Association study of the PDE4D gene and obsessive-compulsive disorder in a Chinese Han population.

OBJECTIVE: Multiple evidence suggests an involvement of the PDE4D in mental disorders. Therefore we investigate the association between obsessive-compulsive disorder and a polymorphism of the single nucleotide polymorphisms of PDE4D gene in the Chinese Han population. METHODS: We genotyped and performed a case-control association analysis of the PDE4D polymorphism rs1838733 in 400 obsessive-compulsive disorder patients and 459 healthy control subjects. RESULTS: The site conformed to Hardy-Weinberg (P > 0.05), three genotypes (AA, AG, GG) of PDE4D gene rs1838733 were detected. We demonstrated three principal results. First, there were no significant differences between the case and health controls in the genotype and allele at rs1838733 (P > 0.05). Second, there were no significant differences in the allele and genotype frequency between different genders obsessive-compulsive disorder (P > 0.05). Third, the genotype of single nucleotide polymorphism rs1838733 was associated with late-onset obsessive-compulsive disorder and female late-onset obsessive-compulsive disorder (P < 0.05). CONCLUSION: The present study is the first to verify the associations of single nucleotide polymorphisms rs1838733 of the PDE4D gene with obsessive-compulsive disorder in a Chinese Han population. We found the genotype of single nucleotide polymorphism rs1838733 was associated with the occurrence of late-onset obsessive-compulsive disorder and female late-onset obsessive-compulsive disorder. Therefore, PDE4D may play a role in the pathogenesis of obsessive-compulsive disorder and may become a potential target for obsessive-compulsive disorder treatment in future research. Further studies should verify the current findings.

Case report: Cytochrome P450 implications for comorbid ADHD and OCD pharmacotherapy.

TOPIC: This case report details the treatment of an early adolescent already receiving treatment for attention-deficit hyperactivity disorder who presents with recurrent obsessive-compulsive disorder. Potential atomoxetine (Strattera) and fluoxetine (Prozac) interactions via Cytochrome P450 (CYP450) pathways are examined and alternate therapies are recommended. PURPOSE: Provide a discussion of psychopharmacogenomics, especially in the case of combining medications, CYP450 enzymes, and clinical implications in the context of the burgeoning field of precision medicine. The following questions are addressed: 1) What are the recommendations for pharmacogenetics testing? 2) How should pharmacogenetics inform medication selection? 3) What impact should CYP450 knowledge have on medication dosing? SOURCES: Peer-reviewed journals, U.S. Health and Human Services, National Institutes of Health, National Medical Library, and the Clinical Pharmacology database. CONCLUSIONS: Genetic testing as a prescriptive tool is not indicated for all medications; however, potential drug-drug interactions, narrow therapeutic drug index, and side effect toxicity contribute to the need for testing. An understanding of CYP450 metabolism and drug interaction as well as metabolism phenotypes should inform prescribing and dosing psychotropic medications.

Behavioral and pharmacological phenotypes of brain-specific diacylglycerol kinase δ-knockout mice.

Diacylglycerol kinase (DGK) is a lipid-metabolizing enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. Previously, we reported that the δ isozyme of DGK was abundantly expressed in the mouse brain. However, the functions of DGKδ in the brain are still unclear. Because conventional DGKδ-knockout (KO) mice die within 24h after birth, we have generated brain-specific conditional DGKδ-KO mice to circumvent the lethality. In the novel object recognition test, the number of contacts in the DGKδ-KO mice to novel and familiar objects was greatly increased compared to the control mice, indicating that the DGKδ-KO mice showed irrational contacts with objects such as compulsive checking. In the marble burying test, which is used for analyzing obsessive-compulsive disorder (OCD)-like phenotypes, the DGKδ-KO mice buried more marbles than the control mice. Additionally, these phenotypes were significantly alleviated by the administration of an OCD remedy, fluoxetine. These results indicate that the DGKδ-KO mice showed OCD-like behaviors. Moreover, the number of long axon/neurites increased in both DGKδ-KO primary cortical neurons and DGKδ-knockdown neuroblastoma Neuro-2a cells compared to control cells. Conversely, overexpression of DGKδ decreased the number of long axon/neurites of Neuro-2a cells. Taken together, these results strongly suggest that a deficiency of DGKδ induces OCD-like behavior through enhancing axon/neurite outgrowth.

The AmpliChip® CYP450 test and response to treatment in schizophrenia and obsessive compulsive disorder: a pilot study and focus on cases with abnormal CYP2D6 drug metabolism.

