The DRD2 gene 957C>T polymorphism is associated with posttraumatic stress disorder in war veterans

Background: Variations in genes related to the dopaminergic pathway have been implicated in neuropsychiatric disorders such as schizophrenia, substance misuse, Alzheimer's disease and Post Traumatic Stress Disorder (PTSD). A single nucleotide polymorphism (SNP) (957C>T) and a deletion polymorphism (‐141delC) in the DRD2 gene and a SNP (Taq1A) in a gene directly downstream of DRD2 have all been implicated in dopamine functioning in the brain. Methods: To test the importance of these three polymorphisms in PTSD susceptibility, a genetic screen was performed in 127 war veterans diagnosed with PTSD and 228 control individuals without a history of PTSD. Results: No significant association was found between PTSD and the Taq1A or ‐141delC polymorphisms. However, a significant association was observed with PTSD and the 957C>T polymorphism. PTSD individuals were more likely to carry the C allele compared to the controls (P=0.021). Conclusions: Our findings suggest that the 957C>T polymorphism in the DRD2 gene is one of the genetic factors for susceptibility to PTSD. Depression Anxiety, 2009. © 2008 Wiley‐Liss, Inc.     

D(2) dopamine receptor (DRD2) polymorphism is associated with severity of alcohol dependence.

The A(1) allele of the D(2) dopamine receptor (DRD2) gene has been associated with alcohol dependence. However, the expression of this allele risk on the severity of drinking behavior in patients with alcohol dependence has not been systematically explored. The present study examines the association between DRD2 A(1)(+) (A(1)/A(1) and A(1)/A(2) genotypes) and A(1)- (A(2)/A(2) genotype) allele status and key drinking parameters in alcohol-dependent patients. A sample of Caucasian adults was recruited from an alcohol detoxification unit. A clinical interview and the Alcohol Dependence Scale (ADS) questionnaire provided data on consumption, dependence, chronology of drinking and prior detoxification. A(1)(+) allele compared to A(1)- allele patients consumed higher quantities of alcohol, commenced problem drinking at an earlier age, experienced a shorter latency between first introduction to alcohol to the onset of problem drinking and had higher ADS scores. Moreover, A(1)(+) allele patients had more detoxification attempts than their A(1)- allele counterparts. In sum, alcohol-dependent patients with the DRD2 A(1) allele compared to patients without this allele are characterized by greater severity of their disorder across a range of problem drinking indices. The implications of these findings are discussed.     

No association between D2 dopamine receptor (DRD2) "A" system alleles, or DRD2 haplotypes, and posttraumatic stress disorder.

BACKGROUND: Association studies between marker alleles at the D2 dopamine receptor gene (DRD2) and various psychiatric illnesses have produced conflicting results. Reports of allelic associations were originally made with alcoholism, but were then extended to other psychiatric disorders, including posttraumatic stress disorder (PTSD). METHODS: We studied allele frequency of the DRD2 TaqI "A," "B," and "D" system markers in 52 European-American subjects with diagnoses of PTSD (based on structured interviews). RESULTS: Frequency of the A1 allele in this sample was .15, not significantly different from the .19 allele frequency seen in 87 control subjects. We were thus unable to replicate the previous reports of allelic association between the DRD2 TaqI "A1" allele and PTSD. There were also no significant differences in allele frequency for the "B" or "D" systems. We then computed three marker (TaqI "A," "B," and "D" system) haplotypes for the sample; DRD2 haplotype frequencies also did not differ between control subjects and subjects with PTSD. CONCLUSIONS: We conclude that DRD2 alleles are not associated with PTSD in this sample, and that genetic variation at the DRD2 locus is not likely to be an important contributor to risk for this disorder.     

Linkage disequilibrium between dopamine D1 receptor gene (DRD1) and bipolar disorder.

