PET Imaging of Serotonin 1A Receptor Binding in Depression Wayne C. Drevets, Ellen Frank, Julie C. Price, David J. Kupfer, Daniel Holt, Phil J. Greer, Yiyun Huang, Clara Gautier, and Chester Mathis Background: The serotonin-1A (5HT1A) receptor system has been implicated in the pathophysiology of major depression by postmortem studies of suicide victims and depressed subjects dying of natural causes. This literature is in disagreement, however, regarding the brain regions where 5HT1A receptor binding differs between depres- sives and controls and the direction of such differences relative to the normal baseline, possibly reflecting the diagnostic heterogeneity inherent within suicide samples. PET imaging using the 5HT1A receptor radioligand, [ 11 C]WAY-100635, may clarify the clinical conditions under which 5HT1A receptor binding potential (BP) is abnormal in depression. Methods: Regional 5HT1A receptor BP values were compared between 12 unmedicated depressives with pri- mary, recurrent, familial mood disorders and 8 healthy controls using PET and [carbonyl- 11 C]WAY-100635. Re- gions-of-interest (ROI) assessed were the mesiotemporal cortex (hippocampus-amygdala) and midbrain raphe, where previous postmortem studies suggested 5HT1A receptor binding is abnormal in depression. Results: The mean 5HT1A receptor BP was reduced 41.5% in the raphe (p  .02) and 26.8% in the mesiotemporal cortex (p  .025) in the depressives relative to the controls. Post hoc comparisons showed the abnormal reduction in 5HT1A receptor BP was not limited to these regions, but extended to control ROI in the occipital cortex and postcen- tral gyrus as well. The magnitude of these abnormalities was most prominent in bipolar depressives (n = 4) and unipolar depressives with bipolar relatives (n = 4). Conclusions: Serotonin-1A receptor BP is abnormally de- creased in the depressed phase of familial mood disorders in multiple brain regions. Of the regions tested, the magnitude of this reduction was most prominent in the midbrain raphe. Converging evidence from postmortem studies of mood disorders suggests these reductions of 5HT1A receptor BP may be associated with histopathological changes involving the raphe. Biol Psychiatry 1999;46:1375–1387 © 1999 Society of Biological Psychiatry Key Words: Major depressive disorder, bipolar disorder, PET, serotonin, raphe, hippocampus Introduction T he serotonin-1A (5HT1A) receptor system has been implicated in depression by evidence that depressed subjects have blunted physiological responses to 5HT1A receptor agonists in vivo and decreased 5HT1A receptor binding postmortem (Bowen et al 1989; Lesch 1992; Lopez et al 1998). During 5HT1A receptor agonist challenge, the incremental increases in plasma corticotropin and cortisol concentrations and the decrease in body temperature seen in healthy controls are attenuated in unmedicated subjects with major depressive disorder (MDD) (Lesch et al 1990a, 1990b; Maes and Meltzer 1995). The significance of these data remained unclear, however, because the ceiling cortisol concentration achieved in response to 5HT1A agonist chal- lenge in these studies was similar in depressives and controls, and the smaller change seen in MDD may have been accounted for by the elevated baseline cortisol levels in the depressives (Lesch 1992). Postmortem studies of cerebral 5HT1A receptor binding and mRNA expression in MDD and bipolar disorder (BD) subjects provided more direct evidence of 5HT1A receptor dysfunction in mood disorders, but these data remained preliminary, being limited to two studies involving small samples: Lopez et al (1998) showed that 5HT1A receptor mRNA levels were abnormally reduced in the hippocampus in six MDD subjects who died by suicide, and Bowen et al (1989) found reduced 5HT1A receptor binding to [ 3 H]8-OH-DPAT in the temporal polar and frontal opercular cortices in seven medicated depressives with MDD or BD dying of natural causes. Other postmortem studies investigated 5HT1A receptor binding in samples of unselected suicide victims, that pre- sumably contained subjects suffering from primary mood disorders as well as subjects suffering from depression arising secondary to other psychiatric and medical condi- From the Department of Psychiatry (WCD, EF, DJK, CG) and Department of Radiology (WCD, JCP, DH, PJG, YH, CM), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Address reprint requests to Wayne C. Drevets, MD, B938 PUH, PET Facility; University of Pittsburgh Medical Center; 200 Lothrop St., Pittsburgh, PA 15213. Received March 8, 1999; revised July 14, 1999; accepted July 16, 1999. © 1999 Society of Biological Psychiatry 0006-3223/99/$20.00 PII S0006-3223(99)00189-4