Epilepsy Associated Depression: An Update on Current Scenario,Suggested Mechanisms,and Opportunities

Depression is one of the most frequent psychiatric comorbidities associated with epilepsy having a major impact on the patient’s quality of life. Several screening tools are available to identify and follow up psychiatric disorders in epilepsy. Out of various psychiatric disorders, people with epilepsy (PWE) are at greater risk of developing depression. This bidirectional relationship further hinders pharmacotherapy of comorbid depression in PWE as some antiepileptic drugs (AEDs) worsen associated depression and coadministration of existing antidepressants (ADs) to alleviate comorbid depression has been reported to worsen seizures. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) are first choice of ADs and are considered safe in PWE, but there are no high-quality evidences. Similar to observations in people with depression, PWE also showed pharmacoresistant to available SSRI/SNRIs, which further complicates the disease prognosis. Randomized double-blind placebo-controlled clinical trials are necessary to report efficacy and safety of available ADs in PWE. We should also move beyond ADs, and therefore, we reviewed common pathological mechanisms such as neuroinflammation, dysregulated hypothalamus pituitary adrenal (HPA) axis, altered neurogenesis, and altered tryptophan metabolism responsible for coexistent relationship of epilepsy and depression. Based on these common pertinent pathways involved in the genesis of epilepsy and depression, we suggested novel targets and therapeutic approaches for safe management of comorbid depression in epilepsy.

     

General practitioners' perceptions of the tolerability of antidepressant drugs: a comparison of selective serotonin reuptake inhibitors and tricyclic antidepressants.

OBJECTIVE: To examine inceptions and discontinuations of antidepressants in general practice. DESIGN: An observational study analysing data from an ongoing cross sectional postal survey. Every three months a representative sample of 250 doctors recorded prescribing activity for four weeks. This provided 4000 general practitioner weeks of recording per year. SETTING: A representative panel of general practitioners in England, Wales, and Scotland. SUBJECTS: Patients who began a new course of an antidepressant or had their treatment stopped or changed by the general practitioner between 1 July 1990 and 30 June 1995. MAIN OUTCOME MEASURES: Numbers of patients prescribed a new course of antidepressant; numbers discontinuing treatment; the ratio of antidepressant discontinuations to antidepressant inceptions; reasons for discontinuation; proportion of switches to another antidepressant. RESULTS: There were 13,619 inceptions and 3934 discontinuations of selective serotonin reuptake inhibitors and tricyclic antidepressants during the study. The number of newly prescribed courses of antidepressants increased by 116%, mostly due to an increase in prescribing of serotonin reuptake inhibitors. The ratio of total discontinuations to inceptions was significantly lower for serotonin reuptake inhibitors (22%) than for tricyclic antidepressants (33%). Differences persisted when controlled for age and sex of patients and severity of depression. However, there was more switching away from selective serotonin reuptake inhibitors when they failed (72%) than from tricyclic antidepressants (58%). CONCLUSIONS: Selective serotonin reuptake inhibitors are less likely than tricyclic antidepressants to be discontinued. A prospective study is needed in general practice to assess the implications of differences in discontinuation rates and switches on clinical and economic outcomes.     

Repeated treatment with mirtazepine induces brain-derived neurotrophic factor gene expression in rats.

