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Biomedical subjects

J W Smoller

Publications and source records attributed to J W Smoller.

At least 19 recordsLinked to original sources
PubMed2007

A study of how socioeconomic status moderates the relationship between SNPs encompassing BDNF and ADHD symptom counts in ADHD families.

Recent animal research suggests that brain-derived neurotrophic factor (BDNF), may mediate response to different environmental stimuli. In this paper, we evaluated the possible role of BDNF as a moderator of attention deficit hyperactivity disorder (ADHD) in the context of different socioeconomic classes. We genotyped ten single nucleotide polymorphisms (SNPs) in and around BDNF in 229 families and evaluate whether there are SNP-by-socioeconomic status (SES) interactions for attention deficit hyperactivity. We developed three quantitative phenotypes for ADHD from nine inattentive and nine hyperactive-impulsive symptoms that were used in SNP-by-SES interaction analyses using a new methodology implemented in the computer program PBAT. Findings were adjusted for multiple comparisons using the false discovery rate. We found multiple significant SNP-by-SES interactions using the inattentive symptom count. This study suggests that different SES classes may modify the effect of the functional variant(s) in and around BDNF to have an impact on the number of ADHD symptom counts that are observed. The two exons within BDNF represent potential functional variants that may be causing the observed associations.

Attention Deficit Disorder with Hyperactivity↗
PubMed2001

Genetic association analysis of behavioral inhibition using candidate loci from mouse models.

Genes influence the development of anxiety disorders, but the specific loci involved are not known. Genetic association studies of anxiety disorders are complicated by the complexity of the phenotypes and the difficulty in identifying appropriate candidate loci. We have begun to examine the genetics of behavioral inhibition to the unfamiliar (BI), a heritable temperamental predisposition that is a developmental and familial risk factor for panic and phobic disorders. Specific loci associated with homologous phenotypes in mouse models provide compelling candidate genes for human BI. We conducted family-based association analyses of BI using four genes derived from genetic studies of mouse models with features of behavioral inhibition. The sample included families of 72 children classified as inhibited by structured behavioral assessments. We observed modest evidence of association (P = 0.05) between BI and the glutamic acid decarboxylase gene (65 kDA isoform), which encodes an enzyme involved in GABA synthesis. No significant evidence of association was observed for the genes encoding the adenosine A(1A) receptor, the adenosine A(2A) receptor, or preproenkephalin. This study illustrates the potential utility of using candidate genes derived from mouse models to dissect the genetic basis of BI, a possible intermediate phenotype for panic and phobic disorders.

Animals↗
PubMed2001

Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions.

Family and twin studies have indicated that genes influence susceptibility to panic and phobic anxiety disorders, but the location of the genes involved remains unknown. Animal models can simplify gene-mapping efforts by overcoming problems that complicate human pedigree studies including genetic heterogeneity and high phenocopy rates. Homology between rodent and human genomes can be exploited to map human genes underlying complex traits. We used regions identified by quantitative trait locus (QTL)-mapping of anxiety phenotypes in mice to guide a linkage analysis of a large multiplex pedigree (99 members, 75 genotyped) segregating panic disorder/agoraphobia. Two phenotypes were studied: panic disorder/agoraphobia and a phenotype ("D-type") designed to capture early-onset susceptibility to anxiety disorders. A total of 99 markers across 11 chromosomal regions were typed. Parametric lod score analysis provided suggestive evidence of linkage (lod = 2.38) to a locus on chromosome 10q under a dominant model with reduced penetrance for the anxiety-proneness (D-type) phenotype. Nonparametric (NPL) analysis provided evidence of linkage for panic disorder/agoraphobia to a locus on chromosome 12q13 (NPL = 4.96, P = 0.006). Modest evidence of linkage by NPL analysis was also found for the D-type phenotype to a region of chromosome 1q (peak NPL = 2.05, P = 0.035). While these linkage results are merely suggestive, this study illustrates the potential advantages of using mouse gene-mapping results and exploring alternative phenotype definitions in linkage studies of anxiety disorder.

