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Previous studies suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly depression in patients with documented insulin resistance or those who are resistant to standard psychopharmacological approaches. This study aimed to assess the effects on depressive symptoms with adjuvant treatment with the PPARγ-agonist pioglitazone. Patients ( N =37) with non-psychotic, non-remitting depression receiving standard psychiatric regimens for depression were randomized across an insulin sensitivity spectrum in a 12-week double blind, randomized controlled trial of pioglitazone or placebo. Improvement in depression was associated with improvement in glucose metabolism but only in patients with insulin resistance. An age effect was also shown in that response to pioglitazone was more beneficial in younger aged patients. Study findings suggest differential improvement in depression severity according to both glucose metabolic status and level of depression at baseline. A greater understanding of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction. [ABSTRACT FROM AUTHOR]

Antidepressant response, the effectiveness of antidepressants in relieving symptoms of depression, is a complex trait influenced by both genetic and environmental factors. However, despite decades of research, the specific genetic variations that contribute to antidepressant response and treatment-resistant depression (TRD) remain largely unknown. In this review, we summarize the current state of knowledge of the genetics of antidepressant response and TRD, including candidate gene association studies, genome-wide association studies (GWAS), polygenic risk score (PRS) analyses, whole genome sequencing studies, research on other genetic and epigenetic changes, and the potential for precision medicine in this field. Although some progress has been made in identifying genetic factors associated with antidepressant response and TRD, much work remains to be done, particularly in terms of larger sample sizes and standardization of outcome measures. Further research in this area has the potential to improve the treatment of depression and increase the chances of successful treatment for individuals with this common and debilitating mental illness., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background & objectives: Genetic factors have potential of predicting response to antidepressants in patients with major depressive disorder (MDD). In this study, an attempt was made to find an association between response to escitalopram in patients with MDD, and serotonin transporter (SLC6A4) and receptor (5HTR1A, 5HTR2A) polymorphisms. Methods: Fifty five patients diagnosed as suffering from MDD, were selected for the study. The patients were treated with escitalopram over a period of 6-8 wk. Severity of depression, response to treatment and side effects were assessed using standardised instruments. Genetic variations from HTR1A (rs6295), HTR2A (rs6311 andrs6313) and SLC6A4 (44 base-pair insertion/deletion at 5-HTTLPR) were genotyped. The genetic data of the responders and non-responders were compared to assess the role of genetic variants in therapeutic outcome. Results: Thirty six (65.5%) patients responded to treatment, and 19 (34.5%) had complete remission. No association was observed for genotype and allelic frequencies of single nucleotide polymorphisms (SNPs) among remitter/non-remitter and responder/non-responder groups, and six most common side-effects, except memory loss which was significantly associated with rs6311 (P=0.03). Interpretation & conclusions: No significant association was found between the SNPs analysed and response to escitalopram in patients with MDD though a significant association was seen between the side effect of memory loss and rs6311. Studies with larger sample are required to find out genetic basis of antidepressant response in Indian patients. [ABSTRACT FROM AUTHOR]

Background: Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). This study aimed to examine whether the pretreatment of SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with treatment outcomes to SERT-targeted antidepressants. Methods: We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. All the patients with MDD had HDRS scores of 18 or more. Results: Pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3. Nonresponders and dropout patients showed a proportionate reduction in SERT binding in the terminal projection regions and midbrain compared to healthy controls. In contrast, a disproportionate reduction in SERT binding in the terminal projection regions relative to midbrain was observed in responders. Conclusions: The results of this study suggested that a disproportionate reduction in SERT binding between terminal projection regions and midbrain may predict better treatment outcomes in patients with MDD. [ABSTRACT FROM AUTHOR]

We propose an extensive review of the literature about BDNF/TRKB/P75NTR polymorphisms and their consequences on antidepressant efficacy in depressed patients. Five genome-wide association studies and 30 association studies were included. Twenty seven studies focused on the Val66Met polymorphism (rs6265), the Met allele being associated with a higher antidepressant efficacy only in Asian patients. Other BDNF/TRKB/P75NTR polymorphisms ( BDNF: rs7103411, rs7124442, rs908867, rs2049046, rs61888800, rs10501087, rs1491850; TRKB: rs10868223, rs11140778, rs1565445, rs1659412; P75NTR: rs2072446) were reported to be associated with antidepressant efficacy but these results were not replicated. Finally, there are 15 positive studies among 30 studies regarding BDNF/TRKB/P75NTR polymorphisms. The only SNP which benefits of at least three positive studies is the BDNF Val66Met polymorphism (rs6265). Consequently, with a lack of good and consistent studies, the clinical utility of BDNF in treatment selection is far from clear. We propose several recommendations for further studies. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) presents neuropsychological alterations which improve after the treatment, but it might be mediated by clinical variables. Our goal is to study whether the speed of remission of MDD bears any relation to the improvement of the patients׳ cognitive functioning after a successful treatment. We carried out clinical and neuropsychological assessments of 51 patients with MDD. After these procedures they underwent a 24-week treatment with fluoxetine, and were assessed again with the same battery used prior to treatment. They were arranged into three groups according to how rapid their symptoms remitted. The patients with a rapid remission presented improvements in working memory, speed of information processing, and some executive functions, unlike the other groups. Rapid remitters also improved in episodic memory and executive functions more than the other patients. [ABSTRACT FROM AUTHOR]

