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Background: Adverse childhood experiences have been described as one of the major environmental risk factors for depressive disorder. Similarly, the deleterious impact of early traumatic experiences on depression seems to be moderated by individual genetic variability. Serotonin transporter (5-HTT) and brain-derived neurotrophic factor (BDNF) modulate the effect of childhood adversity on adult depression, although inconsistencies across studies have been found. Moreover, the gene x environment (GxE) interaction concerning the different types of childhood adversity remains poorly understood. The aim of this study was to analyse the putative interaction between the 5-HTT gene (5-HTTLPR polymorphism), the BDNF gene (Val66Met polymorphism) and childhood adversity in accounting for adult depressive symptoms., Method: A sample of 534 healthy individuals filled in self-report questionnaires of depressive symptomatology [the Symptom Check List 90 Revised (SCL-90-R)] and different types of childhood adversities [the Childhood Trauma Questionnaire (CTQ)]. The 5-HTTLPR polymorphism (5-HTT gene) and the Val66Met polymorphism (BDNF gene) were genotyped in the whole sample., Results: Total childhood adversity (beta=0.27, p<0.001), childhood sexual abuse (CSA; beta=0.17, p<0.001), childhood emotional abuse (beta=0.27, p<0.001) and childhood emotional neglect (beta=0.22, p<0.001) had an impact on adult depressive symptoms. CSA had a greater impact on depressive symptoms in Met allele carriers of the BDNF gene than in the Val/Val group (F=5.87, p<0.0001), and in S carriers of the 5-HTTLPR polymorphism (5-HTT gene) (F=5.80, p<0.0001)., Conclusions: Childhood adversity per se predicted higher levels of adult depressive symptoms. In addition, BDNF Val66Met and 5-HTTLPR polymorphisms seemed to moderate the effect of CSA on adult depressive symptoms.

Background: Dysbindin gene (dystrobrevin-binding-protein 1, DTNBP1) variants have been associated with several psychiatric conditions including mood disorders and antidepressant efficacy. We investigated dysbindin gene (DTNBP1) variants in major depression and clinical response to selective serotonin reuptake inhibitors., Methods: In this study we investigated the role of DTNBP1 gene (rs3213207, rs2005976, rs760761 and rs2619522) in 313 major depressive outpatients and 149 healthy individuals. One hundred and forty-seven depressive patients were treated with citalopram and evaluated for response (4th week) and remission (12th week) by the 1-item Hamilton Depression Rating Scale. Single nucleotide polymorphisms (SNPs) were assayed by using Applied Biosystems TaqMan technology., Results: Genotype and haplotype frequencies for four SNPs within DTNBP1 gene did not significantly differ between patients and controls. Allele distribution of SNP rs760761, however, showed a trend of difference between responders and nonresponders (4th week). Haplotype analyses produced a significant association with response to treatment at week 4. No differences were found in remission (12th week)., Discussion: DTNBP seems to have an effect on short-term clinical response to citalopram. New studies focused on other genes involved in glutamatergic neurotransmission and related proteins could help to elucidate the complex mechanism of clinical response to antidepressants.

Twin, family and recent molecular studies support the hypothesis of genetic overlapping between schizophrenia and bipolar disorder. Brain structural features shared by both psychiatric disorders might be the phenotypic expression of a common genetic risk background. Interleukin-1 (IL-1) cluster (chromosome 2q13) genetic variability, previously associated with an increased risk both for schizophrenia and for bipolar disorder, has been also associated with gray matter (GM) deficits, ventricular enlargement and hypoactivity of prefrontal cortex in schizophrenia. The aim of the present study was to analyze the influence of IL-1 cluster on brain morphology in bipolar disorder. Genetic variability at IL-1B and IL-1RN genes was analyzed in 20 DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition) bipolar patients. Magnetic resonance imaging (MRI) measurements were obtained for whole-brain GM and white matter, dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus, hippocampus and lateral ventricles. MRI data were corrected for age and cranial size using regression parameters from a group of 45 healthy subjects. A -511C/T polymorphism (rs16944) of IL-1B gene was associated with whole-brain GM deficits (P = 0.031) and left DLPFCGM deficits (P = 0.047) in bipolar disorder patients. These findings support the hypothesis of IL-1 cluster variability as a shared genetic risk factor contributing to GM deficits both in bipolar disorder and in schizophrenia. Independent replication in larger samples would be of interest to confirm these results.

Working memory has been described as a neurocognitive probe of prefrontal brain functioning. Genetic variability related with catechol-O-methyltransferase (COMT) gene (Val158Met polymorphism) has received increasing attention as a possible modulator of working memory tasks in both schizophrenic patients and healthy subjects, although inconsistencies across studies have been found. This may be related to the existence of different working memory components, processes and modalities, which may have different sensitivities to subtle changes in dopamine levels and, therefore, the effect of the underlying COMT Val158Met genetic variability. To test this out a large sample of 521 healthy individuals from the general population were tested on the WCST and three working memory tasks that cover the assessment of verbal and spatial working modalities as well as different components and processes (Letter and Number Sequencing, CPT-IP, Backwards Visual Span). All individuals were genotyped for the rs4680 (Val158Met) polymorphism at the COMT gene. Met carriers showed near-significant better performance in the LNS compared with Val/Val individuals (F = 3.9, df = 1, P = 0.046). Moreover, the analysis for linear trend found that Met allele carriers showed significantly better performance than Val/Val individuals (B = 0.58 P = 0.031), although evidence for a linear trend was not found. None of the WCST indices differed among genotypes. Consistent with the hypothesis that Val158Met polymorphism (COMT gene) might account for individual differences on dopamine-dependent prefrontally related neurocognitive functions, the Letter-Number Sequencing task, which requires not only maintenance but also active manipulation of information seemed to be more sensitive to the disadvantageous Val/Val genotype in a large non-clinical sample., (2008 Wiley-Liss, Inc.)

