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The goal of this study was to identify chromosomal regions likely to contain susceptibility alleles for early-onset obsessive-compulsive disorder (OCD). A genome scan was done in 56 individuals from seven families ascertained through pediatric OCD probands; 27 of the 56 subjects had a lifetime diagnosis of definite OCD. Denser mapping of regions on chromosomes 2, 9, and 16 was subsequently done with those subjects and ten additional subjects from the largest family in the study. Direct interviews were completed with 65 of the 66 genotyped individuals. Relatives were interviewed blind to proband status. Of the 65 interviewed individuals, 32 had a lifetime diagnosis of definite OCD. Three of the seven probands had a history of Tourette disorder. Two of the 25 relatives with OCD had a tic history, whereas none of the 33 relatives without OCD had tics. The genome scan consisted of 349 microsatellite markers with an average between-marker distance of 11.3 centiMorgan (cM). Fine mapping was done with 24 additional markers at an average spacing of 1.6 cM. Parametric and nonparametric linkage analyses were conducted using GENEHUNTER(+). The maximum multipoint LOD score with a dominant model was 2.25 on 9p. However, with fine mapping and additional subjects, that LOD score decreased to 1.97. The maximum multipoint nonparametric LOD* score was 1.73 on 19q. The maximum multipoint LOD score with a recessive model was 1.40 on 6p. The results provide suggestive evidence for linkage on 9p and identify regions requiring further study with much larger samples.

Obsessive-compulsive disorder (OCD) is a heterogeneous disorder of unknown etiology. We examined the lifetime history of obsessions, compulsions, and OCD in the first- and second-degree relatives of 35 pediatric probands with OCD and 17 controls with no psychiatric diagnosis. All available first-degree relatives were directly interviewed blind to proband status with two semi-structured interviews. Parents were also interviewed to systematically assess the family psychiatric history of first- and second-degree relatives. Best-estimate lifetime diagnoses were made using all available sources of information. Data were analyzed with logistic regression by the generalized estimating equation method and with robust Cox regression models. The lifetime prevalence of definite OCD was significantly higher in case than control first-degree relatives (22.5% vs. 2.6%, P < 0.05). Compared to controls, case first-degree relatives also had significantly higher lifetime rates of obsessions and compulsions (both P < 0.05). There was no significant difference between case and control second-degree relatives in lifetime rates of OCD. First-degree relatives of case probands with ordering compulsions had a significantly higher lifetime rate of definite and subthreshold OCD than relatives of case probands without ordering compulsions (45.4% vs. 18.8%, P < 0.05). The lifetime prevalence of definite OCD was significantly higher in case first-degree relatives with a history of tics than in case first-degree relatives without a tic history (57.1% vs. 20.9%, P < 0.01). The results provide further evidence that early-onset OCD is highly familial and suggest that two clinical variables are associated with its familial aggregation.

SynopsisUrinary free Cortisol (UFC) excretion was determined in 60 depressed inpatients and in 35 psychiatric inpatients with other disorders. The depressed patients had high daily UFC values, while the other patients excreted normal amounts. Over 40% of the depressed patients had UFC excretions in the range seen in Cushing's disease, while only 6% of the other patients excreted such high amounts of Cortisol. Age and sex differences did not account for the results. Among the depressed patients those with depressive neuroses excreted less than unipolar or bipolar depressives. Following treatment, more normal UFC excretion was found in depressed patients. The estimation of UFC and its clinical utility are discussed in detail. UFC determination is a simple and informative indicator of adrenal cortical activation and its application to psychoendocrine studies is recommended.

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The serotonin transporter (HTT) is a candidate gene for obsessive-compulsive disorder (OCD) that has been associated with anxiety-related traits. The long (1) and short (s) variants of theThe serotonin transporter (HTT = SLC6A4) is a plausible candidate gene for obsessive-compulsive disorder (OCD) and several other psychiatric disorders (Altemus et al. 1996;Lesch et al. 1995;Ogilvie et al. 1996). It has been associated with anxiety-related traits in two predominantly male samples (Gelernter et al. 1995;Ramamoorthy et al. 1993). A complementary deoxyribose nucleic acid (cDNA) encoding the 5-HTT in the human midbrain raphe complex has been isolated, and its identity with the human platelet serotonin (5-HT) transporter site has been demonstrated (Lesch et al. 1993a,b).HTT gene transcription is regulated by a deletion/ insertion polymorphism in the promoter (Heils et al. 1995). The long (I) and short (s) variants of this polymorphic region have different transcriptional efficiencies in transfection assays and lymphoblastoid cell lines Lesch et al. 1996). The short allele reduces the transcriptional efficiency of the HTT gene promoter, resulting in decreased 5-HTT binding and 5-HT uptake in lymphoblasts . Studies of HIT gene expression in lymphoblast cell lines from 10 subjects with different genotypes suggested that the polymorphism has more of a dominant-recessive than a codominant-additive effect, with the short variant ap-0893-133X/98/$19.00 PII S0893-133X(97)00097-3 NEUROPSYCHOPHARMACOLOGY 1998-VOL. 18, NO. 2 pearing dominant to the long variant. However, the dominant mode of action of the short allele has been questioned (Goldman 1996).Because of the small sample size in that study and the importance of the HTT, we examined the relationship between the HTT promoter variant and whole blood 5-HT concentration in 70 individuals from 20 families ascertained through children and adolescents between 10 and 17 years of age with a DSM-III-R diagnosis of OCD. Sampling through early-onset cases can be a useful strategy in identifying a more clearly genetic or homogeneous form of a disorder (Lander and Schork 1994). Family studies have demonstrated that OCD is often familial and that the morbid risk of the disorder is higher among the relatives of early-onset probands than among the relatives of late-onset probands (Bellodi et al. 1992;Pauls et al. 1995).The selective response of OCD to potent 5-HT transporter inhibitors (serotonin reuptake inhibitors, SRis) has suggested that a serotonergic abnormality may be involved in OCD (Goodman et al. 1990;Leonard et al. 1989). The 5-HTT is an initial site of action for those drugs and is crucial to the termination of serotonergic neurotransmission (Amara and Kuhar 1993). Two treatment studies of childhood OCD using clomipramine, a potent 5-HT transporter inhibitor, have demonstrated a significant correlation between clinical improvement and a marked reduction in either platelet 5-HT or whole blood 5-HT content, reflecting the effect of the drug on the platelet uptake site (F...

SynopsisCerebrospinal fluid (CSF) cortisol levels were examined in a total group of 65 patients. Those who were not depressed (ND), and those suffering from depressive neuroses (DN) had marginally elevated values. Patients with unipolar depression (UD) and bipolar depression (BD) had levels twice as high as the ND and DN patients. Psychotic UD and BD patients had the highest values, three to four times as high as the ND and DN subjects. A significant reduction of CSF cortisol levels was observed following treatment and recovery. Manic patients had moderately elevated CSF cortisol values. The CSF results were in good agreement with plasma total cortisol levels and with urinary free cortisol excretion. Age and sex effects were not responsible for the observed differences; similar results were found in patient subgroups studied in Australia and in the United States. Preliminary equilibrium dialysis data are presented for plasma and CSF cortisol binding. CSF cortisol was 20% bound and 80% free. Plasma free cortisol levels were in good agreement with CSF free cortisol values. Depressed patients have increased tissue and central nervous system (CNS) exposure to free, physiologically active glucocorticoids. The appearance of severe depressive symptoms which manifest a diurnal rhythm may be determined in part by excessive CNS exposure to glucocorticoids.

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