Animals↗
PubMed2001

Childhood history of anxiety disorders among adults with social phobia: rates, correlates, and comparisons with patients with panic disorder.

We examined the rates and correlates of a childhood history of anxiety disorders in 100 adults with a primary diagnosis of social phobia (social anxiety disorder). Adulthood and childhood disorders were assessed by experienced clinicians with structured clinical interviews. Rates of childhood anxiety disorders were evaluated to diagnostic comorbidity and a comparison group of patients with panic disorder. Onset of social phobia occurred before age 18 in 80% of the sample. Over half of the sample (54%) met criteria for one or more childhood anxiety disorders other than social phobia: 47% for overanxious disorder, 25% for avoidant disorder, 13% for separation anxiety disorder, and 1% for childhood agoraphobia. A history of childhood anxiety was associated with an early age of onset of social phobia, greater severity of fear and avoidance of social situations, greater fears of negative evaluation, and greater anxiety and depression morbidity. Rates of childhood social phobia, overanxious disorder, and avoidant disorder were significantly higher in patients with social phobia relative to our panic-disordered comparison group. We found approximately equal rates of a childhood history of separation anxiety disorder in patients with social phobia and panic disorder, providing further evidence against a unique relationship between separation anxiety disorder and panic disorder.

Adolescent↗
PubMed2001

On the validity of the TDT test in the presence of comorbidity and ascertainment bias.

Comorbidity, the association of two disorders, occurs commonly with complex diseases. In this paper, we investigate the effects of both true (within-family) comorbidity and spurious comorbidity due to ascertainment bias on the validity of both the parental and sibling control transmission/disequilibrium test. Specifically, we consider settings in which a candidate gene is unlinked to the target phenotype but is in linkage disequilibrium with a comorbid phenotype. We derive conditions under which the presence of true and/or spurious comorbidity will result in an artificial correlation between the target phenotype and the candidate gene.

Bias↗
PubMed2001

The genetics of panic disorder.

Of the anxiety disorders, panic disorder (PD) has been the most extensively studied from a genetic standpoint. Results of family studies have consistently demonstrated that PD runs in families, and twin studies indicate that genes contribute to this familiality. However, phenotypic and genetic complexity has made finding the specific genes involved in PD a challenge. There is still uncertainty about how best to define the phenotype for genetic studies and whether it is the clinical phenotype of PD or more latent psychologic and biologic traits that are inherited. To date, molecular genetic studies have suggested some chromosomal regions and genes that may contribute to risk, but none of these have been established. We review the genetic epidemiology of PD as well as recent molecular genetic studies of the disorder, and conclude with a discussion of promising strategies that attempt to uncover specific genetic loci involved in the etiology of PD.

Epidemiologic Studies↗
PubMed2000

Implications of comorbidity and ascertainment bias for identifying disease genes.

Comorbidity, the co-occurrence of disorders, is frequently observed to occur at higher rates in clinically ascertained samples than in population-based samples. An explanation for this finding is that subjects suffering from multiple illnesses are more likely to seek medical care and receive a diagnostic evaluation. We refer to the component of the comorbidity between illnesses due to such ascertainment bias as "spurious comorbidity." When spurious comorbidity is present, an apparent association between a candidate locus and the phenotype of interest may actually be attributable to an association between the locus and a comorbid phenotype. This phenomenon, which we call "spurious comorbidity bias," could thus produce misleading association findings. In this article, we describe this phenomenon and demonstrate that it may produce marked bias in the conclusions of family-based association studies. Because of the extremely high rates of comorbidity among psychiatric disorders in clinical samples, this problem may be particularly salient for genetic studies of neuropsychiatric disorders. We conclude that ascertainment bias may contribute to the frequent difficulty in replicating candidate gene study findings in psychiatry. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:817-822, 2000.