BACKGROUND: Based on the dopamine hypothesis, the dopamine D1 receptor gene (DRD1) is considered to be a good candidate gene for bipolar disorder (BP). METHODS: In our study, three polymorphisms of the DRD1 gene, -800T/C, -48A/G, and 1403T/C, were analyzed in 286 BP trios. Both the transmission disequilibrium test (TDT) and haplotype TDT were performed on the genotype data to test for the presence of linkage disequilibrium between DRD1 and bipolar disorder. With the extended transmission disequilibrium test (ETDT), we also calculated the maternal transmission and paternal transmission for each allele. RESULTS: Although no association was found for each individual polymorphism, there is a significant association between DRD1 and BP for haplotype TDT analysis (chi(2) = 16.068, df = 3, p =.0011). CONCLUSIONS: These results indicate that DRD1 may play a role in the etiology of bipolar disorder.     

Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder

Gamma-aminobutyric acid (GABA(A)) receptors are thought to play an important role in modulating the central nervous system in response to stress. Animal data have shown alterations in the GABA(A) receptor complex by uncontrollable stressors. SPECT imaging with benzodiazepine ligands showed lower distribution volumes of the benzodiazepine-GABA(A) receptor in the prefrontal cortex of patients with post-traumatic stress disorder (PTSD) in one, but not in another study. The objective of the present study was to assess differences in the benzodiazepine-GABA(A) receptor complex in veterans with and without PTSD using [(11)C]flumazenil and positron emission tomography (PET). Nine drug naive male Dutch veterans with deployment related PTSD and seven male Dutch veterans without PTSD were recruited, and matched for age, region and year of deployment. Each subject received a [(11)C]flumazenil PET scan and a structural magnetic resonance imaging scan. Dynamic 3D PET scans with a total duration of 60 min were acquired, and binding in template based and manually defined regions of interest (ROI) was quantified using validated plasma input and reference tissue models. In addition, parametric binding potential images were compared on a voxel-by-voxel basis using statistical parametric mapping (SPM2). ROI analyses using both template based and manual ROIs showed significantly reduced [(11)C]flumazenil binding in PTSD subjects throughout the cortex, hippocampus and thalamus. SPM analysis confirmed these results. The observed global reduction of [(11)C]flumazenil binding in patients with PTSD provides circumstantial evidence for the role of the benzodiazepine-GABA(A) receptor in the pathophysiology of PTSD and is consistent with previous animal research and clinical psychopharmacological studies.     

No association between dopamine D2 receptor gene (DRD2) and human intelligence

Summary. Significantly diminished intellectual functioning, as indicated by appropriately administered IQ tests with scores below 70, is a frequent mental handicap leading to severe social disadvantages and serves as a paradigm for molecular genetic research of complex disorders and traits due to its multitude of known and unknown, genetic as well as environmental causes. Since the number of confounding variables is expected to be considerably reduced in the normal population at the opposite ends of the IQ distribution, we employed a contrast of extremes approach by comparing adults of high (N = 71) and average IQ (N = 78) in association studies to search for genes involved in the multigenic forms of familial mental retardation. The dopamine D2 receptor gene (DRD2) was chosen as a candidate gene for general cognitive ability (g) since it has been found to be associated with visuospatial ability which in turn is highly correlated with g. Confirming two similar studies in children, however, no significant differences were obtained. Given three negative studies, the DRD2 gene is unlikely to pay a major role in g. Received March 13, 2000; accepted July 27, 2000     

Striatal dopamine D(2) receptor availability in OCD with and without comorbid social anxiety disorder: preliminary findings

