Herman G M Westenberg

Publications (82)308.15 Total impact

• Article: Sympathetic activity and hypothalamo-pituitary-adrenal axis activity during sleep in post-traumatic stress disorder: A study assessing polysomnography with simultaneous blood sampling.

  Saskia van Liempt, Johan Arends, Pierre J M Cluitmans, Herman G M Westenberg, René S Kahn, Eric Vermetten
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  ABSTRACT: BACKGROUND: Nightmares and insomnia in PTSD are hallmark symptoms, yet poorly understood in comparison to the advances toward a biological framework for the disorder. According to polysomnography (PSG), only minor changes in sleep architecture were described. This warrants alternative methods for assessing sleep regulation in PTSD. METHODS: After screening for obstructive sleep apnea and period limb movement disorder, veterans with PTSD (n=13), trauma controls (TCs, n=17) and healthy controls (HCs, n=15) slept in our sleep laboratory on two consecutive nights with an IV catheter out of which blood was sampled every 20min from 22:00h to 08:00h. Nocturnal levels of plasma adrenocorticotropic hormone (ACTH), cortisol, melatonin were assessed in conjunction with PSG registration, as well as subjective sleep parameters. RESULTS: PTSD patients showed a significant increase in awakenings during sleep in comparison to both control groups. These awakenings were correlated with ACTH levels during the night, and with the subjective perception of sleep depth. Also, heart rate (HR) was significantly increased in PTSD patients as compared with both control groups. The diurnal regulation of ACTH, cortisol and melatonin appeared undisturbed. PTSD patients exhibited lower cortisol levels at borderline significance (p=0.056) during the first half of the night. ACTH levels and cortisol levels during the first half of the night were inversely related to slow wave sleep (SWS). CONCLUSION: This study suggests that hypothalamo-pituitary-adrenal (HPA) axis activity is related to sleep fragmentation in PTSD. Also, activity of the sympathetic nervous system (SNS) is increased during sleep in PTSD. Further research is necessary to explore the potential causal relationship between sleep problems and the activity of the HPA-axis and SNS in PTSD.
  Psychoneuroendocrinology 07/2012; · 5.81 Impact Factor
• Article: Wireless implantable micro-stimulation device for high frequency bilateral deep brain stimulation in freely moving mice.

  Ria de Haas, Rolf Struikmans, Geoffrey van der Plasse, Linda van Kerkhof, Jan H Brakkee, Martien J H Kas, Herman G M Westenberg
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  ABSTRACT: Although deep brain stimulation (DBS) has been proven to be an effective treatment for several neuropsychiatric disorders, such as Parkinson's disease, the underlying working mechanisms are still largely unknown. Behavioral animal models are essential in examining the working mechanisms of DBS and especially mouse models are necessary to investigate the genetic component underlying specific behaviors related to psychiatric diseases. Unfortunately, currently available stimulation devices are unsuitable to test behavior in freely-moving mice. As such, no DBS studies in behaving mice have been reported thus far. In order to overcome this limitation we have developed a new light-weight wireless implantable micro stimulator device for mice that delivers biphasic pulse patterns to two individual electrode pairs, mimicking partly the clinical situation. This paper describes in detail the bench-top validation and in vivo implementation of this device. The results in this study indicate that the wireless implantable stimulator in mice reliably delivers continuous bilateral stimulation, importantly, does not restrict the animals mobility and hygiene (grooming behavior). In vivo testing furthermore showed that stimulation of the mice ventral striatum yields similar results as previously shown by others in rats where conventional deep brain stimulation techniques were used. This newly designed device can now be used in the highly needed DBS behavioral studies in mice, to further investigate the underlying mechanisms of DBS in behavioral animal models for psychiatric disorders.
  Journal of neuroscience methods 06/2012; 209(1):113-9. · 2.30 Impact Factor
• Article: Catechol-O-methyltranferase gene expression is associated with response to citalopram in obsessive-compulsive disorder.

