2006 overview: Are treatments combining pharmacotherapy and cognitive-behavioural therapy for anxiety disorders more efficient than either treatment alone?

The efficacy of various psychotropic medications (mainly antidepressants and benzodiazepines) as well as the efficacy of cognitive-behaviour therapy (CBT) for treating anxiety disorders has been established in numerous randomized controlled trials. Since both types of treatment are effective in many patients, it seems reasonable to expect that their combination might enhance the efficacy of either treatment when administered alone. The present review article examines the current status of combination treatments with a focus on randomised controlled trials, meta-analyses and reviews that have been published in 2006.

Panic disorder with or without agoraphobia

In 2006, Furukava et al. (ref. 1) published a meta-analysis involving 21 studies that compare the efficacy of a combination of psychotherapy and antidepressant pharmacotherapy with either treatment alone in patients with panic disorder with or without agoraphobia. With one exception, the psychotherapy administered in the studies was CBT. The authors applied the intention-to-treat principle in their analyses (meta-analyses and meta-regressions) by counting all of the drop-outs as non-responders.

The typical length of the acute-phase active treatment was between 8 and 12 weeks. Nine studies included a follow-up extending over a period of 6-24 months after termination of acute-phase and continuation treatments. In the acute-phase treatment, the combined therapy was superior to antidepressant pharmacotherapy or psychotherapy alone. After termination of the acute-phase treatment, the combined therapy was still more effective than pharmacotherapy alone but no longer more effective than psychotherapy alone.

With regard to the comparison between the combination therapy and antidepressant pharmacotherapy, the combination therapy was found to have no disadvantage in the long term, i.e. there was no evidence for long-term deleterious effects of combined treatments. With regard to the comparison between combination therapy and psychotherapy, there was no evidence of long-term benefit of the former with the latter, i.e. combination treatments were not more effective than CBT alone.

The authors conclude that either combined therapy or CBT alone may be chosen as first-line treatment for panic disorder with or without agoraphobia, depending on the patient's preferences.

Generalized Anxiety Disorder (GAD) and Post-traumatic Stress Disorder (PTSD)

In 2006, no new randomized controlled trials have been published comparing combination treatments with either pharmacotherapy or CBT alone in patients with either GAD or PTSD. The most recent article on combination treatments for GAD and PTSD is by Baldwin and Polkinghorn (ref. 2) who report that it is uncertain whether combination treatments are more efficient for GAD or PTSD than either pharmacotherapy or CBT alone.
 
Obsessive-Compulsive Disorder

In 2006, O’Connor et al. (ref. 3) have reported on the efficacy of combination treatments versus pharmacotherapy or CBT alone and versus placebo in the treatment of OCD. Forty-eight participants (43 completers) were recruited into two protocols. In the first protocol, 21 people with OCD were randomly allocated to either a standard medication (fluvoxamine) or standard placebo condition for a 5-month period.

Both these groups subsequently received CBT for a further 5 months. In the second protocol, 22 people with OCD received CBT, the participants being either stabilized on an antidepressant of choice or drug naive. All active treatments, but not the placebo, showed clinical improvement. In what concerns OCD symptoms there was no difference in treatment response to CBT regardless of whether participants had previously received medication or placebo, but CBT plus medication showed greatest overall clinical improvement in mood.
 
Social phobia

In 2006, the efficacy of combination treatments for social phobia (social anxiety disorder) has been assessed in a new randomized controlled trial by Prasko et al. (ref. 4). The authors conducted a study to assess the 6-months treatment efficacy and 24-month follow up of three different therapeutic programs: moclobemide and supportive guidance, group cognitive-behavioral therapy and pill placebo, and combination of moclobemide and group cognitive-behavioral therapy in patients with a generalized form of social phobia.

81 patients (38 males and 43 females) were randomly assigned to one of the three treatments. 66 patients completed the six month treatment period. 15 patients dropped out. All therapeutic groups showed significant improvement. The combination of CBT and pharmacotherapy yielded the most rapid effect. Moclobemide was superior for the reduction of the subjective general anxiety during the first 3 months of treatment, but its influence on avoidant behavior was less pronounced.

Conversely, CBT was the best choice for reduction of avoidant behavior while a reduction of subjective general anxiety appeared later than in moclobemide. After 6 months of treatment the best results were reached in groups treated with CBT and there was no advantage of the combined treatment. The relapse rate during the 24-month follow up was significantly lower in the group treated with CBT in comparison with the group formerly treated with moclobemide alone.

Novel combination strategies

Three novel combination strategies have recently been explored in the treatment of anxiety disorders: the sequential use of pharmacotherapy and CBT, the combination of virtual reality exposure therapy with pharmacotherapy, and the use of cognitive enhancers such as d-cycloserine in combination with CBT.

In 2006, Heldt et al. (ref. 5) have published one-year outcomes on a sample of 63 patients who completed group CBT for panic disorder after failing to respond adequately to previous pharmacotherapy. Sustained significant benefit was found for all dimensional outcome scores, and nearly two-thirds of the sample met remission criteria. This occurred with reductions in medication use over the follow-up period. The results provide evidence for the efficacy of CBT for medication non-responders with panic disorder.
 
Two new studies published in 2006 provide additional support to previous findings indicating that the efficacy of standard treatments of anxiety disorders may be significantly enhanced using virtual reality exposure therapy. In a case study by Coelho et al. (ref. 6) on virtual reality exposure therapy in acrophobia, participants showed significant progress in anxiety, avoidance, and behavior measurements when confronted with real height circumstances, and the results were maintained at follow-up after one year.

