Serotonin 1A receptor binding and treatment response in late-life depression

Neuropsychopharmacology. 2004 Dec;29(12):2258-65. doi: 10.1038/sj.npp.1300556.

Abstract

Depression in late life carries an increased risk of dementia and brittle response to treatment. There is growing evidence to support a key role of the serotonin type 1A (5-HT(1A)) receptor as a regulator of treatment response, particularly the 5-HT(1A) autoreceptor in the dorsal raphe nucleus (DRN). We used [11C]WAY 100635 and positron emission tomography (PET) to test our hypothesis that 5-HT(1A) receptor binding in the DRN and prefrontal cortex is altered in elderly depressives and that these measures relate to treatment responsivity. We studied 17 elderly subjects with untreated (nonpsychotic, nonbipolar) major depression (four men, 13 women; mean age: 71.4+/-5.9) and 17 healthy control subjects (eight men, nine women; mean age: 70.0+/-6.7). Patients were subsequently treated with paroxetine as part of a clinical trial of maintenance therapies in geriatric depression. [11C]WAY 100635 PET imaging was acquired and binding potential (BP) values derived using compartmental modeling. We observed significantly diminished [11C]WAY 100635 binding in the DRN in depressed (BP = 2.31+/-0.90) relative to control (BP = 3.69+/-1.56) subjects (p = 0.0016). Further, the DRN BP was correlated with pretreatment Hamilton Depression Rating Scores (r = 0.60, p = 0.014) in the depressed cohort. A trend level correlation between DRN binding and time to remission (r = 0.52, p = 0.067) was observed in the 14 depressed patients for whom these data were available. Our finding of decreased [11C]WAY 100635 binding in the brainstem region of the DRN in elderly depressed patients supports evidence of altered 5-HT(1A) autoreceptor function in depression. Further, this work indicates that dysfunction in autoreceptor activity may play a central role in the mechanisms underlying treatment response to selective serotonin reuptake inhibitors in late-life depression.

Publication types

  • Clinical Trial
  • Comparative Study
  • Controlled Clinical Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Brain / anatomy & histology
  • Brain / drug effects
  • Brain / metabolism
  • Carbon Isotopes / pharmacokinetics
  • Case-Control Studies
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / metabolism
  • Drug Interactions
  • Female
  • Geriatric Assessment
  • Humans
  • Male
  • Middle Aged
  • Paroxetine / therapeutic use*
  • Piperazines / pharmacokinetics
  • Positron-Emission Tomography / methods
  • Protein Binding / drug effects
  • Pyridines / pharmacokinetics
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin Antagonists / pharmacokinetics
  • Serotonin Uptake Inhibitors / therapeutic use*

Substances

  • Carbon Isotopes
  • Piperazines
  • Pyridines
  • Serotonin Antagonists
  • Serotonin Uptake Inhibitors
  • Receptor, Serotonin, 5-HT1A
  • Paroxetine
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide