Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Dysregulated relationship of inflammation and oxidative stress in major depression.

Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between IL-6, IL-10, and the IL-6/IL-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n=20) before and after 8 weeks of open-label sertraline treatment (n=17), compared to healthy non-depressed controls (n=20). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with IL-6 concentrations (p<0.05) and were negatively correlated with IL-10 concentrations (p<0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of IL-6/IL-10 (p<0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8 weeks, F2-IsoPs were no longer significantly correlated with IL-6, IL-10 or the IL-6/IL-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mechanisms regulating oxidation and inflammation in healthy individuals become dysregulated in untreated MDD, and may be improved with antidepressant treatment. These findings may help explain the increased risk of comorbid medical illnesses in MDD.

Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response.

Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. When telomeres critically shorten, cells become susceptible to senescence and apoptosis. Telomerase, a cellular ribonucleoprotein enzyme, rebuilds the length of telomeres and promotes cellular viability. Leukocyte telomeres are reportedly shortened in major depression, but telomerase activity in depression has not been previously reported. Further, there are no published reports of the effects of antidepressants on telomerase activity or on the relationship between telomerase activity and antidepressant response. Peripheral blood mononuclear cell (PBMC) telomerase activity was assessed in 20 medication-free depressed individuals and 18 controls. In total, 16 of the depressed individuals were then treated with sertraline in an open-label manner for 8 weeks, and PBMC telomerase activity was reassessed in 15 of these individuals after treatment. Pre- and post-treatment symptom severity was rated with the Hamilton Depression Rating Scale. All analyses were corrected for age and sex. Pre-treatment telomerase activity was significantly elevated in the depressed individuals compared with the controls (P=0.007) and was directly correlated with depression ratings (P<0.05) across all subjects. In the depressed group, individuals with relatively lower pre-treatment telomerase activity and with relatively greater increase in telomerase activity during treatment, showed superior antidepressant responses (P<0.05 and P<0.005, respectively). This is the first report characterizing telomerase activity in depressed individuals. PBMC telomerase activity might reflect a novel aspect of depressive pathophysiology and might represent a novel biomarker of antidepressant responsiveness.

Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23.

Manic depressive illness, or bipolar disorder (BP), is characterized by episodes of elevated mood (mania) and depression. We designed a multistage study in the genetically isolated population of the Central Valley of Costa Rica to identify genes that promote susceptibility to severe BP (termed BPI), and screened the genome ot two Costa Rican BPI pedigrees (McInnes et al., submitted). We considered only individuals who fulfilled very stringent diagnostic criteria for BPI to be affected. The strongest evidence for a BPI locus was observed in 18q22-q23. We tested 16 additional markers in this region and seven yielded peak lod scores over 1.0. These suggestive lod scores were obtained over a far greater chromosomal length (about 40 cM) than in any other genome region. This localization is supported by marker haplotypes shared by 23 of 26 BPI affected individuals studied. Additionally, marker allele frequencies over portions of this region are significantly different in the patient sample from those of the general Costa Rican population. Finally, we performed an analysis which made use of both the evidence for linkage and for association in 18q23, and we observed significant lod scores for two markers in this region.

Genome-wide linkage scan of bipolar disorder in a Colombian population isolate replicates Loci on chromosomes 7p21-22, 1p31, 16p12 and 21q21-22 and identifies a novel locus on chromosome 12q.

BACKGROUND/AIMS: Bipolar disorder (BP) is a severe psychiatric illness, characterised by alternating episodes of depression and mania, which ranks among the top ten causes of morbidity and life-long disability world-wide. We have previously performed a whole-genome linkage scan on 6 pedigrees segregating severe BP from the well-characterised population isolate of Antioquia, Colombia. We recently collected genotypes for the same set of 382 autosomal microsatellite markers in 9 additional Antioquian BP pedigrees. Here, we report the analysis of the combined pedigree set. METHODS: Linkage analysis using both parametric and nonparametric approaches was conducted for 3 different diagnostic models: severe BP only (BPI); mood disorders (BPI, BPII and major depression); and psychosis (operationally defined by the occurrence of at least 1 episode of hallucinations and/or delusions). RESULTS AND CONCLUSION: For BPI only, the most interesting result was obtained for chromosome 7p21.1-p22.2 under a recessive model of inheritance (heterogeneity LOD score = 2.80), a region that had previously been linked to BP in a study on Portuguese Island families. For both BPI and mood disorders, nonparametric analyses identified a locus on chromosome 12ct-q14 (nonparametric linkage = 2.55 and 2.35, respectively). This locus has not previously been reported as a candidate region for BP. Additional candidate regions were found on chromosomes 1p22-31 (mood disorders) and 21q21-22 (BPI), 2 loci that have repeatedly been implicated in BP susceptibility. Linkage analysis of psychosis as a phenotype identified candidate regions on chromosomes 2q24-31 and 16p12-q12. The finding on chromosome 16p is noteworthy because the same locus has been implicated by genome-wide association analyses of BP.

