Therapeutics

Donald F. Klein, M.D., Director

ANXIETY DISORDERS CLINIC
Michael R. Liebowitz, M.D., Director
Abby J. Fyer, M.D., Co-Director
Randall D. Marshall, M.D., Associate Director
Carlos Blanco, MJ.D., Assistant Director
Franklin Schneier, M.D., Research Psychiatrist II

BIOLOGICAL STUDIES UNIT
Laszlo Papp, M.D., Director

DEPRESSION EVALUATION SERVICE
Frederic Quitkin, M.D., Director
Jonathan Stewart, M.D., Research Psychiatrist II
Patrick McGrath, M.D., Research Psychiatrist II
Judith Rabkin, Ph.D., M.P.H., Research Scientist VI



Anxiety Disorders Clinic
The Anxiety Disorders Clinic (ADC) is now under the leadership of Drs. Michael R. Liebowitz, Abby Fyer, Randall Marshall, and Carlos Blanco. The Clinic continues to focus on the advancement of the understanding of the diagnosis, etiology, and treatment of DSM IV anxiety disorders. Dr. Roberto Lewis Fernandez is the Director of the Hispanic Treatment Program. Dr. Brian Fallon is the Director of the Lyme Program.

Panic Disorder
Dr. Joshua Lipsitz is conducting a study of the efficacy of Interpersonnel Therapy in the treatment of panic disorder. 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
Drs. Liebowitz in collaboration with Dr. Richard Heimberg of Temple University compared the acute and long-term effects of phenelzine, cognitive behavior group therapy (CBGT) and their combination in social phobia. This collaborative study is the largest investigator-initiated study of its kind completed to date. All three active treatments, especially combined treatment and phenelzine, are associated with strong within-condition change. However, the degree of response on some dimensional measures suggests that combined treatment confers greater benefit. If, in fact, combined treatment does turn out to have the most robust effect, this finding has important public health implications. It may suggest that all patients who are able to do so should be started in treatment with the combined regimen.

Dr. Franklin Schneier is continuing his RO1 grant using PET and SPECT scans to study dopamine D2 receptor and dopamine transporter binding and dopamine release in social phobia. He completed a clinical trial of citalopram in patients with social phobia and comorbid major depression, which suggested a robust treatment response overall with depression improving before social phobia symptoms. Dr. Schneier was awarded a NARSAD grant.

Obsessive Compulsive Disorder (OCD)
Dr. Simpson and Dr. Liebowitz completed the second of a five year collaborative RO1 with Dr. Edna Foa in Philadelphia: this study examines the efficacy and durability of adjunctive cognitive-behavioral therapy in OCD patients on medications, using a randomized clinical trial design. Dr. Liebowitz’ prior collaborative R01 with Dr. Edna Foa demonstrated that both clomipramine and intensive cognitive-behavioral therapy are superior to pill placebo for OCD and that intensive cognitive-behavioral therapy is superior to clomipramine in some analyses. A collaborative randomized clinical trial of fluoxetine in the treatment of OCD in children and adolescents found that fluoxetine was an effective and safe treatment for child and adolescent OCD, but fluoxetine’s full effects took more than 8 weeks to develop.

With regards to the neurobiology of OCD, Dr. Simpson, in collaboration with Dr. Marc Laruelle in the Division of Functional Brain Mapping, has been examining whether there are abnormalities in the serotonin transporter in OCD patients using positron emission tomography and a novel radiotracer; this project is funded both by the OC Foundation and Dr. Simpson’s K23 Award.

Drs. Brian Fallon and Suzanne Feinstein completed acquisition of data for this study of the efficacy of intravenous clomipramine for patients with refractory OCD. Although IV clomipramine had been shown to be effective compared to placebo, this study did not find a meaningful difference between IV clomipramine and oral clomipramine. However, approximately 25% of the treated patients did improve significantly, raising the possibility that the rapid escalation of dosage was of particular therapeutic benefit.

Posttraumatic Stress Disorder
Dr. Marshall was named Director of Trauma Studies and Services at NYSPI the week before 9/11 Through a grant from the New York Times Corporation Dr. Marshall formed a Consortium with three other major trauma research centers in New York city, brought in experts from around the country to train the new staff in empirically validated treatments, and has been conducting dissemination trainings for the community. The team has held trainings in exposure-based treatment of adults with PTSD for over 200 clinicians since 9/11.

