are few and are limited by methodological issues. However, Cox et al. (1993) reported equal efficacy in a meta-analysis. Despite the fact that biological interventions are more efficacious for OCD patients, psychodynamic factors might be of considerable benefit in understanding what precipitates exacerbations of the disorder and in treating various forms of resistance to treatment, such as noncompliance to medications or to homework assignments. Symptoms may hold important psychological meanings that make patients reluctant to give them up. Therefore, a psychological assessment of the patient’s resistance to treatment may improve compliance. In the absence of controlled studies of insight-oriented psychotherapy for OCD, the anecdotal reports reporting lasting change do not enable a generalization of its efficacy. Also, the efficacy of medications in producing rapid improvement has rendered slow and long-term psychotherapy out of favor. Non-specific approaches, such as supportive psychotherapy, have a place in OCD and may help patients improve their functioning and adjustment. Management should also include attention to family members through the provision of emotional support, reassurance, education, and advice on how to cope with and respond to the patient. Family therapy may reduce marital discord and build a treatment alliance, also to help in the resistance to compulsions. Group therapy is useful for providing a support system for some patients. TREATMENT-RESISTANT OCD Despite the abundance of reports concerning the efficacy of various agents in OCD, about 20–30% of patients do not respond at all and another 20–30% display only partial response. Possible reasons for treatment refractoriness in OCD are presented below, according to Goodman et al. (1993). ∑ Inadequacy of trial ∑ duration too short? ∑ dose too low? ∑ impaired absorption/increased metabolism? ∑ noncompliance? ∑ Coexisting condition limits drug efficacy ∑ Incorrect diagnosis? ∑ Exogenous countertherapeutic influences ∑ family environment? ∑ antiexposure instructions? ∑ Underlying biological heterogeneity ∑ OCD as a syndrome with multiple etiologies ∑ Search for putative subtypes In treating these partial or complete non-responders, sound clinical choices are called for. However, as well-controlled, double-blind studies are lacking, many of these 178 ————— I. IANCU, Y. SASSON, N. NAKASH, M. CHOPRA AND J. ZOHAR clinical decisions are based on case reports and uncontrolled studies, and therefore, these recommendations should be treated cautiously. Athough the focus here is on the pharmacological approach, we suggest that in cases of partial or non-response, an attempt should be made to combine behavioral therapy (BT) with the pharmacological treatments. BT involves imaginary flooding and in vivo exposure and response prevention. In cases of non-response, family therapy, too, should be suggested, in order to assess the family dynamics and to determine whether there is a family member who cooperates with the patient’s disorder—for example, impedes exposure trials—hence preventing any improve- ment. Switching Medications If the patient could not tolerate adequate doses of SSRIs or has not responded to SSRI administered in the upper range of the relevant dose, a trial of CMI is recommended (and vice versa). CMI should be given after an adequate work-up that includes an ECG and ruling out ophthamological problems (i.e. closed angle glau- coma). Although no fixed dose studies were carried out, it seems that high doses of CMI are needed in order to attain responses in OCD patients. The titration to these doses should last for 1–3 weeks. If possible, therapeutic drug monitoring should be performed in order to ascertain blood levels (200–500 ng/ml) for the parent drug plus the desmethyl derivative and to avoid side-effects that result from very high (or even toxic) blood levels. If tolerated, a dose of 200–300 mg/day is considered efficacious in OCD, and this dose would be administered for 10 weeks before determining a lack of response. Caution is necessary if CMI is administered immediately after fluoxetine; in this case, lower initial doses