SSRI Response Research Articles

Cingulate prediction of response to antidepressant and cognitive behavioral therapies for depression: Meta-analysis and empirical application.

We sought to identify baseline (pre-treatment) neural markers associated with treatment response in major depressive disorder (MDD), specific to treatment type, Cognitive Behavioral Therapy (CBT) or pharmacotherapy (selective serotonin reuptake inhibitors; SSRI). We conducted a meta-analysis of functional magnetic resonance imaging (fMRI) studies to identify neural prognostic indicators of response to CBT or SSRI. To verify the regions derived from literature, the meta-analytic regions were used to predict clinical change in a verification sample of participants with MDD who received either CBT (n = 60) or an SSRI (n = 19) as part of prior clinical trials. The meta-analysis consisted of 21 fMRI studies that used emotion-related tasks. It yielded prognostic regions of the perigenual (meta pgACC) and subgenual anterior cingulate cortex (meta sgACC), associated with SSRI and CBT response, respectively. When applying the meta-analytic regions to predict treatment response in the verification sample, reactivity of the meta pgACC was prognostic for SSRI response, yet the effect direction was opposite of most prior studies. Meta sgACC reactivity failed to be prognostic for CBT response. Results confirm the prognostic potential of neural reactivity of ACC subregions in MDD but further research is necessary for clinical translation.

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling

Depression and anxiety are major global health burdens. Although SSRIs targeting the serotonergic system are prescribed over 200 million times annually, they have variable therapeutic efficacy and side effects, and mechanisms of action remain incompletely understood. Here, we comprehensively characterise the molecular landscape of gene regulatory changes associated with fluoxetine, a widely-used SSRI. We performed multimodal analysis of SSRI response in 27 mammalian brain regions using 310 bulk RNA-seq and H3K27ac ChIP-seq datasets, followed by in-depth characterisation of two hippocampal regions using single-cell RNA-seq (20 datasets). Remarkably, fluoxetine induced profound region-specific shifts in gene expression and chromatin state, including in the nucleus accumbens shell, locus coeruleus and septal areas, as well as in more well-studied regions such as the raphe and hippocampal dentate gyrus. Expression changes were strongly enriched at GWAS loci for depression and antidepressant drug response, stressing the relevance to human phenotypes. We observed differential expression at dozens of signalling receptors and pathways, many of which are previously unknown. Single-cell analysis revealed stark differences in fluoxetine response between the dorsal and ventral hippocampal dentate gyri, particularly in oligodendrocytes, mossy cells and inhibitory neurons. Across diverse brain regions, integrative omics analysis consistently suggested increased energy metabolism via oxidative phosphorylation and mitochondrial changes, which we corroborated in vitro; this may thus constitute a shared mechanism of action of fluoxetine. Similarly, we observed pervasive chromatin remodelling signatures across the brain. Our study reveals unexpected regional and cell type-specific heterogeneity in SSRI action, highlights under-studied brain regions that may play a major role in antidepressant response, and provides a rich resource of candidate cell types, genes, gene regulatory elements and pathways for mechanistic analysis and identifying new therapeutic targets for depression and anxiety.

P319. Prediction of SSRI Response in Major Depressive Disorder Using Resting-State Biomarkers

Major depressive disorder (MDD) is a prevalent and disabling disorder that carries significant morbidity. Currently, there are no useful objective measures to help therapists predict response to treatment with SSRIs. This study aimed to compare EEG, fMRI, and eye-tracking biomarkers as predictors of SSRI response.

Multiple Pre-Treatment miRNAs Levels in Untreated Major Depressive Disorder Patients Predict Early Response to Antidepressants and Interact with Key Pathways.

Major depressive disorder (MDD) is a life-impairing disorder, and early successful treatment is important for a favorable prognosis. However, early response to antidepressants differs widely among individuals, and is difficult to predict pre-treatment. As miRNAs have been reported to play important roles in depression, identification of miRNAs associated with antidepressant treatment responses and their interacting genes and pathways will be beneficial in understanding the predictors and molecular mechanisms of depression treatment. This randomized control trial examined miRNAs correlated with the early therapeutic effect of selective serotonin reuptake inhibitors (SSRIs; paroxetine or sertraline) and mirtazapine monotherapy. Before medication, we comprehensively analyzed the miRNA expression of 92 depressed participants and identified genes and pathways interacting with miRNAs. A total of 228 miRNAs were significantly correlated with depressive symptoms improvements after 2 weeks of SSRIs treatment, with miR-483.5p showing the most robust correlation. These miRNAs are involved in 21 pathways, including TGF-β, glutamatergic synapse, long-term depression, and the mitogen-activated protein kinase (MAPK) signaling pathways. Using these miRNAs enabled us to predict SSRI response at week 2 with a 57% difference. This study shows that pre-treatment levels of miRNAs could be used to predict early responses to antidepressant administration, a knowledge of genes, and an identification of genes and pathways associated with the antidepressant response.

