treatment studies with drugs support the need for chronic treatment for more than a year for relapse prevention [6,8]. REFERENCES 1. Versiani M. (submitted) The long-term drug treatment and follow-up of over 250 patients with social anxiety disorder (social phobia) over 10 years. 2. Versiani M. (2000) A review of 19 double-blind placebo-controlled studies in social anxiety disorder (social phobia). World J. Biol. Psychiatry, 1: 27–33. 3. Liebowitz M.R. (1999) Update on the diagnosis and treatment of social anxiety disorder. J. Clin. Psychiatry, 60 (Suppl. 18): 22–26. 4. Versiani M., Amrein R., Montgomery S.A. (1997) Social phobia: long-term treatment outcome and prediction of response—a moclobemide study. Int. Clin. Psychopharmacol., 12: 239–254. 5. Stein D.J., Versiani M., Hair T., Kumar R. (2002) Efficacy of paroxetine for relapse prevention in social anxiety disorder: a 24-week study. Arch. Gen. Psychiatry, 59: 1111–1118. 6. Keller M.B. (2002) Raising the expectations of long-term treatment strategies in anxiety disorders. Psychopharmacol. Bull., 36 (Suppl. 2): 166–174. 7. Katerndahl D.A. (2000) Predictors of the development of phobic avoidance. J. Clin. Psychiatry, 61: 618–623. 8. Katschnig H., Amering M. (1998) The long-term course of panic disorder and its predictors. J. Clin. Psychopharmacol., 18 (Suppl. 2): 6S–11S. 9. Kampman M., Keijsers G.P., Hoogduin C.A., Hendriks G.J. (2002) A random- ized, double-blind, placebo-controlled study of the effects of adjunctive paroxetine in panic disorder patients unsuccessfully treated with cognitive- behavioral therapy alone. J. Clin. Psychiatry, 63: 772–777. 3.13 Behavioural Toxicity of Pharmacotherapeutic Agents Used in Social Phobia Ian Hindmarch and Leanne Trick 1 Stein et al. have identified a wide range of different medications which have been found to be useful therapeutic agents for the management of social phobia. All psychoactive drugs, by definition, change behaviour. While appropriate behavioural changes (a reduction in social anxiety and reduction in avoidance behaviours) would be regarded as positive evidence of clinical efficacy, impairment of cognitive and psychomotor functions, which reduce the patient’s overall quality of life, would be seen as 172 __________________________________________________________________________________________ PHOBIAS 1 Human Psychopharmacology Research Unit, Medical Research Centre, University of Surrey, Egerton Road, Guildford, Surrey GU2 7XP, UK unwanted side effects. Behavioural toxicity refers not only to the extent to which these side effects raise the likelihood of a patient having an accident or cognitive failure while receiving pharmacotherapy, but also to the magnitude of countertherapeutic effects (e.g. somnolence, sleep disturb- ance, memory loss, loss of balance etc.) produced by a particular medication. As behavioural toxicity is an intrinsic property of the pharmacothera- peutic agent, it is assessed in those subjects who are not impaired or suffering from a clinical condition or disorder that, in itself, could change performance on the relevant psychometric. Behavioural toxicity measures are derived from psychometric assess- ments of the effects of drugs on psychomotor and cognitive function. These include tests of memory, sensory speed, mental arithmetic, information processing capacity, mental speed, vigilance, divided attention, reaction time, balance, motor control, motor coordination, manual dexterity, car driving ability etc. In isolation, a singular assessment of the pharmacodynamics of a particular compound reveals little in absolute terms about the behavioural toxicity of that drug. However, if a database is constructed from the totality of information available from reports in peer-reviewed journals, then a reliance can be made on the results of such a ‘‘meta-analysis’’. The present summary reviews the data contained in 90 studies from peer- reviewed literature featuring the drugs found by Stein et al. to have a proven utility in the management of social phobia. To be included in the analysis, the res ults had to be from cross-over studies with placebo controls and where the sensitivity of the psychometrics employed was confirmed by the results from an internal positive control (verum). No acceptable data were found for phenelzine, tranylcypromine, selequine and escitalopram. These drugs are, therefore, removed from further consideration. Data presented in Table 3.13.1 refer to the number of objective psychometrics used in the various studies to assess a particular drug. We include the number of instances in which a statistically significant impairment of cognitive and/or psychomotor function is reported, as well as the total number of tests performed on that particular compound. The number of instances where the results showed no significant impairment from placebo can be deduced from the difference of the two values. In order to compare a discrete clinical entity with the totality of drugs in the database, i.e. the extent to which a particular