A narrow and highly significant linkage signal for severe bipolar disorder in the chromosome 5q33 region in Latin American pedigrees.

We previously reported linkage of bipolar disorder to 5q33-q34 in families from two closely related population isolates, the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (CO). Here we present follow up results from fine-scale mapping in large CVCR and CO families segregating severe bipolar disorder, BP-I, and in 343 population trios/duos from CVCR and CO. Employing densely spaced SNPs to fine map the prior linkage peak region increases linkage evidence and clarifies the position of the putative BP-I locus. We performed two-point linkage analysis with 1134 SNPs in an approximately 9 Mb region between markers D5S410 and D5S422. Combining pedigrees from CVCR and CO yields a LOD score of 4.9 at SNP rs10035961. Two other SNPs (rs7721142 and rs1422795) within the same 94 kb region also displayed LOD scores greater than 4. This linkage peak coincides with our prior microsatellite results and suggests a narrowed BP-I susceptibility regions in these families. To investigate if the locus implicated in the familial form of BP-I also contributes to disease risk in the population, we followed up the family results with association analysis in duo and trio samples, obtaining signals within 2 Mb of the peak linkage signal in the pedigrees; rs12523547 and rs267015 (P = 0.00004 and 0.00016, respectively) in the CO sample and rs244960 in the CVCR sample and the combined sample, with P = 0.00032 and 0.00016, respectively. It remains unclear whether these association results reflect the same locus contributing to BP susceptibility within the extended pedigrees.

Mapping genes for psychiatric disorders and behavioral traits.

In the past year, findings from genetic studies in non-human organisms have yielded a number of exciting insights regarding the genetic basis of complex behaviors. Although there were encouraging developments in the genetic study of human behavioral traits, particularly those involved with cognitive function, there was relatively little progress in genetic mapping of the most common psychiatric phenotypes.

Multimodal techniques for smoking cessation: a review of their efficacy and utilisation and clinical practice guidelines.

AIMS: Nicotine addiction is a complex, chronic condition with physiological and psychological/behavioural aspects that make smoking cessation extremely difficult. This paper reviews current recommendations for smoking cessation and the efficacy of pharmacotherapy and behavioural modification techniques, used either alone or in combination, for smoking cessation. RESULTS: Abstinence rates for pharmacotherapies range from approximately 16% to approximately 30% at 1-year follow-up, with efficacy odds ratios (ORs) compared with placebo of approximately 1.7 for nicotine replacement therapy (NRT), approximately 1.9 for bupropion sustained release and approximately 3.0 for varenicline. Behaviour modification therapies have achieved quit rates of between 8% and 43% for up to 1 year, with ORs in comparison to no treatment of between approximately 1.2 and approximately 2.2. No direct comparisons have been made between pharmacotherapy alone and psychological behaviour strategies alone. However, combining physiological approaches with counselling significantly increases the odds of quitting compared with either technique alone. CONCLUSIONS: Applying multimodal techniques for the treatment of nicotine addiction is the recommended approach and has demonstrated the potential to improve rates of permanent abstinence in smokers attempting cessation. While the numbers of patients receiving help and advice regarding smoking cessation is increasing, the multimodal approach appears to be currently underutilised by clinicians and therefore smoking cessation strategies are not being optimised.

The pharmacogenetics research network: from SNP discovery to clinical drug response.

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.

Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment.

Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1-4 (EGR1-4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.

Increased plasma MHPG in dexamethasone-resistant depressed patients.

Severely depressed patients frequently show inadequate suppression of serum cortisol levels by dexamethasone. In a study of 15 depressed patients, we found a robust correlation between plasma levels of cortisol and 3-methoxy-4-hydroxy-phenylglycol after dexamethasone administration. These results suggest that dexamethasone resistance and adrenergic activation reflect parallel responses to illness-related stress in some depressed patients.

The development of criteria for evaluating psychiatric education programs.

During the last year, the Psychiatry Education Branch of the National Institute of Mental Health undertook an exhaustive review of 530 training proposals from 205 institutions. The scope of such an endeavor, as well as the desire to maintain peer review, necessitated the recruitment of 90 outside consultants. The need for consistency of judgment among a large group of site visitors gave rise to a document that detailed points of concern in the evaluation of psychiatric training programs. Broader dissemination of this document might be useful in a program's self-evaluation, and might further its understanding of the site-visit process. The result of many such evaluations should be the improvement of psychiatric education throughout the country.

