Lourdes Fañanás

An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition.

Observational studies have suggested that psychometric psychosis liability and a functional polymorphism in the catechol-O-methyltransferase (COMT Val158Met) gene moderate the psychosis-inducing effect of cannabis. To replicate and extend this finding, a double-blind, placebo-controlled cross-over design was used in which patients with a psychotic disorder (n=30), relatives of patients with a psychotic disorder (n=12), and healthy controls (n=32) were exposed to Δ-9-tetrahydrocannabinol (Δ-9-THC, the principal component of cannabis) or placebo, followed by cognitive assessment and assessment of current psychotic experiences. Previous expression of psychometric psychosis liability was also assessed. Models of current psychotic experiences and cognition were examined with multilevel random regression analyses to assess (i) main effects of genotype and condition, (ii) interactions between condition and genotype, and (iii) three-way interactions between condition, genotype, and psychometric psychosis liability. Carriers of the Val allele were most sensitive to Δ-9-THC-induced psychotic experiences, but this was conditional on prior evidence of psychometric psychosis liability. Δ-9-THC impacted negatively on cognitive measures. Carriers of the Val allele were also more sensitive to Δ-9-THC-induced memory and attention impairments compared to carriers of the Met allele. Experimental effects of Δ-9-THC on cognition and psychosis are moderated by COMT Val158Met genotype, but the effects may in part be conditional on the additional presence of pre-existing psychosis liability. The association between cannabis and psychosis may represent higher order gene–environment and gene–gene interactions.

5-HTTLPR polymorphism of the serotonin transporter gene predicts non-remission in major depression patients treated with citalopram in a 12-weeks follow up study.

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 (χ2 = 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 (χ2: 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.

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.

Neurocognitive, behavioural and neurodevelopmental correlates of schizotypy clusters in adolescents from the general population

Abstract 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.

Variability in the serotonin transporter gene and increased risk for major depression with melancholia

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 χ2=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.

Evidence for a combined genetic effect of the 5-HT1A receptor and serotonin transporter genes in the clinical outcome of major depressive patients treated with citalopram

In the context of a long-term follow-up study, we analysed the possible implication of the 5-HT1A 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-HT1A 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-HT1A receptor genes could be related to the clinical outcome of depressive patients treated with citalopram.

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.

The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with risk for psychosis: Evidence from a family-based association study

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.

Childhood abuse, the BDNF-Val66Met polymorphism and adult psychotic-like experiences

BACKGROUND The well-established relationship between childhood adversity and psychosis is likely to involve other factors such as genetic variants that can help us to understand why not everyone exposed to adverse events develops psychotic symptoms later in life. AIMS We investigated the influence of childhood abuse and neglect on positive and negative psychotic-like experiences in adulthood and the potential moderating effect of the BDNF-Val66Met polymorphism. METHOD Psychotic-like experiences and childhood adversity were assessed in 533 individuals from the general population. RESULTS Childhood abuse showed a strong independent effect on the positive dimension of psychotic-like experiences (β = 0.16, s.e. = 0.05, P = 0.002). Furthermore, this association was moderated by the BDNF-Val66Met polymorphism (β = 0.27, s.e. = 0.10, P = 0.004). CONCLUSIONS Individuals exposed to childhood abuse are more likely to report positive psychotic-like experiences. Met carriers reported more positive psychotic-like experiences when exposed to childhood abuse than did individuals carrying the Val/Val genotype. Therefore, the observed gene-environment interaction effect may be partially responsible for individual variation in response to childhood abuse.

Relapse of major depression after complete and partial remission during a 2-year follow-up

BACKGROUND Rates of remission and relapse were studied over more than 2 years in a sample of Spanish outpatients with DSM-III-R criteria of unipolar major depressive episodes. METHODS Patients were treated following standardised pharmacological protocols at our centre. In the first visit, the structured clinical interview for DSM-III-R (SCID) was used. The following visits were held monthly. Phases of evolution were recorded using the Hamilton Depression Rating Scale (HDRS), applying the Frank criteria. RESULTS A significantly greater proportion of relapse was observed in the partial remission group compared to the complete remission one. The rate of relapses for patients in complete remission was 15.18%, while for patients in partial remission was 67.61%. Partial remission was significantly associated with relapses. LIMITATIONS The short duration of the study and the decreasing sample size during the follow-up. CONCLUSIONS Partial remission after a depressive episode seems to be strongly associated with relapses. Moreover, this clinical factor could by itself fully predict short-term relapses. CLINICAL RELEVANCE The study shows the importance of reaching complete remission to decrease the rate of short-term relapses.