Jose Manuel Crespo

Differential Association of Circadian Genes with Mood Disorders: CRY1 and NPAS2 are Associated with Unipolar Major Depression and CLOCK and VIP with Bipolar Disorder

Disruptions in circadian rhythms have been described in mood disorders (MD), but the involvement of genetic variation in genes pertaining to the molecular circadian machinery in the susceptibility to MD has not been conclusively determined. We examined 209 single-nucleotide polymorphisms (SNPs) covering 19 circadian genes (ADCYAP1, ARNTL, ARNTL2, BHLHB2, BHLHB3, CLOCK, CRY1, CRY2, CSNK1E, DBP, NPAS2, NR1D1, PER1, PER2, PER3, RORA, TIMELESS, VIP, and VIPR2) in a sample of 534 MD patients (335 with unipolar major mood depression (MDD) and 199 with bipolar disorder (BD)) and 440 community-based screened controls. Nominally, statistically significant associations were found in 15 circadian genes. The gene-wide test, corrected for the number of SNPs analyzed in each gene, identified significant associations in CRY1 (rs2287161), NPAS2 (rs11123857), and VIPR2 (rs885861) genes with the combined MD sample. In the MDD subsample, the same SNPs in CRY1 and NPAS2 of the combined sample remained associated, whereas in the BD subsample CLOCK (rs10462028) and VIP (rs17083008) were specifically associated. The association with an SNP located 3′ near CRY1 gene in MDD remained statistically significant after permutation correction at experiment level (p=0.007). Significant additive effects were found between the SNPs that were statistically significant at the gene-wide level. We also found evidence of associations between two-marker haplotypes in CRY1 and NPAS2 genes and MD. Our data support the contribution of the circadian system to the genetic susceptibility to MD and suggest that different circadian genes may have specific effects on MD polarity.

Efficacy of Functional Remediation in Bipolar Disorder: A Multicenter Randomized Controlled Study

OBJECTIVE The authors sought to assess the efficacy of functional remediation, a novel intervention program, on functional improvement in a sample of euthymic patients with bipolar disorder. METHOD In a multicenter, randomized, rater-blind clinical trial involving 239 outpatients with DSM-IV bipolar disorder, functional remediation (N=77) was compared with psychoeducation (N=82) and treatment as usual (N=80) over 21 weeks. Pharmacological treatment was kept stable in all three groups. The primary outcome measure was improvement in global psychosocial functioning, measured blindly as the mean change in score on the Functioning Assessment Short Test from baseline to endpoint. RESULTS At the end of the study, 183 patients completed the treatment phase. Repeated-measures analysis revealed significant functional improvement from baseline to endpoint over the 21 weeks of treatment (last observation carried forward), suggesting an interaction between treatment assignment and time. Tukeys post hoc tests revealed that functional remediation differed significantly from treatment as usual, but not from psychoeducation. CONCLUSIONS Functional remediation, a novel group intervention, showed efficacy in improving the functional outcome of a sample of euthymic bipolar patients as compared with treatment as usual.

New treatment guidelines for acute bipolar mania: A critical review

A number of treatment guidelines for bipolar disorder have been published and updated in the last few years. They are aimed at providing a synthesis of the best available scientific knowledge, and their application to every-day work should be helpful to clinicians. The aim of this report is to critically review recent guidelines focusing on the treatment of manic/hypomanic and mixed episodes. Guidelines are quite heterogeneous in methodology and conclusions, but they all agree that the treatment of manic/hypomanic and mixed episodes should generally be initiated with a medication such as lithium (Li), valproate (VPA) or atypical antipsychotics (AAP), including aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone as monotherapy. All guidelines agree on stopping ongoing antidepressant medication during mania. Combination therapy including Li or VPA with an AAP is suggested usually as second-line choice, sometimes as first-choice treatment for severe mania. Carbamazepine is mostly suggested as second line and not recommended in combination. Other antiepileptic drugs are not recommended for the treatment of mania, although lamotrigine may be maintained if it was prescribed previously for the prevention of depressive episodes. Main sources of discrepancies among guidelines include benefit-risk ratio issues (how much priority is given to efficacy over safety and tolerability), starting with combination versus monotherapy, and how to deal with treatments which are more experience-based than evidence-based (i.e.: electroconvulsive therapy).

