Generalized anxiety disorder benzodiazepines

Iwata N, Cowley DS, Radel M, et al Relationship between a GABA alpha g Pro385Ser substitution and benzodiazepine sensitivity. Am] Psychiatry 156 1447—1449,1999 Jacobson AF, Dominguez RA, Goldstein B, et al Comparison of buspirone and diazepam in generalized anxiety disorder. Pharmacotherapy 5 290—296, 1985 Jaffe JH, Ciraulo DA, Nies A, et al Abuse potential of halazepam and diazepam in patients recently treated for acute alcohol withdrawal. Clin Pharmacol Ther 34 623-630, 1983... 

Generalized anxiety disorder has been relatively neglected from the point of view of both health economics and pharmacoeconomics. The changing diagnostic criteria have made it difficult to compare data over time, leading researchers to focus on the more clearly defined disorders such as panic and obsessions. Drug treatment has been dominated by the benzodiazepines, usually available genetically and cheaply. However, as the final section of this chapter will show, all this is in flux. 

Benzodiazepines are recommended for acute treatment of generalized anxiety disorder when short-term relief is needed, as an adjunct during initiation of antidepressant therapy, or to improve sleep. 

Enkelmann R (1991) Alprazolam versus buspirone in the treatment of outpatients with generalized anxiety disorder. Psychopharmacology (Berl) 105 428-432 Faravelli C, Rosi S, Truglia E (2003) Treatments benzodiazepines. In Nutt DJ, BaUenger JC (eds) Anxiety disorders. Blackwell Science, Oxford, pp 315-338 Fawcett J, Barkin RL (1998) A meta-analysis of eight randomized, double-blind, controlled clinical trials of mirtazapine for the treatment of patients with major depression and symptoms of anxiety. J Clin Psychiatry 59 123-127 Febbraro GA, Clum GA (1998) Meta-analytic investigation of the effectiveness of self-regulatory components in the treatment of adult problem behaviors. Clin Psychol Rev 18 143-161... 

Ballenger, J.C., McDonald, S., Noyes, R., Rickels, K., Sussman, N., Woods, S., Patin, J., and Singer, J. (1991) The first double-blind, placebo-controlled trial of a partial benzodiazepine agonist abe-carnil (ZK 112—119) in generalized anxiety disorder. Psycho-pharmacol Bull 27 171-179. 

Buspirone has been shown to be very effective in treating generalized anxiety disorder (GAD). It is especially useful when combined with a benzodiazepine, probably because using these two drugs together causes the activation of two neurotransmitter systems (GABA and serotonin). 

Generalized anxiety disorder is still considered the gold standard indication for benzodiazepines (P. J. Perry et al. 1990]. However, buspirone, a serotonin-la partial agonist, has been demonstrated as effective in this disorder... 

Goa and Ward 1986 Pecknold et al. 1989 Rickels et al. 1982]. In contradistinction to benzodiazepines, the therapeutic effect of buspirone has a lag period similar to that of antidepressants in depression, suggesting that its therapeutic benefits derive from receptor modulation. In addition, buspirone seems to act preferentially in those patients who are not responsive to benzodiazepines, suggesting a possible subgrouping of generalized anxiety disorders. 

Several preliminary lines of research have started to suggest that antidepressants, once considered ineffective in generalized anxiety disorder, may be very efficacious [Gorman and Kent 1999]. In particular, venlafaxine has been effective in treating generalized anxiety disorder in both open-label and double-blind trials, and imipramine and paroxetine were as effective as a benzodiazepine in the long-term treatment of generalized anxiety disorder. 

Tropisetron. The 5-FIT3 antagonist tropisetron has also been reported to be effective in the treatment of patients with generalized anxiety disorder [Lecrubier et al. 1993). The anxiolytic effect of tropisetron develops quickly, is dose dependent, and is accompanied by satisfactory tolerability and safety. The incidence of adverse events, including headache, nausea, constipation, and nervousness, is low and the severity is generally mild. The most typical adverse effects of benzodiazepine anxiolytics, such as fatigue, muscle relax-... 

Benzodiazepines, the most commonly used anxiolytic drugs in the treatment of chronic anxiety states, have also been investigated in the treatment of social phobia. These agents have been shown to be effective in the treatment of other anxiety disorders, including panic disorder and generalized anxiety disorder. Three benzodiazepines, all in the high-potency class of benzodiazepines have been investigated in the treatment of social phobia. 

