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1.  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.
PMCID: PMC2700120  PMID: 17687275
nortriptyline; smoking cessation; plasma nortriptyline concentration; therapeutic drug monitoring
2.  Immunogenicity and Smoking Cessation Outcomes for a Novel Nicotine Immunotherapeutic 
NicVAX®, a nicotine vaccine (3’AmNic-rEPA), has been clinically evaluated to determine if higher antibody concentrations are associated with higher smoking abstinence rates and if doses and frequency of administration are associated with increased antibody response. This randomized, double-blinded, placebo-controlled multicenter clinical trial (N=301 smokers) tested 200 and 400 µg doses administered 4 or 5 times over 6 months compared to placebo. 3’AmNic-rEPA recipients with the highest serum anti-nicotine antibody response (top 30% by AUC) were significantly more likely to attain 8 weeks continuous abstinence from weeks 19 through 26 than the placebo recipients (24.6% vs. 12.0%, p=0.024, OR=2.69, 95% CI, 1.14–6.37). The 5 injection 400 µg dose regimen had the greatest antibody response and had significantly higher abstinence rates than placebo. This study demonstrates proof-of-concept that 3’AmNic-rEPA elicits antibodies to nicotine and is associated with higher continuous abstinence rates, justifying its further development as a treatment for nicotine dependence.
PMCID: PMC4106715  PMID: 21270788
3’AmNic-rEPA; NicVAX; nicotine immunotherapeutic; nicotine vaccine; cigarette; smoking cessation; antibody; P. aeruginosa r-Exoprotein A; aminomethyl nicotine; cotinine; CO
3.  Eleven-Year Outcomes from an Integrated Residency Program to Train Research Psychiatrists 
In 2000, to address the critical shortage of psychiatrist researchers, faculty in the Residency Training Program in General Adult Psychiatry at the University of California, San Francisco, School of Medicine developed and implemented a research resident training program (RRTP). In this article, the authors describe the program's development process, including its organizational structure, eligibility criteria for residents, and core program elements, and they report 11 years of outcomes data. Notable RRTP components include: research and career mentorship, individualized training plans, the integration of clinical and research experiences, protected research time, and research funding. From 2000-2011, the RRTP enrolled 48 residents. The authors’ primary outcome of interest in determining the success of the program was whether or not each RRTP resident entered a postdoctoral research fellowship after graduation. The authors found that more than 80% of graduates had matriculated to postdoctoral research fellowships, irrespective of their previous doctoral-level training in the basic or social sciences. The authors conclude that this flexible, individualized, and innovative training program for psychiatry residents was successful in facilitating the entry of participants into primary research careers, reasoning that it may serve as a model for other residency programs with similar goals. More widespread adoption of similar educational models may help to address the critical shortage of psychiatrist researchers.
PMCID: PMC3713635  PMID: 23702520
4.  Psychiatry 
Western Journal of Medicine  1996;164(3):256.
PMCID: PMC1303420
5.  Dr Reus Responds 
Western Journal of Medicine  1996;165(1-2):83.
PMCID: PMC1311731
6.  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.
PMCID: PMC3543492  PMID: 23040794
impulse control; tic disorders; prenatal maternal smoking; rage; co-morbidity
7.  Genetics of Mental Illness 
Western Journal of Medicine  1987;147(1):77-78.
PMCID: PMC1025830  PMID: 18750293
8.  Psychiatry—Epitomes of Progress 
Western Journal of Medicine  1981;134(2):143.
PMCID: PMC1272538  PMID: 18748787
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.
PMCID: PMC3605224  PMID: 22889924
Tourette Syndrome; tics; genetics; GWAS; neurodevelopmental disorder
10.  Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture 
Davis, Lea K. | Yu, Dongmei | Keenan, Clare L. | Gamazon, Eric R. | Konkashbaev, Anuar I. | Derks, Eske M. | Neale, Benjamin M. | Yang, Jian | Lee, S. Hong | Evans, Patrick | Barr, Cathy L. | Bellodi, Laura | Benarroch, Fortu | Berrio, Gabriel Bedoya | Bienvenu, Oscar J. | Bloch, Michael H. | Blom, Rianne M. | Bruun, Ruth D. | Budman, Cathy L. | Camarena, Beatriz | Campbell, Desmond | Cappi, Carolina | Cardona Silgado, Julio C. | Cath, Danielle C. | Cavallini, Maria C. | Chavira, Denise A. | Chouinard, Sylvain | Conti, David V. | Cook, Edwin H. | Coric, Vladimir | Cullen, Bernadette A. | Deforce, Dieter | Delorme, Richard | Dion, Yves | Edlund, Christopher K. | Egberts, Karin | Falkai, Peter | Fernandez, Thomas V. | Gallagher, Patience J. | Garrido, Helena | Geller, Daniel | Girard, Simon L. | Grabe, Hans J. | Grados, Marco A. | Greenberg, Benjamin D. | Gross-Tsur, Varda | Haddad, Stephen | Heiman, Gary A. | Hemmings, Sian M. J. | Hounie, Ana G. | Illmann, Cornelia | Jankovic, Joseph | Jenike, Michael A. | Kennedy, James L. | King, Robert A. | Kremeyer, Barbara | Kurlan, Roger | Lanzagorta, Nuria | Leboyer, Marion | Leckman, James F. | Lennertz, Leonhard | Liu, Chunyu | Lochner, Christine | Lowe, Thomas L. | Macciardi, Fabio | McCracken, James T. | McGrath, Lauren M. | Mesa Restrepo, Sandra C. | Moessner, Rainald | Morgan, Jubel | Muller, Heike | Murphy, Dennis L. | Naarden, Allan