Dopamine D(2) receptor availability in the striatum has been reported to be low in generalized social anxiety disorder (GSAD) and obsessive-compulsive disorder (OCD), but it has not been studied in persons with comorbid OCD and GSAD (OCD+GSAD). D(2) receptor availability was assessed in 7 subjects with OCD+GSAD, 8 with OCD, and 7 matched healthy comparison (HC) subjects, all unmedicated adults. D(2) receptor availability was assessed with single-photon emission computerized tomography (SPECT) to measure binding potential (BP) of the D(2) receptor radiotracer [(123)I] iodobenzamide ([(123)I]IBZM). Mean striatal [(123)I]IBZM BP was significantly lower in the OCD+GSAD group (72.58 mL/g, SD=18.17) than in the HC group (118.41 mL/g, SD=45.40; P=.025). Mean BP in the OCD group (93.08 mL/g, SD=36.90) did not differ significantly from the HC group (P=.247). Trait detachment, as measured by the Detachment subscale of the Karolinska Scales of Personality, was negatively correlated with D(2) availability across all subjects (r(s)= -.55, P=.013). Comorbid GSAD and OCD may be associated with decreased availability of D(2) receptors in the striatum, consistent with prior findings in GSAD. Prior findings of decreased D(2) receptor availability in noncomorbid OCD were not confirmed. Decreased D(2) receptor availability was also associated with trait detachment, supporting prior findings in samples of healthy subjects.     

Dopamine D4 receptor (DRD4) gene polymorphism is associated with attachment disorganization in infants

About 15% of one-year-old infants in non-clinical, low-risk and up to 80% in high-risk (eg maltreated) populations show extensive disorganized attachment behavior(1,2) in the Strange Situation Test.(3) It has also been reported that disorganization of early attachment is a major risk factor for the development of childhood behavior problems.(4) The collapse of organized attachment strategy has been explained primarily by inappropriate caregiving, but recently, the contribution of child factors such as neurological impairments and neonatal behavioral organization(6) has also been suggested. Here we report an association between the DRD4 III exon 48-bp repeat polymorphism and attachment disorganization. Attachment behavior of 90 infants was tested in the Strange Situation and they were independently genotyped for the number of the 48-bp repeats by polymerase chain reaction (PCR). The 7-repeat allele was represented with a significantly higher frequency in infants classified as disorganized compared to non-disorganized infants: 12 of 17 (71%) vs 21 of 73 (29%) had at least one 7-repeat allele (chi2 = 8.66, df = 1, P < 0.005). The estimated relative risk for disorganized attachment among children carrying the 7-repeat allele was 4.15. We suggest that, in non-clinical, low-social-risk populations, having a 7-repeat allele predisposes infants to attachment disorganization.     

Quantitative electroencephalogram (qEEG) in combat veterans with post-traumatic stress disorder (PTSD)

Only a small number of studies have used quantitative electroencephalography (qEEG) in research of the post-traumatic stress disorder (PTSD). The results are not consistent. The aim of the present investigation was to compare qEEG in combat veterans with and without PTSD. The hypothesis is that differences among qEEG characteristics will be found regarding the presence/absence of PTSD. Seventy-nine combat veterans with PTSD comprised the experimental group and 37 veterans without PTSD were included as controls. After the informed consent, they were investigated by the resting EEG recordings. The results demonstrate that PTSD veterans had decreased alpha power and increased beta power. These results suggest an altered neurobiology in PTSD. Various explanations have been offered for alpha activity decrease observed in PTSD veterans. Increased beta rhythm may play a role as a potential marker in differentiating subtypes of PTSD.     

A polymorphism in the dopamine receptor DRD5 is associated with blepharospasm.

Abnormalities in dopamine neurotransmission are thought to underlie the generation of dystonic movements. The authors performed a case-control allelic association study in patients with the focal dystonia blepharospasm, using polymorphisms in the dopamine receptor and transporter genes. Allele 2 of a DRD5 dinucleotide repeat was significantly associated with blepharospasm. This may indicate a pathogenic role for this receptor.     

