RESUMO
OBJECTIVES: Clinical variables were investigated in the 'treatment resistant depression (TRD)- III' sample to replicate earlier findings by the European research consortium 'Group for the Study of Resistant Depression' (GSRD) and enable cross-sample prediction of treatment outcome in TRD. EXPERIMENTAL PROCEDURES: TRD was defined by a Montgomery and Åsberg Depression Rating Scale (MADRS) score ≥22 after at least two antidepressive trials. Response was defined by a decline in MADRS score by ≥50% and below a threshold of 22. Logistic regression was applied to replicate predictors for TRD among 16 clinical variables in 916 patients. Elastic net regression was applied for prediction of treatment outcome. RESULTS: Symptom severity (odds ratio (OR) = 3.31), psychotic symptoms (OR = 2.52), suicidal risk (OR = 1.74), generalized anxiety disorder (OR = 1.68), inpatient status (OR = 1.65), higher number of antidepressants administered previously (OR = 1.23), and lifetime depressive episodes (OR = 1.15) as well as longer duration of the current episode (OR = 1.022) increased the risk of TRD. Prediction of TRD reached an accuracy of 0.86 in the independent validation set, TRD-I. CONCLUSION: Symptom severity, suicidal risk, higher number of lifetime depressive episodes, and comorbid anxiety disorder were replicated as the most prominent risk factors for TRD. Significant predictors in TRD-III enabled robust prediction of treatment outcome in TRD-I.
Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo Resistente a Tratamento/diagnóstico , Transtorno Depressivo Resistente a Tratamento/psicologia , Adulto , Transtornos Psicóticos Afetivos/diagnóstico , Transtornos Psicóticos Afetivos/psicologia , Idoso , Antidepressivos/administração & dosagem , Antidepressivos/uso terapêutico , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/psicologia , Regras de Decisão Clínica , Estudos Transversais , Transtorno Depressivo Resistente a Tratamento/epidemiologia , Cuidado Periódico , Europa (Continente)/epidemiologia , Feminino , Humanos , Pacientes Internados/psicologia , Pacientes Internados/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Risco , Índice de Gravidade de Doença , Ideação Suicida , Resultado do TratamentoRESUMO
Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.
Assuntos
Transtorno Depressivo Resistente a Tratamento , Animais , Antidepressivos/classificação , Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/etiologia , Transtorno Depressivo Resistente a Tratamento/terapia , Descoberta de Drogas , Humanos , FenótipoRESUMO
OBJECTIVE: This multicenter, multinational, cross-sectional study aimed to investigate clinical characteristics and treatment outcomes associated with augmentation/combination treatment strategies in major depressive disorder (MDD). METHOD: Sociodemographic, clinical, and treatment features of 1410 adult MDD patients were compared between MDD patients treated with monotherapy and augmentation/combination medication using descriptive statistics, analyses of covariance (ancova), and Spearman's correlation analyses. RESULTS: 60.64% of all participants received augmentation and/or combination strategies with a mean number of 2.18 ± 1.22 simultaneously prescribed psychiatric drugs. We found male gender, older age, Caucasian descent, higher weight, low educational status, absence of occupation, psychotic symptoms, melancholic and atypical features, suicide risk, in-patient treatment, longer duration of hospitalization, some psychiatric comorbidities (panic disorder, agoraphobia, obsessive-compulsive disorder, and bulimia nervosa), comorbid somatic comorbidity in general and concurrent hypertension, thyroid dysfunction, diabetes, and heart disease in particular, higher current and retrospective Montgomery and Åsberg Depression Rating Scale total scores, treatment resistance, and higher antidepressant dosing to be significantly associated with augmentation/combination treatment. These findings were corroborated when examining the number of concurrently administered psychiatric drugs in the statistical analyses. CONCLUSION: Our findings suggest a clear association between augmentation/combination strategies and treatment-resistant/difficult-to-treat MDD conditions characterized by severe symptomatology and high amount of psychiatric and somatic comorbidities.