Background This study seeks to provide a comprehensive and systematic evaluation of baseline clinical and psychological features and treatment response characteristics that differentiate Major Depressive Disorder (MDD) outpatients with and without melancholic features. Reflecting the emphasis in DSM-5, we also include impairment and distress. Methods Participants were assessed pre-treatment on clinical features (severity, risk factors, comorbid conditions, illness course), psychological profile (personality, emotion regulation), functional capacity (social and occupational function, quality of life) and distress/coping (negativity bias, emotional resilience, social skills, satisfaction with life). Participants were randomized to sertraline, escitalopram or venlafaxine extended-release and re-assessed post-treatment at 8 weeks regarding remission, response, and change in impairment and distress. Results Patients with melancholic features ( n =339; 33.7%) were distinguished clinically from non-melancholics by more severe depressive symptoms and greater exposure to abuse in childhood. Psychologically, melancholic patients were defined by introversion, and a greater use of suppression to regulate negative emotion. Melancholics also had poorer capacity for social and occupational function, and physical and psychological quality of life, along with poorer coping, reflected in less emotional resilience and capacity for social skills. Post-treatment, melancholic patients had lower remission and response, but some of this effect was due to the more severe symptoms pre-treatment. The distress/coping outcome measure of capacity for social skills remained significantly lower for melancholic participants. Limitations Due to the cross-sectional nature of this study, causal pathways cannot be concluded. Conclusions Findings provide new insights into a melancholic profile of reduced ability to function interpersonally or effectively deal with one׳s emotions. This distinctly poorer capacity for social skills remained post-treatment. The pre-treatment profile may account for some of the difficulty in achieving remission or response with treatment. [ABSTRACT FROM AUTHOR]

The cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of most antidepressants. Comedication with a potent CYP2D6 inhibitor can convert patients with extensive metabolizer (EM) or ultra-rapid metabolizer (UM) genotypes into poor metabolizer (PM) phenotypes. Since comedication is frequent in depressed patients treated with antidepressants, we investigated the effect of the CYP2D6 composite phenotype on antidepressant efficacy, taking into account both the CYP2D6 genotype and comedication with CYP2D6 inhibitors. 87 Caucasian in patients with a major depressive episode were prospectively treated with flexible doses of antidepressant monotherapy as well as comedications and genotyped for the major CYP2D6 alleles ( CYP2D6*3 rs35742686, *4 rs3892097, *5 del, *6 rs5030655, and *2xN). They were classified for CYP2D6 composite phenotype and assessed for antidepressant response after 4 weeks. In terms of genotypes (g), 6 subjects were UMg, 6 PMg, and 75 EMg. Ten patients were coprescribed a CYP2D6 inhibitor, resulting in the following composite phenotypes (cp): 5 UMcp, 16 PMcp, and 66 EMcp. Whereas none of the CYP2D6 genotypes were significantly associated with antidepressant response, UMcp had a lower antidepressant response than PMcp or EMcp (respectively: 39.0 ± 17.9, 50.0 ± 26.0, and 61.6 ± 23.4, p = 0.02). Despite small sample size, this study suggests that a CYP2D6 composite phenotype, taking into account both genotype and comedications with CYP2D6 inhibitors, could predict CYP2D6 substrate antidepressants response. Thus, to optimize antidepressant response, CYP2D6 genotype could be performed and comedications with CYP2D6 inhibitors should be avoided, when prescribing CYP2D6 substrate antidepressants. [ABSTRACT FROM AUTHOR]

Background Subcallosal cingulate white matter (SCC) deep brain stimulation (DBS) is an evolving investigational treatment for depression. Mechanisms of action are hypothesized to involve modulation of activity within a structurally defined network of brain regions involved in mood regulation. Diffusion tensor imaging was used to model white matter connections within this network to identify those critical for successful antidepressant response. Methods Preoperative high-resolution magnetic resonance imaging data, including diffusion tensor imaging, were acquired in 16 patients with treatment-resistant depression, who then received SCC DBS. Computerized tomography was used postoperatively to locate DBS contacts. The activation volume around the contacts used for chronic stimulation was modeled for each patient retrospectively. Probabilistic tractography was used to delineate the white matter tracts traveling through each activation volume. Patient-specific tract maps were calculated using whole-brain analysis. Clinical evaluations of therapeutic outcome from SCC DBS were defined at 6 months and 2 years. Results Whole-brain activation volume tractography demonstrated that all DBS responders at 6 months ( n = 6) and 2 years ( n = 12) shared bilateral pathways from their activation volumes to 1) medial frontal cortex via forceps minor and uncinate fasciculus; 2) rostral and dorsal cingulate cortex via the cingulum bundle; and 3) subcortical nuclei. Nonresponders did not consistently show these connections. Specific anatomical coordinates of the active contacts did not discriminate responders from nonresponders. Conclusions Patient-specific activation volume tractography modeling may identify critical tracts that mediate SCC DBS antidepressant response. This suggests a novel method for patient-specific target and stimulation parameter selection. [ABSTRACT FROM AUTHOR]

