Venlafaxine in the treatment of anxiety disorders

Venlafaxine extended-release (Effexor XR, Wyeth-Ayerst Co.) is a novel, dual acting serotonin-norepinephrine reuptake inhibitor antidepressant, which inhibits the synaptic reuptake of both serotonin and norepinephrine. Controlled trials have demonstrated the efficacy and safety of venlafaxine in the treatment of anxiety disorders including social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder, panic disorder and obsessive-compulsive disorder. Generally well-tolerated with side effects that usually abate with continued treatment, venlafaxine is an important alternative to the selective serotonin reuptake inhibitors for patients with anxiety disorders.     

The treatment of panic disorder

PURPOSE OF REVIEW: The aim of this article is to provide an updated review of studies and recommendations published from August 2003 to August 2004 on the treatment of panic disorder. RECENT FINDINGS: Cognitive-behavioral psychotherapy remains the treatment of choice for panic disorder. Recent studies confirm selective serotonin reuptake inhibitors as the first-choice drugs in treating panic disorder. Recommendations for (adjunctive) high-potency benzodiazepines have been published. Psychoeducation and combined pharmacotherapy/psychotherapy improve treatment response. Optimal long-term treatment of panic disorder involves adequate medication and duration of treatment, since relapse is frequent. SUMMARY: Recent studies confirm that cognitive-behavioral therapy, alone or in combination with drug therapy, remains the treatment of choice for panic disorder. Long-term treatment is often necessary due to the chronicity of the illness.     

The Role of High-Potency Benzodiazepines in the Treatment of Panic Disorder

Medication plays a central role in the treatment of panic disorder, with the goal of eliminating panic attacks and restoring normal function (i.e., achieving full remission). Four drug classes have similar efficacy (tricyclic antidepressants, selective serotonin reuptake inhibitors [SSRIs], benzodiazepines, and monoamine oxidase inhibitors). Nonetheless, benzodiazepines remain the most prescribed medication for panic disorder in the United States. The high-potency benzodiaze-pines alprazolam (available as immediate- and extended-release tablets) and clonazepam (available as tablets and orally disintegrating wafers) are the only benzodiazepines approved by the U.S. Food and Drug Administration for the treatment of panic disorder. High-potency benzodiaze-pines, with their proven efficacy in panic disorder exerted through control of the central nervous system excitability by a selective and potent enhancement of inhibitory gamma-aminobutyric acid-mediated neurotransmission, are also a safe and well-tolerated option for potentiation of rapid treatment response when initiating treatment with SSRIs. Judicious use of high-potency benzodiazepines followed by a cautious taper and discontinuation may optimize the benefits and minimize any potential risk associated with this class of drugs.     

Inositol treatment of autism

Summary Recent studies suggest that serotonin reuptake inhibitors are helpful in at least some symptoms of autism. Inositol is a precursor of the second messenger for some serotonin receptors, and has been reported effective in depression, panic disorder and obsessive-compulsive disorder. However a controlled double-blind crossover trial of inositol 200 mg/kg per day showed no benefit in 9 children with autism. Since biochemical studies suggest that inositol may augment serotonin effects, future studies could evaluate inositol in children already receiving serotonin reuptake inhibitors.     

Psychopharmacology of anxiety disorders

Exposure of the general population to a 1:4 lifetime risk of disabling anxiety has inspired generations of fundamental and clinical psychopharmacologists, from the era of the earliest benzodiazepines (BZ) to that of the selective serotonin reuptake inhibitors (SSRIs) and related compounds, eg, the serotonin and norepinephrine reuptake inhibitors (SNRIs). This comprehensive practical review summarizes current therapeutic research across the spectrum of individual disorders: generalized anxiety disorder (GAD), panic disorder (PD) and agoraphobia (social anxiety disorder), compulsive disorder (OCD), phobic disorder (including social phobia), and posttraumatic stress disorder (PTSD). Specific diagnosis is a precondition to successful therapy: despite substantial overlap, each disorder responds preferentially to specific pharmacotherapy. Comorbidity with depression is common; hence the success of the SSRIs, which were originally designed to treat depression. Assessment (multidomain measures versus individual end points) remains problematic, as-frequently-do efficacy and tolerability The ideal anxiolytic remains the Holy Grail of worldwide psychopharmacologic research.     

