Marina Dyskant Mochcovitch

A randomized, naturalistic, parallel-group study for the long-term treatment of panic disorder with clonazepam or paroxetine.

Abstract This long-term extension of an 8-week randomized, naturalistic study in patients with panic disorder with or without agoraphobia compared the efficacy and safety of clonazepam (n = 47) and paroxetine (n = 37) over a 3-year total treatment duration. Target doses for all patients were 2 mg/d clonazepam and 40 mg/d paroxetine (both taken at bedtime). This study reports data from the long-term period (34 months), following the initial 8-week treatment phase. Thus, total treatment duration was 36 months. Patients with a good primary outcome during acute treatment continued monotherapy with clonazepam or paroxetine, but patients with partial primary treatment success were switched to the combination therapy. At initiation of the long-term study, the mean doses of clonazepam and paroxetine were 1.9 (SD, 0.30) and 38.4 (SD, 3.74) mg/d, respectively. These doses were maintained until month 36 (clonazepam 1.9 [SD, 0.29] mg/d and paroxetine 38.2 [SD, 3.87] mg/d). Long-term treatment with clonazepam led to a small but significantly better Clinical Global Impression (CGI)–Improvement rating than treatment with paroxetine (mean difference: CGI-Severity scale −3.48 vs −3.24, respectively, P = 0.02; CGI-Improvement scale 1.06 vs 1.11, respectively, P = 0.04). Both treatments similarly reduced the number of panic attacks and severity of anxiety. Patients treated with clonazepam had significantly fewer adverse events than those treated with paroxetine (28.9% vs 70.6%, P < 0.001). The efficacy of clonazepam and paroxetine for the treatment of panic disorder was maintained over the long-term course. There was a significant advantage with clonazepam over paroxetine with respect to the frequency and nature of adverse events.

Selective serotonin-reuptake inhibitors in the treatment of panic disorder: a systematic review of placebo-controlled studies.

The selective serotonin-reuptake inhibitors are widely used in clinical practice in the treatment of panic disorder (PD). This article undertakes an up-to-date, systematic review of the published double-blind, placebo-controlled, randomized, short-term studies with currently available selective serotonin-reuptake inhibitors in the treatment of PD. Sertraline, paroxetine, citalopram, escitalopram, fluoxetine and fluvoxamine have all been proven to be superior to pill-placebo, although the placebo effect has been shown to be extremely important in patients with PD. The authors also explore the anxiolytic mechanism of action of this antidepressant drug class and the preclinical studies that are being developed to clarify the etiopathogenic mechanisms of PD and, more precisely, the role of the serotoninergic system in this pathogenesis. These steps are considered fundamental for the improvement of pharmacological treatment of PD.

The effects of regular physical activity on anxiety symptoms in healthy older adults: a systematic review

Objective: Anxiety symptoms are common in older adults with or without anxiety disorders. Pharmacological options may be limited for these patients. Alternative treatments, such as physical activity (PA), are often indicated, although few trials have evaluated their efficacy. The aim of this review was to evaluate the efficacy of regular PA on improving anxiety symptoms in older adults without anxiety disorders. Potential neuroendocrine, inflammatory, and oxidative mechanisms, as well as cognitive factors to explain these effects are also discussed. Methods: A systematic literature review was performed to identify randomized controlled trials, cross-sectional, cohort, and case-control studies, as well as case series including healthy previously sedentary older adults. We searched the PubMed and Web of Science databases for articles published in English, with no set time limits. Results: Eight studies evaluating the effect of PA on anxiety symptoms in healthy older adults were included in this review. In all studies, regular and supervised PA was directly related to decreased anxiety symptoms in older individuals. Conclusion: Regular PA may be effective for improving anxiety symptoms in older adults. More studies are needed to identify the ideal PA modality, frequency, duration, and intensity for optimizing the positive effects of exercise on anxiety in this population.