Assuntos
Antidepressivos/administração & dosagem , Antipsicóticos/administração & dosagem , Benzodiazepinas/administração & dosagem , Comorbidade , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Tranquilizantes/administração & dosagem , Adulto , Estudos Transversais , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Resistente a Tratamento/epidemiologia , Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Sinergismo Farmacológico , Quimioterapia Combinada , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Drug-effect phenotypes in human lymphoblastoid cell lines recently allowed to identify CHL1 (cell adhesion molecule with homology to L1CAM), GAP43 (growth-associated protein 43) and ITGB3 (integrin beta 3) as new candidates for involvement in the antidepressant effect. CHL1 and ITGB3 code for adhesion molecules, while GAP43 codes for a neuron-specific cytosolic protein expressed in neuronal growth cones; all the three gene products are involved in synaptic plasticity. Sixteen polymorphisms in these genes were genotyped in two samples (n=369 and 90) with diagnosis of major depressive episode who were treated with antidepressants in a naturalistic setting. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) genome-wide study (n=1861) as both individual genes and through a pathway analysis (Reactome and String databases). Gene-based analysis suggested CHL1 rs4003413, GAP43 rs283393 and rs9860828, ITGB3 rs3809865 as the top candidates due to their replication across the largest original sample and the STAR*D cohort. GAP43 molecular pathway was associated with both response and remission in the STAR*D, with ELAVL4 representing the gene with the highest percentage of single nucleotide polymorphisms (SNPs) associated with outcomes. Other promising genes emerging from the pathway analysis were ITGB1 and NRP1. The present study was the first to analyze cell adhesion genes and their molecular pathways in antidepressant response. Genes and biomarkers involved in neuronal adhesion should be considered by further studies aimed to identify predictors of antidepressant response.
Assuntos
Antidepressivos/uso terapêutico , Moléculas de Adesão Celular Neuronais/genética , Adesão Celular/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Biomarcadores/metabolismo , Moléculas de Adesão Celular/genética , Transtorno Depressivo Maior/metabolismo , Feminino , Proteína GAP-43/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Integrina beta3/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). METHOD: For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. RESULTS: Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. CONCLUSIONS: AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.
Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Alemanha , Humanos , Entrevistas como Assunto , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético , Irmãos , Reino Unido , Adulto JovemRESUMO
Antidepressant pharmacogenetics represents a stimulating, but often discouraging field. The present study proposes a combination of several methodologies across three independent samples. Genes belonging to monoamine, neuroplasticity, circadian rhythm and transcription factor pathways were investigated in two samples (n=369 and 88) with diagnosis of major depression who were treated with antidepressants. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) genome-wide study (n=1861). Top genes were further studied through a pathway analysis. In both original samples, markers associated with outcomes were concentrated in the PPP3CC gene. Other interesting findings were particularly in the HTR2A gene in one original sample and the STAR*D. The B-cell receptor signaling pathway proved to be the putative mediator of PPP3CC's effect on antidepressant response (P=0.03). Among innovative candidates, PPP3CC, involved in the regulation of immune system and synaptic plasticity, seems promising for further investigation.
Assuntos
Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Calcineurina/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Calcineurina/genética , Depressão/genética , Depressão/imunologia , Humanos , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologiaRESUMO
Co-morbid physical illness has been suggested to play an important role among the factors contributing to treatment resistance in patients with major depressive disorder. In the current study we compared the rate of physical co-morbidity, defined by ICD-10, among a large multicenter sample of 702 patients with major depressive disorder. A total of 356 of the participants were defined as treatment resistant depression (TRD) patients-having failed two or more adequate antidepressant trials. No significant difference was found between TRD and non-TRD participants in the prevalence of any ICD-10 category. This finding suggests that although physical conditions such as diabetes, thyroid dysfunction, hypertension, ischemic heart disease, and peptic diseases are often accompanied by co-morbid MDD, they do not necessarily have an impact on the course of MDD or the likelihood to respond to treatment. Marginally higher rates of co-morbid breast cancer, migraine and glaucoma were found among TRD participants. Possible explanations for these findings and their possible relation to TRD are discussed.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Resistência a Medicamentos , Adulto , Neoplasias da Mama/epidemiologia , Comorbidade , Transtorno Depressivo Maior/epidemiologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Europa (Continente)/epidemiologia , Feminino , Glaucoma/epidemiologia , Humanos , Israel/epidemiologia , Masculino , Transtornos de Enxaqueca/epidemiologia , Prevalência , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
Many association studies have reported associations between the catechol-O-methyltransferase (COMT) gene and psychiatric disorders including major depression (MDD). The COMT gene has further been associated with suicidal behaviour, as well as with treatment response, although with conflicting results. In the present study, we further elucidate the impact of COMT in treatment response in MDD patients with suicide risk and/or a personal history of suicide attempts. Two hundred fifty MDD 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 Mini International Neuropsychiatric Interview (MINI) 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 seven SNPs (rs4680, rs2075507, rs737865, rs6269, rs4633, rs4818 and rs165599) within the COMT gene. With regard to suicide risk and personal history of suicide attempts, neither single marker nor haplotypic association was found with any SNP after multiple testing correction. In non-responders, we found significant single marker and haplotypic association with suicide risk, but not in responders. The same holds true for both remitters and non-remitters, and when testing for association with a personal history of suicide attempts and treatment response phenotypes. In conclusion, we found significant association of COMT SNPs with suicide risk in MDD patients not responding to antidepressant treatment. Larger well-defined cohorts will be required to dissect this further.
