Clinical trial NCT01600885: The Effects of Ketamine and Guanfacine on Working Memory in Healthy Subjects
Official title: The Effects of Ketamine and Guanfacine on Working Memory in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
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
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: VA Office of Research and Development
First posted: 2012-05-17
Enrollment: 16
Sex: ALL
Minimum age (years): 21
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of the study is

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

Detailed description: Potential subjects will be interviewed over the phone and, if appropriate, will be scheduled for a screening session. Participants who meet study criteria will participate in two study sessions separated by at least two weeks. The sessions will be identical except on one day they will receive guanfacine and on the other, they will receive a placebo.

This study was initially completed in 2014. Upon analysis of the collected data, it was decided to add additional subjects and gather additional data to verify results seen in the collected data. The study was reopened and new data was added beginning in September 2016. Information about the study beginning in 2016 is available in a separate record.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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
* Known sensitivity to ketamine.
* Body circumference of 52 inches or greater.
* History of claustrophobia
* Any clinically significant impairment of color vision or visual acuity after correction available in the scanner.
* Presence of cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies in vulnerable positions as assessed by a standard pre-MRI screening questionnaire
* Pregnancy or breast-feeding would exclude potential participants and all female subjects will receive a urine pregnancy test at screening and before each MRI scan.
* Donation of blood in excess of 500 mL within 56 days prior to dosing.
* History of sensitivity to heparin or heparin-induced thrombocytopenia.
* Blood pressure must be higher than 90/70. Pulse must be greater than 40 unless the participant is cleared by a study physician

Primary outcomes:
measure: Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Inferior Parietal Lobule
timeFrame: Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion
measure: Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Middle Frontal Gyrus
timeFrame: Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion
measure: Percent Change in Amelioration of Ketamine-related Task Activation as Measured by Functional Magnetic Resonance Imaging in Superior Frontal Gyrus
timeFrame: Within 4 hours of dose administration, after up to 1.25 hours of ketamine infusion
Secondary outcomes:
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Connecticut Mental Health Center
state: Connecticut
city: New Haven
country: United States
facility: Yale Magnetic Resonance Research Center
state: Connecticut
city: West Haven
country: United States
facility: Veterans Affairs Hospital
state: Connecticut
Study officials:
affiliation: Yale University
name: John H Krystal, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale University
name: Naomi R Driesen, Ph.D.
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: Brandt, J. The Hopkins Verbal Learning Test: development of a new memory test with six equivalent forms The Clinical Neuropsychologist 125-142, 1991
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Kaye, S., L. Opler, et al. (1986) Positive and Negative Syndrome Scale. Toronto, Ontario. Multi-Health Systems, Inc.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Newcomer, J., N. Farber, et al. (1999).
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.