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Background: Numerous studies have reported associations between the brain-derived neurotrophic factor (BDNF) gene and psychiatric disorders, including suicidal behavior, although with conflicting results., Methods: A total of 250 major depressive disorder patients were collected in the context of a European multicenter resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and Hamilton Rating Scale for Depression, and treatment response using the HAM-D. Genotyping was performed for the functional Val66Met polymorphism (rs6265) and 7 additional tagging single nucleotide polymorphisms within the BDNF gene., Results: Neither BDNF single markers nor haplotypes were found to be associated with suicide risk and lifetime history of suicide attempts. Gender-specific analyses revealed nonsignificant single marker (rs908867) and haplotypic association with suicide risk in males after multiple testing correction. Analyzing treatment response phenotypes, the functional Val66Met polymorphism as well as rs10501087 showed significant genotypic and haplotypic association with suicide risk in remitters (n=34, 13.6%)., Conclusions: Considering the sample size, the present findings need to be replicated in larger samples to confirm or refute a role of BDNF in the investigated suicidal behavior phenotypes., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

Recently published data have reported associations between cytochrome P450 metabolizer status and suicidality. The aim of our study was to investigate the role of genetic polymorphisms of the cytochrome P450 genes on suicide risk and/or a personal history of suicide attempts. Two hundred forty-three major depressive disorder patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for all relevant variations of the CYP1A2 gene (*1A, *1F, *1C, *1 J, *1 K), the CYP2C9 gene (*2, *3), the CYP2C19 gene (*2, *17) and the CYP2D6 gene (*3, *4, *5, *6, *9, *19, *XN). No association between both suicide risk and personal history of suicide attempts, and the above mentioned metabolic profiles were found after multiple testing corrections. In conclusion, the investigated cytochrome gene polymorphisms do not seem to be associated with suicide risk and/or a personal history of suicide attempts, though methodological and sample size limitations do not allow definitive conclusions.

The extent to which a family history of mood disorders and suicide could impact on clinical features of patients suffering from major depression (MD) and bipolar disorder (BD) has received relatively little attention so far. The aim of the present work is, therefore, to assess the clinical implications of the presence of at least one first- and/or second-degree relative with a history of MD, BD and suicide in a large sample of patients with MD or BD. One thousand one hundred and fifty-seven subjects with MD and 686 subjects with BD were recruited within the context of two large projects. The impact of a family history of MD, BD, and suicide-considered both separately and together-on clinical and socio-demographic variables was investigated. A family history of MD, BD, and suicide was more common in BD patients than in MD patients. A positive family history of mood disorders and/or suicide as well as a positive family history of MD and BD separately considered, but not a positive history of suicide alone, were significantly associated with a comorbidity with several anxiety disorders and inversely associated with age of onset. The clinical implications as well as the limitations of our findings are discussed.

Inflammatory pathways play a crucial role in the pathomechanisms of antidepressant efficacy. The aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within cyclooxygenase-2 (COX-2, rs5275 and rs20417) and oxytocin receptor (OXTR, rs53576 and rs2254298) genes was associated with antidepressant treatment resistance, response or remission. Three hundred seventy-two patients were recruited in the context of a multicenter resistant depression study. They were genotyped for COX-2 and OXTR SNPs. Treatment resistance (according to two different definitions), response and remission were recorded. We did not observe any association between the genotypes or alleles of the selected SNPs within COX-2 and OXTR genes and treatment resistance, response and remission in the whole sample. Our results are consistent with those of some studies but not with those of other ones. Indeed, several factors could be involved in the discrepancy observed across studies. They include sample size, environmental factors, differences in ethnicity, different study designs, and different definitions of treatment resistance., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objectives: In this article we aimed to: (1) review literature concerning the clinical and psychopathologic characteristics of Bipolar (BP) depression; (2) analyze an independent sample of depressed patients to identify any demographic and/or clinical feature that may help in differentiating mood disorder subtypes, with special attention to potential markers of bipolarity., Methods: A sample of 291 depressed subjects, including BP -I (n = 104), BP -II (n = 64), and unipolar (UP) subjects with (n = 53) and without (n = 70) BP family history (BPFH), was examined to evidence potential differences in clinical presentation and to validate literature-derived markers of bipolarity. Demographic and clinical variables and, also, single items from the Hamilton Depression Rating Scale (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Young Mania Rating Scale (YMRS) were compared among groups., Results: UP subjects had an older age at onset of mood symptoms. A higher number of major depressive episodes and a higher incidence of lifetime psychotic features were found in BP subjects. Items expressing depressed mood, depressive anhedonia, pessimistic thoughts, and neurovegetative symptoms of depression scored higher in UP, whereas depersonalization and paranoid symptoms' scores were higher in BP. When compared with UP, BP I had a significantly higher incidence of intradepressive hypomanic symptoms. Bipolar family history was found to be the strongest predictor of bipolarity in depression., Conclusions: Overall, our findings confirm most of the classical signs of bipolarity in depression and support the view that some features, such as BPFH, together with some specific symptoms may help in detecting depressed subjects at higher risk for BP disorder., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In the present study, we aimed to confirm the previous finding of an association between GRIK4 and GNB3 variants (rs195478 and rs5443) and remission and treatment resistance in major depression, using a multicenter sample of 223 patients. We did not find any supporting evidence for such associations. These conflicting data may result from difficulties in the replication of candidate gene association studies., (Copyright © 2012 S. Karger AG, Basel.)

