Enrique Baca-García

Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment†‡

A fundamental difficulty in human genetics research is the identification of the spectrum of genetic variants that contribute to the susceptibility to common/complex disorders. We tested here the hypothesis that functional genetic variants may confer susceptibility to several related common disorders. We analyzed five main psychiatric diagnostic categories (substance‐abuse, anxiety, eating, psychotic, and mood disorders) and two different control groups, representing a total of 3,214 samples, for 748 promoter and non‐synonymous single nucleotide polymorphisms (SNPs) at 306 genes involved in neurotransmission and/or neurodevelopment. We identified strong associations to individual disorders, such as growth hormone releasing hormone (GHRH) with anxiety disorders, prolactin regulatory element (PREB) with eating disorders, ionotropic kainate glutamate receptor 5 (GRIK5) with bipolar disorder and several SNPs associated to several disorders, that may represent individual and related disease susceptibility factors. Remarkably, a functional SNP, rs945032, located in the promoter region of the bradykinin receptor B2 gene (BDKRB2) was associated to three disorders (panic disorder, substance abuse, and bipolar disorder), and two additional BDKRB2 SNPs to obsessive‐compulsive disorder and major depression, providing evidence for common variants of susceptibility to several related psychiatric disorders. The association of BDKRB2 (odd ratios between 1.65 and 3.06) to several psychiatric disorders supports the view that a common genetic variant could confer susceptibility to clinically related phenotypes, and defines a new functional hint in the pathophysiology of psychiatric diseases.

Mood changes after delivery: role of the serotonin transporter gene

BACKGROUNDnPolymorphic 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.nnnAIMSnTo study the role of 5-HTT polymorphic variations in mood changes after delivery.nnnMETHODnOne 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.nnnRESULTSnOne 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.nnnCONCLUSIONSnHigh-expression 5-HTT genotypes may render women more vulnerable to depressive symptoms after childbirth.

Suicidal ideation and suicide attempts in bipolar disorder type I: an update for the clinician

OBJECTIVEnThis article reviews the evidence for the major risk factors associated with suicidal behavior in bipolar disorder.nnnMETHODnReview of the literature studies on bipolar disorder, suicidal behavior and suicidal ideation.nnnRESULTSnBipolar disorder is strongly associated with suicide ideation and suicide attempts. In clinical samples between 14-59% of the patients have suicide ideation and 25-56% present at least one suicide attempt during lifetime. Approximately 15% to 19% of patients with bipolar disorder die from suicide. The causes of suicidal behavior are multiple and complex. Some strong predictors of suicidal behavior have emerged in the literature such as current mood state, severity of depression, anxiety, aggressiveness, hostility, hopelessness, comorbidity with others Axis I and Axis II disorders, lifetime history of mixed states, and history of physical or sexual abuse.nnnCONCLUSIONnBipolar disorder is the psychiatric condition associated with highest lifetime risk for suicide attempts and suicide completion. Thus it is important to clinicians to understand the major risk factors for suicidal behavior in order to choose better strategies to deal with this complex behavior.

A Gender-Specific Association between the Serotonin Transporter Gene and Suicide Attempts

This pilot study tested the gender-specificity of the association between suicide attempts and a polymorphism in the promoter area of the serotonin transporter with two allelic variants, a long (1) variant and a short (s) variant. In a Spanish general hospital, 180 suicide attempters (121 women and 59 men) and 212 control blood donors (93 women and 119 men) were recruited. Subjects were classified as S individuals (s/s or s/l) with low expression of the serotonin transporter, and L individuals (l/l) with high expression. S individuals were significantly overrepresented (or L, underrepresented) in female attempters when compared with female controls and male attempters. Lethality appeared to have a significant influence on the effects of the genotype in suicide since S females were overrepresented among non-lethal female attempters. Further studies are needed to replicate that the serotonin genotype polymorphism may influence suicide attempts only in females.

Extensive Genotyping of the BDNF and NTRK2 Genes Define Protective Haplotypes Against Obsessive-Compulsive Disorder

BACKGROUNDnFamily, twin and molecular studies provide increasing evidence for the importance of genetic factors in obsessive-compulsive disorder (OCD). Recent work suggests that brain-derived neurotrophic factor (BDNF) may be involved in OCD pathophysiology. We used a linkage disequilibrium (LD)-mapping approach to investigate the role that BDNF and its specific receptor neurotrophic tyrosine kinase receptor type 2 (NTRK2) may play in increasing susceptibility to OCD.nnnMETHODSnEight tag single nucleotide polymorphisms (tagSNPs) covering the BDNF gene region and 46 tagSNPs in the NTRK2 region were genotyped in 215 OCD patients and 342 control subjects. Single nucleotide polymorphism association and haplotype analysis were performed. The possible relationship between genetic factors and clinical characteristics including age of OCD onset, tic disorders, clinical dimensions, and family history of OCD were investigated.nnnRESULTSnHaplotype analysis revealed a significant association between OCD and a five-marker protective haplotype located toward the 5 of the BDNF gene (odds ratio [OR] = .80; 95% confidence interval [CI] = .69-.92; permutation p value = .006) containing the functional valine (Val)66-to-methionine (Met) variant. A significant association between a NTRK2 intronic SNP (rs2378672) and OCD was identified (p < .0001) in female patients under an additive model. A protective haplotype located in intron 19 of NTRK2 was also associated with OCD (OR = .76; 95% CI = .66-.87; permutation p value = .001).nnnCONCLUSIONSnThese findings support a role for the BDNF/NTRK2 signaling pathway in genetic susceptibility to OCD.

