Impact of alprazolam in allostatic load and neurocognition of patients with anxiety disorders and chronic stress (GEMA): observational study protocol

Abstract

Introduction: The allostatic load model explains the additive effects of multiple biological processes that accelerate pathophysiology related to stress, particularly in the central nervous system. Stress-related mental conditions such as anxiety disorders and neuroticism (a well-known stress vulnerability factor), have been linked to disturbances of hypothalamo-pituitary-adrenal with cognitive implications. Nevertheless, there are controversial results in the literature and there is a need to determine the impact of the psychopharmacological treatment on allostatic load parameters and in cognitive functions. Gador study of Estres Modulation by Alprazolam, aims to determine the impact of medication on neurobiochemical variables related to chronic stress, metabolic syndrome, neurocognition and quality of life in patients with anxiety, allostatic load and neuroticism.

Methods/analysis: In this observational prospective phase IV study, highly sympthomatic patients with anxiety disorders (six or more points in the Hamilton-A scale), neuroticism (more than 18 points in the Neo five personality factor inventory (NEO-FFI) scale), an allostatic load (three positive clinical or biochemical items at Crimmins and Seeman criteria) will be included. Clinical variables of anxiety, neuroticism, allostatic load, neurobiochemical studies, neurocognition and quality of life will be determined prior and periodically (1, 2, 4, 8, and 12 weeks) after treatment (on demand of alprazolam from 0.75 mg/day to 3.0 mg/day). A sample of n=55/182 patients will be considered enough to detect variables higher than 25% (pretreatment vs post-treatment or significant correlations) with a 1-ß power of 0-80. t Test and/or non-parametric test, and Pearson's test for correlation analysis will be determined.

Ethics and dissemination: This study protocol was approved by an Independent Ethics Committee of FEFyM (Foundation for Pharmacological Studies and Drugs, Buenos Aires) and by regulatory authorities of Argentina (ANMAT, Dossier # 61 409-8 of 20 April 2009), following the law of Habeas Data and psychotherapeutic drug control.

Trial registration number: GEMA 20811.

Keywords: CLINICAL PHARMACOLOGY.

Figure 1

Percentage of reduction of salivary cortisol and 3-methoxy-4-hydroxyphenilglycol (MHPG) levels among alprazolam (0.75–3.0 mg/day) responder patients. Modified from ref.

Figure 2

Upper panel: Repeated stress (S-blue) conditions plus accumulation of allostatic loads (AL-red) result in chronic stress, and with time loss of the individual resilience (R-green) levels. Anxiety (A-yellow) emerges as a reaction of an excessive stress applied to the body. Under chronic stress, cognitive resources are impaired, and with it the possibilities of the affected subject to maintain its quality of life. Consequently, the affected live with a neurobiological environment poorly efficient to solve the daily challenges of life. Middle panel: With a short-term anxiolytic use of alprazolam, symptoms are reduced but demands for treatment persist, as well as the impact of the AL, and the decay of R, are not being significantly modified. Lower panel: With prolonged use of low-dose alprazolam antistress biochemical effects, plus a consequent increase of cognitive functions, may allow the progressive recovering of R, shorten S duration, and may further reduce the impact of AL. Under these new biological conditions, the subject increased its chances to seek for an improved quality of life, and may therefore shorten the demand of palliative medication.

Figure 3

Stage I: Short-term evaluation of 0.75–3.0 mg/day alprazolam on biochemical variables related to chronic stress. Stage II: Short-term evaluation of 0.75–3.0 mg/day alprazolam on cognitive and clinical variables related to chronic stress. Stage III: Intermediate-term evaluation of low alprazolam doses in cognitive, clinical and quality of life indicators (GEMA, Gador study of Estres Modulation by Alprazolam).