Abstract: Background: In several previous biochemical and genetic studies, the Val158Met polymorphism of the gene encoding catechol-O-methyltransferase (COMT) and the C677T polymorphism of Methylenetetrahydrofolate reductase (MTHFR) have been suggested to be involved in the pathogenesis as well as the treatment response of major depressive disorder (MDD), but the results have been inconsistent. In this study, we investigate the association of COMT/MTHFR and their interactions with MDD and antidepressant response in Chinese Han population. Methods: Three hundred and sixty eight depressed patients who met DSM-IV criteria for MDD were recruited for the study. Two hundred and nineteen normal controls were recruited from the local community. Patients and normal controls were genotyped for the functional COMT val158met and MTHFR C677T polymorphisms. Patients were characterized for clinical response to antidepressant treatment as measured by intra-individual changes of Hamilton Depression (HAMD-17) scores over 6 weeks. Results: The T allele (OR=1.81; CI95%=1.40–2.34, P<0.001) and C/T genotype (OR=3.66; CI95% =2.53–5.28, P<0.001) of MTHFR C677T were significantly different between case and control groups. The COMT Met/Val genotype was more common among depressed individuals than among controls (OR=1.52, CI95%=1.04–2.21, P=0.02). Limitation: There is disequilibrium in age and sex between case and control groups. Though we control the two variables in the statistic analysis, to be more accurate, we need to increase sample size in further study. Conclusion: Individuals with the genotype COMT Met/Val and MTHFR C/T have more probability of suffering from MDD. However, there is no association between gene polymorphism and treatment response. [Copyright &y& Elsevier]

Background. Genomewide association studies (GWASs) on antidepressant efficacy have yielded modest results. A possible reason is that response is influenced by other factors, which possibly interact with genetic variation. We used a GWAS model to predict antidepressant response, by including predictors previously known to affect response, such as quality of life (QoL). We also evaluated the association between genes, previously implicated in gene-environment (G " E) interactions, and response using an enrichment analysis. Method. We examined a sample of 1426 depressed patients from the Sequenced Treatment Alternatives to Relieve Depression (STAR"D) trial: 774 responders, 652 non-responders and 418865 single nucleotide polymorphisms (SNPs) were analysed. First, in a GWAS model, we investigated whether genetic variations interact with patients' levels of QoL to predict response, after controlling for demographic characteristics, severity and population stratification. Second, we conducted an enrichment analysis exploring whether candidate genes that have emerged from prior G x E interaction studies on depression are associated with treatment response. Results. The GWAS model, with QoL as a moderator, yielded one SNP (rs520210) associated with response in the NEDD4L gene (p=3.64x10-8). In the Caucasian sample only, we observed a drop in significance for this SNP. The enrichment analysis showed that SNPs within serotonergic genes contained more significant markers that predicted response, compared with a random set of genes in the genome. Conclusions. Our findings point to possible target genes, which are proposed for further independent replication. Our enrichment analysis provides further support, in a genomewide context, of the role of serotonergic genes in influencing antidepressant response. [ABSTRACT FROM AUTHOR]

Aims To investigate the role of genetic polymorphisms in candidate genes associated with the HPA axis and their interactions with environmental stressors in antidepressant response. Methods The remission of depressive symptoms after 8 weeks of antidepressant treatment was tested against 21 single nucleotide polymorphisms ( SNPs) in five candidate genes associated with the HPA axis in a Chinese Han sample suffering from unipolar depression (n = 273). Any history of childhood trauma and recent negative life events were measured using the Childhood Trauma Questionnaire-Short Form ( CTQ- SF) (n = 206) and the Life Event Scale (48 item, LES) (n = 207), respectively. Reporter gene assays were used to evaluate the possible effects of the most significant SNP on gene expression. Results A functional polymorphism at 3′ UTR of the corticotropin-releasing hormone receptor 1 ( CRHR1) gene (rs28364032) and three haplotypes containing it showed significant relationships with antidepressant remission. Further laboratory-based genomic studies showed that the G-to-A change of rs28364032 resulted in a 10-12% decrease in the intensity of luciferase activity. However, we failed to find association of environments and their interaction with HPA system-related genes with antidepressant remission. Conclusions Our results support a definite role for CRHR1 in the pharmacogenetics of antidepressant drugs. This may contribute to interpatient differences in their responses to antidepressant drugs. [ABSTRACT FROM AUTHOR]