Background: Several studies have reported an increase of dermatoglyphic anomalies in schizophrenic patients compared to controls. However, the recognition of specific dermatoglyphic variables related to this disorder and their genetic and/or environmental component are still controversial., Method: We conducted a dermatoglyphic analysis in a new sample of 617 individuals: 205 patients with schizophrenia-spectrum disorders, 224 healthy first degree relatives and 188 healthy controls. The dermatoglyphic variables studied were: the total a-b ridge count (TABRC) and its fluctuating asymmetry (FAABRC), and the presence of ridge dissociations (RD) and abnormal palmar flexion creases (APFC)., Results: Patients, relatives and controls did not differ in TABRC. However, within the patients group those with a low birth weight or absence of psychiatric family history showed lower TABRC than the others. The frequency of ectodermic derivates abnormalities (RD and/or APFC) appeared to be higher in patients and relatives than in controls, while first degree relatives did not differ from patients. Males showed an increased rate of ectodermic derivates abnormalities compared to females in all groups and male patients also presented higher FAABRC than female patients., Conclusions: Our results suggest a different relative weight of genetic and environmental factors on each dermatoglyphic variable analyzed: i) TABRC may be a sensitive marker to environmental factors in schizophrenia, ii) ectodermal derivates abnormalities appear to be influenced by genetic risk factors, which could be involved both in the disrupted development of ectodermic derivates like dermatoglyphics and central nervous system and in the vulnerability for schizophrenia.

Hypoactivity of the dorsolateral prefrontal cortex (DLPFC) during cognitive tasks is among the most consistent findings in schizophrenia. The biological factors contributing to this hypofrontality are only partially known. Previous reports have shown the influence of genes mapped to IL-1 cluster (i) in the risk to develop schizophrenia and (ii) on brain morphological abnormalities in these patients. Moreover, Interleukin-1beta (IL-1beta), encoded by IL-1B gene (IL-1 cluster, chromosome 2q13) has a key role in dopaminergic differentiation and dendrite growth in developing cortical neurons. The authors explored the role of a genetic functional polymorphism at IL-1B gene in relation to DLPFC activity. DLPFC (left and right) metabolic activity was measured in a sample of 19 DSM-IV diagnosed schizophrenic patients of Spanish origin using a procedure based on MRI/PET image fusion. During PET studies, subjects performed a contingent Continuous Performance Test aiming to activate DLPFC. Functional promoter polymorphism -511 C/T (rs16944) of IL-1B gene was genotyped in these patients. Those patients who were allele 2 (-511 T) carriers showed a lower metabolic activity in the left DLPFC with respect to patients homozygous for allele 1 (-511 C) (U = 16, z = -2.32, P = 0.02). Our results suggest that hypofrontality reported in some schizophrenic patients might be explained, at least in part, by this functional polymorphism at IL-1B gene. Genetic variants with influence on brain functionality may account for the neurocognitive heterogeneity observed in schizophrenic patients., (2007 Wiley-Liss, Inc.)

Background: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been observed in major depression. Normalization of HPA axis has been suggested to play a role in the mechanisms of action of antidepressants. Our aim was to investigate the influence of genetic variants in CRHR1, CRHR2, CRH-BP and FKBP5 genes on both the vulnerability for depression and the response to antidepressant treatment., Methods: The sample consisted of 159 depressive outpatients and 96 healthy controls of Spanish origin. Patients were assessed for clinical features including, among others, age of onset, seasonality or suicidal behavior. The episode was treated with citalopram and followed along 12 weeks. Severity of symptoms was evaluated at the inclusion and then monthly along the follow-up using a 21-item Hamilton Depression Rating Score (HDRS). SNPs were assayed using Applied Biosystems SNaP-Shot and TaqMan technology., Results: rs110402, in CRHR1 gene, was associated with an increased risk to present a seasonal pattern and an early age of onset of the first depressive episode. Allele G carriers of rs2270007 of CRHR2 gene, showed a worse overall response to citalopram along time of follow-up (Genotype effect F=7.45, P=0.007). G allele carriers showed 2.93 increased risk (95% CI [1.24-6.90]) for non-responding at 4th week to citalopram treatment (chi(2)=7.59, df=1, P=0.006)., Limitations: On the light of the moderate sample size, associations based on the mentioned polymorphisms need to be considered with caution and require further replication studies in other samples., Conclusions: Variability at genes encoding proteins with a pivotal role in HPA axis regulation seems to influence i) the expression of severity variables of the depressive spectrum including early age of onset or a seasonal pattern and ii) the interindividual variation in clinical response to SSRI antidepressants.