drug produces behavioural toxicity (impairment of the various psychometrics) when compared to all other drugs in the database, a proportional impairment ratio (PIR) is calculated for each substance. PHARMACOTHERAPY OF PHOBIAS: COMMENTARIES _____________________________ 173 The calculation of the PIR is adapted from that used in pharmaco- vigilance [1] and has been previously used successfully in rating the sedative potential of antihistamines [2]. The greater the PIR, the greater the behavioural toxicity. If the PIR value is less than uni ty (1.00), then that particular drug is less behaviourally toxic than the other members of the group. Unit y represents parity with the group and a PIR greater than 1.0 represents a proportionally greater behavioural toxicity than the group (e.g. fluvoxamine and buproprion have no measurable behavioural toxicity, moclobemide possesses a third of the behavioural toxicity of the group as a whole, venlafaxine is as behaviourally toxic as the average for the group, and alprazolam is twice as behaviourally toxic as the average). There are many reasons as to why a particular drug may benefit an individual patien t, but the use of a PIR can identify those substances, other things being equal, which may prove countertherapeutic or increase the chance of accident or cognitive failure. While PIRs may not necessarily be the principal guide for prescribing a particular substance, there is sufficient cause for concern regarding the impact of psychoactive drugs on a patient’s safety and quality of life to seriously consider suc h ratings of a drug’s intrinsic behavioural toxicity when using pharmacotherapy to manage patients suffering from social phobias. 174 __________________________________________________________________________________________ PHOBIAS TABLE 3.13.1 Proportional Impairment Ratios (PIR): behavioural toxicity of drugs used in the management of social phobia Drug No. Studies No. Tests No. Tests Impaired PIR Fluvoxamine 8 168 0 0.00 Buproprion 4 42 0 0.00 Gabapentin 2 164 1 0.03 Fluoxetine 6 90 3 0.15 Clomipramine 2 63 4 0.29 Moclobemide 7 136 10 0.33 Buspirone 11 156 24 0.70 Olanzapine 2 82 16 0.90 Venlafaxine 2 36 8 1.00 Paroxetine 4 26 6 1.10 Atenolol 9 217 53 1.10 Nefazadone 2 62 19 1.40 Sertraline 4 190 64 1.60 Clonazepam 3 76 26 1.60 Alprazolam 24 781 236 2.20 REFERENCES 1. Stather R. (1998) Update on collecting ADRs and new methods of signal generation. Reactions, 718: 3–5. 2. Shamsi Z., Hindmarch I. (2000) Sedation and antihistamines: a review of inter- drug differences using proportional impairment ratios. Hum. Psychopharmacol. Clin. Exper., 15: S3–S30. 3.14 Medication Treatment of Phobias: Theories Hide Effectiveness James C. Ballenger 1 Stein et al. have done a masterful job with the difficult assignment to review the medication treatment of phobias. They summarize the rich literature on the various med ications which are effective in social phobia, a syndrome that is better described as social anxiety disorder, i.e. anxiety specifically about being in social situations which patients secondarily phobically avoid. We now know from controlled trials that both sertraline and venlafaxine are effective in this syndrome. Whether venlafaxine will prove to be more effective than the other antidepressants in social anxiety disorder, as it appears to be in depression, is an important research issue. The medication treatment of agoraphobia without panic disorder is difficult to discuss, because it almost never appears in that form in treatment settings and therefore there are almost no valid studies. Agoraphobia without a history of panic disorder appears largely in epidemiologic surveys but, when studied clinically, many patients actually have subthreshold or full panic disorder. Finally, studies of simple phobia are sparse, because predominant theories have literally inhibited exploration of this area. Recent studies suggest that patients with this disorder are in fact responsive to traditional anti-anxiety medications such as selective serotonin reuptake inhibitors (SSRIs). This is an important finding, because simple phobias are actually the most common mental disorders. Although most are not clinically significant, many do involve significant avoidance (phobic) behaviours which are personally and occupationally disabling. Perhaps the most common is flying phobia, which can significantly hamper some individuals. Similarly, some individuals who fear single objects like spiders and snakes PHARMACOTHERAPY OF PHOBIAS: COMMENTARIES _____________________________ 175 1 Department of Psychiatry, University of South Carolina, 67 President St., Charleston, SC 29425, USA can have significant interference with their lives if they live in areas where exposure to them is likely. Also, certain apparently single/simple phobias like using a public toilet or writing a cheque in public are often pieces of a broader syndrome like social anxiety disorder. Similarly, cultural issues can obscure the true nature of some anxious, phobic