  Nienke C C Vulink, Herman G M Westenberg, Filip van Nieuwerburgh, Dieter Deforce, Sjoerd B A H A Fluitman, Jantien S C Meinardi, Damiaan Denys
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  ABSTRACT: 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.
  International Journal of Psychiatry in Clinical Practice 03/2012; 16(4):277-83. · 0.43 Impact Factor
• Article: Impaired neuroendocrine and immune response to acute stress in medication-naive patients with a first episode of psychosis.

  Janine A E M van Venrooij, Sjoerd B A H A Fluitman, Jeroen G Lijmer, Annemieke Kavelaars, Cobi J Heijnen, Herman G M Westenberg, René S Kahn, Christine C Gispen-de Wied
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  ABSTRACT: 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.
  Schizophrenia Bulletin 03/2012; 38(2):272-9. · 8.80 Impact Factor
• Article: Marked inbred mouse strain difference in the expression of quinpirole induced compulsive like behavior based on behavioral pattern analysis.

  Ria de Haas, Amir Seddik, Hugo Oppelaar, Herman G M Westenberg, Martien J H Kas
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  ABSTRACT: Obsessive-compulsive disorder (OCD) is a chronic and complex psychiatric disorder with a lifetime prevalence of 2-3%. Recent work has shown that OCD rituals were not only characterized by a high rate of repetition but also by an increased behavioral repertoire due to additional non-functional unique acts. These two behavioral characteristics may provide an ethological basis for studying compulsive behavior in an animal model of OCD. Here, quinpirole induced behavior (so far only investigated in rats) has been studied in A/J and C57BL/6J mice by using behavioral pattern analysis. The aim of this study is to investigate whether genetic background is mediating this behavior. Results showed that open field motor activity levels of saline treated C57BL/6J mice was significantly higher compared to A/J treated saline mice. Long-term quinpirole treatment increased open field motor activity levels in A/J, but not in C57BL/6J. Quinpirole treatment induced a strain dependent difference in behavioral repertoire. There was a dose dependent increase in the number of different behavioral patterns in A/J, whereas, in C57BL/6J there was a dose dependent decrease. This data suggest that genetic background is important in expressing quinpirole induced compulsive like behavior. Following quinpirole treatment, A/J mice express a greater behavioral repertoire with a high rate of repetition. This phenotype resembles that of OCD rituals in patients and indicates that this strain is very interesting to further validate for studying neurobiological mechanisms of compulsive behavior.
  European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 02/2012; 22(9):657-63. · 3.68 Impact Factor
• Article: Neuroendocrine and immune responses to a cognitive stress challenge in veterans with and without PTSD.

  Carien S de Kloet, Eric Vermetten, Arthur R Rademaker, Elbert Geuze, Herman G M Westenberg
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  ABSTRACT: PTSD has been associated with altered hypothalamus-pituitary-adrenal-axis (HPA-axis), immune and sympathetic nervous system (SNS) regulation. The purpose of this study was to evaluate the effect of cognitive stress on these systems in PTSD patients and controls. The subjective units of distress score (SUDS), NK-cell response, plasma levels of noradrenalin and ACTH in response to cognitive stress were assessed in male veterans with PTSD (n=15) and age, region and year of deployment matched veterans without psychopathology (n=15). The challenge induced an increase in SUDS, noradrenalin, ACTH and NK-cell response in both groups. Baseline levels of ACTH were lower in PTSD patients. The test was experienced as more stressful by PTSD patients and resulted in an augmented ACTH response in patients. The noradrenalin and NK-cell responses showed no group differences. The ACTH response correlated with the severity of symptoms in patients, and the noradrenalin response correlated with the ACTH and NK-cell response in controls, but not in patients. PTSD patients experience more distress and present with an exaggerated pituitary response to this stressor. In addition, our results suggest an altered interaction between the HPA-axis, SNS and immune system in PTSD.
  European journal of psychotraumatology. 01/2012; 3.
• Article: Obstructive sleep apnea in combat-related posttraumatic stress disorder: a controlled polysomnography study.

