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1.  Prevalence and clinical correlates of explosive outbursts in Tourette Syndrome 
Psychiatry research  2012;205(3):269-275.
The aim of this study was to examine the prevalence and clinical correlates of explosive outbursts in two large samples of individuals with TS, including one collected primarily from non-clinical sources. Participants included 218 TS-affected individuals who were part of a genetic study (N=104 from Costa Rica (CR) and N=114 from the US). The relationship between explosive outbursts and comorbid attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), tic severity, and prenatal and perinatal complications were examined using regression analyses. Twenty percent of participants had explosive outbursts, with no significant differences in prevalence between the CR (non-clinical) and the US (primarily clinical) samples. In the overall sample, ADHD, greater tic severity, and lower age of tic onset were strongly associated with explosive outbursts. ADHD, prenatal exposure to tobacco, and male gender were significantly associated with explosive outbursts in the US sample. Lower age of onset and greater severity of tics were significantly associated with explosive outbursts in the CR sample. This study confirms previous studies that suggest that clinically significant explosive outbursts are common in TS and associated with ADHD and tic severity. An additional potential risk factor, prenatal exposure to tobacco, was also identified.
doi:10.1016/j.psychres.2012.09.029
PMCID: PMC3543492  PMID: 23040794
impulse control; tic disorders; prenatal maternal smoking; rage; co-morbidity
2.  Therapeutic Drug Monitoring of Nortriptyline in Smoking Cessation: A Multistudy Analysis 
Multiple controlled clinical trials support the efficacy of nortriptyline as a smoking cessation agent. While therapeutic plasma nortriptyline concentrations (PNCs) are known for the treatment of depression, little is known about PNCs in smoking cessation treatment. PNCs from three randomized, placebo-controlled smoking cessation trials (N = 244) were analyzed, both pooled and separately. PNCs normalized for dose and weight were not associated with sex or age, but were associated with cigarettes/day and race. Greater smoking was associated with decreased normalized PNCs. In addition, both Asians and Blacks had significantly higher normalized PNCs than Whites. Weak and inconsistent associations between PNCs and self-reported side effects were observed. PNCs were linearly related to end of treatment and long-term biochemically verified smoking abstinence. Maximum therapeutic effects were observed at a range of plasma concentrations somewhat lower than those found effective for the treatment of depression.
doi:10.1038/sj.clpt.6100307
PMCID: PMC2700120  PMID: 17687275
nortriptyline; smoking cessation; plasma nortriptyline concentration; therapeutic drug monitoring
3.  Using Extended Cognitive Behavioral Treatment and Medication to Treat Dependent Smokers 
American journal of public health  2011;101(12):2349-2356.
Objectives
We evaluated smoking-cessation efficacy of an extended course of sustained-release bupropion (bupropion SR) and cognitive-behavioral treatment (CBT).
Methods
Participants who smoked at least 10 cigarettes per day and who smoked within 30 minutes of arising (n=406) completed a 12-week smoking-cessation treatment including group counseling, nicotine-replacement therapy, and bupropion SR. Participants were then randomly assigned to 1 of 5 conditions: (1) no further treatment, (2) active bupropion SR for 40 weeks, (3) placebo for 40 weeks, (4) active bupropion SR and 11 sessions of CBT for 40 weeks (A-CBT), or (5) placebo and 11 sessions of CBT for 40 weeks. Participants were assessed at baseline and at weeks 12, 24, 52, 64, and 104.
Results
A-CBT was not superior to the other 3 extended treatments. From weeks 12 through 104, all extended treatment conditions were superior to standard treatment. At weeks 64 and 104, the 2 CBT conditions produced significantly higher abstinence rates than did the other 3 conditions.
Conclusions
Brief contact with providers can increase abstinence during treatment. CBT may increase long-term abstinence after extended treatment is terminated.
doi:10.2105/AJPH.2010.300084
PMCID: PMC3222443  PMID: 21653904
4.  Serum BDNF Levels Before Treatment Predict SSRI Response in Depression 
OBJECTIVES
The “neurotrophin hypothesis” of depression posits a role of brain-derived neurotrophic factor (BDNF) in depression, although it is unknown whether BDNF is more involved in the etiology of depression or in the mechanism of action of antidepressants. . It is also unknown whether pre-treatment serum BDNF levels predict antidepressant response.
