Anxiety Disorders: den Boer JA

Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, Davidson JR, den Boer JA, Fineberg NA, Knapp M, Scott J, Wittchen HU, Anonymous00170. · Division of Clinical Neurosciences, University of Southampton, Southampton, UK. · J Psychopharmacol. · Pubmed #16272179 No free full text.

Abstract: These British Association for Psychopharmacology guidelines cover the range and aims of treatment for anxiety disorders. They are based explicitly on the available evidence and are presented as recommendations to aid clinical decision making in primary and secondary medical care. They may also serve as a source of information for patients and their carers. The recommendations are presented together with a more detailed review of the available evidence. A consensus meeting involving experts in anxiety disorders reviewed the main subject areas and considered the strength of evidence and its clinical implications. The guidelines were constructed after extensive feedback from participants and interested parties. The strength of supporting evidence for recommendations was rated. The guidelines cover the diagnosis of anxiety disorders and key steps in clinical management, including acute treatment, relapse prevention and approaches for patients who do not respond to first-line treatments.

den Boer JA, Evans DL, Lee S, Salin-Pascual R. · Department of Psychiatry, University Hospital Groningen, Groningen, The Netherlands. · Psychopharmacol Bull. · Pubmed #12490831 links to  free full text

Abstract: Anxiety and depression are commonly encountered in primary care, with a prevalence ranging from 5% to 10%. These disorders are associated with significant and persistent impairment in functioning, risk of suicide, and substantial economic cost. Comorbidity of depression and anxiety is frequent and intensifies the burden of illness. However, patients with anxiety and depression often present to primary care physicians (PCPs) with ill-defined somatic symptoms, and both disorders are under-recognized and under-treated. PCPs should be aware that the typical presentation of anxiety and depression may not be with classical psychological symptoms, but rather with vague somatic symptoms that are often hard to treat and result in frequent repeat visits. Once anxiety and depression are accurately recognized, most patients can successfully be managed in primary care. A wide range of effective drugs is available, allowing selection of an optimal treatment for each patient. Antidepressants are effective as monotherapy in comorbid patients, and newer agents such as selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors have been shown to be effective in the treatment of anxiety and depression. Adherence to medication can be improved if drug treatment is integrated into a package of patient education and support. PCPs have a vital role to play in identifying anxiety and depression amongst their patients, and building a therapeutic partnership to achieve successful treatment.

Slaap BR, den Boer JA. · Department of Psychiatry, Academic Hospital Groningen, Groningen, The Netherlands. · Depress Anxiety. · Pubmed #11668664 No free full text.

Abstract: Several effective pharmacotherapeutic treatments exist for panic disorder; however, not all patients respond to treatment: between 20% to 40% are non-responders. Recent studies have reported several predictors of nonresponse to pharmacotherapy. In this review two questions are addressed: is there consensus with respect to predictors of nonresponse and are there any differences between short-term and long-term predictors? In this review both short-term and long-term outcome studies are discussed. Studies were included if at least DSM-III criteria were used and baseline variables were investigated as possible predictor of response, or nonresponse, to pharmacotherapy. Of each clinical predictor, tallies were made of the particular predictors employed and of those predictors that predicted nonresponse. It appears that a long duration of illness and severe agoraphobic avoidance are robust predictors of nonresponse, particularly in long-term studies. Personality disorders, or even personality traits, are possibly the most robust predictors of nonresponse. Several factors appear to be robust predictors of nonresponse: factors that are present before treatment and exert their influence on short-term and long-term treatment outcome. Prospective studies are needed to further investigate these factors and to test whether it is viable to intervene in an attempt to increase treatment response.

den Boer JA. · Department of Biological Psychiatry, Academic Hospital Groningen, The Netherlands. · Compr Psychiatry. · Pubmed #11086145 No free full text.

Abstract: Some anticipatory anxiety is expected on specific occasions such as giving a speech. However, some individuals have an excessive fear of such situations when they are under scrutiny, believing that their performance will cause them embarrassment or humiliation, frequently leading to deliberate avoidance of these situations. This disabling condition has been termed social anxiety disorder. Social anxiety disorder is common, with a lifetime prevalence of 2% to 5%, but is probably underreported. The sufferer often avoids seeking assistance, leading to comorbid mental disorders, greater disability, and an increased risk of suicide. Consequently, a high burden is placed on the patient's caregivers and on society. The diagnosis of social anxiety disorder is aided by the patient's history together with DSM-IV criteria. Research into the neurobiology of social anxiety disorder suggests a dysfunction of postsynaptic serotonin receptors and a hypersensitivity to challenge with caffeine, CO2, and pentagastrin. Neuroimaging studies suggest a dysfunction of the striatal presynaptic dopamine transporter in social anxiety disorder. Clear guidelines for the management of social anxiety disorder, including both pharmacotherapy and psychotherapy, are yet to be established. Selective serotonin reuptake inhibitors (SSRIs) show the most promise for the future, while cognitive-behavioral therapy may also be helpful. In the meantime, physicians should treat social anxiety disorder promptly and aggressively.