AIM: Genetic factors can result in variance in drug metabolism enzyme function, which is one major mechanism impacting on interindividual variability in response and side effects. We therefore performed a pilot study to investigate genetic variants in the drug metabolizing enzymes CYP2D6 and CYP2C19. METHODS: We evaluated 35 schizophrenic and 39 obsessive compulsive disorder (OCD) patients treated with various antipsychotics and antidepressants. Patients were assessed for treatment response and side effects. Genotyping for CYP2D6 and CYP2C19 was performed using the AmpliChip(®). Statistical analysis was performed using analysis of variance and Fisher's exact test. Cases of poor metabolizers (PMs) or ultrarapid metabolizers (UMs) were examined in further detail to assess medication outcomes. RESULTS: Statistical analysis identified no overall significant association of CYP2D6 metabolizer status with treatment response or occurrence of side effects. Nonetheless, case reports of PM and UM individuals indicated lack of response and/or occurrence of side effects in most of these patients. A secondary analysis comparing OCD subjects with impaired 2D6 function to extensive metabolizers was significant (p=0.021). CONCLUSION: Although not conclusive, there was some association between CYP2D6 impaired metabolic status and medication response. Our case reports suggest a potential clinical benefit of CYP genotyping for specific patients. Further validation of CYP2D6 and CYP2C19 testing in prospective, randomized trials is warranted.

Aromatase and its inhibition in behaviour, obsessive compulsive disorder and parkinsonism.

Oestrogens regulate normal behaviour and have been implicated in modulating pathological behaviour such as obsessive compulsive disorder and neurological disorder such as Parkinsonism. Therefore, by regulating the expression of the oestrogen-synthesising enzyme, aromatase, we may identify what behaviour is regulated by oestrogen. Inhibition of aromatase either genetically or pharmacologically has been reported to induce sexual behaviour impairment, compulsive behaviour and susceptibility to neurodegeneration.

Serum selenium and plasma malondialdehyde levels and antioxidant enzyme activities in patients with obsessive-compulsive disorder.

There is mounting evidence indicating that reactive free radical species are involved in initiation and development of many different forms of human pathologies including psychiatric disorders. In the present study, we aimed to determine whether serum selenium (Se), antioxidant enzyme (glutathione peroxidase, GSH-Px, superoxide dismutase, SOD, and catalase, CAT) activities, and plasma malondialdehyde (MDA) levels, a product of lipid peroxidation, were associated with obsessive-compulsive disorder (OCD). The participants were 28 patients with OCD that were drug-free at least for a month and a control group (n=28) of healthy subjects, matched with respect to age and sex. In both groups, the levels of the erythrocyte MDA, GSH-Px, SOD, Se, and the CAT were measured. The levels of MDA and SOD were statistically significantly higher (p<0.01, p<0.05 respectively) in patients than controls. The activities of CAT, GSH-Px, and serum Se levels were statistically significantly lower (p<0.0001, p<0.001, and p<0.001 respectively) in patients than controls. There was a positive correlation in patients between plasma GSH-Px activity and Se concentration (r=52, p=0.001). However, in patients with OCD, CAT and SOD activities were significantly and negatively correlated with MDA levels (r=-0.45, p=0.017 for CAT and r=-0.54, p=0.020 for SOD). The study shows the presence of a significant relationship of OCD and oxidative stress, and consequently, an involvement of free radicals and of the antioxidant defence.

Platelet monoamine oxidase activity in obsessive-compulsive disorder.

Response to SSRIs suggests the implication of the serotonergic system in obsessive-compulsive disorder (OCD). However, biological studies on serotonergic function in OCD have yielded contradictory results. Platelet monoamine oxidase (MAO) activity has been proposed as an index of cerebral serotonin activity. The aim of this study was to examine platelet MAO activity in 29 OCD patients and 29 healthy controls matched by age, sex and tobacco use. We also explored the relationship between platelet MAO activity and aggressive obsessions in OCD patients. There were no differences in platelet MAO activity between OCD patients and healthy controls. We found a significant correlation between platelet MAO activity and Y-BOCS scores in the group of patients with Y-BOCS scores >15. OCD patients with aggressive obsessions had significantly lower levels of platelet MAO activity than patients without aggressive obsessions. Our results suggest that platelet MAO activity may be a marker of OCD severity, and that low platelet MAO activity may be associated with aggressive obsessions in OCD patients.

The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal-recessive disorder caused by mutations in the PANK2 gene. The authors report clinical and genetic findings of 16 patients with PKAN. The authors identified 12 mutations in the PANK2 gene, five of which were new. Only nine patients could be classified as classic or atypical PKAN, and intermediate phenotypes are described. Two patients presented with motor tics and obsessive-compulsive behavior suggestive of Tourette syndrome.

Lack of association of catechol-O-methyltransferase gene polymorphism in obsessive-compulsive disorder.