behaviour. In Japan, taijin-kyofusho is often considered to be a different syndrome from social anxiety disorder. However, in my meetings with Japanese psychiatrists on this issue, it seems quite clear that it is only superficially different and in fact is the same disorder. Early evidence suggests it is in fact SSRI responsive. It is clear that medications work, but how well? There is the ‘‘rule of thirds’’ here as in many things. In recent trials, usually a third have an excellent response, one third a partial response, and about a third little to no response. The emerging consensus is that we certainly should be treating to remission, i.e. complete or almost complete resolution of symptoms and any functional impairment [1,2]. Remission is what each patient wants, and this is the goal which should guide clinician treatment choices. Clinicians need to continue aggressive treatment until remission is either achieved or realistically seems unattainable. There are increasing data in the anxiety field that treatment beyond the acute phase (6 to 12 weeks) leads to increasing numbers of patients who actually experience a remission. In generalized anxiety disorder, approximately a third of patients reach remission in 6 to 12 weeks, whereas treatment for 6 months generally doubles the number [3]. This requires clinicians to change how they think about partial remission. Whereas most patients and clinicians conclude that a treatment for 6 to 8 weeks is sufficient to determine optimal response, many partial responders will become complete respond ers if treated for 6 months. We should probably contin ue treatment in partial responders, rather than switch to another agent. Stein et al. also touch on an absolutely critical question, i.e. whether treating anxiety disorders which begin in childhood, suc h as social anxiety and panic disorder, could block the full evolution of the adult syndrome and its consequences. Could the low educational and vocational entertain- ment, lower rates of marriage, and high rates of substance abuse and depression in social anxiety disorder be prevented by effective treatm ent of these children? This is a critical question with a disorder that ultimately affects 13% of the population. However, our general unwillingness to treat children with medications has slowed the exploration of this important question. Stein et al. also touch on the issue that although cognitive-behavioural therapy has been demonstrated to be effective in carefully controlled trials, it remains unclear which patients should be treated with psychotherapy alone or in combination with medications. In many 176 __________________________________________________________________________________________ PHOBIAS instances, combination treatment has been demonstrated to have greater efficacy, although this has not been a consistent finding. The larger problem is that cognitive-behavioural therapy is simply unavailable in most cities. However, the delivery of this treatment by manuals or computer programs is under development and is a promising approach to this critical problem. REFERENCES 1. Ballenger J.C. (1999) Clinical guidelines for establishing remission in patients with depression and anxiety. J. Clin. Psychiatry, 60 (Suppl. 22): 29–34. 2. Ballenger J.C. (2001) Treatment of anxiety disorders to remission. J. Clin. Psychiatry,62(Suppl. 12): 5–9. 3. Ballenger J.C., Tylee A. (2003) Anxiety. Mosby, London. PHARMACOTHERAPY OF PHOBIAS: COMMENTARIES _____________________________ 177 _________________________ 4 Psychotherapeutic Interventions for Phobias: A Review David H. Barlow, David A. Moscovitch and Jamie A. Micco Center for Anxiety and Related Disorders at Boston University, 648 Beacon Street, Boston, MA 02215-2002, USA INTRODUCTION There have been considerable advancements in the development of empirically supported treatments for phobias over the past three decades. Prior to the advent of exposure-based treatments for agoraphobia, social phobia and specific phobia, relatively little was known about the application of psyc hotherapeutic interventions to relieve the suffering of individuals who were diagnosed with these disorders. Below, we will provide a critical, comprehensive review of the treatment outcome literature for each of these disorders. We will also describe patient and other treatment variables that may influence therapy response and relapse rates. Finally, we will sum marize the empirical literature as it currently stands and provide directions for future research. AGORAPHOBIA AND PANIC Individuals with panic disorder and agoraphobia experience significant interference in social, occupational and physical aspects of their lives [1,2]. This interference signifies the importance of researching and disseminating the most effective treatments for these individuals. Since the development of agoraphobia is nearly always preceded by full-blown or limited- symptom panic attacks [3,4], it is often necessary to address panic in the Phobias. Edited by Mario Maj, Hagop S. Akiskal, Juan