Perceived parental rearing style in obsessive-compulsive disorder: relation to symptom dimensions

Obsessive-compulsive disorder (OCD) runs in families, but the specific contribution of genetic and environmental factors to its development is not well understood. The aim of this study was to assess whether there are differences in perceived parental child-rearing practices between OCD patients and healthy controls, and whether any relationship exists between parental characteristics, depressive symptoms and the expression of particular OCD symptom dimensions. A group of 40 OCD outpatients and 40 matched healthy controls received the EMBU (Own Memories of Parental Rearing Experiences in Childhood), a self-report measure of perceived parental child-rearing style. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Hamilton Depression Rating Scale (HDRS) were used to assess the severity of obsessive-compulsive and depressive symptoms. The Y-BOCS Symptom Checklist was used to assess the nature of obsessive-compulsive symptoms, considering the following five symptom dimensions: contamination/cleaning, aggressive/checking, symmetry/ordering, sexual/religious and hoarding. Logistic and multiple linear regression analyses were conducted to study the relationship between parental style of upbringing, depressive symptoms and OCD symptom dimensions. Severe OCD (Y-BOCS: 27.0+/-7.4) and mild to moderate depressive symptoms (HDRS: 14.0+/-5.4) were detected in our sample. Compared with healthy controls, OCD patients perceived higher levels of rejection from their fathers. No differences between the groups with respect to perceived levels of overprotection were detected. The seventy of depressive symptoms could not be predicted by scores on any perceived parental characteristics. Hoarding was the only OCD symptom dimension that could be partially predicted by parental traits, specifically low parental emotional warmth. Social/cultural variables such as parental child-rearing patterns, in interaction with biological and genetic factors, may contribute to the expression of the OCD phenotype.

A brain-derived neurotrophic factor (BDNF) haplotype is associated with antidepressant treatment outcome in mood disorders.

Brain-derived neurotrophic factor (BDNF) has been studied extensively in relation to the susceptibility to mood disorders (MD), although it remains to be clarified whether BDNF is a susceptibility locus for MD phenotypes, including therapeutic response to antidepressants. We have performed a single-marker and haplotype association study of eight TagSNPs polymorphisms in the genomic region containing the BDNF gene in 342 control subjects and 374 patients with MD, and have tested the association with antidepressant treatment outcome. None of the eight single nucleotide polymorphisms (TagSNPs) was significantly associated with MD phenotype after Bonferroni correction. In the single-marker analysis, a SNP was found to be associated with the patients state of ‘remitter’ after adequate trial with a single antidepressant phenotype (odds ratio (OR)=2.95; P=0.0025). We also identified a haplotype associated with this phenotype. This study supports the implication of BDNF in antidepressant treatment outcome in MD, with specific association with 5′ upstream region of BDNF gene.

Altered 5-HT2A binding sites and second messenger inositol trisphosphate (IP3) levels in hippocampus but not in frontal cortex from depressed suicide victims

The binding parameters of 5-HT(2A) and levels of its second messenger, 1,4,5-trisphosphate (IP(3)), were simultaneously studied in frontal cortex and hippocampus from the brains of 18 control subjects and 18 depressed suicide victims. All suicides met DSM-III-R criteria for depressive symptoms, suffered a violent death and had not taken any antidepressant drugs for at least 6 months prior to death. A significant decrease in the number of 5-HT(2A) binding sites (154+/-22 vs. 254+/-36 fmol/mg), together with a significantly lower apparent affinity constant (1.02+/- 0.08 vs. 1. 36+/-0.09 nM), was detected in hippocampus but not in frontal cortex from the depressed suicides compared to the control subjects. Furthermore, IP(3) concentrations were significantly increased in hippocampus (3.2+/-0.3 vs. 2.1+/-0.3 pmol/g) but not in frontal cortex (1.3+/-0.3 vs. 2.7+/-0.5 pmol/g) from the suicide victims. The reported results may indicate a significant hypersensitivity of the 5-HT(2A) postsynaptic receptor located in the hippocampus from depressed suicide victims, giving rise to an enhancement of its intracellular signaling system with higher IP(3) production.

A double-blind, randomized, placebo-controlled prophylaxis trial of oxcarbazepine as adjunctive treatment to lithium in the long-term treatment of bipolar I and II disorder.