of CMI should be the rule, due to fluoxetine’s long half-life and the fact that it inhibits cytochrome P450 enzymes (thus increasing the availability of CMI). Switching from SSRIs, with shorter half-lives and less inhibition of cytoch- rome P450 enzymes (such as fluvoxamine and sertraline) to CMI is less problematic. However, the common procedure of slow titration is recommended. Neuroleptics If the diagnosis is OCD and a tic disorder, small doses of pimozide or haloperidol, in addition to the serotonergic drug are associated with a higher therapeutic response. Augmentation Augmentation is called for when there is partial or no response to the above- mentioned approaches, i.e. combination of SSRIs (or SRIs) with other medications. OBSESSIVE-COMPULSIVE DISORDER: BIOLOGY AND TREATMENT ——— 179 To date, only two augmenting agents have been found to be effective in double-blind studies, i.e., risperidone and pindolol, which will be discussed below. However, many other augmenting agents have been tried and may be effective for some refractory patients. These include buspirone, lithium, trazodone, tryptophan and thyroid hor- mones. Risperidone Risperidone in small doses—one to two mg twice a day—was found in one double- blind and three open studies to be effective in alleviating OC symptoms in some partial or non-responders (Ravizza et al., 1996). Pindolol Pindolol augmentation (2.5 mg of pindolol, three times daily) with SSRIs is the second augmenting agent which has been found in double-blind studies to be effective and thus might be placed quite high on the list of augmenting agents (Dannon et al., 2000). However, it appears to give an extra ‘‘push’’ to partial responders rather than actually turning non-responders into responders. Other Options As OCD is considered an anxiety disorder by the DSM-IV (but not by the ICD-10), it is not surprising that anxiolitics have been suggested in the treatment of OCD patients. Thus, alprazolam and clonazepam have been reported as efficient in several uncontrolled studies and case series, and even in a small double-blind randomized, multiple cross-over study. However, since OCD is a chronic disorder, the use of anxiolitics for long periods raises questions of dependency brought about by long- term use of benzodiazepines. Despite reports in open studies regarding the efficacy of trazodone, buspirone and lithium, the results in double-blind studies were negative. Adding drugs affecting dopamine function, especially atypical antipsychotics (risperidone), to SRI therapy in treatment-resistant OCD patients, resulted in improvement in patients with a per- sonal or family history of tics (McDougle et al., 1997). Thyroid supplementation has been reported to be efficacious in open trials as adjunctive agents to SRIs. However, the efficacy of this agent in OCD was not confirmed in a controlled study (Pigott et al., 1991). Clonidine, an alpha-2 adrenergic agonist, has been reported to be effective in treating OC symptoms in the context of Tourette’s syndrome (Cohen et al., 1980) and there are reports of improvement in typical OCD patients (Hollander et al., 180 ————— I. IANCU, Y. SASSON, N. NAKASH, M. CHOPRA AND J. ZOHAR 1988). However, there are no controlled data to support this agent’sefficacy and its side-effect profile discourages its use in OCD. Intravenous Clomipramine Several studies reported on the efficacy of intravenous CMI with intractable OCD. This strategy includes daily infusions of CMI for circa 14 days, the maximum dose being 325 mg. Monoamine Oxidase Inhibitors (MAOIs) A placebo-controlled trial of fluoxetine and phenelzine for OCD provides no evi- dence to support the use of phenelzine in OCD except possibly for patients with symmetry-related or other atypical obsessions. An earlier controlled, comparative study of CMI and clorgyline, a reversible MAO-A inhibitor, also failed to show any beneficial effect of MAOIs. Only one small, controlled study, which compared phenelzine and CMI (without placebo) suggests that they are similar. Doses of phenelzine up to 90 mg/day should be used for at least 10 weeks. As some OCD patients may be hypersensitive to the