BDNF Val 66 Met and 5-HTTLPR genotype moderate the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms: A prospective study

Recent studies have emphasized an important role for neurotrophins, such as brain-derived neurotrophic factor (BDNF), in regulating the plasticity of neural circuits involved in the pathophysiology of stress-related diseases. The aim of the present study was to examine the interplay of the BDNF Val⁶⁶Met and the serotonin transporter promoter (5-HTTLPR) polymorphisms in moderating the impact of early-life adversity on BDNF plasma concentration and depressive symptoms. Participants were taken from an epidemiological cohort study following the long-term outcome of early risk factors from birth into young adulthood. In 259 individuals (119 males, 140 females), genotyped for the BDNF Val⁶⁶Met and the 5-HTTLPR polymorphisms, plasma BDNF was assessed at the age of 19 years. In addition, participants completed the Beck Depression Inventory (BDI). Early adversity was determined according to a family adversity index assessed at 3 months of age. Results indicated that individuals homozygous for both the BDNF Val and the 5-HTTLPR L allele showed significantly reduced BDNF levels following exposure to high adversity. In contrast, BDNF levels appeared to be unaffected by early psychosocial adversity in carriers of the BDNF Met or the 5-HTTLPR S allele. While the former group appeared to be most susceptible to depressive symptoms, the impact of early adversity was less pronounced in the latter group. This is the first preliminary evidence indicating that early-life adverse experiences may have lasting sequelae for plasma BDNF levels in humans, highlighting that the susceptibility to this effect is moderated by BDNF Val⁶⁶Met and 5-HTTLPR genotype.     

BDNF plasma levels after antidepressant treatment with sertraline and transcranial direct current stimulation: Results from a factorial,randomized, sham-controlled trial

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention that modifies cortical excitability according to the stimulation parameters. Preclinical and clinical studies in healthy volunteers suggest that tDCS induces neuroplastic alterations of cortical excitability, which might explain its clinical effects in major depressive disorder (MDD). We therefore examined whether tDCS, as compared to the antidepressant sertraline, increases plasma brain-derived neurotrophic factor (BDNF) levels, a neurotrophin associated with neuroplasticity. Patients (n=73) with major depressive disorder were randomized to active/sham tDCS and sertraline/placebo (four groups) in this 6-week, double-blind, placebo-controlled trial. We measured BDNF plasma levels at baseline and endpoint, observing no significant changes of BDNF levels after treatment. In addition, no significant changes were observed in responders and non-responders as well as no relationships between BDNF levels and clinical and psychopathological variables related to depression. Thus, in one of the few placebo-controlled trials evaluating BDNF changes over an antidepressant treatment course, we did not observe BDNF increase regardless of clinical improvement in depressed patients. Regarding tDCS, BDNF plasma levels might not be a good candidate biomarker to evaluate depression improvement or be a predictor of response in patients treated with tDCS, as our results showed that BDNF increase was not necessary to induce clinical response. Finally, our findings do not support a relationship between BDNF and improvement of depression.     

The effect of COMT Val158 Met genotype on decision-making and preliminary findings on its interaction with the 5-HTTLPR in healthy females

Poor decision-making is inherent to several psychiatric conditions for which a genetic basis may exist. We previously showed that healthy female volunteers homozygous for the short allele (s/s) of the serotonin transporter length polymorphic region (5-HTTLPR) chose more often cards from disadvantageous decks in the Iowa Gambling Task (IGT), which measures decision-making, than long (l) allele carriers. The 5-HTTLPR and catechol-O-methyltransferase (COMT) Val¹⁵⁸ Met polymorphism affect the same set of neuronal structures. Therefore, we explored the effect of the (COMT) Val¹⁵⁸ Met polymorphism on IGT performance and its interaction with the 5-HTTLPR in the same subjects in this study. We observed that subjects homozygous for methionine (Met/Met) chose more disadvantageously than subjects homozygous for valine (Val/Val). s/s-Met/Met-subjects appeared to show the poorest IGT performance of all possible combinations of 5-HTTLPR and COMT allelic variants. Using the Expectancy-Valence model, no differences were found for the three different 5-HTTLPR or COMT genotypes regarding (i) attention to wins versus losses, (ii) updating rate, or (iii) response consistency. However, subjects with at least one Met-allele were paying more attention to wins than subjects with no Met-alleles. We discuss whether a common neuronal mechanism relates to s- and Met-allele-related deficits in updating and/or processing of choice outcome to guide subsequent choices in this gamble-based test.     