Recent studies indicate a role of the brain-derived neurotrophic factor (BDNF) in the pathophysiology of depression, as well as in the mechanism of action of antidepressant drugs (ADs). It has been shown that serum BDNF levels are decreased in depressed patients. Moreover, antidepressant treatment increases serum BDNF levels and it is positively correlated with medication response. In addition, repeated administration of ADs induces an increase in rat hippocampal or cortical BDNF gene expression. Since the most potent effect of ADs on BDNF gene expression was found after prolonged treatment, in the present study we investigated the influence of repeated treatment (twice daily for 14 days) of the new AD mirtazapine (5 or 10 mg/kg) on BDNF mRNA level (the Northern blot) in rat hippocampus and cerebral cortex. Imipramine was used as a reference compound. The experiment was carried out on male Wistar rats. The tissue for biochemical assays was collected 24 h after the last doses of mirtazapine and imipramine. We also studied the effect of repeated mirtazapine on the action of the 5-HT2A receptor agonist (+/-)DOI in the behavioral test (head twitches induced by (+/-)DOI) in rats. The obtained results showed that, like imipramine (10 mg/kg), mirtazapine (10 mg/kg) increased BDNF gene expression in both the examined brain regions: in the hippocampus by 24.0 and 26.5%, in the cerebral cortex by 29.9 and 41.5%, respectively, compared with the vehicle-treated control. Neither mirtazapine nor imipramine administered repeatedly at a lower dose (5 mg/kg) significantly changed BDNF mRNA levels in the hippocampus and cerebral cortex. Repeated treatment with mirtazapine (10, but not 5 mg/kg) inhibited the behavioral syndrome induced by (+/-)DOI. This study provides first conclusive evidence that repeated mirtazapine administration increases BDNF mRNA levels; moreover, it indicates that the enhancement of BDNF gene expression may be essential for the clinical effect of mirtazapine.     

Effect of co-administration of varenicline and antidepressants on extracellular monoamine concentrations in rat prefrontal cortex

Since a substantial proportion of smokers have comorbid mood disorders, the smoking cessation aid varenicline might occasionally be prescribed to patients who are simultaneously treated with antidepressants. Given that varenicline is a selective nicotinic acetylcholine receptor partial agonist and not a substrate or inhibitor of drug metabolizing enzymes, pharmacokinetic interactions with various classes of antidepressants are highly unlikely. It is, however, conceivable that varenicline may have a pharmacodynamic effect on antidepressant-evoked increases in central monoamine release. Interactions resulting in excessive transmitter release could cause adverse events such as serotonin syndrome, while attenuation of monoamine release could impact the clinical efficacy of antidepressants. To investigate this we examined whether varenicline administration modulates the effects of the selective serotonin reuptake inhibitor sertraline and the monoamine oxidase inhibitor clorgyline, given alone and combined, on extracellular concentrations of the monoamines serotonin, dopamine, and norepinephrine in rat brain by microdialysis. Given the important role attributed to cortical monoamine release in serotonin syndrome as well as antidepressant activity, the effects on extracellular monoamine concentrations were measured in the medial prefrontal cortex. Responses to maximally effective doses of sertraline or clorgyline and of sertraline plus clorgyline were the same in the absence as in the presence of a relatively high dose of varenicline, which by itself had no significant effect on cortical monoamine release. This is consistent with the binding profile of varenicline that has insufficient affinity for receptors, enzymes, or transporters to inhibit or potentiate the pharmacologic effects of antidepressants. Since varenicline neither diminished nor potentiated sertraline- or clorgyline-induced increases in neurotransmitter levels, combining varenicline with serotonergic antidepressants is unlikely to cause excessive serotonin release or to attenuate antidepressant efficacy via effects on cortical serotonin, dopamine or norepinephrine release.     

Proenkephalin B Messenger RNA in Porcine Tissues: Characterization, Quantification, and Correlation with Opioid Peptides

Concentrations of proenkephalin B (PENK B) mRNA in porcine brain, pituitary, spinal cord, and peripheral tissues were measured using RNA blotting and solution hybridization. A single hybridizing species of approximately 2,800 bases in size was present in the CNS, with the highest concentration in the caudate nucleus, followed by hypothalamus and hippocampus. The abundance of PENK B mRNA ranged from 22 pg/micrograms of poly(A)-rich RNA in caudate nucleus to less than 0.1 pg/microgram in cerebellum. Concentrations of immunoreactive PENK B-derived peptides showed a similar distribution, with the exception of the hypothalamus, which had lower PENK B mRNA levels than expected from peptide concentrations. PENK B mRNA of the same size as in the brain was also found in the anterior lobe of the pituitary and in the heart ventricle, whereas in intestine, lung, and kidney, smaller mRNA species of 1,800 bases became apparent by RNA blot analysis. An intermediate size of 2,200 bases was found in heart atrium. As revealed by S1 mapping, however, these smaller mRNAs are not completely homologous with PENK B mRNA, but rather may represent closely related mRNAs from a different gene(s).     

