Therapeutic Armamentarium in Anxiety Disorders
J.A. den Boer, B.R. Slaap, G.J. ter Horst, T.I.F.H. Cremers and F.J. Bosker
For decades benzodiazepines have been the mainstay in the treatment of anxiety disorders. It is only during the last decade mat tins situation has changed. With the introduction of serotonin reuptake inhibitors (SSRI's), 5-HT receptor-specific drugs like 5-HT1A agonists and recently, dual action antidepressants, new possibilities have been created for the treatment of panic disorder, obsessive compulsive disorder, social phobia, generalized anxiety disorder and post-traumatic stress disorder. In this chapter the pharmacotherapeutic options for the treatment of these anxiety disorders will be reviewed. We will focus on new developments and not reiterate all the studies performed with old tricyclic antidepressants (TCAs) such as imipramine, as these studies have been mentioned and reviewed in many other textbooks and papers.
Panic disorder (PD) is a chronic and recurring syndrome which requires long-term treatment. The disorder encompasses five essential domains: the panic attacks themselves, the associated anticipatory anxiety, phobic avoidance, and the resultant functional impairment and effects on quality of life. However, the complete resolution of panic attacks, the signal feature of panic disorder, is clearly important to patients. Modern studies on the efficacy in PD should measure symptoms domains outlined above (Shear and Maser, 1994).
Originally, tricyclic antidepressants (TCAs) like imipramine and clomipramine were the first found to be beneficial in panic disorder. Imipramine originally played a role in the sixties in the pharmacological dissection of panic and anxiety, as it was discovered that in patients suffering from anxiety neurosis, panic attacks disappeared during treatment with imipramine. The efficacy of imipramine has been the subject of many studies and this drug was used as a reference drug for years. TCAs, in spite of their proven efficacy, have many drawbacks, including high rates of non-compliance due to anticholinergic side-effects, weight gain, daytime sedation, orthostatic hypotension, lethality in overdose and withdrawal reactions (Wolfe, 1997; Bennett et al., 1998; den Boer, Bosker and Slaap, 2000). After six months treatment with imipramine dry mouth, constipation, sweating was still present as a substantial burden to patients (Mavissakalian and Perel, 2000). It is questionable whether by current standards, TCAs would be marketed if they were introduced today. Many studies have also been performed with BDZs in PD and there is a large database indicating that high potency BDZs such as clonazepam and alprazolam are efficacious in PD. Due to developments in psychopharmacology during the last decade it has, however, been questioned whether BDZs should be the first choice in the treatment of PD in view of their serious side-effects and withdrawal reactions.
There are several placebo-controlled studies suggesting that clonazepam has therapeutic effects in PD. In one of the largest studies with clonazepam conducted so far, Rosenbaum and co-workers (1997) included 413 patients with PD in a fixed-dose placebocontrolled study in a 6-week study followed by a 7-week discontinuation phase. They used dosages ranging from 0.5 mg to 4.0 mg clonazepam daily and found that dosages of clonazepam of 1.0 mg were equally effective in reducing the number of panic attacks. During the discontinuation phase most patients worsened and reported increases in the number of panic attacks. Recently, Valenca et al. (2000) undertook a 6-week placebo-controlled study in 24 PD patients. They found that 11% of the placebo-treated patients were panic free after six weeks, whereas 62% of the clonazepam treated patients were panic free. Because treatment with BDZs has been associated with severe withdrawal reactions, Moroz and Rosenbaum (1999) treated PD patients with 0.25 up to 4.0 mg per day clonazepam for 6 weeks in a double-blind placebo controlled design, followed by a 7-week discontinuation phase during which the doses were gradually tapered. They observed no symptoms suggestive of withdrawal syndrome, nor evidence for rebound during the gradual tapering of clonazepam, but some patients did show worsening of symptomatology, most notably a recurrence of panic attacks. These data show that in the short-term clonazepam is efficacious but treatment in this study was probably too short to achieve full remission of panic attacks. On the other hand, a naturalistic follow-up study for 2 years in 204 patients showed that improvement in global severity of PD did not change during treatment with stable dosages of clonazepam, indicating that there was no development of tolerance (Worthington et al, 1998). In spite of the fact that clonazepam has been marketed in the US for PD, the two pivotal studies did not fulfil all the criteria that were set forth by Shear and Maser (1994), moreover, there is evidence that the higher dosages that are required in many patients are associated with withdrawal symptoms (Davidson et al, 1998).
Two large studies investigating the anxiolytic effects of alprazolam have been conducted in more than 1600 patients suffering from PD. The Cross-National Collaborative Panic Study and the Philadelphia study, which was a maintenance study (Ballenger et al., 1988; Noyes et al, 1988; Pecknold et al, 1988; Rickels et al, 1993; Schweizer et al., 1993). The results of these studies suggested that alprazolam was an effective drug in reducing the number of panic attacks. In spite of these results, these studies were criticized for several points; there was a very high placebo drop-out rate and the average dose was high (mean dose at week 8: 5.6 to 5.8 mg per day). These are important issues as even lower dosages have been shown to lead to impaired recall and other cognitive disturbances (Pomara et al., 1998). In addition, cessation of alprazolam treatment induces