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Serotonergic Function and Behavioural and Psychological Symptoms of Frontotemporal Dementia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00376051
Recruitment Status : Completed
First Posted : September 14, 2006
Last Update Posted : May 5, 2017
Alzheimer Society of Canada
Information provided by:
Sunnybrook Health Sciences Centre

Brief Summary:

Frontotemporal lobar degeneration(FTLD) is a common cause of early-onset dementia. FTLD is characterized multiple behavioral symptoms including mental rigidity, irritability, emotional blunting, disinhibition, apathy, and aggression. These behavioural disturbances are particularly important because they increase caregiver burden and may lead to earlier institutionalization. While the causes of FTLD are largely unknown, there is a great deal of evidence suggesting that a brain chemical called serotonin regulates many of the behaviours that are disturbed in FTLD. Our objective is therefore to determine whether dysfunction in the brain's serotonin system is responsible for behavioural problems among FTLD patients. We hope to take the first steps towards a scientific understanding of the behavioural symptoms of FTD, and use our findings to support a larger study optimizing the treatment of targeted behavioural disturbances in FTLD using the antidepressant citalopram.

Citalopram increases transmission by serotonin; we plan to use this medication to determine whether there are any differences in how the serotonin system functions in FTLD patients who display different levels of behavioural disturbances. Patients will be given citalopram and will have their blood drawn after 2 and 3 hours to determine plasma levels of the hormones cortisol and prolactin at those times. These hormones are good indicators of serotonergic functioning in the central nervous system.

We expect that patients with lower levels of serotonergic functioning will have more severe behavioural disturbances and be less responsive to treatment with citalopram. Following their first test day, we will provide patients with a 6-week supply of citalopram, and assess them for any changes in behaviour at the end of this treatment.

This study aims to obtain a better understanding of how changes in the serotonin system relate to behavioural symptoms in FTLD patients. Using the information from this pilot study, we can plan a larger study to determine whether certain behaviours will respond to treatment with citalopram, and if so, determine whether it is possible to predict which patients, based on individual characteristics, are most likely to respond to this treatment. This methodology will therefore not only provide a scientific rationale for treatment of FTLD, but also provide guidance for ongoing, individualized therapy.

Condition or disease Intervention/treatment Phase
Frontotemporal Dementia Drug: Citalopram Phase 4

Detailed Description:

Objectives: A hallmark of frontotemporal lobar degeneration(FTLD) is its associated behavioural disturbances (BPSD), which include disinhibition, aggression, apathy, agitation, depression, and inappropriate affect. Current evidence suggests that secondary changes in the serotonergic system may be key to many of the symptoms of FTLD. Our primary objective is to evaluate the ability of serotonergic dysfunction, as measured through oral citalopram challenge, to predict subsequent behavioural response to pharmacotherapy with citalopram. As a secondary objective, we will explore the relationship between specific BPSDs and the level of serotonergic dysfunction.

Hypotheses: We predict that patients with FTLD who respond to citalopram pharmacotherapy will show greater dysfunction in the serotonergic system, as measured by citalopram challenge, than patients who do not respond. This hypothesis will be evaluated in vivo using peak change in plasma concentrations of cortisol and prolactin as indicators of serotonergic dysfunction following oral citalopram challenge.

Research Plan: A consecutive sample of patients attending FTLD clinics who exhibit significant BPSD will be recruited into this study.Because serotonin promotes cortisol and prolactin secretion via the hypothalamic-pituitary-adrenal (HPA) axis, these hormones have been shown to be a reliable marker of serotonergic functioning. Their levels will therefore be measured from blood samples taken at baseline and 2 and 3 hours after the administration of 20 mg citalopram. Changes in cortisol levels after citalopram administration will be used as the primary measure of serotonergic functioning. We expect to find an inverse correlation between the cortisol response to citalopram challenge and the severity of BPSD according to the total Neuropsychiatric Inventory (NPI) score. Subsequent to the citalopram challenge, participants will be treated for their BPSD with open-label citalopram (20-40 mg) for 6 weeks. At the end of this period, patients will be re-assessed with the NPI. The magnitude of response, based on changes in NPI scores, will be correlated with the citalopram challenge test results. It is expected that patients who show more severe serotonergic dysfunction will have a better response to daily citalopram treatment.