Jose ´ Lo ´ pez-Ibor and Ahmed Okasha. &2004 John Wiley & Sons Ltd: ISBN 0-470-85833-8 _________________________________________________________________________________________________ CHAPTER treatment of agoraphobia. Over the past several decades, however, it has been traditional to separate treatments for agoraphobia and panic disorder into two categories: (a) treatments for agoraphobia and other avoidance behaviours; and (b) treatments targeting panic attacks and anxiety focused on pan ic [5]. The review of psychosocial treatments presented here will follow this tradition, beginning with treatments for agoraphobia. Agoraphobia Initial treatments for agoraphobia were developed in the 1960s and 1970s. These mainly consisted of systematic desensitization, with little attention given to panic attacks [6]. Systematic desensitization involves imaginal exposure to the feared situation, simultaneously accompanied by muscle relaxation. This techn ique was used primarily because it was thought that actual exposure to feared situations would be too overwhelming for agoraphobic patients. However, studies evaluating the use of systematic desensitization for treatment of agoraphobia have found the technique to be ineffective [7,8]. Around the same time, some researchers began success- fully treating people with agoraphobia using in v ivo exposure [9], whereby patients were encouraged to venture away from ‘‘safe places’’ and enter their feared situations. Since then, in vivo exposure has become the most widely studied psychotherapy for agoraphobia. Basic Components of In Vivo Exposure In vivo exposure begins with the construction of a hierarchy of situations that the agoraphobic individual fears and avoids, arranged from least to most frightening. Common items on a fear and avoidance hierarchy include ‘‘driving alone on the highway’’, ‘‘eating at a crowded restaurant’’, ‘‘shopping at the mall’’ and ‘‘riding on the subway’’. Patients are then encouraged to repeatedly and systematically enter the situations on their hierarchy and remain in the situations for as long as possible, often with the use of coping strategies learned in session. Although the pres ence of the therapist during in vivo exposure may be necessary for it to be effective with severely agoraphobic individuals [10], those with mild to moderate levels of agoraphobia are usually able to engage in exposures on their own or with a friend or family member serving as a supportive coach [5]. 180 __________________________________________________________________________________________ PHOBIAS Efficacy of In Vivo Exposure Research has consistently supported the efficacy of in vivo exposure for treating agoraphobia. By the mid-1980s, studies revealed that 60–70% of agoraphobic patients who completed in vivo exposure treatment showed significant clinical improvement, with follow-up assessments indicating that treatment gains were maintained for four or more years [11–17]. These results were replicated in several controlled studies, which used no- treatment or placebo control groups [18–20]. In vivo exposure for agoraphobia has been the subject of more recent research as well. Fava et al. [21] completed a long-term follow-up study of 90 patients who received 12 sessions of graduated, self-paced exposure treatment, conducted biweekly over a 6-month period. At post-treatment assessment, 87% were panic-free and ‘‘much improved’’ on global clinical measures. The authors used survival analysis to predict the probability that treatment responders would remain in remission, and they determined that 96% of treatment responders remained panic-free through the first two years, 77% through five years, and 67% through seven years. Predictors of relapse in this study included the presence of residual agoraphobia and comorbid personality disorders; this finding emphasizes the importance of thoroughly treating all vestiges of avoidance before termination. A number of studies have shown that other cognitive-behavioural techniques combined with in vivo exposure are no more effective for the treatment of agoraphobia than in vivo exposure alone [22–24]. On the other hand, one study by Michelson et al. [25] showed that the addition of cognitive therapy to situational exposure can be significantly beneficial to people with agoraphobia and panic, especially when compared to exposure treatment plus relaxation training. Other controlled studies have shown that relaxation or breathing exercises confer no treatment advantage over in vivo exposure [26–28]. A study by Schmidt et al. [28] suggested that patients with panic disorder and agoraphobia receiving breathing retraining tended to have lower end-state functioning at follow-up when compared to patients not receiving breathing retraining. These findings suggest that breathing retraining and relaxation training may put patients with panic and agoraphobia at risk for relapse, perhaps because the exercises teach patients to minimize and distract from physical sensations during situational exposure, with breathing and relaxation becoming ‘‘safety behaviours’’ [5]. Combined In Vivo Exposure and Pharmacotherapy A number of studies have studied the efficacy of in vivo exposure combined with tricyclic antidepressants, with most studies showing that the combined PSYCHOTHERAPEUTIC INTERVENTIONS FOR PHOBIAS: A REVIEW ___________ 181 [...]