Unlabelled: Working memory (WM) has hardly been explored in non-psychotic relatives of schizophrenic patients despite its potential suitability as a neurocognitive endophenotype. Indeed, WM modalities, components and processes have rarely been compared in the same group of relatives. The present study examined neurocognitive performance in healthy siblings of schizophrenic patients, including both spatial and verbal WM modalities and tests tapping maintenance (Spatial Span Backwards and CPT-IP d') and manipulative (Letters and Numbers Sequencing) WM processes., Methods: 68 schizophrenia patients, 38 healthy siblings and 63 controls were assessed on IQ, attention, memory, WM, and executive functions. Cluster A symptoms were screened out in siblings and controls., Results: Siblings had an intermediate performance between that of schizophrenic patients and controls. They performed worse than controls on IQ, LNS, animal naming, backwards spatial span, phonemic fluency, numbers d', and forward spatial span., Discussion: Consistent with the WM literature in schizophrenia, both verbal and spatial WM differed significantly between siblings and controls, suggesting that WM deficits are modality independent. Our results failed to support the hypothesis that tests tapping WM manipulative processes heavily loading on DLFPC are quantitatively more impaired in relatives and, therefore, more sensitive to liability for schizophrenia. However, firm conclusions cannot be drawn until more studies assessing both maintenance and manipulative WM processes in relatives are available.

The synaptic vesicular monoamine transporter (SVMT) plays a key role in monoaminergic neurotransmission determining the size of neurotransmitter vesicular pools available for exocytotic release. Recently, several lines of evidence have suggested that altered functions of SVMT may be involved in the pathogenesis of certain neuropsychiatric diseases, including psychotic and mood disorders. In the present study, we tested the potential involvement of SVMT gene variants in the etiology of schizophrenia and bipolar disorder. Five different SNPs (T440G, C1368T, T2666C, A2683C, and A745G) were included in the analysis covering a region of about 35 kb along the SVMT gene. Analyses were performed in a case-control sample consisting of 88 bipolar patients, 107 subjects with schizophrenia, and 164 controls. Two risk haplotypes for both schizophrenia and bipolar disorder in SVMT gene were identified. Particularly, 2666T-2683A-745G (TAG) and 2666C-2683C-745A (CCA) combinations were significantly more frequent in both bipolar and schizophrenic patients than in controls. UNPHASED package estimated haplotype effects for all patients yielded relative risks of 4.1 (95%CI: 1.83-9.21) for TAG combination and 2.336 (95%CI: 1.28-4.26) for CCA haplotype. Conversely, 2666T-2683C-745A (TCA) and 2666C-2683A-745G (CAG) haplotypes seemed to protect against these mental disorders, since the estimated frequency in control chromosomes was 12% whilst such haplotypes were not observed in any bipolar or schizophrenic subject (P < 0.0000). Our results strongly suggest that SVMT gene or certain regions of it may constitute a genetic substrate of susceptibility for both schizophrenia and bipolar disorder., ((c) 2007 Wiley-Liss, Inc.)

Schizophrenia (SZ) is a prevalent and severe mental disorder. One of the most favored hypotheses for the etiology of SZ is the neurodevelopmental hypothesis. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth factor family, promotes the development, regeneration, and survival of neurons and has been linked to the neuropathology of SZ. The present study tested, in a sample of 94 nuclear families, the hypothesis that the BDNF gene Val66Met polymorphism is associated to SZ and its psychopathologic phenotype using a multidimensional symptom approach. Furthermore, considering a reported reduction of BDNF in the frontal cortex of patients with SZ, we studied the relationship between this polymorphism and prefrontal function. The transmission disequilibrium test (TDT) showed a preferential transmission of allele Val from heterozygous parents to the affected offspring (P = 0.002), suggesting a possible role of this gene in the vulnerability to SZ spectrum disorders. The findings remained essentially unchanged when the analysis was restricted to the subgroup of patients with SZ (P = 0.009) and when a multidimensional approach to the diagnosis was used. Quantitative transmission disequilibrium test (QTDT) analyses did not demonstrate a significant association between the prefrontal tests assessed (Wisconsin Card Sorting Test and Trail Making Test) and the transmission of the BDNF alleles. Our finding suggests that the investigated BDNF polymorphism plays an important role in the phenotype of psychosis, but not in the performance of tests of prefrontal cognitive functions analyzed in these patients., ((c) 2006 Wiley-Liss, Inc.)

Introduction and Objectives: There is convincing evidence of interactions between serotonergic and dopaminergic systems and it seems that an increase of dopamine concentration in the whole brain could be a limiting factor for the antidepressant like effect of antidepressants. The COMT gene might be a good candidate for explaining some aspects of the pharmacological response to SSRIs., Methods: The aim of our study was to analyse the Val 158 Met functional polymorphism on COMT gene and clinical response (4 weeks) and clinical remission (6/8 and 12 weeks) in two samples of depressive patients (DSM-IV) treated with SSRIs of Italian and Spanish origin. Clinical outcome was measured using 21 items Hamilton scale, weekly in the Italian sample (along 6 weeks) and monthly in the Spanish one (along 12 weeks)., Results: No overall effect of genotype or genotypextime interaction was detected. However, we observed a genotypextime interaction on HDRS decrease for citalopram treatment (F((4.6,317.5)) = 3.38, P = 0.007) in the Spanish sample. No clear effect was observed in the Italian sample. The three samples were pooled in order to test if carrying the Met/Met genotype confers an increased risk for non-remission at 6-8 weeks. The results showed that Met/Met carriers have an odds ratio of 2.21 (95% CI [1.20-4.12]) for non-remission (chi(2) = 7.43, df = 2, P = 0.006). The Met/Met effect was not observed in response at 4th week (for all SSRI treatments) or in remission at 12th week (citalopram treatment)., Conclusions: COMT gene could have a small and indirect effect of clinical response to SSRIs by slowing-down the antidepressant action along the follow-up, basically in citalopram treatment.