Cost-effectiveness of psychological and pharmacological interventions for generalized anxiety disorder and panic disorder

OBJECTIVE: To assess from a health sector perspective the incremental cost-effectiveness of interventions for generalized anxiety disorder (cognitive behavioural therapy [CBT] and serotonin and noradrenaline reuptake inhibitors [SNRIs]) and panic disorder (CBT, selective serotonin reuptake inhibitors [SSRIs] and tricyclic antidepressants [TCAs]). METHOD: The health benefit is measured as a reduction in disability-adjusted life years (DALYs), based on effect size calculations from meta-analyses of randomised controlled trials. An assessment on second stage filter criteria ("equity", "strength of evidence", "feasibility" and "acceptability to stakeholders") is also undertaken to incorporate additional factors that impact on resource allocation decisions. Costs and benefits are calculated for a period of one year for the eligible population (prevalent cases of generalized anxiety disorder/panic disorder identified in the National Survey of Mental Health and Wellbeing, extrapolated to the Australian population in the year 2000 for those aged 18 years and older). Simulation modelling techniques are used to present 95% uncertainty intervals (UI) around the incremental cost-effectiveness ratios (ICERs). RESULTS: Compared to current practice, CBT by a psychologist on a public salary is the most cost-effective intervention for both generalized anxiety disorder (A$6900/DALY saved; 95% UI A$4000 to A$12 000) and panic disorder (A$6800/DALY saved; 95% UI A$2900 to A$15 000). Cognitive behavioural therapy results in a greater total health benefit than the drug interventions for both anxiety disorders, although equity and feasibility concerns for CBT interventions are also greater. CONCLUSIONS: Cognitive behavioural therapy is the most effective and cost-effective intervention for generalized anxiety disorder and panic disorder. However, its implementation would require policy change to enable more widespread access to a sufficient number of trained therapists for the treatment of anxiety disorders.     

Effects of tiagabine on cholecystokinin-tetrapeptide (CCK-4)-induced anxiety in healthy volunteers

There is increasing evidence that a dysregulation of the gamma-aminobutyric acid (GABA) system plays a role in the pathophysiology of panic disorder. Selective enhancement of GABAergic neurotransmission has been shown to improve anxiety in experimental animals and in patients with panic disorder. Tiagabine is an antiepileptic drug, which increases GABA via selective blockade of GABA reuptake. Apart from its anticonvulsant activity anxiolytic properties could therefore be suggested. To investigate the putative anxiolytic properties of the GABA reuptake blocker tiagabine, we studied the impact of tiagabine treatment on cholecystokinin tetrapeptide (CCK-4)-induced panic. Fifteen healthy volunteers received 15 mg tiagabine daily for 1 week. A CCK-4 challenge was performed before and after treatment. Panic was assessed using the API- and PSS-score. There was a marked improvement of CCK-4-induced panic after 1 week of treatment. Both API- and PSS-scores showed a significant reduction. Our results suggest anxiolytic properties of tiagabine in humans, which provide sufficient rationale to assess its putative anxiolytic effects in patients with panic disorder under controlled conditions.     

SSRIs and SNRIs: broad spectrum of efficacy beyond major depression

Originally studied and introduced for the treatment of depression, the selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) have proven effective for a broad range of psychiatric illnesses, including several anxiety disorders, bulimia, and dysthymia. These drugs have in common important effects on the serotonergic (5-HT) neurotransmission system, which is involved in mediating a substantial number of important functions, including mood, aggression, sexual behavior, and pain. In addition, some of the new antidepressants, like venlafaxine/venlafaxine XR, also have effects on the noradrenergic neurotransmission system, which also appears important in mood and anxiety disorders. These new drugs, because of their specificity for the serotonin and norepinephrine reuptake proteins, lack most of the adverse side effects of tricyclic antidepressants and monoamine oxidase inhibitors. Consequently, in addition to being the usual first-line treatments for major depression, they are also first-line for panic disorder, obsessive-compulsive disorder, social phobia, posttraumatic stress disorder, and bulimia. They may also be the best medication treatments for dysthymia and generalized anxiety disorder. Further advances in psychopharmacology will be driven by discoveries from brain imaging and molecular biological research.     

