[Treatment of generalized anxiety: new pharmacologic approaches].

First defined as a residual diagnostic category in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM), Generalized Anxiety Disorder (GAD) was until recently one of the least studied and least clearly conceptualized of the anxiety disorders. The clinical definition of GAD has however improved up to the fourth edition of the DSM where the disorder is now characterized as a chronic state of apprehensive expectation and uncontrollable worry concerning multiple daily life events or activities and accompanied with at least 3 symptoms belonging to a list of six common manifestations of psychic or motor tension. Clinical research demonstrating the stability and the specificity of somatic symptoms clearly support the validity of the diagnosis of GAD despite possible difficulties in the differential diagnosis with other chronic conditions or axis II disorders such as dysthymia or mixed anxiety-depressive disorder. After benzodiazepines (BZD) and 5-HT1A agonists like buspirone, several other types of new anxiolytic drugs have been developed for the treatment of GAD. Partial agonists at GABA-BZD receptor sites may offer the advantage of a better efficacy vs side-effects ratio over classical BZDs; however, systematic comparative clinical trials will have to demonstrate the clinical relevance of the encouraging results obtained with these drugs, at the experimental level, during studies in healthy volunteers and during the first placebo-controlled trials. Furthermore, the recent description of GABA-receptor's subunits clearly suggest that the development of drugs acting at this level and devoided of psychomotor or withdrawal side-effects is a target that is worth pursuing. On the other hand, the development of 5-HT2 and 5-HT3 antagonists is also of interest for the treatment of GAD since it could provide new anxiolytic drugs without these side-effects and thus easier to administer on a long-term basis corresponding to the chronicity of GAD. However, it will also be important to know if wether or not the efficacy of these new drugs, like that of buspirone, is associated with some effects on depressive symptomatology, develops only progressively over time and is different in previous BZD users compared to GAD patients who did not receive BZD before the new drug. Among these drugs in development for GAD, the most likely to reach the market in a near future are a BZD partial agonist (abecarnil), 5-HT1A agonists like ipsapirone and 5-HT3 antagonists like ondansetron. However, another area of new developments concerning the drug treatment of GAD is the use of antidepressants, which have demonstrated efficacy in this indication even in patients without depressive features or panic attacks symptoms. Considering the chronic nature of GAD, these drugs, like those acting on the 5-HT-system, would be more adapted than BZD for the long-term management of this condition. If confirmed by clinical trials involving antidepressants other than tricyclics, the efficacy of these drugs in GAD may suggest that common neurobiological mechanisms are involved in the pathogenesis of both anxiety and depressive disorders. Despite the potential interest of these new treatments of GAD, recent years have shown that the development of new anxiolytic drugs often appears limited by high-rates of placebo response in numerous clinical trials. This phenomenon may be related--in part--to the increasingly sophisticated designs used in such trials, such as extensive diagnostic workups, repeated evaluations and inclusion criteria selecting the less severe types of anxiety. As emphasized by other authors, much more research needs to be done to establish what effects various ways of conducting a trial have on the trial's results in order to facilitate the emergence of new psychopharmacological approaches in the treatment of GAD.