The Effects of Ketamine and Guanfacine on Working Memory in Healthy Subjects

NCT01600885 | Completed Results

• 1 other identifier: 0807004092
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 3

Brief Summary

The purpose of the study is

1. 1.To establish the feasibility of fMRI studies of the interaction of guanfacine and ketamine.
2. 2.To explore the possibility that guanfacine can ameliorate the negative effects of ketamine on task-related prefrontal activation.
3. 3.To assess the strength of any interaction between guanfacine and ketamine.

Conditions

NMDA Receptor Function

Keywords

Guanfacine; Ketamine; Functional Magnetic Resonance Imaging; Prefrontal Cortex Activity; Receptors, N-Methyl-D-Aspartate; Receptors, Adrenergic, alpha-2; Memory, Short-Term; Schizophrenia

Outcome Measures

Primary Outcomes (3)

• Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Inferior Parietal Lobule

  Scans will be analyzed for task-related prefrontal activation Difference Score: Percent Signal Change in Regions of Interest (ketamine - saline)

  Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion

• Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Middle Frontal Gyrus

  Difference Score: Percent Signal Change in Regions of Interest (ketamine - saline)

  Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion

• Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Superior Frontal Gyrus

  Difference Score: Percent Signal Change in Regions of Interest (ketamine - saline)

  Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion

Study Arms (2)

Guanfacine then Placebo

ACTIVE COMPARATOR

During the first study session, the participant will receive guanfacine before undergoing a ketamine-infusion fMRI. During the second study session, at least two weeks later, the participant will receive a placebo before undergoing a ketamine-infusion fMRI.

Drug: Guanfacine; Drug: Placebo

Placebo then Guanfacine

ACTIVE COMPARATOR

During the first study session, the participant will receive a placebo before undergoing a ketamine-infusion fMRI. During the second study session, at least two weeks later, the participant will receive guanfacine before undergoing a ketamine-infusion fMRI.

Drug: Guanfacine; Drug: Placebo

Interventions

Guanfacine DRUG

Subjects will be given 3mg of guanfacine before the fMRI scan. Then when in the scanner, a bolus of ketamine (0.23mg/kg over 1 min) will be given during the visual fixation scan. Immediately after completion of the 1 min bolus, the participant will receive a steady state ketamine infusion of 0.58 mg/kg/hour and brain activation will be measured during a spatial working memory task. The entire scan will last approximately two and a half hours and the ketamine infusion will be up to one hour and 15 minutes.

Guanfacine then Placebo; Placebo then Guanfacine

Placebo DRUG

Subjects will be given a placebo before the fMRI scan. Then when in the scanner, a bolus of ketamine (0.23mg/kg over 1 min) will be given during the visual fixation scan. Immediately after completion of the 1 min bolus, the participant will receive a steady state ketamine infusion of 0.58 mg/kg/hour and brain activation will be measured during a spatial working memory task. The entire scan will last approximately two and a half hours and the ketamine infusion will be up to one hour and 15 minutes.

Guanfacine then Placebo; Placebo then Guanfacine

Eligibility Criteria

• Age: 21 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age between 21 and 45, inclusive
• Right-handed
• Have at least a 12th grade education level or equivalent
• Able to read and write English as a primary language
• Willing to refrain from caffeine and alcohol use for one week prior to each MRI session.

You may not qualify if:

• Abnormality on physical examination
• A 12 lead ECG at screening has clinically significant abnormalities as determined by the physician reading the ECG
• A positive pre-study urine drug screen or, at the study physicians' discretion on any drug screens given before the scans
• Abnormality on clinical chemistry or hematology examination at the pre-study medical screening.
• History of positive HIV or Hepatitis B.
• Has received either prescribed or over-the-counter (OTC) centrally active medicine or herbal supplements within the week prior to the MRI scan.
• History of any substance abuse disorder meeting DSM-IV criteria with the exception of nicotine
• Any history of DSM-IV Axis I psychiatric disorders,
• Any history of major medical or neurological disorders
• Any history indicating learning disability, mental retardation, or attention deficit disorder.
• First-degree relative with Axis I DSM-IV disorder including substance abuse or dependence.
• Any clinically significant abnormalities on screening electrocardiogram
• Any history of head injury
• Any evidence of psychosis-like symptoms, as indicated by elevated scores on the Perceptual Aberration-Magical Ideation (Chapman, Chapman et al. 1978; Eckblad, Chapman et al. 1983) and the revised Social Anhedonia scales(Eckblad, Chapman et al. unpublished)
• A positive urine toxicology screen for illicit substance use or positive alcohol breathalyzer test conducted at screening interview and prior to each MRI session

Sponsors & Collaborators

• Yale University: lead
• VA Office of Research and Development: collaborator

Study Sites (3)

Connecticut Mental Health Center

New Haven, Connecticut, 06511, United States

Location

Yale Magnetic Resonance Research Center

New Haven, Connecticut, 06520, United States

Location

Veterans Affairs Hospital

West Haven, Connecticut, 06516, United States

Location

Related Publications (29)

• Arnsten AF, Cai JX. Postsynaptic alpha-2 receptor stimulation improves memory in aged monkeys: indirect effects of yohimbine versus direct effects of clonidine. Neurobiol Aging. 1993 Nov-Dec;14(6):597-603. doi: 10.1016/0197-4580(93)90044-c.