L. | Ochoa, William Cornejo | Ophoff, Roel A. | Osiecki, Lisa | Pakstis, Andrew J. | Pato, Michele T. | Pato, Carlos N. | Piacentini, John | Pittenger, Christopher | Pollak, Yehuda | Rauch, Scott L. | Renner, Tobias J. | Reus, Victor I. | Richter, Margaret A. | Riddle, Mark A. | Robertson, Mary M. | Romero, Roxana | Rosàrio, Maria C. | Rosenberg, David | Rouleau, Guy A. | Ruhrmann, Stephan | Ruiz-Linares, Andres | Sampaio, Aline S. | Samuels, Jack | Sandor, Paul | Sheppard, Brooke | Singer, Harvey S. | Smit, Jan H. | Stein, Dan J. | Strengman, E. | Tischfield, Jay A. | Valencia Duarte, Ana V. | Vallada, Homero | Van Nieuwerburgh, Filip | Veenstra-VanderWeele, Jeremy | Walitza, Susanne | Wang, Ying | Wendland, Jens R. | Westenberg, Herman G. M. | Shugart, Yin Yao | Miguel, Euripedes C. | McMahon, William | Wagner, Michael | Nicolini, Humberto | Posthuma, Danielle | Hanna, Gregory L. | Heutink, Peter | Denys, Damiaan | Arnold, Paul D. | Oostra, Ben A. | Nestadt, Gerald | Freimer, Nelson B. | Pauls, David L. | Wray, Naomi R. | Stewart, S. Evelyn | Mathews, Carol A. | Knowles, James A. | Cox, Nancy J. | Scharf, Jeremiah M.
PLoS Genetics  2013;9(10):e1003864.
The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
Author Summary
Family and twin studies have shown that genetic risk factors are important in the development of Tourette Syndrome (TS) and obsessive compulsive disorder (OCD). However, efforts to identify the individual genetic risk factors involved in these two neuropsychiatric disorders have been largely unsuccessful. One possible explanation for this is that many genetic variations scattered throughout the genome each contribute a small amount to the overall risk. For TS and OCD, the genetic architecture (characterized by the number, frequency, and distribution of genetic risk factors) is presently unknown. This study examined the genetic architecture of TS and OCD in a variety of ways. We found that rare genetic changes account for more genetic risk in TS than in OCD; certain chromosomes contribute to OCD risk more than others; and variants that influence the level of genes expressed in two regions of the brain can account for a significant amount of risk for both TS and OCD. Results from this study might help in determining where, and what kind of variants are individual risk factors for TS and OCD and where they might be located in the human genome.
PMCID: PMC3812053  PMID: 24204291
11.  Genomewide Linkage Analysis of Obsessive Compulsive Disorder Implicates Chromosome 1p36 
Biological psychiatry  2012;72(8):629-636.
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.
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.
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.
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.
PMCID: PMC3437244  PMID: 22633946
linkage; genomewide; pedigree; obsessive-compulsive; genetics; multigenerational
12.  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.
PMCID: PMC3606459  PMID: 23533600
13.  Using Extended Cognitive Behavioral Treatment and Medication to Treat Dependent Smokers 
American journal of public health  2011;101(12):2349-2356.
We evaluated smoking-cessation efficacy of an extended course of sustained-release bupropion (bupropion SR) and cognitive-behavioral treatment (CBT).
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.
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.
Brief contact with providers can increase abstinence during treatment. CBT may increase long-term abstinence after extended treatment is terminated.
PMCID: PMC3222443  PMID: 21653904
14.  Serum BDNF Levels Before Treatment Predict SSRI Response in Depression 
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.
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.
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).
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.
PMCID: PMC3159044  PMID: 21749907
Depression; brain-derived neurotrophic factor (BDNF); neurotrophin; antidepressant; SSRI
15.  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.
PMCID: PMC3247917  PMID: 18324565
tobacco dependence; treatment; older smokers
16.  Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress - Preliminary Findings 
PLoS ONE  2011;6(3):e17837.
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.
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).
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.
PMCID: PMC3063175  PMID: 21448457
17.  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.
PMCID: PMC2725024  PMID: 19063914
Dehydroepiandrosterone; DHEA; DHEAS; neuroprotection; neurogenesis; apoptosis; depression; schizophrenia; dementia; cortisol
18.  Extended treatment of older cigarette smokers 
Addiction (Abingdon, England)  2009;104(6):1043-1052.
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.
Open randomized clinical trial.
A free-standing, smoking treatment research clinic.
A total of 402 smokers of ≥ 10 cigarettes per day, all 50 years of age or older.
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).
Primary outcome variable was 7-day point prevalence cigarette abstinence verified biochemically at weeks 24, 52, 64 and 104.
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.
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.
PMCID: PMC2718733  PMID: 19392908
Bupropion; chronic disorders; cigarette smoking; NRT; older adults; tobacco dependence

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