Therapeutic Effects Of Antidepressants Research Articles

Exposure to Enriched Environment Restores the mRNA Expression of Mineralocorticoid and Glucocorticoid Receptors in the Hippocampus and Ameliorates Depressive-like Symptoms in Chronically Stressed Rats

Chronic stress can cause emotional dysfunction, but exposure to an enriched environment (EE) can benefit emotional homeostasis. Recent studies have demonstrated that EE can ameliorate stress-induced depressive-like behaviors. Whether hypothalamic-pituitary-adrenal (HPA) axis activity and corticosteroid receptors are involved in these effects of EE is not known. In our current study, we examined HPA axis activity and hippocampal mineralocorticoid receptor/glucocorticoid receptor (MR/GR) mRNA levels following chronic stress in rats. Our study showed that stress reduced body weight, decreased sucrose intake and sucrose preference, and increased immobility in a forced swimming test. These effects were ameliorated by EE. Also we found that 21 days of restraint stress resulted in low HPA axis activity, and a reduction of MR mRNA and MR/GR ratio in the hippocampus of rats, which was restored by EE. Thus, our current results emphasizes the efficiency of EE in the amelioration of stress-induced decrease in the mRNA expression of MR and MR/GR ratio as well as behavioral depression, providing initial evidence for a possible mechanism by which an enriched environment can restore stress-induced deficits.

Gene expression profile analysis of genes in rat hippocampus from antidepressant treated rats using DNA microarray.

BackgroundThe molecular and biological mechanisms by which many antidepressants function are based on the monoamine depletion hypothesis. However, the entire cascade of mechanisms responsible for the therapeutic effect of antidepressants has not yet been elucidated.ResultsWe used a genome-wide microarray system containing 30,000 clones to evaluate total RNA that had been isolated from the brains of treated rats to identify the genes involved in the therapeutic mechanisms of various antidepressants, a tricyclic antidepressant (imipramine). a selective serotonin reuptake inhibitor (fluoxetine), a monoamine oxidase inhibitor (phenelzine) and psychoactive herbal extracts of Nelumbinis Semen (NS). To confirm the differential expression of the identified genes, we analyzed the amount of mRNA that was isolated from the hippocampus of rats that had been treated with antidepressants by real-time RT-PCR using primers specific for selected genes of interest. These data demonstrate that antidepressants interfere with the expression of a large array of genes involved in signaling, survival and protein metabolism, suggesting that the therapeutic effect of these antidepressants is very complex. Surprisingly, unlike other antidepressants, we found that the standardized herbal medicine, Nelumbinis Semen, is free of factors that can induce neurodegenerative diseases such as caspase 8, α-synuclein, and amyloid precursor protein. In addition, the production of the inflammatory cytokine, IFNγ, was significantly decreased in rat hippocampus in response to treatment with antidepressants, while the inhibitory cytokine, TGFβ, was significantly enhanced.ConclusionsThese results suggest that antidepressants function by regulating neurotransmission as well as suppressing immunoreactivity in the central nervous system.

Neuroadaptive responses to citalopram in rats using pharmacological magnetic resonance imaging

The majority of psychoactive compounds, including antidepressants in clinical practice, were discovered largely by serendipity. The underlying neuropharmacological mechanisms of action of these compounds leading to resolution of depressive symptomatology are targets of the current research. Pharmacological magnetic resonance imaging (phMRI), a rapidly developing advancement of blood oxygenation level dependent (BOLD) contrast offers the potential to localize the regional sites of action in the CNS. Acute and chronic effects of the clinically effective selective serotonin reuptake inhibitor (SSRI) citalopram were examined for changes in BOLD contrast using phMRI in rats. To pharmacologically characterize the specific involvement of the 5-HT(1A) receptors, citalopram was co-administered with a highly selective 5-HT(1A) receptor antagonist WAY100635. Acute citalopram treatment (10 and 20 mg/kg i.p.) produced a widespread and dose-dependent activation throughout the whole brain. Following 14 days of chronic daily administration of citalopram (20 mg/kg i.p.), localized effects were observed; regions integral in the therapeutic antidepressant effects included the hypothalamus, hippocampus, and cortical regions, suggesting desensitization of serotonergic receptors in the midbrain contributing to elevated levels of 5-HT. Co-administration with WAY100635 (0.3 mg/kg s.c.) increased BOLD activation in the frontal cortex and decreased BOLD contrast in the hypothalamus, hippocampus, and hindbrain structures. The present findings highlight the adaptive nature of responses to citalopram which exhibits regional and pharmacological specificity. These findings translate well to the clinical findings and suggest that this approach may offer the opportunity to develop more efficacious antidepressants with a faster clinical response.