The COMT gene has been implicated to be involved in the pathogenesis of obsessive-compulsive disorder (OCD) and various other psychiatric disorders. COMT enzyme activity is governed by a common genetic polymorphism at codon 158 that results in substantial 3- to 4-fold variation in enzymatic activity [a high-activity COMT variant (H) and a low activity variant (L)]. This study evaluates the association between OCD and the COMT gene polymorphism. Fifty-nine OCD patients that were diagnosed according to DSM-IV criteria and 114 healthy control subjects were included in the study. PCR technique was used for molecular analysis. The genotypic pattern of distribution of the COMT gene (H/H, H/L, and L/L genotypes) was not different between the OCD patients and controls. There were no significant differences among the patients with positive family history for OCD, those with negative family history for OCD, and the controls with respect to allele frequencies of the COMT gene polymorphisms. Patients that were homozygous or heterozygous for the L allele had significantly higher insight scores (i.e., poorer insight) on Y-BOCS compared to those homozygous for the H allele. We did not find an association between OCD, family history for OCD, and the COMT gene polymorphism. This study suggests that the COMT gene polymorphism is not directly associated with OCD in our patient group.

Hypothalamic digoxin deficiency in obsessive compulsive disorder and la Tourette's syndrome.

The isoprenoid pathway related cascade was assessed in 15 patients with obsessive compulsive disorder (OCD) and la Tourette's syndrome (TS). The pathway was also assessed in right hemispheric dominant, left hemispheric dominant, and bihemispheric dominant individuals to assess whether hemispheric dominance has any correlation with these disease states. The levels of serum digoxin, HMG CoA reductase activity, and dolichol were found to be decreased in OCD and la Tourette's syndrome as well as in left hemispheric dominant individuals with a corresponding increase in RBC Na(+)-K+ ATPase activity, serum ubiquinone, and magnesium levels. There was an increase in tyrosine and its catabolites, and a reduction in tryptophan and its catabolites in the serum. The total and individual glycosaminoglycan (GAG) fractions, carbohydrate residues of glycoproteins, and the concentration of glycolipids decreased in the serum. The activity of GAG degrading enzymes and glycohydrolases were decreased. The RBC membrane glycoconjugates were increased while the membrane cholesterol:phospholipid ratio was decreased. The activity of free radical scavenging enzymes increased while the concentration of free radicals decreased significantly. On the other hand, there was hyperdigoxinemia and the reverse biochemical patterns in those with right hemispheric dominance. Membrane Na(+)-K+ ATPase stimulation can result in decreased intracellular Ca2+ and increased magnesium levels. Increased levels of dopamine can lead to a tic syndrome, while reduced levels of serotonin and increased dopamine can both lead to obsessive compulsive disorder. Decrease in fucose and sialo-ligands, increased immunosuppressive morphine levels, decreased T-cell calcineurin signal transduction related to decreased intracellular calcium, reduced free radical production, and altered presentation of bacterial glycoconjugate antigens can lead to a hypoimmune response and recurrent respiratory infection in OCD patients. OCD and la Tourette's syndrome are associated with left hemispheric chemical dominance.

Antioxidant enzyme activities and malondialdehyde levels in patients with obsessive-compulsive disorder.

To examine the importance of free radicals in the pathogenesis of obsessive-compulsive disorder (OCD), we aimed to evaluate whether malondialdehyde (MDA), a product of lipid peroxidation, and antioxidant enzyme [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT)] activity levels were associated with OCD. The patients were divided into two subgroups according to whether DSM-IV major depressive disorder (MDD) was accompanied (OCD + MDD) or not (OCD - MDD). The MDA and antioxidant enzyme levels both in patients and controls were determined. SOD activity levels were significantly higher in the OCD + MDD group compared with the control and the OCD - MDD group. Although the OCD - MDD group had slightly higher SOD activity levels as compared with the controls, the difference was not statistically significant. GSH-Px activity levels were statistically significantly higher in both groups compared with controls. Likewise, there was a significant difference in GSH-Px activity levels between the OCD + MDD and OCD - MDD group. CAT activity levels were slightly higher in the OCD + MDD group compared with the OCD - MDD and control group. MDA levels in both groups were significantly higher than in controls. In addition, the difference in MDA levels between both groups was statistically significant. In conclusion, our results suggest that OCD is associated with free radicals and that it may be a heterogeneous subtype including some biological indications of anxiety and affective disorders. More comprehensive and detailed studies are needed to decipher the exact role of free radicals in OCD.

Decreased inhibitory activity of PKC in OCD patients after six months of treatment.

