Influence of CYP2D6 and CYP2C19 gene variants on antidepressant response in obsessive-compulsive disorder.

Numerous studies have reported on pharmacogenetics of antidepressant response in depression. In contrast, little is known of response predictors in obsessive-compulsive disorder (OCD), a disorder with among the lowest proportion of responders to medication (40-60%). Our study is the largest investigation to date (N=184) of treatment response and side effects to antidepressants in OCD based on metabolizer status for CYP2D6 and CYP2C19. We observed significantly more failed medication trials in CYP2D6 non-extensive compared with extensive metabolizers (P=0.007). CYP2D6 metabolizer status was associated with side effects to venlafaxine (P=0.022). There were nonsignificant trends for association of CYP2D6 metabolizer status with response to fluoxetine (P=0.056) and of CYP2C19 metabolizer status with response to sertraline (P=0.064). Our study is the first to indicate that CYP genes may have a role in antidepressant response in OCD. More research is required for a future clinical application of genetic testing, which could lead to improved treatment outcomes.

Genome-wide association study of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.

Meta-analysis of association between obsessive-compulsive disorder and the 3' region of neuronal glutamate transporter gene SLC1A1.

The neuronal glutamate transporter gene SLC1A1 is a candidate gene for obsessive-compulsive disorder (OCD) based on linkage studies and convergent evidence implicating glutamate in OCD etiology. The 3' end of SLC1A1 is the only genomic region with consistently demonstrated OCD association, especially when analyzing male-only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome-wide association and meta-analysis studies have not incorporated all previously associated SLC1A1 SNPs. To clarify the nature of association between SLC1A1 and OCD, pooled analysis was performed on all available relevant raw study data, comprising a final sample of 815 trios, 306 cases and 634 controls. This revealed weak association between OCD and one of nine tested SLC1A1 polymorphisms (rs301443; uncorrected P = 0.046; non-significant corrected P). Secondary analyses of male-affecteds only (N = 358 trios and 133 cases) demonstrated modest association between OCD and a different SNP (rs12682807; uncorrected P = 0.012; non-significant corrected P). Findings of this meta-analysis are consistent with the trend of previous candidate gene studies in psychiatry and do not clarify the putative role of SLC1A1 in OCD pathophysiology. Nonetheless, it may be important to further examine the potential associations demonstrated in this amalgamated sample, especially since the SNPs with modest associations were not included in the more highly powered recent GWAS or in a past meta-analysis including five SLC1A1 polymorphisms. This study underscores the need for much larger sample sizes in future genetic association studies and suggests that next-generation sequencing may be beneficial in examining the potential role of rare variants in OCD.

The serotonin-1Dbeta receptor gene and severity of obsessive-compulsive disorder in women with bulimia nervosa.

BACKGROUND: There is significant evidence that eating disorders have an important biological overlap with obsessive-compulsive disorder (OCD), though the specific mediators of this relationship remain unclear. Recent evidence suggests that the G861C polymorphism of the 5HT-1Dbeta receptor gene and the G allele in particular may play a role in OCD. We thus hypothesized that, among a heterogenous group of probands with bulimia nervosa (BN), this same G allele might predict the presence and/or severity of OCD pathology. METHODS: 165 consecutive female probands with BN were genotyped for the G861C polymorphism of the 5HT-1Dbeta receptor gene. Rates of full syndrome OCD, partial syndrome OCD and no OCD were compared across the three genotypic groups defined by this polymorphism. RESULTS: 45 out of 165 BN probands (27.3%) had either full or partial syndrome OCD. In the full sample, there was a significant difference in the distribution of the three diagnostic groups by genotype (chi2=10.07, df=4, p=.039). The G861C polymorphism did not strongly predict which probands had any vs. no OCD pathology. However, among the 45 probands with OCD symptoms, the G861C polymorphism did strongly differentiate full syndrome vs. partial syndrome OCD (chi2=9.26, df=2, p=.01; odds ratio for full syndrome OCD with GG genotype=7.69, 95% CI=1.45-40.9). DISCUSSION: In women with BN, the G861C polymorphism of the 5HT-1Dbeta gene does not appear to be associated with the generation of OCD symptoms; however, it might directly or indirectly be associated with a modulatory effect on syndrome severity in probands otherwise predisposed to OCD. While preliminary and in need of replication in other samples, this is the first association study to suggest how a particular gene might influence OCD pathology in an eating disorder population.