Antidepressants: knowledge and use among nursing students

This study examined the knowledge of nursing students in regard to using antidepressant medication and proposes actions such that nurses contribute to a safe and effective antidepressant therapy. This cross-sectional and descriptive study was conducted in a public nursing school in the state of São Paulo, Brazil, between March and November 2008. Fifty-two (19%) out of the 273 participants were using or had used antidepressants. Instruction concerning the use of antidepressants was provided by physicians. Even after receiving instruction concerning the antidepressant treatment before its administration, the majority of users (chi(1)2=0.07, p> 0.05) still had doubts about its use. Fluoxetine was the most prevalent antidepressant. Actions to improve knowledge concerning the use of antidepressant medications, their side and therapeutic effects, seem to be necessary and relevant.

Genome Search Reveals Clues to Antidepressant Response

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessGenome Search Reveals Clues to Antidepressant ResponseJun YanJun YanSearch for more papers by this authorPublished Online:7 May 2010https://doi.org/10.1176/pn.45.9.psychnews_45_9_004AbstractNumerous mutations, some of which were found in unexpected places in the genome, have been linked to therapeutic response to antidepressants among patients with depression, a new genomic study reported.Research in this area hopes to explain individual variations in patient response to different antidepressant drugs and one day help clinicians tailor the most effective treatment to each patient.This study, published online in AJP in Advance on April 1, was part of the larger Genome-Based Therapeutic Drugs for Depression (GENDEP) project, a multinational collaboration by researchers in the United Kingdom, Poland, Croatia, Germany, Denmark, Italy, Belgium, Slovenia, Canada, and France.More than 800 adult patients with a diagnosis of moderate to severe unipolar depression participated in the intervention part of the study, and 706 of the patients provided DNA samples for analysis. All participants were of white European ancestry.Most of the participants were randomly assigned to receive either escitalopram or nortriptyline for 12 weeks on an open-label basis. A minority of patients who had contraindications to one of these antidepressants were assigned to the other drug.The two drugs were chosen for their different mechanisms of action: Escitalopram is highly selective for inhibiting the serotonin reuptake receptor with no binding to the norepinephrine reuptake receptor, while nortriptyline is a strong inhibitor of norepinephrine reuptake with very weak binding to the serotonin reuptake receptor. Among the patients who were included in the study, 394 received escitalopram and 312 received nortriptyline.To find genetic variations that may significantly influence patients' response to either antidepressant, the researchers tried two approaches to uncover ties between genetic variations and antidepressant response. In the first approach, they scanned the entire genome using more than half a million single nucleotide polymorphism (SNP) markers to pick up any signs of association. In the second approach, they focused on variants in 72 candidate genes and the DNA regions around these genes.The clinical response to either antidepressant was measured by the change in Montgomery-Asberg Depression Rating Scale (MADRS) scores from baseline to the end of treatment.In the genomewide analysis, polymorphisms in the gene encoding for uronyl 2-sulphotransferase were significantly associated with patients' response to nortriptyline. This association was the strongest in the entire study. Uronyl 2-sulphotransferase is an enzyme involved in neurogenesis and the migration of neurons. The observation that the gene for this enzyme is associated with response to nortriptyline appears to corroborate the neurogenesis theory of antidepressant effects, the researchers pointed out.They also identified SNPs concentrated in two intergenic regions on chromosomes 1 and 10 as potentially associated with response to antidepressants. Intergenic regions are stretches of DNA that neither code for any genes nor regulate the expression of close-by genes. However, when DNA strands are folded, they may have a spatial or structural influence on the expression of certain genes that are linearly far away. These regions had not been associated with a clinical response to antidepressants in past research, and a possible mechanism for this connection is unknown.In addition, variants in the gene encoding for interleukin-11 (IL-11), a cytokine, were linked to response to escitalopram.The targeted analysis of 72 preselected candidate genes did not generate any strong association with antidepressant response. However, a potential but weak link was identified between response to escitalopram and the gene coding for interleukin-6, which is closely related to the gene for IL-11. This and the significant association with the IL-11 gene support the theory that inflammatory cytokines play a role in the therapeutic effect of antidepressants. Both cytokines are extensively expressed in the brain and have been shown to play a role in serotonin signaling.The authors noted that because the study sample was not large enough to provide sufficient statistical power, genes with moderate effects on the clinical response were likely to be missed by the analysis.The GENDEP project was supported primarily by a European Commission grant. GlaxoSmithKline and several U.K. organizations provided additional funding. Lundbeck, a Danish drug company, donated both study drugs.“Genome-Wide Pharmacogenetics of Antidepressant Response in the GENDEP Project” is posted at <http://ajp.psychiatryonline.org/cgi/reprint/appi.ajp.2009.09070932v1>. ISSUES NewArchived

