Maura Boldrini

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.

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.

HIPPOCAMPAL ANGIOGENESIS AND PROGENITOR CELL PROLIFERATION ARE INCREASED WITH ANTIDEPRESSANT USE IN MAJOR DEPRESSION

BACKGROUND Adult neurogenesis is coupled to angiogenesis in neurogenic niches in the dentate gyrus (DG) and increased by antidepressants in rodents. We hypothesized that, in major depressive disorder (MDD), antidepressants increase neural progenitor cells (NPCs) and capillaries in the human DG. METHODS Neural progenitor cells and capillaries, detected on hippocampal sections by immunohistochemistry for neural stem cell protein, were quantified by stereology in matched MDDs (untreated, n = 12), MDD treated with selective serotonin reuptake inhibitors (MDD*SSRI, n = 6) or tricyclic antidepressants (MDD*TCA, n = 6), and nonpsychiatric control subjects (n = 12), all confirmed by psychological autopsy. RESULTS The MDD*SSRI had a larger capillary area and more NPCs versus MDDs (p = .034 and p = .008, respectively) and control subjects (p = .010 and p = .002, respectively) in the whole DG, more NPCs in the anterior (pes, p = .042) and central (midbody, p = .004) DG, and greater capillary area in the pes (p = .002) and midbody (p = .021). The NPC number and capillary area correlated positively in the whole sample (R2 = .454, p < .001) and in treated subjects (R2 = .749, p = .001). We found no NPCs or antidepressant-related angiogenesis in CA1 and parahippocampal gyrus. The DG volume correlated positively with NPC number (p = .004) and capillary area (p < .001) and differed between groups in whole hippocampus (p = .013) and midbody (p = .036). Age negatively correlated with NPC number (p = .042), capillary area (p = .037), and bifurcations (p = .030). No gender effect was detected. CONCLUSIONS Antidepressants increase human hippocampal NPCs and angiogenesis selectively in the anterior and mid DG. These results raise the possibility of a causal relationship between angiogenesis and neurogenesis, as seen in other proliferating tissues, and support their possible role in the mechanism of action of antidepressants.

More tryptophan hydroxylase in the brainstem dorsal raphe nucleus in depressed suicides

Deficient serotonin neurotransmission in suicide is indicated by reduced brainstem serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), fewer 5-HT(1A) autoreceptors and reduced cortical serotonin transporter binding in suicide victims. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of 5-HT, and alterations in TPH could explain some of these findings. We sought to determine the amount of TPH immunoreactivity (TPH-IR) in the dorsal (DRN) and median (MRN) raphe nuclei in suicides and controls. Brainstems of suicide victims and controls (n = 11 pairs) were collected at autopsy, matched for age, sex and postmortem interval, frozen and sectioned (20 microm). Immunoautoradiography, using an antibody to label TPH, was performed, slides exposed to film and autoradiograms quantified by a computer-based image analysis system. We examined sections every 1000 microm throughout the whole length of the nucleus, performing statistical analysis only on those subjects for whom the raphe was complete (n = 8 pairs). TPH-IR (microCi/g) was higher in suicides than controls (S: 300.8 +/- 70.8 vs. C: 259.6 +/- 40.7, t = 2.57, df = 7, P = 0.04) in the dorsal raphe nucleus (DRN), and not different between suicides and controls (S: 251.3 +/- 44.2 vs. C: 235.9 +/- 27.4, t = 1.49, df = 7, P = 0.18) in the MRN. DRN TPH-IR was higher in male suicide victims (MS) compared to male controls (MC; MS: 318.4 +/- 54.4 vs. MC: 271.9 +/- 22.5, t = 2.66, df = 6, P = 0.03). The analysis of TPH-IR area and density at each DRN rostrocaudal levels showed higher area and density in suicides compared to controls in the rostral DRN and lower area and density in the caudal DRN. TPH-IR, an index of the amount of TPH enzyme, in the DRN is higher in depressed suicides. More TPH may be an upregulatory homeostatic response to impaired serotonin release or less autoreceptor activation. Alternatively, the serotonin impairment in suicide may be due to hypofunctional serotonin-synthesizing enzyme.

Hippocampal Granule Neuron Number and Dentate Gyrus Volume in Antidepressant-Treated and Untreated Major Depression

Smaller hippocampal volume is reported in major depressive disorder (MDD). We hypothesize that it may be related to fewer granule neurons (GN) in the dentate gyrus (DG), a defect possibly reversible with antidepressants. We studied age-, sex-, and postmortem interval-matched groups: no major psychopathology (controls); unmedicated-MDD; and MDD treated with serotonin reuptake inhibitors (MDD*SSRI) or tricyclics (MDD*TCA). Frozen right hippocampi were fixed, sectioned (50 μm), immunostained with neuronal nuclear marker (NeuN), and counterstained with hematoxylin. GN and glial number, and DG and granule cell layer (GCL) volumes were stereologically estimated. Fewer GNs in the anterior DG were present in unmedicated-MDDs compared with controls (p=0.013). Younger age of MDD onset correlated with fewer GNs (p=0.021). Unmedicated-MDDs had fewer mid-DG GNs than MDD*SSRIs (p=0.028) and controls (p=0.032). Anterior GCL glial number did not differ between groups. Anterior/mid GCL volume was smaller in unmedicated-MDDs vs controls (p=0.008) and larger in MDD*SSRIs vs unmedicated-MDDs (p<0.001), MDD*TCAs (p<0.001), and controls (p<0.001). Anterior GCL volume and GN number (r=0.594, p=0.001), and mid DG volume and GN number (r=0.398, p=0.044) were correlated. Anterior DG capillary density correlated with GN number (p=0.027), and with GCL (p=0.024) and DG (r=0.400, p=0.047) volumes. Posterior DG volume and GN number did not differ between groups. Fewer GNs in unmedicated-MDD without fewer neuronal progenitor cells, as previously reported, suggests a cell maturation or survival defect, perhaps related to MDD duration. This may contribute to a smaller hippocampus and is potentially reversed by SSRIs. Postmortem studies are correlative and animal studies are needed to test implied causal relationships.

