Irene M. van Vliet

Psychopharmacological treatment of social phobia; a double blind placebo controlled study with fluvoxamine

Previous studies have shown selective and non-selective monoamine oxidase inhibitors (MAOIs) to be effective in the treatment of social phobia. In this study we investigated the efficacy of selective serotonin reuptake inhibitors (SSRIs) in social phobia. Thirty patients with social phobia (DSM-IIIR) were treated with the SSRI fluvoxamine (150 mg daily) using a 12-week double-blind placebo controlled design. A substantial improvement was observed in seven (46%) patients on fluvoxamine and in one (7%) on placebo. Statistically significant effects were seen on measures of social anxiety and general (or anticipatory) anxiety in patients treated with fluvoxamine compared with placebo. The level of phobic avoidance decreased also but the difference at endpoint between fluvoxamine and placebo failed to reach statistical significance. It is concluded that treatment with the SSRI fluvoxamine has beneficial effects in patients suffering from social phobia, suggesting that serotonergic mechanisms might be implicated in social anxiety.

Routine outcome monitoring and feedback on physical or mental health status: evidence and theory

OBJECTIVES Routine Outcome Monitoring (ROM) is an important quality tool for measuring outcome of treatment in health care. The objective of this article is to summarize the evidence base that supports the provision of feedback on ROM results to (mental) health care professionals and patients. Also, some relevant theoretical aspects are considered. METHODS Literature study (Pubmed, Medline, PsychINFO, Embase Psychiatry, 1975-2009) concerning randomized controlled trials (RTCs) of ROM and feedback on physical or mental health status of patients of all ages. Main search terms were routine outcome monitoring/measurement, feedback, health status measurement, patient reported outcome measures. RESULTS Included were 52 RCTs concerning ROM and feedback with adult or older patients: of these seven RCTs were exclusively focused on physical health and 45 RCTs (also) on the mental health of the patient, although not always in a mental health care setting or as primary outcome measure. There appears to be a positive impact of ROM on diagnosis and monitoring of treatment, and on communication between patient and therapist. Other results were less clear. There were no published RCTs on this topic with children or adolescents. CONCLUSIONS ROM appears especially effective for the monitoring of patients who are not doing well in therapy. Further research into this topic and the clinical-and cost-effectiveness of ROM is recommended, especially in mental health care for both adults and children. Also, more theory-driven research is needed with relevant conceptualizations such as Feedback Intervention Theory, Therapeutic Assessment.

Psychopharmacological treatment of social phobia: clinical and biochemical effects of brofaromine, a selective MAO-A inhibitor

There is circumstantial evidence that antidepressants, particularly monoamine oxidase inhibitors (MAOIs) and beta-blockers, may have some beneficial effects in social phobia. In this study 30 patients with social phobia (DSM-IIIR) were treated with the selective and reversible MAO-A inhibitor brofaromine, using a 12-week double-blind placebo controlled design. A clinical relevant improvement was seen in 80% of the patients treated with brofaromine (150 mg daily). A significant improvement was found on measures of social anxiety, phobic avoidance, general (or anticipatory) anxiety and interpersonal sensitivity in patients on brofaromine, but not on placebo. Biochemical measurements revealed a decrease in turnover of noradrenaline, serotonin and dopamine as assessed by the plasma metabolite levels, and an increase in nocturnal release of melatonin. Most prominent side-effect was middle sleep disturbance. No changes in blood pressure were observed. During a follow-up period of 12 weeks a further improvement was found in patients treated with brofaromine.

Increased Serotonin and Dopamine Transporter Binding in Psychotropic Medication–Naïve Patients with Generalized Social Anxiety Disorder Shown by 123I-β-(4-Iodophenyl)-Tropane SPECT

There is circumstantial evidence for the involvement of serotonergic and dopaminergic systems in the pathophysiology of social anxiety disorder. In the present study, using SPECT imaging we examined the 123I-β-(4-iodophenyl)-tropane binding potential for the serotonin and dopamine transporters in patients with a generalized social anxiety disorder and in age- and sex-matched healthy controls. Methods: Twelve psychotropic medication–naïve patients with social anxiety disorder, generalized type (5 women and 7 men) and 12 sex- and age-matched healthy controls were studied. Volumes of interest were constructed on MRI-coregistered SPECT scans. Binding ratios were compared using the Mann–Whitney U test. Possible correlations between binding patterns and symptomatology were assessed using the Spearman rank correlation coefficient. Results: Significantly higher binding potentials were found for the serotonin in the left and right thalamus of patients. Patients had also a significantly higher binding potential for the dopamine transporter in the striatum. Conclusion: The present study provided direct evidence for abnormalities in both the dopaminergic and the serotonergic systems in patients with generalized social anxiety disorder.