The neurodevelopmental hypothesis of schizophrenia suggests that adverse genetic loading in conjunction with environmental factors early in fetal life causes a disruption of neural development, decades before the symptomatic manifestation of the disease. Neurocognitive deficits have been observed early on the course of schizophrenia, and their association with an early developmental brain lesion has been postulated. Dermatoglyphics have been analyzed in schizophrenia as markers of prenatal brain injury because of their early fetal ontogenesis and susceptibility to the same environmental factors that can also affect cerebral development. The aim of our study was to conduct a comparative examination of neurocognitive functions and dermatoglyphic variables in 89 sibling pairs discordant for schizophrenia spectrum disorders. Therefore, we investigated the association between these two markers to explore the prenatal origin of cognitive deficits in schizophrenia. The affected siblings were significantly impaired on all the cognitive variables assessed (Wisconsin Card Sorting Test, Trail Making Test and Continuous Performance Test) and had a greater number of dermatoglyphic anomalies. These results suggest the influence of intrauterine environmental factors in the siblings affected with schizophrenia. However, we did not detect a significant association between these two vulnerability markers in the schizophrenic patients, suggesting the role of genetic or late environmental factors in the origin of the neurocognitive deficits found in these patients.

Magnetic resonance imaging (MRI) studies have shown some morphological and volumetric peculiarities in brains of schizophrenic patients. The authors explored the influence of genetic polymorphisms at interleukin-1beta (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) genes on these abnormalities. Hippocampus, lateral ventricles, and dorsolateral prefrontal cortex gray matter volumes were measured in a sample of 23 DSM-IV diagnosed schizophrenic patients of Spanish origin using MRI scans; MRI data were adjusted for age and brain volume using regression parameters from a healthy control group (n = 45). IL-1B and IL-1RN genes, involved in neurodevelopment and neurodegenerative processes, were analyzed in the patient sample. Patients carrying VNTR-allele*2 of IL-1RN gene showed a significant enlargement of both left (P = 0.002) and right (P = 0.01) ventricles. Sex and illness duration were controlled for in the analyses. Our results, though preliminary, suggest that IL-1RN gene might contribute to the ventricular volumetric changes observed in schizophrenic patients.

Background: Patients with schizophrenia show deviances in their dermatoglyphics, in particular reductions in palmar a-b ridge counts (ABRCs), which are evidence of an early developmental deviance. However, the severity or the origin of these ABRC changes has not been established., Method: (i) We examined the published literature on the ABRC in patients with schizophrenia against controls with a random effects meta-analysis. (ii) We used linear regression to study the ABRC in our sample of families including 125 patients with schizophrenia, 107 of their unaffected relatives and 98 controls. (iii) The effect of obstetric complications on the patient's ABRC was examined using the Lewis Murray scale., Results: The pooled standardised effect size of ABRC differences between patients and controls obtained by our meta-analysis was 0.39 (95% CI: 0.05-0.73; p=0.03). In our sample, there were no significant differences in ABRCs between those with schizophrenia, their relatives and controls. Only those patients with obstetric complications had significantly reduced ABRC compared to controls (p=0.01)., Conclusions: We confirmed the presence of significant yet mild ABRC reductions in schizophrenia. These represent a subtle deviance from the norm and could be present in certain subsets of patients, possibly those who suffered early developmental insults.

In the context of a long-term follow-up study, we analysed the possible implication of the 5-HT(1A) receptor gene (HTR1A) -1018C/G polymorphism in the clinical outcome of major depressive patients treated with citalopram. We had previously reported an association between variation on the SERT gene (SLC6A4) and clinical remission after citalopram treatment. In the present 12-week follow-up study, the combined effect of HTR1A and SLC6A4 genes in clinical outcome and response to citalopram was also evaluated. The sample consisted of 130 patients, all of Spanish origin, who were diagnosed as having a current major depressive episode according to DSM-IV criteria. A 21-item Hamilton Depression Rating Scale was used to assess severity of symptoms at the beginning and during the follow-up to determine the outcome and remission status at week 12. Patients were genotyped for HTR1A gene and, in addition, for two polymorphisms at the CYP2C19 gene, which together account for the 87% of the Caucasian poor metabolizer phenotype. Data were analysed adjusting for the effect of poor metabolizers in clinical response. No independent effect was found for the 5-HT(1A) receptor gene in relation to clinical outcome or remission after citalopram treatment. However, a combined genetic effect of HTR1A and SLC6A4 genes was found to influence the clinical outcome of patients [F(4,102) = 2.89, p= 0.02]. When considering the remission status, an increase of patients carrying the risk genotype combination (S/S-G/G) was found among those subjects who did not reach remission (Fisher's exact test = 0.009). Our results suggest that the combined effect of the serotonin transporter and the 5-HT(1A) receptor genes could be related to the clinical outcome of depressive patients treated with citalopram.

