Serotonin Transporter Occupancy and the Functional Neuroanatomic Effects of Citalopram in Geriatric Depression
The functional neuroanatomic changes associated with selective serotonin reuptake inhibitor (SSRI) treatment have been the focus of positron emission tomography (PET) studies of cerebral glucose metabolism in geriatric depression.
To evaluate the underlying neurochemical mechanisms, both cerebral glucose metabolism and serotonin transporter (SERT) availability were measured before and during treatment with the SSRI, citalopram. It was hypothesized that SERT occupancy would be observed in cortical and limbic brain regions that have shown metabolic effects, as well as striatal and thalamic regions that have been implicated in prior studies in midlife patients.
Psychiatric outpatient clinic.
Seven depressed patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for current major depressive episode were enrolled.
Patients underwent a 12-week open-label trial of the SSRI, citalopram.
Patients underwent high-resolution research tomography PET scans to measure changes in cerebral glucose metabolism and SERT occupancy by citalopram treatment (after 8-10 weeks of treatment).
Three different tracer kinetic models were applied to the [¹¹C]-DASB region-of-interest data and yielded similar results of an average of greater than 70% SERT occupancy in the striatum and thalamus during citalopram treatment. Voxel-wise analyses showed significant SERT occupancy in these regions, as well as cortical (e.g., anterior cingulate, superior and middle frontal, precuneus, and limbic (parahippocampal gyrus) areas that also showed reductions in glucose metabolism.
The findings suggest that cortical and limbic SERT occupancy may be an underlying mechanism for the regional cerebral metabolic effects of citalopram in geriatric depression.
Available from: Amy Kathleen Wagner
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ABSTRACT: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in the United States, and the incidence has been increasing within the geriatric age group as the population ages. There are many factors that are unique to this subgroup, including normal aging processes, differences in pathophysiology, and inherent medical comorbidities that affect their outcomes, treatment, and therefore, the allocation of medical and social services. The geriatric population has age-appropriate strength, coordination and balance deficits that make them predisposed to falls and subsequent TBI. The aging brain often has premorbid atrophy and increased susceptibility to the inflammatory, excitatory, and vascular processes that facilitate neurologic damage during the acute phases after injury. The aged also can have premorbid neurodegenerative and medical comorbidities that also affect their rehabilitation course, recovery, and outcomes once a TBI has occurred. Pharmacological strategies to maximize rehabilitation and recovery require specific considerations of the potential for adverse effects and contraindications specific to common comorbidities in the aged population. The management of geriatric TBI requires a coordinated effort between physicians and other healthcare providers with focus on risk factor modification, medical optimization, and successful return to the community by setting goals that emphasize level of function and quality of life.
09/2012; 1(3). DOI:10.1007/s13670-012-0021-6
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 12/2011; 19(12):985-8. DOI:10.1097/JGP.0b013e31823922c9 · 4.24 Impact Factor
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ABSTRACT: When fluoxetine, the first of the presently used serotonin-specific reuptake inhibitors (SSRIs), was approved in 1987, two effects of the drug had been established: inhibition of serotonin reuptake by the serotonin transporter (SERT), and partial displacement of serotonin binding to cultured astrocytes, which have no SERT expression. At that time astrocytes were generally assumed to be unimportant for brain function. Accordingly, inhibition of SERT has since been regarded as the mechanism responsible for SSRIs effects in spite of several problems: the delay in therapeutic activity, although the inhibition of serotonin uptake is immediate; lack of quantitative correlation between potency of inhibition by different SSRIs and their therapeutic plasma levels (even considering protein binding); and 80% SERT occupancy at minimum-effective doses. Moreover, little information has been obtained about the molecular mechanisms alleviating major depression and obsessive-compulsive disorder (OCD). In 1987 the 5-HT2B receptor was unknown, but it is now established to have the highest affinity between 5-HT receptors for SSRIs, with especially high affinity during chronic treatment. Here we summarize data from cultured mouse astrocytes and astrocytes obtained from the brains of fluoxetinetreated mice, supporting the role of the astrocytic binding: only small differences in affinity for the 5-HT2B receptor between different SSRIs; a week-long-delayed upregulation of the phospholipase, cPLA2a, and the kainate receptor GluK2, with simultaneous increased editing of the latter, reducing its possible stimulation of neuronal glutamatergic signaling. These effects are genetically and functionally correlated with major depression and OCD, including the therapeutic potential of drugs inhibiting glutamatergic activity.
Current Signal Transduction Therapy 01/2012; 7(1):65-80. DOI:10.2174/1574362799278154 · 0.45 Impact Factor
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