Cervical dystonia is associated with a polymorphism in the dopamine (D5) receptor gene

The objective was to assess whether polymorphisms in the dopamine receptor and transporter genes are associated with development of primary cervical dystonia. A case-control allelic association study is described of 100 patients with cervical dystonia and 100 controls using polymorphisms within D1-5 receptor and dopamine transporter genes. No significant association was found between patient and control allele frequencies for polymorphisms in genes for the D1 to 4 receptors and dopamine transporter. Significant associations, however, were found for alleles 2 and 6 of the D5 receptor microsatellite. Carriage of allele 2 was associated with cervical dystonia, whereas allele 6 was overrepresented in the control group, implying a possible protective effect. The association with allele 6 remained significant after Bonferroni correction. In conclusion, the finding of a significant association with an allele in the D5 receptor gene in patients with cervical dystonia may indicate a pathogenic role of this gene (or neighbouring genes). Further studies are required to confirm this finding and to assess whether these alleles are part of distinct haplotypes associated with other polymorphisms imparting a functional effect on the D5 receptor.     

Increased response variability as a marker of executive dysfunction in veterans with post-traumatic stress disorder

The stability of cognitive control processes over time can be indexed by trial-to-trial variability in reaction time (RT). Greater RT variability has been interpreted as an indicator of executive dysfunction, inhibitory inefficiency, and excessive mental noise. Previous studies have demonstrated that combat veterans with post-traumatic stress disorder (PTSD) show substantial impairments in inhibitory control, but no studies have examined response variability in this population. In the current experiment, RT variability in the Go/NoGo response inhibition task was assessed for 45 veterans with PTSD and 34 control veterans using the intra-individual coefficient of variation (ICV) and ex-Gaussian analysis of RT distributions. Despite having mean RTs that were indistinguishable from controls, the PTSD patients had significantly greater RT variability as measured by ICV. More variable RTs were in turn associated with a greater number of false alarm errors in the patients, suggesting that less consistent performers were less successful at inhibiting inappropriate responses. RT variability was also highly correlated with self-reported symptoms of PTSD, depression, and attentional impulsiveness. Furthermore, response variability predicted diagnosis even when controlling for PTSD symptom severity. In turn, PTSD severity was correlated with self-rated attentional impulsiveness. Deficits in the top-down cognitive control processes that cause greater response variability might contribute to the maintenance of PTSD symptomology. Thus, the distractibility issues that cause more variable reaction times might also result in greater distress related to the trauma.     

Dopamine transporters,D2 receptors,and dopamine release in generalized social anxiety disorder

Background: Dopamine D₂ receptor and dopamine transporter (DAT) availability in the striatum (STR) have each been reported abnormal in generalized social anxiety disorder (GSAD) in studies using single photon emission computerized tomography (SPECT). D₂ receptors and DAT have not previously been studied within the same GSAD subjects, however, and prior GSAD studies have not assessed dopamine release or subdivided the STR into functional subregions. Methods: Unmedicated adults with GSAD (N=17) and matched healthy comparison (HC) subjects (N=13) participated in this study. Of these, 15 GSAD and 13 HC subjects completed baseline assessment of D₂ receptor availability using positron emission tomography (PET) with the radiotracer [¹¹C]raclopride. Twelve GSAD and 13 HC subjects completed a repeat scan after intravenous administration of d ‐amphetamine to study dopamine release. Twelve of the GSAD subjects and 10 of the HC subjects also completed SPECT with the radiotracer [¹²³I] methyl 3β‐(4‐iodophenyl) tropane‐2β‐carboxylate ([¹²³I]β‐CIT) to assess DAT availability. Results: GSAD and HC groups did not differ significantly in striatal DAT availability, the overall striatal or striatal subregion D₂ receptor availability at baseline, or change in D₂ receptor availability after d ‐amphetamine. Receptor availability and change after d ‐amphetamine were not significantly associated with severity of social anxiety or trait detachment. Conclusions: These findings do not replicate previous findings of altered striatal DAT and D₂ receptor availability in GSAD subjects assessed with SPECT. The differences from results of prior studies may be due to differences in imaging methods or characteristics of samples. Depression and Anxiety, 2009. Published 2009 Wiley‐Liss, Inc.     