A pilot genetic study of the continuum between compulsivity and impulsivity in females: The serotonin transporter promoter polymorphism

According to some authors the obsessive-compulsive (OC) spectrum includes on one extreme, the Obsessive-Compulsive Disorder (OCD) and on the other extreme the most impulsive behaviors. This is a controversial idea and other authors define the OC spectrum in different ways. The serotonin transporter (5-HTT) gene is one of the main genes that control serotonergic function. A polymorphism in the promoter area of this gene classifies subjects with low expression as S individuals (s/s or s/l) and subjects with high expression as L individuals (l/l). This polymorphism was studied in female OCD patients (n = 24), non-impulsive controls (n = 112) and impulsive suicidal patients (n = 118) to support the OC spectrum hypothesis from a genetic perspective. A linear association exists among the serotonin transporter promoter functional genotypes (S versus L individuals) (chi2 linear by linear association = 8.9; df = 1; p = 0.003). The frequency of S individuals (s/l or s/s) was lowest in OCD (54%, 13/24); intermediate in non-impulsive controls (71%, 80/112) and highest in impulsive suicide attempters (82%, 96/117). More importantly, future studies need to consider that genetics may be related to behavioral dimensions (compulsivity to impulsivity) instead of to specific psychiatric disorders defined in clinical terms.

Machine learning and data mining: strategies for hypothesis generation

Strategies for generating knowledge in medicine have included observation of associations in clinical or research settings and more recently, development of pathophysiological models based on molecular biology. Although critically important, they limit hypothesis generation to an incremental pace. Machine learning and data mining are alternative approaches to identifying new vistas to pursue, as is already evident in the literature. In concert with these analytic strategies, novel approaches to data collection can enhance the hypothesis pipeline as well. In data farming, data are obtained in an ‘organic’ way, in the sense that it is entered by patients themselves and available for harvesting. In contrast, in evidence farming (EF), it is the provider who enters medical data about individual patients. EF differs from regular electronic medical record systems because frontline providers can use it to learn from their own past experience. In addition to the possibility of generating large databases with farming approaches, it is likely that we can further harness the power of large data sets collected using either farming or more standard techniques through implementation of data-mining and machine-learning strategies. Exploiting large databases to develop new hypotheses regarding neurobiological and genetic underpinnings of psychiatric illness is useful in itself, but also affords the opportunity to identify novel mechanisms to be targeted in drug discovery and development.

Executive dysfunction in chronic cocaine users: An exploratory study

INTRODUCTIONnChronic cocaine use is associated with some executive deficits. We assessed executive functions using ecologically valid tests in chronic cocaine users.nnnOBJECTIVESnTo investigate the relationship between executive deficits and three measures of severity of cocaine use: years of use, quantity used, and frequency of use.nnnMETHODSnTwenty-four cocaine users were compared with twenty-seven community controls. We used Students t-test and Chi-squared to compare means and categorical variables, respectively. Linear regression analyses for the adjusted comparative analysis between cases and controls, and severity of cocaine use among cocaine users were performed.nnnRESULTSnChronic cocaine users performed worse on measures of attention and working memory (Forward and Backward Digit Span, p<.001), set-shifting abilities (difference score between the Trail Making B and A, TMB-A, p=.006), cognitive test of mental flexibility and response inhibition (Rule Shift Cards) (p<.001), and prefrontal functioning (Wisconsin Card Sorting Test, WCST, p=.023) than controls. Years of cocaine use were associated with deficits in the Backward Digit Span (p=.041; CI 95%: -.760 to -.002), the TMB-A (p=.026; CI 95%: .687 to 9.761), the Zoo Map (p=.034; CI 95%: -.480 to -.021), and the Rule Shift Cards (p=.006; CI 95%: -.836 to -.164), among others. Quantity of cocaine use was associated with executive deficits measured by the Forward Digit Span (p=.007; CI 95%: -.727 to -.133), the TMB-A (p=.021; CI 95%: 5.304-57.945), and the number of perseverative errors in the WSCT (p=.002; CI 95%: -10.654 to -2.800). Frequency of cocaine was associated with deficits in the Backward Digit Span (p=.042; CI 95%: -1.548 to -.030).nnnCONCLUSIONSnChronic use of cocaine is associated with executive deficits, which may influence patients functionality, prognosis, and therapeutic failure.

Diagnostic stability and evolution of bipolar disorder in clinical practice: a prospective cohort study

Objective:u2002 To evaluate the long‐term stability of International Classification of Diseases‐10th revision bipolar affective disorder (BD) in multiple settings.

Suicidal behavior in schizophrenia and depression : A comparison

The aim of this study was to compare the frequencies and suicide attempt characteristics in patients with schizophrenia (N = 25) and major depression in absence of schizophrenia (N = 107). There were no significant differences in attempt methods, but attempters with schizophrenia reported a lower number of life events influencing the attempt (2.0 vs. 2.6), less influence of life events on the attempt (42% vs. 83%) and lower GAF scores (36 vs. 50). Schizophrenia was not associated with higher impulsivity scores but with significantly more lethal attempts (40% vs. 29%) and with a trend toward (p = 0.08) higher scores in aggressive behavior history.