Abstract: Background: The aim of this study was to investigate the presence of a relationship between affective temperament and antidepressant treatment response in mood disorder patients. Methods: The lifetime history of antidepressant response of 90 bipolar disorder patients and 88 major depressive disorder patients were retrospectively evaluated and then assigned to one of four subgroups: complete response (CR), partial response (PR), no response (NR), and antidepressant associated mania response (AAMR). Using TEMPS-Rio de Janeiro – the brief Brazilian version of TEMPS-A – we compared affective temperament subscale scores across these groups. Results: We observed a statistically significant relationship between depressive and anxious affective temperaments and no antidepressant response. In bipolar disorder patients, cyclothymic temperament (p<0.01) and hyperthymic temperament (p<0.05) were associated with antidepressant-associated mania. Hyperthymic temperament was associated with complete antidepressant responses in major depressive disorder patients. Limitations: The evaluation of antidepressant response was retrospective. Conclusions: Our data are consistent with the theory that affective temperament traits are factors that can influence the antidepressant response and the recovery from depressive episodes, but more longitudinal studies are needed to confirm this theory and our findings. [Copyright &y& Elsevier]

Highlights: [•] CRF and CRF system play a major role in the regulation of the stress response. [•] Clinical development of CRFR1 antagonists as antipressant has not been rewarded by clinical efficacy so far but is still being explored. [•] The accumulated genetic findings, mostly those related to variants within CRFR1, point to a role of the CRF system in the pathophysiology of depression and anxiety. [ABSTRACT FROM AUTHOR]

Abstract: Background: The prediction of remission in pharmacologically-treated MDD patients has been scarcely studied. The goal of our work is to study the possible effect of clinical variables, neuropsychological performance, and the 5HTTLPR, the rs25531 of the SLC6A4 gene, and the val108/58Met of the COMT gene polymorphisms on the prediction of the speed of remission in MDD patients. Methods: Seventy-two depressed patients were genotyped according to the aforementioned polymorphisms and were clinically and neuropsychologically assessed before a 12-week fluoxetine treatment. Results: From this original sample 51 patients were considered as remitters at the end of week 12. Thirteen out of those showed a rapid response pattern, 24 showed an oscillating response pattern, and 14 showed a slow response pattern. The following variable combination is capable of showing a statistically significant relationship with the pattern of remission of patients with MDD: initial Hamilton score, age at first depressive episode, AG and GG alleles of the val108/58Met COMT polymorphism, Stroop PC, and SWM Strategy. Limitations: We have a slightly small sample size, which came to prominence during the data analysis since we were working with 3 subgroups. In this study, the placebo effect has not been controlled. Discussion: Our data suggest that the patients with MDD who remit after a 12-week treatment with fluoxetine show one of the following time-course patterns: a rapid symptomatic improvement, or a slow or oscillating pattern of remission. A combination of clinical, neuropsychological, and genetic variables allows us to predict these response patterns. [Copyright &y& Elsevier]

Objective Whether responses to antidepressants differ in bipolar and unipolar depression remains unresolved. Method We analyzed patient characteristics and outcomes of antidepressant treatment of 1036 depressed patients with bipolar- I or bipolar- II disorder, or unipolar major depression, using bivariate and multivariate methods and survival analysis, testing the hypothesis that responses would be superior in unipolar depression. Results Antidepressants were given to 84.8% (878/1036) of depressed patients: 58.9% of 93 bipolar-I, 80.1% of 117 bipolar- II, and 91.3% of 668 unipolar disorder cases. The 158 not given antidepressants had more manias/year, spent more months in mania and depression, and were far more likely to receive mood stabilizers or antipsychotics long term. Improvement of HDRS21 depression ratings ranked: bipolar- II (69.6%) > bipolar-I (62.9%) > unipolar (57.9%; P < 0.0001), independent of initial illness severity. Responder rates (≥50% improved without switching) ranked: bipolar- II (77.0%) > bipolar-I (71.6%) > unipolar (61.7%; P < 0.0001). Remission rates (final HDRS < 7) ranked: 54.0%, 50.6%, and 40.8% respectively ( P = 0.02); 67.5% remitted within 12 weeks of treatment. Survival-computed median time to remission (15.0 weeks, overall) was shortest for bipolar- II patients (10.7 weeks). The 3-month risk of switching into mania-hypomania ranked: bipolar- II (15.8%) > bipolar-I (8.60%) > unipolar (0.56%). Multivariate modeling found bipolar diagnosis, shorter latency to remission, more recent trial year, and fewer weeks depressed before treatment to be associated with greater percent improvement of HDRS ratings. Conclusion Selective use of antidepressants with or without mood stabilizers in non-agitated, depressed bipolar disorder patients for short periods was effective with moderate risk of potentially dangerous, manic mood elevation. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is responsible for an increasing individual and global health burden. Extensive research on the genetic disposition to develop MDD and to predict the response to antidepressant treatment has yet failed to identify strong genetic effects. The concept of gene x environment interaction takes into account that environmental factors have been identified as important components in the development of MDD and combines both, genetic predisposition and environmental exposure, to elucidate complex traits such as MDD. Here, we review the current research on gene x environment interactions with regard to the develop-ment of MDD as well as response to antidepressant treatment. We hypothesize that gene x environment inter-actions delineate specific biological subtypes of depression and that individuals with such pathophysiological distinct types of depression will likely respond to different treatments. The elucidation of gene x environment interactions may thus not only help to understand the pathophysiology of MDD but could also provide markers for a personalized antidepressant therapy. [ABSTRACT FROM AUTHOR]