activation of their serotoner- gic systems, specific attention should be paid, on the one hand, to the dangerous combination of SSRIs and MAOIs, and, on the other hand, to the longer wash-out periods for serotonergic medication needed by OCD patients before initiating MAO treatment. Hence the wash-out period needed for discontinuation of CMI and other SSRIs having a relatively short half-life (such as fluvoxamine and sertraline) for OCD patients should be at least four weeks, whereas with fl uoxetine it should be even longer (at least six weeks). Last-line Therapies The evidence accumulated so far with regard to Electroconvulsive Therapy (ECT) is not compelling, and altogether, it seems that the pure anti-obsessional effect of ECT is questionable. ECT should probably be reserved for the symptomatic (antidepress- ive) treatment of severely depressed and suicidal OCD patients. Neurosurgery has been reported to be effective in some OCD patients, with procedures that disconnect the outflow pathways originating from the orbitofrontal cortex. Cingulotomy can help some intractable patients, but while immediate results may be striking, the long-term prognosis is more reserved (Jenike et al., 1991). A treatment algorithm for resistant OCD is presented in Figure 9.1. OBSESSIVE-COMPULSIVE DISORDER: BIOLOGY AND TREATMENT ——— 181 Decision 1: Comorbid Tic and OCD Add neuroleptic Decision 2: Switching SSRI < –– > CMI Decision 3: Augmentation Lithium Antipsychotic medications Thyroid hormone Tryptophan Buspirone Trazodone Decision 4: Other options I.V. CMI MAOInh Clonazepam Clonidine Atypical neuroleptics Decision 5: Decision 6: ECT Neurosurgery SSRIs or CMI TH FIGURE 9.1 Treatment decisions for resistant OCD Review of Treatments in OCD The first-line treatment consists of either an SSRI or a CMI. One of the five SSRIs provides an effective and safe option. The choice of a particular SSRI depends on the drug’s pharmacokinetic profile, as well as on the physician’s acquaintance with the drug. The dose should be higher than in depression (40–60 mg fluoxetine, for example) and the trial should last at least 12 weeks. In choosing CMI, cardiovascular problems and closed angle glaucoma should first be ruled out. Doses of 200–300 mg of CMI are needed. Titration should last for 1–3 weeks and this dose should be continued for at least 12 weeks before determining response. If the patient cannot tolerate the first drug (i.e. SSRI) or did not respond, a trial of a drug from the other group is advised (CMI and vice versa). If the first line was a SSRI, CMI should be administered. The third stage in non-responders and in cases of partial response, includes small doses of antipsychotics (especially in TS), a combina- tion of SRIs and CMI, the addition of lithium or trazodone, buspirone or tryptophan. The fourth stage consists of either atypical neuroleptics, thyroid supplementation, clonidine, MAOIs, I.V. CMI, or clonazepam. In resistant cases, ECT or neurosur- gery should be tried. CONCLUSION Until 20 years ago, the approach to treating OCD was characterized by pessimism. 182 ————— I. IANCU, Y. SASSON, N. NAKASH, M. CHOPRA AND J. ZOHAR Since then, effective treatments have been developed, using BT and the SRIs. Although introduced for OCD in 1967, it was only in the 1980s that double-blind studies confirmed the efficacy of CMI, an SRI. This was followed by the further introduction of the SSRIs, which also proved effective for OCD. The antiobsessive activity of these drugs was found to be independent from the drug’s antidepressant effect, as established by efficacy in both depressed and non-depressed patients. Overall, serotonergic therapies have enabled a better outlook for these patients and have enlarged our understanding of the pathophysiology of OCD (Zohar and Insel, 1987; Dolberg et al., 1996). Previously thought to be a rare and untreatable disorder, OCD is now recognized as common, and there is now good reason to expect that OCD patients will benefit substantially from behavior therapy and potent SRIs. Many OCD patients do not seek treatment and the illness tends to be chronic. There is a 10-year lag between the onset of symptoms and the seeking of professional help, due to feelings of embarrassment. Further delay is often the case until correct diagnosis and treatment are obtained (Hollander, 1997). US census data suggest that over 8 billion dollars are spent each year on the management of OCD, one-fifth of that spent on cardiac disease (DuPont et al., 1995). 