Is the 5-HT(1Dbeta) receptor gene implicated in the pathogenesis of obsessive-compulsive disorder?

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a psychiatric condition for which strong evidence of a genetic component and serotonergic system involvement exists. Recent studies have shown that sumatriptan, a selective ligand of the serotonin (5-HT)(1Dbeta) autoreceptor, modifies OCD symptoms. The aim of this study was to investigate the presence of linkage disequilibrium between the 5-HT(1Dbeta) receptor gene, which has a variant caused by a silent G to C substitution at nucleotide 861 of the coding region, and OCD. METHOD: DNA was collected from 67 probands who met DSM-IV criteria for OCD and from their living parents or siblings. Transmission Disequilibrium Test/sib-Transmission Disequilibrium Test analyses were then conducted with the DNA data. RESULTS: Thirty-two families were informative for the analysis, which showed a preferential transmission of the G allele to the affected subjects. CONCLUSIONS: If the results are confirmed, there may be important implications for the 5-HT(1Dbeta) receptor gene in the pathogenesis and treatment of OCD.

Effect of swallowed isosorbide dinitrate on blood pressure, heart rate and exercise capacity in patients with coronary artery disease.

Blood pressures and heart rates were measured with the patients supine and standing after a placebo and small (5 to 10 mg) and large (10 to 30 mg) doses of isosorbide dinitrate were given orally in double-blind fashion to six patients. Compared to the findings after the placebo, the blood pressure level fell and the heart rate increased after the ingestion of isosorbide dinitrate. The changes were more striking with the patients standing than with them supine, and the larger dose of the drug produced greater changes than the smaller dose. The hemodynamic effects were usually apparent at 15 minutes, peaked between 30 and 120 minutes, and were still present at 240 minutes. Two hours after swallowing a 7.5 to 20 mg dose of isosorbide dinitrate or placebo, administered in random fashion, 10 patients with coronary artery disease and angina pectoris underwent graded, treadmill, exercise testing designed to provoke angina only after 3 minutes or more. Nine of them exercised longer and achieved higher maximal heart rates after taking the isosorbide dinitrate. Thus, in man, swallowed isosorbide dinitrate has a dose-related, "long-acting," pharmacologic effect, and when tested by properly designed protocols, it improves exercise capacity. However, because the problems of nitrate tolerance and dependence have not been resolved, the place of oral nitrates in the management of patients with angina pectoris remains uncertain.

Association between homozygosity at the COMT gene locus and obsessive compulsive disorder.

A functional polymorphism in the coding region of the catechol O-methyltransferase (COMT) gene has been reported in previous studies to be associated with obsessive compulsive disorder (OCD), particularly in males [Karayiorgou et al., 1997, 1999]. Using a family-based population analysis, we attempted to replicate these findings in a group of 72 OCD patient/parent trios collected from Buffalo, New York, and Toronto, Canada. Analysis of allele and genotype frequencies using the haplotype relative risk (HRR) and transmission disequilibrium test (TDT) did not identify an association between a particular allele and OCD as had been previously reported. Furthermore, no evidence was found to support the findings of a gender-based association for COMT when the patients and the parents of the same gender were compared. However, our genotype results (n = 72) demonstrate a tendency for association between homozygosity at the COMT locus and OCD (homozygosity analysis: chi(2) = 5.66, P = 0.017; genotypic analysis: chi(2) = 5.78, P = 0.056). Although these findings do not replicate the previous reports, they do provide limited support to demonstrate a trend for homozygosity at the COMT locus in the OCD patients and, in turn, further implicate a potential role for COMT in the genetic etiology of OCD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:721-724, 2000.

Clinical features distinguishing patients with Tourette's syndrome and obsessive-compulsive disorder from patients with obsessive-compulsive disorder without tics.