Impact of CYP2C19 metaboliser status on SSRI response: a retrospective study of 9,500 participants of the Australian Genetics of Depression Study

Impact of CYP2C19 metaboliser status on SSRI response: a retrospective study of 9,500 participants of the Australian Genetics of Depression Study

Applications of Precision Medicine in the Treatment of Psychiatric Disorders: A Literature Review

Background: Scientific understanding of precision medicine is rapidly evolving as new associations are made between genetic variants and tolerance to pharmaceuticals [1]. Although pharmacogenetic testing and guidelines exist for many medications, there is limited clinical application of these technologies in part due to limitations of the evidence supporting its use in psychiatric treatment as well as lack of awareness by providers and patients [2]. This narrative literature review aims to assess and summarize the past decade of research in the field of psychiatric pharmacogenetics. Specifically, it will focus on the relationship between antidepressant/antipsychotic drug responses and polymorphisms in nine commonly studied genes: CYP1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4, CYP3A5, SLC6A4, HTR2A, and DRD2. Methods: Literature from PubMed and Embase that was published between the years 2010 and 2020 was found using strategic keywords and search phrases. Each study represented was a randomized controlled trial or clinical trial tested in adults over the age of eighteen. Results: Of the six CYP450 enzymes that were evaluated, all displayed impacts on the metabolism of psychiatric drugs except CYP3A4, although only one polymorphism (*1B) was included in analysis of that particular gene. Inconclusive results were discovered regarding SLC6A4 5-HTTLPR polymorphisms and further review should be done to determine its relationship with SSRI response. Additionally, review of literature pertaining to DRD2 showed unsubstantial evidence, as four out of seven articles found no connection between treatment or adverse drug reactions (ADR) associated with DRD2. In contrast, influential findings were documented by literature concerning HTR2A polymorphisms and therapeutic consequences and the evidence collected on benefits of pharmacogenomic testing supports the implementation of testing to guide psychiatric treatment with confidence that use may result in fewer failed trials prior to response or remission. Conclusion: Many polymorphic mutations have a significant impact on individual responses to psychiatric treatment and implementation of pharmacogenomic testing in a clinic setting may be beneficial to psychiatric patients. Further review of polymorphic relationships should be done, especially in the case of SLC6A4 and DRD2 variations.

52.2 AN UPDATE ON GENE-MEDICATION INTERACTIONS RELEVANT TO PEDIATRIC PSYCHOPHARMACOTHERAPY

Pharmacogenetic studies of pediatric patients are scarce, but clinicians frequently obtain pharmacogenetic testing in children and adolescents. This presentation will review the influence of pharmacokinetic and pharmacodynamic genes on response to antidepressants in youth. A review of the evidence for key pharmacokinetic and pharmacodynamic genes that impact medication tolerability and response in youth will be provided. Specifically, recent studies from our group reporting how: 1) CYP2C19 influences sertraline and escitalopram tolerability; 2) pharmacodynamic genes encoding the serotonin transporter and receptor 2A, SLC6A4, and HTR2A, influence SSRI response; and 3) MTHFR and L-methylfolate do not influence response to antidepressants. Two large retrospective studies in pediatric patients with anxiety and/or depressive disorders reported how CYP2C19 influences response and tolerability to escitalopram (N = 248) and sertraline (N = 352). Another study in a similar population (N = 164) indicated that the response to fluoxetine was associated with SLC6A4 and HTR2A variants but not CYP2D6. One prospective study of patients with anxiety disorders (N = 26) demonstrated that CYP2C19, SLC6A4, and HTR2A were associated with escitalopram response trajectory. In a retrospective analysis of patients that had MTHFR genotyping (n = 292), 23% received L-methylfolate supplementation. Neither the MTHFR genotypes nor L-methylfolate supplementation influenced response to antidepressants. Pharmacogenes are associated with both response and tolerability in youth treated with antidepressants in retrospective studies. Child and adolescent psychiatrists should know the evidence behind these studies as they consider use of pharmacogenetic testing in their clinical practice.