SSRIs vs. TCAs in the treatment of panic disorder: a meta-analysis

OBJECTIVE: To compare the short-term efficacy of selective serotonin reuptake inhibitors (SSRIs) vs. tricyclic antidepressants (TCAs) in the treatment of panic disorder (PD) a meta-analysis was conducted. METHOD: Included were 43 studies (34 randomized, nine open), pertaining to 53 treatment conditions, 2367 patients at pretest and 1804 at post-test. Outcome was measured with the proportion of patients becoming panic-free, and with pre/post Cohen's d effect sizes, calculated for four clinical variables: panic, agoraphobia, depression, and general anxiety. RESULTS: There were no differences between SSRIs and TCAs on any of the effect sizes, indicating that both groups of antidepressants are equally effective in reducing panic symptoms, agoraphobic avoidance, depressive symptomatology and general anxiety. Also the percentage of patients free of panic attacks at post-test did not differ. The number of drop-outs, however, was significantly lower in the group of patients treated with SSRIs (18%) vs. TCAs (31%). CONCLUSION: SSRIs and TCAs are equal in efficacy in the treatment of panic disorder, but SSRIs are tolerated better.     

Dizziness and Panic Disorder: A Review of the Association Between Vestibular Dysfunction and Anxiety

Dizziness is a common and costly condition that causes significant distress and impairment yet often confounds appropriate diagnosis and treatment. Among patients presenting for evaluation and treatment of dizziness, rates of panic disorder are elevated to 5 to 15 times the general population rates. In addition, the limited studies to date of dizziness in patients with panic disorder suggest that panic patients frequently experience significant dizziness and often demonstrate evidence of vestibular dysfunction. In this paper we review studies investigating the relationship between panic disorder and vestibular dysfunction. Currently, there are three main explanatory models for the association between panic disorder and vestibular dysfunction: the psychosomatic model, the somatopsychic model, and the network alarm theory. Systematic investigations of the treatment of patients with vestibular symptoms and panic disorder are lacking, though prevalence, associated costs, and disability suggest that they are needed. Serotonin selective reuptake inhibitors are good candidates for future treatment studies.     

Management of panic disorder

Selective serotonin reuptake inhibitors are the first-line treatment for panic disorder. They are effective and well tolerated. Although tricyclic antidepressants are equally effective, they are less well tolerated than the selective serotonin reuptake inhibitors. Monoamine oxidase inhibitors can be efficacious but have a range of unwanted effects that preclude their use as first-line treatments. Benzodiazepines should be reserved for short-term use and for treatment-resistant patients who do not have a history of dependence and tolerance. Also, they can be combined with selective serotonin reuptake inhibitors in the first weeks of treatment to tide the patient over before the onset of the response. Cognitive behavioral therapy is the psychologic treatment of first choice. The methods of combining drug and nondrug treatments need careful and thorough exploration.     

Use of selective serotonin reuptake inhibitors for the treatment of childhood panic disorder: a pilot study.

This preliminary study examines the effectiveness and safety of selective serotonin reuptake inhibitors (SSRIs) for the treatment of panic disorder in children and adolescents. In a prospective open label study, 12 children and adolescents with panic disorder were treated with SSRIs, and if necessary, with benzodiazepines, for a period of 6-8 weeks and were followed for approximately 6 months. During the trial, clinician-based and self-report rating scales for anxiety and depression, functioning, and side effects, were administered. Using the Clinical Global Impression Scale (CGIS) 75% of patients showed much to very much improvement with SSRIs without experiencing significant side effects. After controlling for changes in depressive symptoms, self-report and clinician-based anxiety scales also showed significant improvement. At the end of the trial, 67% of patients no longer fulfilled criteria for panic disorder and 4 patients remained with significant residual symptoms. In conclusion, SSRIs appear to be a safe and promising for the treatment of children and adolescents with panic disorder, however, randomized controlled trials evaluating the effects of SSRIs and other interventions (e.g., cognitive therapy) for treating panic disorder in children and adolescents are warranted. It appears that until the SSRIs begin to exert their effects, a benzodiazepine adjunct treatment might be helpful for patients with severe panic disorder.     

Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder

BACKGROUND: Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) as well as benzodiazepines have been shown to be effective for the treatment of panic disorder. The introduction of SSRIs has enabled a greater understanding of the role of serotonin in the etiology of panic disorder; however, the role of norepinephrine has been more challenging to ascertain. The aim of this study was to determine the efficacy and tolerability of reboxetine, a novel selective norepinephrine reuptake inhibitor, in patients with panic disorder with and without agoraphobia. METHOD: Eighty-two patients (aged 18-65 years) with DSM-III-R panic disorder, with or without agoraphobia, were randomly assigned to receive 6 to 8 mg/day of reboxetine (42 patients) or placebo (40 patients) for 8 weeks in this placebo-controlled, parallel-group, double-blind clinical trial. RESULTS: Of the 82 patients enrolled in the trial, 75 were considered in the analysis (37 patients in the reboxetine group and 38 patients in the placebo group). At last assessment, there was a significant reduction in the mean number of panic attacks (range, 9.3-1.2) and phobic symptoms (range, 8.1-3.2) in the reboxetine group compared with the placebo group (ranges, 8.5-5.8 and 7.7-5.2, respectively; p < .05). Improvement in Hamilton Rating Scale for Depression, Hopkins Symptom Checklist-90, and Sheehan Disability Scale scores were also greater in the reboxetine group compared with the placebo group. Adverse events reported more frequently with reboxetine than placebo included dry mouth (36% vs. 16%), constipation (27% vs. 22%), and insomnia (26% vs. 22%). CONCLUSION: Reboxetine was effective and well tolerated in the treatment of panic disorder.     

New developments in panic disorder

Panic disorder is a distressing and disabling disorder characterized by recurring panic attacks; anticipatory anxiety about having additional attacks; and agoraphobic fear and avoidance of situations in which attacks have occurred, ready escape is difficult, or help is unavailable in the event of an attack. It is typically associated with impairment in social, emotional, and vocational functioning, as well as excessive utilization of the medical care system. A number of pharmacologic agents and cognitive-behavioral treatments have proven effective for the treatment of panic disorder. Selective serotonin reuptake inhibitors are becoming first-line pharmacotherapy because of their favorable side effect profile and greater spectrum of efficacy in comparison with older classes of agents. In this article, we provide an overview of the prevalence, associated health care utilization, impairment in quality of life, and treatment of panic disorder.     

Panic Disorder and Chest Pain: Mechanisms, Morbidity, and Management

Approximately one quarter of patients who present to physicians for treatment of chest pain have panic disorder. Panic disorder frequently goes unrecognized and untreated among patients with chest pain, leading to frequent return visits and substantial morbidity. Panic attacks may lead to chest pain through a variety of mechanisms, both cardiac and noncardiac in nature, and multiple processes may cause chest pain in the same patient. Panic disorder is associated with elevated rates of cardiovascular diseases, including hypertension, cardiomyopathy, and, possibly, sudden cardiac death. Furthermore, patients with panic disorder and chest pain have high rates of functional disability and medical service utilization. Fortunately, panic disorder is treatable; selective serotonin reuptake inhibitors, benzodiazepines, and cognitive-behavioral psychotherapy all effectively reduce symptoms. Preliminary studies have also found that treatment of patients who have panic disorder and chest pain with benzodiazepines results in reduction of chest pain as well as relief of anxiety.     

Rational Treatment of Panic Disorder with Antidepressants

Rational treatment of panic disorders with antidepressants rests on decisions of drug choice, dosage, and duration of treatment. In this paper, we selectively review the author's research with the standard antidepressant, imipramine, in the treatment of panic disorder with agoraphobia as it relates to practical issues. We develop general guidelines for treatment, suggest researchable ways of increasing the net effectiveness of treatment with this class of drugs, and discuss limited generalizations to the extant literature on selective serotonin reuptake inhibitors in panic disorders.     

Paroxetine in panic disorder: clinical management and long-term follow-up

Panic disorder is one of the most common anxiety disorders and has a lifetime prevalence of 3-5%. Panic attacks can begin at any age, but commonly have their onset in early adulthood between the ages of 20 and 40 years. Naturalistic data has shown that panic disorder has a chronic and relapsing course. Panic disorder is reported to be associated with an increased risk of suicidal behavior and comorbid psychiatric diagnoses such as depression and substance abuse. Currently, recommended treatment modalities for panic disorder include the use of antidepressant pharmacotherapy and/or cognitive behavioral therapy. Paroxetine is unique among the selective serotonin reuptake inhibitors since, in addition to its effect on the CNS serotonergic neurotransmission, it also has mild noradrenergic properties demonstrated to be effective in the treatment of anxiety disorders and depression. Paroxetine treatment has the potential to cause weight gain and sexual dysfunction, primarily anorgasmia and ejaculatory dysfunction for the long term. In the short-term, treatment causes nausea, gastrointestinal disturbances, irritability, headaches and eating and sleeping difficulties. Paroxetine is an example of an selective serotonin reuptake inhibitor agent, which has been well studied in the treatment of panic disorder and is efficacious and well-tolerated. Paroxetine pharmacotherapy has been recommended to be continued for 1 year as specified in the treatment guidelines set by the American Psychiatric Association in the treatment of panic disorder.     