Alleles↗
PubMed2000

Anxiety disorders and tic severity in juveniles with Tourette's disorder.

OBJECTIVE: It was hypothesized that comorbidity with anxiety disorders would predict tic severity in youths with Tourette's disorder (TD). METHOD: Subjects were 190 youths meeting DSM-III-R diagnostic criteria for TD who were consecutively referred to a pediatric psychopharmacology program between 1994 and 1997. Subjects were initially evaluated with a clinical interview and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic version. Statistical analysis used t tests, chi 2 tests, and logistic regression analysis. RESULTS: One hundred thirty-four subjects were classified as mild/moderate and 56 as severe TD cases. No meaningful differences were found in socioeconomic status, gender distribution, or age at onset of TD between the 2 groups. The 2 groups could not be differentiated by the presence of comorbid mood or disruptive behavior disorders including attention-deficit hyperactivity disorder. Although obsessive-compulsive disorder (OCD) was overrepresented among the severe TD cases, the difference failed to reach statistical significance. Excluding social and simple phobias, all other anxiety disorders were more clearly overrepresented among subjects with severe TD; separation anxiety disorder most robustly predicted tic severity, irrespective of the presence of OCD or other anxiety disorders. CONCLUSION: Findings suggest that non-OCD anxiety disorders in general and separation anxiety disorder in particular may be significantly associated with tic severity in referred TD patients.

Anxiety Disorders↗
PubMed1999

Using recursive partitioning for exploration and follow-up of linkage and association analyses.

We first conducted a genome-wide screen for association with discordant sibships using the multi allelic and diallelic SDT. Markers at D4S1628, D8S1109, D9S66 and D7S1797 showed multi-allelic association. Deleterious diallelic association was found for markers at D1S1613, D1S534, D3S2459, D7S1817, and D9S131. Protective association was found at markers D8S1109, D8S1136, and D9S66. We then incorporated these findings with previous linkage findings in the exploration of oligogenes and epistasis using recursive partitioning. We conclude that recursive partitioning can be a useful adjunct to traditional linkage and association analyses in the exploration of these effects.

Alcoholism↗
PubMed1999

Anxiety in patients with pulmonary disease: comorbidity and treatment.

Anxiety is a common and sometimes disabling symptom among patients with respiratory disease. Anxiety disorders appear to be the most prevalent psychiatric disorders in clinical samples of patients with pulmonary disease. Recognition that the differential diagnosis of dyspnea and anxiety includes both pulmonary and psychiatric conditions can be crucial to appropriate medical management and minimizing iatrogenic harm. This article reviews the epidemiology, comorbidity, diagnosis, and treatment of anxiety syndromes in patients with pulmonary disease. Successful treatment of anxiety disorders can substantially improve quality of life and a variety of treatment options are available. Safe and effective pharmacotherapy requires attention to potential adverse drug effects on pulmonary function and drug-to-drug interactions. Nonpharmacological treatments such as cognitive/behavioral therapies offer effective treatment without the risk of medication side effects.

Antidepressive Agents↗
PubMed1998

Panic, dyspnea, and asthma.

Dyspnea, a cardinal symptom of asthma, is also a common feature of panic attacks. Patients with asthma have high rates of anxiety disorders, and respiratory illness may be a risk factor in the development of panic disorder. The diagnosis of anxiety disorders in patients with asthma can be challenging, but successful identification and treatment of anxiety can reduce morbidity and improve quality of life in these patients. Serotonergic anxiolytic medications and cognitive-behavioral therapy appear to be the treatments of choice for pathologic anxiety in patients with asthma.

Anti-Anxiety Agents↗
PubMed1998

Panic and phobic anxiety: defining phenotypes for genetic studies.