Early changes of serum BDNF and SSRI response in adolescents with major depressive disorder

BackgroundRecent evidence suggests that brain-derived neurotrophic factor (BDNF) levels and their early changes may predict antidepressant response in adults with major depressive disorder (MDD). However, in adolescents, BDNF levels in depression and their changes during antidepressant treatment are relatively unknown. We aimed to investigate whether pre-treatment BDNF levels and their early changes predict antidepressant response in depressed adolescents. MethodsThe study included 83 MDD adolescents and 52 healthy controls aged 12 to 17 years. All depressed adolescents were treated with escitalopram in an 8 week, open-label trial. Depression severity and serum BDNF level at baseline, and weeks 2 and 8 were measured with the Children's Depression Rating Scale-Revised (CDRS-R) and ELISA, respectively. ResultsResponders showed a significant decrease in BDNF levels at week 2 but non-responders and healthy controls had no changes in BDNF levels at week 2. The early decrease (baseline – week 2) of BDNF levels predicted SSRI response with moderate sensitivity and specificity. Logistic regression analysis revealed that early BDNF decrease predicted SSRI response at week 8 after controlling for other demographic and clinical variables. LimitationsThe follow-up duration of the study was limited in 8 weeks. It remains possible that serum BDNF levels would have changed with longer treatment. ConclusionsThis is the first longitudinal study to investigate the effect of antidepressants on BDNF levels in adolescents with MDD. Our findings suggest that a decrease of serum BDNF levels in early phase of SSRI treatment may be associated later SSRI response in adolescents with MDD.

5.37 Early Changes of Serum Brain-Derived Neurotrophic Factor (BDNF) and SSRI Response in Youth With MDD: A Preliminary Analysis

5.37 Early Changes of Serum Brain-Derived Neurotrophic Factor (BDNF) and SSRI Response in Youth With MDD: A Preliminary Analysis

Using acute tryptophan depletion to investigate predictors of treatment response in adolescents with major depressive disorder: study protocol for a randomised controlled trial

BackgroundSelective serotonin reuptake inhibitors (SSRIs) are amongst the most prescribed antidepressants for adolescents with depressive symptoms and major depressive disorder. However, SSRIs have significant shortcomings as a first-line treatment considering that not all patients respond to these antidepressants. Amongst paediatric populations, meta-analyses indicate that up to approximately 40% of patients do not respond, and for those who do show benefit, there is substantial heterogeneity in response onset. The neurotransmitter serotonin (5-HT) plays a role in the clinical effectiveness and mechanisms of action of SSRIs. However, the exact and complete mechanism of action and reasons for the low response rate to SSRIs in some adolescent populations remains unknown.MethodsTo examine SSRI response and the role of 5-HT, this study will employ a randomised double-blind within subject, repeated measures design, recruiting adolescent patients with major depressive disorder. Participants will be subjected to acute tryptophan depletion (ATD) and the balanced control condition on two separate study days within a first study phase (Phase A), and the order in which these conditions (ATD/balanced control condition) occur will be random. This phase will be followed by Phase B, where participants will receive open label pharmacological treatment as usual with the SSRI fluoxetine and followed-up over a 12-week period.DiscussionATD is a neurodietary method typically used to investigate the impact of lowered brain 5-HT synthesis on mood and behaviour. The major hypothesis of this study is that ATD will be negatively associated with mood and cognitive functioning, therefore reflecting individual serotonergic sensitivity and related depressive symptoms. Additionally, we expect the aforementioned effects of ATD administration on mood to predict clinical improvement with regard to overall depressive symptomatology 12 weeks into SSRI treatment.Trial registrationAustralian and New Zealand Clinical Trials Registry (ANZCTR) ACTRN12616001561471. Registered on 11 November 2016.