Publications included a comparison between the biology of panic disorder vs. PTSD finding differences in baseline cortisol and MHPG as well as response to clonidine challenge; a large multi-center trial (N=551) of paroxetine in adults with PTSD that found superiority for paroxetine over placebo for all 3 symptom clusters of PTSD, and for men and women equally; and an analysis of nearly 9000 persons attending Anxiety Disorder Screening Day that found significant impairment, comorbid depression, and suicidal ideation in persons with subthreshold PTSD.

Hypochondriasis
The results from the first placebo-controlled SRI study for hypochondriasis found fluoxetine to have significantly greater effect than placebo. While hypochondiasis did significantly improve, no significant difference between treatment groups was noted in the severity of self-reported somatic symptoms. Thus, while fluoxetine may be helpful for illness obsessions and associated compulsions, it may not be helpful for somatization.

Lyme Disease
There have been several major events which served to further the development of a Center at Columbia devoted to the research of Chronic Lyme Disease and other Tick-borne disorders. A major fundraiser in March 2001 by the Wilton Lyme Disease Task Force, raised over $150,000 for Lyme research at Columbia and elsewhere. This fund-raiser established a permanent endowment both for research and for the Dr. Charles Ray Jones Neuropsychiatry Medical Student Summer Fellowship. A major gala in April 2001 sponsored by the Greenwich Lyme Disease Task Force, raised over $600,000 for the Center.

Pathological Gambling
Dr. Carlos Blanco is conducting studies on the pathophysiology and treatment of pathological gambling. He is working to make NYSPI a major center for the research and treatment of this prevalent and disabling but little studied condition.

Hispanic Treatment Program
The Hispanic Treatment Program, under the direction of Dr. Roberto Lewis-Fernández, significantly increased its clinical and research activities during this past year. Dr. Lewis-Fernández obtained grant support from the Robin Hood Foundation, The New York Times and the September 11th Fund of the New York Community Trust to study the impact of the World Trade Center attack and the crash of American Airlines flight 587 on the Washington Heights community.

Biological Studies Unit
The Biological Studies Unit (BSU), under the leadership of Drs. Laszlo Papp, Jack Gorman and Justine Kent, 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.

Also aided by an NIH-sponsored “Core Grants for Enhancing Neuroscience Translation” grant (CoGent) to Dr. Gorman, the BSU core (core PI: Dr. Papp) supports a series of pilot projects in addition to providing logistic support to its 10 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
The NIMH Multicenter Panic Treatment project (PI: Dr. Gorman), investigating the long-term effects of treatment paradigms consisting of cognitive behavioral therapy (CBT) followed by maintenance CBT, no treatment or a medication algorithm, is nearing completion. Interim results have been reported and already influenced the management of patients with panic disorder. The Late-life Anxiety Treatment project (PI: Dr. Papp), also sponsored by NIMH, using CBT for elderly anxious patients who remain symptomatic in spite of pharmacotherapy, has been completed and published. 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 completed 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, in a pilot project, examined the relationship among personality, life events and relapse in patients with panic disorder. Dr. Jan Mohlman is studying the efficacy of CBT augmented with learning aids in anxious older adults and the impact of executive dysfunction on therapy outcome.

In the context of an NIH sponsored longitudinal treatment study of panic disorder, Drs. Gorman and Sullivan are examining the predictors and psycho-physiological concomitants of relapse following successful treatment. Recent findings from this study suggest abnormal brain control of cardiac repolarization in panic disorder that normalizes with treatment. We have reported the benefits and risks of pregabalin treatment in panic disorder (PI: Dr. Papp) and are completing a promising trial of venlafaxine in late-life anxiety disorders (PI: Dr. Papp). The efficacy of escitalopram will be tested for Irritable Bowel Syndrome (PI: Dr. Coplan) and comorbid anxiety and asthma (PI: Dr. Papp). Carbon dioxide inhalation has been successfully tested as a strategy for evaluating new classes of anxiolytics.

Neuroimaging/Neurobiology
Under the leadership of Drs. Jack Gorman, Justine Kent and Jeremy Coplan, efforts have been focused on expanding a neuroimaging program in anxiety to encompass both positron emission tomography and functional magnetic resonance imaging. Ongoing efforts with Dr. Marc Laruelle and the Division of Functional Brain Mapping have proved fruitful in delineating neurobiological and neuroreceptor correlates in anxiety. In collaboration with Dr. Joy Hirsch and the Functional Magnetic Resonance Imaging Center of Columbia University, new protocols in the areas of anxiety (panic disorder, social anxiety disorder) and depression have been initiated using a number of diverse stimuli programs. In addition to functional studies, clinical structural (volumetric) and neurochemical studies are also being conducted using magnetic resonance spectroscopy (MRS).