Daily Left Prefrontal Transcranial Magnetic Stimulation Therapy for Major Depressive Disorder

Daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) has been studied as a potential treatment for depression, but previous work had mixed outcomes and did not adequately mask sham conditions. To test whether daily left prefrontal rTMS safely and effectively treats major depressive disorder. Prospective, multisite, randomized, active sham-controlled (1:1 randomization), duration-adaptive design with 3 weeks of daily weekday treatment (fixed-dose phase) followed by continued blinded treatment for up to another 3 weeks in improvers. Four US university hospital clinics. Approximately 860 outpatients were screened, yielding 199 antidepressant drug-free patients with unipolar nonpsychotic major depressive disorder. We delivered rTMS to the left prefrontal cortex at 120% motor threshold (10 Hz, 4-second train duration, and 26-second intertrain interval) for 37.5 minutes (3000 pulses per session) using a figure-eight solid-core coil. Sham rTMS used a similar coil with a metal insert blocking the magnetic field and scalp electrodes that delivered matched somatosensory sensations. In the intention-to-treat sample (n = 190), remission rates were compared for the 2 treatment arms using logistic regression and controlling for site, treatment resistance, age, and duration of the current depressive episode. Patients, treaters, and raters were effectively masked. Minimal adverse effects did not differ by treatment arm, with an 88% retention rate (90% sham and 86% active). Primary efficacy analysis revealed a significant effect of treatment on the proportion of remitters (14.1% active rTMS and 5.1% sham) (P = .02). The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95% confidence interval, 1.32-13.24). The number needed to treat was 12. Most remitters had low antidepressant treatment resistance. Almost 30% of patients remitted in the open-label follow-up (30.2% originally active and 29.6% sham). Daily left prefrontal rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham. clinicaltrials.gov Identifier: NCT00149838.

Gene expression in the brain from antidepressants treated mouse using DNA microarray

The molecular and biological bases for the mechanisms of antidepressants are based on the monoamine depletion hypothesis. However, we do not yet know the full cascade of mechanisms responsible for the therapeutic effect of antidepressants. To identify the genes involved in the therapeutic mechanisms of various antidepressants, we used a cDNA microarray system containing 30000 clones with isolated total RNA from each treated rat brain. In the present study, we demonstrated gene expression changes of treatment with a tricyclic antidepressant (imipramine), a selective serotonin reuptake inhibitor (fluoxetine), monoamine oxidase inhibitor (phenelzine) and psychoactive herbal extracts of PM011. The expression of 35, 20, 37 and 44 genes were decreased and 21, 49, 35 and 27 were over‐expressed by imipramine, fluoxetine, phenelzine and PM011, respectively.Members of signal transduction, factors related to protein metabolism, cell survival, ligand‐receptor interaction, were some of the genes with altered expression. These data demonstrate that antidepressants interfere with the expression of a large array of genes involved in signaling, survival and protein metabolism.The results support the hypothesis that the therapeutic effect of these antidepressants is much more complex and not confined to a reuptake inhibition of neurotransmitters and inhibition of MAOThis work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government(MEST) (No. 2009‐0063466).

