Subjects with MDD showed a statistically significant decrease in radioligand binding of [3H]MPPF, the serotonin-1A receptor antagonist, in the rostral orbitofrontal cortex ( and ). There was a significant MDD-related decrease in antagonist binding in layer I (16 percent decrease, F = 16.88, df = 20, p = 0.0005), layer II (18 percent decrease, F = 13.11, df = 20, p = 0.0017), and layer III (21 percent decrease, F = 5.43, df = 20, p = 0.0304). In contrast, there was no statistically significant difference between controls and depressives in the binding of [3H]DPAT, the serotonin-1A receptor agonist, in layer I (F = 3.81, df = 19, p = 0.0658) or in layer II (F = 3.42, df = 19, p = 0.0799) ( and ). In the mixed model covariate analysis, none of the three covariates (age, postmortem interval, or tissue pH) made a statistically significant contribution to the model, and the statistical differences noted above with the ANOVA were essentially replicated (data not shown). Specifically, subjects with MDD showed a significant decrease in antagonist but not agonist binding to serotonin-1A receptors when co-varying for age, postmortem interval, or tissue pH.
Fig. 1 Autoradiograms of [3H]MPPF (A, B) and [3H]8-OH-DPAT (C, D) binding to serotonin-1A receptors in adjacent sections of orbitofrontal cortex. Calibrated serotonin-1A autoradiograms from a control subject (A, C) and the age-matched subject with MDD (B, D) (more ...)
Fig. 2 Radioligand binding to serotonin-1A receptors in orbitofrontal cortex in subjects with major depressive disorder (MDD) compared with psychiatrically-normal control subjects. [3H]MPPF (top) and [3H]8-OH-DPAT (bottom) binding in the outer cortical laminae (more ...)
The potential influence of gender, clinical variability, suicide or allele or genotype frequency was also considered. The observation of a statistically significant decrease in [3H]MPPF but not [3H]DPAT binding was noted in both male and female depressed subjects (mean ± SEM, fmol/mg; layer I, control males: 163.6 ±04.6, MDD males: 147.2 ± 3.4, p = 0.0157; layer II, control males: 189.1 ± 4.6, MDD males: 161.4 ±10.0, p = 0.0304; layer I, control females: 166.6 ± 9.9, MDD females: 127.3 ±5.8, p = 0.009; layer II, control females: 183.1 ± 12.4, MDD females: 144.4 ± 9.2, p = 0.0329. A statistically significant decrease in [3H]MPPF but not [3H]DPAT binding was also noted when the following four depressed subjects were omitted: one subject with MDD that was in full remission, one subject with comorbid polysubstance dependence, one subject with sertraline present in plasma, and one subject with comorbid polysubstance abuse and amitriptyline present in plasma (mean±SEM, fmol/mg; layer I, control: 165.0 ± 4.9, MDD: 139.9 ± 4.8, p = 0.0032; layer II, control: 186.8 ± 5.8, MDD: 156.6 ± 9.2, p = 0.0101). The binding value for the depressed subject in remission was less than the mean of the depression cohort. There were no significant correlations between the age of onset (layer I, r = 0.0137, p = 0.967; layer II, r = −0.137, p = 0.967) or the duration (layer I, r = -0.3503, p = 0.286; layer II, r = 0.0599, p = 0.860) of depression and binding values for [3H]MPPF. Regardless of whether the depressed subject committed suicide, the binding to antagonist-labeled serotonin-1A receptors was also decreased in depression, compared to control subjects (mean ± -SEM, fmol/mg; layer I, control: 165.0 ± 4.9, suicide: 139.4 ± 5.3, p = 0.0047; control: 165.0 ± 4.9, non-suicide: 136.6 ± 7.8, p = 0.0067; layer II, control: 186.8 ± 5.8, suicide: 159.9 ± 9.9, p = 0.0243; control: 186.8 ± 5.8, non-suicide: 146.0 ± 10.0, p = 0.0023). Based on χ2 analysis of genotype frequencies and comparing allele frequencies with Fisher’s exact test, no statistically significant difference in the allele or genotype frequency between control and depressed subjects for the novel C(-1019)G polymorphism was observed (A. Burns and P. Albert, unpublished observation).