Citalopram to Enhance Cognition in HD

NCT00271596 | Completed Phase 2 Results DMC

• 3 other identifiers: 2005097465K23NS055733A-2063
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 3

Brief Summary

This research plan proposes to conduct a double-blind, placebo-controlled pilot clinical trial in 36 adults with mild Huntington's disease (HD) to address the following research aims:

1. 1.To determine the effect of citalopram compared to placebo in patients with early HD on executive function and other outcome variables including functional measures (health-related quality of life, work productivity, and self-reported attention), motor performance, and psychiatric status,
2. 2.To study the relationship between executive function and functional status in patients with early HD after selective serotonin reuptake inhibitor (SSRI) treatment, and
3. 3.To examine the effect of citalopram treatment on volumetric and metabolic (i.e, N-acetyl-aspartate concentration) measures in the neostriatum among patients with recently diagnosed Huntington's disease.

Conditions

Huntington Disease; Chorea; Executive Dysfunction

Keywords

Huntington Disease; Citalopram; Celexa; Chorea; Focus; ADD; ADHD; HD; SSRI

Outcome Measures

Primary Outcomes (1)

• Executive Function Composite Score Comparing Visit 2 (Week 0) to Visits 5 (Week 12) & 6 (Week 15) for the Citalopram Cohort Versus Placebo Cohort.

  Full Scale Name: The Executive Composite Score (ECS). Definition: Subscales were averaged to compute this composite total score. The ECS is the weighted average of performance on 6 subtests of executive function, including (1) the Controlled Oral Word Association Test, (2) Symbol Digit Modalities test; (3) Stroop Color Word Test (Interference Trial), (4) Trail Making test (Part B), (5) Letter-Number Sequencing, and (6) Animal Naming. Construct Measured: Thinking tasks involving planning, working memory, attention, problem solving, verbal reasoning, inhibition, mental flexibility, and task switching. ECS Scale Range: The ECS score ranges from -5 to +5 on a standardized (Z) score scale, where lower scores indicate poorer performance on executive functioning tasks. Change Calculation Details: Compares change in executive functioning performance from visit 2 (week 0) to the weighted average of visits 5 (week 12) \& 6 (week 15) for the citalopram versus placebo cohort.

  after 15 weeks of treatment

Secondary Outcomes (9)

• Letter Number Sequencing Score Comparing Visit 2 (Week 0) to Visits 5 (Week 12) & 6 (Week 15) for the Citalopram Cohort Versus Placebo Cohort

  after 15 weeks of treatment

• Semantic Fluency Score Comparing Visit 2 (Week 0) to Visits 5 (Week 12) & 6 (Week 15) for the Citalopram Cohort Versus Placebo Cohort

  after 15 weeks of treatment

• Symbol-Digit Modalities Score Comparing Visit 2 (Week 0) to Visits 5 (Week 12) & 6 (Week 15) for the Citalopram Cohort Versus Placebo Cohort

  after 15 weeks of treatment

• Verbal Fluency Score Comparing Visit 2 (Week 0) to Visits 5 (Week 12) & 6 (Week 15) for the Citalopram Cohort Versus Placebo Cohort

  after 15 weeks of treatment

• Stroop Interference Score Comparing Visit 2 (Week 0) to Visits 5 (Week 12) & 6 (Week 15) for the Citalopram Cohort Versus Placebo Cohort

  after 15 weeks of treatment

Study Arms (2)

Citalopram

EXPERIMENTAL

20mg daily citalopram

Drug: 20mg daily citalopram

Placebo

PLACEBO COMPARATOR

Matching daily placebo

Drug: Placebo

Interventions

20mg daily citalopram DRUG

a selective serotonin reuptake inhibitor (SSRI) treatment administered over 16 weeks

Also known as: Celexa

Citalopram

Placebo DRUG

a daily matching placebo administered over 16 weeks

Also known as: Matching daily placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Gene positive HD test (or, if untested, an HD diagnosis) with some abnormal motor signs (i.e., diagnostic confidence level of greater than or equal to 1 as measured by the UHDRS).
• Aged between 18 and 75
• Ability to provide written informed consent
• Mild stage HD (Shoulson and Fahn Scale Stage 1 or 2)
• Mild executive dysfunction: Participants must have complaints of poor cognition, mild functional decline, or demonstrate objective evidence of decline from their premorbid level
• Participants are able to complete all study assessments

You may not qualify if:

• Age under 18 or greater than 75
• Current major depression deemed significant by the investigator at the screening visit or current suicidal ideation.
• Any unstable or severe psychiatric disease including diagnoses of schizophrenia, bipolar affective disorder, dementia, delirium, severe anxiety and/or substance abuse/dependence.
• Current use of an SSRI or other treatment for depression (e.g., use of an MAOI) or treatment with an SSRI within the past 14 days.
• Current use of St. John's wort within the past 14 days.
• To ensure performance on cognitive measures are not affected by specific concomitant medications, participants taking methylphenidate, amphetamine/dextroamphetamine, atomoxetine, an acetyl cholinesterase inhibitor, an atypical antipsychotic, kava kava, Ginkgo Biloba, or an anxiolytic drug may be excluded unless their dose and dosing frequency have remained stable for 30 days prior to receiving study drug. Continued participation also requires the dose and dosing frequency remain stable throughout the study.
• Patients who are pregnant, nursing, or planning to become pregnant during the study.
• Patients who are unable to participate in the study assessments (cognitive, functional, psychiatric and motor scales) due to cognitive, motor, or sensory impairments (i.e., significant vision or hearing deficits).
• Other serious medical conditions such as cardiovascular or cerebrovascular disease; head injury deemed clinically significant by the PI; neurological disorder or insult other than HD.
• Learning disability or other medical condition that is likely to affect cognitive function; history of symptoms indicative of attention deficit hyperactivity disorder (ADHD) in childhood; or a diagnosis of ADHD.
• It is important to note that participants who are unable to receive an MRI scan may still participate in this study

Sponsors & Collaborators

• University of Iowa: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• Cure Huntington's Disease Initiative (CHDI): collaborator
• University of Rochester: collaborator
• Mayo Clinic: collaborator

Study Sites (3)

Mayo Clinic Arizona

Scottsdale, Arizona, 85259, United States

Location

The University of Iowa

Iowa City, Iowa, 52242, United States

Location

University of Rochester

Rochester, New York, 14618, United States

Location

Related Publications (20)

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• Bauer A, Zilles K, Matusch A, Holzmann C, Riess O, von Horsten S. Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation. J Neurochem. 2005 Aug;94(3):639-50. doi: 10.1111/j.1471-4159.2005.03169.x.

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• Bonelli RM, Wenning GK, Kapfhammer HP. Huntington's disease: present treatments and future therapeutic modalities. Int Clin Psychopharmacol. 2004 Mar;19(2):51-62. doi: 10.1097/00004850-200403000-00001.

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• Como PG, Rubin AJ, O'Brien CF, Lawler K, Hickey C, Rubin AE, Henderson R, McDermott MP, McDermott M, Steinberg K, Shoulson I. A controlled trial of fluoxetine in nondepressed patients with Huntington's disease. Mov Disord. 1997 May;12(3):397-401. doi: 10.1002/mds.870120319.

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• Duan W, Guo Z, Jiang H, Ladenheim B, Xu X, Cadet JL, Mattson MP. Paroxetine retards disease onset and progression in Huntingtin mutant mice. Ann Neurol. 2004 Apr;55(4):590-4. doi: 10.1002/ana.20075.

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• Fennema-Notestine C, Archibald SL, Jacobson MW, Corey-Bloom J, Paulsen JS, Peavy GM, Gamst AC, Hamilton JM, Salmon DP, Jernigan TL. In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease. Neurology. 2004 Sep 28;63(6):989-95. doi: 10.1212/01.wnl.0000138434.68093.67.

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• Kish SJ, Shannak K, Hornykiewicz O. Elevated serotonin and reduced dopamine in subregionally divided Huntington's disease striatum. Ann Neurol. 1987 Sep;22(3):386-9. doi: 10.1002/ana.410220318.

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• Menza M, Marin H, Kaufman K, Mark M, Lauritano M. Citalopram treatment of depression in Parkinson's disease: the impact on anxiety, disability, and cognition. J Neuropsychiatry Clin Neurosci. 2004 Summer;16(3):315-9. doi: 10.1176/jnp.16.3.315.

  PMID: 15377738 BACKGROUND

• Murman DL, Giordani B, Mellow AM, Johanns JR, Little RJ, Hariharan M, Foster NL. Cognitive, behavioral, and motor effects of the NMDA antagonist ketamine in Huntington's disease. Neurology. 1997 Jul;49(1):153-61. doi: 10.1212/wnl.49.1.153.

  PMID: 9222184 BACKGROUND

• Naarding P, Kremer HP, Zitman FG. Huntington's disease: a review of the literature on prevalence and treatment of neuropsychiatric phenomena. Eur Psychiatry. 2001 Dec;16(8):439-45. doi: 10.1016/s0924-9338(01)00604-6.

  PMID: 11777733 BACKGROUND

• Patel SV, Tariot PN, Asnis J. L-Deprenyl augmentation of fluoxetine in a patient with Huntington's disease. Ann Clin Psychiatry. 1996 Mar;8(1):23-6. doi: 10.3109/10401239609149087.

