Catechol-O-methyltranferase gene expression is associated with response to citalopram in obsessive-compulsive disorder.

OBJECTIVE: To determine whether polymorphisms of the dopamine D(2) receptor (DRD2) and catechol-O-methyl-transferase (COMT) receptor genes affect the efficacy of quetiapine addition to citalopram in patients with OCD. METHODS: Sixty-four drug-free or drug-naïve patients meeting DSM-IV criteria for OCD were randomized to 10 weeks double-blind treatment with citalopram (60 mg/day) with quetiapine (300 -450 mg/day) or with placebo. The change from baseline to endpoint on the total Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the response to treatment were the primary outcome measures. Response was defined as a 25% decrease in Y-BOCS score. Responders and nonresponders were stratified according to DRD2 TaqI A and COMT Val(158)Met genotypes. RESULTS: No significant differences in genotype distribution or allele frequencies of the COMT or DRD2 receptor were found between responders and nonresponders to citalopram with quetiapine. However, nearly half of responders to citalopram with placebo carried the Met/Met (48%) genotype of the COMT polymorphism compared to none of the nonresponders (χ(2) = 10.06, df = 2, P = 0.007). CONCLUSIONS: The Met allele load of the COMT receptor gene was associated with response to 10 weeks of treatment with citalopram in drug-free or drug-naïve OCD patients.

Lipopolysaccharide-induced cytokine production in obsessive-compulsive disorder and generalized social anxiety disorder.

The immune system is implicated in the pathophysiology of various psychiatric disorders. In anxiety disorders such as obsessive-compulsive disorder (OCD) and generalized social anxiety disorder (GSAD), immunological findings are equivocal and sparse. In this study, we investigated the lipopolysaccharide (LPS)- stimulated cytokine levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-8 (IL-8) by peripheral blood leukocytes in 26 OCD patients, 26 GSAD patients, and 52 healthy controls. We found that leukocytes of OCD patients produced less IL-6 compared with matched controls, whereas no cytokine differences were found between GSAD patients and matched controls. When both patient groups were compared, a trend toward lower IL-6 levels in OCD patients was observed. This supports the idea of immunological involvement in the pathophysiology of OCD and suggests that GSAD and OCD might be different in immunological respect.

Effects of paroxetine and venlafaxine on immune parameters in patients with obsessive compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) has been associated with an altered activity of the immune system. This study was carried out to investigate whether treatment with paroxetine and venlafaxine modifies the immune function in OCD and whether this modification is related to treatment outcome. METHODS: Ex vivo production of TNF-alpha, IL-4, IL-6, IL-10, and IFN-gamma in whole blood cultures, and NK-cell activity and peripheral blood NK-cell-, monocytes-, T-cell-, and B-cell- percentages were measured in 42 outpatients with OCD who participated in a 12-week, double-blind SRI trial. RESULTS: Paroxetine and venlafaxine treatment did not affect immune parameters and clinical response was not directly related to altered activity of the immune system. Responders, defined as having a >or=25% decrease on the Y-BOCS, differed from non-responders with regard to the change of TNF-alpha values. CONCLUSIONS: The present results suggest that paroxetine and venlafaxine do not affect immune parameters and that clinical response is not related to altered activity of the immune system in OCD. Nonetheless, our data yielded interesting preliminary results that warrant further discussion and investigation.

Prazosin addition to fluvoxamine: A preclinical study and open clinical trial in OCD.

The efficacy of selective serotonin reuptake inhibitors (SRIs) in psychiatric disorders may be "augmented" through the addition of atypical antipsychotic drugs. A synergistic increase in dopamine (DA) release in the prefrontal cortex has been suggested to underlie this augmentation effect, though the mechanism of action is not clear yet. We used in vivo microdialysis in rats to study DA release following the administration of combinations of fluvoxamine (10 mg/kg) and quetiapine (10 mg/kg) with various monoamine-related drugs. The results confirmed that the selective 5-HT1A antagonist WAY-100635 (0.05 mg/kg) partially blocked the fluvoxamine-quetiapine synergistic effect (maximum DA increase dropped from 325% to 214%). A novel finding is that the α1-adrenergic blocker prazosin (1 mg/kg), combined with fluvoxamine, partially mimicked the effect of augmentation (maximum DA increase 205%; area-under-the-curve 163%). As this suggested that prazosin augmentation might be tested in a clinical study, we performed an open clinical trial of prazosin 20 mg addition to SRI in therapy-resistant patients with obsessive-compulsive disorder applying for neurosurgery. A small, non-significant reduction in Yale Brown Obsessive Compulsive Scale (Y-BOCS) scores was observed in 10 patients and one patient was classified as a responder with a reduction in Y-BOCS scores of more than 25%. We suggest that future clinical studies augmenting SRIs with an α1-adrenergic blocker in less treatment resistant cases should be considered. The clinical trial "Prazosin in combination with a serotonin reuptake inhibitor for patients with Obsessive Compulsive disorder: an open label study" was registered at 24/05/2011 under trial number ISRCTN61562706: http://www.controlled-trials.com/ISRCTN61562706.