Brunello N, den Boer JA, Judd LL, Kasper S, Kelsey JE, Lader M, Lecrubier Y, Lepine JP, Lydiard RB, Mendlewicz J, Montgomery SA, Racagni G, Stein MB, Wittchen HU. · Centre of Neuropharmacology, Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. · J Affect Disord. · Pubmed #10940449 No free full text.

Abstract: Social phobia is a common disorder associated with significant psychosocial impairment, representing a substantial public health problem largely determined by the high prevalence, and the lifelong chronicity. Social phobia starts in early childhood or adolescence and is often comorbid with depression, other anxiety disorders, alcohol and substance abuse or eating disorders. This cascade of comorbidity, usually secondary to social phobia, increases the disability associated with the condition. The possibility that social phobia may be a trigger for later developing comorbid disorders directs attention to the need for early effective treatment as a preventive measure.The most recent drug class to be investigated for the psychopharmacological treatment of social phobia is the SSRI group for which there is growing support. The other drug classes that have been evaluated are monoamine oxidase inhibitors (MAOIs), benzodiazepines, and beta-blockers. The SSRIs represent a new and attractive therapeutic choice for patients with generalized social phobia. Recently the first, large scale, placebo-controlled study to assess the efficacy of drug treatment in generalized social phobia has been completed with paroxetine. Paroxetine was more effective in reducing the symptoms than placebo and was well tolerated. Many now regard SSRIs as the drugs of choice in social phobia because of their effectiveness and because they avoid the problems of treatment with benzodiazepines or classical MAOIs.

Slaap BR, Boshuisen ML, van Roon AM, den Boer JA. · Department of Psychiatry, Academic Hospital Groningen, The Netherlands. · Int Clin Psychopharmacol. · Pubmed #11892720 No free full text.

Abstract: Using spectral analysis of heart rate, several studies have shown that panic disorder patients are characterized by a reduced heart rate variability (HRV), indicative of abnormalities in autonomous nervous system (ANS) function. We recently reported that patients with panic disorder, who did not respond to pharmacotherapy, were characterized at baseline by a higher heart rate. In this study, ANS functioning is investigated as a possible predictor of nonresponse to pharmacotherapy. Twenty-eight medication-free panic disorder patients entered a 12-week open-label treatment study with mirtazapine. Five-minute HRV recordings were obtained before treatment and were analysed using spectral analysis. The data of 17 patients could be used. The total spectrum and low frequency power of responders to mirtazapine were significantly higher than those of nonresponders. Our findings suggest that nonresponders to short-term mirtazapine treatment are characterized at baseline by a lowered output of the ANS. The results are preliminary in view of the small sample studied.

Boshuisen ML, Slaap BR, Vester-Blokland ED, den Boer JA. · Department of Psychiatry, AZG, Groningen, The Netherlands. · Int Clin Psychopharmacol. · Pubmed #11712626 No free full text.

Abstract: In this open label pilot study, we studied the efficacy of mirtazapine (Remeron) in panic disorder. Twenty-eight patients with a DSM-IV diagnosis of panic disorder, with or without agoraphobia (10 males/18 females), were included and 19 patients completed the study. The 15-week trial started with a 3-week single-blind placebo run-in period. After this run-in period, the 12-week active treatment phase started. As primary efficacy measures, we studied the decrease in the number of full symptom panic attacks and the number of patients completely free of panic during the last 3 weeks of the study. Seventy-four percent of the patients were considered responders, according to a decrease of at least 50% in panic attack frequency. All primary and secondary efficacy measures showed a significant improvement from the second week of active treatment onwards to endpoint. The main side-effects were different from the usual side-effects in selective serotonin reuptake inhibitors (SSRIs) (initial drowsiness, weight gain and pain in the legs). The results of this open label study in panic disorder suggest that mirtazapine seems to be a fast and effective treatment alternative for SSRIs in panic disorder.

Boshuisen ML, den Boer JA. · Department of Biological Psychiatry, Psychiatric University Clinic of the Academic Hospital of Groningen, The Netherlands. · Psychopharmacology (Berl). · Pubmed #11041318 No free full text.

