Frontotemporal Dementia Clinical Trial
Official title:
Serotonergic Function and Behavioural and Psychological Symptoms of Frontotemporal Dementia
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.
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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