F174. Higher Baseline Plasma Serotonin, and a Greater Decrease in Serotonin Over Treatment, is Associated With Better SSRI Response in MDD

F174. Higher Baseline Plasma Serotonin, and a Greater Decrease in Serotonin Over Treatment, is Associated With Better SSRI Response in MDD

944. Structural Connectivity Correlates of CBT and SSRI Response in a Transdiagnostic Sample: A Preliminary RDoC Study

944. Structural Connectivity Correlates of CBT and SSRI Response in a Transdiagnostic Sample: A Preliminary RDoC Study

TPH, SLC6A2, SLC6A3, DRD2 and DRD4 Polymorphisms and Neuroendocrine Factors Predict SSRIs Treatment Outcome in the Chinese Population with Major Depression.

This study was intended to determine whether antidepressant outcome to SSRIs was associated with catecholamine gene polymorphisms and neuroendocrine factors in patients of Chinese Han ethnicity with MDD. A total of 290 MDD patients were recruited and received a 6-week randomized double-blinded treatment. Cortisol, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), 3'-triiodothyronine (T3), thyroxine (T4), free triiodothyronine (fT3), and free thyroxine (fT4) levels were measured at the baseline. Allele, genotype, and haplotype frequencies of catecholamine genes were compared between responders and non-responders, remission and non-remission groups respectively. We found that genotype frequency of the rs1800544 polymorphism in the DRD4 gene was significantly different between responders and non-responders (P<0.05). Also the frequency of the rs1800544 CG genotype was significantly higher (P<0.05) in responders (51.4%) than that in non-responders (35.8%). No significant difference was found between responders and non-responders, remission and non-remission groups in the SNPs polymorphisms in the TPH, SLC6A2, SLC6A3, or DRD2 genes. The combination of all neuroendocrine factors, clinical characteristics and gene polymorphisms predicted 74.8% of the variation in SSRI response and 65.5% in SSRI remission. Polymorphisms of the DRD4 gene were associated with SSRI response in Chinese Han MDD patients. A combination of clinical characteristics, neuroendocrine factors, and gene polymorphisms might be able to predict the outcome to SSRIs.

Brain-derived neurotrophic factor Val66Met polymorphism association with antidepressant efficacy: a systematic review and meta-analysis.

Previous studies of the association of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with antidepressant efficacy are inconsistent. Thus, we conducted a systematic review and meta-analysis. We searched MEDLINE, PubMed, EMBASE, and Chinese Databases (Biomedical Literature Database, National Knowledge Infrastructure, Weipu, and WanFang) up to March 2013 for relevant studies (584 retrieved, 16 met inclusion criteria). We conducted six comparisons for both response and remission rates for three genotypes in Caucasians and Asians (4 weeks or ≥6 weeks; selective serotonin reuptake inhibitors [SSRIs], serotonin-noradrenaline reuptake inhibitors, or mixed antidepressants). Met carriers had a better response rate than Val/Val. In Asians, the Met carrier was positively associated with response rate (odds ratio; 95% confidence interval: 1.48; 1.02-2.14) in the SSRI group (1.81; 1.10-2.97) and with treatments ≥6 weeks. Met/Val showed a positive association with the response rate versus homozygotes (1.60; 1.20-2.13) and for ≥6 weeks (mixed antidepressant, 1.36; 1.04-1.77; SSRI, 1.55; 1.11-2.17). There was a weak effect of Met/Val versus Val/Val in response to SSRIs (mixed time, 2.07; 1.48-2.89; ≥6 weeks, 2.25; 1.53-3.32). For remission, Met/Val was better than the homozygotes (1.71; 1.09-2.68, Asians, SSRIs only). Our meta-analysis confirms the effects of the BDNF polymorphism on SSRI response in Asians. This effect may be dependent on ethnic origin because BDNF had a lesser influence on response in mixed race studies. Antidepressants were more effective in groups with a treatment duration ≥6 weeks. Thus, future investigators should carefully consider their outcome observation end point.

