Victoria Arango

Antidepressants increase neural progenitor cells in the human hippocampus

Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) increase neurogenesis in the dentate gyrus (DG) of rodents and nonhuman primates. We determined whether SSRIs or TCAs increase neural progenitor (NPCs) and dividing cells in the human DG in major depressive disorder (MDD). Whole frozen hippocampi from untreated subjects with MDD (N=5), antidepressant-treated MDD (MDDT, N=7), and controls (C, N=7) were fixed, sectioned, and immunostained for NPCs and dividing cell markers (nestin and Ki-67, respectively), NeuN and GFAP, in single and double labeling. NPC and dividing cell numbers in the DG were estimated by stereology. Clinical data were obtained by psychological autopsy, and by toxicological and neuropathological examination performed on all subjects. NPCs decreased with age (p=0.034). Females had more NPCs than males (p=0.023). Correcting for age and sex, MDDT receiving SSRIs had more NPCs than untreated MDD (p⩽0.001) and controls (p⩽0.001), NPCs were not different in SSRI- and TCA-treated MDDT (p=0.169). Dividing cell number, unaffected by age or sex, was greater in MDDT receiving TCAs than in untreated MDD (p⩽0.001), SSRI-treated MDD (p=0.001), and controls (p⩽0.001). The increase of NPCs and dividing cells in MDDT was localized to the rostral DG. MDDT had a larger DG volume compared with untreated MDD or controls (p=0.009). Antidepressants increase NPC number in the anterior human DG. Whether this finding is critical or necessary for the antidepressants effect remains to be determined.

Localized alterations in pre-and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims.

Altered serotonin indices have been reported in the brain of suicide victims. We sought to localize the changes in presynaptic and postsynaptic serotonin receptors and identify an area of prefrontal cortex that may influence suicide risk. Quantitative autoradiography was performed in coronal sections of prefrontal cortex to determine whether serotonin 5-HT1A receptor (postsynaptic in cortex) and serotonin transporter (presynaptic) binding are different in suicide victims compared to matched controls. 5-HT1A receptor binding was higher in 85 of the 103 sampled areas in the suicide group (n = 18 pairs; P < 0.0001). The increase ranged from 17 to 30%. The increase was more pronounced in the ventrolateral prefrontal cortex. Serotonin transporter binding was found to be lower in the suicide group in all but one of the 43 sampled regions (n = 22 pairs; P < 0.0001). The reduction in binding was most pronounced in the ventrolateral prefrontal cortex, where the difference between suicides and controls ranged between 15 and 27%. Serotonin transporter and 5-HT1A binding were negatively correlated (r = -0.35 to -0.44, P = 0.04 to 0.007) within the same brain areas, suggesting common regulatory factors with opposite effects on binding to the two receptors. We conclude that suicide victims have an abnormality in the serotonin system involving predominantly the ventrolateral prefrontal cortex, and hypothesize that the serotonergic dysfunction in this brain region contributes to the risk for suicidal behavior.

The Neurobiology and Genetics of Suicide and Attempted Suicide:: A Focus on the Serotonergic System

Numerous abnormalities have been found in the serotonergic system in suicide attempters and completers. There is considerable evidence that the serotonergic system is partly under genetic control and that as yet unknown genetic factors mediate the risk for suicidal behavior independently of the genetic factors responsible for the heritability of major psychiatric conditions associated with suicide. An argument is made that there is a relationship of genetic variants to intermediate phenotypes, such as impulsivity, psychomotor change, pathological aggression and biological abnormalities including specific gene products. A variety of biological indices have been generated by new approaches using postmortem tissue and in vivo imaging that will provide a rich substrate for further genetic studies.

Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice

BACKGROUND As a key regulator of serotonergic activity and target of many antidepressant treatments, the serotonin transporter (SERT) represents a potential mediator of anxiety- and depression-related behaviors. Using mice lacking the SERT (SERT KO), we examined the role of SERT function in anxiety- and depression-related behaviors and serotonergic neuron function. METHODS Serotonin transporter knockout mice were evaluated in paradigms designed to assess anxiety-, depression-, and stress-related behaviors. Dorsal raphe nucleus (DRN) function was assessed by quantitative serotonergic cell counting and extracellular electrical recording of neuronal firing properties. RESULTS Serotonin transporter knockout mice showed an increase in latency to feed in a novel situation, more immobility in a forced swim, increased escape latency in a shock escape paradigm, and decreased immobility in tail suspension. No differences in anxiety-related behaviors were seen in the open field and the elevated plus maze. Serotonin transporter knockout mice exhibit a 50% reduction in serotonergic cell number and a fourfold decrease in firing rate in the DRN. CONCLUSIONS Developmental loss of SERT produces altered behaviors in models of depression that are generally opposite to those produced by antidepressant treatment. The reduced serotonergic cell number and firing rate in the DRN of adult SERT KO mice suggest a mechanism for these altered behaviors.

Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study.

BACKGROUND Serotonin 1A receptors (5-HT(1A)) are implicated in the pathophysiology of major depressive disorder (MDD) and in the action of selective serotonin reuptake inhibitors (SSRI). SSRI desensitize 5-HT(1A) and down-regulate 5-HT transporters (5-HTT) with the latter persisting for weeks after discontinuation of SSRI. MDD subjects are more likely to be homozygous for the functional 5-HT(1A) G(-1019) allele of the promoter polymorphism and are postulated to have higher 5-HT(1A) than healthy volunteers (controls). We measure 5-HT(1A) in MDD, assess the effects of antidepressant exposure (AE), and examine the role of the C(-1019)G polymorphism. METHODS Genotyped and determined 5-HT(1A) binding potential (BP) by positron emission tomography (PET) using [carbonyl-C-11]-WAY-100635 in 28 medication-free MDD subjects during a current major depressive episode and 43 controls. RESULTS No difference in BP between controls and MDD subjects (p = .235). There was a difference in BP comparing the controls, antidepressant naive (AN) MDD subjects, and subjects with AE across all regions (p = .013). Post hoc testing reveals higher BP in AN compared to controls (p = .008) and to AE (p = .007). The GG genotype is overrepresented in MDD subjects (p = .059), and BP appears higher with the G allele. CONCLUSIONS AN have higher 5-HT(1A) than controls and AE suggesting a model of depression characterized by an over expression of autoinhibitory somatodendritic 5-HT(1A) receptors, perhaps due to the higher expressing G allele, that may result in reduced terminal field 5-HT release. AE appears to have long-term effects on 5-HT(1A).

Serotonin 1A Receptors, Serotonin Transporter Binding and Serotonin Transporter mRNA Expression in the Brainstem of Depressed Suicide Victims

Suicide and depression are associated with reduced serotonergic neurotransmission. In suicides, there is a reduction in serotonin transporter (SERT) sites and an increase in postsynaptic 5-HT1A receptors in localized regions of the prefrontal cortex. In depression, there is a diffuse decrease in SERT binding throughout the dorsoventral extent of the prefrontal cortex. Serotonergic innervation of the prefrontal cortex arises predominantly from neurons in the brainstem dorsal raphe nucleus (DRN). We, therefore, examined postmortem SERT binding and mRNA expression, as well as 5-HT1A autoreceptor binding in the DRN of 10 matched pairs of controls and depressed suicide victims. The concentration of SERT sites, SERT mRNA, and 5-HT1A binding was not different between controls and suicides (p > .05). In the DRN of suicides, the volume of tissue defined by 5-HT1A binding was 40% smaller than controls. An index of the total number of 5-HT1A receptors (receptor binding × volume of receptor distribution) was 43.3% lower in the DRN of suicides, compared with controls. The suicide group had 54% fewer DRN neurons expressing SERT mRNA compared with controls. In the serotonin neurons that expressed the SERT gene, expression per neuron was greater in suicides. Less total 5-HT1A and SERT binding is consistent with results of in vivo studies in depression. Less feedback inhibition of serotonin DRN firing via 5-HT1A autoreceptors and enhancement of serotonin action due to less uptake of serotonin, is consistent with compensatory changes in response to hypofunction in depressed suicides.

Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression.

Magnetic resonance imaging (MRI) studies in depressed subjects report smaller volumes of amygdala, hippocampus, inferior anterior cingulate, and the orbital prefrontal cortex (OPFC), components of the limbic-cortico-thalamic circuit. Major depression occurs more commonly in women, raising the possibility of an additional psychopathological process affecting women and not men. We sought to determine whether volumetric differences related to mood disorders are dependent on sex. Eight male and 10 female depressed subjects, meeting DSM III R criteria for a major depressive episode, and eight male and 10 female healthy volunteers had MRI scans on a 1.5 T GE Signa Advantage scanner. The regions of interest included amygdala, hippocampus, inferior anterior cingulate, and OPFC. In all analyses, regional volumes were normalized for total cerebral volume. Volumetric changes in the ROIs showed a significant sex by diagnosis interaction, indicating a different pattern of volumetric changes in depressed males compared with females relative to controls. Relative to sex-matched controls, the left inferior anterior cingulate was smaller in depressed males (23%) compared with depressed females (11%). Depressed females but not depressed males had smaller amygdala compared with controls (F-value=4.946, p=0.033). No significant volumetric differences were noted in the hippocampus or OPFC. No volumetric correlations were noted with clinical variables, depression subtypes, or a reported history of sexual or physical abuse. Sex may affect volumetric deficits in amygdala and anterior cingulate cortex in mood disorders, but no effects were found in the hippocampus or OPFC. The biology of mood disorders in females may differ in some aspects from males, and may contribute to the higher rate of depression in women.

Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A receptor binding potential measured by PET using [C-11]WAY-100635.

Serotonin (5-HT) 1A receptors have been implicated in a variety of conditions including, depression, suicidal behavior, and aggression. Post-mortem brain studies and in vivo imaging studies report a variety of age and sex effects on brain 5-HT(1A) binding. Behavioral data from 5-HT(1A) specific pharmacological challenges suggest a role for 5-HT(1A) receptors in aggression. The goal of the present study was to determine age, sex, and severity of life-time aggression effects on 5-HT(1A) binding potential (BP) in vivo using positron emission tomography (PET) and the high affinity 5-HT(1A) antagonist, [carbonyl-C-11]WAY-100635 in 12 healthy females (ages 41.0+/-15.7 years) and 13 healthy males (ages 39.6+/-15.5 years). Regions of interest included the dorsal raphe, anterior cingulate cortex, cingulate body, hippocampus, amygdala, medial prefrontal cortex (PFC), and orbital PFC. No significant correlation between age and BP was detected in any brain region. MANOVA of the first three principle components demonstrated a significantly higher BP in females compared with males (P=0.0127). Post-hoc tests confirmed sex differences (P<0.05) in the following regions: dorsal raphe, amygdala, anterior cingulate, cingulate body, medial PFC, and orbital PFC. The cerebellar volume of distribution was also significantly higher in females. There is a significant negative correlation between binding in several regions and lifetime aggression. We have replicated our post-mortem finding of higher 5-HT(1A) binding in females compared to males. We did not detect an age dependent decrease in binding in males or females. Lower 5-HT(1A) binding in more aggressive individuals is consistent with pharmacological challenge studies. Future studies should determine whether the binding is a state or trait effect.

Candidate Endophenotypes for Genetic Studies of Suicidal Behavior

Twin, adoption, and family studies have established the heritability of suicide attempts and suicide. Identifying specific suicide diathesis-related genes has proven more difficult. As with psychiatric disorders in general, methodological difficulties include complexity of the phenotype for suicidal behavior and distinguishing suicide diathesis-related genes from genes associated with mood disorders and other suicide-associated psychiatric illness. Adopting an endophenotype approach involving identification of genes associated with heritable intermediate phenotypes, including biological and/or behavioral markers more proximal to genes, is an approach being used for other psychiatric disorders. Therefore, a workshop convened by the American Foundation for Suicide Prevention, the Department of Psychiatry at Columbia University, and the National Institute of Mental Health sought to identify potential target endophenotypes for genetic studies of suicidal behavior. The most promising endophenotypes were trait aggression/impulsivity, early-onset major depression, neurocognitive function, and cortisol social stress response. Other candidate endophenotypes requiring further investigation include serotonergic neurotransmission, second messenger systems, and borderline personality disorder traits.

Using the Gene Ontology for Microarray Data Mining: A Comparison of Methods and Application to Age Effects in Human Prefrontal Cortex

One of the challenges in the analysis of gene expression data is placing the results in the context of other data available about genes and their relationships to each other. Here, we approach this problem in the study of gene expression changes associated with age in two areas of the human prefrontal cortex, comparing two computational methods. The first method, “overrepresentation analysis” (ORA), is based on statistically evaluating the fraction of genes in a particular gene ontology class found among the set of genes showing age-related changes in expression. The second method, “functional class scoring” (FCS), examines the statistical distribution of individual gene scores among all genes in the gene ontology class and does not involve an initial gene selection step. We find that FCS yields more consistent results than ORA, and the results of ORA depended strongly on the gene selection threshold. Our findings highlight the utility of functional class scoring for the analysis of complex expression data sets and emphasize the advantage of considering all available genomic information rather than sets of genes that pass a predetermined “threshold of significance.”