Monoamine oxidase A (MAOA) has been suggested to be involved in human behaviour and physiology due to its key role in the metabolism of several different biological amines including the neurotransmitters serotonin, norepinephrin and dopamine.Recently, a 30 bp repeat in the MAOA gene promoter (uMAOA) has been demonstrated to be polymorphic and to affect transcriptional activity. In the context of an association case-control study design, we analysed the uMAOA polymorphism in 389 unrelated patients affected by severe mood disorders (88 bipolar subjects and 301 major depressive individuals) and in 156 controls. No association was found between the uMAOA locus and bipolar disorder or major depression. However, an increase of high-activity uMAOA alleles was found in major depression female patients presenting a seasonal pattern (chi2=3.013, P=0.05) or psychotic symptoms in their episodes (chi2=2.679, P=0.07). In female bipolar disorder patients, long alleles were associated with longest times of admission (F=4.604, P=0.037). A trend for association with seasonal pattern was also defined in this group (data not corrected for multiple testing). Our results suggest that MAOA gene variation may modulate the expression of some clinical aspects of severe mood disorders, especially in females, and support the existence of a genetic and aetiologic heterogeneity underlying the diagnoses of bipolar disorder and major depression.

Owing to the role of the nuclear phosphoprotein p53 in the regulation of neurodegeneration and neurodevelopmental processes, some authors have suggested TP53 as a candidate gene for schizophrenia and/or the neurocognitive deficits commonly observed in these patients. In the present study we have analyzed two polymorphisms (Pro72Arg and 16 bp insertion) located on the TP53 gene in order to investigate their role in the risk of developing schizophrenia and their effect on the neurocognitive profile of these patients in the context of an association study. The distribution of genotypes, alleles and haplotypes did not differ between cases and controls. Additionally, we did not detect any influence of this genetic variability in the neurocognitive functions of schizophrenic patients. Our findings suggest that the analyzed variability of the TP53 gene does not influence (i) the risk of suffering from schizophrenia and (ii) the deficits in the neurocognitive profile of these patients.

Objective: Using a sample of sibling pairs discordant for psychosis, the authors attempted to replicate the findings of previous studies suggesting that the functional genetic polymorphism Val158Met in the catechol O-methyltransferase (COMT) gene influences prefrontal cognitive function and increases the risk for schizophrenia., Method: Eighty-nine sibling pairs discordant for psychosis were genotyped for this polymorphism and were assessed with the Wisconsin Card Sorting Test, a measure of prefrontal function. Additionally, the preferential transmission of alleles for this polymorphism was analyzed in a sample of 89 nuclear families in order to examine the genetic association., Results: In the healthy siblings, a linear relationship was seen in which performance on the Wisconsin Card Sorting Test was associated in an allele dosage fashion with COMT genotype (i.e., fewer perseverative errors with higher number of methionine alleles). However, this association was not observed in patients. Furthermore, no evidence of genetic association with psychosis was detected., Conclusions: These results seem to confirm the role of COMT genotype in the modulation of executive functions related to frontal lobe function in healthy individuals but not in schizophrenia patients.

Interleukin-1beta (IL-1beta), as well as other cytokines, has been classically implicated in the pathophysiology of major psychiatric disorders such as schizophrenia and major depression, and recent studies have implicated the IL-1beta gene and schizophrenia. Nevertheless, new approaches to this complex phenotype are necessary to clarify the risk conferred by this gene, either to the disorder or to its clinical manifestations. The aim of the present study was to explore the effect of a genetic polymorphism of the promoter region of the IL-1beta gene, in schizophrenia defined with: (i) a categorical diagnosis and (ii) a multidimensional symptom approach. We studied 356 individuals from 89 nuclear families consisting of one affected individual and the unaffected father, mother, and sib, in a family-based association study design. We find a trend for biased transmission of allele 2 from heterozygous parents to affected offspring, categorically defined (P = 0.07). This tendency was not observed in the healthy offspring. Using a multidimensional symptom approach to the diagnosis, the association was confirmed in psychotic patients showing the depressive symptom-dimension (P = 0.02)., (Copyright 2003 Wiley-Liss, Inc.)

In the context of a long term follow-up study, we analysed the possible implication of the 5-HTTLPR polymorphism at the serotonin transporter gene in clinical response and remission of major depressive patients treated with citalopram. The sample consisted of 131 patients, all of Spanish origin, diagnosed according to DSM-IV criteria. A 21-item Hamilton Depression Rating Scale (HDRS) was used to evaluate severity of the symptoms during the follow-up and to determine clinical response and remission condition of the patients at 4th and 12th week, respectively. Our results showed that S/S genotype of the 5-HTTLPR polymorphism was associated with the non-Remission condition at 12th week (chi2 = 8.7, P = 0.013). Moreover, homozygous for the allele S presented three times more risk for non reaching remission of depressive episode after citalopram treatment than patients with any other 5-HTTLPR genotype combination (chi2: 7.29, P = 0.006; OR = 3.23 [95%CI: 1.24-8.5]). In conclusion, our results show that genetic variation of serotonin transporter is involved in clinical remission of major depressive episodes after twelve weeks of citalopram treatment.