Influence of RGS2 on Sertraline Treatment for Social Anxiety Disorder

Only a minority of patients with social anxiety disorder (SAD) has a robust therapeutic response to evidence-based serotonin reuptake inhibitor (SSRI) treatment. To help improve the personalized medicine approach to psychiatric care, we evaluated several candidate genetic predictors of SSRI response in SAD. At the start of a randomized controlled trial (NCT00282828), 346 patients with SAD at three sites received protocol-driven, open-label treatment with sertraline, up to 200. mg/d over 10 weeks. Efficacy was determined using a continuous measure of outcome (Liebowitz Social Anxiety Scale (LSAS)) and dichotomous indicators of response (LSAS ≤ 50) and remission (LSAS ≤ 30). Predictors of efficacy were examined in multivariate regression models that included eight polymorphic variants in four candidate genes (four in RGS2, two in HTR2A, one in SLC6A2, and one in SLC6A4). Adjusting for genetic ancestral cluster and non-genetic predictors of response, all four single-nucleotide polymorphisms (SNPs) in RGS2 predicted change in LSAS over time, at study-wise significance (p=0.00833), with the minor allele associated with less improvement over time. After adjusting for genetic ancestral cluster and non-genetic predictors of remission, two of the four RGS2 SNPs predicted likelihood of remission at or just below study-wise significance (p=0.025): rs4606 (AOR=0.49 (95% CI=0.27-0.90), p=0.022) and rs1819741 (AOR=0.50 (95% CI=0.28-0.92), p=0.027). Variation in RGS2, a gene previously shown to be associated with social anxiety phenotypes and serotonergic neurotransmission, may be a biomarker of the likelihood of substantially benefiting from sertraline among patients with SAD.

Head movement: A novel serotonin-sensitive behavioral endpoint for tail suspension test analysis

The tail suspension test (TST) as an antidepressant and depression-related behavior screen, has many advantages over the forced swim test (FST) in terms of procedural simplicity and consistent SSRI response. However, the FST has traditionally offered more specific neuromodulatory information by differentiating between serotonin (5-HT) and norepinephrine sensitive behavior categories. Head movement is a newly characterized behavior endpoint in the FST and TST with a selective 5-HT sensitivity. In this investigation, we show that the baseline and drug response profile of head movement previously found in the 129S6 strain of mice (Lockridge et al., 2010) is reproducible in the C57 strain. Head movement is inversely correlated to FST swimming and elevated in the TST by SSRI administration. The use of a weighted bin sample analysis method differentiates TST behaviors into fluoxetine-responsive head movement and desipramine-responsive struggling. The use of 5-HT subtype receptor agonists, after depleting endogenous 5-HT with pCPA, shows the head movement suppressing effect of 5-HT2A and 5-HT2C postsynaptic receptor activation. 5-HT1A and 5-HT1B agonists were ineffective. We propose that a head movement focused analysis can add sensitive and reliable 5-HT detection capability to mouse TST testing with minimal effort but significant reward.

Saliva levels of 3‐methoxy‐4‐hydroxyphenylglycol and clinical efficacy of mirtazapine or selective serotonin reuptake inhibitors in patients with major depression

This study compared saliva levels of 3-methoxy-4-hydroxyphenylglycol (sMHPG) in patients with major depressive disorder (MDD) to levels in healthy controls and explored whether sMHPG levels in patients with MDD were a predictive marker for antidepressant efficacy. sMHPG levels were compared in 53 patients with MDD and 275 age-matched healthy controls. Patients' depressive symptoms were assessed by the 17-item Hamilton Rating Scale for Depression at baseline and 4 weeks after treatment with selective serotonin reuptake inhibitors (SSRIs, n = 23) or mirtazapine (n = 30), followed by saliva sampling. The mirtazapine group included nine patients who had been treated with an SSRI for more than 4 weeks without any improvement. sMHPG levels were measured by gas chromatography-mass spectrometry. sMHPG levels in MDD patients were significantly higher than in controls. The responder rate to drug treatment at 4 weeks was 62% for mirtazapine (13/21), 57% for SSRIs (13/23), and 89% (8/9) for SSRI plus mirtazapine. sMHPG at baseline in 13 responders treated with SSRIs, but not mirtazapine, was significantly higher than that in non-responder group and showed consequent reduction 4 weeks after treatment. The area under the receiver operating characteristic (ROC) curves of sMHPG for discrimination of SSRI responders and non-responders was 0.86 ± 0.10 (95% confidence interval: 0.64-1.0, p = 0.005). In contrast, the ROC curve of sMHPG levels for discrimination of mirtazapine responders and non-responders was not significant. Adjunctive treatment with mirtazapine to SSRI non-responders was effective, regardless of baseline sMHPG levels. sMHPG in patients with MDD was higher than in healthy controls. High baseline sMHPG levels in patients with MDD maybe a predictive marker for SSRI response.

