Paul Thuras

D-Cycloserine Augmented Exposure Therapy for Obsessive-Compulsive Disorder

BACKGROUND D-cycloserine (DCS), a glutamatergic partial N-methyl-d-aspartate (NMDA) agonist, can facilitate extinction learning related to cued fear in animals and humans. We predicted that DCS would accelerate obsession-related distress reduction in patients with obsessive-compulsive disorder (OCD) undergoing extinction-based exposure therapy. METHODS We administered DCS (125 mg) or placebo in a double-blind fashion to individuals with OCD approximately 2 hours before each exposure session. RESULTS D-cycloserine decreased both the number of exposure sessions required to achieve clinical milestones and the rate of therapy dropout. After four exposure sessions, patients in the DCS group reported significantly greater decreases in obsession-related distress compared with the placebo group; however, after additional sessions, the placebo group tended to catch up. CONCLUSIONS D-cycloserine augmentation has the potential to increase the efficiency, palatability, and overall effectiveness of standard exposure therapy for OCD.

GABAA receptor downregulation in brains of subjects with autism

Gamma-aminobutyric acid A (GABAA) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate system dysregulation. We investigated the expression of four GABAA receptor subunits and observed significant reductions in GABRA1, GABRA2, GABRA3, and GABRB3 in parietal cortex (Brodmann’s Area 40 (BA40)), while GABRA1 and GABRB3 were significantly altered in cerebellum, and GABRA1 was significantly altered in superior frontal cortex (BA9). The presence of seizure disorder did not have a significant impact on GABAA receptor subunit expression in the three brain areas. Our results demonstrate that GABAA receptors are reduced in three brain regions that have previously been implicated in the pathogenesis of autism, suggesting widespread GABAergic dysfunction in the brains of subjects with autism.

Shame and Posttraumatic Stress Disorder

Guilt about surviving a traumatic event is thought to be an associated feature of posttraumatic stress disorder (PTSD). Shame is an emotion closely related to guilt but is a distinct affective state. Little is known regarding the role of shame in PTSD and there are no studies of PTSD where shame and guilt are examined simultaneously. We used a measure of shame- and guilt-proneness in 107 community residing former prisoner of war veterans all of whom had been exposed to trauma. The measure of shame-proneness was positively correlated with PTSD symptom severity whereas guilt-proneness was not. This study provides the first empirical data regarding a possible role for shame in PTSD and may have important therapeutic and theoretical implications.

Imipramine Plus Cognitive-Behavioral Therapy in the Treatment of School Refusal

OBJECTIVE To investigate the efficacy of 8 weeks of imipramine versus placebo in combination with cognitive-behavioral therapy (CBT) for the treatment of school-refusing adolescents with comorbid anxiety and major depressive disorders. METHOD This was a randomized, double-blind trial with 63 subjects entering the study and 47 completing. Outcome measures were weekly school attendance rates based on percentage of hours attended and anxiety and depression rating scales. RESULTS Over the course of treatment, school attendance improved significantly for the imipramine group (z = 4.36, p < .001) but not for the placebo group (z = 1.26, not significant). School attendance of the imipramine group improved at a significantly faster rate than did that of the placebo group (z = 2.39, p = .017). Over the 8 weeks of treatment, there was a significant difference between groups on attendance after controlling for baseline attendance; mean attendance rate in the final week was 70.1% +/- 30.6% for the imipramine group and 27.6% +/- 36.1% for the placebo group (p < .001). Defining remission as 75% school attendance, 54.2% of the imipramine group met this criterion after treatment compared with only 16.7% from the placebo group (p = .007). Anxiety and depression rating scales decreased significantly across treatment for both groups, with depression on the Childrens Depression Rating Scale-Revised decreasing at a significantly faster rate in the imipramine group compared with the placebo group (z = 2.08, p = .037). CONCLUSIONS Imipramine plus CBT is significantly more efficacious than placebo plus CBT in improving school attendance and decreasing symptoms of depression in school-refusing adolescents with comorbid anxiety and depression.

Expression of GABAB receptors is altered in brains of subjects with autism

Autism is a neurodevelopmental disorder that is often comorbid with seizures. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in brain. GABAB receptors play an important role in maintaining excitatory–inhibitory balance in brain and alterations may lead to seizures. We compared levels of GABAB receptor subunits GABAB receptor 1 (GABBR1) and GABAB receptor 2 (GABBR2) in cerebellum, Brodmann’s area 9 (BA9), and BA40 of subjects with autism and matched controls. Levels of GABBR1 were significantly decreased in BA9, BA40, and cerebellum, while GABBR2 was significantly reduced in the cerebellum. The presence of seizure disorder did not have a significant impact on the observed reductions in GABAB receptor subunit expression. Decreases in GABAB receptor subunits may help explain the presence of seizures that are often comorbid with autism, as well as cognitive difficulties prevalent in autism.

mRNA and Protein Levels for GABAAα4, α5, β1 and GABABR1 Receptors are Altered in Brains From Subjects With Autism

We have shown altered expression of gamma-aminobutyric acid A (GABAA) and gamma-aminobutyric acid B (GABAB) receptors in the brains of subjects with autism. In the current study, we sought to verify our western blotting data for GABBR1 via qRT-PCR and to expand our previous work to measure mRNA and protein levels of 3 GABAA subunits previously associated with autism (GABRα4; GABRα5; GABRβ1). Three GABA receptor subunits demonstrated mRNA and protein level concordance in superior frontal cortex (GABRα4, GABRα5, GABRβ1) and one demonstrated concordance in cerebellum (GABΒR1). These results provide further evidence of impairment of GABAergic signaling in autism.