  Saskia van Liempt, Herman G M Westenberg, Johan Arends, Eric Vermetten
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  ABSTRACT: Obstructive sleep apnea (OSA) may be highly prevalent in posttraumatic stress disorder (PTSD) and may exacerbate PTSD complaints. Our objective was to determine whether the prevalence of OSA was high in a sample of Dutch veterans with PTSD as compared to age- and trauma-matched controls, and whether OSA was associated with more severe PTSD complaints. We determined the apnea hypopnea indices (AHI) with polysomnographic registrations in 20 veterans with PTSD, 24 veterans without PTSD, and 17 healthy controls. PTSD severity and nightmare complaints were assessed with the Clinician-Administered PTSD Scale (CAPS). The prevalence of an AHI>10 was 29% in PTSD, 21% in trauma controls, and 29% in healthy controls (χ(2)= 0.60, df=2, p=n.s.). The mean CAPS score in patients with OSA (n=6) was significantly higher than in patients without OSA (p<0.05), while nightmare severity was similar in PTSD patients with OSA as compared to PTSD patients without OSA (p=n.s.). Furthermore, there was a significant correlation between AHI and CAPS score in PTSD patients (r=0.46, p<0.05, df=14). Our results indicate that PTSD is not necessarily associated with a higher prevalence of OSA. However, PTSD severity was related to OSA, which may possibly mean that comorbid OSA leads to an increase in PTSD complaints. However, future research should indicate whether OSA exerts a negative influence on PTSD, and treatment of OSA alleviates PTSD symptoms.
  European journal of psychotraumatology. 01/2011; 2.
• Article: Paroxetine augmentation in patients with generalised social anxiety disorder, non-responsive to mirtazapine or placebo.

  Sara I J Schutters, Harold J G M van Megen, J Frederieke Van Veen, Koen R J Schruers, Herman G M Westenberg
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  ABSTRACT: The aim of the study was to investigate if combination of mirtazapine with paroxetine causes a greater therapeutic effect and less sexual side effects than paroxetine monotherapy in social anxiety disorder (SAD). Twenty one patients with generalised SAD, non-responsive to a 12 week trial with mirtazapine and 22 patients, non-responsive to placebo received paroxetine (20-40 mg) in addition to their double-blind treatment with mirtazapine or placebo for another 12 weeks. The Liebowitz Social Anxiety Scale (LSAS) and the Clinical Global Impression-Improvement (CGI-I) scale were used to measure efficacy. Sexual functioning was assessed by the Arizona Sexual Experiences Scale (ASEX). Both treatments showed a significant LSAS reduction and their response rates (based on LSAS reduction ≥ 40% and CGI-I ≤ 2) were similar (paroxetine and mirtazapine: 52.4%, paroxetine and placebo: 59.1%). Sexual dysfunction (based on ASEX ≥ 19) was found in half of patients treated with paroxetine and placebo, and in 38% of patients treated with paroxetine and mirtazapine. The present study did not find support for a greater efficacy of combination pharmacotherapy in SAD, however results suggest that combination of paroxetine with mirtazapine might cause less sexual dysfunction than treatment with paroxetine alone. Copyright © 2011 John Wiley & Sons, Ltd.
  Human Psychopharmacology Clinical and Experimental 01/2011; 26(1):72-6. · 2.48 Impact Factor
• Article: Behavioral pattern analysis and dopamine release in quinpirole-induced repetitive behavior in rats.