The origins of cerebral abnormalities in psychotic patients remain unknown. Dermatoglyphics are suitable markers of prenatal injury due to their fetal ontogenesis and their susceptibility to some of the factors that also affect cerebral development. In a previous study, positive associations between brain volumetric measures and a dermatoglyphic marker, the ab-ridge count, were reported. The present study is an attempt to replicate that finding in an independent sample. Magnetic resonance imaging (MRI) scans and dermatoglyphic measures were available for 29 schizophrenia patients (Research Diagnostic Criteria [RDC] criteria) and 26 unrelated healthy controls. The images were processed using an automated procedure, yielding volumes of total grey matter, white matter, cerebrospinal fluid (CSF), and total brain volume. The ab-ridge count was not positively associated with brain volumes in either patients or controls. The present findings do not support the hypothesis that the changes in brain volume seen in patients with schizophrenia are of prenatal origin.

Introduction: Studies on the neurocognitive correlates of schizotypy dimensions have found inconsistent results. This might stem from the fact that correlational methods, in contrast to cluster analysis, do not account for the possibility that a subject presents high scores on more than one dimension simultaneously. We aimed to establish clusters of normal adolescents based on schizotypy dimensions and compare them on neurocognitive, behavioural, and neurodevelopmental markers., Methods: Two hundred seventy normal adolescents from the general population (mean age 13.4, SD=0.72) attending obligatory education were evaluated., Results: A K-means iterative cluster analysis was performed with the Perceptual Aberration, Revised Social Anhedonia and Physical Anhedonia Scales. A forced four-cluster model yielded the following clusters: 'negative schizotypy', 'high or mixed schizotypy', 'positive schizotypy', and 'normal scorers'. Comparisons with ANOVAs showed that 'high schizotypes' performed poorly on neurocognition (Wechsler Intelligence Scales for Children-Revised (WISC-R) and Verbal Fluency (FAS)) and obtained the highest teacher ratings (TRF) of behavioural problems. 'Negative schizotypes' had the worst WCST results and more dermatoglyphic abnormalities. Both clusters had more neurological soft signs than 'normal scorers' and 'positive schizotypes'., Conclusions: Our results with community adolescents found the same cluster structure than the previous cluster analytic studies conducted in adult college subjects. Furthermore, we showed differences among them on neurocognitive and malneurodevelopment markers consistent with the adult literature on schizotypy.

Background: Several studies have reported alterations in finger and a-b ridge counts, and their derived measures of asymmetry, in schizophrenia compared to controls. Because ridges are fully formed by the end of the second trimester, they may provide clues to disturbed early development. The aim of this study was to assess these measures in a sample of patients with psychosis and normal controls., Methods: Individuals with psychosis (n = 240), and normal controls (n = 228) were drawn from a catchment-area case-control study. Differences in finger and a-b ridge count and Fluctuating Asymmetry were assessed in three group comparisons (non-affective psychosis versus controls; affective psychosis versus controls; non-affective psychosis versus affective psychosis). The analyses were performed separately for males and females., Results: There were no significant group differences for finger nor a-b ridge counts. While there were no group difference for Directional Asymmetry, for Fluctuating Asymmetry measures men with non-affective psychosis had significantly higher fluctuating asymmetry of the index finger ridge count (a) when compared to controls (FA-correlation score, p = 0.02), and (b) when compared to affective psychosis (adjusted FA-difference score, p = 0.04)., Conclusion: Overall, measures of finger and a-b ridge counts, and their derived measures of directional and fluctuating asymmetry were not prominent features of psychosis in this sample. While directional asymmetry in cerebral morphology is reduced in schizophrenia, this is not reflected in dermatoglyphic variables.

Despite extensive research, our knowledge of structural or functional pathology of severe mental disorders such as schizophrenia and major affective disorders is limited. The only etiological factor with reasonably firm foundation is inheritance, as evidenced by family, twin and adoption studies, however, the molecular basis of this heritability is not established yet. In the absence of clear knowledge about the biological substrate for these psychiatric disorders all the genes expressed in the human brain are potential candidate genes. Association studies analyze genetic variants (polymorphisms) in genes with presumed functional significance in the pathophysiology of the disease (candidate genes). These genetic studies compare the frequency of the hypothetical risk variant in people affected by the disease and in healthy control representatives of the same population. Also, simplex families with an affected child (trios) or with discordant affected offspring (quadruplets), can be used in the association studies. This strategy constitutes a tool to identify the small and moderate effects of genes in these complex phenotypes. Likewise, these kinds of studies could be useful to explain the effect of genes in some specific traits and symptoms present in functional psychoses. Some of our own results on serotoninergic system genes and major depression are included in this chapter as an example of case-control association developed studies in mental disorders.