The use of benzodiazepines in anxiety disorders represents a difficult issue because of the well-known addictive properties of this substance class furthermore, the depressogenic lability of benzodiazepines represents a major problem in the treatment of generalized anxiety disorders, in which concomitant depressive symptoms occur in up to 50% of patients [Gulley and Nemeroff 1993 Rickels and Schweizer 1993]. Therefore, a compound mimicking endogenous anxiolytic effects, and that might further possess potential antidepressive properties, is warranted. Neuroactive steroids could represent such a substance class. However, the following issues need to be addressed in this respect ... 

Alpidem. Alpidem is an imidazopyridine partial agonist that also shows relative selectivity for the type I benzodiazepine receptor. Studies have shown an anxiolytic effect comparable with the classic benzodiazepines, but with an improved adverse effect profile [Pancheri et al. 1993). It has also been compared with buspirone in patients with generalized anxiety disorder and shown to be more rapidly effective and again to have a more favorable adverse effect profile [Legris et al. 1993). Longer-term studies with alpidem have shown that tolerance does not occur, and no significant problems of withdrawal on discontinuation were found [Chevalier et al. 1993). Alpidem was licensed in France for the treatment of anxiety but has now been suspended because of recent reports of alpidem-induced hepatic dysfunction. The reason for this is unclear, but it may be a reflection of the fact that alpidem also binds to peripheral benzodiazepine receptors, which are present in high density in the liver. 

Suriclone. Suriclone is one of the most potent of all agents known to act at the benzodiazepine receptor. Its anxiolytic effects have been clearly demonstrated in rodents (Doble et al. 1992). It has also been demonstrated to be efficacious in the treatment of generalized anxiety disorder in humans (Ansseau et al. 1991). Animal work has shown it to have fewer side effects and less potential for interacting with alcohol than do benzodiazepines. These would represent significant advantages if they were also seen in humans. Repeated doses have failed to show tolerance and do not produce the change in set point of the GABAj receptor seen with the benzodiazepines. The reason for this is unclear but may be linked to a difference in the interaction of the cyclo-pyrrolones with the receptor compared with that of the benzodiazepines. 

Ballenger JG, McDonald S, Noyes R, et al The first double bhnd, placebo controlled trial of a partial benzodiazepine agonist abecarnil (ZK 112-119) in generalized anxiety disorder. Psychopharmacol Bull 27 171-179, 1991 Ballenger JG, Wheadon DE, Steiner M, et al Double-blind, fixed-dose, placebo-con-trolled study of paroxetin in the treatment of panic disorder. Am J Psychiatry 155 36-42, 1998... 

Generalized anxiety disorder Buspirone, benzodiazepines, venlafaxine, SSRIs... 

TABLE 12-3. Buspirone versus placebo ora benzodiazepine for generalized anxiety disorder... 

DeMartinis N, Ryan M, Rickels K, et al. Prior benzodiazepine use and buspirone response in the treatment of generalized anxiety disorder. J Clin Psychiatry 2000 61 91-94. 

Disadvantages of the benzodiazepines include the risk of dependence, depression of central nervous system functions, and amnestic effects. In addition, the benzodiazepines exert additive central nervous system depression when administered with other drugs, including ethanol. The patient should be warned of this possibility to avoid impairment of performance of any task requiring mental alertness and motor coordination. In the treatment of generalized anxiety disorders and certain phobias, newer antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are now considered by many authorities to be drugs of first choice (see Chapter 30). 

We have discussed how various antidepressants, especially venlafaxine XR, are being used increasingly for the treatment of generalized anxiety disorder. Buspirone remains a first-line generalized anxiolytic for chronic anxiety, and benzodiazepines are used largely for short-term treatment of intermittent anxiety symptoms. 

Antidepressant drugs, however, might have direct anxiolytic effects. That is, certain antidepressants such as paroxetine (Paxil) or venlafaxine (Effexor) can help reduce anxiety independent of their effects on depression.1,47 These antidepressants have therefore been advocated as an alternative treatment for anxiety, especially for people who cannot tolerate the side effects of traditional anxiolytics, or who might be especially susceptible to the addictive properties of drugs like the benzodiazepines.1,9,46 Moreover, antidepressants such as paroxetine or venlafaxine are now considered effective as the primary treatment for several forms of anxiety, including generalized anxiety disorder, social phobia, and panic disorder.4,29,53 Antidepressants, either used alone or in combination with antianxiety drugs, have become an important component in the treatment of anxiety. 

Davidson JR. Use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and posttrau-matic stress disorder. J Clin Psychiatry. 2004 65(suppl 5) 29-33. 

---