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(1989) Anxiety and cerebral blood flow during behavioral challenge. Arch Gen Psychiatry 46: 505–510. Zohar J, Judge R (1996) Paroxetine versus clomipramine in the treatment of obsessive- compulsive disorder. Br J Psychiat 169: 468–474. 186 ————— I. IANCU, Y. SASSON, N. NAKASH, M. CHOPRA AND J. ZOHAR ———————————————————————————————— CHAPTER 10 Generalised Anxiety Disorder N. Caycedo and E.J.L. Griez Barcelona, Spain and Maastricht University, Maastricht, The Netherlands INTRODUCTION: ABOUT A DISPUTED CONCEPT In 1896, Kraepelin classified the psychiatric disorders into 13 categories. One of them, the ‘‘psychogenic neurosis’’ was the first attempt to classify anxiety disorders. However, common opinion regarded anxiety as an aspecific phenomenon, a mere symptom that was present in a variety of disorders rather than the expression of a disease in itself. The Freudian concept of ‘‘anxiety neurosis’’ may represent the first attempt to consider severe and chronic anxiety as a true medical condition deserving the status of an independent nosologic entity. Later, a distinction was introduced between ‘‘anxiety neurosis’’ and ‘‘hysteric anxiety’’. The first edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-I) in the early 1950s adopted a large part of the Freudian view. Anxiety disorders were classified under ‘‘anxious reaction’’, which concept referred to Freud’s anxiety neurosis, and ‘‘phobic reaction’’, which referred to the hysteric neurosis. In 1968, the DSM-II introduced some modifications into the neurosis concept, but remained under the influence of the psychoanalytic system. ‘‘Neuroses’’ were divided into anxiety neurosis, hysteric neurosis, phobic neurosis, obsessive-compulsive neurosis, depressive neurosis, hypochondriac neuro- sis, neurasthenic neurosis and depersonalisation neurosis (APA, 1968). Traditional doctrines about pathological anxiety were challenged in the early 1960s, when the first effective psychotropics became available. Klein first noticed that patients with the so-called ‘‘anxiety neurosis’’ appeared to respond in two different ways to treatment with the new psychotropics (Klein, 1964). Indeed, while the first benzodiazepines had proven remarkably effective for anxiety, some patients with ‘‘anxiety neurosis’’ failed to improve with the new anxiolytics. Paradoxically, those patients benefited from imipramine, which had just been introduced as an antide- pressant. Klein observed that the patients who failed to benefit from benzodiazepines, but improved with imipramine, were those who reported to have frequent bursts of paroxysmal anxiety, in addition to a chronic background. It appeared that imi- pramine was able to block their repetitive ‘‘attacks’’ that represented their worse symptoms. In contrast, subjects who did benefit from benzodiazepines failed to report Anxiety Disorders: An Introduction to Clinical Management and Research. Edited by E. J. L. Griez, C. Faravelli, D. Nutt and J. Zohar. © 2001 John Wiley & Sons, Ltd. Anxiety Disorders. Edited by E. J. L. Griez, C. Faravelli, D. Nutt and D. Zohar. Copyright © 2001 John Wiley & Sons Ltd Print ISBN 0-471-97893-6 Electronic ISBN 0-470-84643-7 [...]