Decreased TNF-alpha and NK activity in obsessive-compulsive disorder.

BACKGROUND: Accumulating evidence points towards the involvement of autoimmune mechanisms in the pathophysiology of some subgroups of obsessive-compulsive disorder (OCD). This study was carried out to investigate whether obsessive-compulsive disorder is associated with altered activity of the immune system, and whether these changes are related to particular clinical characteristics. METHODS: Ex vivo production of TNF-alpha, IL-4, IL-6, IL-10, and IFN-gamma in whole blood cultures, and NK-cell activity and peripheral blood NK cell-, monocytes-, T-cell-, and B-cell- percentages were measured in 50 medication-free outpatients with OCD and 25 controls. RESULTS: In OCD patients, we found a significant decrease in production of TNF-alpha (p < 0.0001) and NK-activity (p = 0.002) in comparison with controls. No significant differences were observed in the other immune variables. Patients with first-degree relatives with OCD had significant lower NK-activity than patients who had no relatives with OCD (p = 0.02), and patients with a childhood onset of OCD had significantly lower number of NK-cells than patients with a late onset (p= 0.003). CONCLUSIONS: Changes in TNF-alpha and NK activity suggest a potential role of altered immune function in the pathophysiology of obsessive-compulsive disorder.

Impaired neuroendocrine and immune response to acute stress in medication-naive patients with a first episode of psychosis.

Little is known about how the biological stress response systems--the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal (HPA) axis, and the immune system--function during psychosis. Results of studies on the effect of stress on the immune and autonomic system in patients with schizophrenia are inconsistent. The present study investigates whether the stress response is impaired in medication-naive patients with a first episode of psychosis. Ten male patients with a first episode of psychosis and 15 controls were exposed to the stress of public speaking. Parameters of the ANS (heart rate and catecholamines), the HPA axis (plasma adrenocorticotropic hormone [ACTH] and cortisol), and the immune system (number and activity of natural killer [NK] cells) were measured. Peak responses were calculated to examine the relationship between stress-induced activation of the different systems. Subjective stress and anxiety before and during the task were assessed. Patients and controls displayed similar autonomic responses to acute stress. However, there was an impaired HPA axis response, slow onset and return of ACTH, and flattened cortisol response and a reduced increase in number NK cells and NK cell activity in patients with a first episode of psychosis. Furthermore, in patients, the relationship between the different stress response systems was weaker or absent compared with controls. These findings indicate that impairments in stress processing are associated with the endophenotype of psychosis and are not a result of illness progression or antipsychotic medication.

Electroconvulsive therapy has acute immunological and neuroendocrine effects in patients with major depressive disorder.

BACKGROUND: Major depressive disorder is associated with alterations in the neuroendocrine as well as immune system. Few studies examined the impact of electroconvulsive therapy (ECT) on these systems in patients with major depressive disorder (MDD). METHODS: In this explorative study 12 patients suffering from medication-resistant MDD or MDD with psychotic features were studied during the first, the fifth and eleventh session of ECT. Blood samples were taken immediately prior to the electrostimulus and 5, 15 and 30 min after the electrostimulus to assess various lipopolysaccharide (LPS) stimulated or T-cell mitogen induced cytokines, immune cell numbers, Natural Killer cell activity, cortisol and ACTH. RESULTS: Acute ECT increased the LPS-stimulated production of the cytokines IL-6 and TNF-α by peripheral monocytes but not the production of the anti-inflammatory cytokine IL-10. Acute ECT decreased T cell mitogen-induced levels of IFN-γ but IL-10 and IL-4 levels were left unaffected while NK cell activity increased momentarily but significantly. Cortisol and ACTH rose significantly after electrostimulus. Repeated ECT had no significant effect on any of the parameters. LIMITATIONS: The study had a small group size. Also the patient group was heterogeneous as it consisted of patients with therapy-resistant depression with or without psychotic features. CONCLUSIONS: Results suggest that acute ECT is associated with transient immunological and neuro-endocrine changes, while repeated ECT does not have an additive effect on the immune and neuroendocrine functions.