  Ria de Haas, Annelies Nijdam, Tjalke A Westra, Martien J H Kas, Herman G M Westenberg
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  ABSTRACT: Obsessive-compulsive disorder (OCD) is a chronic and disabling psychiatric disease with a lifetime prevalence of 2-3%. People with OCD suffer from intrusive, unwanted and recurrent thoughts (obsessions) and/or repetitive ritualistic behaviors (compulsions). The aim of this study is to quantify the dimensions of ritualistic 'compulsive-like' behavior in quinpirole-induced behavior in rats by using T-pattern behavioral analysis. In addition, we investigated whether the behavioral effects elicited by quinpirole sensitization remained after 2 weeks of cessation of treatment. Finally, to study the neurobiological underpinnings of this 'compulsive-like' behavior, we investigated the effect of quinpirole treatment on the extracellular dopamine levels in the nucleus accumbens. Once established, 'compulsive-like' behavior is dependent upon quinpirole administration, as this behavior rapidly normalized after cessation of treatment. After a single dose of quinpirole the dopamine level decreased more in saline pre-treated animals as compared with animals given quinpirole treatment continuously. Furthermore, T-pattern analysis revealed that quinpirole-induced behavior consists, unlike OCD rituals, of a smaller behavioral repertoire. As seen in patients with OCD, quinpirole-treated animals performed these behaviors with a high rate of repetition. These findings suggest that quinpirole-induced behavior mimics only part of the compulsive behavior as shown in OCD patients.
  Journal of Psychopharmacology 12/2010; 25(12):1712-9. · 3.04 Impact Factor
• Article: Electroconvulsive therapy has acute immunological and neuroendocrine effects in patients with major depressive disorder.

  Sjoerd B A H A Fluitman, Cobi J Heijnen, Damiaan A J P Denys, Willem A Nolen, Ferdi J Balk, Herman G M Westenberg
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  ABSTRACT: 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). 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. 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. 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. 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.
  Journal of affective disorders 12/2010; 131(1-3):388-92. · 3.76 Impact Factor
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  Available from: Damiaan Denys

  Article: Mirtazapine in generalized social anxiety disorder: a randomized, double-blind, placebo-controlled study.

  Sara I J Schutters, Harold J G M Van Megen, Jantien Frederieke Van Veen, Damiaan A J P Denys, Herman G M Westenberg
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  ABSTRACT: This study is aimed at investigating the efficacy and tolerability of mirtazapine in a generalized social anxiety disorder. Sixty patients with generalized social anxiety disorder were randomly allocated to receive mirtazapine (30-45 mg/day) (n= 30) or placebo (n= 30) for 12 weeks in a double-blind study design. Primary efficacy was assessed by the Liebowitz Social Anxiety Scale (LSAS) and response to treatment was defined as a reduction of 40% on the LSAS and an improvement on the Clinical Global Impression scale of 'much or very much improved'. An intent-to-treat analysis showed no difference between mirtazapine and placebo on the absolute LSAS scores with a mean decrease of 13.5 +/- 16.9 and 11.2 +/- 17.8 respectively, and on the number of responders, 13 and 13%, respectively. In conclusion, mirtazapine (30-45 mg/day) failed to be effective in the generalized social anxiety disorder.
  International clinical psychopharmacology 09/2010; 25(5):302-4. · 3.35 Impact Factor
• Article: Disgust affects TNF-alpha, IL-6 and noradrenalin levels in patients with obsessive-compulsive disorder.

  Sjoerd B A H A Fluitman, Damiaan A J P Denys, Cobi J Heijnen, Herman G M Westenberg
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  ABSTRACT: 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.
  Psychoneuroendocrinology 07/2010; 35(6):906-11. · 5.81 Impact Factor
• Article: Sensory gating and sensorimotor gating in medication-free obsessive-compulsive disorder patients.

  Aart S de Leeuw, Bob Oranje, Harold J G M van Megen, Chantal Kemner, Herman G M Westenberg
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  ABSTRACT: Obsessive-compulsive disorder (OCD) is associated with deficits in inhibition mechanisms. This is reflected in reports showing impaired sensorimotor and sensory gating in OCD patients, as measured with prepulse inhibition (PPI) of the startle reflex and P50 suppression paradigms. However, most of the patients in these studies used medication and the results were not controlled for menstrual cycle phase in women. In this study PPI and P50 suppression were tested in 25 medication-free OCD patients and 25 healthy controls, using auditory stimuli and controlling for menstrual cycle effects. Subgroups were established, based on clinical variables (e.g. 'washers' and 'checkers'). No impairments in PPI or P50 suppression were found in the OCD group when compared with healthy controls. However, a subgroup of OCD patients ('checkers', n=12) showed increased P50 suppression. It was concluded that sensorimotor and sensory gating is not impaired in drug-free OCD patients, taking into account the menstrual cycle effects in women. These results do not support hypotheses linking deficits in these inhibition paradigms and the pathogenesis of OCD. The finding of an increased P50 suppression in the subgroup of 'checkers' deserves further investigation and underlines the value of studying subgroups of OCD.
  International clinical psychopharmacology 07/2010; 25(4):232-40. · 3.35 Impact Factor
• Article: Compulsivity in mouse strains homologous with chromosomes 7p and 15q linked to obsessive-compulsive disorder.