OBJECTIVE: It is not clear whether obsessive-compulsive disorder (OCD) in the context of Tourette's syndrome (TS) is the same as that disorder found in patients with OCD alone. This study evaluated the severity and characteristics of the obsessive-compulsive symptoms in adult patients with OCD and TS compared to adult patients with OCD alone. METHOD: Thirteen subjects with both DSM-III-R TS and OCD and 13 subjects with OCD alone were recruited. Obsessive-compulsive severity was determined by using the Yale-Brown Obsessive Compulsive Scale. The Tourette Syndrome Association Unified Tic Rating Scale was administered to determine tic severity, and the adult version of the Attention Deficit and Hyperactivity Checklist was used to detect a history of childhood attention-deficit hyperactivity disorder (ADHD). RESULTS: Subjects with OCD alone had very few obsessions and compulsions that were not also experienced by subjects with both TS and OCD. In contrast, subjects with TS and OCD were significantly more likely to report obsessions involving nonviolent images, excessive concern with appearance, and need for symmetry. Touching, blinking or staring, and counting compulsions were also significantly more common in this group. Eight subjects with OCD and TS had a childhood history of ADHD, compared to none of the pure OCD subjects. CONCLUSION: There are subtle but definite differences in symptomatology of subjects with pure OCD compared to those with OCD and TS consistent with putative differences in pathophysiology between the 2 groups, i.e., abnormalities in the serotonergic system in OCD patients and serotonergic and dopaminergic abnormalities in those with OCD and TS. These observations may be consistent with genetic heterogeneity within both OCD and TS.

Investigation of dopamine system genes in obsessive-compulsive disorder.

Evidence from anatomical, pharmacological, and animal studies on the involvement of the dopamine system in obsessive-compulsive disorder (OCD) is mounting. This, along with evidence for a genetic diathesis provided by family and twin studies, prompted us to conduct genetic association studies of dopamine system genes in OCD. We genotyped OCD patients (n > 100) and matched controls for four loci: (1) a 40-base-pair repeat in the dopamine transporter gene; (2) the TaqIA polymorphism and the serine/cysteine variation in the D2 dopamine receptor gene; (3) an MscI polymorphism in the D3 dopamine receptor gene; and (4) a 48-base-pair repeat in the D4 dopamine receptor gene. Significant differences in allele frequencies were found between patients and controls for the D4 receptor gene, although replication is required with family-based controls before any conclusions can be entertained. This study represents the first comprehensive assessment of the roles of dopamine system genes in OCD.

Artificial donor insemination: fresh versus frozen semen; the patient as her own control.

The efficacies of fresh versus cryopreserved semen in the treatment of male factor infertility by artificial insemination by donor (AID) semen were directly compared by using the patient as her own control. In any one cycle, either fresh or frozen semen was used. The type of semen preparation was randomly assigned for the first cycle and varied thereafter according to donor availability. The same donor was used for a given patient in six consecutive cycles. We treated 381 patients in this way. In 676 cycles fresh semen was used and 128 pregnancies were achieved. Fecundability, the chance of getting pregnant per cycle of exposure, was 18.9% with fresh semen. In 1200 cycles cryopreserved semen was used and 60 pregnancies occurred, for a fecundability of 5.0%. Therefore, in our clinic, fresh semen is more than three times as likely to induce pregnancy as frozen semen. The design that has been used in this therapeutic protocol provides a technique for internal quality control of the cryopreservation process and for the investigation of other variables potentially affecting the success rates with AID.

The Tridimensional Personality Questionnaire in obsessive-compulsive disorder.

This study examined the Tridimensional Personality Questionnaire in 32 patients with obsessive-compulsive disorder. Scores on the Harm Avoidance (HA) dimension alone were found to distinguish the patient from normal volunteers. The impact of multiple anxiety disorders and of the specific lower-order HA trait of fear of uncertainty was also demonstrated.

Obsessive-compulsive disorder and the five-factor model of personality: distinction and overlap with major depressive disorder.

Research on individual differences in obsessive-compulsive disorder (OCD) has focused largely on analogue models with participants experiencing sub-clinical obsessions and/or compulsions. Few studies have examined the association between normal, dimensional personality traits and obsessive-compulsive symptomatology in a clinical sample. The purpose of this study was to examine personality differences in patients with a primary diagnosis of OCD (n = 98) or major depression (n = 98) using the domains and facets of the five-factor model of personality (FFM). Patients completed the self-report version of the Revised NEO Personality Inventory (NEO PI-R). When contrasted with community controls (Revised NEO Personality Inventory (NEO-PI-R) and NEO Five-Factor Inventory (NEO-FFI) professional manual, Psychological Assessment Resources, Odessa, FL, 1992), participants with OCD were found to differ across the domains (and facets) of neuroticism, extraversion, and conscientiousness and the facets of openness and agreeableness. Further, when compared to depressed participants, those with OCD were found to be more extraverted, agreeable, conscientious and less neurotic. With the exception of the conscientiousness domain (and facets), these significant differences were maintained even after controlling for depression severity. These results highlight the unique associations between trait domains and facets of the FFM and OCD.