Dopamine is involved in the antidepressant-like effect of allopregnanolone in the forced swimming test in female rats

Evidence from both animal and human studies suggests a role for dopamine in the therapeutic effect of antidepressant drugs. Consistently, dopamine receptor antagonists antagonize the effect of antidepressant drugs in different experimental models of depression. Neurosteroids, and in particular allopregnanolone, seem to be involved both in the pathophysiology of depression and in the mechanism of action of antidepressant drugs, and their role seems to be particularly important in the understanding of mood disturbances related to the different phases of the reproductive life in women. The aim of this study was to investigate the possible role of dopamine on the antidepressant-like effect of allopregnanolone in a model of depression. Thus, we examined (i) the behaviour of female Sprague-Dawley rats in the forced swimming test during estrus and diestrus and their response to allopregnanolone treatment (0.5, 1 and 2 mg/kg), and (ii) the effect of the dopamine D1-like and D2-like receptor antagonists SCH 23390 (0.01 and 0.025 mg/kg) and raclopride (0.05 and 0.2 mg/kg) on the antidepressant-like effect of allopregnanolone (2 mg/kg) in the same experimental model. We failed to observe differences in depressive-like behaviour between estrous phases, and allopregnanolone administration in both estrus and diestrus resulted in an antidepressant-like effect consisting in an increase of swimming behaviour. The allopregnanolone effect was unaffected by a dose of the dopamine D1-like receptor antagonist SCH 23390 displaying a marked inhibitory effect on basal activity, while it was turned into a potentiation of the depressive-like behaviour of the forced swimming condition by treatment with the higher dose of raclopride. The present results indicate an involvement of dopamine transmission in the allopregnanolone antidepressant-like effect in the forced swimming model of depression, and suggest that this effect depends mainly on stimulation of dopamine D2-like receptors.

Enhanced sensitivity of the MRL/MpJ mouse to the neuroplastic and behavioral effects of acute and chronic antidepressant treatments.

Adult hippocampal neurogenesis has been implicated in the pathophysiology of depression and in the therapeutic effects of antidepressant drugs. Current immunohistochemical methods that study neurogenesis are time consuming and labor intensive. Therefore, a significantly more rapid flow cytometric method was characterized to measure neurogenesis in the adult mouse brain. The sensitivity of mice to the effects of antidepressant treatments is dependent on genetic background. Thus, studies were conducted comparing the responsiveness of 2 inbred mouse strains, MRL/MpJ and C57BL/6J, to the acute and chronic effects of antidepressants on neurochemistry and behavior. Acutely, MRL/MpJ mice displayed more robust behavioral and neurochemical responses to pharmacologically distinct antidepressants than C57BL/6J mice. Chronic administration of the antidepressant drugs fluoxetine and desipramine produced robust elevations in hippocampal cell proliferation and brain-derived neurotrophic factor (BDNF) protein levels in MRL/MpJ mice. C57BL/6J mice treated similarly with antidepressant drugs were mainly unresponsive on these measures. Mice were tested in the novelty-induced hypophagia (NIH) paradigm to examine a behavioral response associated with chronic, but not acute, antidepressant treatment. Only MRL/MpJ mice were behaviorally responsive to chronic antidepressant administration in the NIH paradigm. The positive effects of chronic antidepressants on hippocampal cell proliferation and BDNF paralleled the ability of these drugs to produce changes in NIH behavior. These studies highlight the advantages of using flow cytometry to study hippocampal neurogenesis and identify the MRL/MpJ mouse as a strain with superior response to antidepressant drug treatments that may lead to a better understanding of the genetics behind antidepressant efficacy and sensitivity.