OBJECTIVE: With recent advances in molecular genetics, the rate-limiting step in identifying susceptibility genes for psychiatric disorders has become phenotype definition. The success of psychiatric genetics may require the development of a "genetic nosology" that can classify individuals in terms of the heritable aspects of psychopathology. The authors' aim is to begin to apply this analysis to the anxiety disorders, focusing on panic and phobic disorders. METHOD: Two parallel traditions of defining anxiety phenotypes are reviewed: the first, more closely identified with clinical psychiatry, has identified categorical diagnoses (e.g., panic disorder and social phobia). The other, more closely identified with psychological studies of personality development, has examined dimensional traits (e.g., neuroticism) and anxious temperament (e.g., behavioral inhibition). RESULTS: The authors suggest that a genetic nosology of panic and phobic disorders may incorporate features of both traditions and discuss strategies for optimizing genetic approaches to anxiety including 1) studying phenotypic extremes, 2) identifying biological trait markers, and 3) using animal models to identify candidate loci. CONCLUSIONS: An important dividend from the effort to define the boundaries of heritable phenotypes for genetic studies of anxiety may be a refinement of the nosology of anxiety disorders.

Agoraphobia↗
PubMed1998

How do clinicians respond to patients who miss appointments?

BACKGROUND: Although patients miss up to 60% of scheduled outpatient appointments, little is known about how clinicians respond to "no-shows." In an effort to determine how clinicians customarily handle missed appointments, we surveyed mental health clinicians and internists at 2 academic hospitals: a private psychiatric hospital and an urban general hospital. METHOD: An anonymous questionnaire survey was mailed to psychiatrists, psychologists, and social workers at both hospitals and to internists at the general hospital. Clinicians were surveyed about their usual response to psychotherapy, psychopharmacology, and internal medicine patients who miss appointments. RESULTS: Among the 356 responses (39.5%) to 902 mailed questionnaires, there was substantial variability in clinicians' reported handling of "no-show" patients, although psychiatrists tended to be initially less active in pursuing patients than were nonphysician therapists and internists. A number of clinical variables were associated with clinicians' responses including the perceived risk of a bad outcome, hospital site, support staff availability, and billing practices. CONCLUSION: The results suggest that clinicians' responses to missed appointments are determined by a complex mixture of influences rather than adherence to a readily definable "standard of care."

Adult↗
PubMed1997

Intermittent luteal phase sertraline treatment of dysphoric premenstrual syndrome.

BACKGROUND: Dysphoric premenstrual syndrome (PMS) has been associated with serotonergic dysregulation, and serotonergic medications have been reported to alleviate the symptoms of PMS. We investigated the effects of the serotonin reuptake inhibitor sertraline given during only the luteal phase in women with dysphoric PMS. METHOD: After baseline ratings were obtained during two menstrual cycles, 15 women with dysphoric PMS who also met DSM-IV criteria for premenstrual dysphoric disorder (PMDD) entered single-blind treatment with sertraline 100 mg/day for one full menstrual cycle. Women who responded to this treatment were randomly assigned to a four-cycle double-blind placebo-controlled crossover study in which sertraline 100 mg/day or placebo was each given only during luteal phases of two consecutive menstrual cycles. RESULTS: Eleven (79%) of fourteen women responded to single-blind full-cycle treatment with sertraline and were randomly assigned to the double-blind crossover study. Three patients dropped out of the study while taking placebo owing to nonresponse. For the remaining patients, sertraline given during the luteal phase produced significant improvements in depression, impairment, and global ratings compared with placebo and was equivalent in efficacy to sertraline given during the entire menstrual cycle. CONCLUSION: Women with dysphoric PMS who responded to continuous sertraline treatment responded equally well to sertraline treatment that was restricted to the luteal phase. Luteal phase treatment may have advantages in side effect burden and costs. Larger controlled trials are warranted to confirm this finding.

1-Naphthylamine↗
PubMed1996

Panic anxiety, dyspnea, and respiratory disease. Theoretical and clinical considerations.