Assuntos
Antidepressivos/uso terapêutico , Catecol O-Metiltransferase/genética , Transtorno Depressivo Maior/genética , Tentativa de Suicídio/psicologia , Suicídio/psicologia , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/tratamento farmacológico , Resistência a Medicamentos , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Escalas de Graduação Psiquiátrica/estatística & dados numéricosRESUMO
BACKGROUND: A number of scales are used to estimate the severity of depression. However, differences between self-report and clinician rating, multi-dimensionality and different weighting of individual symptoms in summed scores may affect the validity of measurement. In this study we examined and integrated the psychometric properties of three commonly used rating scales. METHOD: The 17-item Hamilton Depression Rating Scale (HAMD-17), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI) were administered to 660 adult patients with unipolar depression in a multi-centre pharmacogenetic study. Item response theory (IRT) and factor analysis were used to evaluate their psychometric properties and estimate true depression severity, as well as to group items and derive factor scores. RESULTS: The MADRS and the BDI provide internally consistent but mutually distinct estimates of depression severity. The HAMD-17 is not internally consistent and contains several items less suitable for out-patients. Factor analyses indicated a dominant depression factor. A model comprising three dimensions, namely 'observed mood and anxiety', 'cognitive' and 'neurovegetative', provided a more detailed description of depression severity. CONCLUSIONS: The MADRS and the BDI can be recommended as complementary measures of depression severity. The three factor scores are proposed for external validation.
Assuntos
Transtorno Depressivo/diagnóstico , Escalas de Graduação Psiquiátrica , Humanos , Psicometria , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
We report the results of a 10 cM density genome-wide scan and further fine mapping of three chromosomal candidate regions in 10 Belgian multigenerational families with bipolar (BP) disorder. This two-stage approach revealed significant evidence for linkage on chromosome 10q21.3-10q22.3, showing a maximum multipoint parametric heterogeneity logarithm of odds (HLOD) score of 3.28 and a nonparametric linkage (NPL) score of 4.00. Most of the chromosome 10q evidence was derived from a single, large Ashkenazi Jewish pedigree. Haplotype analysis in this pedigree shows that the patients share a 14-marker haplotype, defining a chromosomal candidate region of 19.2 cM. This region was reported previously as a candidate region for BP disorder in several independent linkage analysis studies and in one large meta-analysis. It was also implicated in a linkage study on schizophrenia (SZ) in Ashkenazi Jewish families. Additionally, we found suggestive evidence for linkage on chromosome 19q13.2-13.4 (HLOD 2.01, NPL 1.09) and chromosome 7q21-q22 (HLOD 1.45, NPL 2.28). Together, these observations suggest that a gene located on chromosome 10q21.3-10q22.3 is underlying the susceptibility both for SZ and for BP disorder in at least the Ashkenazi Jewish population.
Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 10 , Saúde da Família , Predisposição Genética para Doença , Adulto , Mapeamento Cromossômico/métodos , Feminino , Ligação Genética , Genótipo , Humanos , Judeus , Escore Lod , Masculino , Razão de ChancesRESUMO
Controversial evidence exists regarding the presence of the phenomenon of anticipation in affective disorder. To further evaluate this hypothesis on the unipolar pattern of the disease, we examined 21 two-generation pairs of first and second degree relatives with unipolar recurrent major depression. Biases from index-patient and from unaffected sibs were taken into consideration. A significant difference in the age at onset and episode frequency (as measure of disease severity) between parental and offspring generation was observed. The median age at onset of the parental generation was 37+/-8.2 years compared to 22+/-8.3 years in the offspring generation (p=0.001). The offspring generation also experienced an episode frequency two times greater than the parent generation (p=0.001). Anticipation was demonstrated in 95% of pairs regarding age at onset and in 84% of pairs in episode frequency. However, the observation of a birth cohort effect may possibly explain the differences in age at onset between generations in our sample.
