Roser Guillamat

Increased morbid risk for schizophrenia in families of in-patients with bipolar illness.

BACKGROUND It has been reported that relatives of probands with severe, psychotic forms of bipolar illness have increased rates of schizophrenia but not the relatives of individuals with milder, non-psychotic forms of disorder. In this study, we examined the prevalence of psychiatric disorders in the first degree relatives of a sample of 103 inpatients with bipolar disorder and in a matched control sample of 84 healthy individuals. METHOD Relatives of cases and controls were interviewed using the FH-RDC to determine familial morbid risk for schizophrenia and bipolar disorder. Age- and sex-adjusted morbidity risks were calculated in both samples according to the method of Strömgren. RESULTS The morbid risks for both bipolar disorder (4.9%) and schizophrenia (2.8%) were higher in relatives of patients than in relatives of controls (0.3% and 0.6% respectively). The relative risks were 14.2 [95% confidence interval (CI)=3.1-64.2] for bipolar disorder and 4.9 (95% CI=1.3-18.8) for schizophrenia. Relatives of women with early onset of bipolar illness had the highest morbid risks for both bipolar illness and schizophrenia. The presence of more than one patient with bipolar disorder in a family increased the risk for schizophrenia nearly fourfold (RR=3.5, 95% CI=1.2-10.2). There was no additional effect of presence of psychotic features. CONCLUSION Our results suggest that the transmission of psychosis is not disorder-specific. Bipolar illness characterised by a high familial loading is associated with increased risk of schizophrenia in the relatives.

Serotonin Transporter Gene and Risk for Bipolar Affective Disorder: An Association Study in a Spanish Population

BACKGROUND The serotonin transporter (5-HTT) is an important candidate gene for the genetic transmission of manic depressive illness. Many studies of patients with affective disorders have found abnormalities in serotonin metabolism and dysregulation of the transporter itself. In the present study, we hypothesize that genetic variation in the 5-HTT gene (17q11.1-17q12) may have an effect in the etiology of manic depression. METHODS To test this hypothesis, we analyzed allele, genotype, and haplotype frequencies of two polymorphisms recently described in the 5-HTT gene (a variable number of tandem repeats in intron 2 and a deletion/insertion polymorphism in the transcriptional control region) in a sample of 88 patients with manic-depressive illness and 113 controls. Cases and controls were matched for ethnic and geographic origin. RESULTS No associations were found between any of these polymorphisms, tested individually or as haplotypes, and manic depression. Moreover, the genetic analysis by sex, presence/absence of psychiatric family history, and age of onset did not reveal significant differences in allele or genotype distributions. CONCLUSIONS Our results suggest that the genetic variability of the 5-HTT gene is not a major risk factor for manic depression.

Mood changes after delivery: role of the serotonin transporter gene

BACKGROUND Polymorphic variations in the serotonin transporter gene (5-HTT) moderate the depressogenic effects of tryptophan depletion. After childbirth there is a sharp reduction in brain tryptophan availability, thus polymorphic variations in 5-HTT may play a similar role in the post-partum period. AIMS To study the role of 5-HTT polymorphic variations in mood changes after delivery. METHOD One thousand, eight hundred and four depression-free Spanish women were studied post-partum. We evaluated depressive symptoms at 2-3 days, 8 weeks and 32 weeks post-partum. We used diagnostic interview to confirm major depression for all probable cases. Based on two polymorphisms of 5-HTT (5-HTTLPR and STin2 VNTR), three genotype combinations were created to reflect different levels of 5-HTT expression. RESULTS One hundred and seventy-three women (12.7%) experienced major depression during the 32-week post-partum period. Depressive symptoms were associated with the high-expression 5-HTT genotypes in a dose-response fashion at 8 weeks post-partum, but not at 32 weeks. CONCLUSIONS High-expression 5-HTT genotypes may render women more vulnerable to depressive symptoms after childbirth.

Allelic association analysis of the 5-HT2C receptor gene in bipolar affective 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.

Association of common copy number variants at the glutathione S -transferase genes and rare novel genomic changes with schizophrenia

Copy number variants (CNVs) are a substantial source of human genetic diversity, influencing the variable susceptibility to multifactorial disorders. Schizophrenia is a complex illness thought to be caused by a number of genetic and environmental effects, few of which have been clearly defined. Recent reports have found several low prevalent CNVs associated with the disease. We have used a multiplex ligation-dependent probe amplification-based (MLPA) method to target 140 previously reported and putatively relevant gene-containing CNV regions in 654 schizophrenic patients and 604 controls for association studies. Most genotyped CNVs (95%) showed very low (<1%) population frequency. A few novel rare variants were only present in patients suggesting a possible pathogenic involvement, including 1.39 Mb overlapping duplications at 22q11.23 found in two unrelated patients, and duplications of the somatostatin receptor 5 gene (SSTR5) at 16p13.3 in three unrelated patients. Furthermore, among the few relatively common CNVs observed in patients and controls, the combined analysis of gene copy number genotypes at two glutathione S-transferase (GST) genes, GSTM1 (glutathione S-transferase mu 1) (1p13.3) and GSTT2 (glutathione S-transferase theta 2) (22q11.23), showed a statistically significant association of non-null genotypes at both loci with an additive effect for increased vulnerability to schizophrenia (odds ratio of 1.92; P=0.0008). Our data provide complementary evidences for low prevalent, but highly penetrant chromosomal variants associated with schizophrenia, as well as for common CNVs that may act as susceptibility factors by disturbing glutathione metabolism.

Genetic variation of the 5-HT2A receptor gene and bipolar affective disorder.