Management of anxiety in late life

Epidemiologic data are used as a framework to discuss the pharmacologic and cognitive-behavioral management of anxiety disorders in late life. Generalized anxiety disorder (GAD) and phobias account for most cases of anxiety in late life. The high level of comorbidity between GAD and major depression, and the observation that the anxiety usually arises secondarily to the depression, suggests that antidepressant medication should be the primary pharmacologic treatment for many older people with GAD. Most individuals with late-onset agoraphobia do not have a history of panic attacks and the illness often starts after a traumatic event. Exposure therapy is the treatment of choice for agoraphobia without panic. It is uncommon for obsessive-compulsive disorder (OCD) and panic disorder to start for the first time in old age, but these disorders can persist from younger years into late life. Case reports and uncontrolled case series suggest that elderly people with OCD or panic disorder can benefit from pharmacologic and cognitive-behavioral treatments that are known to be effective in younger patients. However, it is not known whether the rate of response among elderly patients is adversely affected by the chronicity of these disorders. The prevalence and incidence of post-traumatic stress disorder in late life are not known. Uncontrolled data support the use of selective serotonin reuptake inhibitors in war veterans with chronic symptoms of post-traumatic stress disorder; other treatments for this condition await evaluation in the elderly.     

Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia?

OBJECTIVE: Recently, pharmacological treatment guidelines for panic disorder have changed as newer treatment options have become available. The authors examined how the use of psychotropic drugs has shifted over the course of 10 years to determine if prescribing patterns have changed to reflect these revised treatment guidelines. METHOD: A total of 443 patients with panic disorder were enrolled in the Harvard/Brown Anxiety Research Project, a prospective longitudinal study of anxiety disorders. These patients were interviewed over the course of 10 years to examine their use of psychotropic medications. RESULTS: Despite efforts aimed at increasing the use of selective serotonin reuptake inhibitors (SSRIs) in patients with panic disorder (e.g., APA's practice guideline for panic disorder, Food and Drug Administration approval of particular SSRIs for the treatment of panic disorder), only a modest increase in their use was found. Treatment patterns for psychotropic drugs appear to have remained stable over the past decade, with benzodiazepines being the most commonly used medication for panic disorder. In comparison, SSRI use throughout the follow-up period has remained low. Patients using an SSRI did not have a more favorable clinical course than those using a benzodiazepine, nor were there significantly better rates of remission in patients using SSRIs and benzodiazepines concomitantly. CONCLUSIONS: These results highlight a gap between pharmacological treatment guidelines and actual delivery of care in that recommendations to use SSRIs to treat panic disorder are not being followed. Factors potentially associated with promoting and ignoring treatment recommendations are discussed.     

A randomized,double-blind,placebo-controlled study of the effects of adjunctive paroxetine in panic disorder patients unsuccessfully treated with cognitive-behavioral therapy alone

BACKGROUND: Both cognitive-behavioral therapy and treatment with selective serotonin reuptake inhibitors (SSRIs) have proved to be effective in the treatment of panic disorder. The present study examined the effects of paroxetine added to continued cognitive-behavioral therapy in patients who were unsuccessfully treated with initial cognitive-behavioral therapy alone. METHOD: 161 patients with panic disorder with or without agoraphobia (DSM-IV criteria) underwent a manual-guided cognitive-behavioral therapy of 15 sessions. Forty-three unsuccessfully treated patients from this group were included in a double-blind, placebo-controlled, next-step treatment study consisting of continued cognitive-behavioral therapy plus adjunctive paroxetine at a dose of 40 mg/day or continued cognitive-behavioral therapy plus placebo. RESULTS: Overall, patients in the cognitive-behavioral therapy plus paroxetine condition improved significantly on agoraphobic behavior (p < .05) and anxiety discomfort (p < .01), whereas patients in the cognitive-behavioral therapy plus placebo condition did not. Effect sizes in the cognitive-behavioral therapy plus paroxetine condition ranged from 1.0 to 1.8 and in the cognitive-behavioral therapy plus placebo condition, from 0.4 to 1.0. CONCLUSION: Patients with panic disorder who are unsuccessfully treated with initial cognitive-behavioral therapy may benefit from the addition of an SSRI as a second treatment modality. The importance of timely evaluation of treatment results is emphasized.