Disgust affects TNF-alpha, IL-6 and noradrenalin levels in patients with obsessive-compulsive disorder.

Neurobiological research of obsessive-compulsive disorder (OCD) has rarely taken in account the context dependent evocation of obsessive-compulsive symptoms. To bypass this obstacle, this study investigated neurobiological parameters during a standardized disgust provocation paradigm in patients with OCD and healthy controls. Ten OCD patients and 10 healthy controls were exposed to 9 disgust related items using a standardized provocation paradigm. Catecholamines and cortisol in plasma and lipopolysaccharide (LPS) stimulated levels of TNF-alpha and IL-6 by peripheral leucocytes were assessed along with severity of obsessive-compulsive symptoms, disgust, and anxiety levels using Visual Analogue Scales prior, during and after a provocation paradigm. Noradrenalin levels increased, while LPS stimulated TNF-alpha and IL-6 by peripheral leucocytes decreased during exposure to disgust related objects in OCD patients but not in healthy controls. Cortisol levels were not affected by exposure neither in patients nor in controls, but overall cortisol levels of OCD patients were increased compared to controls. In conclusion, our data suggests that symptom provocation in OCD patients with contamination fear is accompanied by alterations in the immune and neuroendocrine systems but does not affect cortisol levels.

Quetiapine augments the effect of citalopram in non-refractory obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled study of 76 patients.

OBJECTIVE: To assess the efficacy of quetiapine addition to citalopram in treatment-naive or medication-free obsessive-compulsive disorder (OCD) patients. METHOD: Seventy-six patients who met DSM-IV criteria for OCD and who were drug-free or drug-naive at entry were randomly assigned in a 10-week, double-blind trial with citalopram (60 mg/day) plus quetiapine (300-450 mg/day) or placebo; treatment-refractory OCD patients were excluded. Of the 76 eligible patients, 66 patients completed the trial-31 in the quetiapine and 35 in the placebo group. The change from baseline to endpoint on the total Yale-Brown Obsessive Compulsive Scale (YBOCS) and the response to treatment in the quetiapine addition compared with the placebo addition group were the primary outcome measures. Response was defined as a 35% or greater reduction on the YBOCS and a Clinical Global Impressions-Improvement (CGI-I) score at endpoint of 1 or 2. The study was conducted from November 2003 to June 2005 at the University Medical Centre Utrecht, The Netherlands. RESULTS: As measured by the mean reduction in YBOCS scores following an intent-to-treat, last-observation-carried-forward analysis, quetiapine addition (11.9) was significantly superior to placebo (7.8; p = .009). Quetiapine addition was also significantly superior to placebo on the CGI-I scale, with a mean +/- SD CGI-I score of 2.1 +/- 1.3 versus 1.4 +/- 1.2, respectively (p = .023). Quetiapine addition (N = 22, 69%) was also associated with a significantly greater number of patients responding to treatment compared with placebo addition (N = 15, 41%; p = .019). More patients receiving quetiapine (N = 8) than placebo (N = 2; NS) discontinued treatment due to adverse events. CONCLUSIONS: The combination of quetiapine and citalopram was more effective than citalopram alone in reducing OCD symptoms in treatment-naive or medication-free OCD patients. TRIAL REGISTRATION: www.trialregister.nl Identifier NTR116.

Associations between alcohol intake and brain volumes in male and female moderate drinkers.

BACKGROUND: Alcohol-dependent individuals have brain volume loss. Possibly, moderate drinkers who are not alcohol dependent have similar but less prominent brain damage. The authors investigated whether current or lifetime alcohol intake is related to volumes of total brain, cerebellum, ventricles, peripheral cerebrospinal fluid, and cerebral gray and white matter in moderate drinkers. METHODS: The relation between current or lifetime alcohol intake and brain volumes of 47 male moderate drinkers (current alcohol intake 20 drinks per week, lifetime alcohol intake 240 kg) and 44 female moderate drinkers (current alcohol intake 15 drinks per week, lifetime alcohol intake 170 kg), all without a personal or family history of alcohol dependence, was determined using high-resolution magnetic resonance images, corrected for intracranial volume, age, and sex. RESULTS: In males, mean lifetime alcohol intake was positively associated with cerebral white matter volume, particularly in the frontal region. In females, mean lifetime alcohol intake was not associated with brain volumes. Current alcohol intake was unrelated to brain volumes in either males or females. CONCLUSIONS: Neither current nor lifetime alcohol intake is associated with decreases in brain volumes in male or female moderate drinkers. Because all participants had a negative personal and family history of alcohol dependence, the current results relatively purely concern the effects of moderate alcohol intake on brain volumes.