METHODS
Thirty un-medicated depressed subjects were treated with escitalopram (N=16) or sertraline (N=14) for eight weeks. Twenty-five of the depressed subjects completed 8 weeks of antidepressant treatment and had analyzable data. Twenty-eight healthy controls were also studied. Serum for BDNF assay was obtained at baseline in all subjects and after 8 weeks of treatment in the depressed subjects. Depression ratings were obtained at baseline and after 8 weeks of treatment in the depressed subjects.
RESULTS
Pre-treatment BDNF levels were lower in the depressed subjects than the controls (p= 0.001) but were not significantly correlated with pre-treatment depression severity. Depression ratings improved with SSRI treatment (p< 0.001), and BDNF levels increased with treatment (p= 0.005). Changes in BDNF levels were not significantly correlated with changes in depression ratings. However, pre-treatment BDNF levels were directly correlated with antidepressant responses (p<0.01), and “Responders” to treatment (≥ 50% improvement in depression ratings) had higher pre-treatment BDNF levels than did “Non-responders” (p< 0.05).
CONCLUSIONS
These results confirm low serum BDNF levels in unmedicated depressed subjects and confirm antidepressant-induced increases in BDNF levels, but they suggest that antidepressants do not work simply by correcting BDNF insufficiency. Rather, these findings are consistent with a permissive or facilitatory role of BDNF in the mechanism of action of antidepressants.
doi:10.1016/j.pnpbp.2011.06.013
PMCID: PMC3159044  PMID: 21749907
Depression; brain-derived neurotrophic factor (BDNF); neurotrophin; antidepressant; SSRI
5.  Older versus Younger Treatment-Seeking Smokers: Differences in Smoking Behavior, Drug and Alcohol Use, and Psychosocial and Physical Functioning 
Quitting smoking benefits older individuals, yet there are few recent data describing older smokers. The goal of this paper was to test a series of hypotheses about differences between smokers age 50 years and older (50+) and those younger than age 50 (<50), presenting to the same treatment facility during 2002–2004 for participation in two randomized clinical trials: one exclusively for smokers age 50+, and a second open to smokers age18 and older. As predicted, smokers age 50+ were more tobacco dependent, had better psychological functioning, and poorer physical functioning than those <50. Contrary to predictions, there were no differences in motivation to quit cigarette smoking or in alcohol use. Women age 50+ were less likely to report marijuana use than women <50, and less likely to receive a positive diagnosis for alcohol abuse then men. Despite higher scores on measures of tobacco dependence, older smokers were less likely to be diagnosed as tobacco dependent or having tobacco withdrawal using DSM-IV criteria. Rates of DSM-IV alcohol abuse and dependence were high in both age groups but were higher for smokers <50. There were no striking differences between studies in reasons for exclusion, but in both, the proportion of individuals excluded due to current antidepressant use was high. Implications for the assessment and treatment of older adults are discussed.
doi:10.1080/14622200801901922
PMCID: PMC3247917  PMID: 18324565
tobacco dependence; treatment; older smokers
6.  Neurobiological and Neuropsychiatric Effects of Dehydroepiandrosterone (DHEA) and DHEA Sulfate (DHEAS) 
DHEA and DHEAS are steroids synthesized in human adrenals, but their function is unclear. In addition to adrenal synthesis, evidence also indicates that DHEA and DHEAS are synthesized in the brain, further suggesting a role of these hormones in brain function and development. Despite intensifying research into the biology of DHEA and DHEAS, many questions concerning their mechanisms of action and their potential involvement in neuropsychiatric illnesses remain unanswered. We review and distill the preclinical and clinical data on DHEA and DHEAS, focusing on (i) biological actions and putative mechanisms of action, (ii) differences in endogenous circulating concentrations in normal subjects and patients with neuropsychiatric diseases, and (iii) the therapeutic potential of DHEA in treating these conditions. Biological actions of DHEA and DHEAS include neuroprotection, neurite growth, and antagonistic effects on oxidants and glucocorticoids. Accumulating data suggest abnormal DHEA and/or DHEAS concentrations in several neuropsychiatric conditions. The evidence that DHEA and DHEAS may be fruitful targets for pharmacotherapy in some conditions is reviewed.
doi:10.1016/j.yfrne.2008.11.002
PMCID: PMC2725024  PMID: 19063914
Dehydroepiandrosterone; DHEA; DHEAS; neuroprotection; neurogenesis; apoptosis; depression; schizophrenia; dementia; cortisol
7.  Extended treatment of older cigarette smokers 
Addiction (Abingdon, England)  2009;104(6):1043-1052.
Aims
Tobacco dependence treatments achieve abstinence rates of 25–30% at 1 year. Low rates may reflect failure to conceptualize tobacco dependence as a chronic disorder. The aims of the present study were to determine the efficacy of extended cognitive behavioral and pharmacological interventions in smokers ≥ 50 years of age, and to determine if gender differences in efficacy existed.
Design
Open randomized clinical trial.
Setting
A free-standing, smoking treatment research clinic.
Participants
A total of 402 smokers of ≥ 10 cigarettes per day, all 50 years of age or older.
Intervention
Participants completed a 12-week treatment that included group counseling, nicotine replacement therapy (NRT) and bupropion. Participants, independent of smoking status, were then assigned randomly to follow-up conditions: (i) standard treatment (ST; no further treatment); (ii) extended NRT (E-NRT; 40 weeks of nicotine gum availability); (iii) extended cognitive behavioral therapy (E-CBT; 11 cognitive behavioral sessions over a 40-week period); or (iv) E-CBT plus E-NRT (E-combined; 11 cognitive behavioral sessions plus 40 weeks nicotine gum availability).
Measurements
Primary outcome variable was 7-day point prevalence cigarette abstinence verified biochemically at weeks 24, 52, 64 and 104.
Findings
The most clinically important findings were significant main effects for treatment condition, time and the treatment × time interaction. The E-CBT condition produced high cigarette abstinence rates that were maintained throughout the 2-year study period [(week 24 (58%), 52 (55%), 64 (55%) and 104 (55%)], and was significantly more effective than E-NRT and ST across that period. No other treatment condition was significantly different to ST. No effects for gender were found.
Conclusions
Extended cognitive behavioral treatments can produce high and stable cigarette abstinence rates for both men and women. NRT does not add to the efficacy of extended CBT, and may hamper its efficacy. Research is needed to determine if these results can be replicated in a sample with a greater range of ages, and improved upon with the addition of medications other than NRT.
doi:10.1111/j.1360-0443.2009.02548.x
PMCID: PMC2718733  PMID: 19392908
Bupropion; chronic disorders; cigarette smoking; NRT; older adults; tobacco dependence
8.  Psychiatry 
Western Journal of Medicine  1996;164(3):256.
PMCID: PMC1303420
9.  Genome-wide association study of Tourette Syndrome 
Scharf, Jeremiah M. | Yu, Dongmei | Mathews, Carol A. | Neale, Benjamin M. | Stewart, S. Evelyn | Fagerness, Jesen A | Evans, Patrick | Gamazon, Eric | Edlund, Christopher K. | Service, Susan | Tikhomirov, Anna | Osiecki, Lisa | Illmann, Cornelia | Pluzhnikov, Anna | Konkashbaev, Anuar | Davis, Lea K | Han, Buhm | Crane, Jacquelyn | Moorjani, Priya | Crenshaw, Andrew T. | Parkin, Melissa A. | Reus, Victor I. | Lowe, Thomas L. | Rangel-Lugo, Martha | Chouinard, Sylvain | Dion, Yves | Girard, Simon | Cath, Danielle C | Smit, Jan H | King, Robert A. | Fernandez, Thomas | Leckman, James F. | Kidd, Kenneth K. | Kidd, Judith R. | Pakstis, Andrew J. | State, Matthew | Herrera, Luis Diego | Romero, Roxana | Fournier, Eduardo | Sandor, Paul | Barr, Cathy L | Phan, Nam | Gross-Tsur, Varda | Benarroch, Fortu | Pollak, Yehuda | Budman, Cathy L. | Bruun, Ruth D. | Erenberg, Gerald | Naarden, Allan L | Lee, Paul C | Weiss, Nicholas | Kremeyer, Barbara | Berrío, Gabriel Bedoya | Campbell, Desmond | Silgado, Julio C. Cardona | Ochoa, William Cornejo | Restrepo, Sandra C. Mesa | Muller, Heike | Duarte, Ana V. Valencia | Lyon, Gholson J | Leppert, Mark | Morgan, Jubel | Weiss, Robert | Grados, Marco A. | Anderson, Kelley | Davarya, Sarah | Singer, Harvey | Walkup, John | Jankovic, Joseph | Tischfield, Jay A. | Heiman, Gary A. | Gilbert, Donald L. | Hoekstra, Pieter J. | Robertson, Mary M. | Kurlan, Roger | Liu, Chunyu | Gibbs, J. Raphael | Singleton, Andrew | Hardy, John | Strengman, Eric | Ophoff, Roel | Wagner, Michael | Moessner, Rainald | Mirel, Daniel B. | Posthuma, Danielle | Sabatti, Chiara | Eskin, Eleazar | Conti, David V. | Knowles, James A. | Ruiz-Linares, Andres | Rouleau, Guy A. | Purcell, Shaun | Heutink, Peter | Oostra, Ben A. | McMahon, William | Freimer, Nelson | Cox, Nancy J. | Pauls, David L.