Somatic symptoms in anxious-depressed school refusers

OBJECTIVE To identify the most common physical complaints in a sample of adolescent school refusers with comorbid anxiety and depressive disorders. Whether somatic symptoms are more likely to be associated with high levels of anxiety or high levels of depression was also explored. METHOD Forty-four adolescents in a treatment study were evaluated at baseline with structured psychiatric interviews and measures of anxiety, depression, and somatization. RESULTS The most common somatic complaints were in the autonomic and gastrointestinal categories. In simple regression analyses, anxiety level as measured with the Revised Childrens Manifest Anxiety Scale and depression level as measured with the Beck Depression Inventory each significantly predicted the severity of somatic symptoms. The correlation between percentage of days absent from school and severity of somatic symptoms approached significance (r = .27, p = .074). CONCLUSIONS Knowledge that somatic complaints are commonly an expression of underlying anxiety and depression may facilitate more rapid referral for psychiatric assessment and treatment and thereby help avoid unnecessary medical workups and sequelae from school refusal.

Integrated Psychiatric/Medical Care in a Chronic Hepatitis C Clinic: Effect on Antiviral Treatment Evaluation and Outcomes

OBJECTIVES:Psychiatric and substance use disorders are common in hepatitis C patients and represent barriers to antiviral treatment. We evaluated the effect of integrating psychiatric and medical care on evaluation for and initiation of antiviral treatment in a cohort of 184 patients with chronic hepatitis C.METHODS:Integrated care consisted of screening for psychiatric problems with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), Beck Depression Inventory (BDI), Urine Drug Screen (UDS), and Primary Care Posttraumatic Stress Disorder (PC-PTSD) screens, referral based on specified cutoff scores to an established mental health (MH) provider, to a colocated psychiatric clinical nurse specialist (PCNS), or both. Data were collected retrospectively by chart review.RESULTS:Most patients (149/184, 81.0%) had at least one positive screen, 25.5% had a positive UDS. Among patients with positive screens, 38.3% had established MH providers, 47.0% had no MH provider and were referred to the PCNS, and 15.0% refused any psychiatric referral. Patients receiving integrated care with a colocated PCNS were significantly more likely to complete evaluation for and start antiviral treatment than other patients with positive screens, and at a rate similar to that of patients with negative screens. Patients with positive screens followed by any MH provider had significantly greater adherence to antiviral therapy than patients without positive screens.CONCLUSION:An integrated MH and medical approach was associated with rates of antiviral therapy recommendation and initiation similar to patients without risks for psychiatric or substance use problems. MH care was associated with improved adherence to antiviral therapy. Integrated care offers promise as an approach for addressing psychiatric comorbidity in this traditionally difficult to treat population.

Prenatal viral infection causes alterations in nNOS expression in developing mouse brains.

&NA; Epidemiological evidence points to prenatal viral infection being responsible for some forms of schizophrenia and autism. We hypothesized that prenatal human influenza viral infection in day 9 pregnant mice may cause changes in the levels of neuronal nitric oxide synthase (nNOS), an important molecule involved in synaptogenesis and excitotoxicity, in neonatal brains. Brains from 35‐ and 56‐day‐old mice were prepared for SDS‐gel electrophoresis and Western blotting using polyclonal anti nNOS antibody. Quantification of nNOS showed time and region‐dependent changes in the levels of nNOS protein. Mean rostral brain area value from prenatally infected animals showed a significant (p = 0.067) increase of 147% in nNOS levels at 35 days postnatally, with an eventual 29% decrease on day 56. Middle and caudal brain areas showed reductions in nNOS in experimental mice at 35 and 56 days, with a significant 27% decrease in nNOS in the middle segment of day 56 brains (p = 0.016). Significant interactions were found between group membership and brain area (Wilks lambda = 0.440, F(2.9) = 5.72, p = 0.025); there was also a significant interaction between brain area, group and age (Wilks lambda = 0.437, F(2.9) = 5.79, p = 0.024). These results provide further support for the notion that prenatal viral infection affects brain development adversely via the pathological involvement of nNOS expression.

Attachment Style Classification and Posttraumatic Stress Disorder in Former Prisoners of War

Adult attachment style and post-traumatic stress disorder (PTSD) symptomatology were investigated in 107 former prisoner of war veterans. Those with secure attachment styles scored significantly lower on measures of PTSD than did those with insecure styles, and attachment style was a stronger predictor of PTSD symptom intensity than was trauma severity. The suggested association between attachment style and PTSDs development and persistence are discussed in relation to research and clinical practice.