  Martien J H Kas, Cigdem Gelegen, Filip van Nieuwerburgh, Herman G M Westenberg, Dieter Deforce, Damiaan Denys
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  ABSTRACT: Obsessive-compulsive disorder (OCD) is a severe anxiety disorder characterized by obsessions and compulsions. The core symptom of OCD is compulsivity, the inability to stop thinking or acting when you want to, despite being aware of the uselessness of the content or the adverse consequences. To initiate a systematic search for genetic mechanisms underlying the pathophysiology of compulsivity, a panel of chromosome substitution (CS) strains, derived from mice that suppress (C57BL/6J strain) or maintain (A/J strain) high levels of repetitive wheel running during 2 hr of daily limited food access, was screened for this compulsive behavior. Following the genetic screen, we found linkage between compulsive wheel running and mouse chromosomes 2, 6, and 7 that show overlap with recently identified human linkage regions for OCD on chromosomes 7p and 15q. In the overlapping (human/mouse) genomic region, the CRH receptor 2 (CRHR2) gene was tested in a human case-control study. An initial exploration in OCD cases versus controls failed to detect an association between four-candidate CRH2R SNP's within this homologous linkage region and OCD. Genetic fine mapping of compulsivity in mice provides new opportunities to reveal mechanisms underlying this significant psychiatric trait.
  American Journal of Medical Genetics Part B Neuropsychiatric Genetics 07/2009; 153B(1):252-9. · 3.70 Impact Factor
• Article: Haloperidol counteracts the ketamine-induced disruption of processing negativity, but not that of the P300 amplitude.

  Bob Oranje, Christine C Gispen-de Wied, Herman G M Westenberg, Chantal Kemner, Marinus N Verbaten, René S Kahn
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  ABSTRACT: Antagonists of the N-methyl-D-aspartate (NMDA) receptors such as ketamine, induce abnormalities in healthy subjects similar to those found in schizophrenia. However, recent evidence, suggests that most of the currently known NMDA antagonists have a broader receptor profile than originally thought. Besides exerting an antagonistic effect on NMDA receptors, they have agonistic effects on dopamine D2 receptors. Can haloperidol (D2 antagonist) counteract the disruptive effects of ketamine on psychophysiological parameters of human attention? In a randomized, double-blind, placebo-controlled experiment 18 healthy male volunteers received placebo/placebo, placebo/ketamine (0.3 mg/kg i.v.) and haloperidol (2 mg)/ketamine (0.3 mg/kg i.v.) on three separate test days, after which they were tested in an auditory selective-attention paradigm. Haloperidol/ketamine reduced task performance compared to placebo/placebo, while the task performance in these two treatments did not differ from placebo/ketamine. Furthermore, placebo/ketamine reduced processing negativity compared to both placebo/placebo and haloperidol/ketamine, while processing negativity did not differ between placebo/placebo and haloperidol/ketamine treatments. However, both placebo/ketamine and haloperidol/ketamine reduced P300 amplitude compared to placebo/placebo, while P300 amplitude did not differ between placebo/ketamine and haloperidol/ketamine treatments. The combined effects of haloperidol and ketamine reduced task performance, suggesting that this is dependent on dopaminergic D2 activity, probably in the prefrontal cortex. In addition, ketamine reduced both P300 amplitude and processing negativity. In contrast to the P300 amplitude, the disruptive effects of ketamine on processing negativity could be prevented by pretreatment with haloperidol. The current results suggest that ketamine reduced P300 amplitude by its antagonistic effect on glutamatergic activity, while it reduced processing negativity by its agonistic effect on dopaminergic D2 activity.
  The International Journal of Neuropsychopharmacology 02/2009; 12(6):823-32. · 4.58 Impact Factor
• Article: Recent advances in understanding and treating social anxiety disorder.

