Abby J. Fyer

An open trial of fluoxetine in the treatment of panic attacks

Fluoxetine is a new antidepressant with pharmacologic effects apparently limited to blockade of neuronal serotonin reuptake. We entered 20 patients who met DSM-III criteria for either panic disorder or agoraphobia with panic attacks into an open, uncontrolled pilot study of fluoxetine. Four responded to placebo in the week before fluoxetine administration and were dropped from the study. Of the remaining 16 patients, nine were nonresponders and seven were responders, with complete cessation of their panic attacks. Eight of the nine nonresponders were unable to tolerate the side effects of fluoxetine. In contrast, all of the responders (and one nonresponder) experienced minimal side effects. Fluoxetine may be effective in the treatment of panic attacks, perhaps implicating the serotonergic system in the pathophysiology of panic disorder. Future studies should use very low doses of fluoxetine to initiate treatment. (J Clin Psychopharmacol 1987;7:329–332)

Is obsessive-compulsive disorder an anxiety disorder, and what, if any, are spectrum conditions? A family study perspective.

BACKGROUND Experts have proposed removing obsessive-compulsive disorder (OCD) from the anxiety disorders section and grouping it with putatively related conditions in DSM-5. The current study uses co-morbidity and familiality data to inform these issues. METHOD Case family data from the OCD Collaborative Genetics Study (382 OCD-affected probands and 974 of their first-degree relatives) were compared with control family data from the Johns Hopkins OCD Family Study (73 non-OCD-affected probands and 233 of their first-degree relatives). RESULTS Anxiety disorders (especially agoraphobia and generalized anxiety disorder), cluster C personality disorders (especially obsessive-compulsive and avoidant), tic disorders, somatoform disorders (hypochondriasis and body dysmorphic disorder), grooming disorders (especially trichotillomania and pathological skin picking) and mood disorders (especially unipolar depressive disorders) were more common in case than control probands; however, the prevalences of eating disorders (anorexia and bulimia nervosa), other impulse-control disorders (pathological gambling, pyromania, kleptomania) and substance dependence (alcohol or drug) did not differ between the groups. The same general pattern was evident in relatives of case versus control probands. Results in relatives did not differ markedly when adjusted for demographic variables and proband diagnosis of the same disorder, though the strength of associations was lower when adjusted for OCD in relatives. Nevertheless, several anxiety, depressive and putative OCD-related conditions remained significantly more common in case than control relatives when adjusting for all of these variables simultaneously. CONCLUSIONS On the basis of co-morbidity and familiality, OCD appears related both to anxiety disorders and to some conditions currently classified in other sections of DSM-IV.

Familiality of Factor Analysis-Derived YBOCS Dimensions in OCD-Affected Sibling Pairs from the OCD Collaborative Genetics Study

BACKGROUND Identification of familial, more homogenous characteristics of obsessive-compulsive disorder (OCD) may help to define relevant subtypes and increase the power of genetic and neurobiological studies of OCD. While factor-analytic studies have found consistent, clinically meaningful OCD symptom dimensions, there have been only limited attempts to evaluate the familiality and potential genetic basis of such dimensions. METHODS Four hundred eighteen sibling pairs with OCD were evaluated using the Structured Clinical Interview for DSM-IV and the Yale-Brown Obsessive Compulsive Scale (YBOCS) Symptom Checklist and Severity scales. RESULTS After controlling for sex, age, and age of onset, robust sib-sib intraclass correlations were found for two of the four YBOCS factors: Factor IV (hoarding obsessions and compulsions (p = .001) and Factor I (aggressive, sexual, and religious obsessions, and checking compulsions; p = .002). Smaller, but still significant, familiality was found for Factor III (contamination/cleaning; p = .02) and Factor II (symmetry/ordering/arranging; p = .04). Limiting the sample to female subjects more than doubled the familiality estimates for Factor II (p = .003). Among potentially relevant comorbid conditions for genetic studies, bipolar I/II and major depressive disorder were strongly associated with Factor I (p < .001), whereas ADHD, alcohol dependence, and bulimia were associated with Factor II (p < .01). CONCLUSIONS Factor-analyzed OCD symptom dimensions in sibling pairs with OCD are familial with some gender-dependence, exhibit relatively specific relationships to comorbid psychiatric disorders and thus may be useful as refined phenotypes for molecular genetic studies of OCD.