Assuntos
Antecipação Genética , Transtorno Depressivo/genética , Transtornos do Humor/genética , Adolescente , Adulto , Idade de Início , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Núcleo Familiar , LinhagemRESUMO
The available data from preclinical and pharmacological studies on the role of the C-O-methyl transferase (COMT) support the hypothesis that abnormal catecholamine transmission has been implicated in the pathogenesis of mood disorders (MD). We examined the relationship of a common functional polymorphism (Val108/158Met) in the COMT gene, which accounts for four-fold variation in enzyme activity, with 'early-onset' (EO) forms (less than or equal to 25 years) of MD, including patients with major depressive disorder (EO-MDD) and bipolar patients (EO-BPD), in a European multicenter case-control sample. Our sample includes 378 MDD (120 EO-MDD), 506 BPD (222 EO-BPD) and 628 controls. An association was found between the high-activity COMT Val allele, particularly the COMT Val/Val genotype and EO-MDD. These findings suggest that the COMT Val/Val genotype may be involved in EO-MDD or may be in linkage disequilibrium with a different causative polymorphism in the vicinity. The COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders.
Assuntos
Transtorno Bipolar/genética , Catecol O-Metiltransferase/genética , Transtorno Depressivo Maior/genética , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores Etários , Substituição de Aminoácidos/genética , Transtorno Bipolar/enzimologia , Estudos de Casos e Controles , Transtorno Depressivo Maior/enzimologia , Europa (Continente) , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Valores de Referência , Fatores de RiscoRESUMO
Increasing amounts of data suggest that affective disorders might be related to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, one of the stress-response systems. Arginine vasopressin (AVP) influences several symptoms, relevant to affective disorders, notable memory processes, pain sensitivity, synchronization of biological rhythms and the timing and quality of REM sleep. We examined whether genetic variations in the AVP receptor 1b gene (AVPR1b) could be associated with increased susceptibility to affective disorders using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). Five SNPs were identified in AVPR1b and genotyped in two well-diagnosed samples of patients with recurrent major depression and matched controls. In the Swedish sample, we observed significant allele (P=0.02) and genotype (P=0.01) association with SNP AVPR1b-s3, and in the Belgian sample, a borderline significant association with SNP AVPR1b-s5 (P=0.04). In both patient-control samples, the haplotype defined by alleles A-T-C-A-G for the AVPR1b-s SNPs s1-s2-s3-s4-s5 was significantly over-represented in controls compared to patients. Our data support a protective effect of this major haplotype for recurrent major depression.
Assuntos
Transtorno Depressivo/genética , Transtorno Depressivo/prevenção & controle , Polimorfismo de Nucleotídeo Único/genética , Receptores de Vasopressinas/genética , Idoso , Sequência de Bases , Bélgica , Feminino , Haplótipos , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Sistema Hipófise-Suprarrenal/fisiologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Valores de Referência , SuéciaRESUMO
The aim of the present study was to investigate impairment in social adjustment and self-esteem of bipolar patients (n=144) in remission for at least 3 months. Patients were recruited among four different centres: Sofia, Athens, Jerusalem and Milan, and were individually matched to control subjects in relation to sex, age and geographical origin. Subjects completed the Rosenberg self-esteem scale (SES) and the self-report version of the social adjustment scale (SAS). Bipolar patients reported to experience more difficulties in social adjustment than controls, specifically for leisure and work activities. Further, our results show that bipolar patients have significantly lower self-esteem compared to controls, even after remission.
