Therapeutics

The Anxiety Disorders Clinic (ADC), under the leadership of Drs. Michael R. Liebowitz, Abby Fyer, and Franklin Schneier, continues to focus on the advancement of the understanding of the diagnosis, etiology, and treatment of DSM-IV anxiety disorders. The Hispanic Treatment Program includes studies of depression in its research focus.

Panic Disorder The clinic is conducting an industry sponsored multi-center trial of pagoclone which is a novel nonbenzodiazepine agent belonging to the cyclopyrrolone family. Pagoclone is a potent and selective modulator of the GABA_A receptor complex, displaying potent anxiolytic activity and minimal sedative effects. We are also collaborating with Drs. Donald Klein and Smit Sinha on a sleep paradigm to study endogenous CO₂ sensitivity and apneic threshold in adult patients with panic disorder and in normal adult controls.

Social Phobia Dr. Pable Altieri was awarded a minority fellowship as a supplement to Dr. Franklin Schneier's RO1 grant using PET and SPECT scans to study dopamine D₂ receptor and dopamine transporter binding and dopamine release in social phobia. Dr. Schneier reported in the American Journal of Psychiatry that social phobia is associated with the trait of detachment, also reported to be associated with low D₂ binding.

Dr. Liebowitz is continuing his NIMH funded collaboration with Dr. Richard Heimberg of Temple University comparing the acute and long term effects of phenelzine, cognitive behavior group therapy (CBGT), and their combination in social phobia. As an NIMH minority supplement to this grant, Dr. Lewis-Fernández is adapting cognitive behavioral group therapy to a population of low-income, Spanish-monolingual Hispanics.

Post-Traumatic Stress Disorder Dr. Marshall continues with his five-year K08 grant from NIH to study "Paroxetine, Prolonged Exposure, and Biology in PTSD". A feasibility study of long-term psychodynamic psychotherapy and psychoanalysis was published, in which it was found that 1) high rates of Axis I and Axis II disorders are seen in long-term psychotherapy clinics, and 2) naturalistic study of these patients over one year showed that the services being received did lead to significant reductions in symptomatology.

Obsessive-Compulsive Disorder (OCD) Dr. Liebowitz and Dr. Simpson have been awarded a collaborative R01 with Dr. Edna Foa in Philadelphia to study the efficacy and durability of adjunctive cognitive-behavioral therapy in OCD patients on medications, using a randomized clinical trial design. Dr. Liebowitz, in collaboration with Dr. Foa, has completed the collaborative R10 grant from NIMH to compare clomipramine, behavior therapy, and their combination in OCD patients. Preliminary analyses indicate that both clomipramine and behavior therapy are superior to pill placebo for OCD, that behavior therapy is superior to clomipramine. and that the combination of behavior therapy and clomipramine is not clearly better than intensive behavior therapy alone.

Dr. Blair Simpson has been awarded a K23 training award from NIMH entitled "Improving the Outcome of Patients with OCD." This award enables her to continue her training and research on OCD. In addition, Dr. Simpson continues to examine whether there are abnormalities in the serotonin transporter in OCD patients using positron emission tomography and a novel radiotracer; this project is a collaboration with Dr. Marc Laruelle in the Functional Brain Mapping division, and is funded both by the OC Foundation and Dr. Simpson's K23 Award. Dr. Lisa Kochan in collaboration with Dr. Fallon has pioneered a novel method of delivering clomipramine that avoids the first-pass metabolism of oral administration and the hassles of IV administration.

Lyme Disease Under the direction of Dr. Brian Fallon, the Lyme Disease Research Program has continued to expand its activities. Under a $4.7 million NIH-funded study of Chronic Lyme Encephalopathy, critical questions about treatment and pathophysiology are being examined in collaboration with numerous NYSPI and Columbia investigators (Drs. Sackeim, Van Heertum, DelaPaz, Dwyer, Dobkin, Britton, Keilp, Tager, and others). Other awards over the last year have been received by private foundations to study other aspects of chronic Lyme Disease in adults and children. The essential questions about the role of brain imaging in the evaluation of patients with Lyme encephalopathy and questions about the efficacy of repeated antibiotic therapy require the focused investigative efforts of this multidisciplinary team.