Cytokines plasma levels during antidepressant treatment with sertraline and transcranial direct current stimulation (tDCS): results from a factorial,randomized, controlled trial

Rationale

The inflammatory hypothesis of depression states that increased levels of pro-inflammatory cytokines triggered by external and internal stressors are correlated to the acute depressive state. This hypothesis also suggests that pharmacotherapy partly acts in depression through anti-inflammatory effects. Transcranial direct current stimulation (tDCS) is a novel, promising, non-invasive somatic treatment for depression, although its antidepressant mechanisms are only partly understood.

Objectives

We explored the effects of tDCS and sertraline over the immune system during an antidepressant treatment trial.

Methods

In a 6-week, double-blind, placebo-controlled trial, 73 antidepressant-free patients with unipolar depression were randomized to active/sham tDCS and sertraline/placebo (2?×?2 design). Plasma levels of several cytokines (IL-2, IL-4, IL-6, IL-10, IL-17a, IFN-γ, and TNF-α) were determined to investigate the effects of the interventions and of clinical response on them.

Results

All cytokines, except TNF-α, decreased over time, these effects being similar across the different intervention-groups and in responders vs. non-responders.

Conclusions

tDCS and sertraline (separately and combined) acute antidepressant effects might not specifically involve normalization of the immune system. In addition, being one of the first placebo-controlled trials measuring cytokines over an antidepressant treatment course, our study showed that the decrease in cytokine levels during the acute depressive episode could involve a placebo effect, highlighting the need of further placebo-controlled trials and observational studies examining cytokine changes during depression treatment and also after remission of the acute depressive episode.     

Three-way interaction effect of 5-HTTLPR,BDNF Val66Met,and childhood adversity on depression: A replication study

Both the serotonin transporter linked promoter region (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms have been shown to interact with unfavourable environment in relation to depression symptoms and to depression diagnosis. Several attempts have been made to study a three-way interaction effect of these factors on depression, however with contradictory results. We aimed to test the hypothesis of a three-way interaction effect and to attempt at replication in an independent population-based sample. Family maltreatment, sexual abuse and depression were self-reported by an adolescent population-based cohort (N=1393) from the county of Västmanland, Sweden. DNA was isolated from saliva, and used for genotyping of the 5-HTTLPR and BDNF Val66Met polymorphisms. Neither 5-HTTLPR or BDNF genotypes separately, nor in interaction with each other had any relation to depression, however in an environment adjusted model a two-way interaction and a three-way interaction effect was found. Both 5-HTTLPR and BDNF Val66Met interacted with unfavourable environment in relation to depressive symptoms (Adj R²=0.19). Depressive symptoms and depression were more common among carriers of either the ss/sl+Val/Val or the ll+Met genotypes in the presence of early-life adversities. This three-way effect was more pronounced among girls. The current study, with a virtually similar set-up compared to previous studies, can partially confirm previous findings and their generalizability. The study also shows the importance of genetic plasticity in individuals with different environmental exposure, for different phenotypic expression.     

Effects of pramipexole on the processing of rewarding and aversive taste stimuli

Rationale

Serotonin transporter (5-HTT) gene polymorphisms are linked with antidepressant response to selective serotonin reuptake inhibitor drugs (SSRIs), though the favorable allelic variant differs by ethnic group (Caucasian versus Korean or Japanese). In Caucasian patients, response also is linked to measures of platelet 5-HTT function.

Objectives

Here, we study both 5-HTT gene polymorphisms and 5-HTT function as determinants of antidepressant response to SSRIs in Korean patients.

Methods

We enrolled 99 patients with major depression and 48 control subjects. For statistical power, both samples were enriched with the l/l 5-HTTLPR polymorphism, which is uncommon in Koreans. Patients were treated with fluoxetine or sertraline. Response was assessed at 6 weeks. Subjects were genotyped for s/l polymorphism in the 5-HTT promoter region (5-HTTLPR). Platelet 5-HTT activity was determined as maximal uptake rate (Vmax) and affinity constant (Km).

Results

Response was differentially associated with the s allele of 5-HTTLPR, which also was significantly associated with Vmax. These associations are opposite to those reported in Caucasian populations. Responders had significantly higher Vmax and Km than nonresponders. In Koreans as well as Caucasians, high Vmax is related to antidepressant response to SSRIs, though the 5-HTTLPR polymorphism associations with both response and function differ by ethnicity.

