Michael Liebowitz - US grants

DESCRIPTION (Applicant's abstract): Social Phobia is a highly prevalent, disabling, and chronic anxiety disorder associated with substantial vocational, social, and academic impairment in adults as well as children. It increases the risk of depression, substance abuse and financial dependence. Nevertheless, social phobia has received less attention than other anxiety disorders, and there are no universally accepted treatments for this condition. However, specific psychosocial and psychopharmacological treatments have demonstrated efficacy. Cognitive Behavioral Group Therapy (CBGT), developed by Dr. Heimberg, has proven superior to control therapies, while the MAOI phenelzine, first studied by Dr. Liebowitz, has proven superior to placebo in several controlled trials. In a novel and highly successful collaboration that has become a model in the field, Drs. Heimberg and Liebowitz together compared phenelzine, CBGT, pill placebo, and a credible psychosocial control treatment, and found phenelzine and CBGT superior on a variety of measures and of distinct clinical benefit. Phenelzine was faster acting and more effective than CBGT on some measures, while CBGT was more durable following treatment discontinuation. While phenelzine and CBGT produced positive effects, a number of patients, especially among generalized social phobics, did not respond sufficiently. There was also significant relapse following phenelzine discontinuation. Therefore, there is still a need for treatments for social phobia that are more effective and more durable than these two treatments as typically administered. Importantly, the combination of an MAOI and CBGT has never been evaluated. For many reasons, the combination treatment may be more effective than either individual therapy, more durable than medication alone, and especially effective for patients with generalized social phobia. If so, combined phenelzine/CBGT treatment would be of distinct benefit to many patients whose clinical needs are currently not well met. To address the acute efficacy issues, Drs. Liebowitz and Heimberg were funded to compare CBGT, phenelzine, the combination of these two treatments, and pill placebo in a 12-week trial of social phobia, and this trial is now underway. Outcome is evaluated by blind independent assessor interviews, self-report questionnaires, and standardized behavioral tests. The contributions of subtype and treatment site to outcome are also being examined. To date, a substantial number of patients have been enrolled, and combined treatment does appear to be more efficacious than either phenelzine or CBGT administered individually. However, two years of additional funding are being requested to complete study enrollment. When completed, this study should substantially enhance our knowledge of effective treatments for social phobia.

Obsessive-Compulsive Disorder (OCD) is a not uncommon, chronic, debilitating condition for which few effective treatments exist. While neuropsychiatric abnormalities have long been noted, of the disorder are poorly understood. Recently spurred by findings of therapeutic efficacy of potent serotonin (5HT) reuptake blockers, a 5HT dysregulation theory has been proposed. Limitations of existing findings and theories for OCD include: 1) only small samples have been studied; 2) inconsistent biochemical and neuropsychiatric findings across studies; 3) no attempts to integrate biochemical and neuropsychiatric findings; 4) only a subset (50%) of OCD patients respond to 5HT reuptake blockers, suggesting pathophysiological heterogeneity; 5) where 5HT abnormalities are found, they are almost aways in the direction of increased, not decreased, 5HT activity and sensitivity; 6) the high baseline 5HT subgroup appears to be the subgroup responsive to chronic 5HT reuptake blocker therapy. This proposal will e 70 OCD patients, 35 normal controls and 35 anxiety disorder (Social Phobic) controls on a number of serotonergic (behavioral and neuroendocrine responses to the selective 5HT agonist M-UP), neuropsychiatric (neurological soft signs) and neuropsychological measures. The neuropsychological battery specifically explores frontal lobe and septohippocampal dysfunction in OCD. Data will be analyzed to see if serotonergic, neuropsychiatric and/or neuropsychological abnormalities in OCD can be identified; how neuropsychiatric and biochemical findings correlate; how neuropsychological abnormalities cluster with these findings. Overall, the studies should delineate whether pathophysiologically distinct (biochemically and neurologically impaired) subgroups of OCD patients exist. They should also help to clarify the biochemical and neuropsychiatric contributions to aberrant neuropsychological functioning in OCD. Future studies will address how these baseline markers correlate with treatment outcome, and how they are affected by treatment.