Attention Deficit/Hyperactivity Disorder (ADHD) is a pervasive neurodevelopmental disorder characterized by 3 clusters of age-inappropriate cardinal symptoms: inattention, hyperactivity and impulsivity. These clinical/behavioural symptoms are assumed to result from disturbances within brain systems supporting executive functions including working memory (WM), which refers to the ability to transiently store and flexibly manipulate task-relevant information. Ongoing or past medications, co-morbidity and differences in task performance are potential, independent confounds in assessing the integrity of cerebral patterns in ADHD. In the present study, we recorded WM-related cerebral activity during a memory updating N-back task using functional Magnetic Resonance Imaging (fMRI) in control children and never medicated, prepubescent children with ADHD but without comorbid symptoms. Despite similar updating performance than controls, children with ADHD exhibited decreased, below baseline WM-related activation levels in a widespread cortico-subcortical network encompassing bilateral occipital and inferior parietal areas, caudate nucleus, cerebellum and functionally connected brainstem nuclei. Distinctive functional connectivity patterns were also found in the ADHD in these regions, with a tighter coupling in the updating than in the control condition with a distributed WM-related cerebral network. Especially, cerebellum showed tighter coupling with activity in an area compatible with the brainstem red nucleus. These results in children with clinical core symptoms of ADHD but without comorbid affections and never treated with medication yield evidence for a core functional neuroanatomical network subtending WM-related processes in ADHD, which may participate to the pathophysiology and expression of clinical symptoms.

Objective: The management of treatment-resistant depression is a much debated issue. In particular, the evidence supporting the commonly suggested sequential use of antidepressants from 2 different pharmacological classes is weak. This retrospective study was undertaken to investigate whether there is a better response in nonresponders switched to a different class of antidepressants (across-class) compared with nonresponders switched to an antidepressant from the same class (within-class)., Methods: Three hundred forty patients with primary major depressive disorder were recruited in the context of a European multicenter project. Subjects whose current depressive episode had failed to respond to a first antidepressant trial of adequate dose and duration were included., Results: There was no significant difference in response or remission rates between the across-class and within-class groups after controlling for possible confounders., Conclusions: In depressed nonresponders to a previous antidepressant treatment, switching to a different class of antidepressants was not associated with a better response or remission rate.

OBJECTIVES. Evidence in favour of switching between selective serotonin reuptake inhibitor (SSRI) and tricyclic (TCA) antidepressants in treatment resistant depression has been tested in a few studies only, consequently a prospective study was undertaken to evaluate the impact of switching strategies. METHODS. One hundred eighty-nine patients who failed to respond to a previous antidepressant were randomised to four arms: firstly they received citalopram or desipramine for a 4-week period; secondly, those who failed to respond were treated for a further 4-week period with the same antidepressant (citalopram-citalopram and desipramine-desipramine arms) or switched to the alternate one (citalopram-desipramine and desipramine-citalopram arms). RESULTS. There was no difference in the first 4-week phase between patients receiving citalopram versus desipramine in Hamilton Rating Scale for Depression (HRSD), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression (CGI) scores. In the second 4-week phase remitter rates were higher among non-switched patients (P = 0.04). Moreover, considering HRSD and MADRS, switched patients reported significantly higher scores (P ≤ 0.02 for both scales at each time-point). CONCLUSIONS. This study supports the thesis that switching from an SSRI to a TCA (and vice versa) in non-responders to a 4-week trial of an SSRI/TCA is not associated with improved response. The result goes in the opposite direction to that predicted by current guidelines.