Conclusions

Both ethnicity and function must be considered in evaluating candidate gene biomarkers of response to SSRIs in depression.     

Prefrontal serotonin transporter availability is positively associated with the cortisol awakening response

Stress sensitivity and serotonergic neurotransmission interact, e.g. individuals carrying the low-expressing variants (S and L_G) of the 5-HTTLPR promoter polymorphism of the serotonin transporter (SERT) gene are at higher risk for developing mood disorders when exposed to severe stress and display higher cortisol responses when exposed to psychosocial stressors relative to high expressing 5-HTTLPR variants. However, it is not clear how the relation between SERT and cortisol output is reflected in the adult brain. We investigated the relation between cortisol response to awakening (CAR) and SERT binding in brain regions considered relevant to modify the cortisol awakening response. Methods: thirty-two healthy volunteers underwent in vivo SERT imaging with [¹¹C]DASB-Positron Emission Tomography (PET), genotyping, and performed home-sampling of saliva to assess CAR. Results: CAR, defined as the area under curve with respect to increase from baseline, was positively coupled to prefrontal SERT binding (p=0.02), independent of adjustment for 5-HTTLPR genotype. Although S- and L_G-allele carriers tended to show a larger CAR (p=0.07) than L_A homozygous, 5-HTTLPR genotype did not modify the coupling between CAR and prefrontal SERT binding as tested by an interaction analysis (genotype×CAR). Conclusion: prefrontal SERT binding is positively associated with cortisol response to awakening. We speculate that in mentally healthy individuals prefrontal serotonergic neurotransmission may exert an inhibitory control on the cortisol awakening response.     

Systematic review and meta-analysis of serotonin transporter genotype and discontinuation from antidepressant treatment

There is evidence that 5-HTTLPR is associated with response following treatment from selective serotonin reuptake inhibitors (SSRIs). The short (S) allele has reduced serotonin transporter expression, compared to the long (L) allele, and has been reported to be associated with poorer response in Europeans, with the effect in other populations unclear. However the published literature is inconsistent. A systematic review and meta-analysis was performed to investigate the effect of 5-HTTLPR on discontinuation from antidepressant treatment. Data were obtained from 17 studies including 4309 participants. The principal outcome measure was the allelic odds ratio (OR) for the 5-HTTLPR S allele and discontinuation status. A random effects meta-analysis provided no evidence that the S allele was associated with increased odds of discontinuation from SSRIs in Europeans (OR 1.09, 95% CI 0.83–1.42, p=0.53; 10 studies, n=2504) but in East Asians there was evidence of a reduced odds of discontinuation (OR 0.28, 95% CI 0.12–0.64, p=0.002; 2 studies, n=136). There was a suggestion of small study bias (p=0.05). This meta-analysis provides no evidence of an association between 5-HTTLPR and discontinuation from antidepressant treatment in Europeans. The low number of studies in East Asian samples using SSRIs reduces confidence in our evidence that the S allele decreases the odds of discontinuation in this population. At present, there is no evidence of an association between 5-HTTLPR and discontinuation from SSRI treatment in a European population with further studies required to investigate its effects in different populations.     

BDNF Val66Met is Associated with Introversion and Interacts with 5-HTTLPR to Influence Neuroticism

Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met × 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism.     

Allelic variation in the serotonin transporter promoter affects neuromodulatory effects of a selective serotonin transporter reuptake inhibitor (SSRI)

Rationale. Antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs) has been shown to depend on functional polymorphisms within the promoter region of the serotonin transporter gene (5-HTTLPR). This gene gives rise to a biallelic polymorphism designated long (l) and short (s). Homozygosity for the long variant (ll-genotype) is associated with a two times more efficient 5-HT uptake compared to the s/l- or s/s-genotype. Paired pulse transcranial magnetic stimulation is a feasible tool in detecting changes of motor cortex excitability induced by SSRIs. Objective. Our study aimed to measure neuromodulatory effects of SSRIs on cortical excitability in healthy volunteers characterized by distinct genotypes of the 5-HTTLPR. Methods. Cortical excitability was determined in eight genetically defined subjects pre- and post-ingestion of 60 mg citalopram. Results. Subjects with the ll-genotype of the 5-HTTLPR showed a significant enhancement of a particular component of motor cortex excitability (intracortical inhibition) as compared to volunteers without the ll-genotype. Conclusion. Distinct neuromodulatory effects after intake of citalopram based on allelic variations of the 5-HTTLPR may explain variable response of patients treated with SSRIs. Electronic Publication     