Depression is a complex phenotype probably heterogeneous in its biology and in its aetiology. Genetic studies have contributed to clarifying some aspects of that heterogeneity, but we are still far from being able to establish its molecular foundations, although a certain degree of genetic variability in genes of the serotoninergic system appear to contribute to the risk of the disease and to certain of its clinical aspects. The risk of a major depressive episode increases in relation to the number of genes shared with an affected person but, in genetic terms and given the differential risks found, there is also a certain overlap with bipolar disorder and schizophrenia. These data lead to reflection on the meaning of genetic risk detected in families and its specificity. Perhaps genetic studies will have to leave the categorical definition of phenotypes and begin to use the dimensions of psychopathology for delimiting the biological and genetic subgroups present in functional psychoses.

The presence of abnormal palmar flexion creases (APFC) and dermatoglyphic ridge dissociation (RD) may constitute enduring evidence of a prenatal insult that occurred before the third trimester of intrauterine life. We examined these dermatoglyphic abnormalities in a twin study of psychotic disorders. RD and APFC were analyzed in a monozygotic (MZ) twin sample from the Maudsley Hospital in London (11 normal control pairs, 16 pairs concordant for psychosis, 9 pairs discordant for psychosis, 1 concordant triplet, and 1 triplet with one affected member). The risk of either RD or APFC was 44 percent in affected twins and 20 percent in nonaffected twins (odds ratio = 3.25, 95% confidence interval: 1.03-10.31; one-sided p = 0.023). In the group of MZ twins discordant for psychosis, discordance for RD or APFC always paralleled discordance for psychosis (one-sided p = 0.078), suggesting the operation of nongenetic factors. The results confirm previous work suggesting the possibility that nongenetic factors early in pregnancy contribute to the liability to develop psychosis in later life.

Several lines of evidence suggest that genetic factors constitute an important determinant of suicidal behavior. A significant association between the 5-HT(2A)-C allele and suicidality has recently been reported. The aim of this study was to investigate whether the proposed association between 5-HT(2A)-102T/C polymorphism and suicidality could be replicated in a larger and independent sample of Spanish patients with major depression. The 102T/C polymorphism of the 5-HT(2A) receptor gene was analyzed in 159 patients with major depression (DSM-IV criteria) and 164 unrelated and healthy controls using a case control design. All individuals were subjects of Spanish origin. Significant differences in allele (chi-square = 4.13, df = 1, P = 0.04) and genotype (chi-square = 6.19, df = 2, P = 0.04) distributions were found between non-suicide attempters and suicide attempters. Moreover, those patients carrying 5-HT(2A)-C allele had more than five times the risk for attempting suicide than noncarriers (OR = 5.50, 95% CI = 1.18-35.20, P = 0.01). Our results replicate the proposed association between 5HT(2A)-C allele and suicidality in major depression. Moreover, no overall associations are detected when patients with major depression and controls are compared for 102T/C frequencies, suggesting that the increased risk for suicidality conferred by 5-HT(2A)-C allele is primarily associated with suicidal behavior and not with the diagnosis of major depression itself., (Copyright 2001 Wiley-Liss, Inc.)

The 102-T/C polymorphism of the 5-HT(2A) receptor gene was analysed in 159 patients with major depression and 164 unrelated and healthy controls using a case-control design. Allele and genotype frequencies did not differ between cases and controls. No differences according to sex, age of onset, melancholia, suicidal behaviour or family history of psychiatric illness were found. However, genotype distributions significantly differed between patients with seasonal pattern in their episodes (MDS) and patients with no seasonal pattern (N-MDS) (chi(2) = 10.63; P = 0.004). A seasonal pattern was 7.57 times more frequent in 102C-allele carriers than in 102T homozygous (95.1% of patients MDS carried 102C-allele vs 72% of patients N-MDS (chi(2) = 9.45, df=1, P = 0.002; OR = 7.57 (95% CI: 1.65--48.08)). These results suggest that variation in the 5-HT2A receptor gene may play a role in the development of major depression with seasonal pattern and support the existence of a genetic and etiological heterogeneity underlying the diagnosis of major depression.

Introduction: It has been suggested that evidence of developmental disturbance of cognition and lateralisation in schizophrenia can be best understood from the perspective of developmental stability (DS), an indicator of the extent to which an individual develops according to a specified ontogenic programme in the presence of environmental noise. Higher levels of fluctuating asymmetry (FA; the difference between right and left side of a quantitative morphological trait such as dermatoglyphics) are thought to reflect less DS. We examined this issue for dimensions of schizotypy., Methods: Associations between FA, measures of laterality and cognitive function on the one hand, and negative and positive dimensions of schizotypy on the other, were examined in a sample of 260 healthy adolescents aged 11.9-15.6years. FA was measured as a-b ridge count right-left differences. Neuropsychological measures yielded a general cognitive ability score and a frontal function score. Laterality was assessed with the Annett scale., Results: Measures of psychosis proneness were normally distributed. Negative schizotypy was associated with more FA and lower general cognitive ability in a dose-response fashion. The association with FA was more apparent in boys. No associations existed with laterality or frontal function., Conclusion: The negative dimension of schizotypy may be associated with early developmental instability, resembling the pattern seen in the negative symptom dimension of schizophrenia. Measures of fluctuating asymmetry may be more sensitive with regard to the schizotypy phenotype than measures of laterality.