Abstract: RATIONALE: Non-selective serotonin (5-HT) receptor agonists like meta-chlorophenylpiperazine and MK-212 have been used to explore the role of 5-HT in obsessive compulsive disorder (OCD). The results of these studies and the findings of autoradiography and neuroimaging studies, pointed to a possible role of the 5-HT1B/1D receptor in the pathophysiology of OCD. Recently the selective 5-HT1B/1D receptor agonist sumatriptan was used to further explore the role of the 5-HT1B/1D receptor in OCD. Equivocal results with respect to the increase of obsessive compulsive symptoms in patients with OCD were reported. In one study a significant increase in plasma growth hormone (GH) concentration was observed, although sumatriptan does not pass the blood-brain barrier. OBJECTIVES: In order to further explore the role of the 5-HT1B/1D receptor in the pathophysiology of OCD, we performed this study, following the same design as Ho Pian et al. (Psychopharmacology 140:365-370). METHODS: In the present study we performed a randomized, double-blind, placebo-controlled, cross-over design with zolmitriptan (5 mg per os), a selective 5-HT1B/1D receptor agonist with better brain penetrating properties than sumatriptan. RESULTS: We could not detect any changes in obsessive compulsive symptoms, mood, or anxiety levels, although we found a (nonsignificant) increase in plasma GH levels. CONCLUSIONS: Based upon these findings, no evidence was found for a specific role of the 5-HT1B/1D receptor in OCD. It should be noted, however, that challenge studies in OCD are difficult to perform. Perhaps in the future better challenge paradigms will make it possible to further explore the role of specific receptor types in OCD.

Katerberg H, Cath DC, Tijssen MA, van Balkom AJ, van de Leemput YL, den Boer JA, Heutink P, Baas F. · Department of Biological Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. · Psychiatr Genet. · Pubmed #18349702 No free full text.

This publication has no abstract.

van Apeldoorn FJ, van Hout WJ, Mersch PP, Huisman M, Slaap BR, Hale WW, Visser S, van Dyck R, den Boer JA. · University Medical Center Groningen, Groningen, The Netherlands. · Acta Psychiatr Scand. · Pubmed #18307586 No free full text.

Abstract: OBJECTIVE: To establish whether the combination of cognitive-behavioral therapy (CBT) and pharmacotherapy (SSRI) was more effective in treating panic disorder (PD) than either CBT or SSRI alone, and to evaluate any differential effects between the mono-treatments. METHOD: Patients with PD (n = 150) with or without agoraphobia received CBT, SSRI or CBT + SSRI. Outcome was assessed after 9 months, before medication taper. RESULTS: CBT + SSRI was clearly superior to CBT in both completer and intent-to-treat analysis (ITT). Completer analysis revealed superiority of CBT + SSRI over SSRI on three measures and no differences between CBT and SSRI. ITT analysis revealed superiority of SSRI over CBT on four measures and no differences between CBT + SSRI and SSRI. CONCLUSION: Both the mono-treatments (CBT and SSRI) and the combined treatment (CBT + SSRI) proved to be effective treatments for PD. At post-test, CBT + SSRI was clearly superior to CBT, but differences between CBT + SSRI and SSRI, and between SSRI and CBT, were small.

Udo de Haes JI, Kortekaas R, Van Waarde A, Maguire RP, Pruim J, den Boer JA. · Department of Biological Psychiatry, University Medical Center Groningen, 30.001, 9700 RB Groningen, The Netherlands. · Psychopharmacology (Berl). · Pubmed #16220327 No free full text.

Abstract: RATIONALE: The dopaminergic system has been implicated in the pathogenesis and treatment of a variety of neuropsychiatric disorders. It has been shown that information on endogenous dopamine (DA) release can be obtained noninvasively by combining positron emission tomography with a dopaminergic challenge. This approach is based on the assumption that an injected radiolabeled ligand competes with the neurotransmitter for the same receptor. Increases in DA release will therefore result in a decreased binding of the radioligand. OBJECTIVES: We investigated the effect of the DA reuptake blocker methylphenidate (MP) on the binding of the D(2) receptor ligand [(11)C]-raclopride (RAC). METHODS: The effect of a 0.25 mg/kg intravenous dose of MP was studied in six healthy volunteers. RAC was administered as a bolus followed by constant infusion, and subjective effects were assessed using verbal rating scales. RESULTS: Control scans without MP administration showed that the mean RAC binding reached stable values approximately 30 min after start of the infusion. MP administration induced a 24% decrease in RAC binding in the total striatum. Correlations were found between the MP-induced change in euphoria and the percent change in binding potential (DeltaBP) in the dorsal striatum and between baseline anxiety and DeltaBP in the dorsal and middle striatum. We also found a negative correlation between baseline BP in the dorsal striatum and change in euphoria. CONCLUSIONS: Our results comply with previous findings, indicating the feasibility of the bolus infusion design combined with a relatively low MP dose to study dopaminergic (dys)function.

