Coulston CM, Berk M. Potential mechanisms of action of lithium in bipolar disorder. Current understanding. CNS Drugs. 2013 Feb;27(2):135-53. doi: 10.1007/s40263-013-0039-0. PMID 23371914

Identifiers

NCT: NCT07750925 · 333056 · 226787/Z/22/Z

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