Abstract: Currently electroconvulsive therapy (ECT) is one of the only available therapies for treatment resistant depression (TRD). While effective, ECT is complicated by side effects, including cognitive impairment. One promising potential alternative is magnetic seizure therapy (MST). To date, no research has explored the effects of 100Hz MST on brain activity or the brain changes associated with response to treatment. Therefore the aim of this study was to determine the effects of a treatment course of 100Hz MST on regional brain glucose metabolism. Ten patients with treatment resistant depression underwent positron emission tomography with fluorodeoxyglucose before and after a treatment course of MST. Changes in the relative metabolic rate of a priori brain regions were investigated. Areas of increased relative metabolism after treatment were seen in the basal ganglia, orbitofrontal cortex, medial frontal cortex and dorsolateral prefrontal cortex. A secondary analysis showed trend-level differential findings in brain activation between responders and non-responders, namely in the ventral anterior cingulate. These results primarily indicate that MST is affecting regions consistent with the limbic-cortical dysregulation model of depression. Exploratory analysis indicated some differential findings in brain activation between responders and non-responders were also evident; however, the small sample size precludes any firm conclusions. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Objective. To summarize current concepts on neuroendocrine and genetic principles underlying stress-related depression and to discuss the challenges of personalized treatment in depression. Methods. Review of the literature pertaining to genetic and neuroendocrine basis of stress-related depression including aspects of treatment response with a focus on the hypothalamus-pituitary-adrenal (HPA) axis. Results. There is increasing evidence that genetic polymorphisms and dysregulation of the HPA axis are associated with the pathophysiology of stress-related depression. Individual stress hormone reactivity seems to be determined by a combination of genetic and environmental factors, contributing to both, resilience or vulnerability. Conclusions. Although substantial progress has been made, current knowledge is still limited. Further basic and clinical research is needed to identify specific subgroups and to minimize heterogeneity of the depression phenotype. A better characterization is essential to detect genetic and functional predictors of antidepressant treatment response to follow the vision of personalized therapy in psychiatry. [ABSTRACT FROM AUTHOR]

Objective The aim of our work is to study the possible role of clinical variables, neuropsychological performance, and the 5HTTLPR, rs25531, and val108/58Met COMT polymorphisms on the prediction of depression remission after 12 weeks' treatment with fluoxetine. These variables have been studied as potential predictors of depression remission, but they present poor prognostic sensitivity and specificity by themselves. Methods Seventy-two depressed patients were genotyped according to the aforementioned polymorphisms and were clinically and neuropsychologically assessed before a 12-week fluxetine treatment. Results Only the La allele of rs25531 polymorphism and the GG and AA forms of the val 108/158 Met polymorphism predict major depressive disorder remission after 12 weeks' treatment with fluoxetine. None of the clinical and neuropsychological variables studied predicted remission. Conclusions Our results suggest that clinical and neuropsychological variables can initially predict early response to fluoxetine and mask the predictive role of genetic variables; but in remission, where clinical and neuropsychological symptoms associated with depression tend to disappear thanks to the treatment administered, the polymorphisms studied are the only variables in our model capable of predicting remission. However, placebo effects that are difficult to control require cautious interpretation of the results. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Two opposing models for the action of ghrelin in the behavioral responses to stress were recently proposed. Some studies suggest that an increase in ghrelin contributes to the mechanisms responsible for the development of stress-induced depression and anxiety, while others suggest that it helps minimize what otherwise would be more severe manifestations of depression and anxiety following stress. Methods: We measured serum ghrelin levels, Profile of Mood States (POMS) scores and State-Trait Anxiety Inventory scores in nonresponders (treatment-resistant patients; 30) and responders (38) with major depressive disorder (MDD), nonresponders (29) and responders (51) with panic disorder and 97 healthy controls. Results: The ghrelin concentration in nonresponders with MDD was higher than that of responders with MDD and normal controls. The ghrelin concentration in nonresponders with panic disorder was higher than that of normal controls. POMS vigor scores in patients with MDD and panic disorder were significantly decreased compared with those in healthy controls. Other POMS scores in patients with MDD and panic disorder were significantly increased compared with those of healthy controls. Trait and state anxiety of the State-Trait Anxiety Inventory in MDD and panic disorder patients were higher than those in healthy controls. Conclusions: These results indicate that decreased serum ghrelin levels might be associated with antidepressant treatment to confer the maximum therapeutic effect in patients with MDD and panic disorder. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Response to antidepressants is interindividually variable. It has been suggested that this variability is a direct consequence of etiological heterogeneity. Therefore, the same genes, environments, and gene-environment interactions implicated in different etiological pathways to depression may also predict response to treatment. This article reviews the evidence relevant to this hypothesis by first outlining the roles of genes, environments, and gene-environment interplay in the etiology of depression, and then considering the same factors in treatment response. Environmental exposures, such as childhood maltreatment, are potent predictors of both depression and treatment response. Although alone genetic factors have failed to consistently predict either phenotype, several polymorphisms have been shown to moderate the effects of environmental adversity on the development of depression and treatment response. These findings suggest that the dissection of etiological pathways to depression may provide the key to understanding and predicting response to antidepressants. [ABSTRACT FROM AUTHOR]