Predictors of Pharmacotherapy Response in Generalized Anxiety Disorder: A Systematic Review

Background Pharmacotherapy for generalized anxiety disorder (GAD) may be effective in reducing symptoms in the majority of patients. The study of moderators and predictors of treatment response may help clinicians both to select appropriate interventions to maximize the probability of response and to inform the general prognosis. Methods A systematic literature search of electronic databases, selected authors, and reference lists was used to identify articles that reported trials of drug monotherapy in GAD. Data on predictors and moderators were extracted. Quality of evidence was determined by the presence of a priori hypotheses, number of variables investigated, adequate quality of the measurement, and use of interaction-effects testing. Results From the 98 articles meeting inclusion criteria, 24 reported a total of 22 factors associated with treatment response. The reported results were heterogeneous, ranging over sociodemographic, clinical, comorbidity, genetic, and functional-imaging studies. Major depressive symptoms were found to moderate treatment outcome in favor of antidepressants versus benzodiazepines. Neuroticism, previous treatment, genetic polymorphisms (including serotonin receptor gene 2A), and functional activation of the anterior cingulate cortex and amygdala were identified as potential predictors of treatment response. Conclusions Correlates of poor emotion regulation predicted poor treatment response, but subclinical depression was the only variable capable of informing treatment selection in this review. Future research should focus on further exploring the value of depression as a moderator and on a narrower list of potential genetic, brain-imaging, and temperament predictors of response to pharmacotherapy in GAD.

Agomelatine in Panic Disorder: A 6-Week Follow-Up Case Series.

To the Editors: A successful panic disorder (PD) treatment is defined as a full remission of panic symptoms such as panic attacks, phobic avoidance, or anticipatory anxiety. Despite progress in the treatment of PD, a significant number of patients do not respond to standard first-line treatments because 45% of patients treated with a selective serotonin reuptake inhibitors (SSRIs) in controlled trials failed to achieve a panic-free status. Agomelatine is an antidepressant with a novel mechanism of being a selective melatonergic MT1/MT2 receptor agonist with serotonin 5-HT2c and 5-HT2b receptor antagonist activities, whereas most antidepressants act via the inhibition of the neuronal reuptake of monoamines (mainly serotonin and noradrenaline), with resultant increases in monoamine neurotransmission in the central nervous system. Besides its antidepressant action, randomized controlled studies have also demonstrated the anxiolytic properties of agomelatine. So far, a single case reported a successful treatment with agomelatine (25 mg/d) initiated after the recurrence of PD symptoms. The second study, an 8-week open-label trial, found a significant decrease in panic symptoms severity. The aim of the study was to evaluate the efficacy of agomelatine in a small case series with nondepressed PD patients

Pharmacological Treatment with the Selective Serotonin Reuptake Inhibitors

The selective serotonin reuptake inhibitors (SSRI) are considered drugs of first choice for the treatment of panic disorder (PD) due to their clinical efficacy demonstrated by 11 randomized placebo-controlled trials and favorable side effects profile. SSRI’s mechanism of action in PD treatment still not completely understood, but the role of serotonin in the pathophysiology of this disorder has been studied for the last few years by neuroimaging, neurochemical and challenge studies. In this chapter, efficacy studies, common side effects and drug interactions of the SSRI are described as well as general recommendations for their clinical use in PD.

Prospective, Open, Randomized 3-years Long-term Treatment of Panic Disorder with Clonazepam, Paroxetine, or Their Combination and Follow-up During Additional 6 Years

Objective: To describe therapeutic features of 120 panic disorder (PD) patients treated with clonazepam, paroxetine, or clonazepam + paroxetine for 3 years and their follow-up for more 6 years. Method: A prospective open study randomized 120 PD patients to 2 mg/day clonazepam or 40 mg/day paroxetine. Poor responders were switched after 8 weeks to combined treatment with ∼2 mg/day clonazepam + ∼40 mg/day paroxetine. Tapered withdrawal of all treatments was performed after 3 years. Efficacy, safety, and cumulative relapse and remission were studied over the following 6 years, using panic attack (PA) count, clinical global impression-severity (CGI-S), and Hamilton anxiety scale (HAMA). Results: 94 patients completed 3 years treatment. All were free of panic attacks since at least one year before undergoing tapered drug withdrawal. After two months of tapering, 80% of clonazepam patients were drug-free, versus 55% on paroxetine. No serious or severe adverse event were observed but PA/month, CGI-S, and HAMA worsened slightly. In annually studied patients the relapse rates were similar after the 3 treatments with an advantage of clonazepam over the combination (p=0.0035) and paroxetine (p=0.08, exact Fisher) at the first year after drug withdrawal. C umulative relapses rate were 41%, 77%, and 94% at years 1, 4, and 6, but relapse therapy with either clonazepam or paroxetine was successful in nearly all cases. Conclusion: PD is a chronic disorder, with many patients relapsing after 3 years treatment. Response to retreatment was excellent. Paroxetine and clonazepam were associated with similar long-term prognoses but clonazepam was better tolerated.