... 2: 66 5 66 9 de Ruiter C., Rijken H., Garssen B., Kraaimaat F (1989) Breathing retraining, exposure, and a combination of both in the treatment of panic disorder with agoraphobia Behav Res Ther., 27: 66 3 67 2 Schmidt N.B., Woolaway-Bickel K., Trakowski J., Santiago H., Storey J., Koselka M., Cook, J (2000) Dismantling cognitive-behavioral treatment for 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27... plus self-exposure at mid-treatment (8 weeks), post-treatment ( 16 weeks) and 12-month follow-up on a composite measure of social phobia symptom severity that included both patient self-report and clinician-administered ratings Patients in the medication and placebo conditions showed small but equal improvements on the composite measure of social phobia at the midand end-point assessments At post-treatment,... treatment compared to non-prescriptive treatment of panic disorder Arch Gen Psychiatry, 51: 395–401 PSYCHOTHERAPEUTIC INTERVENTIONS FOR PHOBIAS: A REVIEW 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 _ 205 Shear M.K., Houck P., Greeno C., Masters S (2001) Emotion-focused psychotherapy for patients with panic disorder Am J Psychiatry, 158: 1993–1998 Milrod B., Busch F., Leon A.C., Aronson A., Roiphe... treatments: (a) a single session of therapist-assisted exposure, (b) a spider phobia-specific self-help manual used at home, (c) a spider phobiaspecific self-help manual used at the clinic, (d) a non-specific self-help manual used at home, and (e) a non-specific manual used at the clinic The percentages of patients showing significant improvement were 80%, 10%, 63 %, 9% and 10%, respectively These results... 14: 545–5 56 Burns L.E., Thorpe C.L., Cavallaro L.A (19 86) Agoraphobia 8 years after behavioral treatment: a follow-up study with interview, self-report, and behavioral data Behav Ther., 17: 580–591 Cohen S.D., Monteiro W., Marks I.M (1984) Two-year follow-up of agoraphobics after exposure and imipramine Br J Psychiatry, 144: 2 76 281 Emmelkamp P.M.G., Kuipers A.C.M (1979) Agoraphobia: a follow-up study... Using massed exposures over a ten-day period to treat severely agoraphobic patients, Feigenbaum [ 46] compared ungraded to graded exposures and found that both were equally effective at posttreatment and eight-month follow-up At five-year follow-up, however, PSYCHOTHERAPEUTIC INTERVENTIONS FOR PHOBIAS: A REVIEW _ 183 ungraded exposures proved to be more effective The long-term efficacy of ungraded exposures... agoraphobia: a two-year naturalistic follow-up Acta Psychiatr Scand., 99: 59 67 Emmelkamp P.M.G., Ultee K.A (1974) A comparison of ‘‘successive approximation’’ and ‘‘self-observation’’ in the treatment of agoraphobia Behav Ther., 5: 60 6 61 3 Emmelkamp P.M.G., Wessels H (1975) Flooding in imagination vs flooding in vivo: a comparison with agoraphobics Behav Res Ther., 13: 7–15 Hafner R.J (19 76) Fresh symptom... treatment of emotional disorders Clin Psychol.: Sci Pract., 6: 80–94 Feigenbaum W (1988) Long-term efficacy of ungraded versus graded massed exposure in agoraphobics In Panic and Phobias: Treatments and Variables 204 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 PHOBIAS Affecting Course and Outcome (Eds I Hand, H Wittchen), pp 83–88 SpringerVerlag, Berlin... were assessed at pre- and post-treatment, and at 6- month follow-up on a number PSYCHOTHERAPEUTIC INTERVENTIONS FOR PHOBIAS: A REVIEW _ 191 of measures, including self-report questionnaires and behavioural tests The findings indicated that none of the variables predicted treatment outcome across every domain of measurement, and subsequent studies have corroborated these results [1 06, 107] However, of... treatment for social phobia: a meta-analysis Behav Ther., 26: 69 5–720 Taylor S (19 96) Meta-analysis of cognitive-behavioral treatments for social phobia J Behav Ther Exp Psychiatry, 27: 1–9 Gould R.A., Buckminster S., Pollack M.H., Otto M.W., Yap L (1997) Cognitivebehavioral and pharmacological treatment for social phobia: a meta-analysis Clin Psychol Sci Pract., 4: 291–3 06 Federoff I.C., Taylor S (2001) . 16 0.90 Venlafaxine 2 36 8 1.00 Paroxetine 4 26 6 1.10 Atenolol 9 217 53 1.10 Nefazadone 2 62 19 1.40 Sertraline 4 190 64 1 .60 Clonazepam 3 76 26 1 .60 Alprazolam 24 781 2 36 2.20 REFERENCES 1. Stather. PIR Fluvoxamine 8 168 0 0.00 Buproprion 4 42 0 0.00 Gabapentin 2 164 1 0.03 Fluoxetine 6 90 3 0.15 Clomipramine 2 63 4 0.29 Moclobemide 7 1 36 10 0.33 Buspirone 11 1 56 24 0.70 Olanzapine 2 82 16 0.90 Venlafaxine. 36 (Suppl. 2): 166 –174. 7. Katerndahl D.A. (2000) Predictors of the development of phobic avoidance. J. Clin. Psychiatry, 61 : 61 8 62 3. 8. Katschnig H., Amering M. (1998) The long-term course of