Basal serum thyroid-stimulating hormone (TSH) levels may predict antidepressant efficacy in patients with major depressive episodes (MDE), but data are inconsistent. As the SS genotype of the 5-HTTLPR polymorphism has been associated with a lower antidepressant efficacy in women with MDE, we aimed at assessing the relationship between normal basal TSH, 5-HTTLPR, and antidepressant efficacy in women. A total of 71 women and 28 men, with normal baseline TSH serum levels, hospitalized for a MDE, were assessed for 5-HTTLPR genotypes and prospectively followed for short-term antidepressant efficacy. Women with SS genotype had higher TSH levels (P=0.002) and a worse antidepressant response (P=0.046) than the women with LL/LS genotype, whereas no significant difference was shown in men. In multivariate analyses, antidepressant response in women was explained by TSH and 5-HTTLPR, but not by other variables. Further research is needed to understand the underlying mechanism explaining interactions between sex, TSH, and serotonergic function. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Major depressive disorder (MDD) is treated with antidepressants, but only between 50% and 70% of the patients respond to the initial treatment. Several authors suggested different factors that could predict antidepressant response, including clinical, psychophysiological, neuropsychological, neuroimaging, and genetic variables. However, these different predictors present poor prognostic sensitivity and specificity by themselves. The aim of our work is to study the possible role of clinical variables, neuropsychological performance, and the 5HTTLPR, rs25531, and val108/58Met COMT polymorphisms in the prediction of the response to fluoxetine after 4weeks of treatment in a sample of patient with MDD. Methods: 64 patients with MDD were genotyped according to the above-mentioned polymorphisms, and were clinically and neuropsychologically assessed before a 4-week fluoxetine treatment. Fluoxetine response was assessed by using the Hamilton Depression Rating Scale. We carried out a binary logistic regression model for the potential predictive variables. Results: Out of the clinical variables studied, only the number of anxiety disorders comorbid with MDD have predicted a poor response to the treatment. A combination of a good performance in variables of attention and low performance in planning could predict a good response to fluoxetine in patients with MDD. None of the genetic variables studied had predictive value in our model. Limitations: The possible placebo effect has not been controlled. Our study is focused on response prediction but not in remission prediction. Conclusions: Our work suggests that the combination of the number of comorbid anxiety disorders, an attentional variable, and two planning variables makes it possible to correctly classify 82% of the depressed patients who responded to the treatment with fluoxetine, and 74% of the patients who did not respond to that treatment. [Copyright &y& Elsevier]

Abstract: Trace amines are putative regulatory elements in the brain whose activity may be relevant to the pathophysiology of depressive episodes. TAAR6 is an orphan receptor probably associated with trace amines. Its genetic variations have been associated with bipolar and schizophrenic disorders. In this study we investigated for the first time the possible association between a set of TAAR6 genetic variations (rs7452939; rs4305745; rs6903874; rs6937506; and rs8192625) with clinical features of depression including antidepressant treatment response in a sample of 187 depressive patients all of Korean origins. rs6903874 T/T carriers had a statistically significant better improvement, and rs6937506 C/C genotype was found to be more frequent in patients without a history of suicide attempt (incomplete or unsuccessful suicide). Haplotype analyses confirmed the association with suicide attempt behavior being haplotype G–T at SNPs rs7452939 and rs6937506 at risk of suicide. These results suggest a possible role of TAAR6 in antidepressant response and suicide behavior in patients with depressive disorder. Heterogeneity of treatment, possible stratification bias not controlled by the statistical analyses, and the risk of false-positive finding mandate further analysis in this direction. [Copyright &y& Elsevier]