Repeated citalopram treatment but not stress exposure attenuates hypothalamic-pituitary-adrenocortical axis response to acute citalopram injection

Many experimental, clinical and epidemiological studies have shown a direct connection between exposure to stress or adverse life events and disease, but little is known about the effect of stress on the action of drugs. The aim of this study was to test the hypothesis that previous exposure to stress changes the action of the antidepressant drug citalopram (10 mg/kg, i.p.) on hypothalamic-pituitary-adrenocortical (HPA) axis function, gene expression of selected neuropeptides and serotonin reuptake. Three different stress models were used, which included immobilization, restraint and unpredictable stress stimuli. Samples of plasma for hormone measurement were taken from conscious cannulated animals. Changes in corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) gene expression in the paraventricular nucleus of the hypothalamus and the anterior pituitary, respectively, and the ability of citalopram to inhibit serotonin reuptake were investigated. The exposure to three different stress models did not influence citalopram action on individual parameters of HPA axis and on serotonin reuptake. On the other hand, repeated administration of the drug led to significant attenuation of ACTH and CRH mRNA responses. The present results allow to suggest that the stressors used did not influence serotonergic neurotransmission to the extent that would modify HPA axis response to citalopram challenge. Activation of HPA axis by acute citalopram treatment was found to be accompanied by increased CRH gene expression in the hypothalamus. Repeated administration of the drug led to the development of tolerance to activation of central and peripheral components of HPA axis, but not to serotonin reuptake inhibition.     

Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study

ObjectivesTo determine the association between inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding.DesignRetrospective cohort study from population based databases.SettingOntario, Canada.Participants317 824 elderly people observed for more than 130 000 person years. The patients started taking an antidepressant between 1992 and 1998 and were grouped by how much the drug inhibited serotonin reuptake. Patients were observed until they stopped the drug, had an upper gastrointestinal bleed, or died or the study ended.ResultsOverall, 974 bleeds were observed, with an overall bleeding rate of 7.3 per 1000 person years. After controlling for age or previous gastrointestinal bleeding, the risk of bleeding significantly increased by 10.7% and 9.8%, respectively, with increasing inhibition of serotonin reuptake. Absolute differences in bleeding between antidepressant groups were greatest for octogenarians (low inhibition of serotonin reuptake, 10.6 bleeds/1000 person years v high inhibition of serotonin reuptake, 14.7 bleeds/1000 person years; number needed to harm 244) and those with previous upper gastrointestinal bleeding (low, 28.6 bleeds/1000 person years v high, 40.3 bleeds/1000 person years; number needed to harm 85).ConclusionsAfter age or previous upper gastrointestinal bleeding were controlled for, antidepressants with high inhibition of serotonin reuptake increased the risk of upper gastrointestinal bleeding. These increases are clinically important for elderly patients and those with previous gastrointestinal bleeding.

What is already known on this topic

A case-control study found that the risk of upper gastrointestinal bleeding increases with intake of antidepressants that extensively inhibit serotonin reuptakeThe study''s validity was questioned because antidepressants were not specifically classified by the extent that they inhibit serotonin reuptake, and absolute differences in bleeding rates between antidepressants were unavailable

What this study adds

The risk of upper gastrointestinal bleeding in elderly and depressed patients increases with antidepressants having the greatest extent of inhibition of serotonin reuptakeThis increased risk of bleeding is clinically important for patients with a high risk of bleeding—namely, octogenarians and those with previous upper gastrointestinal bleedingThe extent that an antidepressant inhibits serotonin reuptake should be considered when drugs are required for depression in high risk patients     

