Switching antidepressant class does not improve response or remission in treatment-resistant depression.

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.

European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that persists into adulthood in the majority of cases. The evidence on persistence poses several difficulties for adult psychiatry considering the lack of expertise for diagnostic assessment, limited treatment options and patient facilities across Europe. METHODS: The European Network Adult ADHD, founded in 2003, aims to increase awareness of this disorder and improve knowledge and patient care for adults with ADHD across Europe. This Consensus Statement is one of the actions taken by the European Network Adult ADHD in order to support the clinician with research evidence and clinical experience from 18 European countries in which ADHD in adults is recognised and treated. RESULTS: Besides information on the genetics and neurobiology of ADHD, three major questions are addressed in this statement: (1) What is the clinical picture of ADHD in adults? (2) How can ADHD in adults be properly diagnosed? (3) How should ADHD in adults be effectively treated? CONCLUSIONS: ADHD often presents as an impairing lifelong condition in adults, yet it is currently underdiagnosed and treated in many European countries, leading to ineffective treatment and higher costs of illness. Expertise in diagnostic assessment and treatment of ADHD in adults must increase in psychiatry. Instruments for screening and diagnosis of ADHD in adults are available and appropriate treatments exist, although more research is needed in this age group.

Paraplegia as a presentation of primary hyperoxaluria.

30% of the patients suffering from hyperoxaluria type 1 are diagnosed only when they already had reached end-stage renal disease. We report the case of a 57-year-old woman with history of chronic kidney failure presenting with paraplegia due to spinal cord compression by thoracic mass-like lesions. Bone biopsy specimen obtained by decompressive laminectomy revealed calcium oxalate deposits. Once diagnosis of primary hyperoxaluria was confirmed, she underwent haemodialysis with incomplete improvement of her neurological disorders and was registered on the waiting list for transplantation.

Current issues in bipolar disorder: a critical review.

Although awareness on bipolar disorder has increased during the last decade, this condition remains characterized by a disabling burden, in terms of morbidity and functional impairment. This paper aims to review some critical issues in the current knowledge on Bipolar disorder. Although large European epidemiological studies are lacking, Bipolar disorder is characterized by a set of severe features, including an early age of onset, a chronic outcome and an important suicidal risk. A majority of bipolar patients also experience a comorbid Axis I condition, including substance abuse, anxiety disorder and attention-deficit hyperactivity disorder. This situation presents a therapeutic challenge, since antidepressants or methylphenidate may be associated with the risk of inducing mania. Recently, a large number of studies have provided evidence for the efficacy of new compounds in the treatment of both mania and bipolar depression, but also in long-term relapse prevention. Recent research has also allowed for the redefinition of the concept of mood stabilizer and for improving existing guidelines on the clinical management of Bipolar disorder.

Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study.

Based on our preclinical data showing a potential accelerating effect of acetylsalicylic acid (ASA) in combination with fluoxetine in an animal model of depression, we examined the effect of ASA augmentation therapy on selective reuptake inhibitors (SSRI) in major depressed non-responder patients. Twenty-four non-responder patients having received at least 4 weeks of an adequate SSRI treatment were included in a pilot open-label study. Participants were treated openly during 4 weeks with 160 mg/day ASA in addition to their current antidepressant treatment. The combination SSRI-ASA was associated with a response rate of 52.4%. Remission was achieved in 43% of the total sample and 82% of the responder sample. In the responder group, a significant improvement was observed within week 1 (mean Hamilton Depression Rating Scale-21 items at day 0=29.3+/-4.5, at day 7=14.0+/-4.1; P<0.0001) and remained sustained until day 28. Despite limitations due to the open nature of this study, our preliminary results confirm our preclinical findings and are in favour of an accelerating effect of ASA in combination with SSRIs in the treatment of major depression. Potential physiological and biochemical mechanisms may involve an anti-inflammatory and/or neurotrophic effect.