  PMID: 8743645 BACKGROUND

• Ranen NG, Lipsey JR, Treisman G, Ross CA. Sertraline in the treatment of severe aggressiveness in Huntington's disease. J Neuropsychiatry Clin Neurosci. 1996 Summer;8(3):338-40. doi: 10.1176/jnp.8.3.338.

  PMID: 8854307 BACKGROUND

• Reynolds GP, Dalton CF, Tillery CL, Mangiarini L, Davies SW, Bates GP. Brain neurotransmitter deficits in mice transgenic for the Huntington's disease mutation. J Neurochem. 1999 Apr;72(4):1773-6. doi: 10.1046/j.1471-4159.1999.721773.x.

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• Reynolds GP, Pearson SJ. Decreased glutamic acid and increased 5-hydroxytryptamine in Huntington's disease brain. Neurosci Lett. 1987 Jul 22;78(2):233-8. doi: 10.1016/0304-3940(87)90639-2.

  PMID: 2442679 BACKGROUND

• Rosas HD, Koroshetz WJ, Chen YI, Skeuse C, Vangel M, Cudkowicz ME, Caplan K, Marek K, Seidman LJ, Makris N, Jenkins BG, Goldstein JM. Evidence for more widespread cerebral pathology in early HD: an MRI-based morphometric analysis. Neurology. 2003 May 27;60(10):1615-20. doi: 10.1212/01.wnl.0000065888.88988.6e.

  PMID: 12771251 BACKGROUND

• Shoulson I, Goldblatt D, Charlton M, Joynt RJ. Huntington's disease: treatment with muscimol, a GABA-mimetic drug. Ann Neurol. 1978 Sep;4(3):279-84. doi: 10.1002/ana.410040316.

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• Yohrling IV GJ, Jiang GC, DeJohn MM, Robertson DJ, Vrana KE, Cha JH. Inhibition of tryptophan hydroxylase activity and decreased 5-HT1A receptor binding in a mouse model of Huntington's disease. J Neurochem. 2002 Sep;82(6):1416-23. doi: 10.1046/j.1471-4159.2002.01084.x.

  PMID: 12354289 BACKGROUND

• Beglinger LJ, Adams WH, Fiedorowicz JG, Duff K, Langbehn D, Biglan K, Caviness J, Olson B, Paulsen JS. Practice Effects and Stability of Neuropsychological and UHDRS Tests Over Short Retest Intervals in Huntington Disease. J Huntingtons Dis. 2015;4(3):251-60. doi: 10.3233/JHD-150159.

  PMID: 26444022 DERIVED

• Beglinger LJ, Adams WH, Langbehn D, Fiedorowicz JG, Caviness J, Biglan K, Olson B, Paulsen JS. Does interval between screening and baseline matter in HD cognitive clinical trials? J Huntingtons Dis. 2014;3(2):139-44. doi: 10.3233/JHD-140100.

  PMID: 25062857 DERIVED

• Beglinger LJ, Adams WH, Langbehn D, Fiedorowicz JG, Jorge R, Biglan K, Caviness J, Olson B, Robinson RG, Kieburtz K, Paulsen JS. Results of the citalopram to enhance cognition in Huntington disease trial. Mov Disord. 2014 Mar;29(3):401-5. doi: 10.1002/mds.25750. Epub 2013 Dec 27.

  PMID: 24375941 DERIVED

Related Links

• The University of Iowa's Huntington's Disease Center of Excellence

MeSH Terms

Conditions

Huntington Disease; Chorea; Attention Deficit Disorder with Hyperactivity

Interventions

Citalopram

Condition Hierarchy (Ancestors)

Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Dyskinesias; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

Statistical power was limited.

Results Point of Contact

• Title: Leigh Beglinger, PhD
• Organization: University of Iowa; Elks Rehab Hospital

leigh-beglinger@elksrehab.org

319-353-4489

Study Officials

• Leigh J Beglinger, Ph.D.

  The University of Iowa Psychiatry Department

  PRINCIPAL INVESTIGATOR

• Jess G Fiedorowicz, M.D., Ph.D.

  University of Iowa Psychiatry Department

  PRINCIPAL INVESTIGATOR

• Kevin Biglan, M.D., M.P.H.

  University of Rochester

  PRINCIPAL INVESTIGATOR

• John Caviness, M.D.

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

• Ricardo Jorge, M.D.

  University of Iowa Psychiatry Department

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: December 30, 2005
• First Posted: January 2, 2006
• Study Start: November 1, 2005
• Primary Completion: April 1, 2011
• Study Completion: November 1, 2011
• Last Updated: March 13, 2013
• Results First Posted: March 13, 2013

Record last verified: 2013-02

Locations

US (3)