Depression, suicidality and antidepressants: A coincidence?

Byline: Vithyalakshmi. Selvaraj, Snehamala. Veeravalli, Sriram. Ramaswamy, Richard. Balon, Vikram. Yeragani Major depressive disorder is currently one of the leading causes of disability world-wide and projected by the World Health Organization (WHO) to become the second leading cause of disability after heart disease by the year 2020. Suicidal ideation and behavior are the most serious and common psychiatric emergencies among the depressed population. In 2004, suicide was the eleventh leading cause of death in the U.S.[sup] [1] The overall rate was 10.9 suicide deaths per 100,000 people. An estimated 8 to 25 attempted suicides occur per every suicide death. It is reassuring that depressed patients usually respond to treatment with antidepressants. In fact, population-based studies examining rates of antidepressant use and suicide over time, have generally found lower rates of suicide with increasing rates of antidepressant use.[sup] [2],[3],[4],[5],[6],[7],[8] However, in 2003, publication of data linking antidepressant use to suicide and suicidal behavior in children and teenagers sparked off worldwide public health concern. This prompted the US Food and Drug Administration (FDA) to mandate manufacturers of all antidepressants (including tricyclic antidepressants [TCAs] and monoamine oxidase inhibitors) to include a warning stating that antidepressants may increase the risk of suicidal ideation and behavior in children, adolescents and young adults less than 25 years old. The 'black box' warning, although meant to safeguard public health has had serious spillover effects on pharmacotherapy of depression. There have been recent reports of a rise in suicide rates among the youth and a decline in depression care among the older adults. We critically evaluate this association in order to provide more clarity while assessing the benefits of antidepressant use versus any risk of self-harm associated with them. Impact of Depression Depression is a pathological and pervasive state of mood. The lifetime risk of developing major depressive disorder is 16.2% in the United States. Recurrence is the rule, and about one-third of patients go on to develop chronic depression. Depression increases mortality because it worsens many medical conditions such as cardiovascular disease and diabetes and increases the risk of suicide. Depressed patients are high utilizers of healthcare services and typically perform poorly in the workplace. The mean age of onset, from a number of studies, is in the late 20s. Although twice as many females as males report or receive treatment for clinical depression, this gap has significantly narrowed in the recent past. Also, this difference disappears after the age of 50-55, when most females are post-menopausal. Suicidal ideation and attempts are common in depressed patients. Each year, about 30,000 people in the United States and one million worldwide die by suicide. Approximately 650,000 people in the United States receive emergency treatment each year after attempting suicide. Antidepressants Benefits and Risks Mono amine oxidase inhibitors (MAOI) and tricyclic antidepressants (TCA) were the mainstays of treatment for depression until the introduction of Serotonin Reuptake Inhibitors (SSRIs) in the late 1980's. Currently, SSRIs are the most commonly prescribed antidepressants. The therapeutic effects of antidepressants are believed to be related to their ability to facilitate serotonin, norepinephrine and/or dopamine neurotransmission. Despite the early increase in concentration of monoamine neurotransmitters at receptor sites, clinical antidepressant benefits are not evident until several weeks. One explanation for this therapeutic lag is the theory that down-regulation of neurotransmitter receptors is a consequence of excess signaling, a process that takes several weeks and ultimately responsible for the alleviation of depressive symptoms. Overall, antidepressants are very effective in treating depression and its associated complications. …

PP86 Sister chromatid exchanges as marker of genomic instability in familial breast cancer patients

The mechanisms by which antidepressants have their effects are not clear and the reasons for variability in treatment outcomes are also unknown. However, there is evidence from candidate gene research that indicates gene expression changes may be involved in antidepressant action. In this study, we examined antidepressant-induced alterations in gene expression on a transcriptome-wide scale, exploring associations with treatment response. Blood samples were taken from a subset of depressed patients from the GENDEP study (n=136) before and after eight weeks of treatment with either escitalopram or nortriptyline. Transcriptomic data were obtained from these samples using Illumina HumanHT-12 v4 Expression BeadChip microarrays. When analysing individual genes, we observed that changes in the expression of two genes (MMP28 and KXD1) were associated with better response to nortriptyline. Considering connectivity between genes, we identified modules of genes that were highly coexpressed. In the whole sample, changes in one of the ten identified coexpression modules showed significant correlation with treatment response (cor=0.27, p=0.0029). Using transcriptomic approaches, we have identified gene expression correlates of the therapeutic effects of antidepressants, highlighting possible molecular pathways involved in efficacious antidepressant treatment.