Molecular psychiatry  2012;18(6):721-728.
Tourette 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.
doi:10.1038/mp.2012.69
PMCID: PMC3605224  PMID: 22889924
Tourette Syndrome; tics; genetics; GWAS; neurodevelopmental disorder
10.  Genomewide Linkage Analysis of Obsessive Compulsive Disorder Implicates Chromosome 1p36 
Biological psychiatry  2012;72(8):629-636.
Background
Obsessive compulsive disorder (OCD) has a complex etiology involving both genetic and environmental factors. However, the genetic causes of OCD are largely unknown, despite the identification of several promising candidate genes and linkage regions.
Methods
Our objective was to conduct genetic linkage studies of the type of OCD thought to have the strongest genetic etiology (i.e., childhood-onset OCD), in 33 Caucasian families with ≥2 childhood-onset OCD-affected individuals from the United States (US) (N=245 individuals with genotype data). Parametric and non-parametric genome-wide linkage analyses were conducted with Morgan and Merlin in these families using a selected panel of single nucleotide repeat polymorphisms (SNPs) from the Illumina 610-Quad Bead Chip. The initial analyses were followed by fine-mapping analyses in genomic regions with initial heterogeneity LOD (HLOD) scores of ≥2.0.
Results
We identified five areas of interest (HLOD score ≥2) on chromosomes 1p36, 2p14, 5q13, 6p25, and 10p13. The strongest result was on chromosome 1p36.33-p36.32 (HLOD=3.77, suggestive evidence for linkage after fine-mapping). At this location, several of the families showed haplotypes co-segregating with OCD.
Conclusions
The results of this study represent the strongest linkage finding for OCD in a primary analysis to date, and suggest that chromosome 1p36, and possibly several other genomic regions, may harbor susceptibility loci for OCD. Multiple brain-expressed genes lie under the primary linkage peak (approximately 4 mb in size). Follow-up studies, including replication in additional samples and targeted sequencing of the areas of interest, are needed to confirm these findings and to identify specific OCD risk variants.
doi:10.1016/j.biopsych.2012.03.037
PMCID: PMC3437244  PMID: 22633946
linkage; genomewide; pedigree; obsessive-compulsive; genetics; multigenerational
11.  CNV Analysis in Tourette Syndrome Implicates Large Genomic Rearrangements in COL8A1 and NRXN1 
PLoS ONE  2013;8(3):e59061.
Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions.
doi:10.1371/journal.pone.0059061
PMCID: PMC3606459  PMID: 23533600
12.  Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress - Preliminary Findings 
PLoS ONE  2011;6(3):e17837.
Background
Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of “accelerated aging” in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation.
Methodology
Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex.
Principal Findings
The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (≥9.2 years' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of “accelerated cell aging.” Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05).
Conclusions
These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure.
doi:10.1371/journal.pone.0017837
PMCID: PMC3063175  PMID: 21448457
13.  Dr Reus Responds 
Western Journal of Medicine  1996;165(1-2):83.
PMCID: PMC1311731
14.  Genetics of Mental Illness 
Western Journal of Medicine  1987;147(1):77-78.
PMCID: PMC1025830  PMID: 18750293
15.  Psychiatry—Epitomes of Progress 
Western Journal of Medicine  1981;134(2):143.
PMCID: PMC1272538  PMID: 18748787

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