Background. Response and remission defined by cut-off values on the last observed depression severity score are commonly used as outcome criteria in clinical trials, but ignore the time course of symptomatic change and may lead to inefficient analyses. We explore alternative categorization of outcome by naturally occurring trajectories of symptom change. Method. Growth mixture models were applied to repeated measurements of depression severity in 807 participants with major depression treated for 12 weeks with escitalopram or nortriptyline in the part-randomized Genome-based Therapeutic Drugs for Depression study. Latent trajectory classes were validated as outcomes in drug efficacy comparison and pharmacogenetic analyses. Results. The final two-piece growth mixture model categorized participants into a majority (75%) following a gradual improvement trajectory and the remainder following a trajectory with rapid initial improvement. The rapid improvement trajectory was over-represented among nortriptyline-treated participants and showed an antidepressant-specific pattern of pharmacogenetic associations. In contrast, conventional response and remission favoured escitalopram and produced chance results in pharmacogenetic analyses. Controlling for drop-out reduced drug differences on response and remission but did not affect latent trajectory results. Conclusions. Latent trajectory mixture models capture heterogeneity in the development of clinical response after the initiation of antidepressants and provide an outcome that is distinct from traditional endpoint measures. It differentiates between antidepressants with different modes of action and is robust against bias due to differential discontinuation. [ABSTRACT FROM AUTHOR]

We studied seven genes that reflect events relevant to antidepressant action at four sequential levels: (1) entry into the brain, (2) binding to monoaminergic transporters, and (3) distal effects at the transcription level, resulting in (4) changes in neurotrophin and neuropeptide receptors. Those genes are ATP-binding cassette subfamily B member 1 (ABCB1), the noradrenaline, dopamine, and serotonin transporters (SLC6A2, SLC6A3 and SLC6A4), cyclic AMP-responsive element binding protein 1 (CREB1), corticotropin-releasing hormone receptor 1 (CRHR1) and neurotrophic tyrosine kinase type 2 receptor (NTRK2). Sequence variability for those genes was obtained in exonic and flanking regions. A total of 56 280 000 bp across were sequenced in 536 unrelated Mexican Americans from Los Angeles (264 controls and 272 major depressive disorder (MDD)). We detected in those individuals 419 single nucleotide polymorphisms (SNPs); the nucleotide diversity was 0.00054±0.0001. Of those, a total of 204 novel SNPs were identified, corresponding to 49% of all previously reported SNPs in those genes: 72 were in untranslated regions, 19 were in coding sequences of which 7 were non-synonymous, 86 were intronic and 27 were in upstream/downstream regions. Several SNPs or haplotypes in ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1 and NTRK2 were associated with MDD, and in ABCB1, SLC6A2 and NTRK2 with antidepressant response. After controlling for age, gender and baseline 21-item Hamilton Depression Rating Scale (HAM-D21) score, as well as correcting for multiple testing, the relative reduction of HAM-D21 score remained significantly associated with two NTRK2-coding SNPs (rs2289657 and rs56142442) and the haplotype CAG at rs2289658 (splice site), rs2289657 and rs2289656. Further studies in larger independent samples will be needed to confirm these associations. Our data indicate that extensive assessment of sequence variability may contribute to increase understanding of disease susceptibility and drug response. Moreover, these results highlight the importance of direct re-sequencing of key candidate genes in ethnic minority groups in order to discover novel genetic variants that cannot be simply inferred from existing databases. [ABSTRACT FROM AUTHOR]

Abstract: Background: Four serotonin-related genes including guanine nucleotide binding protein beta polypeptide 3 (GNB3), 5-hydroxytryptamine receptor 1A (HTR1A; serotonin receptor 1A), 5-hydroxytryptamine receptor 2A (HTR2A; serotonin receptor 2A), and solute carrier family 6 member 4 (SLC6A4; serotonin neurotransmitter transporter) have been suggested to be candidate genes for influencing antidepressant treatment outcome. The aim of this study was to explore whether interaction among these genes could contribute to the pharmacogenomics of short-term antidepressant response in a Taiwanese population with major depressive disorder (MDD). Methods: Included in this study were 101 MDD patients who were treated with antidepressants, 35 of whom were rapid responders and 66 non-responders after 2weeks of treatment. We genotyped four single nucleotide polymorphisms (SNPs), including GNB3 rs5443 (C825T), HTR1A rs6295 (C-1019G), HTR2A rs6311 (T102C), and SLC6A4 rs25533, and employed the generalized multifactor dimensionality reduction (GMDR) method to investigate gene–gene interactions. Results: Single-locus analyses showed the GNB3 rs5443 polymorphism to be associated with short-term antidepressant treatment outcome (P-value=0.029). We did not correct for multiple testing in these multiple exploratory analyses. Finally, the GMDR approach identified a significant gene–gene interaction (P-value=0.025) involving GNB3 and HTR2A, as well as a significant 3-locus model (P-value=0.015) among GNB3, HTR2A, and SLC6A4. Conclusions: These results support the hypothesis that GNB3, HTR2A, and SLC6A4 may play a role in the outcome of short-term antidepressant treatment for MDD in an interactive manner. Future research with independent replication using large sample sizes is needed to confirm the functions of the candidate genes identified in this study as being involved in short-term antidepressant treatment response. [Copyright &y& Elsevier]