Obsessive compulsive disorder (OCD) is chronic, debilitating and prevalent. Adult OCD has recently received much research attention. Medications with potent serotonin reuptake blocking effects are of substantial help to approximately 50% of such patients. The investigational drug chlorimipramine (CMI) is the most widely studied, but fluoxetine appears equally promising in open clinical trials. If effective in controlled studies, fluoxetine has important advantages over CMI, such as already being marketed in the U.S. for depression, and what appear to be more favorable safety and side effect profiles. OCD is common in childhood and adolescence, with recent estimates of 200,000 or more such cases in the U.S.. Despite evidence that is a paucity of research in childhood/adolescent OCD. The few studies that do exist suggest phenomenological and pharmacological similarities to the adult form, and CMI appears effective. There are, however, no reported studies of fluoxetine in this age group. Despite this, practitioners are now using fluoxetine for childhood and adolescent OCD because of the drug's availability. Based on promising pilot data, an 8 week placebo controlled evaluation of fluoxetine in adolescent OCD is proposed. Seventy five patients will be randomized to drug or placebo. Patients responding by the end of 8 weeks to either treatment will be continued on a double blind basis for an 8 week maintenance phase to test the durability of response and whether further improvement occurs. The immediate goal is to assess whether fluoxetine is effective for the acute treatment of adolescent OCD. Long term goals are to establish guidelines for both the acute and long term pharmacological and psychosocial treatment of childhood/adolescent OCD, and to understand its pathophysiology. Intervention at a young age may be more effective that in the often more chronic adults form, and also prevent long term suffering and impairment.

This competing continuation proposal is one-half of a jointly proposed two-site study by Foa and Liebowitz, who are submitting separate similar proposals. Obsessive-compulsive disorder (OCD) is chronic, debilitating, and prevalent. Controlled trials indicate that clomipramine (CMI) and exposure behavior therapy (BT), the two best established treatments for OCD, each help about 50% of treatment seekers. BT may help patients partially or unresponsive to CMI and may also reduce the high relapse rate with CMI discontinuation. To date, a conclusive comparison of CMI, BT, and their interactive effects is not available. Begun in 1990, this research compares BT, CMI, CMI + BT, and pill placebo (PBO) at a BT oriented site and at a pharmacologically oriented site, thus providing state-of-the-art treatment in each mode. This collaboration has been successful to date. Notably, however, higher than expected refusal, exclusion, and attrition rates have resulted in lower than expected enrollment. Therefore, we propose to extend the study for 3 years to accrue intent-to-treat and completer samples of sufficient size to allow adequate power to test our original hypotheses. The goals are to: 1) compare the efficacy of CMI, BT, CMI + BT, and OCD in a 12-week trial; 2) compare relapse after B and CMI are discontinued by following responders for an additional 12 weeks; 3) compare the efficacy of CMI and BT for OCD at the two centers; and 4) explore predictors of response to treatment. In the proposed research, we will study 84 patients (42 in Philadelphia and 42 in NY). When these are combined with the 85 enrolled in the previous 5 years of the project, the total N will be 169 (approximately 46 per active treatment group and approximately 29 in the PBO group). This N will allow sufficient power to test treatment and site effects. This study offers a model for pharmacotherapy-psychotherapy comparisons because experts in each modality deliver both treatment modalities. This guards against expert bias for either treatment. Its results promise to allow definitive conclusions about the relative efficacy of BT and CMI, to clarify the generalizability of both treatments and to influence clinical practice widely.

mental disorder diagnosis; anxiety disorders; patient /disease registry; medical outreach /case finding; biomedical facility; health care referral /consultation; diagnosis quality /standard; human subject;