Hypochondriasis Under the direction of Dr. Fallon, two pharmacologic research studies on hypochondriasis were completed this year. One assessed the utility of fluvoxamine in an open trial. The second assessed the utility of fluoxetine in a placebo controlled trial. Both agents appear highly effective in the treatment of hypochondriasis.

Hispanic Treatment Program (HTP) The HTP has continued work on major depression in Hispanics. Drs Sánchez-Lacay and Lewis-Fernández are following up findings of elevated rates of treatment dropout among Hispanics on anti-depressant medication with an industry-sponsored study examining patients' treatment expectations and causes of drop-out in order to identify predictors of medication adherence in this population.

Training Efforts The ADC continues to increase its training functions. We now have two research track PGY-III residents in the ADC seeing patients and receiving supervision part time for 12 months, as well as PGY-IV residents on electives. Dr. Blanco is a third-year fellow in our program. Dr. Blanco's interests are in affective disorders and pathological gambling.

The Biological Studies Unit (BSU), under the leadership of Drs. Laszlo Papp, Jeremy Coplan, and Jack Gorman, has expanded significantly during the reporting period. While maintaining its traditional role as a centralized research laboratory, serving the need of investigators throughout the Medical Center, the BSU also received several new grants, added new research staff, and developed a series of collaborative projects. Current performance sites for BSU studies include the Phobia Clinic of North-Shore LIJ Health System, neuroscience laboratories of NYU, outpatient clinics of the Cornell campus, and animal facilities of Downstate Medical Center in addition to several clinical departments and basic laboratories within PI and New York Presbyterian Hospital.

Aided by the recently awarded "Core Grants for Enhancing Neuroscience Translation" grant (CoGent) to Dr. Gorman, the BSU core (core Principal Investigator, Dr. Papp) is able to support a series of pilot projects in addition to providing logistical support to its core grants in mood and anxiety disorders. BSU infrastructure support includes the maintenance of five subject rooms, an examination room and two control rooms on the third floor of PI, the availability of state-of-the-art psychophysiology equipment such as a fully functional respiratory laboratory, ambulatory monitors of cardio-pulmonary functions, and all the facilities needed for collecting and storing biological specimens.

Treatment Studies within the BSU Our NIMH Multicenter Panic Treatment project (Principal Investigator, Dr. Gorman), investigating the long-term effects of a treatment paradigm consisting of cognitive behavioral therapy (CBT) followed by maintenance CBT, no treatment, or a medication algorithm is in its second phase. Our four-year, Late-life Anxiety Treatment project (Principal Investigator, Dr. Papp), also sponsored by NIMH, using CBT for elderly anxious patients who remain symptomatic in spite of pharmacotherapy, has been completed this year. One of the most consistent findings of these treatment trials is that cognitive behavioral therapies represent a powerful alternative to pharmacological interventions and in many instances should be the preferred approach over medications. Dr. Papp received an Independent Investigator Award from NARSAD to study treatment strategies for elderly patients who suffer from co-morbid anxiety and depression. Again, a first-line CBT approach followed by a medication algorithm seems most promising in this population. Dr. Marc Kleber received PIRSG funding to examine the relationship among personality, life events, and relapse in patients with panic disorder. Dr. Jan Mohlman, a fellow in geriatrics, is studying the efficacy of CBT augmented with learning aids in anxious older adults and the impact of executive dysfunction on therapy outcome.

An NIH sponsored longitudinal treatment study of panic disorder (Principal Investigator, Dr. Gorman) is underway to examine the predictors and psycho-physiological concomitants of relapse following successful treatment. We have reported the benefits and risks of nefazodone treatment in panic disorder (Principal Investigator, Dr. Papp) and are in the middle of a promising trial of venlafaxine in late-life anxiety disorders (Principal Investigator, Dr. Papp). The efficacy of citalopram will be tested for Irritable Bowel Syndrome (Principal Investigator, Dr. Coplan).