In a controlled clinical trial, Rothbaum et al. (ref. 7)  tested virtual reality exposure therapy (VRET) for the fear of flying (FOF), a relatively new and innovative way to do exposure therapy, and compared it to standard (in vivo) exposure therapy (SE) and a wait list (WL) control with a 6- and 12-month follow-up. Eighty-three participants with FOF were randomly assigned to VRET, SE, or WL. Seventy-five participants, 25 per group, completed the study.

Twenty-three WL participants completed randomly assigned treatment following the waiting period. Treatment consisted of 4 sessions of anxiety management training followed either by exposure to a virtual airplane (VRET) or an actual airplane at the airport (SE) conducted over 6 weeks.

Results indicated that VRET was superior to WL on all measures, including willingness to fly on the post-treatment flight (76% for VRE and SE; 20% for WL). VRET and SE were essentially equivalent on standardized questionnaires, willingness to fly, anxiety ratings during the flight, self-ratings of improvement, and patient satisfaction with treatment.

Follow-up assessments at 6 and 12 months indicated that treatment gains were maintained, with more than 70% of respondents from both groups reporting continued flying at follow-up. Based on these findings, the use of VRET in the treatment of FOF was supported in this controlled study, suggesting that experiences in the virtual world can change experiences in the real world.

The first cognitive enhancer to be used in addition to CBT in the treatment of anxiety disorders is D-cycloserine (DCS), a partial agonist at the N-methyl-d-aspartate receptor that has previously been shown to improve extinction of fear in rodents. Fear reduction in exposure therapy being similar to extinction learning, DCS has been used recently in two investigations, one regarding the treatment of acrophobia, the other the treatment of social phobia, to determine whether DCS will also improve extinction of fear in human phobic patients undergoing behavioral exposure therapy. 

The potential of DCS as an enhancer of exposure therapy was first shown in 2004 by Ressler et al. (ref. 8) in patients with acrophobia.

In 2006, Hofmann et al. (ref. 9) conducted a randomized, double-blind, placebo-controlled augmentation trial examining the combination of DCS or pill placebo with exposure therapy for SAD. 27 participants meeting DSM-IV criteria for SAD with significant public speaking anxiety participated in the trial. Participants received 5 therapy sessions delivered in either an individual or group therapy format.

The first session provided an introduction to the treatment model and was followed by 4 sessions emphasizing exposure to increasingly challenging public speech situations with videotaped feedback of performances. One hour prior to each session, participants received single doses of DCS or placebo. Symptoms were assessed by patient self-report and by clinicians blind to the randomization condition before treatment, after treatment, and 1 month after the last session.

Participants receiving DCS in addition to exposure therapy reported significantly less social anxiety compared with patients receiving exposure therapy plus placebo. Controlled effect sizes were in the medium to large range. 
 
Conclusion

The hope that combination treatments might significantly increase the efficacy of current treatments for anxiety disorders has not been confirmed by recent empirical data. This fact is disappointing, all the more since a substantial proportion of patients do not respond or do not fully respond to either pharmacotherapy or CBT alone.

In the acute phase, current treatments for anxiety disorders combining pharmacotherapy and CBT do not seem to be associated with greater overall efficacy than that achieved with either treatment given alone. In the long-term treatment of anxiety disorders, combination treatments may be more effective than pharmacotherapy alone, but not more effective than CBT alone.   

Data from the recent literature suggest a complex relationship between pharmacotherapy and CBT and highlight the need for more extensive studies, concerning, in particular, the long-term efficacy and effectiveness of combination treatments, the effect of discontinuation of either treatment after combined treatment, and the use of new strategies for combining pharmacotherapy and CBT.

References

1. Furukawa TA, Watanabe N, Churchill R. Psychotherapy plus antidepressant for panic disorder with or without agoraphobia: systematic review. British Journal of Psychiatry 2006; 188; 305-312

2. Baldwin DS, Polkinghorn C. Evidence-based pharmacotherapy of Generalized Anxiety Disorder. International Journal of Neuropsychopharmacology 2005; 8 (2); 293-302. [Epub 2004 Dec 3]

3. O'Connor KP, Aardema F, Robillard S, Guay S, Pelissier MC, Todorov C, et al. Cognitive behaviour therapy and medication in the treatment of obsessive-compulsive disorder. Acta Psychiatrica Scandinavica 2006; 113 (5); 408-419

4. Prasko J, Dockery C, Horacek J, Houbova P, Kosova J, Klaschka J, et al. Moclobemide and cognitive behavioral therapy in the treatment of social phobia. A six-month controlled study and 24 months follow up. Neuro Endocrinology Letters 2006; 27 (4); 473-481

5. Heldt E, Gus Manfro G, Kipper L, Blaya C, Isolan L, Otto MW. One-year follow-up of pharmacotherapy-resistant patients with panic disorder treated with cognitive-behavior therapy: Outcome and predictors of remission. Behaviour Research and Therapy 2006; 44 (5); 657-665. [Epub 2005 Jul 20]

6. Coelho CM, Santos JA, Silverio J, Silva CF. Virtual reality and acrophobia: one-year follow-up and case study. Cyberpsychology & Behavior 2006; 9 (3); 336-341

7. Rothbaum BO, Anderson P, Zimand E, Hodges L, Lang D, Wilson J. Virtual reality exposure therapy and standard (in vivo) exposure therapy in the treatment of fear of flying. Behaviour Therapy 2006; 37 (1); 80-90. [Epub 2006 Feb 24]

8. Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Archives of General Psychiatry 2004; 61 (11); 1136-1144

9. Hofmann SG, Meuret AE, Smits JA, Simon NM, Pollack MH, Eisenmenger K, et al. Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Archives of General Psychiatry 2006; 63 (3); 298-304