The Course of Adverse Events in Venlafaxine XR Treatment in Generalized Anxiety Disorder.

PURPOSE: The time course of adverse events is an important factor for patient management. Clinicians are better able to prepare patients for specific adverse events, which leads to better treatment adherence. METHODS: Adverse events were followed longitudinally for 6 months during the open-label phase of a relapse prevention trial with 264 patients with generalized anxiety disorder. Adverse events were assessed at each treatment visit using a 21-item checklist. Logistic regression modeling, continuation ratio modeling, and hierarchical linear modeling were used to determine whether adverse events led to early attrition and whether adverse events decreased in enrolled patients over time. FINDINGS: Adverse events were found to have decreased highly significantly during treatment. A highly significant race effect was found in that whites had a significantly higher adverse event rate than did nonwhites. Early attrition rates were predicted by presence of nausea and fatigue, late attrition by dizziness, nervousness, and sexual dysfunction. IMPLICATIONS: Our findings provide information for clinicians on the course of adverse events over treatment, useful to prepare patients for treatment adherence.

Benzodiazepines in anxiety disorders: Reassessment of usefulness and safety.

Importance: Benzodiazepines (BZs) are still widely prescribed for the treatment of anxiety disorders despite many publications in the literature which favour antidepressants (ADs) instead. What is the evidence?Observations: Treatment guidelines favour ADs over BZs for treatment of anxiety disorders without any head-to-head comparison of both drug groups with placebo. BZs are claimed to cause less efficacy and more safety issues than ADs, yet ADs also cause disturbing adverse events and, similar to BZs, discontinuation symptoms. Until evidence-based data become available, a look at two 6-month generalized anxiety disorder trials conducted by the same research group, one with a BZ and the other with an AD, might provide some guidance for the clinician. Most improvement with a BZ was obtained by 4 weeks, suggesting that BZ treatment longer than 4 weeks should only be offered to patients maximally improved at 4 weeks. In contrast, ADs may have to be prescribed for 3-6 months to obtain maximal benefits.Conclusion: Results of a controlled trial as proposed will go a long way in providing clinicians missing information to guide them in the appropriate use of both BZs and ADs in anxiety disorders.

Benzodiazepines as a Monotherapy in Depressive Disorders: A Systematic Review.

BACKGROUND: The aim of this paper was to perform a systematic review and, when feasible, a meta-analysis of randomized controlled trials (RCT) which used benzodiazepines (BZD) as a monotherapy versus placebo, antidepressant drugs (AD), or both. METHODS: Keyword searches were conducted for identifying RCT comparing BZD and AD, and/or placebo in the treatment of depression, using electronic databases from their inception up to April 2017. We selected reports of RCT in which BZD were compared to AD and/or placebo in the treatment of adult patients with a primary diagnosis of depressive disorder or anxious depression. When feasible, data were subjected to meta-analysis. RESULTS: A total of 38 studies met the criteria for inclusion and were then included in the systematic review. Only 1 study concerned a newer AD, fluvoxamine. For the meta-analysis, we submitted data on response rate from 22 RCT, considering BZD versus placebo (8 comparisons) and BZD versus tricyclic antidepressants (TCA) (20 comparisons). There was a lack of significant differences as to response rate between BZD and placebo, as well as between BZD and TCA. Analysis of individual studies disclosed that, in more than half of the studies comparing BZD to TCA and/or placebo, BZD were significantly more effective than placebo and as effective as TCA. CONCLUSIONS: BZD are a therapeutic option in anxious depression and there are no indications that AD are preferable. There is a pressing need for RCT of adequate methodological quality and follow-up comparing BZD to second-generation AD and placebo in anxious depression.

Contribution of parasympathetic muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia.

Atypical antipsychotic drugs have been associated with the development of obesity and diabetes. In particular, olanzapine can induce peripheral insulin resistance and compensatory hyperinsulinemia independent of weight gain or psychiatric disease. To determine if this compensatory increase in insulin is mediated by parasympathetic muscarinic stimulation, we randomized 15 healthy subjects 2:1 to receive double-blind olanzapine or placebo for 9 days under diet- and activity-controlled inpatient conditions. Before and after 7 days of study drug administration, subjects underwent frequently sampled intravenous glucose tolerance tests with either saline or atropine infused on subsequent days to assess insulin secretion and hepatic insulin extraction in the absence or presence of muscarinic blockade. We found that olanzapine led to an increase in the acute insulin response to glucose, which was not seen with placebo, and was attenuated in the olanzapine group by atropine. Deconvolution of C-peptide data confirmed an increase in insulin secretion with olanzapine, which was blocked by atropine, with a modest reduction in hepatic insulin extraction with olanzapine. These results support the contribution of muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia, and provide a mechanism for the compensatory hyperinsulinemia that normally serves to prevent deterioration of glucose tolerance under conditions of metabolic challenge.

The Clinical Inadequacy of the Placebo Model and the Development of an Alternative Conceptual Framework.