  Herman G M Westenberg
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  ABSTRACT: The common occurrence and high level of morbidity and burden associated with social anxiety disorder (SAD) are gaining widespread recognition. Interest in understanding and treating the disorder has also grown in response to large-scale investigations that have demonstrated high levels of efficacy with both pharmacologic and nonpharmacologic treatments. Such trials indicate that many patients with generalized SAD (roughly 40% to 60%) respond (eg, Clinical Global Impressions-Improvement rating 1 or 2) after an adequate treatment trial, despite having suffered with disabling symptoms for most of their adult lives. First-line therapy options include the selective serotonin reuptake inhibitors and the dual-acting serotonin-norepinephrine reuptake inhibitor venlafaxine. Second-line options consist of anticonvulsants (gabapentin, pregabalin, valproic acid) and benzodiazepines (clonazepam). Reversible and irreversible monoamine oxidase inhibitors (moclobemide and phenelzine, respectively), while effective, are not widely used. Nonpharmacologic approaches, such as cognitive-behavioral therapy (CBT), are also effective for SAD. Newer treatment strategies such as levetiracetam, atypical antipsychotics, or D-cycloserine in combination with CBT appear promising but require further investigation. Finding a well-tolerated, safe, and effective treatment for each individual patient is crucial as most will require ongoing treatment in order to maintain benefits, prevent SAD relapse, and to experience optimal outcomes in the long term.
  CNS spectrums 02/2009; 14(2 Suppl 3):24-33. · 2.20 Impact Factor
• Article: Neuropsychological performance is related to current social and occupational functioning in veterans with posttraumatic stress disorder.

  Elbert Geuze, Eric Vermetten, Carien S de Kloet, Ron Hijman, Herman G M Westenberg
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  ABSTRACT: Several studies have reported deficits in both immediate and delayed recall of verbal memory in patients with posttraumatic stress disorder (PTSD). However, most of these studies had several methodological disadvantages. None of these studies assessed parameters related to social or occupational functioning. Fifty Dutch veterans of UN peacekeeping missions (25 with PTSD and 25 without PTSD) were assessed with a comprehensive neuropsychological test battery consisting of four subtests of the Wechsler Adult Intelligence Scale-III, California Verbal-Learning Test, and the Rey Auditory Verbal-Learning Test. Veterans with PTSD were free of medication and substance abuse. Veterans with PTSD had similar total intelligence quotient scores compared to controls, but displayed deficits of figural and logical memory. Veterans with PTSD also performed significantly lower on measures of learning and immediate and delayed verbal memory. Memory performance accurately predicted current social and occupational functioning. Deficits of memory performance were displayed in a sample of medication- and substance abuse-free veterans with PTSD. Deficits in memory performance were not related to intelligence quotient, length of trauma exposure, or time since trauma exposure. This study showed that cognitive performance accurately predicted current social and occupational functioning in veterans with PTSD.
  Depression and Anxiety 10/2008; 26(1):7-15. · 4.18 Impact Factor
• Article: Neural correlates of associative learning and memory in veterans with posttraumatic stress disorder.