Memory and confidence in memory judgements among individuals with obsessive compulsive disorder and non-clinical controls.

The present study investigated episodic memory functioning in: (1) obsessive compulsive disorder (OCD) patients with primarily checking symptoms (i.e. checkers); (2) OCD patients without checking symptoms (i.e. non-checkers); and (3) non-clinical control participants. On a measure of recall, all groups were statistically equivalent with respect to the proportion of words correctly recalled. Using a recognition measure, checkers were unimpaired in episodic memory, as compared to non-checkers and non-clinical controls. However, relative to the other groups, patients with checking symptoms showed decreased confidence in their correct and incorrect recognition memory judgements, according to their item-by-item self-report confidence ratings. When checkers correctly identified previously seen words, they were also slower to respond than were the other groups, supporting the view that they were less confident in their memory judgments relative to the other groups, which did not differ on this measure. The results of the present study suggest that OCD checking is not related to memory impairments per se but rather that checking in OCD is a symptom of decreased confidence in memory.

Symptom structure in obsessive-compulsive disorder: a confirmatory factor-analytic study.

Although obsessive-compulsive disorder (OCD) has long been a unitary diagnosis, there is much recent interest in its potential heterogeneity, as manifested by symptom subgroups. This study evaluated existing models of symptom structure in a sample of 203 individuals with OCD. Using confirmatory factor analysis, we examined the ability of each model to account for two levels of data: a priori symptom groupings (second-order) and individual symptoms, identified by the Yale-Brown Obsessive Compulsive Scale symptom checklist. Four models were examined: a single-factor, a two-factor (i.e., obsessions and compulsions), and two multidimensional models, comprising three and four factors. Adequate fit was found solely for the four-factor model--specifying obsessions/checking, symmetry/ordering, contamination/cleaning, and hoarding--but only at the second-order level; it did not account for relationships among discrete symptoms. Parameter estimates showed within-factor heterogeneity, as well as overlap between factors, most notably the two representing checking and contamination-related symptoms. The implications of these findings are discussed. Results provide evidence for the multidimensionality of OCD symptoms, but suggest that a comprehensive model has yet to be identified. They also point to the inadequacy of groupings based solely upon overt behavioural similarities (e.g., 'checking'). Recommendations are made for future research.

Bleeding ectopic decidua as a cause of intraabdominal hemorrhage. A case report.

Severe ectopic decidual reaction of the peritoneal surface as the etiology of unexpected intraabdominal hemorrhage is rare. Such a situation occurred in one of our patients after an uneventful vaginal delivery. The bleeding was discovered during postpartum sterilization, and hysterectomy was performed to control it. Six cases reported previously presented with peripartum shock and/or an acute abdomen. Three died, all of intraabdominal hemorrhage and two of them without laparotomy. Various etiologies of this disorder have been postulated, but a consistent explanation remains to be found. Intraabdominal hemorrhage, whatever its cause, must be controlled directly at laparotomy.

A comparison of three assessment instruments for obsessive-compulsive symptoms.

The psychometric characteristics and relationship among the Leyton Obsessional Inventory, Maudsley Obsessional-Compulsive Inventory, and Yale-Brown Obsessive-Compulsive Scale were examined in a sample of 30 obsessive-compulsive patients diagnosed using a structured interview. The majority of the subscales of the various measures were found to have good internal consistency across gender and the mean scores were similar to those reported in other studies. There were also moderate correlations between several of the measures and clinician ratings of depression. The results suggest that (1) gender differences should be further explored in future research (2) caution should be used when extrapolating the results of treatment studies that use different OCD measures, and (3) a measure of depression should always be included in OCD studies to control for the possible effects of depressed mood.

Effects of acetylpromazine or morphine on urine production in halothane-anesthetized dogs.