No implication of brain-derived neurotrophic factor (BDNF) gene in unipolar affective disorder: evidence from Belgian first and replication patient-control studies.

Several lines of evidence have suggested an implication of brain-derived neurotrophic factor (BDNF) in unipolar affective disorder (UPAD). In the present study, we investigated the role of BDNF gene in UPAD in two independent samples of 92 patients/92 controls and 156 patients/197 controls. Two single nucleotide polymorphisms (SNPs) were investigated. We found no significant differences of BDNF gene SNPs distribution between UPAD patients and controls in both samples. Haplotype analyses were performed on both samples. A statistical difference was found between cases and controls in the first sample but not in the second. These results are not in favour of an implication of BDNF in UPAD but need to be replicated before final conclusion.

Molecular genetics of affective disorders.

Evidence for familial aggregation in Affective Disorders (AD) has been provided in classical studies. Linkage and association genetic studies have been proposed to detect genetic factors implicated in AD. However, findings from molecular genetic studies remain inconclusive. Nevertheless, current research is focusing on the phenotypes, both sub- and endophenotypes. In addition, recent advances in technology, such as microarrays, provide new tools in psychiatric genetics. These different approaches offer a new optimism era in the search of genetic factors in AD.

Lack of association between the 5HT2A receptor polymorphism (T102C) and unipolar affective disorder in a multicentric European study.

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.

Citalopram versus desipramine in treatment resistant depression: effect of continuation or switching strategies: a randomized open study.

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.

Brain-derived neurotrophic factor gene polymorphisms: influence on treatment response phenotypes of major depressive disorder.

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.

The impact of catechol-O-methyltransferase SNPs and haplotypes on treatment response phenotypes in major depressive disorder: a case-control association study.

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.

Dysbindin gene (DTNBP1) in major depressive disorder (MDD) patients: lack of association with clinical phenotypes.

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.

Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study.

OBJECTIVES: Very few studies have investigated clinical features associated with treatment-resistant depression (TRD) defined as failure of at least 2 consecutive antidepressant trials. The primary objective of this multicenter study was to identify specific clinical and demographic factors associated with TRD in a large sample of patients with major depressive episodes that failed to reach response or remission after at least 2 consecutive adequate antidepressant treatments. METHOD: A total of 702 patients with DSM-IV major depressive disorder, recruited from January 2000 to February 2004, were included in the analysis. Among them, 346 patients were considered as nonresistant. The remaining 356 patients were considered as resistant, with a 17-item Hamilton Rating Scale for Depression score remaining greater than or equal to 17 after 2 consecutive adequate antidepressant trials. Cox regression models were used to examine the association between individual clinical variables and TRD. RESULTS: Among the clinical features investigated, 11 variables were found to be associated with TRD. We found anxiety comorbidity (p < .001, odds ratio [OR] = 2.6), comorbid panic disorder (p < .001, OR = 3.2) and social phobia (p = .008, OR = 2.1), personality disorder (p = .049, OR = 1.7), suicidal risk (p = .001, OR = 2.2), severity (p = .001, OR = 1.7), melancholia (p = .018, OR = 1.5), a number of hospitalizations > 1 (p = .003, OR = 1.6), recurrent episodes (p = .009, OR = 1.5), early age at onset (p = .009, OR = 2.0), and nonresponse to the first antidepressant received lifetime (p = .019, OR = 1.6) to be the factors associated with TRD. CONCLUSIONS: Our findings provide a set of 11 relevant clinical variables associated with treatment resistance in major depressive disorder that can be explored at the clinical level. The statistical model used in this analysis allowed for a hierarchy of these variables (based on the OR) showing that comorbid anxiety disorder is the most powerful clinical factor associated with TRD.

Patient-control association study of substance P-related genes in unipolar and bipolar affective disorders.