Landman-Peeters KM, Hartman CA, van der Pompe G, den Boer JA, Minderaa RB, Ormel J. · Department of Psychiatry, University of Groningen, Hanzepiein 1, PO Box 30.001, 9700 Groningen, The Netherlands. · Soc Sci Med. · Pubmed #15814180 No free full text.

Abstract: Gender differences in the buffer-effect of social support in the relation between stressful circumstances and the development of depression and anxiety disorders are widely assumed, but few studies address this three-way interaction between gender, stress, and support. Data in the present study came from the baseline assessment of the Adolescents at Risk for Anxiety and Depression (ARIADNE) study in 502 adolescent and young-adult children of 356 parents in the Netherlands with a depression, panic disorder and/or obsessive-compulsive disorder. Results indicate that the daughters benefit more from social support than the sons when problems in parent-offspring communication are high, but that this effect holds only for depression symptoms and particularly in relation to problems in father-offspring communication. Social support does not seem to play a role in the development of anxiety.

Slaap BR, Nielen MM, Boshuisen ML, van Roon AM, den Boer JA. · Department of Psychiatry, Academic Hospital Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. · J Affect Disord. · Pubmed #14706724 No free full text.

Abstract: BACKGROUND: Recent studies have used spectral analysis of heart rate variability (HRV) to study autonomous nervous system (ANS) function in panic disorder (PD). Most studies reported a reduced HRV in resting PD patients, suggesting increased sympathetic and decreased parasympathetic tone. In obsessive-compulsive disorder (OCD) inconsistent findings have been reported on ANS function and to date no studies have been carried out with spectral analysis of HRV. In this HRV study we compared ANS function in patients with PD, OCD and normal controls. METHODS: Standardized HRV measurement was carried out in 24 PD patients, 26 OCD patients and 24 age-matched normal controls. All patients were drug free. As this comparison yielded unexpected results, the PD and normal control samples were enlarged to 53 and 54 subjects, respectively, to verify our first measurement. RESULTS: OCD patients were not characterized by a reduced HRV, as compared to normal controls. This was also found in PD patients, even in the enlarged sample. CONCLUSIONS: HRV analysis in patients with OCD or PD showed that these patients were not characterized by ANS abnormalities, as no evidence was found of diminished HRV in a large sample of resting OCD and PD patients, measured sitting on a hospital bed.

Boshuisen ML, Ter Horst GJ, Paans AM, Reinders AA, den Boer JA. · Department of Psychiatry, Division of Biological Psychiatry, Graduate School of Behavioral and Cognitive Neurosciences, Groningen University Hospital, The Netherlands. · Biol Psychiatry. · Pubmed #12114004 No free full text.

Abstract: BACKGROUND: Our goal was to identify brain structures involved in anticipatory anxiety in panic disorder (PD) patients compared to control subjects. METHODS: Seventeen PD patients and 21 healthy control subjects were studied with H(2)(15)O positron emission tomography scan, before and after a pentagastrin challenge. RESULTS: During anticipatory anxiety we found hypoactivity in the precentral gyrus, the inferior frontal gyrus, the right amygdala, and the anterior insula in PD patients compared to control subjects. Hyperactivity in patients compared to control subjects was observed in the parahippocampal gyrus, the superior temporal lobe, the hypothalamus, the anterior cingulate gyrus, and the midbrain. After the challenge, the patients showed decreases compared to the control subjects in the precentral gyrus, the inferior frontal gyrus, and the anterior insula. Regions of increased activity in the patients compared to the control subjects were the parahippocampal gyrus, the superior temporal lobe, the anterior cingulate gyrus, and the midbrain. CONCLUSIONS: The pattern of regional cerebral blood flow activations and deactivations we observed both before and after the pentagastrin challenge was the same, although different in intensity. During anticipatory anxiety more voxels were (de)activated than during rest after the challenge.

Nielen MM, Veltman DJ, de Jong R, Mulder G, den Boer JA. · Department of Psychiatry, Academic Hospital Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. · J Affect Disord. · Pubmed #12103475 No free full text.