There is intriguing evidence suggesting pathophysiologic relationships among dyspnea, hyperventilation, and panic anxiety. The symptoms of panic attacks and pulmonary disease overlap, so that panic anxiety can reflect underlying cardiopulmonary disease and dyspnea can reflect an underlying anxiety disorder. The pathogenesis of panic may be related to respiratory physiology by several mechanisms: the anxiogenic effects of hyperventilation, the catastrophic misinterpretation of respiratory symptoms, and/or a neurobiologic sensitivity to CO2, lactate, or other signals of suffocation. In a subset of patients with PD, incipient pulmonary dysfunction may also contribute to their anxiety symptoms. Patients with pulmonary disease, particularly those with obstructive lung disease, have a high rate of panic symptoms and PD. There is reason to believe that pulmonary disease constitutes a risk factor for the development of panic related to repeated experiences with dyspnea and life-threatening exacerbations of pulmonary dysfunction, repeated episodes of hypercapnia or hyperventilation, the use of anxiogenic medications, and the stress of coping with chronic disease. Panic in pulmonary patients may carry significant morbidity, including phobic avoidance of activity, overly aggressive treatment with anxiogenic medications, and more prolonged and frequent hospitalization. Successful treatment of panic in these patients can improve functional status and quality of life by relieving anxiety and dyspnea. Nonpharmacologic treatment of panic, including cognitive-behavioral approaches, can be useful in patients with concomitant respiratory disease. Sedating medications such as benzodiazepines should be used with caution in patients with pulmonary disease to avoid respiratory depression. Serotonergic antidepressants (SSRIs) and anxiolytics (buspirone) may be effective treatments for panic or generalized anxiety in pulmonary patients and have relatively little potential for significant adverse effects.

Anxiety↗
PubMed1996

Venlafaxine for panic disorder: results from a double-blind, placebo-controlled study.

Venlafaxine has demonstrated efficacy for depression, and recent reports and clinical experience suggest that it may be effective for the treatment of anxiety disorders as well. We present what we believe are the first data from a controlled study designed to test the efficacy of venlafaxine for the treatment of panic disorder. There were 25 patients enrolled at one site of a five-center study; 13 received venlafaxine and 12 received placebo. There were more dropouts for placebo than for venlafaxine (8/12 vs. 2/13) in this 8-week acute trial. Patients treated with venlafaxine experienced significantly greater global improvement than those on placebo and exhibited trends toward greater improvement on anxiety and depression symptoms as assessed by the Hamilton rating scales. These data encourage further evaluation of venlafaxine for the treatment of panic disorder.

Adult↗
PubMed1995

Genetic map of rat chromosome 5 including the fatty (fa) locus.

Thirteen loci, including the obesity gene fatty (fa), were incorporated into a linkage map of rat Chromosome (Chr) 5. These loci were mapped in obese (fa/fa) progeny of a cross between BN x 13M-fal+F1 animals. Obese rats were scored for BN and 13M alleles at four loci (Ifna, D1S85h, C8b, and Lck1) by restriction fragment length polymorphisms and at eight additional loci (Glut1, Sv4j2, R251, R735, R980, R252, R371, and R1138) by simple sequence length polymorphisms (SSLP). The resulting map spans 67.3 cM of Chr5, presenting nine previously unmapped loci and one locus (Lck1) previously assigned to Chr 5 by use of somatic cell hybrid lines. Seven of the eight SSLP loci are newly identified; the SSLP linkage group alone spans 56.8 cM. The order of the loci is Sv4j2-R251-R735-R980-R1138-Ifna-fa-+ ++D1S85h-C8b-(Glut1-R252-R371)-Lck1. One locus, D1S85h, was found to lie only 0.4 cM from fa, close enough to serve as a reliable marker for the prediction of phenotype from genotype, and will be useful also for studies on the development of obesity in the fatty rat.

Alleles↗