A significant fraction of infants born to mothers taking selective serotonin reuptake inhibitors (SSRIs) during late pregnancy display clear signs of antidepressant withdrawal indicating that these drugs can penetrate fetal brain in utero at biologically significant levels. Previous studies in rodents have demonstrated that early exposure to some antidepressants can result in persistent abnormalities in adult behavior and indices of monoaminergic activity. Here, we show that chronic neonatal (postnatal days 8-21) exposure to citalopram (5 mg/kg, twice daily, s.c.), a potent and highly selective SSRI, results in profound reductions in both the rate-limiting serotonin synthetic enzyme (tryptophan hydroxylase) in dorsal raphe and in serotonin transporter expression in cortex that persist into adulthood. Furthermore, neonatal exposure to citalopram produces selective changes in behavior in adult rats including increased locomotor activity and decreased sexual behavior similar to that previously reported for antidepressants that are nonselective monoamine transport inhibitors. These data indicate that the previously reported neurobehavioral effects of antidepressants are a consequence of their effects on the serotonin transporter. Moreover, these data argue that exposure to SSRIs at an early age can disrupt the normal maturation of the serotonin system and alter serotonin-dependent neuronal processes. It is not known whether this effect of SSRIs is paralleled in humans; however, these data suggest that in utero, exposure to SSRIs may have unforeseen long-term neurobehavioral consequences.

Background According to clinical studies, depression and cerebrovascular disease influence each other. Despite this evidence, no studies have investigated the relationship between major depressive disorder (MDD) and cerebrovascular disease at the cellular level. Astrocytic processes are a crucial interface between blood vessels and neurons, and astrocyte density is reduced in MDD. This study investigated the coverage of vessels by astrocyte endfeet in the prefrontal cortex in MDD. Methods Thirteen pairs of MDD and non-psychiatric control subjects were used for double immunofluorescent staining and confocal image analysis. Frozen sections of gray matter from orbitofrontal area 47 and white matter from the ventro-medial prefrontal cortex were examined. Astrocytic processes (labeled with antibodies for aquaporin-4, AQP4 or glial fibrillary acidic protein, GFAP) were co-localized with blood vessels (labeled with an antibody to collagen IV) to measure the coverage of vessel walls by astrocyte processes. Results The coverage of blood vessels by endfeet of AQP4-immunoreactive (IR) astrocytes was significantly reduced by 50 percent in subjects with MDD as compared to controls (ANCOVA: F(1,23)=5.161, p=0.033). This difference was detected in orbitofrontal gray matter but not in white matter. Conversely, the coverage of vessels by GFAP-IR processes did not significantly differ between the groups. Conclusions A significant reduction in the coverage of gray matter vessels by AQP4-IR astrocyte processes in MDD suggests alterations in AQP4 functions such as regulation of water homeostasis, blood flow, glucose transport and metabolism, the blood brain barrier, glutamate turnover and synaptic plasticity.

Accumulating evidence suggests dysfunction of the gamma-aminobutyric acid (GABA) system in major depressive disorder (MDD). Neuroimaging studies consistently report reductions of cortical GABA in depressed patients. Our post-mortem analyses demonstrate a reduction in the density and size of GABAergic interneurons in the dorsolateral prefrontal cortex (PFC) in MDD. The goal of this study was to test whether the level of glutamic acid decarboxylase (GAD), the GABA synthesizing enzyme, will also be reduced in the same cortical region in MDD. Levels of GAD-65 and GAD-67 proteins were investigated by Western blotting in samples from the dorsolateral PFC (BA9) in 13 medication-free subjects with MDD, and 13 psychiatrically healthy controls. The overall amount of GAD-67 was significantly reduced (−34 %) in depressed subjects as compared to matched controls. Since recent neuroimaging studies demonstrate that antidepressants modulate GABA levels, additional experiments were performed to examine the levels of GAD in 8 depressed subjects treated with antidepressant medications. Levels of GAD-67 were unchanged in these depressed subjects as compared to their respective controls (n=8). The overall amounts of GAD-65 were similar in depressed subjects compared to matched controls, regardless of antidepressant medication. Reduced levels of GAD-67, which is localized to somata of GABA neurons, further support our observation of a decreased density of GABAergic neurons in the PFC in depression. It is likely that a decrease in GAD-67 accounts for the reduction in GABA levels revealed by neuroimaging studies. Moreover, our data support previous neuroimaging observations that antidepressant medication normalizes GABA deficits in depression.