Evidence that serotonin reuptake modulators increase the density of serotonin innervation in the forebrain

The mechanism of action of commonly used antidepressants remains an issue of debate. In the experiments reported here we studied the effects of three representative compounds, the selective serotonin reuptake inhibitor fluoxetine, the selective serotonin reuptake enhancer tianeptine and the selective norepinephrine reuptake inhibitor desipramine on the structure of central serotonin pathways after a 4-week administration. We found that the serotonin modulators fluoxetine and tianeptine, but not desipramine, increase the density of 5-HT and serotonin transporter (SERT)-immunoreactive axons in the neocortical layer IV and certain forebrain limbic areas, such as piriform cortex and the shell region of nucleus accumbens. These changes were noted in the absence of a significant effect of serotonin antidepressants on the expression of tryptophan hydroxylase (TPH-2), i.e. the rate-limiting enzyme for 5-HT biosynthesis and of SERT at the mRNA level. In addition, we found that anterogradely filled terminal axons from injections of biotinylated dextran amine into the dorsal raphe showed significantly more branching in animals treated with fluoxetine compared with animals treated with liposyn vehicle. Our findings suggest that antidepressants may exert very selective structural effects on their cognate monoamine systems in normal animals and raise the possibility that neurotrophic mechanisms may play a role in their clinical efficacy.     

"Broad spectrum" antidepressants: is more better for the treatment of depression?

The majority of antidepressants in current use selectively inhibit the reuptake of serotonin and/or norepinephrine. "Broad spectrum" antidepressants are compounds that inhibit the reuptake of norepinephrine, serotonin and dopamine, the three biogenic amines most closely linked to depression. The pharmacological profile of one such compound has recently been described (European Journal of Pharmacology, 461 (2003) 99). DOV 21,947, an azabicyclo[3.1.0]hexane, potently inhibits norepinephrine, serotonin and dopamine reuptake by the corresponding human transporter proteins. DOV 21,947 is orally active in the forced swim and tail suspension tests, preclinical procedures that are highly predictive of antidepressant action in patients. A closely related compound, DOV 216,303 is safe and well-tolerated in Phase I studies. The plasma concentrations of DOV 216,303 following both single and multiple doses appear sufficient to inhibit norepinephrine, serotonin, and dopamine reuptake. Based on the pivotal role proposed for dopamine in depression, it has been hypothesized that a broad spectrum antidepressant will produce a more rapid onset and/or higher efficacy than agents inhibiting the reuptake of serotonin and/or norepinephrine.     

Venlafaxine enhances the effect of bupropion on extracellular dopamine in rat frontal cortex

Venlafaxine is recognised as an effective treatment for depression and is known to inhibit the reuptake of serotonin (5-HT) and noradrenaline (NA). Another antidepressant, bupropion, acts to inhibit dopamine (DA) and NA reuptake and is commonly co-administered with other antidepressants to improve the efficacy of the antidepressant effect. The present study was designed to investigate the acute effect of combining the 2 drugs on extracellular levels of 5-HT, DA, and NA in rat frontal cortex using brain microdialysis, with the drugs being administered by intraperitoneal injection (i.p). Bupropion (10 mg/kg body mass, i.p.) alone had no effect on extracellular 5-HT levels, whereas venlafaxine (10 mg/kg, i.p.) alone significantly elevated extracellular 5-HT over basal values. As expected, bupropion alone elevated extracellular dopamine above basal values at 40 min post-drug administration, and this effect lasted for a further 2 h. Venlafaxine alone did not statistically elevate extracellular dopamine. The co-administration of venlafaxine with bupropion resulted in a dramatic increase in extracellular dopamine, and this effect was significantly greater than that seen with bupropion alone. In the frontal cortex, NA was elevated by bupropion alone and venlafaxine alone, relative to the control animals. The combination of bupropion and venlafaxine resulted in a marked elevation of NA.     

Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice

This study investigated the effect of berberine (BER) in the mouse forced swim test (FST) and in the tail suspension test (TST), two models predictive of antidepressant activity. We also investigated the antidepressant-like mechanism of BER by the combination of the desipramine [DES, an inhibitor of reuptake of noradrenaline (NA) and serotonin (5-HT)], maprotiline (MAP, selective NA reuptake inhibitor), fluoxetine (FLU, selective 5-HT reuptake inhibitor) and moclobemide [MOC, monoamine oxidase (MAO) A inhibitor). Then we further measured the levels of monoamines [NA, dopamine (DA) and 5-HT) in mice striatum, hippocampus and frontal cortex. The results show that BER (10, 20 mg/kg, p.o.), significantly reduced the immobility time during the FST and the TST. The immobility time after treatment with BER (20 mg/kg, p.o.) in FST was augmented by DES, FLU and MOC, and not affected by MAP. Furthermore, BER (20 mg/kg, p.o.) increased NA and 5-HT levels in the hippocampus and frontal cortex. Our findings support the view that BER exerts antidepressant-like effect. The antidepressant-like mechanism of BER may be related to the increase in NA and 5-HT levels in the hippocampus and frontal cortex.     

Effects of repeated antidepressant treatment of type 4A phosphodiesterase (PDE4A) in rat brain

In a previous study, an up-regulation of rolipram-sensitive, low-Km, cyclic AMP phosphodiesterase (PDE4) subtype PDE4A in rat cerebral cortex following repeated treatment of desipramine was observed. To determine whether this effect is shared by antidepressants from different pharmacological classes, PDE4A expression was examined using immunoblot analyses following repeated treatment with the norepinephrine re-uptake inhibitor desipramine, the monoamine oxidase inhibitor phenelzine, the atypical antidepressant trazodone, and the serotonin reuptake inhibitor fluoxetine. Desipramine, phenelzine, and fluoxetine all increased the intensities of the PDE4A bands in hippocampal preparations; trazodone did not. In preparations of cerebral cortex, the intensities of the PDE4A bands were increased following desipramine treatment, not changed following phenelzine or fluoxetine treatment, and decreased following trazodone treatment. It appears that repeated treatment with antidepressant drugs from different pharmacological classes produces similar effects on the expressions of PDE4A variants in hippocampus. This effect is not correlated with the changes in beta-adrenergic receptor densities, suggesting these antidepressants may at some point alter intracellular signal transduction pathways in a similar manner.     

Role of proto-oncogenes in the regulation of proenkephalin mRNA expression induced by repeated nicotine injections in rat adrenal medulla

We have studied the effect of repeated systemic administrations of nicotine (3 mg/kg) at 30 min intervals on proenkephalin (proENK) mRNA level in rat adrenal gland. Northern blot analysis has shown that proENK mRNA expression was enhanced by repeated nicotine administrations. Additionally, repeated administrations of nicotine transiently induced the c-fos and c-jun mRNA levels after the first-third nicotine administration, and the c-fos and c-jun mRNA levels were returned to the basal level after the seventh administration of nicotine. c-Fos, c-Jun and Fra-2 protein levels were persistently increased until the seventh administration. The repeated nicotine administrations also elevated phospho-CREB without altering total CREB level in all tested groups. Immunohistochemical analysis showed that the increase of c-Fos and c-Jun proteins by repeated nicotine administrations is mostly medulla specific, while Fra-2 immuno reactivity was shown both in medulla and cortex. The repeated nicotine administrations enhanced the AP-1 and ENKCRE-2 DNA binding activities. Furthermore, the cross-competition studies revealed that the AP-1 proteins, rather than CREB, actively bind to ENKCRE-2 DNA domain. These results suggest that proENK mRNA expression induced by repeated nicotine administrations may be mediated by AP-1 proteins, such as c-Fos, c-Jun and Fra-2 rather than CREB via interacting to the ENKCRE-2 DNA binding domain in rat adrenal medulla.     