Our study aims at replicating our previous finding of an association between COMT rs4680 G/A polymorphism and early onset major depression (MD). We included 462 MD, 147 bipolar disorders (BD) subjects and 295 healthy controls. We could partially replicate previous findings. In particular, rs4680 GG+AG genotypes were more represented in the subgroup of early onset MD patients (p=0.04). Additionally, we observed an association between rs737865 alleles and early onset MD (p=0.04). Rs4680 genotype was associated with early onset BD as well (p=0.01). In conclusion, we partially replicated our previous findings confirming a possible influence of COMT variants in MD and BD, particularly in early onset subjects, though not with the same risk genotypes., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

In the present study, aimed at investigating whether a set of single nucleotide polymorphisms (SNPs) within PTGS2 gene (rs4648276, rs2066826 and rs689466) could be associated with antidepressant response, remission and treatment resistance in a sample of major depression patients, we did not find evidence supporting any of such associations., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family of neurotrophins, has pivotal roles in neuronal survival, proliferation, and synaptic plasticity in the brain. Both clinical and pharmacological studies have implicated the common single nucleotide polymorphism (SNP) at position 196, Val66Met in the pathophysiology of major depressive disorder (MDD), and antidepressant response. However, inconsistent results were found between Val66Met (rs6265) polymorphism and treatment response phenotypes in genetic association studies. The functional Val66Met polymorphism and seven other tagging SNP markers selected to capture the major allelic variations across BDNF locus were analyzed in depressed patients, treated with antidepressants, and 76 control patients. Two hundred and six patients with Diagnostic and Statistical Manual of Mental Disorders-IV MDD were recruited for this study and genotyped for eight BDNF tagging SNPs (rs11030096, rs925946, rs10501087,rs6265, rs12273363, rs908867, rs1491850, and rs1491851)to investigate the functional impact of genotypes/haplotypes in the susceptibility of depression and on treatment response. None of the eight SNPs, including the rs6265, were significantly associated with MDD after permutation correction. However, we found an association for rs10501087, rs6265 with nonresponse to antidepressant treatment (corrected permutation P:0.03599; 0.0399 and power: 0.1420; 0.1492, respectively).Analysis of each two-marker, three-marker, and four-marker sliding window haplotypes showed significance in haplotype combinations. Especially rs10501087 (C), rs6265 (A), and rs149,1850 (C) together or with the other SNP haplotypes showed a similar pattern in all treatment response phenotypes. Despite the limited power of analysis, our results suggest that these three SNPs may play a role in antidepressant treatment response phenotypes in MDD.

Background: The transcription factor Cyclic adenosine monophosphate Response Element Binding (CREB) protein has been repeatedly involved in the aetiology and pharmacotherapy of major depression (MD). The aim of this study was to investigate the potential association of a set of single nucleotide polymorphisms (SNPs) in CREB1 gene and both MD and response, remission and treatment resistance to antidepressants., Methods: One hundred-ninety MD patients collected in the context of a resistant depression study and treated with antidepressants for at least 4weeks were genotyped for 5 CREB1 SNPs (rs2709376, rs2253206, rs7569963, rs7594560, and rs4675690). Response, remission and treatment resistance were recorded., Results: An allele of rs7569963 as well as rs2253206-rs7569963 A-A and rs7569963-rs4675690 A-C haplotypes were associated with the status of treatment resistance. Additionally, rs7569963 GG genotype was positively associated with remission. No further significant associations were observed., Limitations: Limitations of the present study include a relatively small sample size and the incomplete ascertainment of data which could influence the outcome., Conclusions: Our results preliminary suggest that some genetic polymorphisms in CREB1 could be associated to treatment resistance. Although such finding needs to be replicated in larger samples, it increases current knowledge about the genetic predictors of response to antidepressants that will probably lead to enhance treatment outcomes by addressing each individual to the most appropriate treatment strategy in the early stages of treatment., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objectives: Dystrobrevin binding protein 1 (Dysbindin) is a plausible candidate gene for major depressive disorders (MDD) due to its involvement in synaptic signaling, plasticity and localization in the brain., Methods: Two intronic SNPs of DTNBP1; rs760761 (P1320) and rs2619522 (P1763) were analyzed in 206 patients with DSM-IV MDD to investigate the functional impact of genotypes on susceptibility for depression and some clinical phenotypes. The Sequenom iPLEX assay (Sequenom, Cambridge, MA) was used for genotyping., Results and Conclusions: Despite the limited power of analysis, our results showed that these two SNPs in DTNPB1 gene were not related to clinical phenotypes such as melancholia, age at onset, suicidality and co-morbid anxiety disorders, as well as to treatment response phenotypes.