Assuntos
Transtorno Bipolar/psicologia , Autoimagem , Ajustamento Social , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Many authors have described these last years the difficulty to establish a differential diagnosis between schizophrenia and frontotemporal dementia. However treatment and prognosis of these two separate diseases are not the same. Schizophrenia is a chronic syndrome with an early onset during teenage or young adulthood period and the major features consist of delirious ideas, hallucinations and psychic dissociation. However a large variety of different symptoms describes the disease and creates a heterogeneous entity. The diagnosis, exclusively defined by clinical signs, is then difficult and has led to the research of specific symptoms. These involve multiple psychological processes, such as perception (hallucinations), reality testing (delusions), thought processes (loose associations), feeling (flatness, inappropriate affect), behaviour (catatonia, disorganization), attention, concentration, motivation (avolition), and judgement. The characteristic symptoms of schizophrenia have often been conceptualised as falling into three broad categories including positive (hallucination, delision), negative (affective flattening, alogia, avolition) and disorganised (poor attention, disorganised speech and behaviour) symptoms. No single symptom is pathogonomonic of schizophrenia. These psychological and behavioural characteristics are associated with a variety of impairments in occupational or social functioning. Cognition impairments are also associated with schizophrenia. Since the original clinical description by Kraepelin and Bleuler, abnormalities in attentional, associative and volitional cognitive processes have been considered central features of schizophrenia. Long term memory deficits, attentional and executive dysfunctions are described in the neurocognitive profile of schizophrenic patients, with a large degree of severity. The pathophysiology of schizophrenia is not well known but may be better understood by neuronal dysfunctions rather than by a specific anatomical abnormality. Frontotemporal lobar degeneration (FTLD) is one of the most common causes of cortical dementia. FTLD is associated with an anatomical atrophy that can be generalised, with a frontotemporal or focal lobar predominance. Histologically there is severe neuronal loss, gliosis and a state of spongiosis. In a minority of case Pick cells and Pick bodies are also found. The usual clinical features of FTLD are divided in three prototypic syndromes: frontotemporal dementia (FTD), progressive non-fluent aphasia (PA) and semantic dementia (SD). FTD is the most common clinical manifestation of FTLD. FTD is first characterised by profound alteration in personality and social conduct, characterised by inertia and loss of volition or social disinhibition and distractibility. There is emotional blunting and loss of insight. Speech output is typically economical, leading ultimately to mutism, although a press of speech may be present in some overactive, disinhibited patients. Memory is relatively preserved in the early stage of the disease. Cognitive deficits occur in the domains of attention, planning and problems solving, whereas primary tools of language, perception and spatial functions are well preserved. PA is an initial disorder of expressive language, characterised by effortful speech production, phonologic and grammatical errors. Difficulties in reading and writing also occur but understanding of word meaning is relatively well preserved. In SD a severe naming and word comprehension impairment occur on the beginning in the context of fluent, effortless, and grammatical speech output. There is also an inability to recognise the meaning of visual percepts. The clinical syndromes of FTLD are associated with the brain topography of the degeneration. So considerable clinical overlap can exist between schizophrenia and FTLD and the object of the following case report is to remind the difficulty to make a differential diagnosis between these two pathologies. CASE REPORT: A 34 year old non-married man is admitted in mental health district of a general hospital for behavioural disturbances that include repeated aggressions towards his family. At initial interview visual and auditives hallucinations are described. The patient doesn't care about these abnormalities and a poverty of speech is observed. The affects, globally blunted, show some degree of sadness however. The patient's birth and early development were unremarkable. At the age of 26, the patient dismissed from his job because of poor performance and absenteeism. He spent a lot of time watching TV, showed poverty of speech and become sometimes angry and violent without an explanation. He was hospitalised for several months and a schizophrenia including predominant negative features, hallucinations and delusion was diagnosed. He was treated with bromperidol, could go back to home and was followed by a general practitioner for 8 years. The patient had a stereotyped way of life during these years with a poor communication and little activity. During the months preceding the current hospitalisation, these characteristics and avolition emphasised, urinary incontinence appeared. The patient receives risperidone 8 mg/day associated with citalopram 40 mg/day during several months of hospitalisation. No significant evolution is observed regarding apathic and stereotyped way of live. The capacity of communication remains very poor. Neurocognitive assessments reveal multiple and severe dysfunctions. Memory, executive and attentional tasks are extremely disturbed. Physical and neurological examinations reveal an isolated bilateral Babinski sign. Cerebral scanner and magnetic resonance show bifrontal atrophy and PET scan is normal. There are no significant abnormalities found on blood and urine samples and on lumbar puncture. The patient is sent to a chronic neuropsychiatric hospital and the treatment is stopped. One year later, a comparative evaluation is realised. The general clinical state shows no evolution. Neurocognitive assessments are repeated and severe dysfunctions are observed with more perseverations. DISCUSSION: A diagnosis of FTLD for this patient can be discussed regarding clinical features, neurocognitive testings and neuroradiological findings. Schizophrenia is a major differential diagnosis. Psychotic symptoms like hallucinations and age of onset are essential observations for the diagnosis of schizophrenia but can not exclude FTLD. Memory, intellectual functions, executive and attentional abilities may all be disturbed in schizophrenia and FTLD. Cerebral abnormalities well established in schizophrenia are lateral ventricles enlargements. Frontal lobar atrophy is a major argument for FTLD and is only a sporadic finding in schizophrenic populations. Schizophrenia and FTLD could be comorbid diseases by several ways. CONCLUSION: A differential diagnosis between schizophrenia and FTLD is difficult to establish. Schizophrenia is a heterogeneous disease with a large variety of cognitive dysfunctions. Neurocognitive tools may improve our knowledge of schizophrenia.