Placebo effects are often attributed to clinical interactions and contextual factors that affect expectations of the patient about the treatment and result in symptom changes. The prevailing conceptualization consists of an undifferentiated placebo response that needs to be minimized in controlled investigations and maximized in clinical practice. However, treatment outcome is the cumulative result of the interaction of several classes of variables with a selected treatment: living conditions (housing, nutrition, work environment, social support), patient characteristics (age, sex, genetics, general health conditions, personality, well-being), illness features and previous therapeutic experience, self-management, and treatment setting (physician's attitude and attention, illness behavior). Such variables may be therapeutic or countertherapeutic, and are unlikely to be simply additive. In certain patients their interactive combination may lead to clinical improvement, whereas in other cases it may produce no effect, and, in a third group, it may lead to worsening of the condition. Maximizing patients' expectations does not necessarily result in sustained effects and, in due course, may actually lead to worsening of the condition (violation of expectations). In this paper, we outline a multifactorial conceptual model that may have implications for the design of clinical trials as well as for clinical practice, with special reference to psychopharmacology and psychotherapy. The effects of drug treatment may be potentiated by specific nonpharmacological treatment strategies, and this synergism may disclose significant differences against placebo. Medical outcomes may be unsatisfactory not because technical interventions are missing, but because our conceptual models and thinking are inadequate.

Genome-wide association study of treatment response to venlafaxine XR in generalized anxiety disorder.

We conducted the first genome-wide association study (GWAS) in Generalized Anxiety Disorder (GAD) to identify potential predictors of venlafaxine XR treatment outcome. Ninety-eight European American patients participated in a venlafaxine XR clinical trial for GAD, with Hamilton Anxiety Scale (HAM-A) response/remission at 24 weeks as the primary outcome measure. All participants were genotyped with the Illumina PsychChip, and 266,820 common single nucleotide polymorphisms (SNPs) were analyzed. Although no SNPs reached genome-wide significance, 8 SNPs were marginally associated with treatment response/remission and HAM-A reduction at week 12 and 24 (p<0.00001). Several identified genes may indicate markers crossing neuropsychiatric diagnostic categories.

Metabolic Impairments Precede Changes in Hunger and Food Intake Following Short-Term Administration of Second-Generation Antipsychotics.

The second-generation antipsychotics (SGAs) are associated with weight gain and an increased incidence of metabolic diseases. The metabolic impairments are assumed a consequence of increased body adiposity secondary to central nervous system-associated increases in food intake. We have previously reported that, independent of weight gain, 9 days of olanzapine administration to control subjects is associated with insulin resistance and increases in postprandial levels of insulin and glucagon-like peptide 1 to a mixed meal challenge. This current report describes previously unpublished data on the effects of the SGAs olanzapine and aripiprazole compared with placebo on detailed hunger and satiety responses over the 12-day inpatient evaluation as well as postprandial ghrelin and leptin responses prior to and following administration of the 2 SGAs. We found no changes in hunger, fullness, or in the orexigenic hormone ghrelin or satiety hormone leptin, consistent with our previous report indicating no change in weight during this study. The results indicate that the SGAs are associated with metabolic changes prior to changes in hunger, satiety, and food intake, and this temporal separation suggests that there are differential mechanisms mediating SGA-associated changes in metabolism and food intake.

Pharmacological treatment for generalized anxiety disorder in adults: an update.

INTRODUCTION: Modest response and remission rates for the selective serotonin reuptake inhibitors and the serotonin-norepinephrine reuptake inhibitors, coupled with mounting evidence that the tolerability of the antidepressants (ADs) may have been overstated in the literature, has contributed to changes in prescribing patterns for generalized anxiety disorder (GAD). New interest in the absence of evidence that supports these standard therapies as superior to benzodiazepines stimulated a review of the literature. AREAS COVERED: A literature search was conducted in the MedLine database with search terms 'generalized anxiety disorder' and 'treatment' for purposes of including relevant literature related to pharmacologic treatment of GAD. Aside from a review of pivotal literature, the authors also included newer studies that evaluated novel drug treatments. Last, the database was searched for benzodiazepine comparisons to standard therapy secondary to concerns that such literature is sparse. The review of newer modalities and the decision to include related literature was also based on the strength of the evidence and the status of their approval for the treatment of GAD. EXPERT OPINION: Although ADs remain the most frequently prescribed medications for GAD, alternative and off-label therapies such as pregabalin, the atypical antipsychotics and vortioxetine are garnering interest. Based on the evidence available to us, it is our recommendation that along with the ADs, benzodiazepines be considered a possible first-line therapy in eligible patients based on the discretion and clinical judgment of the treating physician.

Combined medication and CBT for generalized anxiety disorder with African American participants: reliability and validity of assessments and preliminary outcomes.

Using data from a study of combined cognitive behavioral therapy (CBT) and venlafaxine XR in the treatment of generalized anxiety disorder (GAD), the current article examines the reliability and convergent validity of scales, and preliminary outcomes, for African American compared with European American patients. Internal consistency and short-term stability coefficients for African Americans (n=42) were adequate and similar or higher compared with those found for European Americans (n=164) for standard scales used in GAD treatment research. Correlations among outcome measures among African Americans were in general not significantly different for African Americans compared with European Americans. A subset of patients with DSM-IV-diagnosed GAD (n=24 African Americans; n=52 European Americans) were randomly selected to be offered the option of adding 12 sessions of CBT to venlafaxine XR treatment. Of those offered CBT, 33.3% (n=8) of the African Americans and 32.6% (n=17) of the European Americans accepted and attended at least one CBT treatment session. The outcomes for African Americans receiving combined treatment were not significantly different from European Americans receiving combined treatment on primary or secondary efficacy measures.

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.