Serotonin transporter-linked polymorphic region (5-HTTLPR) genotype is associated with cortisol responsivity to naloxone challenge

Rationale

The serotonergic and opioidergic neurotransmitter systems are critical regulators of the hypothalamic?Cpituitary?Cadrenal (HPA) axis through their respective excitatory and inhibitory inputs. Serotonin transporter (5-HTT) genotype has been studied as a marker of HPA axis dysregulation and for predicting risk of psychopathology, with mixed findings.

Objectives

We stimulated the HPA axis with naloxone, an opioid receptor antagonist, to examine cortisol reactivity based on 5-HTT-linked polymorphic region (5-HTTLPR) genotypes.

Methods

Healthy community volunteers (N?=?78) received intravenous (IV) placebo followed by sequential doses of IV naloxone (50, 100, 200, and 400???g/kg) every 30?min. Plasma cortisol was measured every 15?min. Participants were genotyped for the long (L) and short (S) alleles of the 5-HTT gene and for rs25531 (A/G) in the 5-HTTLPR repetitive element and compared by the 5-HTTLPR/rs25531 genotype (triallele) and by the 5-HTTLPR genotype (biallele) classification.

Results

In triallele analyses, individuals with one or more L _A alleles showed higher cortisol response to naloxone compared with individuals with no L _A alleles. In biallele analyses, less robust effects were found, although individuals with two L alleles showed a higher cortisol response compared with other genotypes.

Conclusions

Naloxone blockade leads to a greater activation of the HPA axis among individuals with the L _A allele. Including rs25531 in the analysis with the 5-HTTLPR genotype appears more sensitive in detecting genetic differences in naloxone-induced cortisol than when using only the 5-HTTLPR genotype. Future research should investigate the interactive effects between the serotonergic and opioidergic systems on HPA axis dysregulation and psychopathophysiology.     

Evidence of a role for the 5-HTTLPR genotype in the modulation of motor response to antidepressant treatment

Rationale Serotonergic mechanisms are thought to play an important role in the regulation of mood, motor activity and sleep patterns. Serotonin reuptake is controlled by the serotonin transporter (5-HTT) and by a common functional insertion/deletion polymorphism in the corresponding genes promoter region (5-HTTLPR). Homozygosity for the long variant may confer a favourable response to treatment with serotonin reuptake inhibitors (SSRIs), and to sleep deprivation.Objectives The study assessed the role of the 5-HTTLPR genotype in determining motor side effects of antidepressant medication.Methods Motor activity patterns of 62 patients with major depression who were being treated with either SSRIs or tricyclic antidepressants (TCAs) were monitored over a 24-h period using a wrist-actograph. Additionally, motor activity was rated in a semi-structured interview using the motor agitation and retardation scale (MARS).Results Night-time motor activity was significantly increased in homozygous carriers of the long 5-HTTLPR allele (LL-genotype) who were being treated with SSRIs in comparison to short allele carriers (LS-genotype and SS-genotype), regardless of the type of antidepressant treatment (P<0.001). It was also significantly increased in comparison to patients with the LL-genotype who were being treated with TCAs (P<0.01). Differences in actographic motor activity were most prominent between 11 p.m. and 4 a.m. Clinical ratings of motor activity also showed a trend toward higher agitation scores in patients with the LL-genotype who received SSRI treatment.Conclusions Homozygosity for the long variant of the 5-HTTLPR may cause a predisposition to increased night-time motor activity in conjunction with SSRI treatment.     

Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression

The limitations of antidepressant drugs to treat depression has warranted ongoing research to identify pharmacological agents and strategies which offer a faster onset of action and greater therapeutic efficacy. Noradrenaline and serotonin are widely reported to be involved in the mechanism of action of antidepressants and the recent development of selective reuptake inhibitors of these transmitters has provided the opportunity to determine the effects of targeting these transmitter systems, alone and in combination, in an antidepressant response. The present study investigated the effects of reboxetine, a new antidepressant that selectively inhibits noradrenaline reuptake, sertraline, a selective serotonin reuptake inhibitor and a combination treatment composed of the two drugs in the olfactory bulbectomized (OB) rat model of depression. Sub-acute (2 days) administration of reboxetine (2.5, 5, and 10 mg/kg, i.p.) to sham-operated and OB rats reduced the immobility time in the forced swim test. Repeated (14 days) reboxetine (10 mg/kg) treatment attenuated the OB-related behavioural hyperactivity in the `open-field' test. Examination of the onset of the antidepressant effect in the `open-field' test demonstrated that reboxetine (10 mg/kg), sertraline (5 mg/kg) and the combination reduced the behavioural hyperactivity after 14 days but not before this following 3, 7 or 10 days of treatment. Reduced 5-hydroxyindoleacetic acid (5-HIAA) concentrations in amygdaloid cortex of both sham and OB rats following sertraline and combination treatments are likely to be related to acute pharmacological effects on the reuptake of 5-hydroxytryptamine (5-HT). Attenuation of the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.05 mg/kg s.c.) and clonidine (0.1 mg/kg s.c.) occurred in the reboxetine and sertraline combination treated groups following both 7 and 14 days administration indicating changes to 5-HT_1A receptor and α₂-adrenoceptor sensitivity. The results indicate that changes to 8-OH-DPAT and clonidine-induced responses occur quicker with the combination treatment than with either reboxetine or sertraline treatments alone.     

Monoamine transporter gene polymorphisms affect susceptibility to depression and predict antidepressant response

Rationale  Serotonin transporter (5-HTT) and norepinephrine transporter (NET) are the primary targets of many antidepressants. We aimed to determine the potential correlations of 5-HTT/NET gene polymorphisms with the susceptibility to depression and the antidepressant response to selective serotonin reuptake inhibitors (SSRIs) or dual selective serotonin/norepinephrine reuptake inhibitors (SNRIs). Methods  A total of 579 depressed patients and 437 healthy controls, all of Chinese Han region, were collected and genotyped by polymerase chain reactions (PCR). All patients were under treatment of SSRI or SNRI for 6 weeks, and were evaluated using a 17-item Hamilton Depression Rating Scale (HAMD). Results  Five hundred sixty-seven of 579 patients completed the total treatment, of which 362 were in SSRI and 205 in SNRI group. It was shown that the NET-T182C, interacting with 5-HTTLPR, was associated with the susceptibility to depression. Patients with both NET-T182C C/C and 5-HTTLPR S/S genotypes had lower baseline HAMD scores. Patients with 5-HTTLPR L/L or STin2 12/12 genotype experienced better clinical response to the SSRI treatment. Besides, the STin2 12/12 carriers showed a superior reduction to HAMD scores over treatment period. No correlation between NET T182C/G1287A polymorphisms and antidepressant response was observed. Conclusions  Our study revealed a positive association of the NET-T182C polymorphism with susceptibility to and severity of depression, and a positive association between the 5-HTT polymorphisms and the antidepressant response to SSRI. Combinations of these polymorphisms provided some potential gene–gene interaction effects. These findings might be of some clinical values in optimization of depression treatment. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Differential effects of 5-HTTLPR genotypes on mood,memory, and attention bias following acute tryptophan depletion and stress exposure

Rationale  Polymorphisms of the serotonin transporter gene (5-HTTLPR) may be associated with increased vulnerability to acute tryptophan depletion (ATD) and depression vulnerability especially following stressful life events. Objective  The aim of the present study was to investigate the effects of ATD in subjects with different 5-HTTLPR profiles before and after stress exposure on affective and cognitive–attentional changes. Materials and methods  Eighteen subjects with homozygotic short alleles (S′/S′) and 17 subjects with homozygotic long alleles (L′/L′) of the 5-HTTLPR participated in a double-blind, placebo-controlled, crossover design to measure the effects of ATD on mood, memory, and attention before and after acute stress exposure. Results  ATD lowered mood in all subjects independent of genotype. In S′/S′ genotypes, mild acute stress increased depressive mood and in L′/L′ genotypes increased feelings of vigor. Furthermore, S′/S′ genotypes differed from L′/L′ genotypes on measures of attention independent of treatment and memory following ATD. Conclusions  Polymorphisms of the 5-HTTLPR differentially affect responses to mild stress and ATD, suggesting greater vulnerability of S′/S′ carriers to serotonergic manipulations and supporting increased depression vulnerability.     