We evaluated the prophylactic efficacy and the long-term tolerability of oxcarbazepine administration in the treatment of bipolar I and II disorder as an adjunctive therapy to lithium. We conducted a 52-wk, double-blind, randomized, placebo-controlled, parallel-group, multicentre, clinical trial. Bipolar I and II DSM-IV outpatients, having had two or more episodes in the last year, but currently being in remission, were randomly assigned on a 1:1 ratio to oxcarbazepine (n=26) or placebo (n=29) as adjuncts to ongoing treatment with lithium. The primary efficacy variable was the length of the remission period assessed by means of the Young Mania Rating Scale (YMRS) and Montgomery-Asberg Depression Rating Scale (MADRS). Other assessments were the Clinical Global Impression (CGI-BP-M), functional activity (GAF), anxiety (HAMA) and impulsiveness (BIS-11). The average time until first recurrence of any type was 19.2+/-13.9 wk and 18.6+/-17.0 wk for oxcarbazepine and placebo respectively (p=0.315). Ten (38.46%) patients had a recurrence of any kind in the oxcarbazepine group vs. 17 (58.62%) in the placebo group (p=0.1354). There was a trend for depressive episodes being less likely in the oxcarbazepine group compared to the placebo group (11.54% and 31.03% respectively, p=0.085), and for better functionality with the GAF (p=0.074). Impulsivity was significantly better prevented by oxcarbazepine (p=0.0443). Overall, oxcarbazepine was well tolerated. This pilot, randomized clinical trial, suggests that oxcarbazepine might have some prophylactic efficacy with regards to impulsivity and perhaps mood episodes in patients taking lithium, although further, adequately powered controlled trials are needed to confirm these findings.

Verbal memory as a mediator in the relationship between subthreshold depressive symptoms and functional outcome in bipolar disorder.

BACKGROUND Most studies on the factors involved in the functional outcome of patients with bipolar disorder have identified subsyndromal depressive symptoms and cognitive impairment as key players. However, most studies are cross-sectional and very few have analyzed the interaction between cognition and subclinical depression. The present study aimed to identify the role of cognition, and particularly verbal memory, and subthreshold depressive symptoms in the functional outcome of patients with bipolar I and II disorder at one year follow-up. METHOD A confirmatory analysis was performed using the path analysis. A total of 111 euthymic patients were included to test the role of verbal memory as a mediator in the relationship of subthreshold depressive symptoms and functional outcome at one year follow-up. Measures of verbal memory, subthreshold depressive symptoms and functioning (at baseline, at 6 months and at one year follow-up) were gathered through the use of a neuropsychological assessment and validated clinical scales. RESULTS The hypothesized mediation model displayed a good fit to data (Chi=0.393, df=2, p=0.625; RMSEA<0.001 with CI: 0.001-0.125 and CFI=1.00). Functional outcome at one year follow-up was predicted by the functional outcome at baseline, which in turn, was related to subthreshold depressive symptoms at baseline and to the verbal composite memory scores as a mediator variable. CONCLUSION The results of this study prospectively confirm previous findings on the disabling role of subthreshold depressive symptoms and verbal memory impairment on psychosocial functioning. However, these results come from a sample with moderate to severe functional impairment; hence, as a limitation, this may hinder the generalization of these results.

Risk factors for suicide in schizophrenia: systematic review and clinical recommendations.

To identify risk factors associated with suicide of patients with schizophrenia and provide clinical recommendations, which integrate research findings into a consensus based on clinical experience and evidence.

Functional remediation in bipolar disorder: 1-year follow-up of neurocognitive and functional outcome

BACKGROUND Few randomised clinical trials have examined the efficacy of an intervention aimed at improving psychosocial functioning in bipolar disorder. AIMS To examine changes in psychosocial functioning in a group that has been enrolled in a functional remediation programme 1 year after baseline. METHOD This was a multicentre, randomised, rater-masked clinical trial comparing three patient groups: functional remediation, psychoeducation and treatment as usual over 1-year follow-up. The primary outcome was change in psychosocial functioning measured by means of the Functioning Assessment Short Test (FAST). Group×time effects for overall psychosocial functioning were examined using repeated-measures ANOVA (trial registration NCT01370668). RESULTS There was a significant group×time interaction for overall psychosocial functioning, favouring patients in the functional remediation group (F = 3.071, d.f. = 2, P = 0.049). CONCLUSIONS Improvement in psychosocial functioning is maintained after 1-year follow-up in patients with bipolar disorder receiving functional remediation.