P-706 - Major depressive disorder is influenced by a genetic interaction of VEGF and TNF alpha

Altered serum levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor alpha (TNFalpha) have been implicated in therapy response of depression. We analyzed effects of 4 functional SNPs of VEGF and TNF alpha genes on MDD to test their possible role in pathomechanism of MDD.We recruited 293 inpatients diagnosed for major depressive disorder (MDD) and 443 healthy volunteers. MDD was diagnosed by DSM-IV criteria and measured by Montgomery-Asberg Depression Scale (MADRS). DNA was extracted from buccal mucosa samples given by all participants. Likelihood ratio tests for case-control and mutlivariate linear analysis for quantitative phenotype models were performed in SPSS 17.0 software. We identified a protective allele against MDD as the frequency of G allele of rs1800629 (previously associated with lower TNFa serum level) was 2.7 fold higher in the control group compared to MDD group (LRT = 4.197; p = 0.040). Higher frequency of the same allele was found among SSRI responders compared to non-responders (LRT = 6.281; p = 0.012). Significant GxG interactions were shown within MDD group: epistatic effect of allele variants and also genotypes of the four investigated SNPs were significant on MADRS score (for risk alleles: p modell = 0.024; p interaction = 0.005; Adj.R 2 = 0.259; for genotypes: p modell = 0.035; p interaction = 0.007; Adj.R 2 = 0.371). These findings suggest that TNFalpha and VEGF genes are associated with MDD and SSRI response. Our results support the molecular crosstalk between VEGF and TNFalpha pathway by a genetic interaction.This study was supported by the Hungarian Scientific Research Fund Grant (OTKA CK 80289/2009).

The Serotonin Transporter Promoter Polymorphism (5-HTTLPR) Affects the Relation between Antidepressant Serum Concentrations and Effectiveness in Major Depression

Both the serotonin transporter promotor polymorphism (5-HTTLPR) and serum concentrations of SSRIs have been shown to affect response to SSRIs. Results, however, are inconsistent. The aim of this study was to investigate whether remission or response to SSRIs is influenced by an interaction of 5-HTTLPR and SSRI serum concentrations. 49 patients with major depression and SSRI treatment were genotyped for the 5-HTTLPR locus including the rs25531. Drug serum concentrations and depression severity were measured weekly. Logistic regression analysis revealed a significant association between 5-HTTLPR, SSRI serum concentrations and response to treatment. A favourable treatment outcome correlated with SSRI serum concentration in 5-HTTLPR-L(A) allele carriers (r² = 34.3 %; p = 0.001), but not in S/L(G)-allele carriers (p = 0.31). In the group of L(A) allele carriers, those MDD patients with a high antidepressant serum concentrations responded better to treatment than patients with a low serum concentration. We conclude that the 5-HTTLPR might affect reponse to SRRI subject to serum concentrations. If replicated this might be a starting point for prospective clinical trials.

Serum BDNF levels before treatment predict SSRI response in depression

The "neurotrophin hypothesis" of depression posits a role of brain-derived neurotrophic factor (BDNF) in depression, although it is unknown whether BDNF is more involved in the etiology of depression or in the mechanism of action of antidepressants. It is also unknown whether pre-treatment serum BDNF levels predict antidepressant response. Thirty un-medicated depressed subjects were treated with escitalopram (N=16) or sertraline (N=14) for 8 weeks. Twenty-five of the depressed subjects completed 8 weeks of antidepressant treatment and had analyzable data. Twenty-eight healthy controls were also studied. Serum for BDNF assay was obtained at baseline in all subjects and after 8 weeks of treatment in the depressed subjects. Depression ratings were obtained at baseline and after 8 weeks of treatment in the depressed subjects. Pre-treatment BDNF levels were lower in the depressed subjects than the controls (p=0.001) but were not significantly correlated with pre-treatment depression severity. Depression ratings improved with SSRI treatment (p<0.001), and BDNF levels increased with treatment (p=0.005). Changes in BDNF levels were not significantly correlated with changes in depression ratings. However, pre-treatment BDNF levels were directly correlated with antidepressant responses (p<0.01), and "Responders" to treatment (≥ 50% improvement in depression ratings) had higher pre-treatment BDNF levels than did "Non-responders" (p<0.05). These results confirm low serum BDNF levels in un-medicated depressed subjects and confirm antidepressant-induced increases in BDNF levels, but they suggest that antidepressants do not work simply by correcting BDNF insufficiency. Rather, these findings are consistent with a permissive or facilitatory role of BDNF in the mechanism of action of antidepressants.