Laura A. Mandos

Pharmacological treatment of generalized anxiety disorder

Introduction: Generalized anxiety disorder (GAD) is a chronic, relapsing, debilitating disorder, associated with markedly impaired social and occupational functioning. Pharmacological treatment is considered standard care and several drug classes are now FDA approved for the treatment of GAD. While there are clear data for the efficacy of short-term acute treatment, long-term treatment and treatment-resistant GAD remain challenging. Areas covered: This article describes current pharmacological treatment options for GAD, with focus on benzodiazepines, azapirones, antidepressants and anticonvulsant and antipsychotic drugs. Recent findings from placebo-controlled clinical trials are reviewed and evidence-based clinical implications are discussed. A PubMed search was completed using the terms: ‘generalized anxiety disorder AND treatment’ and ‘generalized anxiety disorder AND therapy’. Additional pivotal trials were included for a historical perspective (older landmark trials that established efficacy and safety for older drug classes in the treatment of GAD). Expert opinion: Efficacy for treatment of GAD has been established for several different drug classes. At present, based on clear efficacy and good tolerability, first-line treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) is indicated. If an initial, at least moderate, clinical response is achieved under antidepressant therapy, treatment should be at least continued for 12 months.

Gepirone and diazepam in generalized anxiety disorder: a placebo-controlled trial.

This randomized, double-blind clinical trial involving 198 generalized anxiety disorder (GAD) patients was conducted to more clearly define gepirones role for the treatment of anxiety in daily dosages of 10 to 45 mg compared with diazepam and placebo. A secondary goal was to test for possible discontinuation symptoms after abrupt discontinuation of therapy. After a 1-week washout period, patients were treated for 8 weeks and then abruptly shifted under single-blind conditions for 2 weeks on placebo. The highest attrition rate occurred with patients on gepirone (58%) and the lowest on diazepam (34%). Medication intake for week 4 was 19.5 +/- 12.5 mg/day diazepam and 19.0 +/- 11.5 mg/day gepirone and was similar at week 8. The major adverse events were light-headedness, nausea, and insomnia for gepirone and drowsiness and fatigue for diazepam. Clinical improvement data showed gepirones anxiolytic response to be delayed, being significant from placebo beginning at week 6, whereas diazepam caused significantly more relief than placebo from week 1 onward. Taper results showed that only diazepam, but not gepirone, caused a temporary worsening of anxiety symptoms or rebound.

Pharmacologic strategies for discontinuing benzodiazepine treatment.

Benzodiazepines have been shown to have broad-spectrum activity, rapid onset of action, and a wide therapeutic window compared with other anxiolytic medications. Yet the use of benzodiazepines has been limited by concern regarding dependence, withdrawal, and abuse. Agents such as antidepressants, serotonergic anxiolytics, anticonvulsants, and beta-blockers have been used with varying degrees of success to help facilitate the tapering of benzodiazepines. Carbamazepine, imipramine, valproate, and trazodone have been beneficial in the management of benzodiazepine discontinuation, but not in decreasing the severity of benzodiazepine withdrawal. A stepwise approach to discontinuing benzodiazepines is offered.

Physician Withdrawal Checklist (PWC-20).

Abstract Anxiety disorders are the most common mental illnesses in the United States. Despite having a number of medication options readily available, benzodiazepines (BZs) and antidepressants have achieved remission rates of only 35% after 8 weeks of acute treatment. In the development of new anxiolytics, particularly those that affect the γ-aminobutyric acid system, it is essential to assess the new compounds potential to cause discontinuation symptoms after stopping the medication as part of both short- and long-term treatment. This report describes the development of the 20-item Penn Physician Withdrawal Checklist (PWC), a smaller version of the original 35-item PWC, and examines its validity, internal consistency, test-retest and interrater reliability, and factor structure. The PWC scores, assessed at the peak of withdrawal severity, were selected from 143 of our patients for an orthogonal factor analysis. Our results suggest that the Penn Physician Withdrawal Checklist is a simple and accurate method to assess anxiolytic discontinuation symptoms.

Nefazodone in major depression : Adjunctive benzodiazepine therapy and tolerability

One hundred sixty-six patients suffering from major depressive disorders were treated for 8 weeks with nefazodone in an open study in dosage ranges from 200 to 600 mg. This report focuses primarily on the first week of therapy and on the concomitant use of several benzodiazepines, one of which is not metabolized by the cytochrome system (temazepam). Triazolam response was further evaluated as a function of two nefazodone dosage regimens provided during the first week of therapy, one group receiving nefazodone 200 mg/day for 7 days, and another group receiving nefazodone 200 mg/day for 3 days, followed by 4 days with 400 mg/day. Finally, a comparison of three different nefazodone dosages, the third being 400 mg from day 1 on, was also carried out. Outcome measures included Hamilton Rating Scale for Depression total and the total of the three Hamilton Rating Scale for Depression insomnia items, as well as global improvement, a daily completed sleep questionnaire, and adverse event assessment. A combination of nefazodone with a benzodiazepine (BZ) caused more sedation than nefazodone alone; triazolam, the BZ with the shortest half-life and the highest dependence on the cytochrome 450 system for its metabolism, caused the least amount of sedation, and alprazolam and diazepam, the two daytime benzodiazepines, caused the most sedation. Triazolam caused significant and identical reduction of insomnia in both nefazodone groups. Compared with nefazodone 200 mg given as monotherapy, insomnia was significantly improved--not only by triazolam, but also alprazolam and diazepam, but not temazepam. The addition of nefazodone raised triazolam plasma levels to almost 500%, the plasma level of desmethyl-diazepam 87%, and that of alprazolam 34%. Temazepam plasma levels remained unchanged. When prescribing nefazodone with a benzodiazepine, one should expect an improved sleep pattern initially, but at the cost of clinically relevant daytime sedation. The prediction that temazepam, the only BZ not dependent on the cytochrome mechanism for metabolism, should be the least sedating, and triazolam, because of its cytochromic metabolism interference with nefazodone should be the most sedating, could not be confirmed. In fact, triazolam 0.25 mg capsules seem to be the safest treatment of choice when one has to combine a benzodiazepine with nefazodone in initial stages of therapy, at least of the four benzodiazepines tested in this study.

