DCS is an established drug for the chronic treatment of tuberculosis in humans. It has also been used to improve negative symptoms in schizophrenia (16
), social behavior in autistic disorder (52
), and cognitive functioning in Alzheimer’s disease (62
). Despite some early promise in the treatment of either schizophrenia or Alzheimer’s disease, the weight of the evidence has been disappointing. For example, across 13 studies between 1995 and 2005, no significant effects were obtained in at least half of the trials (49
). Likewise, a systematic review of 4 studies using DCS for Alzheimer’s disease revealed that the drug was generally ineffective (27
). The authors also noted that there was no significant difference between the DCS and placebo treated groups in dropouts due to side effects at any dose. Although the results were disappointing from the efficacy point of view, these studies were reassuring regarding tolerability of DCS, which was used in an elderly and generally medication-sensitive population. As noted, one potential reason for the lack of efficacy for DCS in these trials may be the reliance on chronic rather than isolated dosing strategies.
Exposure-based treatments in humans rely on extinction to treat the core fears underlying anxiety disorders, and the efficacy of DCS in animal models led to the recent application of DCS for humans with anxiety disorders. In an initial effort to demonstrate the utility of DCS as a method to enhance exposure therapy in humans, Ressler and colleagues (56
) randomized 28 subjects with a Diagnostic and Statistical Manual-IV (DSM-IV) diagnosis (1
) of specific phobia of heights (acrophobia) to 2 sessions of virtual reality exposure therapy preceded in double blind fashion by administration of single doses of placebo or DCS (50 or 500 mg) taken 2–4 h prior to each of the sessions. Exposure therapy combined with DCS resulted in significantly larger reductions of acrophobia symptoms at one week and 3 months following treatment with no difference in efficacy between the 2 doses and no reports of adverse effects from DCS administration. Subjects receiving DCS also showed significantly greater decreases in post-treatment skin conductance fluctuations during the virtual exposure and significantly greater improvement compared to placebo on general measures of real-world acrophobia symptoms that was evident early in treatment and was maintained at 3 months.
In another double-blind placebo-controlled study that was conducted at three U.S. sites, 27 patients with a principal DSM-IV diagnosis of social anxiety disorder (social phobia) were assigned to either receive exposure therapy plus DCS (50 mg) or exposure therapy plus pill placebo. The exposure practices of increasing difficulty consisted of giving speeches about topics chosen by the therapists in front of the other group members or confederates and a video camera. At the conclusion of each exposure session, patients were encouraged to continue to apply home-practice strategies (such as giving speeches in front of a mirror). Although treatment primarily focused on public speaking, 51.9% of the subjects had a generalized subtype of social anxiety disorder, and 40.7% had at least one additional DSM-IV Axis I diagnosis. The level of social anxiety was assessed at baseline, post-treatment, and one month after the last session (1-month follow-up). The primary treatment outcome measure was the Social Phobia and Anxiety Inventory (SPAI; 64). Additional measures included the Liebowitz Social Anxiety Scale (36
), and the Clinical Global Impression Scale, Severity (22
). As shown in , the difference between the DCS and placebo group increased linearly with time, with the greatest treatment effects of DCS being evident at follow-up. Similar results were found for the other measures.
Fig. 1 Means and standard errors of self-reported social anxiety among treatment completers. Figure reprinted from ref. 24 with permission from American Medical Association.
Together, the clinical outcome studies by Hofmann et al. (24
) and Ressler et al. (56
) provide support for the use of DCS as augmentation treatment of exposure therapy in patients with anxiety disorders. In contrast, research with nonclinical adults has yet to document an advantage for DCS augmentation of exposure. In particular, Gaustella and colleagues have conducted two sets of studies of DCS with nonclinical participants. In the first series of studies, the authors examined the effects of DCS vs. placebo in enhancing extinction in a de novo
fear conditioning paradigm (20
). No effect for DCS was found when fear acquisition and extinction were conducted on the same day. Likewise, in a revised design using fear-relevant stimuli (i.e., pictures of snakes for snake-anxious participants) and the separation of acquisition and extinction on separate days, no effect for DCS was evident.
Furthermore, Guastella and colleagues (20
) used DCS in two studies of spider-fearful participants treated in a single session with information, cognitive-therapy, and up to two hours of exposure. All participants tended to respond well (e.g., in one study all participants were able to complete a post-treatment exposure test), and no difference between DCS and placebo augmentation was evident. These disappointing results may well be explained by the use of non-clinical participants and relatively strong (for the task) exposure interventions. In de novo
fear conditioning, little extinction is commonly required to return healthy participants to pre-conditioning levels of arousal (46
), and in the treatment of non-clinical as well as clinical fears of spiders, single session interventions lead to significant and long lasting changes (47
). By way of contrast, studies showing a successful DCS enhancement effect (24
) utilized clinical fears and one-third to one-half the standard number of exposure sessions. In reducing the strength of exposure interventions, these studies were fully in line with the animal research, where only half the standard number of extinction trials is used to allow sufficient levels of residual fear to detect the DCS enhancement effect (66
Accordingly, in the studies by Guastella and colleagues (19
) the combination of weak levels of fear (i.e., de novo
and non-clinical fears), combined with relatively strong exposure interventions may have created extinction conditions where there was little room to show DCS enhancement due to ceiling effects. Nonetheless, the studies by Guastella and associates do provide a challenge to the field to better identify the setting conditions where strong DCS effects can be observed.