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). 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). 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. 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. [ABSTRACT FROM AUTHOR]

Objective Previous studies of mixed aged and older adult samples with major depressive disorder (MDD) reported reduced depression response in anxious patients, but a systematic review and analysis has not been performed. Our aim was to determine if anxiety predicts antidepressant response in previously identified placebo-controlled trials of second generation antidepressants for late-life depression. Method From a previous systematic review that identified ten randomized, placebo-controlled trials of community dwelling patients aged 60 or older with major depression, anxious patients were identified by a score ≥7 on the anxiety/somatization factor of the Hamilton Depression Rating Scale (HDRS). Response was defined as 50% or greater improvement on the HDRS or the Montgomery Asberg Depression Rating Scale. A meta-analysis was performed using a random effects model to calculate Odds Ratios (OR). Results Data were available from eight trials having ten drug-placebo contrasts that included 2322 anxious and 1387 non-anxious patients. The odds ratio for response to drug compared to placebo in anxious patients was 1.57 (95% CI 1.15, 2.14; z = 2.86, n = 10, p < 0.001), in non-anxious patients was 1.44 (95% CI 1.15, 1.80, z = 3.21, n = 10, p < 0.001), and did not differ between groups. Pooled response rates to drug and placebo respectively were 49.4% vs 37.4% in anxious patients and 44.2 vs 35.5% in non-anxious patients. Conclusions In randomized, placebo-controlled trials, anxiety in late-life depression was not associated with decreased response to second generation antidepressants. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Most patients with major depressive disorder (MDD) experience a period of lengthy trial and error when trying to find optimal antidepressant treatment; identifying biomarkers that could predict response to antidepressant treatment would be of enormous benefit. We tested the hypothesis that pretreatment anterior cingulate cortex (ACC) activity could be a putative biomarker of rapid antidepressant response to ketamine, in line with previous findings that investigated the effects of conventional antidepressants. We also investigated patterns of ACC activity to rapid presentation of fearful faces compared with the normal habituation observed in healthy subjects. Methods: We elicited ACC activity in drug-free patients with MDD (n = 11) and healthy control subjects (n = 11) by rapidly presenting fearful faces, a paradigm known to activate rostral regions of the ACC. Spatial-filtering analyses were performed on magnetoencephalographic (MEG) recordings, which offer the temporal precision necessary to estimate ACC activity elicited by the rapid presentation of stimuli. Magnetoencephalographic recordings were obtained only once for both patients and control subjects. Patients were subsequently administered a single ketamine infusion followed by assessment of depressive symptoms 4 hours later. Results: Although healthy subjects had decreased neuromagnetic activity in the rostral ACC across repeated exposures, patients with MDD showed robust increases in pretreatment ACC activity. Notably, this increase was positively correlated with subsequent rapid antidepressant response to ketamine. Exploratory analyses showed that pretreatment amygdala activity was negatively correlated with change in depressive symptoms. Conclusions: Pretreatment rostral ACC activation may be a useful biomarker that identifies a subgroup of patients who will respond favorably to ketamine''s antidepressant effects. [Copyright &y& Elsevier]

Abstract: Some forms of electroconvulsive therapy (ECT) can result in generalized seizures that lack efficacy, therefore physiological markers of treatment adequacy would be helpful. EEG measures of seizure quality, such as EEG regularity and post-ictal suppression, have largely supplanted seizure duration as a marker for seizure adequacy, yet no predictive algorithm has gained wide clinical acceptance. Electrographic seizure durations of less than 25 s still prompt re-stimulation in many settings. We re-examined the utility of EEG seizure duration and other measures of EEG seizure as predictors of antidepressant response to right unilateral (RUL) ECT. Methods: Seventy-two adult patients with major depression were randomized to either titrated RUL ECT at 2.25 times initial seizure threshold or RUL ECT at a fixed dose of 403 mC. Intent-to-treat responder status (defined by 60% reduction in HRSD scores and final score of 12 or less after the last RUL ECT session) was identified as the dependent variable in a nominal logistic regression model including EEG seizure quality candidate variables, controlled for age and gender. Results: A model including EEG seizure duration, EEG regularity, post-ictal suppression, age and gender and randomization status was significantly predictive of intent-to-treat responder status at treatment 2 (R2=.21 p <.003; N =66) and treatment 4 (R2=.27 p <.0004; N =67). The model remained significant at these time points even when randomization status (titrated moderately suprathreshold vs. high fixed dosage) was removed (Treatment 2: R2=.18 p <.007; Treatment 4: R2=.23 p <.0007). Conclusion: EEG markers of seizure adequacy, including EEG seizure duration, are modestly predictive of antidepressant response for both titrated moderately suprathreshold and high fixed dosage RUL ECT. [Copyright &y& Elsevier]