MAO inhibitors in panic disorder: clinical effects of treatment with brofaromine. A double blind placebo controlled study.

There is considerable evidence that antidepressants, particularly serotonin uptake inhibitors, are effective in the treatment of panic disorder (PD). Monoamine oxidase inhibitors (MAOI) may also have beneficial effects in PD. In this study 30 patients with PD with or without agoraphobia (DSM-III-R) were treated with the selective and reversible MAO-A inhibitor brofaromine (150 mg daily) in a 12-week double-blind placebo controlled design. A clinical relevant improvement was found in more than 70% of the patients treated with brofaromine, whereas no significant improvement was observed on placebo. After an increase in anxiety in the first week, a clinically relevant improvement in anxiety symptoms was found, followed by a subsequent reduction in agoraphobic avoidance in patients treated with brofaromine. A similar improvement was observed on distress scores related to panic attacks, although there was no significant reduction in the number of panic attacks. The most prominent side-effects were middle sleep disturbance and nausea. No increase in blood pressure was observed. During a follow-up period of another 12 weeks a further improvement was found in patients treated with brofaromine.

Basal cortisol levels in relation to dimensions and DSM-IV categories of depression and anxiety.

The Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV classification may fail to adequately distinguish neuroendocrine factors involved in the etiology of depressive and anxiety disorders. Continuous phenotypic dimensions may correlate better with underlying neuroendocrine dysregulations. We compared the categorical DSM-IV diagnoses with a dimensional approach in the same group of outpatients with depressive (n=36), anxiety (n=18), and comorbid depressive and anxiety (n=19) disorders, who were free of psychotropic medication, and in 36 healthy controls. The Mood and Anxiety Symptom Questionnaire (MASQ) was used to measure the three dimensions of the tripartite model, i.e., anhedonic depression, anxious arousal, and general distress. The salivary cortisol awakening response (CAR) (0, 30, 45, and 60 min after awakening), and diurnal cortisol decline (11:00 h, 15:00 h, 19:00 h, and 23:00 h) were analyzed for linear and nonlinear associations. The CAR showed statistically significant nonlinear relationships with two MASQ dimensions, i.e., anhedonic depression and general distress, but no differences between DSM-IV categories. The diurnal cortisol decline was linearly related to the MASQ dimensions anhedonic depression and general distress and significantly higher AUC(diurnal) levels and a steeper slope were found in depressive patients compared to controls using DSM-IV categories. The present study shows that linear and nonlinear associations with salivary cortisol are detected when using phenotypic dimensions and may be complementary to phenotypic DSM-IV categories when doing neuroendocrine research.

Salivary cortisol, serum lipids, and adiposity in patients with depressive and anxiety disorders

Depressive and anxiety disorders are associated with an increased risk of cardiovascular disease. Chronic stress induces hypothalamus-pituitary-adrenal (HPA)-axis perturbations, which might subsequently induce atherogenic lipoprotein profiles and adiposity. The aim of the present study was to investigate the relationship between basal saliva cortisol levels and serum lipids and adiposity in psychiatric patients. Eight salivary cortisol samples (awakening; 30, 45, and 60 minutes after awakening; 11:00 AM, 3:00 PM, 7:00 PM, and 11:00 PM) on 2 consecutive days in medication-free outpatients with depressive and/or anxiety disorders (n = 72) and in healthy controls (n = 42) were used to derive 2 measures of HPA-axis function: basal cortisol concentrations (ie, area under the curve [AUC(cortisol)]) and circadian cortisol variability (variability(cortisol)). Index z scores were calculated for dyslipidemia (from serum triglycerides, inverse high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol) and adiposity (from body mass index and waist-to-hip ratio). Regression analyses were conducted to determine the contribution of AUC(cortisol) and variability(cortisol) in explaining the variance of, respectively, the lipid and adiposity index. Patients showed a higher mean AUC(cortisol) compared with healthy controls (t = 2.7, P = .01). Both cortisol parameters were independently associated with dyslipidemia in patients after adjustment for age, alcohol use, and smoking habits (beta = .31, P = .02 and beta = -.29, P = .02, respectively), but not in controls. Cortisol measures were not associated with adiposity in either group. We conclude that elevated basal cortisol concentrations and lower circadian cortisol variability were independently associated with a less favorable lipoprotein profile in patients with depressive and/or anxiety disorders. These data lend support to the hypothesis that the relationship between affective disorders and cardiovascular disease is partly mediated by HPA-axis perturbations.