Neuroimaging/Neurobiology In collaboration with the Division of Functional Brain Mapping, Drs. Justine Kent and Jeremy Coplan have been investigating potential abnormalities of cerebral blood flow in panic disorder. They are also using neuroreceptor imaging techniques to study the serotonin sytem in social anxiety and generalized anxiety disorders. Dr. David Gutman, a first-year fellow, in collaboration with Dr. Joy Hirsch, is piloting a cognitive stimulus for a fMRI study of neural networks involved in fear and anxiety and, with the help of Dr. Elizabeth Phelps, he is evaluating the role of fear conditioning in the pathophysiology of anxiety disorders. Dr. Sanjay Matthew, an incoming fellow, has begun a primate neuroimaging study with Dr. Coplan. His PIRSG-funded study measures differences in hippocampal and other brain region function between adversely and non-stressfully reared monkeys. The role of the thyroid system in depression is the subject of an ongoing NIH study (Principal Investigator, Dr. Gorman). Drs Gorman and Sullivan are examining the relationship of a thyroid transport protein to brain thyroid hormone levels and HPA hormone activity. Dr. Gregory Sullivan, working with Dr. Joseph LeDoux at NYU, developed a novel model of anxious behavior in the rat. He presented his work at the annual meeting of the American College of Neuropsychopharmacology this year.

Dr. Jeremy Coplan took on new responsibilities at SUNY Downstate but continued his exciting work at the BSU. He received NIH funding to study adverse early rearing and glutamatergic function in non-human primates and continues his investigations of the effects of novel compounds on differentially reared groups of monkeys. Dr. Janet Fairbanks continued her work with children of patients with anxiety disorders. Her complex behavioral paradigms are combined with sophisticated tests of respiratory function.

The Depression Evaluation Service (DES) was selected to participate as a pivotal Regional Coordinating Center for a large NIMH-funded multi-center contract to study treatment-resistant depression; the study is called STAR*D (Sequenced Treatment Alternatives for Relief of Depression). Drs. Quitkin, McGrath, and Stewart participated in planning and protocol development for this critical study of treatment effectiveness which will enroll 4,000 subjects nationwide. The study will be the first to test in a randomized trial of adequate power the effectiveness standard treatment strategies for patients who are unresponsive to a first SSRI trial for Major Depression. The results of this trial are expected to have a major impact in informing treatment guidelines for depression.

In 2000, Dr. McGrath continued his work as Principal Investigator on a large NIMH- funded clinical trial of loss of effect of the antidepressant fluoxetine during maintenance treatment. This study seeks to clarify the nature of loss of response in patients who relapse while continuing maintenance antidepressant treatment. Dr. McGrath also reported preliminary results at national meetings for two treatment trials of medications for patients who either relapsed on fluoxetine or did not respond. Both bupropion and the investigational antidepressant reboxetine showed preliminary efficacy in this group of patients, encouraging trials of antidepressants of different mechanisms of action in patients who relapse on an SSRI.

Dr. McGrath also published two studies concerning atypical depression. The first showed that an SSRI is no more effective than a tricyclic in the treatment of atypical depression, which has important clinical relevance to the selection of antidepressant treatment and the development of new treatments for this subtype. The second study suggested that atypical depression is more likely to respond transiently to an SSRI and then relapse than is depression with a more endogenous symptom pattern.

Under the leadership of Dr. Frederic Quitkin, the DES began a clinical trial of gepirone, the first of a new class of antidepressants, in the treatment of atypical depression. The DES had previously published a study which led to the testing of this medication for a specific subtype of depression, never before targeted in medication development.

Alcoholism Under the direction of Dr. McGrath, the DES began participation in a collaborative study of the effectiveness of a new depot form of naltrexone for the treatment of alcoholism. If effective, this may have a major advantage of ensuring adherence to medication treatment for this devastating psychiatric disorder.

HIV Clinical Research Program In 2000, we received an NIMH grant to conduct a clinical trial and also an endocrine substudy of DHEA. In the eight-week placebo-controlled clinical trial, we are evaluating the efficacy of DHEA in the treatment of mild depression among HIV+ men and women, as well as possible anabolic effects (energy and muscle mass) and androgenic effects (libido). In a substudy conducted at the General Clinical Research Center at Cornell, the basic endocrinology of adrenal steroid metabolism is explored including stimulation tests and hormone assays performed before and at the end of the clinical trial. Study enrollment began in November 2000 and six patients were enrolled by the end of the year.

Two ongoing studies include an eight-week double-blind placebo-controlled study comparing the relative antidepressant efficacy of testosterone and fluoxetine for HIV+ men with major depression or dysthymia. To date, 86 men have completed the trial and another 25% have dropped out. The second study is an extension of a fluoxetine/placebo study whose major results were published in 1999, in order to include women, who were poorly represented in the original study. To date, 16 women completed the trial and four were either dropouts or were administrative removals.