  PMID: 7905189 BACKGROUND

• Bjarnadottir M, Misner DL, Haverfield-Gross S, Bruun S, Helgason VG, Stefansson H, Sigmundsson A, Firth DR, Nielsen B, Stefansdottir R, Novak TJ, Stefansson K, Gurney ME, Andresson T. Neuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: differential synaptic function in NRG1+/- knock-outs compared with wild-type mice. J Neurosci. 2007 Apr 25;27(17):4519-29. doi: 10.1523/JNEUROSCI.4314-06.2007.

  PMID: 17460065 BACKGROUND

• Brandt, J. The Hopkins Verbal Learning Test: development of a new memory test with six equivalent forms The Clinical Neuropsychologist 125-142, 1991

  BACKGROUND

• Buccafusco JJ. Neuropharmacologic and behavioral actions of clonidine: interactions with central neurotransmitters. Int Rev Neurobiol. 1992;33:55-107. doi: 10.1016/s0074-7742(08)60691-1. No abstract available.

  PMID: 1350577 BACKGROUND

• Chapman LJ, Chapman JP, Raulin ML. Body-image aberration in Schizophrenia. J Abnorm Psychol. 1978 Aug;87(4):399-407. doi: 10.1037//0021-843x.87.4.399. No abstract available.

  PMID: 681612 BACKGROUND

• Cho HS, D'Souza DC, Gueorguieva R, Perry EB, Madonick S, Karper LP, Abi-Dargham A, Belger A, Abi-Saab W, Lipschitz D, Bennet A, Seibyl JP, Krystal JH. Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine. Psychopharmacology (Berl). 2005 Apr;179(1):136-43. doi: 10.1007/s00213-004-2066-5. Epub 2005 Jan 29.

  PMID: 15682309 BACKGROUND

• da Silva TL, Pianca TG, Roman T, Hutz MH, Faraone SV, Schmitz M, Rohde LA. Adrenergic alpha2A receptor gene and response to methylphenidate in attention-deficit/hyperactivity disorder-predominantly inattentive type. J Neural Transm (Vienna). 2008;115(2):341-5. doi: 10.1007/s00702-007-0835-0. Epub 2008 Jan 16.

  PMID: 18200436 BACKGROUND

• Driesen NR, Leung HC, Calhoun VD, Constable RT, Gueorguieva R, Hoffman R, Skudlarski P, Goldman-Rakic PS, Krystal JH. Impairment of working memory maintenance and response in schizophrenia: functional magnetic resonance imaging evidence. Biol Psychiatry. 2008 Dec 15;64(12):1026-34. doi: 10.1016/j.biopsych.2008.07.029. Epub 2008 Sep 27.

  PMID: 18823880 BACKGROUND

• Eckblad M, Chapman LJ. Magical ideation as an indicator of schizotypy. J Consult Clin Psychol. 1983 Apr;51(2):215-25. doi: 10.1037//0022-006x.51.2.215. No abstract available.

  PMID: 6841765 BACKGROUND

• Friedman JI, Adler DN, Temporini HD, Kemether E, Harvey PD, White L, Parrella M, Davis KL. Guanfacine treatment of cognitive impairment in schizophrenia. Neuropsychopharmacology. 2001 Sep;25(3):402-9. doi: 10.1016/S0893-133X(01)00249-4.

  PMID: 11522468 BACKGROUND

• Glantz LA, Lewis DA. Dendritic spine density in schizophrenia and depression. Arch Gen Psychiatry. 2001 Feb;58(2):203. doi: 10.1001/archpsyc.58.2.203. No abstract available.

  PMID: 11177126 BACKGROUND

• Glantz LA, Lewis DA. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry. 2000 Jan;57(1):65-73. doi: 10.1001/archpsyc.57.1.65.

  PMID: 10632234 BACKGROUND

• Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, Berrettini WH, Bakshi K, Kamins J, Borgmann-Winter KE, Siegel SJ, Gallop RJ, Arnold SE. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med. 2006 Jul;12(7):824-8. doi: 10.1038/nm1418. Epub 2006 Jun 11.

  PMID: 16767099 BACKGROUND

• Hunt RD, Arnsten AF, Asbell MD. An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1995 Jan;34(1):50-4. doi: 10.1097/00004583-199501000-00013.

  PMID: 7860456 BACKGROUND

• Jakala P, Riekkinen M, Sirvio J, Koivisto E, Kejonen K, Vanhanen M, Riekkinen P Jr. Guanfacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology. 1999 May;20(5):460-70. doi: 10.1016/S0893-133X(98)00127-4.