Leukocyte glucocorticoid receptor expression and immunoregulation in veterans with and without post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is associated with a dysregulation of the hypothalamus-pituitary-adrenal axis (HPA axis). In addition, there is evidence for altered glucocorticoid receptor (GR) expression and function in peripheral blood mononuclear cells. The aim of the present study was to differentiate between the effect of trauma exposure and PTSD on leukocyte GR expression and glucocorticoid immune regulation. Leukocyte GR binding characteristics and glucocorticoid sensitivity of immune activity, determined as the effect of dexamethasone (DEX) on in vitro cytokine release and T-cell proliferation, were compared between veterans with PTSD, traumatized veterans without PTSD and healthy controls. Leukocyte GR density was significantly lower in veterans with and without PTSD compared to healthy controls. DEX-induced inhibition of T-cell proliferation was significantly lower in PTSD compared to trauma and healthy controls. DEX-induced increase in lipopolysaccharide-stimulated interleukin-10 was less pronounced in traumatized veterans with and without PTSD compared to healthy controls. No group differences were observed in the effect of DEX on other cytokines or in baseline immune activity, except for lower tumor necrosis factor-alpha production in PTSD patients compared to healthy controls. The results suggest that trauma exposure is sufficient to induce changes in GR binding characteristics, whereas resistance of T-cell proliferation to DEX only occurs in PTSD. DEX resistance of in vitro immune activity was not a general phenomenon, but was restricted to specific immune functions.     

Association of depression,anxiety and post-traumatic stress disorder with migraine: Data from Kosovo

Introduction

Migraine is ranked as the seventh leading cause of disability worldwide, and it is characterized by a manifestation of combined neurological, gastrointestinal, and autonomic symptoms linked with different provoking factors.

Changes in dopamine D2-receptor binding are associated to symptom reduction after psychotherapy in social anxiety disorder

The dopamine system has been suggested to play a role in social anxiety disorder (SAD), partly based on molecular imaging studies showing reduced levels of striatal dopaminergic markers in patients compared with control subjects. However, the dopamine system has not been examined in frontal and limbic brain regions proposed to be central in the pathophysiology of SAD. In the present study, we hypothesized that extrastriatal dopamine D2-receptor (D2-R) levels measured using positron emission tomography (PET) would predict symptom reduction after cognitive behavior therapy (CBT). Nine SAD patients were examined using high-resolution PET and the high-affinity D2-R antagonist radioligand [¹¹C]FLB 457, before and after 15 weeks of CBT. Symptom levels were assessed using the anxiety subscale of Liebowitz Social Anxiety Scale (LSAS_anx). At posttreatment, there was a statistically significant reduction of social anxiety symptoms (P<0.005). Using a repeated measures analysis of covariance, significant effects for time and time × LSAS_anx change on D2-R-binding potential (BP_ND) were shown (P<0.05). In a subsequent region-by-region analysis, negative correlations between change in D2-R BP_ND and LSAS_anx change were found for medial prefrontal cortex and hippocampus (P<0.05). This is the first study to report a direct relationship between symptom change after psychological treatment and a marker of brain neurotransmission. Using an intra-individual comparison design, the study supports a role for the dopamine system in cortical and limbic brain regions in the pathophysiology of SAD.     

Health functioning impairments associated with posttraumatic stress disorder, anxiety disorders, and depression

Although anxiety disorders have been associated with impairments in self-reported health functioning, the relative effect of various anxiety disorders has not been studied. We compared health functioning of patients with a principal diagnosis of posttraumatic stress disorder (PTSD), panic disorder (PD), generalized anxiety disorder (GAD), and major depressive disorder (MDD). Patients with PTSD and MDD were equally impaired on overall mental health functioning, and both were significantly worse than patients with PD and GAD. PTSD was associated with significantly worse physical health functioning relative to PD, GAD, and MDD. Hierarchical regression showed that the association of PTSD with physical health functioning was unique and was not caused by the effects of age, depression, or comorbid anxiety disorders. Both PTSD and comorbid anxiety accounted for unique variance in mental functioning. These results highlight the association of PTSD with impaired physical and mental functioning and suggest that effective treatment of PTSD may affect overall health.