Mitochondrial DNA sequences from Georgians and Kurds were analyzed in order to test the possible correlation between female lineages and languages in these two neighboring West Eurasian groups. Mitochondrial sequence pools in both populations are very similar despite their different linguistic and prehistoric backgrounds. Both populations present mtDNA lineages that clearly belong to the European gene pool, as shown by 1) similar nucleotide and sequence diversities; 2) a large number of sequences shared with the rest of European samples; 3) nonsignificant genetic distances; and 4) classification of the present lineages into the major European mtDNA haplogroups already described. The outlier position of the populations from the Caucasus according to classical genetic markers is not recognized in the present Georgian mtDNA sequence pool. This result suggests that the differentiation of mtDNA sequences in West Eurasia and the outlier features of Caucasian populations should be attributed to different processes. Moreover, the putative linguistic relationship between Caucasian groups and the Basques, another outlier population within Europe for classical genetic markers, is not detected by the analysis of mtDNA sequences., (Copyright 2000 Wiley-Liss, Inc.)

The serotonin transporter (SERT) gene is a particularly interesting candidate for genetic involvement in affective disorders owing to its role in both the regulation of serotonergic neurotransmission and the mechanism of action of many antidepressant drugs. In this study, variability in the SERT gene was analyzed for the first time in a sample of patients with major depression with melancholia (MDDM) in the context of a genetic association study. Two different polymorphisms of the SERT gene (17q11.1-17q12) were analyzed: a variable number of tandem repeats (VNTR) polymorphism in intron 2, and a deletion/insertion polymorphism (5-HTTLPR) in the promoter region of the gene, the short variant of which (allele 484) reduces the transcriptional efficiency of the SERT gene. Our sample consisted of 74 unrelated subjects who strictly met DSM-IV criteria for MDDM and 84 healthy controls, all of Spanish origin. The analysis of haplotype distribution for both polymorphisms showed significant differences between cases and controls (log-likelihood ratio chi2=11.15, df=4, P=0.025). Moreover, when the frequencies of the 484-STin2.10 haplotype were considered in comparison with any other haplotype combination, a significant increase in this haplotype was found in patients with MDDM [z=2.53 (95% CI, 1.21-5.34), P=0.007]. According to these results, variability in the SERT gene has a small effect on liability to MDDM. Our findings are compatible with an additive effect of both the 484 low-activity allele and a mutation elsewhere within the transporter gene or a susceptibility locus nearby in linkage disequilibrium with the VNTR marker.

Dermatoglyphic alterations may be the result of early prenatal disturbances thought to be implicated in the aetiology of psychiatric illness. In order to test this hypothesis in the particular case of bipolar disorder, we assessed two congenital dermatoglyphic malformations (ridge dissociation (RD) and abnormal features (AF)) and two metric dermatoglyphic traits (total finger ridge count (TFRC) and total a-b ridge count (TABRC)) in a sample of 118 patients with chronic DSM-III-R bipolar illness, and 216 healthy controls. Bipolar cases showed a significant excess of RD and AF (OR = 2.80; 95% CI: 2.31-3.38) when compared with controls. In the cases, the presence of anomalies was associated with earlier age of onset. No differences were found for TFRC and TABRC. No associations were found with sex or familial morbid risk of psychiatric disorders. Our findings add further weight to the suggestion that early developmental disruption is a risk factor for later bipolar disorder.

Objective: Catechol O-methyltransferase (COMT) is an enzyme that inactivates catecholamines. Two common COMT alleles determine high and low activity of the enzyme. Previous studies using biochemical methods found lower enzyme activity in patients with major depression and bipolar disorder in comparison with control values, suggesting that a dysfunction in catecholamine metabolism may be related to the etiology of depression., Method: The authors studied two recently described DNA polymorphisms at the COMT gene (a silent C256G mutation and a structural mutation, Val-108-Met) in 88 patients with bipolar disorder and in 113 healthy comparison subjects, all of Spanish origin., Results: The frequency of the C256 allele was 0.58 in the patients and 0.54 in the comparison subjects. The frequency of the Val108 variant was 0.57 for both the patients and the comparison subjects. No allelic or genotypic associations were observed., Conclusions: The lack of association suggests that the COMT gene is not a major risk factor for bipolar disorder.

We have examined a structural variant of the 5-HT2C receptor (Cys23Ser) for allelic association with bipolar affective disorder in 88 cases and 113 controls. Overall, there was no significant difference in allele frequencies between the two groups, indicating that the 5-HT2C gene is not a major risk factor for bipolar affective disorder. However, when the subjects were analysed according to sex, there was a small excess of the serine ser23 allele in female cases (P = 0.04) and this effect was also seen if the ser23 allele was considered recessive (P = 0.03). A small increase in significance was found if only female cases with a known family history were included (P = 0.01). These results suggest that the ser23 allele may increase susceptibility to bipolar affective disorder in women.

Polymorphic variants of A1A2B0 and MNSs systems were analysed in a sample of 300 alcoholic patients subdivided according to gender and family history of alcoholism. There was agreement between observed and expected frequencies assuming genetic equilibrium. No association between phenotypes or genes of the A1A2B0 polymorphism and alcoholism was found when the Woolf method was used to evaluate possible associations. In the MNSs polymorphism, when the Woolf method was applied, significant values of chi 2 suggest a possible association between alcoholism and this blood marker, but after Bonferroni correction this association was rejected.