Assuntos
Demência , Demência/fisiopatologia , Lobo Frontal/fisiopatologia , Transtornos Psicóticos/complicações , Esquizofrenia/complicações , Esquizofrenia/diagnóstico , Adulto , Transtornos Cognitivos/diagnóstico , Demência/complicações , Demência/diagnóstico , Demência/patologia , Diagnóstico Diferencial , Humanos , Masculino , Testes Neuropsicológicos , Índice de Gravidade de DoençaRESUMO
We previously identified 18q21-q22 as a candidate region for bipolar (BP) disorder and constructed a yeast artificial chromosome (YAC) contig map. Here we identified three potential CpG islands using CCG/CGG YAC fragmentation. Analysis of available genomic sequences using bioinformatic tools identified an exon of 3639 bp downstream of a CpG island of 1.2 kb containing a putative transcription initiation site. The exon contained an open reading frame coding for 1212 amino acids with significant homology to the SART-2 protein; weaker homology was found with a series of sulphotransferases. Alignment of cDNA sequences of corresponding ESTs and RT-PCR sequencing predicted a transcript of 9.5 kb which was confirmed by Northern blot analysis. The transcript was expressed in different brain areas as well as in multiple other peripheral tissues. We performed an extensive mutation analysis in 113 BP patients. A total of nine single nucleotide polymorphisms (SNPs) were identified. Five SNPs predicted an amino acid change, of which two were present in BP patients but not in 163 control individuals.
Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 18 , Ilhas de CpG/genética , Substituição de Aminoácidos/genética , Antígenos de Neoplasias/genética , Cromossomos Artificiais de Levedura , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Expressão Gênica , Humanos , Proteínas de Neoplasias/genética , Fases de Leitura Aberta/genética , Polimorfismo de Nucleotídeo Único , Expansão das Repetições de TrinucleotídeosRESUMO
BACKGROUND: While there is ample evidence that the prevalence rates for major depressive disorder (MDD) in the general population are higher in women than in men, there is little data on gender differences as regard to symptoms, causal attribution, help-seeking, coping, or the consequences of depression. METHOD: The large DEPRES Study dataset covering representative population samples of six European countries (wave I: 38,434 men and 40,024 women; wave II: 563 men and 1321 women treated for depression) was analyzed for gender differences. RESULTS: In wave I marked gender differences were found in the six-month prevalence rate for major depression but less so for minor depression; the gender differences for major depression persisted across all age groups. Even after stratification by clinically significant impairment and paid employment status, men reported fewer symptoms than women; as a consequence, men reached the diagnostic threshold less often. In wave II there were clear gender differences in causal attribution and in coping. Men coped by increasing their sports activity and consumption of alcohol and women through emotional release and religion. Women felt the effects of depression in their quality of sleep and general health, whereas men felt it more in their ability to work. LIMITATIONS: The second wave of the study comprises treated depressives only and may be less representative than the first wave.
Assuntos
Transtorno Depressivo Maior/epidemiologia , Adaptação Psicológica , Adolescente , Adulto , Idoso , Ansiedade/diagnóstico , Ansiedade/epidemiologia , Ansiedade/etiologia , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/etiologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , França/epidemiologia , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Aceitação pelo Paciente de Cuidados de Saúde , Projetos Piloto , Prevalência , Qualidade de Vida , Índice de Gravidade de Doença , Distribuição por Sexo , Papel do Doente , Espanha/epidemiologia , Reino Unido/epidemiologiaRESUMO
Self-esteem (SE) and social adjustment (SA) are often impaired during the course of affective disorders; this impairment is associated with suicidal behaviour. The aim of the present study was to investigate SE and SA in unipolar or bipolar patients in relation to demographic and clinical characteristics, especially the presence of suicidality (ideation and/or attempt). Forty-four patients, 28 bipolar and 16 unipolar, in remission for at least 3 months, and 50 healthy individuals were examined through a structured clinical interview. SE and SA were assessed by the Rosenberg self-esteem scale and the social adjustment scale, respectively. The results have shown that bipolar patients did not differ from controls in terms of SE, while unipolar patients had lower SE than bipolars and controls. No significant differences in the mean SA scores were found between the three groups. Suicidality during depression was associated only in bipolar patients with lower SE at remission; similar but not as pronounced was the association of suicidality with SA. It is concluded that low SE lasting into remission seems to be related to the expression of suicidality during depressive episodes of bipolar patients, while no similar pattern is evident in unipolar patients.