Dr. David Gutman is piloting a cognitive stimulus for an fMRI study of neural networks involved in fear and anxiety and is evaluating the role of fear conditioning in the pathophysiology of anxiety disorders. Dr. Sanjay Matthew has begun a primate neuroimaging study with Dr. Coplan. Dr. Mathew and Dr. Coplan are studying the effects of treatment on MRSI measures in order to test the notion that antidepressants and anxiolytics modify measures reflective of neuronal viability and membrane turnover. They began a clinical trial of a novel anti-glutamatergic agent (riluzole) in the treatment of anxiety disorders. The role of the thyroid system in depression is the subject of an ongoing NIH study (PI: 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 developed a novel model of anxious behavior in the rat.

Dr. Jeremy Coplan took on new responsibilities at SUNY Downstate, but continues 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. Major developments include the finding of a striking reduction of a marker of neuronal viability using magnetic resonance spectroscopy imaging. The marker N-Acetyl-Aspartate (NAA) was reduced in the anterior cingulated gyrus of the prefrontal cortex of fully-grown adversely-reared primates in comparison to non-stressfully-reared controls. In the same key anatomical area, a high “GIx” signal was noted in the adversely reared animals, believed to be reflective of regional glutamate concentrations, a potentially neurotoxic amino acid.

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.

K Awards from NIMH provide continued support to Drs. Gorman, Papp, and Fairbanks. Dr. Mathew received a two-year award from the American Foundation for Suicide Prevention to study volumetric MRSI in adult subjects with depression who were at high risk for suicide as adolescents.

Depression Evaluation Services
Under the direction of Dr. Frederic M. Quitkin, the DES completed a study comparing the first of a new class of antidepressants, gepirone, to fluoxetine and placebo in 51 outpatients with atypical depression. As a follow-up to this study, Dr. Quitkin has begun a study comparing gepirone to paroxetine and placebo in the treatment of DSM-IV Major Depressive Disorder with atypical features.

The Depression Evaluation Service was selected to participate as a pivotal Regional Coordinating Center for a large NIMH-funded multi-center contract to study treatment-resistant depression 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. Work at this site is proceeding.

Both Dr. Stewart and Dr. McGrath have received two-year NARSAD awards. Dr. Stewart, who received his award in September 2001, is investigating mega dose tranylcypromine treatment of refractory depression (i.e., depressed patients who have not improved following several adequate medication trials). To date, 13 patients have entered this study. Dr. McGrath in collaboration with Dr. Eric Rubin, was funded by NARSAD to conduct a PET imaging study of regional cerebral metabolism in patients who relapse despite continuing antidepressant medication. Dr. McGrath also continues work on a NIMH-funded study that he received in 2001 to evaluate the effect of alcohol abuse on treatment outcome with antidepressant treatment.

HIV Clinical Research Program
Under the direction of Dr. Rabkin, work continued on a clinical trial of DHEA to treat non-major depression in HIV+ patients, together with an endocrine sub-study conducted at Cornell. In the 8-week placebo controlled clinical trial, the goal is to evaluate the safety, tolerance and the efficacy of DHEA in the treatment of mild but persistent depression among HIV+ men and women, as well as possible anabolic effects (energy and muscle mass) and androgenic effects (libido). DHEA responders are maintained for an additional 8 weeks while placebo non-responders are offered 4 months of open label treatment. At that time, an additional 4 months of extension treatment is offered to assess longer-term side effects and efficacy. In a sub-study conducted at the General Clinical Research Center at Cornell, the basic endocrinology of adrenal steroid metabolism is being studied, including stimulation tests and hormone assays performed before and at the end of the clinical trial. Study enrollment began in November 2000 and 6 patients were enrolled by the end of the year. By 3/02, an additional 62 patients were enrolled. Another federally funded study was completed in 2001, an 8-week double-blind placebo-controlled study comparing the relative antidepressant efficacy of testosterone and fluoxetine for HIV+ men with major depression or dysthymia. A total of 123 men were randomized and 90 completed the trial, with 30 completers in each treatment arm. Preliminary data analyses show an elevated placebo response rate (53%) which precludes finding either active treatment significantly superior. Subgroup analyses are underway.