Functional expression of the norepinephrine transporter in cultured rat astrocytes

We assessed the functional expression of the norepinephrine (NE) transporter (NET) in cultured rat cortical astrocytes. Specific [3H]NE uptake increased in a time-dependent manner, and this uptake involves temperature- and Na+-sensitive mechanisms. The Na+-dependent [3H]NE uptake was saturable, and the Km for the process was 539.3 +/- 55.4 nm and the Vmax was 1.41 +/- 0.03 pmol/mg protein/min. Ouabain, a Na+-K+ ATPase inhibitor, significantly inhibited Na+-dependent [3H]NE uptake. The selective NE uptake inhibitor nisoxetine, the tricyclic antidepressants desipramine and imipramine, and the serotonin and NE reuptake inhibitor (SNRI) milnacipran very potently inhibited Na+-dependent [3H]NE uptake. On the other hand, GBR-12935 (a selective dopamine uptake inhibitor), fluvoxamine (a selective serotonin reuptake inhibitor), venlafaxine (a SNRI) and cocaine had weaker inhibitory activities. RT-PCR demonstrated that astrocytes expressed mRNA for the cloned NET protein, which was characterized as neuronal NET. Western blots indicated that anti-NET polyclonal antibody recognized a major band of 80 kDa in astrocytes. These data indicate that the neuronal NET is functionally expressed in cultured rat astrocytes. Glial cells may exert significant control of noradrenergic activity by inactivating NE that escapes neuronal re-uptake in sites distant from terminals, and are thus cellular targets for antidepressant drugs that inhibit NE uptake.     

Effects of Electroconvulsive Shock on Tetrahydrobiopterin and GTP-Cyclohydrolase Activity in the Brain and Adrenal Gland of the Rat

The effects of a single and repeated electroconvulsive shock (ECS) (300 mA, 0.2 s) on tetrahydrobiopterin (BH4) levels and GTP-cyclohydrolase activity in the brain and adrenal glands of rats were examined. Twenty-four hours after the last ECS treatment (one/day for 7 days), biopterin levels were significantly elevated in the locus coeruleus, hippocampus, frontal cortex, hypothalamus, ventral tegmental area, and adrenal gland. There were no changes in biopterin levels after a single application of ECS. GTP-cyclohydrolase activity was significantly increased in the locus coeruleus, frontal cortex, hippocampus, hypothalamus, and adrenal gland 24 h after repeated ECS and remained elevated in certain tissues up to 8 days after the last treatment. Kinetic analysis of adrenal and locus coeruleus GTP-cyclohydrolase 1 day after 7 days of ECS showed significant changes in both Km and Vmax values. These data suggest that the long-term increases in BH4 levels and GTP-cyclohydrolase activity after repeated ECS may play a part in the mediation of the antidepressant effects of ECS.     

Localization, transport, and uptake of D-aspartate in the rat adrenal and pituitary glands