In the search of genes potentially implicated in the aetiology of affective disorders (AD), SUBSTANCE P (SP) pathway is receiving increased interest. SP receptor antagonists, such as MK-869 and L-759274, have been shown to have antidepressant effect. Results from preclinical and human studies implicate SP and its pathway in the pathophysiology of mood disorders. We investigated a possible association between 20 single nucleotide polymorphisms (SNPS) among four SP-related genes and unipolar and bipolar ad (UPAD and BPAD) in a first sample of 92 UPAD patients and 92 control individuals and in a replication sample of 92 UPAD patients and 92 control individuals. An additional sample of 113 BPAD patients has also been ascertained. Our results showed a significant association between the angiotensin-converting enzyme gene (ACE1) and UPAD in our first sample, but not in the replication sample. No significant evidence of association was found in other SP-related genes. We did not find any association in the BPAD sample. When pooling first and replication UPAD samples, an association was found between ACE1 and a subgroup of patients remaining depressed after an adequate antidepressant treatment. In conclusion, our findings do not support a major contribution of SP-related genes in UPAD and BPAD, but provides some evidence of an ace influence in treatment response to antidepressants.

Molecular genetics of affective disorders.

Family studies have provided evidence for familial transmission in suicide in major psychiatric disorders, and in particular affective disorders. Even though they may seem contradictory, linkage studies have suggested several genetic regions implicated in affective disorders. Association studies have mainly focused on genes related to serotonergic and monoaminergic pathways. Other genes involved in GABAergic and substance P pathways have also been studied in association studies. Another way to approach the genetics of affective disorders is the definition of more detailed phenotypes. Suicidal behaviour is one of the more largely studied subphenotypes within affective disorders. Tryptophan hydroxylase and serotonin transporter genes, related to the serotonergic pathway, have been found to be associated to suicidal behaviour, in particular violent suicidal behaviour but need to be replicated before definitive conclusion. Improved methodologies and updated tools in genetic studies will improve in the future our knowledge of affective disorders.

Molecular genetics in the analysis of suicide.

Each year, one million people die of suicide. Among the different identified risk factors, genetic factors seem to be part of a multidimensional behavior, including psychiatric, psychosocial, biological factors and physical illness. Family studies have provided evidence for familial transmission in suicide, confirmed in twin and adoption studies. At a molecular level, serotonin seems to be one of the key neurotransmitters implicated in suicidal behavior. Therefore, genes coding for proteins involved in serotonergic neurotransmission have been extensively studied in case-control association studies on suicide. Major findings concern Tryptophan hydroxylase (TPH) gene, particularly in violent suicidal behavior. Though they may seem contradictory, studies on Serotonin transporter (5-HTT), Monaomine oxidase (MAOA), Serotonin 2A and 2C receptors (5-HT2A and 5-HT2C) and Tyrosine hydroxylase (TH) genes are promising. In spite of those observations having some limitations, it appears that genetic factors are a serious risk factor, besides environmental aspects of suicidal behavior.

Non-replication of the brain-derived neurotrophic factor (BDNF) association in bipolar affective disorder: a Belgian patient-control study.

This patient-control association study was conducted to investigate a possible association of two single nucleotide polymorphisms (SNPs), g.11757C > G and g.196G > A, in the brain-derived neurotrophic factor (BDNF) with bipolar affective disorder (BPAD). Two hundred seventy-five individuals of Belgian origin (at least two generations of Belgian ancestors) were genotyped (112 BPAD and 163 controls). No significant differences were found in the frequency of genotypes and alleles of g.196G > A (P = 0.37 and 0.94, respectively) and g.11757C > G (P = 0.49 and 0.59, respectively) between controls and BPAD patients. An haplotype analysis revealed no difference between patients and controls (P = 0.44). We failed to replicate previous findings implicating BDNF in the aetiology of BPAD. However, BDNF remains an interesting target for future genetic studies and should be tested in prospective pharmacogenetic therapeutic trials.