Haplotype analysis of single nucleotide polymorphisms in the vascular endothelial growth factor (VEGFA) gene and antidepressant treatment response in major depressive disorder

Vascular endothelial growth factor (VEGF) has been implicated in neurotrophy and neurogenesis, which play a pivotal role in brain development and may be involved in antidepressant therapeutic mechanisms. Recent animal studies demonstrate that VEGF levels are increased by several antidepressants, including selective serotonin reuptake inhibitors, and that VEGF signalling is required for antidepressant-induced behavioural response. We hypothesized that common genetic variants in the VEGF gene (official gene name: VEGFA) may be associated with the therapeutic response to antidepressants in major depressive disorders (MDD). Seven VEGFA polymorphisms were genotyped in 351 patients with MDD who were treated with selective serotonin reuptake inhibitor (fluoxetine or citalopram) antidepressants and who were were studied in a therapeutic evaluation for at least 4 weeks. Of the 351 patients, 158 completed an 8-week therapeutic evaluation. No significant association with either 4-week or 8-week antidepressant therapeutic effect was shown in the alleles and genotypes of single loci, or haplotypes from two blocks constructed from these polymorphisms. Our findings suggested that VEGFA genetic variants do not play a major role in the response to selective serotonin reuptake inhibitors.

The effect of serotonergic and noradrenergic antidepressants on face emotion processing in depressed patients

Background In healthy volunteers, exposure to antidepressants increases the recognition of positive face emotions and decreases recognition of negative emotions. It has been proposed that this may underlie therapeutic effects of antidepressants, but to date this has not been tested in clinical populations. Method Recognition of facial emotions was measured at baseline ( N = 108) and after 2 ( N = 59) and 6 weeks ( N = 69) of treatment in depressed primary care patients who had been randomised to treatment with either citalopram (SSRI) or reboxetine (NaRI) in an open-label study. Changes in emotional processing were compared to clinical outcome after 6 weeks of treatment. Results Significant increases in recognition accuracy of disgust, happiness and surprise occurred by two-weeks of treatment with both antidepressants, and did not further change at 6 weeks. There was a significant correlation between the increased accuracy in recognition of happy faces over the first two-weeks of treatment and the clinical improvement after six-weeks of treatment. Limitations There was no control group and changes over time may be due to practice effects. Conclusions Antidepressants altered emotional processing in depressed patients with some similarities to the effects seen in healthy volunteers. The largest effect seen was increased recognition of disgust that may be specific to depressed patients. The correlation between increased accurate recognition of happy faces at two-weeks of treatment and clinical outcome at six-weeks of treatment suggests that early changes in emotional processing may underlie clinical response to antidepressants.

Ageing abolishes the effects of fluoxetine on neurogenesis

Depression constitutes a widespread condition observed in elderly patients. Recently, it was found that several drugs employed in therapies against depression stimulate hippocampal neurogenesis in young rodents and nonhuman primates. As the rate of neurogenesis is dramatically reduced during ageing, we examined the influences of ageing on neurogenic actions of antidepressants. We tested the impact of fluoxetine, a broadly used antidepressant, on hippocampal neurogenesis in mice of three different age groups (100, 200 and over 400 days of age). Proliferation and survival rate of newly generated cells, as well as the percentage of cells that acquired a neuronal phenotype were analyzed in the hippocampus of mice that received fluoxetine daily in a chronic manner. Surprisingly, the action of fluoxetine on neurogenesis was decreasing as a function of age and was only significant in young animals. Hence, fluoxetine increased survival and the frequency of neuronal marker expression in newly generated cells of the hippocampus in the young adult group (that is 100 days of age) only. No significant effects on neurogenesis could be detected in fluoxetine-treated adult and elderly mice (200 and over 400 days of age). The data indicate that the action of fluoxetine on neurogenesis is highly dependent on the age of the treated individual. Although the function of neurogenesis in the clinical manifestation of depression is currently a matter of speculation, this study clearly shows that the therapeutic effects of antidepressants in elderly patients are not mediated by neurogenesis modulation.