Large amounts of D-aspartate (D-Asp) are present in the rat adrenal and pituitary glands. D-Asp is thought to be synthesized in the mammalian body and also accumulates in various tissues following intraperitoneal or intravenous administration. This report examines the origins of D-Asp in the adrenal and pituitary glands. We administered D-Asp to male rats intraperitoneally and immunolocalized this exogenous D-Asp in adrenal and pituitary tissue, using an anti-D-Asp antiserum which was previously developed in our laboratory. D-Asp levels in the rat adrenal gland have been shown to undergo a transient increase at 3 weeks of age and to decrease rapidly thereafter. We found that in the adrenal gland, exogenous D-Asp administered intraperitoneally was incorporated into the same region of the adrenal cortex in which endogenous D-Asp was present. By Northern and Western blot analysis and immunohistochemistry of glutamate (Glu) transporter, we also found that expression of the Glu transporter (GLAST), which has an affinity for D-Asp, transiently increased at 3 weeks of age and that localization patterns of the Glu transporter within the tissue were almost coincident with those of endogenous D-Asp. These observations suggest that D-Asp in the adrenal cortex of 3-week-old male rats is primarily acquired by uptake from the vascular system. We have previously shown that D-Asp is specifically localized in prolactin (PRL)-containing cells in the anterior lobe of the adult rat pituitary gland. Here we report that in the pituitary gland, exogenous D-Asp accumulated in endothelial cells, but not in PRL-containing cells. Northern and Western blot analysis and immunohistochemistry of Glu transporter revealed that developmental changes in the Glu transporter (GLAST) expression did not correlate with tissue levels of D-Asp and that the Glu transporter was not expressed in PRL-containing cells. These observations suggest that, in contrast to the adrenal gland, most of the D-Asp in the pituitary gland of adult male rats originates inside the gland itself.     

Steric Hindrance Mutagenesis in the Conserved Extracellular Vestibule Impedes Allosteric Binding of Antidepressants to the Serotonin Transporter

The serotonin transporter (SERT) controls synaptic serotonin levels and is the primary target for antidepressants, including selective serotonin reuptake inhibitors (e.g. (S)-citalopram) and tricyclic antidepressants (e.g. clomipramine). In addition to a high affinity binding site, SERT possesses a low affinity allosteric site for antidepressants. Binding to the allosteric site impedes dissociation of antidepressants from the high affinity site, which may enhance antidepressant efficacy. Here we employ an induced fit docking/molecular dynamics protocol to identify the residues that may be involved in the allosteric binding in the extracellular vestibule located above the central substrate binding (S1) site. Indeed, mutagenesis of selected residues in the vestibule reduces the allosteric potency of (S)-citalopram and clomipramine. The identified site is further supported by the inhibitory effects of Zn²⁺ binding in an engineered site and the covalent attachment of benzocaine-methanethiosulfonate to a cysteine introduced in the extracellular vestibule. The data provide a mechanistic explanation for the allosteric action of antidepressants at SERT and suggest that the role of the vestibule is evolutionarily conserved among neurotransmitter:sodium symporter proteins as a binding pocket for small molecule ligands.     

Neonatal fluoxetine exposure alters motor performances of adolescent rats

Growing evidence from human and animal studies has shown adverse consequences of maternal usage of antidepressants in their newborn babies. To study the effects of early antidepressant exposure on motor function later in life, we treated neonatal rat pups with fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI)-type antidepressant, from the day of birth to postnatal day 4 and examined motor performance during adolescence. FLX-treated rats had reduced locomotor activities in an open field and poorer motor performance on an accelerating rotarod compared to the control group of saline-treated animals. Nevertheless, the poorer motor performance largely improved after repetitive practices. To elucidate the structural alterations in the motor system, we examined the structure of neurons in motor-related brain regions. The shape, density, and soma size of cerebellar Purkinje cells were comparable in the two groups, however, density of dendritic spine in medial spiny neurons of striatum and Layer 5 pyramidal neurons in the primary motor cortex (M1) were reduced in FLX-rats. Furthermore, the basilar dendrites in M1 Layer 5 neurons had reduced dendritic complexity than those of the control animals. The impaired dendritic structure in striatal and cortical neurons in FLX-treated rats might account for their poorer motor performances. Together, the structure and function of the motor system are affected by early FLX exposure, the long-term effects of early exposure to SSRI-type antidepressants should be concerned.     

Genetic Predictors of Response to Serotonergic and Noradrenergic Antidepressants in Major Depressive Disorder: A Genome-Wide Analysis of Individual-Level Data and a Meta-Analysis

Background

It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way.

Methods and Findings

The NEWMEDS consortium, an academia–industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10⁻⁸). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10⁻⁸) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D.

Conclusions

No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors'' Summary