Depressive symptoms and cognitive decline in nondemented elderly women: a prospective study.

BACKGROUND: The association between depressive disorders and subsequent cognitive decline is controversial. We tested the hypothesis that elderly women (aged 65 years and older) without dementia but with depressive symptoms have worse cognitive function and greater cognitive decline than women with few or no symptoms. METHODS: As part of an ongoing prospective study, we evaluated 5781 elderly, mostly white, community-dwelling women. Women completed the Geriatric Depression Scale short form. Three cognitive tests--Trails B, Digit Symbol, and a modified Mini-Mental State Examination--were administered at baseline and approximately 4 years later. Baseline, follow-up, and change scores for the cognitive tests were analyzed by analysis of covariance and Kruskal-Wallis analysis; the odds of cognitive deterioration (> or =3-point decline on the modified Mini-Mental State Examination) were determined by logistic regression. RESULTS: At baseline, 211 (3.6%) of the women had 6 or more depressive symptoms. Only 16 (7.6%) of these women were receiving antidepressant medication. Increasing symptoms of depression were associated with worse performance at baseline and follow-up on all 3 tests of cognitive function (P<.001 for all comparisons). For example, the baseline Digit Symbol score (mean +/- SD) was 45.5 +/- 10.7 among women with 0 to 2 symptoms of depression, 40.3 +/- 10.7 for women with 3 to 5 symptoms, and 39.0 +/- 11.3 for women with 6 or more symptoms. After adjusting for the baseline score, cognitive change scores were also inversely associated with the number of depressive symptoms (P<.001 for all comparisons). Odds ratios for cognitive deterioration using 0 to 2 symptoms as the reference were 1.6 (95% confidence interval, 1.3-2.1) for 3 to 5 symptoms and 2.3 (95% confidence interval, 1.6-3.3) for 6 or more symptoms. Results were similar after being adjusted for education, age, health status, exercise, alcohol use, functional status, and clinic site. CONCLUSIONS: Depressive symptoms in older women are associated with both poor cognitive function and subsequent cognitive decline. Mechanisms underlying the association between these 2 common conditions need further exploration.

Nortriptyline and cognitive-behavioral therapy in the treatment of cigarette smoking.

BACKGROUND: A history of major depressive disorder (MDD) predicts failure to quit smoking. We determined the effect of nortriptyline hydrochloride and cognitive-behavioral therapy on smoking treatment outcome in smokers with a history of MDD. The study also addressed the effects of diagnosis and treatment condition on dysphoria after quitting smoking and the effects of dysphoria on abstinence. METHODS: This was a 2 (nortriptyline vs placebo) x 2 (cognitive-behavioral therapy vs control) x 2 (history of MDD vs no history) randomized trial. The participants were 199 cigarette smokers. The outcome measures were biologically verified abstinence from cigarettes at weeks 12, 24, 38, and 64. Mood, withdrawal, and depression were measured at 3, 5, and 8 days after the smoking quit date. RESULTS: Nortriptyline produced higher abstinence rates than placebo, independent of depression history. Cognitive-behavioral therapy was more effective for participants with a history of depression. Nortriptyline alleviated a negative affect occurring after smoking cessation. Increases in the level of negative affect from baseline to 3 days after the smoking quit date predicted abstinence at later assessments for MDD history-negative smokers. There was also a sex-by-depression history interaction; MDD history-positive women were less likely to be abstinent than MDD history-negative women, but depression history did not predict abstinence for men. CONCLUSIONS: Nortriptyline is a promising adjunct for smoking cessation. Smokers with a history of depression are aided by more intensive psychosocial treatments. Mood and diagnosis interact to predict relapse. Increases in negative affect after quitting smoking are attenuated by nortriptyline.

Pituitary-adrenal disinhibition as the independent variable in the assessment of behavioral symptoms.

The dexamethasone suppression test (DST) has proven to be of clinical utility in the diagnosticc assessment of patients with primary endogenous depressive illness. Studies comparing individuals who show suppression of plasma cortisol after dexamethasone with those showing nonsuppression have thus far been unable to elicit clinical variables that might differentiate the two groups. Some investigators have suggested as an alternative strategy the usage of the biological variable of interest as the independent rather than the dependent variable. In this study we compared the objective and subjective characteristics of 118 psychiatric inpatients who underwent the DST and were divided on the basis of their response into suppressor and nonsuppressor categories. In the first analysis the diagnostic classification of the patient was not considered. In a secondary analysis the clinical characteristics of only those patients with primary endogenous depression are examined. The data show that independent of diagnosis nonsuppressors are noted to have a greater incidence of subjective complaints. These differences between groups are no longer evident on discharge illustrating a significantly better prognosis for the nonsuppression group.