OBJECTIVE: To assess the influence of preanesthetic administration of acetylpromazine or morphine and fluids on urine production, arginine vasopressin (AVP; previously known as antidiuretic hormone) concentrations, mean arterial blood pressure (MAP), plasma osmolality (Osm), PCV, and concentration of total solids (TS) during anesthesia and surgery in dogs. ANIMALS: 19 adult dogs. PROCEDURE: Concentration of AVP, indirect MAP, Osm, PCV, and concentration of TS were measured at 5 time points (before administration of acetylpromazine or morphine, after administration of those drugs, after induction of anesthesia, 1 hour after the start of surgery, and 2 hours after the start of surgery). Urine output and end-tidal halothane concentrations were measured 1 and 2 hours after the start of surgery. All dogs were administered lactated Ringer's solution (20 ml/kg of body weight/h, i.v.) during surgery. RESULTS: Compared with values for acetylpromazine, preoperative administration of morphine resulted in significantly lower urine output during the surgical period. Groups did not differ significantly for AVP concentration, Osm, MAP, and end-tidal halothane concentration; however, PCV and concentration of TS decreased over time in both groups and were lower in dogs given acetylpromazine. CONCLUSIONS AND CLINICAL RELEVANCE: Preanesthetic administration of morphine resulted in significantly lower urine output, compared with values after administration of acetylpromazine, which cannot be explained by differences in AVP concentration or MAP When urine output is used as a guide for determining rate for i.v. administration of fluids in the perioperative period, the type of preanesthetic agent used must be considered.

Effects of subject velocity on force plate-measured ground reaction forces in healthy greyhounds at the trot.

Force plate gait analysis was used to study the effects of subject velocity on ground reaction forces. Seven adult Greyhounds were trotted at 3 distinct velocities: 1.5 to 1.8 m/s, 2.1 to 2.4 m/s, and 2.7 to 3.0 m/s. Forelimb and hind limb peak vertical forces increased with increase in velocity (P < 0.05). Forelimb and hind limb vertical impulses decreased as velocity increased (P < 0.05). Significant variations were not observed for craniocaudal or mediolateral peak forces or impulses. It was concluded that velocity significantly (P < 0.05) influenced ground reaction forces and impulses, and must be controlled in experimental design.

Effects of anesthesia, surgery, and intravenous administration of fluids on plasma antidiuretic hormone concentrations in healthy dogs.

OBJECTIVE: To evaluate effects of anesthesia, surgery, and intravenous administration of fluids on plasma concentrations of antidiuretic hormone (ADH), concentration of total solids (TS), PCV, arterial blood pressure (BP), plasma osmolality, and urine output in healthy dogs. ANIMALS: 22 healthy Beagles. PROCEDURE: 11 dogs did not receive fluids, and 11 received 20 ml of lactated Ringer's solution/kg of body weight/h. Plasma ADH adn TS concentrations, PCV, osmolality, and arterial BP were measured before anesthesia (T0) and after administration of preanesthetic agents (T1), induction of anesthesia (T2), and 1 and 2 hours of surgery (T3 and T4, respectively). Urine output was measured at T3 and T4. RESULTS: ADH concentrations increased at T1, T3, and T4, compared with concentrations at T0. Concentration of TS and PCV decreased at all times after administration of preanesthetic drugs. Plasma ADH concentration was less at T3 in dogs that received fluids, compared with those that did not. Blood pressure did not differ between groups, and osmolality did not increase > 1% from To value at any time. At T4, rate of urine production was less in dogs that did not receive fluids, compared with those that did. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma ADH concentration increased and PCV and TS concentration decreased in response to anesthesia and surgery. Intravenous administration of fluids resulted in increased urine output but had no effect on ADH concentration or arterial BP. The causes and effects of increased plasma ADH concentrations may affect efficacious administration of fluids during the perioperative period in dogs.

Dose response to butorphanol administered subcutaneously to increase visceral nociceptive threshold in dogs.

Butorphanol (0.025, 0.05, 0.1, 0.2, 0.4, and 0.8 mg/kg of body weight, and placebo) was given SC to 8 healthy unmedicated dogs to determine its efficacy for visceral analgesia, using a colonic balloon for minimal threshold nociceptor stimulation. Degree of sedation; systolic, diastolic, and mean arterial pressure; and pulse rate were recorded. The highest 3 dosages, 0.2, 0.4, and 0.8 mg/kg, were found to be most effective, with 0.8 mg/kg the only dosage that was significantly different from control responses at the 45-minute interval. Duration of analgesia ranged from 23 to 53 minutes for all 6 dosages and dosing durations were not significantly different from one another. Blood pressures did not change, but pulse rate was significantly decreased by 0.8 mg of butorphanol/kg. We concluded that butorphanol is an effective visceral analgesic of relatively short duration in the dog.