Relevance: The results of this study will further the scientific understanding of the neurochemical basis underlying BPSD in FTLD. To date, the treatment of FTLD patients has relied largely on the understanding of treatments for other dementias, due to the lack of research in the area of FTLD. Therefore, our work may aid in the development of targeted therapies specific to FTLD.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Serotonergic Function and Behavioural and Psychological Symptoms of Frontotemporal Dementia
Study Start Date : September 2006
Actual Primary Completion Date : July 2009
Actual Study Completion Date : September 2009

Intervention Details:
  • Drug: Citalopram
    Titrates from 10mg/day to 40mg/day, increases 10mg per week.

Primary Outcome Measures :
  1. Neuropsychiatric Inventory (NPI) [ Time Frame: Screening, Baseline, 4 weeks and 6 weeks ]

Secondary Outcome Measures :
  1. Frontal Behavioural Inventory (FBI) [ Time Frame: Baseline, 4 weeks, 6 weeks ]
  2. Clinical Global Impression (CGI) [ Time Frame: Screening, 4 week, 6 week ]
  3. Cornell Scale for Depression in Dementia [ Time Frame: Baseline, 4 weeks and 6 weeks ]
  4. Disability Assessment for Dementia Scale (DAD) [ Time Frame: Baseline, 4 weeks and 6 weeks ]
  5. Functional Assessment Staging (FAST) [ Time Frame: Baseline, 4 weeks and 6 weeks ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Meet the DSM-IV criteria for primary degenerative dementia
  • Meet standard clinical criteria for frontotemporal dementia (ie., frontotemporal degeneration including both the frontal/behavioural variant and primary progressive aphasia)
  • Have significant behavioural problems as demonstrated by a score of at least eight on the Neuropsychiatric Inventory (NPI) an
  • An independent clinical decision to receive psychotropic medication for behavioural disorders

Exclusion Criteria:

  • An abnormal biochemical screening (blood cell count, vitamin B12 or thyroid function tests)
  • Significant medical illness or other medical/neurological conditions which diminish cognitive function (including: drug overdose, severely disturbed liver, kidney, lung or heart function, anemia, hypothyroidism, vitamin B12 or folic acid deficiency, syphilis, uncontrolled diabetes, Parkinson's disease, Huntington's chorea, progressive supranuclear paralysis, brain tumour, subdural hematoma, multiple sclerosis, or brain trauma);
  • An Hachinski ischemic score ≥444;
  • Electrocardiographic, laboratory or physical evidence of significant cardiovascular disease;
  • Hypertension >160 mmHg systolic or >100 mmHg diastolic;
  • A brain computed tomographic scan that could not be interpreted as consistent with FTLD;
  • Presence of premorbid or current psychiatric diagnosis (including: major depression, schizophrenia, psychotic symptoms of a severity likely to provoke violent or dangerous behaviour such as command hallucinations to harm people or persecutory delusions that provoke violent reactions, psychoactive substance abuse or dependence);
  • Contraindications to receiving citalopram (such as concomitant MAOI or within 2 weeks, or hypersensitivity to citalopram); or
  • Ongoing need for psychotropic medications (i.e., unsuitable for washout) or administration of a depot antipsychotic injection within one treatment cycle of visit 1

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00376051

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Canada, Ontario
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada, M4N 3M5
The Baycrest Centre for Geriatric Care
Toronto, Ontario, Canada, M6A 2E1
Sponsors and Collaborators
Sunnybrook Health Sciences Centre
Alzheimer Society of Canada
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Principal Investigator: Krista Lanctot, PhD Sunnybrook Health Sciences Centre
Principal Investigator: Nathan Herrmann, MD Sunnybrook Health Sciences Centre
Publications of Results:
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Responsible Party: Dr. Nathan Herrmann, Sunnybrook Health Sciences Centre Identifier: NCT00376051    
Other Study ID Numbers: 218-2006
First Posted: September 14, 2006    Key Record Dates
Last Update Posted: May 5, 2017
Last Verified: November 2009
Keywords provided by Sunnybrook Health Sciences Centre:
frontotemporal lobar degeneration
frontotemporal dementia
behavioural disturbances
Additional relevant MeSH terms:
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Frontotemporal Dementia
Aphasia, Primary Progressive
Pick Disease of the Brain
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Neurodegenerative Diseases
Frontotemporal Lobar Degeneration
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Speech Disorders
Language Disorders
Communication Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antidepressive Agents