... Costa, an American army physician, described the syndrome of irritable heart (Da Costa, 1871; Paul, 1987), he described a post-traumatic syndrome within the cultural context of his time (Gersons and Carlier, 1992; Kinzie and Goetz, 19 96) The Anxiety Disorders: An Introduction to Clinical Management and Research Edited by E J L Griez, C Faravelli, D Nutt and J Zohar © 2001 John Wiley & Sons, Ltd 2 06 ———————————————————————————... CAYCEDO AND E.J.L GRIEZ therapy might be an interesting alternative in GAD treatment (Power et al., 1990; Chambless and Gillis, 1993; Schweizer and Rickels, 19 96) The aim of cognitive-behaviour therapy is to help the patient recognise and alter patterns of distorted thinking and dysfunctional behaviour and, by these processes, to alleviate the suffering and interference that the disorder causes (Harvey and. .. McGee R (1987) DSM-III disorders in preadolescent children: Prevalence in a large sample from the general population Arch Gen Psychiatry 44: 67 – 76 Angst J (1993) Comorbidity of anxiety, phobia, compulsion and depression Int Clin Psychopharmacol 8 Suppl 2: 21–25 Barlow DH (1988) Anxiety and its Disorders: The Nature and Treatment of Anxiety and Panic New York: Guilford Barlow DH, Blanchard EB, Vermilyea... factor in anxiety disorders Arch Gen Psychiatry 40: 1085–1089 Torgensen S (19 86) Childhood and family characteristics in panic and generalized anxiety disorders Am J Psychiatry 143: 63 0 63 2 Uhde TW, Boulenger J, Roy-Byrne PP et al (1985) Longitudinal course of panic disorder: Clinical and biological considerations Progr Neuro-Psychopharmacol Biol Psychiatry 9: 39–50 Uhlenhuth EH, Mitchel BB, Ban TA et... 18 .6% 9.8% 45.7% Source: Reproduced from data by permission of Noyes et al., 1992 GENERALISED ANXIETY DISORDER ————————————————— 195 than PD patients, and PD patients showed more cardiovascular symptomatology (Hoehn-Saric, 1982; Hoehn-Saric et al., 1989) Anderson and co-workers compared PD and GAD subjects for symptomatology, age of onset, course, and outcome of illness GAD patients showed less autonomic... social phobia: An interim report of a placebo-controlled comparison of phenelzine and atenolol J Clin Psychiatry 49: 252–257 Lydiard RB, Brawman-Mintzer O, Ballenger JC (19 96) Recent developments in the psychopharmacology of anxiety disorders J Consult Clin Psychol 64 : 66 0 66 8 Maser JD (1998) Generalized anxiety disorder and its comorbidities: Disputes at the boundaries Acta Psychiatr Scand 98 Suppl... GAD and other anxiety and affective disorders, especially panic disorder, social phobia, major depression and other mood disorders IS GAD AN INDEPENDENT NOSOLOGIC ENTITY? In the light of the above, the validity of GAD as a separate entity has been widely discussed (Breslau and Davis, 1985) The symptomatic profile of GAD fails to make a sharp distinction with other anxiety disorders, especially panic disorders. .. benzodiazepines and other psychotherapeutic medications: II Pharmacotherapy of anxiety disorders J Affective Dis 35: 153– 162 Verburg K, Griez E, Meijer J, Pols H (1995) Discrimination between panic disorders and generalized anxiety disorder by 35% CO2 challenge Am J Psychiatry 152: 1081–10 86 Weissman MM (1990) Panic and generalized anxiety: Are they separate disorders? J Psychiat Res 24: 157– 162 Wittchen... DSM-III-R generalized anxiety disorder in the National Comorbidity Survey Arch Gen Psychiatry 51: 355– 364 Yonkers KA, Warshaw MG, Massion AO, Keller MB (19 96) Phenomenology and course of generalized anxiety disorder Br J Psychiatry 168 (3): 308–313 Anxiety Disorders Edited by E J L Griez, C Faravelli, D Nutt and D Zohar Copyright © 2001 John Wiley & Sons Ltd Print ISBN 0-4 7 1-9 789 3 -6 Electronic ISBN 0-4 7 0-8 464 3-7 ... subcategory of anxiety neurosis was changed into ‘ anxiety states’’ and included panic disorder (PD), generalised anxiety disorder (GAD) and obsessive-compulsive disorder (OCD), contrasting with ‘‘phobic states’’, which included simple and social phobia GAD was defined as a generalised and persistent feeling of anxiety Persistent was operationalised as complaints of at least one month’s duration The symptoms . failed to report Anxiety Disorders: An Introduction to Clinical Management and Research. Edited by E. J. L. Griez, C. Faravelli, D. Nutt and J. Zohar. © 2001 John Wiley & Sons, Ltd. Anxiety Disorders. . CAYCEDO AND E.J.L. GRIEZ Anxiety Neurosis (Freud, 1894) Generalised Anxiety Disorder (DSM-I, DSM-II, Klein, RDC, ICD-9, DSM-III) DSM-III (1980) DSM-III-R (1987) DSM-IV (1994) persistent anxiety 1. Brawman-Mintzer and Lydiard, 19 96; (based on data from Sanderson and Barlow, 1990; Angst, 1993). Summarising, GAD is a common and chronic disorder, which frequently leads to significant distress and