Effects of the 5-HT1A receptor agonist flesinoxan in panic disorder

The effects of flesinoxan, a potent and selective 5-HT1A agonist, were studied in two pilot studies in panic disorder patients to explore the role of 5-HT1A receptors in the mechanism of action of antipanic agents. This paper reports on the results of these two studies with flesinoxan. In study I, using a single-blind crossover design, five patients were treated for 1 week with placebo, 4 weeks with flesinoxan (up to 2.4 mg per day), and 2 weeks with placebo. In study II, 15 patients were enrolled in a double-blind, three-armed study with placebo and two dosages of flesinoxan. After a single-blind placebo run-in phase of 1 week, patients were treated for 8 weeks with placebo, 0.6 or 1.2 mg/day flesinoxan. In pilot study I patients’ condition worsened during the 4-week flesinoxan treatment period. Anxiety was frequently reported as an adverse event. Symptoms returned to the pre-treatment level during the 2-week placebo washout period. In pilot study II, no treatment effects in either group were observed. Anxiety as an adverse event was less prominent than in the first pilot study. A lowering of mood was seen in some patients. The sample sizes of these two pilot studies are too small to draw firm conclusions on the efficacy of flesinoxan in panic disorder, but the present data are not encouraging in this respect. The worsening of symptoms seen with the highest dose of flesinoxan is intriguing and might give a clue to the understanding of the mechanism underlying similar effects seen with antidepressants in panic disorder patients.

A Double-blind Comparative Study of Brofaromine and Fluvoxamine in Outpatients With Panic Disorder

Previous studies have shown that both selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) are effective in the treatment of panic disorders (PD). In this study, the SSRI fluvoxamine (Fluv) was compared with the MAO-A-I brofaromine (Brof). Thirty patients with the diagnosis of PD with or without agoraphobia were treated with either Fluv or Brof (150 mg daily) in a double-blind design. After 12 weeks of treatment, 93% of the Brof group and 87% of the Fluv group considered themselves much or very much improved. Taking a reduction in the Hamilton Rating Scale for Anxiety score of 50% or more, 33% of the Fluv patients and 47% of the Brof patients were responders to treatment. After an increase in anxiety in the 1st week, which was more severe in Fluv-treated patients than for Brof, a clinically relevant decrease in anxiety symptoms and reduction in panic attacks and avoidance behavior was observed. There was no significant difference between the treatment groups. The most prominent side effects were middle-sleep disturbance (Brof), tiredness (Fluv), and nausea after taking the medication (Brof and Fluv). During a double-blind follow-up period of another 12 weeks, a further improvement was found in both treatment groups without significant differences between the two groups. The selective and reversible MAO-A-I brofaromine and the SSRI fluvoxamine are equally effective in the treatment of PD. Both compounds lead to a reduction in the number of panic attacks and a subsequent reduction in agoraphobic avoidance.

Tryptophan depletion affects the autonomic stress response in generalized social anxiety disorder

In generalized social anxiety disorder (gSAD), serotonergic dysfunctions are found, as well as abnormalities of the autonomic nervous system (ANS) in basal conditions and of the hypothalamic pituitary adrenal (HPA) axis in response to psychological challenges. These findings raise the question whether these phenomena are interrelated. Therefore we designed a study in which two groups with nine pair wise age and gender matched gSAD patients (total of 10 men and 8 women), who were successfully treated with a selective serotonin reuptake inhibitor (SSRI), underwent a tryptophan depletion challenge (TD) or a placebo condition. A TD procedure temporarily decreases serotonergic neurotransmission. In order to activate the stress system the TD/placebo challenge was combined with a public speaking task. We assessed ANS responses, as measured with the promising new marker salivary alpha-amylase (sAA), and HPA-axis responses, as measured with salivary cortisol. The most important result was that the TD group showed a significant larger sAA response to the public speaking task as compared to the placebo group, reflecting hyperresponsivity of the ANS in this group, whereas no differences were seen in cortisol responses. This suggests that in gSAD there is a vulnerability of the ANS more than the HPA-axis.