Imipramine and Buspirone in Patients With Panic Disorder Who Are Discontinuing Long-term Benzodiazepine Therapy

Pretreatment with imipramine, buspirone, or placebo was compared in 40 patients meeting the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria for panic disorder and in patients who were discontinuing long-term benzodiazepine use. The average duration of benzodiazepine use was 75 ± 64 months, and the average benzodiazepine intake expressed as diazepam equivalents was 25.7 ± 19 mg/d. We hypothesized that pretreatment with either imipramine or buspirone, in contrast to pretreatment with placebo, would lead to a significant decrease of symptoms of anxiety and depression before tapering benzodiazepines, thus making the taper process easier to complete. All 3 treatments (imipramine, buspirone, and placebo) caused a reduction in anxiety and depression symptoms as measured by changes in the Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale. Neither discontinuation severity nor taper-free status 12 weeks posttaper differed between the 3 treatment groups.

Evidence for the use of vilazodone in the treatment of major depressive disorder.

Introduction: Major depressive disorder (MDD) is characterized by dysfunction in cognition, behavior, and physical functioning, and is associated with a chronic clinical course. There are barriers to successful treatment, which often result in early discontinuation and relapse. Adverse effects (AEs) remain the most commonly cited reason for discontinuation of treatment with conventional antidepressants, particularly early on in therapy. This often translates into relapse of symptoms or recurrence of the depressive episode. The delay to therapeutic response also has a meaningful implication for treatment adherence. Areas covered: This article focuses on the implications of a novel entity for the treatment of depression; the first new molecule developed for this indication in the last 10 years. Vilazodone is a novel dual-acting serotonergic antidepressant, which is a selective and potent inhibitor of serotonin reuptake, as well as a selective partial agonist of the 5-HT1A receptor. Expert opinion: The data available in the literature so far indicate clinical efficacy over placebo and a rather benign adverse event profile. Whether the early onset of clinical efficacy observed in one of the two pivotal studies represents a true or only a chance phenomenon, only future studies can tell. Adverse effects are mostly mild–moderate and most GI type AEs disappear in about one week, at a time when all patients are still on a clinically suboptimal daily dosage (10 mg/d during the first week). Sexual AEs did not differ from placebo. Vilazodone represents an interesting addition to the arsenal of available antidepressants.

Remission of Generalized Anxiety Disorder after 6 Months of Open-Label Treatment with Venlafaxine XR

Background: Remission has become one of the leading outcome criteria in clinical trials. Data collected by this research group assessed the rate of remission after 6 months of treatment of generalized anxiety disorder (GAD) with venlafaxine XR, to search for predictors of remission and to define how early on in treatment later remission can be predicted. Method: Two hundred sixty-eight patients with a GAD diagnosis enrolled into an open-label 6-month-treatment trial with venlafaxine XR (75-225 mg/day). Remission was defined by a Hamilton anxiety scale total score ≤7. Logistic regression approaches were used to find out how early on in treatment later remission could be predicted, as well as to determine predictors of remission. In addition, adverse events were also followed over time. Results: While the total enrolled patient sample (n = 268) had a remission rate of 53%, 6-month completers (n = 159) had a remission rate of 79%. The only statistically significant predictor of remission, independent of baseline anxiety and depression levels, was a low Eysenck neuroticism score. The remission status outcome could best be predicted after 8 weeks of treatment when a CGI-I score of 1 or 2 predicted later remission with 78% accuracy and later nonremission with 91% accuracy. The incidence of adverse events decreased over the 6-month period, with sexual adverse events decreasing the least. Conclusion: The only significant predictor of remission was a low score on the Eysenck neuroticism scale. The earliest reliable prediction of later remission, based on improvement, could be made after 8 weeks of treatment with 91% accuracy.

Prescribing practices for fluoxetine: a brief survey.

Fluoxetine, the first of a much-heralded «new generation» of antidepressants with increased neurochemical selectivity, has met with rapid acceptance and remarkably widespread use, even for nonapproved diagnoses. A byproduct of its ease of use appears to be a much higher rate of adequate antidepressant therapy than reported in previous studies of tricyclics

Contents Vol. 82, 2013

R. Balon, Detroit, Mich. A. Barbosa, Lisboa P. Bech, Hillerød M. Biondi, Roma M. Bouvard, Chambery G. Chouinard, Montréal, Qué. P.M.G. Emmelkamp, Amsterdam S. Fassino, Torino M. Fava, Boston, Mass. H.J. Freyberger, Greifswald/Stralsund S. Grandi, Bologna J.I. Hudson, Belmont, Mass. I.M. Marks, London M.W. Otto, Boston, Mass. E.S. Paykel, Cambridge P. Porcelli, Castellana Grotte C. Rafanelli, Bologna C.D. Ryff , Madison, Wisc. U. Schnyder, Zürich J. Scott, Newcastle T. Sensky, London T. Th eorell, Stockholm E. Vieta, Barcelona T. Wise, Falls Church, Va. J.H. Wright, Louisville, Ky. R. Zachariae, Aarhus Offi cial Journal of the International College of Psychosomatic Medicine (ICPM) Offi cial Journal of the International Federation for Psychotherapy (IFP)