Responses of “generalized” and “discrete” social phobics during public speaking☆☆☆

Abstract Thirty-six patients meeting DSM-IIIR social phobia criteria (28 “generalized,” 8 “discrete”) and 14 controls were monitored during a 10-minute simulated speech. Both patient groups reported less overall confidence in public speaking than controls. Generalized social phobic patients also exceeded controls in both subjective and manifest anxiety during the simulated speech. Discrete social phobic patients exceeded controls in anticipatory anxiety prior to the speaking challenge and in heart rate prior to and during the challenge. Generalized patients exceeded discrete social phobic patients in lack of confidence in public speaking and in subjective anxiety during the speech, but discrete patients exceeded generalized in heart rate elevation before and during the speech. The results underline the necessity of subtyping social phobia during psychobiological study, and suggest mechanisms by which symptoms are mediated in the two subtypes.

Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q.

Obsessive-compulsive disorder (OCD) is the tenth most disabling medical condition worldwide. Twin and family studies implicate a genetic etiology for this disorder, although specific genes have yet to be identified. Here, we present the first large-scale model-free linkage analysis of both extended and nuclear families using both ‘broad’ (definite and probable diagnoses) and ‘narrow’ (definite only) definitions of OCD. We conducted a genome-scan analysis of 219 families collected as part of the OCD Collaborative Genetics Study. Suggestive linkage signals were revealed by multipoint analysis on chromosomes 3q27–28 (P=0.0003), 6q (P=0.003), 7p (P=0.001), 1q (P=0.003), and 15q (P=0.006). Using the ‘broad’ OCD definition, we observed the strongest evidence for linkage on chromosome 3q27-28. The maximum overall Kong and Cox LODall score (2.67) occurred at D3S1262 and D3S2398, and simulation based P-values for these two signals were 0.0003 and 0.0004, respectively, although for both signals, the simulation-based genome-wide significance levels were 0.055. Covariate-linkage analyses implicated a possible role of gene(s) on chromosome 1 in increasing the risk for an earlier onset form of OCD. We are currently pursuing fine mapping in the five regions giving suggestive signals, with a particular focus on 3q27–28. Given probable etiologic heterogeneity in OCD, mapping gene(s) involved in the disorder may be enhanced by replication studies, large-scale family-based linkage studies, and the application of novel statistical methods.

Significant Linkage to Compulsive Hoarding on Chromosome 14 in Families With Obsessive-Compulsive Disorder: Results From the OCD Collaborative Genetics Study

OBJECTIVE Individuals with obsessive-compulsive disorder (OCD) who have compulsive hoarding behavior are clinically different from other OCD-affected individuals. The objective of this study was to determine whether there are chromosomal regions specifically linked to compulsive hoarding behavior in families with obsessive-compulsive disorder. METHODS The authors used multipoint allele-sharing methods to assess for linkage in 219 multiplex OCD families collected as part of the OCD Collaborative Genetics Study. The authors treated compulsive hoarding as the phenotype of interest and also stratified families into those with and without two or more relatives affected with compulsive hoarding. RESULTS Using compulsive hoarding as the phenotype, there was suggestive linkage to chromosome 14 at marker D14S588 (Kong and Cox logarithm of the odds ratio [LOD] [KAC(all)=2.9]). In families with two or more hoarding relatives, there was significant linkage of OCD to chromosome 14 at marker C14S1937 (KAC(all)=3.7), whereas in families with fewer than two hoarding relatives, there was suggestive linkage to chromosome 3 at marker D3S2398 (KAC(all)=2.9). CONCLUSIONS The findings suggest that a region on chromosome 14 is linked with compulsive hoarding behavior in families with OCD.

