Serotonin receptors and suicide, major depression, alcohol use disorder and reported early life adversity

Abstract

Serotonin neurotransmitter deficits are reported in suicide, major depressive disorder (MDD) and alcohol use disorder (AUD). To compare pathophysiology in these disorders, we mapped brain serotonin transporter (SERT), 5-HT1A, and 5-HT2A receptor binding throughout prefrontal cortex and in anterior cingulate cortex postmortem. Cases and controls died suddenly minimizing agonal effects and had a postmortem interval ≤24 h to avoid compromised brain integrity. Neuropathology and toxicology confirmed absence of neuropathology and psychotropic medications. For most subjects (167 of 232), a DSM-IV Axis I diagnosis was made by psychological autopsy. Autoradiography was performed in right hemisphere coronal sections at a pre-genual level. Linear model analyses included sex and age with group and Brodmann area as interaction terms. SERT binding was lower in suicides (p = 0.004) independent of sex (females < males, p < 0.0001), however, the lower SERT binding was dependent on MDD diagnosis (p = 0.014). Higher SERT binding was associated with diagnosis of alcoholism (p = 0.012). 5-HT1A binding was greater in suicides (p < 0.001), independent of MDD (p = 0.168). Alcoholism was associated with higher 5-HT1A binding (p < 0.001) but only in suicides (p < 0.001). 5-HT2A binding was greater in suicides (p < 0.001) only when including MDD (p = 0.117) and alcoholism (p = 0.148) in the model. Reported childhood adversity was associated with higher SERT and 5-HT1A binding (p = 0.004) in nonsuicides and higher 5-HT2A binding (p < 0.001). Low SERT and more 5-HT1A and 5-HT2A binding in the neocortex in depressed suicides is dependent on Axis I diagnosis and reported childhood adversity. Findings in alcoholism differed from those in depression and suicide indicating a distinct serotonin system pathophysiology.

Conflict of interest statement

J.M. receives royalties for the commercial use of the C-SSRS from the Research Foundation for Mental Hygiene. V.A., M.D.U. A.J.D. S.A.K., M.J.B. declare that they have no conflict of interest.

Figures

Fig. 1. Representative autoradiograms of receptor binding of [3H]-Cyanoimipramine to the serotonin transporter (left), [3H]-8-OH-DPAT to the 5-HT1A receptor (center) and [3H]-Ketanserin to the 5-HT2A receptor (right).

The autoradiograms are from sections cut from the right hemisphere of a representative nonpsychiatric control. The upper row has images of total binding, the middle row is of nonspecific binding and the lower row has subtracted images of specific binding. See methods for displacers and assay conditions. The images were calibrated to fmol/mg tissue using radioactivity standards and color-mapped to a single scale on the right

Fig. 2. Serotonin transporter (SERT) binding in the prefrontal cortex.

A suicide and major depressive disorder (MDD), B alcohol use disorder and C early life adversity (ELA). SERT sites were labeled with [3H]-Cyanoimipramine. Note that: SERT is less in depressed suicide decedents and with MDD. With AUD there is more SERT but only in suicides, and there is more in ELA but only in nonsuicides. Values are expressed as mean ± SEM

Fig. 3. 5-HT1A receptor binding in the prefrontal cortex.

A suicide and major depressive disorder (MDD), B alcohol use disorder and C early life adversity (ELA). 5-HT1A receptors were labeled with [3H]-8-OH-DPAT. There is no data for BA8 or BA24 for MDD nonsuicides because there was only one case with these regions. Note: 5-HT1A binding was greater in suicides independent of MDD, AUD was associated with higher 5-HT1A binding but only in suicides, and ELA is associated with more 5-HT1A receptor binding. Values are expressed as mean ± SEM

Fig. 4. 5-HT2A receptor binding in the prefrontal cortex.

A suicide and major depressive disorder (MDD), B alcohol use disorder and C early life adversity (ELA). 5-HT2A receptors were labeled with [3H]-Ketanserin. Note that: there is more 5-HT2A binding in suicides but no difference with MDD; there is more binding in AUD and ELA, but only in suicides. Values are expressed as mean ± SEM