We investigated 5-HT reuptake and protein kinase of type C (PKC) activation in platelets of 14 OCD patients at baseline and after six months of treatment with different serotonin (5-HT) reuptake inhibitors (SRIs). The results showed that all SRIs provoked a significant increase in both the maximal velocity (V(max)) and the Michaelis-Menten constant (K(m)) of 5-HT reuptake, as compared with baseline values. The activation of PKC by means of 4-beta-12-tetradecanoylphorbol 13-acetate provoked a significant decrease in V(max) values, but the effect was not as evident as at baseline. These findings could indicate that, in OCD patients, SRIs increase the rate of reuptake and decrease the inhibitory effect of PKC and that the two phenomena may be linked, the first perhaps depending upon the second.

Association between the COMT locus and obsessive-compulsive disorder in females but not males.

A polymorphism in the coding region of catechol-O-methyltransferase gene (COMT) was previously reported to be associated with obsessive-compulsive disorder (OCD), particularly in male probands. We attempted to replicate the previous finding using a family-based genetic design in haplotype relative risk (HRR) and transmission disequilibrium (TDT) analyses. Fifty-six OCD probands and their parents were genotyped for the COMT locus using established methods. Analysis of allele and genotype frequencies between the proband genotypes and the control (parental nontransmitted) genotypes failed to replicate the previous finding of gender divergence, gave no evidence of overall association, nor was linkage detected by TDT. However, further analysis of the COMT allele frequencies by proband gender gave evidence of a mildly significant association with the low-activity COMT allele in female probands (P=0.049), but not in male probands. These findings indicate that COMT may be etiologically relevant to OCD in a gender-specific manner opposite to that shown in previous studies.

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.

Altered cAMP-dependent protein kinase A in platelets of patients with obsessive-compulsive disorder.

OBJECTIVE: The purpose of this study was to assess cAMP-dependent protein kinase A in patients with obsessive-compulsive disorder (OCD). METHOD: The levels and the activity of protein kinase A were evaluated in whole platelets obtained from 12 unmedicated patients with OCD and 15 healthy comparison subjects. RESULTS: The immunolabeling of protein kinase A regulatory subunits type I and II were significantly greater but that of the catalytic subunit significantly lower in patients with OCD than in healthy subjects. The cAMP-stimulated activity in patients with OCD was significantly lower than that in healthy subjects. CONCLUSIONS: These data suggest a possible role of protein kinase A in the pathophysiology of OCD.

Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder.

In the present study, we address the role of the gene for catechol-O-methyltransferase (COMT), a key modulator of dopaminergic and noradrenergic neurotransmission, in the genetic predisposition to obsessive-compulsive disorder (OCD). We show that a common functional allele of this gene, which results in a 3- to 4-fold reduction in enzyme activity, is significantly associated in a recessive manner with susceptibility to OCD, particularly in males. This association is further supported by psychiatric evaluation of patients who carry microdeletions encompassing the comt gene. The mechanism underlying this sex-selective association remains to be defined and may include a sexual dimorphism in COMT activity, although close linkage with a nearby disease susceptibility locus cannot be excluded at this point.

Platelet sulfotransferase in different psychiatric disorders.

The aim of our study was to measure and compare platelet phenolsulfotransferase (PST) activity in patients affected by different psychiatric disorders and in healthy volunteers. The results showed that the activity of both of the two forms of PST was significantly higher in 30 patients with obsessive-compulsive disorder and in 25 manic patients than in 20 healthy volunteers. On the contrary, normal values were found in 11 dysthymic patients, 12 bipolar depressives, and 14 patients with panic disorder, whereas lower values were found in 12 unipolar depressives and 30 patients with migraine. It would therefore seem that different neuropsychiatric disorders are associated with different levels of PST activity.

[Obsessive-compulsive disorder in children and adolescents. Epidemiological and clinical aspects]. / Obsessiv-kompulsiv tilstand hos børn og unge. Epidemiologi og klinisk billede.

Obsessive-compulsive disorder (OCD) in children and adolescents is apparently a much more common disorder than previously believed. The literature on OCD in children and adolescents is reviewed, and OCD is described as a severe disorder with a poor prognosis for about half of the patients. The clinical picture seems to be the same across different cultures. The most common symptoms are obsessions about dirt and contamination and washing rituals.

Serum cholinesterase in obsessive-compulsive disorder.

Levels of serum cholinesterase (PsChe) were measured in 32 drug-free patients with obsessive-compulsive disorder (OCD) and 32 sex- and age-matched healthy normal volunteers. No significant differences between OCD patients and normal subjects were found in PsChe levels. A significant positive correlation between patients' PsChe levels and the severity of anxiety, as measured by the Hamilton Rating Scale for Anxiety, was found, in agreement with the hypothesis of a relationship between state anxiety and PsChe activity. In contrast to findings in other reports, PsChe levels significantly increased after 10 weeks of antiobsessional pharmacological treatment, underscoring the potential influence of drugs on PsChe activity.