Evidence for Genetic Linkage Between a Polymorphism in the Adenosine 2A Receptor and Panic Disorder

Data from clinical and behavioral pharmacological studies have implicated adenosine in anxiety behaviors, while genetic studies have suggested that adenosine receptors may be associated with panic disorder. We have undertaken an analysis of several DNA sequence variations in the adenosine 2A receptor (ADORA2A) in a large sample of panic disorder pedigrees. Individuals from 70 panic disorder pedigrees, and 83 child–parent ‘trios’, were genotyped at five single-nucleotide polymorphisms (SNPs) in and near the ADORA2A gene and were analyzed for genetic linkage and association. Linkage analysis revealed elevated LOD scores for a silent substitution (1083C/T, SNP-4) in the second coding exon. This SNP has been previously reported to be associated with panic disorder. We observed a maximal heterogeneity LOD score of 2.98 (θ=0) under a recessive genetic model and narrow diagnostic model. Other SNPs showed no evidence for linkage. Association tests were not significant for any of the five ADORA2A SNPs. When SNP haplotypes were assessed in the triads with TRANSMIT, one 3-marker haplotype (SNPs 1, 4, 5) was nominally significantly associated with panic disorder (p=0.029). Pairwise estimations of linkage disequilibrium between the SNPs showed strong patterns of linkage disequilibrium across the ADORA2A locus. Analyses carried out by broadening the panic disorder phenotype to include agoraphobia continued to support linkage to ADORA2A. Our findings provide evidence for a susceptibility locus for panic disorder, and possibly including agoraphobia, either within the ADORA2A gene or in a nearby region of chromosome 22, and serves as the first successful candidate gene replication study in panic disorder.

Results of a genome-wide genetic screen for panic disorder.

Panic disorder is characterized by spontaneous and recurrent panic attacks, often accompanied by agoraphobia. The results of family, twin, and segregation studies suggest a genetic role in the etiology of the illness. We have genotyped up to 23 families that have a high density of panic disorder with 540 microsatellite DNA markers in a first-pass genomic screen. The thirteen best families (ELOD > 6.0 under the dominant genetic model) have been genotyped with an ordered set of markers encompassing all the autosomes, at an average marker density of 11 cM. Over 110,000 genotypes have been generated on the whole set of families, and the data have been analyzed under both a dominant and a recessive model, and with the program SIBPAIR. No lod scores exceed 2.0 for either parametric model. Two markers give lod scores over 1.0 under the dominant model (chromosomes 1p and 20p), and four do under the recessive model (7p, 17p, 20q, and X/Y). One of these (20p) may be particularly promising. Analysis with SIBPAIR yielded P values equivalent to a lod score of 1.0 or greater (i.e., P < .016, one-sided, uncorrected for multiple tests) for 11 marker loci (2, 7p, 8p, 8q, 9p, 11q, 12q, 16p, 20p and 20q).

The relationship of social phobia subtypes and avoidant personality disorder

The diagnoses of social phobia (SP) and avoidant personality disorder (APD) have evolved from different historical sources, but their criteria appear to converge in DSM-III-R. Fifty anxiety disorder clinic patients with DSM-III-R SP were evaluated for presence of DSM-III-R APD. APD was present in 89% of those with the generalized subtype of SP (GSP) and 21% of those with the discrete subtype of SP (DSP). The findings are discussed in conjunction with other recent reports showing substantial overlap between GSP and APD.

Sapap3 and pathological grooming in humans: Results from the OCD collaborative genetics study.

SAP90/PSD95‐associated protein (SAPAP) family proteins are post‐synaptic density (PSD) components that interact with other proteins to form a key scaffolding complex at excitatory (glutamatergic) synapses. A recent study found that mice with a deletion of the Sapap3 gene groomed themselves excessively, exhibited increased anxiety‐like behaviors, and had cortico‐striatal synaptic defects, all of which were preventable with lentiviral‐mediated expression of Sapap3 in the striatum; the behavioral abnormalities were also reversible with fluoxetine. In the current study, we sought to determine whether variation within the human Sapap3 gene was associated with grooming disorders (GDs: pathologic nail biting, pathologic skin picking, and/or trichotillomania) and/or obsessive‐compulsive disorder (OCD) in 383 families thoroughly phenotyped for OCD genetic studies. We conducted family‐based association analyses using the FBAT and GenAssoc statistical packages. Thirty‐two percent of the 1,618 participants met criteria for a GD, and 65% met criteria for OCD. Four of six SNPs were nominally associated (P < 0.05) with at least one GD (genotypic relative risks: 1.6–3.3), and all three haplotypes were nominally associated with at least one GD (permuted P < 0.05). None of the SNPs or haplotypes were significantly associated with OCD itself. We conclude that Sapap3 is a promising functional candidate gene for human GDs, though further work is necessary to confirm this preliminary evidence of association.