Abstract: BACKGROUND: Neuro-imaging studies in OCD report the orbitofrontal cortex to be functionally abnormal. As these areas are presumed to be involved in decision making, studying this behavior in OCD may provide further insight into the cognitive deficits accompanying the disorder. METHODS: Performance of 27 drug-free OCD patients and 26 healthy volunteers was compared on the decision making task of Bechara et al. [Cognition, 50 (1994) 7-15]. RESULTS: OCD patients and volunteers displayed comparable decision-making behavior. Within OCD patients, risk taking was independently related to both anxiety and OCD severity. LIMITATIONS: Results must be regarded as preliminary, due to the limited number of OCD patients included and the lack of a clinical control group. CONCLUSIONS: Although VMpfc function is not generally impaired, it seems to be involved in OCD; possibly in another way than could be measured with this task. CLINICAL RELEVANCE: Clarification of cognitive distortions underlying OCD may guide development of new strategies for cognitive-behavioral therapy.

Cremers TI, de Boer P, Liao Y, Bosker FJ, den Boer JA, Westerink BH, Wikström HV. · Department of Medicinal Chemistry, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, Netherlands. · Eur J Pharmacol. · Pubmed #10844100 No free full text.

Abstract: Pharmacokinetic and pharmacodynamic parameters of the selective serotonin reuptake inhibitor 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-5-phtalancarbonitril (citalopram) were determined in order to find optimal conditions for augmentation of its effect on extracellular serotonin [5-hydroxytryptamine (5-HT)] through blockade of 5-HT(1A) and 5-HT(1B) autoreceptors. Citalopram dose-dependently (0.3-10 micromol/kg s.c.) increased serotonin levels in ventral hippocampus of conscious rats. At plasma levels above approximately 0.15 microM, the effect of citalopram on extracellular 5-HT was augmented by both a 5-HT(1A) [N-[2-[4-(2-mehoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridil) cyclohexa necarboxamide trihydrochloride (Way 100635), 1 micromol/kg s.c.] and a 5-HT(1B) receptor antagonist (2'-methyl-4'-(5-methyl-[1,2, 4]oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy]-3-(4-methylpiperazin-1-yl)phenyl]amide (GR 127935), 1 micromol/kg s.c.). However, at plasma levels of the selective serotonin reuptake inhibitor below 0.15 microM, the effects of the antagonists diverged viz. the 5-HT(1B) receptor antagonist was still able to potentiate citalopram's effect on extracellular 5-HT, while the 5-HT(1A) receptor antagonist was no longer effective. These results suggest that in contrast to 5-HT(1B) autoreceptors, indirect activation of 5-HT(1A) autoreceptors by citalopram is critically related to the dose of selective serotonin reuptake inhibitor administered. The latter may have consequences for selective serotonin reuptake inhibitor augmentation strategies with 5-HT(1A) receptor antagonists in the therapy of depression and anxiety disorders.

Rinne T, Westenberg HG, den Boer JA, van den Brink W. · De Geestgronden Institute of Mental Health Care, Bennebroek, The Netherlands. · Biol Psychiatry. · Pubmed #10715361 No free full text.

Abstract: BACKGROUND: Disturbances of affect, impulse regulation, and autoaggressive behavior, which are all said to be related to an altered function of the central serotonergic (5-HT) system, are prominent features of borderline personality disorder (BPD). A high coincidence of childhood physical and sexual abuse is reported in these patients. Animal studies indicate that early, sustained stress correlates with a dysfunctional central 5-HT system. Therefore, we hypothesize that sustained traumatic stress in childhood affects the responsivity of the postsynaptic serotonergic system of traumatized BPD patients. METHODS: Following Axis I, Axis II, and trauma assessment, a neuroendocrine challenge test was performed with the postsynaptic serotonergic agonist meta-chlorophenylpiperazine (m-CPP) in 12 impulsive and autoaggressive female patients with BPD and 9 matched healthy volunteers. RESULTS: The cortisol and prolactin responses to the m-CPP challenge in BPD patients were significantly lower compared to those in controls. Within the group of patients with BPD, the net prolactin response showed a high inverse correlation with the frequency of the physical (r = -.77) and sexual abuse (r = -.60). CONCLUSIONS: Our data suggest that severe and sustained traumatic stress in childhood affects the 5-HT system and especially 5-HT(1A) receptors. This finding confirms the data from animal research. The blunted prolactin response to m-CPP appears to be the result of severe traumatization and independent of the BPD diagnosis.