Brain-Derived Neurotrophic Factor and Antidepressant Action: Another Piece of Evidence from Pharmacogenetics

EVALUATION OF: Gratacòs M, Soria V, Urretavizcaya M et al.: A brain-derived neurotrophic factor (BDNF) haplotype is associated with antidepressant treatment outcome in mood disorders. Pharmacogenomics J. 8, 101-112 (2008). The neurotrophin hypothesis of depression and antidepressant drug action postulates that reduced activity of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), plays an important role in the pathogenesis of major depression, and that its restoration may represent a critical mechanism underlying antidepressant therapeutic effect. This hypothesis is supported by numerous animal studies; however, evidence from clinical studies is lacking. This study is the first to use both single-marker as well as haplotype analysis to test the effect of genetic variants of BDNF on the therapeutic effects of antidepressant treatment in mood disorder. Among eight BDNF TagSNPs tested, one allele (rs908867) is associated with antidepressant response, with heterozygote carriers showing a better response than homozygous analog. The authors also identified a haplotype associated with the therapeutic response. This study provides clinical evidence to support the role of BDNF in antidepressant therapeutic mechanisms. However, further work is needed to confirm the findings, for several reasons. First, the study included not only major depression but also bipolar disorder patients; second, various antidepressants were used in this study, which could affect patients' responses; third, the frequency of the haplotype associated with treatment response is rare; and fourth, previous studies of the effects of single BDNF polymorphisms on antidepressant action have reported conflicting findings. Several suggestions for further work are discussed below.

Targeting TrkB neurotrophin receptor to treat depression

Background: An increasing number of findings point out the key role of the BDNF (brain-derived neurotrophic factor) receptor, tyrosine kinase receptor B (TrkB), in the regulation of antidepressant drug actions. Therefore, targeting TrkB receptors might be a rational strategy to develop novel antidepressant drugs. Objective/methods: In this review we will discuss several approaches to targeting the TrkB receptor using existing or novel drugs. We will mainly concentrate on the following issues: i) synthesis, release and cleavage of neurotrophins; ii) augmentation of the actions of neurotrophins; iii) synthesis of TrkB; iv) developing agonists for TrkB; and v) TrkB transactivation. Conclusions: Different molecular approaches can be used to screen antidepressant drugs acting through TrkB receptors but it remains to be seen whether they demonstrate therapeutic antidepressant effects.

The Antidepressant Fluoxetine Restores Plasticity in the Adult Visual Cortex

We investigated whether fluoxetine, a widely prescribed medication for treatment of depression, restores neuronal plasticity in the adult visual system of the rat. We found that chronic administration of fluoxetine reinstates ocular dominance plasticity in adulthood and promotes the recovery of visual functions in adult amblyopic animals, as tested electrophysiologically and behaviorally. These effects were accompanied by reduced intracortical inhibition and increased expression of brain-derived neurotrophic factor in the visual cortex. Cortical administration of diazepam prevented the effects induced by fluoxetine, indicating that the reduction of intracortical inhibition promotes visual cortical plasticity in the adult. Our results suggest a potential clinical application for fluoxetine in amblyopia as well as new mechanisms for the therapeutic effects of antidepressants and for the pathophysiology of mood disorders.