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.     

BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF^Val/Val) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF^Met/Met). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF^Met/Met mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF^Met/Met mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.     

Serotonin transporter polymorphism and response to SSRIs in major depression and relevance to anxiety disorders and substance abuse

The selective serotonin re-uptake inhibitors (SSRIs) which modulate serotonergic activity are effective in the treatment of serotonin-related mental disorders, such as depression and anxiety. These agents bind to the serotonin transporter (5-HTT) and inhibit its capacity to transport serotonin (5-hydroxytryptamine; 5-HT). A functional polymorphism in the promoter region of 5-HTT (5-HTTLPR) has been described. The insertion variant of this polymorphism (long allele) is associated with higher expression of brain 5-HTT compared to the deletion variant (short allele). An association between the 5-HTTLPR polymorphism and mental disorders has been reported by some, but not all, investigators. In addition, the 5-HTT gene polymorphisms were found to be associated with a better and faster response to SSRIs with or without pindolol augmentation in depressed patients. Further studies are needed to clarify the relationship between the 5-HTT genotype, the susceptibility to mental disorders, the response to serotonergic agents and the side effect profile.     

Serotonin Transporter Genotype and Action Monitoring Dysfunction: A Possible Substrate Underlying Increased Vulnerability to Depression

A variable number of tandem repeats (short (S) vs long (L)) in the promoter region of the serotonin transporter gene (5-HTTLPR) and a functional variant of a single-nucleotide polymorphism (rs25531) in 5-HTTLPR have been recently associated with increased risk for major depressive disorder (MDD). In particular, relative to L/L or L_A homozygotes (hereafter referred to as L′ participants), S carriers or L_g-allele carriers (S′ participants) have been found to have a higher probability of developing depression after stressful life events, although inconsistencies abound. Previous research indicates that patients with MDD are characterized by executive dysfunction and abnormal activation within the anterior cingulate cortex (ACC), particularly in situations requiring adaptive behavioral adjustments following errors and response conflict (action monitoring). The goal of this study was to test whether psychiatrically healthy S′ participants would show abnormalities similar to those of MDD subjects. To this end, 19 S′ and 14 L′ participants performed a modified Flanker task known to induce errors, response conflict, and activations in various ACC subdivisions during functional magnetic resonance imaging. As hypothesized, relative to L′ participants, S′ participants showed (1) impaired post-error and post-conflict behavioral adjustments; (2) larger error-related rostral ACC activation; and (3) lower conflict-related dorsal ACC activation. As similar behavioral and neural dysfunctions have been recently described in MDD patient samples, the current results raise the possibility that impaired action monitoring and associated ACC dysregulation may represent risk factors increased vulnerability to depression.     

Smoking moderates association of 5-HTTLPR and in vivo availability of serotonin transporters

Although preclinical studies clearly indicate an effect of 5-HTTLPR genotype on 5-HT transporter (5-HTT) expression, studies in humans provided inconclusive results, hypothetically due to environmental factors and differences in individual behavior. For example, nicotine and other constituents of tobacco smoke elevate serotonin (5-HT) levels in the brain and may thereby cause homeostatic adaptations in 5-HTT availability that moderate effects of 5-HTTLPR genotype. To test whether 5-HTT availability in the midbrain is affected by smoking status and 5-HTTLPR genotype, we pooled data from prior studies on in vivo 5-HTT availability (BP_ND) measured with positron emission tomography (PET) and [¹¹C]DASB. In total, we reanalyzed 5-HTT availability in 116 subjects using ANCOVA statistics. ROI analysis revealed that current smokers and non-smokers do not differ in midbrain BP_ND. Interestingly, smoking status significantly interacted with 5-HTTLPR genotype: active smoking was associated with reduced 5-HTT availability only in LL subjects but not in carriers of the S-allele. From the perspective of genotype effects, non-smokers showed the expected association with 5-HTTLPR, i.e. higher 5-HTT availability in LL subjects compared to carriers of the S-allele, whereas this pattern was actually reversed for active smokers. Our study indicates that smoking status moderates the association of 5-HTTLPR genotype and 5-HTT expression, which may help to explain inconsistent findings in previous studies. Regarding the mechanism, we suggest that smoking may induce epigenetic processes such as methylation of SLC6A4, which can differ depending on its genetic constitution.