Abnormalities of the serotonergic system have classically been associated with the origin of affective disorders through the biochemical action of therapeutic agents and their role in affective and perceptual states. In the present study, we hypothesized that genetic variation in the 5-hydroxytryptamine (serotonin) type 2A (5-HT2A ) receptor gene (HTR2A) might have an effect on the aetiology of bipolar affective disorder. Four different polymorphisms in the HTR2A gene were studied in 88 patients with bipolar affective disorder and 113 healthy controls, all of Spanish origin. No significant association was observed between any of the four polymorphisms at the HTR2A locus, whether tested individually or as haplotypes, and bipolar affective disorder. The lack of association suggests that HTR2A is not a major risk factor for bipolar affective disorder.

An association between plasma ferritin concentrations measured 48 h after delivery and postpartum depression

CONTEXT Iron deficiency is the most common nutritional problem experienced by childbearing women, and postpartum depression (PPD) is the most common psychiatric disorder seen during the first year after delivery. The possible link between iron deficiency and PPD is not clear. OBJECTIVE To evaluate whether iron status 48 h after delivery was associated with PPD. Our hypothesis was that iron deficiency would be associated with PPD. DESIGN This was a prospective cohort study of depression-free women studied in the postpartum period. SETTING Women who give birth at obstetric units in several general hospitals in Spain. PARTICIPANTS A subsample of 729 women was included in the present study after exclusion of women with high C-reactive protein (CRP) and other diseases known to interfere with iron metabolism. MAIN OUTCOME MEASURES We evaluated depressive symptoms at 48 h, 8 weeks and 32 weeks postpartum and used a diagnostic interview to confirm the diagnosis of major depression. A blood sample obtained 48 h after delivery was used to measure the following iron storage parameters: ferritin, transferrin (Tf), free iron and transferrin saturation (TfS) and the inflammatory marker CCRP. RESULTS Overall, the women in the study had low iron concentrations (8.8 ± 6.9 μmol/L) and low TfS (12.6 ± 9.6%) but normal ferritin and Tf concentrations. A total of 65 women (9%) developed PPD during the 32 week postpartum period; these women also had a lower ferritin concentration (15.4 ± 12.7 μg/L vs. 21.6 ± 13.5 μg/L, P = 0.002). A strong association between ferritin and PPD was observed (odds ratio = 3.73, 95% CI: 1.84-7.56; P = 0.0001 for ferritin cutoff value of 7.26 μg/L). In our study, ferritin concentrations have a high specificity but low sensitivity in predicting PPD. CONCLUSIONS These findings support the role of iron in the etiology of PPD and the use of ferritin as a marker of iron deficiency in the postpartum period. We believe that this topic deserves further investigation.

Association study of 44 candidate genes with depressive and anxiety symptoms in post-partum women

The post-partum period is a time of extreme vulnerability for a whole spectrum of psychiatric disorders. Delivery may be considered an important risk factor in genetically susceptible women. Five hundred and eight SNPs in 44 genes at candidate pathways putatively related to mood changes after delivery were genotyped in a multicenter cohort of 1804 women from Spain. Participants completed two scales at 2-3 days, 8 weeks, and 32 weeks post-partum, the Edinburgh Post-partum Depression Scale (EPDS) and the Spielberger State-Trait Anxiety Inventory (STAI). Those women who scored 9 or more on EPDS were evaluated for major depression using the Diagnostic Interview for Genetics Studies (DIGS) adapted for post-partum depression. Association with major depression was assessed using likelihood ratio tests under a codominant genotype model. Association with scale scores was tested using linear mixed models to take into account repeated measures over time. Two intronic SNPs, one at the serotonin transporter gene (SLC6A4) and another at dopa decarboxylase (DDC), were significantly associated to STAI anxiety scores after multiple testing correction (nominal P=0.0000513 and 0.000097, respectively). In addition, post hoc analysis at the unphased haplotype level using nominal significant SNPs revealed an association with a combination of three SNPs at protein kinase C, beta (PRKCB) with major depression, significant after multiple testing correction (nominal global P=0.0001596). In conclusion, we detected a role of SLC6A4 in mood changes after stressful events, and revealed new putative associations involving DDC and PRKCB. Therefore, these genes deserve further investigation to confirm these results.

Congenital dermatoglyphic malformations in severe bipolar disorder

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.

Thyroid function 48 h after delivery as a marker for subsequent postpartum depression

Physiological changes during gestation and after delivery are associated with postpartum thyroid dysfunction, which is due to thyroid autoimmunity in some cases. Postpartum thyroid dysfunction, in turn, has been associated with postpartum depression (PPD). The aim of the present study was to evaluate whether thyroid function immediately after delivery can predict postpartum depression at 8 weeks and 32 weeks after delivery. This study examined 1053 postpartum Spanish women without a previous history of depression. We evaluated depressive symptoms at 48h, 8 weeks and 32 weeks postpartum and used a diagnostic interview to confirm major depression for all probable cases. Free thyroxin (fT4), thyroid-stimulating hormone (TSH), thyroid peroxidase antibodies (TPOAb) and C-reactive protein (CRP) were assayed at 48h postpartum. Binary and multivariate logistic regression analyses were performed to determine independent risk factors for PPD. Although 152 women (14.4%) had high TPOAb (>27IU/mL) and slightly elevated TSH concentrations with normal fT4, we did not find any association between thyroid function and PPD. This thyroid dysfunction was not associated with CRP concentrations that were outside of the normal range (>3mg/L). We conclude that thyroid function at 48h after delivery does not predict PPD susceptibility.