Glycogen synthase kinase-3β gene is associated with antidepressant treatment response in Chinese major depressive disorder

Evidence suggests that glycogen synthase kinase-3beta (GSK3B) activity is increased significantly in the brain of patients with major depressive disorders (MDD). Inhibition of GSK3B is thought to be a key feature in the therapeutic mechanism of antidepressants. To investigate whether common genetic variants in the GSK3B gene are associated with MDD and the therapeutic response to antidepressants, four polymorphisms (rs334558 (-50 T>C), rs13321783 (IVS7+9227 A>G), rs2319398 (IVS7+11660 G>T) and rs6808874 (IVS11+4251 T>A)) of the GSK3B gene were genotyped in 230 Chinese MDD patients and 415 controls. Among the MDD patients, 168 accepted selective serotonin reuptake inhibitor (SSRI) (fluoxetine or citalopram) antidepressant treatment and therapeutic evaluation for 4 weeks and 117 for 8 weeks. Significant association with MDD was not shown in the alleles and genotypes of single loci or four-locus haplotypes. However, three of the four polymorphisms investigated were significantly associated with 4-week antidepressant therapeutic effect (P=0.002-0.011). Of the four-locus haplotype analysis, the GSK3B TAGT carriers showed a poorer response to antidepressants in 4-week (P<0.0001) and 8-week (P=0.015) evaluation compared with other haplotype groups and would quite likely be the non-remitter to 8-week antidepressant treatment (P=0.006). Our findings show, for the first time, that GSK3B genetic variants play a role in the SSRI antidepressant therapeutic response and support the hypothesis that drugs regulating GSK3B activity may represent a novel treatment strategy for MDD.

The Effects of Antidepressants in Parkinson’s Disease: A Meta-Analysis

This study explored the therapeutic effect of antidepressants in Parkinson's disease (PD) using a meta-analysis. Altogether, 24 placebo-controlled trials qualified for inclusion and revealed that tricyclic antidepressants (TCAs) had a greater antidepressant effect relative to selective serotonin reuptake inhibitors (SSRIs), Qb(1) = 8.87, p < .01, and the mono-amine-oxidase inhibitor, selegiline, Qb(1) = 7.90, p < .01. Whereas TCAs produced a significant side effect profile (odds ratio = 3.07), adverse events were negligible with SSRIs (odds ratio = 1.83) and selegeline (odds ratio = 1.63). Antidepressants can be beneficial for patients with PD. However, the choice of antidepressants needs to take depressive symptomatologies into account while monitoring side effects.

Antidepressants induce acute CREB phosphorylation and CRE-mediated gene expression in glial cells: a possible contribution to GDNF production

Recently, the changes of neuronal and glial plasticity related gene expression following the increase of monoamine are suggested to be important for the therapeutic effect of antidepressants. We previously showed that antidepressants increased glial cell line-derived neurotrophic factor (GDNF) expression, which was dependent on acute activation of protein tyrosine kinase (PTK) and extracellular signal-regulated kinase (ERK) in rat C6 glioma cells (C6 cells) and normal human astrocytes (NHA). Transcription of many genes including GDNF is directed by the cAMP responsive element (CRE) and its cognate transcription factor CRE binding protein (CREB). In this study, we showed that amitriptyline, a tricyclic antidepressant, acutely increased phosphorylation of CREB, without altering the level of total CREB in C6 cells as well as in NHA. In contrast, acute amitriptyline treatment did not affect phosphorylation of CREB in SH-SY5Y cells, a human neuroblastoma cell line. Different classes of antidepressants as well as amitriptyline acutely increased phosphorylation of CREB, but haloperidol and diazepam did not. The amitriptyline-induced phosphorylation of CREB was completely blocked by U0126 [a mitogen-activated protein (MAP) kinase kinase 1 inhibitor] and genistein (a PTK inhibitor), but not by inhibitors of protein kinase A, p38 MAP kinase, or Ca 2+/calmodulin-dependent kinase. Amitriptyline treatment also increased the expression of luciferase reporter gene regulated by CRE elements. The amitriptyline-induced luciferase activity was completely inhibited by U0126 in the same as phosphorylation of CREB. These results suggest that antidepressants acutely increase CREB activity in PTK and ERK-dependent manners, which might contribute to gene expression including GDNF in glial cells.