This study is the first investigation to identify clinical factors associated with treatment resistance in bipolar depression (TRBD). TRBD is defined as failure to respond to at least two consecutive adequate antidepressant trials. The primary objective of this European Multicenter Study was to identify specific clinical and demographic factors associated with TRBD in a sample of bipolar patients treated for a major depressive episode. A total of 261 bipolar patients with major depressive episode were included in the analysis. Among them, 162 patients were considered as responders to treatment and the remaining 99 patients were considered as treatment resistant with a 17-item Hamilton Rating Scale for Depression Score remaining superior or equal to 17 after two consecutive adequate antidepressant trials. Cox regression analysis was used to examine the association between individual clinical variables and TRBD. We found four clinical variables to be significantly associated with TRBD: melancholia [P=0.01, odds ratio (OR)=2.4], comorbidity with social phobia (P=0.02, OR=2.3), current suicidal risk (P=0.02, OR=1.8) and severe intensity of current depressive episode (P=0.01, OR=1.8). Our findings identify four clinical variables associated with TRBD, which could be further investigated in controlled prospective trials.

Catechol-O-methyltransferase (COMT) has been suggested to be involved in the pathogenesis and pharmacological treatment of affective disorders. The nonsynonymous single nucleotide polymorphism (SNP) in exon 4 (Val108/158Met; rs4680) influences the COMT enzyme activity. Inconsistent results were found between Val158Met polymorphism (rs4680) and treatment response phenotypes in genetic association studies. However, the haplotype combinations of alleles at the Val108/158Met SNP with the other synonymous SNPs in the COMT gene region have shown association between enzyme activity/amount and COMT-dependent phenotypes. We carried out this study to define the functional impact of COMT genotypes/haplotypes on susceptibility and on treatment response phenotypes of major depressive disorder (MDD). Three hundred and ninety-six patients with MDD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [(DSM)-IV] and 295 healthy controls were recruited for this study and genotyped for the seven COMT SNPs (rs2075507, rs737865, rs6269, rs4633, rs4818, rs4680, and rs165599). This is the first study with all these SNPs to investigate for MDD and treatment response phenotypes. Our results show that none of the seven SNPs, including the rs4680, was significantly associated with MDD after permutation correction in single SNP analyses. Although several haplotype combinations showed significance, the combinations of G-T-G-G haplotype for rs6269, rs4633, rs4818 and rs4680 were only present in the MDD group (G-T 4.5%, corrected sim P=0.0001; G-T-G 3.87%, corrected sim P=0.001; G-T-G-G 3.3% corrected sim P=0.0025). In the treatment response phenotypes, the GG genotype of the rs2075507 SNP (located in the promoter region of MB-COMT) was less common in resistant patients in a single SNP analysis with low corrected sim P=0.052 and power=0.086. However, in the haplotype analysis, the haplotypes of exonic SNPs, rs4633, rs4818, and rs4680, were related to the treatment response phenotypes investigated, especially the phenotype of the response to antidepressant treatment. The C-C-A haplotype of these SNPs was overrepresented (almost four-and eight-fold) in the responders compared with the nonresponders and controls, respectively, after Bonferroni correction (corrected sim P=0.048, 0.0001, respectively). Both nonsynonymous and synonymous SNPs within haplotypes may be more relevant than the single SNP in conferring MDD susceptibility and treatment response phenotypes. Despite the limited power of our analysis, this finding suggests that the polymorphic COMT gene that influences catecholaminergic neurotransmission may play a role in the individual response to antidepressants.

The 5HT2A (5HTR2A) and 5HT1A receptor (5HTR1A) genes are plausible candidate genes for major depressive disorders. Two single nucleotide polymorphisms, the rs7997012 in 5HTR2A and the -1019C/G in 5HTR1A, were analyzed in 206 patients with Diagnostic and Statistical Manual of Mental Disorders, fourth edition major depressive disorder. Patients were retrospectively characterized for clinical response to antidepressant treatment. We found a significant difference in the rs7997012 allele frequency between resistant and nonresistant patients. However, following the Bonferroni correction we could not find any association between this single nucleotide polymorphism and treatment resistance phenotype. Nevertheless, given the limited power of our analysis, we are not able to conclude that these results reflect a lack of association. Additional studies are needed to confirm or to disprove our result.

Background: Being overweight or obese may be associated with poor response to antidepressants. The present report explores the moderation of antidepressant response by body weight to establish the specificity to antidepressant mode of action, type of depressive symptoms and gender., Methods: Height and weight were measured in 797 men and women with major depression treated with escitalopram or nortriptyline for twelve weeks as part of the Genome Based Therapeutic Drugs for Depression (GENDEP) project. Body mass index (BMI) and obesity (BMI>30) were tested as predictors of change in depressive symptoms using mixed linear models., Results: Higher BMI and obesity predicted poor response to nortriptyline but did not significantly influence response to escitalopram. The moderation of response by body weight was due to differential improvement in neurovegetative symptoms, including sleep and appetite. The relationship between body weight and change in neurovegetative symptoms was moderated by gender with obese men responding less to nortriptyline and obese women having poorer response to both antidepressants., Limitations: As no placebo arm was included, the specificity of findings to antidepressants is relative. Lack of specific measures precluded accounting for differences in body fat distribution., Conclusions: Body weight should be considered in the assessment of depression as it may inform the selection of antidepressant treatment.