Habituation and cortisol dysregulation in depression.

The relationship between hypothalamic-pituitary-adrenal (HPA) dysregulation and skin conductance measures of habituation, stimulus specificity, and dishabituation was investigated in psychiatric patients exhibiting depressed affect. As a group, depressed patients showed a relative failure to dishabituate when compared with control subjects. Nonsuppression of cortisol following dexamethasone was associated with decreased response specificity as reflected in direct response measures and baseline skin conductance level. The impairment of response specificity to a novel stimulus is consistent with previous studies demonstrating a role for cortisol in the regulation of selective attention processes.

MRI deep white matter hyperintensity in a psychiatric population.

The authors evaluated magnetic resonance imaging (MRI) of deep white matter hyperintensity (DWMH) in 90 adult psychiatric inpatients in whom MRIs were clinically indicated and 25 age-matched, medically healthy controls. Forty-two percent of the psychiatric patients and 12% of the controls had evidence of DWMH on MRI. Both incidence and severity of DWMH were significantly correlated with age in both groups. Even after controlling for age in the psychiatric population, DWMH was significantly associated with hypertension, history of myocardial infarction or angina, abnormal electrocardiogram, and abnormal neurological examinations.

d-Amphetamine: effects on memory in a depressed population.

The effect of intravenous d-amphetamine on memory functions in a group of depressed patients was examined in a double-blind placebo-controlled study. Active drug administration resulted in an increase in verbal free recall but no change in cued recall, suggesting specific effects on memory processes. The level of psychological processing of the presented stimulus was shown to interact with drug-induced facilitation of recall. Improvement in memory of more shallowly processed material under amphetamine related significantly to subjects' base-line indices of noradrenergic function. Drug-induced changes in mood did not correlate with improvement in cognitive functioning. The interrelationships between biochemical determinants of mood and memory are discussed in light of these findings.

Cortisol and response to dexamethasone as predictors of withdrawal distress and abstinence success in smokers.

BACKGROUND: Glucocorticoids have been linked to self-administration of a wide range of drugs in animals and are increased endogenously by chronic nicotine intake. Corticosteroids have also been shown to regulate nicotine receptor sensitivity and to be involved in behavioral sensitization to nicotine. METHODS: Cortisol levels and cortisol suppression in response to dexamethasone were measured in a sample of smokers participating in a smoking cessation treatment trial. RESULTS: Cortisol levels dropped significantly during the early quitting process (2 weeks post-quit) and returned to a level below baseline 1 month post-quit. The magnitude of the initial drop in cortisol was strongly related to post-quit distress and marginally predictive of abstinence. Neither baseline nor post-quit changes in percent cortisol suppression after dexamethasone were related to abstinence success or withdrawal distress. CONCLUSIONS: Withdrawal from cigarette smoking is marked by a reduction in cortisol levels that appears to be related to the degree of distress experienced during the early quitting period. Further work is needed to determine whether withdrawal-related cortisol changes or distress are predictive of abstinence success.

Estrogen replacement therapy and cognitive decline in memory-impaired post-menopausal women.

BACKGROUND: Estrogen replacement therapy (ERT) may delay dementia-related cognitive decline in post-menopausal women, but few studies have longitudinally examined this relationship and none has controlled for baseline functioning or concurrent medication. METHODS: We report the results of a 1-year retrospective longitudinal study examining cognitive functioning in female estrogen and nonestrogen users (n = 3128) who presented to the state of California memory disorder clinics in a naturalistic multisite study of senile dementia, Alzheimer's type (SDAT), and other cognitive impairments. RESULTS: At baseline, estrogen users had significantly lower rates of SDAT diagnoses (possible and probable) than nonestrogen users, and significantly higher rates of the lesser diagnoses of "cognitive impairment" and "no dementia." ERT was significantly associated with higher cognitive functioning at baseline and at 1 year follow-up (n = 358). Nonestrogen users deteriorated significantly from baseline to follow-up; estrogen users did not. Results were similar in groups matched on baseline Blessed-Roth Dementia Rating Scale (BRDRS) ratings (n = 32) and in a variety of subpopulations. CONCLUSIONS: These findings are consistent with estrogen acting as a protective factor against cognitive deterioration in post-menopausal women with SDAT and other cognitive impairments, and may suggest an increased effect in earlier stages of cognitive impairment.