DESCRIPTION (Adapted from the Applicant's Abstract): This is one-half of a two-site study proposed jointly by Foa and Franklin at the University of Pennsylvania, and Liebowitz and Simpson at Columbia University, who are submitting separate but similar proposals (collaborative CSMD). Obsessive-compulsive disorder (OCD) is prevalent, chronic, and debilitating. Both cognitive behavior therapy (CBT) by exposure and ritual prevention (EX/RP) and serotonin reuptake inhibitors (SRIs) are recommended for OCD. However, recommended doses of the widely used SRIs leave many patients with substantial residual symptoms and a need for more help. This proposal addresses an important problem in treating OCD: how to augment the limited efficacy of SRIs. This study will examine the immediate and long-term value of adding an established CBT for OCD, i.e., EX/RP, to continuing SRI treatment, for reducing residual symptoms and increasing general functioning. Participants will be 136 individuals (68/site) with clinically significant OCD despite having benefited somewhat from an adequate trial of a SRI. While continuing on an SRI, patients will be randomized to adjunctive EX/RP or another CBT, Stress Management Training (SMT). SMT targets generalized anxiety symptoms, but has not been found effective for OCD. As a credible comparison therapy, SMT will control for time, attention, and other non-specific effects of CBT. Both adjunctive CBT treatments will occur twice a week for 2 months. Responders will enter a 6 month Maintenance Phase, during which they will continue their medication and receive monthly 45 min. maintenance sessions. Those who remain in remission will then enter a 6 month Follow-up Phase, in which they will be allowed to reduce or discontinue medication, and will have no further CBT. Non-responders and relapsers will be treated appropriately and evaluated every 3 months. Assessments will focus on OCD symptoms and on general functioning; they will occur during an Acute Phase (0, 1, 2 mos) and every 3 months thereafter (5, 8, 11, 14 months). The proposed sample will allow sufficient power to test both treatment and site effects. This study has several unique features. 1. It offers a model for pharmacotherapy-psychotherapy studies because experts in each modality will deliver both treatments; this guards against expert biases for either treatment. 2. We wanted the results to be directly applicable to OCD patients seen in routine clinical practice. Accordingly, exclusion criteria are few. 3. The EX/RP protocol was designed to maintain efficacy while maximizing practicality. 4. Patients who are unable to remain in the treatment protocol for any reason will continue to be assessed; this will allow us to describe the long-term outcome of the whole sample. Long-term goals are: a) to provide clinicians with new strategies for treating OCD patients who remain symptomatic despite an adequate trial of a SRI and b) to establish effective treatments that reduces the considerable social costs of unremittant OCD.

DESCRIPTION (provided by applicant): Social anxiety disorder is a prevalent, chronic and disabling condition. Paroxetine has received FDA approval on the basis of its acute efficacy for this disorder, but much about longer-term management remains uncertain. There are virtually no data regarding next steps in treatment despite evidence that most patients who receive acute paroxetine therapy still exhibit significant residual symptoms. Furthermore, there are also no data regarding methods for minimizing relapse when medication is discontinued despite evidence that relapse rates in such circumstances are high. Cognitive-behavioral therapy (CBT) is a good candidate for augmenting paroxetine response and reducing relapse after medication discontinuation as it has been shown to be an effective treatment in its own right and often associated with lesser relapse than medication alone. Although CBT has been found to be useful in these circumstances for depression and panic disorder, there have been no similar studies in social anxiety disorder. This application will examine the ability of CBT to augment acute paroxetine response and reduce relapse following paroxetine discontinuation in social anxiety disorder. It will also examine the degree of residual symptoms and disability as well as rates of remission and improvements in quality of life in response to paroxetine alone or with the addition of CBT. Predictors of acute response and relapse after treatment is discontinued will also be explored. To achieve these ends, two hundred fifty patients will receive 12 weeks of open treatment with paroxetine. Patients showing at least some benefit will be randomized to continued paroxetine with or without CBT for 16 additional weeks. All treatment will then be tapered and patients will be followed for 24 additional weeks. Overall, this study should provide important information about the augmentation of paroxetine treatment for patients with social anxiety disorder, effective methods for reducing relapse, and who may benefit from paroxetine treatment or relapse when medication is withdrawn. It will also increase understanding of the interplay of psychosocial and pharmacological treatment methods and psychological and biological factors in patients' total response to treatment.