Selective cognitive deficits in obsessive- compulsive disorder compared to panic disorder with agoraphobia

Objective:  Visual‐spatial and executive functions deficits have been reported in obsessive‐compulsive disorder (OCD). We investigated their specificity comparing cognitive function in OCD, panic disorder with agoraphobia (PD/A) and controls by a comprehensive neuropsychological battery.

Prevalence of psychiatric disorders in thyroid diseased patients.

Several studies have underlined the high prevalence of psychiatric symptoms and disorders in thyroid diseases. The aim of this study was to evaluate the prevalence of psychiatric disorders in 93 inpatients affected by different thyroid diseases during their lifetimes, by means of a standardized instrument, i.e., the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-III-Revised, Upjohn Version (SCID-UP-R). The results showed higher rates of panic disorder, simple phobia, obsessive-compulsive disorder, major depressive disorder, bipolar disorder and cyclothymia in thyroid patients than in the general population. These findings would suggest that the co-occurrence of psychiatric and thyroid diseases may be the result of common biochemical abnormalities.

Eating disorders and body image disturbances among ballet dancers, gymnasium users and body builders.

Background: Eating disorders are frequent among elite performers of certain sports or physical activities; however, little is known about non-professional performers. Method: 113 female non-elite ballet dancers, 54 female gymnasium users, 44 male non-competitive body builders, 105 female controls and 30 male controls were evaluated using the Body Uneasiness Test, the State-Trait Anxiety Inventory, the Beck Depression Inventory, and the Eating Disorder Examination 12th edition (EDE-12). Results: Non-elite ballet dancers reported the highest prevalence of eating disorders (anorexia nervosa 1.8%; bulimia nervosa 2.7%; eating disorders not otherwise specified 22.1%), followed by gymnasium users (anorexia nervosa 2.6%; eating disorders not otherwise specified 18%). Significant differences (p < 0.01) between athletes and their controls were found in the following parameters (median values): Beck Depression Inventory (female dancers 5.7, gymnasium users 6.1, female controls 2.8, body builders 1.6, and male controls 1.3), Body Uneasiness Test (female dancers 1.08, gymnasium users 0.62, female controls 0.54, body builders 0.35, and male controls 0.27), EDE total scores (female dancers 1.6, gymnasium users 1.7, female controls 1.0, body builders 1.0, and male controls 0.4), EDE – restraint subscale scores (female dancers 0.8, gymnasium users 1.6, female controls 0.0, body builders 0.8, and male controls 0.0), EDE – eating concern subscale scores (female dancers 0.4, gymnasium users 0.2, female controls 0.0, body builders 0.0, and male controls 0.0), EDE – weight concern subscale scores (female dancers 2.1, gymnasium users 2.1, female controls 1.6, body builders 1.4, and male controls 0.5), and EDE – shape concern subscale scores (female dancers 2.7, gymnasium users 2.8, female controls 2.0, body builders 2.1, and male controls 0.9). EDE scores were highly related to Body Uneasiness Test scores, especially in non-elite ballet dancers and in non-competitive body builders (p < 0.01). Conclusion: Non-professional performers of sports emphasising thinness or muscularity, such as ballet and body-building, show a high degree of body uneasiness and inappropriate eating attitudes and behaviours.

Human Hippocampal Neurogenesis Persists throughout Aging

Adult hippocampal neurogenesis declines in aging rodents and primates. Aging humans are thought to exhibit waning neurogenesis and exercise-induced angiogenesis, with a resulting volumetric decrease in the neurogenic hippocampal dentate gyrus (DG) region, although concurrent changes in these parameters are not well studied. Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis. It is possible that ongoing hippocampal neurogenesis sustains human-specific cognitive function throughout life and that declines may be linked to compromised cognitive-emotional resilience.

Impact of Social Status and Antidepressant Treatment on Neurogenesis in the Baboon Hippocampus

Adult hippocampal neurogenesis is critically implicated in rodent models of stress and anxiety as well as behavioral effects of antidepressants. Whereas similar factors such as psychiatric disorder and antidepressant administration are correlated with hippocampal volume in humans, the relationship between these factors and adult neurogenesis is less well understood. To better bridge the gap between rodent and human physiology, we examined the numbers of proliferating neural precursors and immature cells in the hippocampal dentate gyrus (DG) as well as in vivo magnetic resonance imaging (MRI)-estimated whole hippocampal volume in eight socially dominant- or subordinate-like (SL) baboons administered the antidepressant fluoxetine or vehicle. SL baboons had lower numbers of proliferating cells and immature neurons than socially dominant-like baboons. Fluoxetine treatment was associated with a larger whole hippocampal volume but surprisingly resulted in lower numbers of immature neurons. These findings are the first to indicate that adult neurogenesis in the baboon hippocampal DG may be functionally relevant in the context of social stress and mechanisms of antidepressant action.