  PMID: 10192826 BACKGROUND

• Kaye, S., L. Opler, et al. (1986) Positive and Negative Syndrome Scale. Toronto, Ontario. Multi-Health Systems, Inc.

  BACKGROUND

• Kirkpatrick B, Xu L, Cascella N, Ozeki Y, Sawa A, Roberts RC. DISC1 immunoreactivity at the light and ultrastructural level in the human neocortex. J Comp Neurol. 2006 Jul 20;497(3):436-50. doi: 10.1002/cne.21007.

  PMID: 16736468 BACKGROUND

• Krystal JH, Perry EB Jr, Gueorguieva R, Belger A, Madonick SH, Abi-Dargham A, Cooper TB, Macdougall L, Abi-Saab W, D'Souza DC. Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function. Arch Gen Psychiatry. 2005 Sep;62(9):985-94. doi: 10.1001/archpsyc.62.9.985.

  PMID: 16143730 BACKGROUND

• Leung HC, Gore JC, Goldman-Rakic PS. Sustained mnemonic response in the human middle frontal gyrus during on-line storage of spatial memoranda. J Cogn Neurosci. 2002 May 15;14(4):659-71. doi: 10.1162/08989290260045882.

  PMID: 12126506 BACKGROUND

• Ma CL, Arnsten AF, Li BM. Locomotor hyperactivity induced by blockade of prefrontal cortical alpha2-adrenoceptors in monkeys. Biol Psychiatry. 2005 Jan 15;57(2):192-5. doi: 10.1016/j.biopsych.2004.11.004.

  PMID: 15652880 BACKGROUND

• McClure MM, Barch DM, Romero MJ, Minzenberg MJ, Triebwasser J, Harvey PD, Siever LJ. The effects of guanfacine on context processing abnormalities in schizotypal personality disorder. Biol Psychiatry. 2007 May 15;61(10):1157-60. doi: 10.1016/j.biopsych.2006.06.034. Epub 2006 Sep 1.

  PMID: 16950221 BACKGROUND

• Newcomer, J., N. Farber, et al. (1999).

  BACKGROUND

• Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia. 1971 Mar;9(1):97-113. doi: 10.1016/0028-3932(71)90067-4. No abstract available.

  PMID: 5146491 BACKGROUND

• Polanczyk G, Zeni C, Genro JP, Guimaraes AP, Roman T, Hutz MH, Rohde LA. Association of the adrenergic alpha2A receptor gene with methylphenidate improvement of inattentive symptoms in children and adolescents with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2007 Feb;64(2):218-24. doi: 10.1001/archpsyc.64.2.218.

  PMID: 17283289 BACKGROUND

• Small KM, Brown KM, Seman CA, Theiss CT, Liggett SB. Complex haplotypes derived from noncoding polymorphisms of the intronless alpha2A-adrenergic gene diversify receptor expression. Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5472-7. doi: 10.1073/pnas.0601345103. Epub 2006 Mar 27.

  PMID: 16567612 BACKGROUND

• Swartz BE, Kovalik E, Thomas K, Torgersen D, Mandelkern MA. The effects of an alpha-2 adrenergic agonist, guanfacine, on rCBF in human cortex in normal controls and subjects with focal epilepsy. Neuropsychopharmacology. 2000 Sep;23(3):263-75. doi: 10.1016/S0893-133X(00)00101-9.

  PMID: 10942850 BACKGROUND

• Szabo B. Imidazoline antihypertensive drugs: a critical review on their mechanism of action. Pharmacol Ther. 2002 Jan;93(1):1-35. doi: 10.1016/s0163-7258(01)00170-x.

  PMID: 11916539 BACKGROUND

• Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AF. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 2007 Apr 20;129(2):397-410. doi: 10.1016/j.cell.2007.03.015.

  PMID: 17448997 BACKGROUND

• Wang Q, Jaaro-Peled H, Sawa A, Brandon NJ. How has DISC1 enabled drug discovery? Mol Cell Neurosci. 2008 Feb;37(2):187-95. doi: 10.1016/j.mcn.2007.10.006. Epub 2007 Oct 23.

  PMID: 18055216 BACKGROUND

MeSH Terms

Conditions

Schizophrenia

Interventions

Guanfacine

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Guanidines; Amidines; Organic Chemicals; Phenylacetates; Acids, Carbocyclic; Carboxylic Acids

Results Point of Contact

• Title: John Krystal, MD
• Organization: Yale University

john.krystal@yale.edu

203-785-6396

Study Officials

• John H Krystal, M.D.

  Yale University

  PRINCIPAL INVESTIGATOR

• Naomi R Driesen, Ph.D.

  Yale University

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2012
• First Posted: May 17, 2012
• Study Start: August 1, 2008
• Primary Completion: December 1, 2014
• Study Completion: December 1, 2014
• Last Updated: August 21, 2017
• Results First Posted: October 28, 2014

Record last verified: 2017-07

Locations

US (3)