  Elbert Geuze, Eric Vermetten, Matthias Ruf, Carien S de Kloet, Herman G M Westenberg
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  ABSTRACT: Impaired attention and memory are symptoms frequently associated with posttraumatic stress disorder (PTSD). Although patients with PTSD frequently report memory difficulties and empirical research provides support for a memory deficit in PTSD, as of yet, no fMRI study has adequately investigated the neural correlates of learning and memory of neutral (i.e. not trauma related) material in patients with PTSD compared to controls. Twelve male veterans with PTSD, and twelve male veterans without PTSD, were recruited, and matched for age, region and year of deployment. Encoding and retrieval of 12 word-pair associates was assessed during fMRI in both experimental groups. Compared to controls veterans with PTSD revealed underactivation of the frontal cortex, and overactivation of the temporal cortex during the encoding phase. Retrieval of the paired associates resulted in underactivation of right frontal cortex, bilateral middle temporal gyri, and the left posterior hippocampus/parahippocampal gyrus in patients with PTSD. Deficits in memory performance in PTSD appear to be related to altered activity in fronto-temporal areas during both the encoding and retrieval phase of memory processing.
  Journal of Psychiatric Research 08/2008; 42(8):659-69. · 4.66 Impact Factor
• Article: Thinner prefrontal cortex in veterans with posttraumatic stress disorder.

  Elbert Geuze, Herman G M Westenberg, Armin Heinecke, Carien S de Kloet, Rainer Goebel, Eric Vermetten
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  ABSTRACT: Structural neuroimaging studies in posttraumatic stress disorder (PTSD) have focused primarily on structural alterations in the medial temporal lobe, and only a few have examined grey matter reductions in the cortex. Recent advances in computational analysis provide new opportunities to use semi-automatic techniques to determine cortical thickness, but these techniques have not yet been applied in PTSD. Twenty-five male veterans with PTSD and twenty-five male veterans without PTSD matched for age, year and region of deployment were recruited. All the subjects were scanned using MRI. Subjects' brains were aligned using cortex-based alignment in a region of interest based approach. Individual cortical thickness maps were calculated from the MR images. Regions of interest examined included the bilateral superior frontal gyri, bilateral middle frontal gyri, bilateral inferior frontal gyri, bilateral superior temporal gyri, and bilateral middle temporal gyri. In a large number of patients and controls, IQ scores and memory scores were also obtained. Individual cortical thickness maps were calculated from the MR images. Veterans with PTSD revealed reduced cortical thickness in the bilateral superior and middle frontal gyri, the left inferior frontal gyrus, and the left superior temporal gyrus. Veterans with PTSD performed significantly worse on memory measures compared to control veterans. Cortical thickness correlated with memory measures in the veterans without PTSD, but not in the veterans with PTSD. Cortical thinning in these regions may thus correspond to functional abnormalities observed in patients with PTSD.
  NeuroImage 08/2008; 41(3):675-81. · 5.89 Impact Factor
• Article: Hypersensitivity of 5-HT2 receptors in OCD patients. An increased prolactin response after a challenge with meta-chlorophenylpiperazine and pre-treatment with ritanserin and placebo.

  Aart S de Leeuw, Herman G M Westenberg
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  ABSTRACT: Several studies in obsessive compulsive disorder (OCD) have provided circumstantial evidence that the 5-HT-system is involved in the pathophysiology of OCD. To further examine the role of 5-HT receptors we studied the behavioural and neuroendocrine effects of different doses of meta-chlorophenylpiperazine (mCPP) in OCD patients and healthy controls, after pre-treatment with ritanserin, a 5-HT2 receptor antagonist, and placebo. Twenty patients and 20 healthy controls received 0.1, 0.3 or 0.5 mg/kg mCPP or placebo orally. Each subject was tested two times, receiving both times the same dosage of mCPP or placebo with ritanserin or placebo pre-treatment. All was done under double-blind conditions. OC-symptoms and hormone levels were measured. The increase in prolactin level after mCPP administration was more robust in patients than in controls. The prolactin response following 0.5 mg/kg of mCPP was partially blocked by ritanserin in patients, but totally blocked in healthy controls. The cortisol responses in both groups did not differ statistically significant from each other and were entirely blocked by ritanserin. None of the subjects experienced an exacerbation of obsessive compulsive symptoms. The neuroendocrine results show an enhanced susceptibility of OCD patients for the mCPP-induced prolactin response, which effect seems to be due to an increased sensitivity of 5-HT2 receptors.
  Journal of Psychiatric Research 07/2008; 42(11):894-901. · 4.66 Impact Factor