Cytochrome P450 genes are involved in the metabolism of antidepressants and could influence treatment response. The aim of this study was to investigate the role of allelic variations of the cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes in antidepressant treatment response and remission rates. Two hundred and seventy-eight patients affected by major depression, responders (N = 81) and nonresponders (N=197) to at least one adequate antidepressant treatment, were recruited with a multicentre design for resistant depression and genotyped for all relevant variations. None of the considered metabolic profiles (e.g. poor, intermediate, extensive and ultrarapid metabolizers) was found to be associated with either response or remission rates. In conclusion, the investigated cytochrome genes do not seem to play a major role in antidepressant response in the present sample of depressive patients. Nevertheless, methodological and sample size limitations of this study do not allow definitive conclusions.

The principal objective of this study was to evaluate the occurrence of various dissociative phenomena in patients with major depressive disorder (MDD) and their possible implications in manifestation and course of depression. We administered the Dissociative Experiences Scale (DES) and a self-questionnaire of life events to 27 patients with MDD and to 40 healthy participants in order to collect information on traumatic events. Patients who scored >or= 20 on the DES were also assessed to determine the presence of dissociative disorder. Patients with MDD reported a significantly higher mean score on the DES than the comparison healthy participants. In all, 12 out of 27 patients with MDD reported childhood trauma, and their mean score on the DES representing absorption and imaginative involvement was significantly higher than that of participants without childhood trauma. Also, 7% of our MDD patients were diagnosed with dissociative disorder during this study. The principal limitations of the study were its small sample size and the use of a nonstandardized trauma measure. These findings indicate that dissociative phenomena should not be overlooked in MDD. Screening methods and structured interview for dissociative disorders are useful in psychiatric and psychological practice. Further studies should analyze the role and clinical consequence of different forms of dissociation experiences.

We report here a case-control association study with T102C polymorphism in the serotonin 2A receptor gene (HTR2A) in patients affected by unipolar affective disorder (UPAD) and in controls. A total of 284 subjects were genotyped (142 UPAD and 142 controls). All subjects were interviewed using standard diagnostic interviews and matched. A homogenous population of unipolar patients with suicidal attempt was identified. Conditional logistic regression was applied. No association of the HTR2A polymorphism was found in the overall sample of 142 UPAD-control pairs regarding allele and genotype frequencies (P=0.36 and P=0.52 respectively) and homo-heterozygote distributions (P=0.91). This study confirms, in a multicentric European sample, the earlier observations that the T102C HTR2A polymorphism is not associated with UPAD. Nevertheless, a type 2 statistical error cannot be excluded. Therefore, to exclude the implication of HTR2A in UPAD, this result must be replicated in larger samples and in other populations using the transmission disequilibrium test and different polymorphisms around HTR2A.

Several microdialysis studies have investigated the effects of acute ethanol on extracellular amino acids in various rat brain regions. However, these studies led to conflicting results, suggesting that individual differences between rat strains and lines may play an important role. In the present study, high-alcohol sensitive (HAS) and low-alcohol sensitive (LAS) rats were used to investigate the possible relationship between ethanol sensitivity and the concentrations of extracellular amino acids in the nucleus accumbens. Several groups of HAS and LAS rats were injected with either saline or ethanol (1.0, 2.0 or 3.0 g/kg, i.p.) and the concentrations of amino acids in the nucleus accumbens microdialysates were assayed by electrochemical detection. Acute ethanol induced a dose-dependent increase in extracellular taurine concentrations. However, this increase was significantly reduced at 2.0 and 3.0 g/kg ethanol in HAS rats relative to LAS rats. Since the biological functions of taurine suggest its implication in the reduction of ethanol adverse effects, a higher increase in taurine concentrations may contribute to the lower ethanol sensitivity of LAS rats. Although 2.0 and 3.0 g/kg ethanol did not affect extracellular glutamate concentrations, a significant increase in glutamate was observed after 1.0 g/kg ethanol to HAS rats but not to LAS rats. Such an effect remains unexplained but suggests that discrepancies between the results of previous microdialysate studies may be related to differences in the ethanol sensitivities of various rat strains.