Biological Psychiatry
Harold A. Sackeim, Ph.D.,
Chief of Psychiatric Research
D. P. Devanand, M.D., Psychiatrist (Research) II
Sarah H. Lisanby, M.D., Psychiatrist (Research) II
James R. Moeller, Ph.D., Research Scientist V
Bobba Moody, M.S.W., Research Scientist III
Mitchell S. Nobler, M.D., Psychiatrist (Research) II
Joan Prudic, M.D., Psychiatrist (Research) II
Yaakov Stern, Ph.D., Research Scientist VI
The Department of Biological Psychiatry is engaged in a wide range of
preclinical and clinical research efforts. These include the operation
of four outpatient research clinics: Brain Behavior Clinic, Late Life
Depression Clinic, Huntington’s Disease Center of Excellence, and
Memory Disorders Center. The Department also has two programs for the
study of psychiatric treatments in non-human primate models, laboratories
and clinical research programs in Electroconvulsive Therapy (ECT), Transcranial
Magnetic Stimulation (TMS), and Vagus Nerve Stimulation (VNS). It is developing
a new brain stimulation program, exploring the utility of deep brain stimulation
(DBS) in the study and treatment of specific psychiatric disorders. In
addition, the large Brain Imaging Division of the Department of Biological
Psychiatry focuses on image acquisition and analysis, using structural
MRI, functional MRI (fMRI, MRS), and functional imaging with Positron
Emission Tomography (PET). This year we highlight the advances made in
the research programs on ECT and TMS.
Electroconvulsive Therapy (ECT)
The current ECT research program began in 1979 and continues to be the
premier research effort on this treatment modality world-wide. In the
past year, there have been four key advances.
1. A large multi-site collaborative trial was completed. This study was
chaired by Dr. Sackeim and funded by the National Institute of Mental
Health (NIMH). The study was conducted at the Western Psychiatric Institute
and Clinic, Carrier Foundation, and the University of Iowa, with the study
directed and coordinated by the Department of Biological Psychiatry at
the New York State Psychiatric Institute. Patients with unipolar, major
depression who remitted following treatment with ECT were randomized to
continuation pharmacotherapy with placebo alone, nortriptyline alone (a
tricyclic antidepressant medication), or the combination of nortriptyline
and lithium carbonate. The key results were reported in the Journal of
the American Medical Association (JAMA). The relapse rate, over a 6-month
postECT period, was extraordinarily high when patients were treated with
placebo (84%). While statistically superior to placebo, the relapse rate
with nortriptyline alone was unacceptable (60%). In contrast, there was
a marked reduction in relapse with the combination of nortriptyline and
lithium (39%). Based on this work, continuation therapy with nortriptyline
and lithium has become increasingly used by the clinical community to
sustain the beneficial effects of ECT.
2. A key finding in previous work was that virtually all of the instances
of relapse on the combination treatment occurred within 5 weeks of ECT
termination. This meant that if early relapse would be prevented virtually
all patients could achieve sustained remission. Thus, in the past year,
the NIMH funded a new collaborative research trial, also chaired by Dr.
Sackeim. There are two strategies that may be effective in reducing the
rate of early relapse. One approach would be to gradually taper acute
ECT treatment, providing coverage during the 5-8 week period of heightened
risk. The second strategy is to start antidepressant coverage at the start
of ECT, providing protection during the period of increased risk. The
new multi-site study examines the effectiveness of the second strategy.
The participating sites are Wake Forest University, Washington University
(in St. Louis), and the Western Psychiatric Institute and Clinic, again
with the study directed and coordinated by the Department of Biological
Psychiatry at the New York State Psychiatric Institute. In the first study
phase, 630 patients are randomized to treatment with either high dosage
right unilateral ECT or low dosage bilateral ECT. The patients are simultaneously
randomized to treatment with placebo, nortriptyline, or venlafaxine. In
a second study phase, patients who remit following ECT are eligible for
a controlled, six-month continuation trial. Those patients who received
placebo during ECT are randomized to treatment with either nortriptyline
and lithium or venlafaxine and lithium. Those patients who received an
active antidepressant medication during the first phase continue on the
antidepressant and have lithium added under double-masked conditions.
In entering its second year, the study has met or exceeded enrollment
targets.
3. The optimization of ECT technique remains a goal of our work. The standard
width of the brief electrical pulse used in ECT is much wider (longer
in duration) than that necessary to produce neuronal depolarization. In
an ongoing trial, conducted at NYSPI and supported by the NIMH, patients
with major depression are randomized to treatment with an ultra-brief
electrical stimulus (0.3 ms) or a standard pulse width (1.5 ms). They
are also randomized to treatment with high dosage right unilateral ECT
(6 times seizure threshold) or high dosage bilateral ECT (2.5 times seizure
threshold). The interim findings in this indicate that the ultrabrief
pulse is about 4 times more efficient than the standard brief pulse in
seizure elicitation. The ultrabrief pulse appears to markedly reduce adverse
cognitive side effects. Furthermore, the ultrabrief pulse combined with
the right unilateral electrode placement has the most benign side effect
profile yet appears to retain the astounding efficacy of ECT. These findings,
if confirmed at the end of the trial, will have direct impact on clinical
practice.
4. Key limitations of the electrical stimulation used in ECT are poor
control over the spatial distribution in the brain of the electrical current
and poor control over current density or dosage in the brain. The fourth
advance, therefore, is the development of magnetic seizure therapy (MST)
which overcomes these by use of TMS. Magnetic stimuli induce current flow
in the brain unimpeded by the scalp and skull and the induced electrical
field can be precisely spatially targeted with control over intracerebral
dosage. After more than a decade of development, Drs. Lisanby and Sackeim
have been carrying out a randomized, sham-controlled, non-human primate
study, supported by the NIMH, contrasting the cognitive, neurophysiological,
neurochemical, and neuroanatomic effects of magnetic seizure therapy (MST)
and (ECT). Among the key findings, this work, in collaboration with Dr.
Herbert Terrace at the Department of Psychology, Columbia University and
Drs. Arango, Dwork and Underwood in the Department of Neuroscience, NYSPI,
has shown that ECT in monkeys results in a marked increase in the proliferation
of new cells in the dentate gyrus of the hippocampus, an effect not seen
with MST. Similar findings have emerged in work conducted by Drs. Perera,
Lisanby, Dwork, and Sackeim (Department of Biological Psychiatry, NYSPI),
in collaboration with Dr. Coplan and others at the Downstate Medical Center.
During the past year, the first human trial was completed evaluating the
effects of MST. Directed by Dr. Lisanby, this study compared the acute
cognitive side effects of MST and ECT using a within-patient, double-masked
design. There were several indications that MST had a superior side effect
profile, even in comparison to an optimized form of ECT. This work, supported
by a Clinical Trials award, has been followed by a Stanley Foundation
award to examine the efficacy of focal and more diffuse stimulation with
MST. This randomized multi-site study, also directed by Dr. Lisanby, is
underway. The development of MST, a long-term project in the Department
of Biological Psychiatry, may offer the field a potent way to explore
the brain networks involved in antidepressant effects, as well as an effective
treatment with minimal side effects.
Transcranial Magnetic Stimulation
(TMS)
In addition to the research on MST, there were many active projects involving
TMS. During the past year, Drs. Stern, Lisanby, and Sackeim received funding
from the Department of Defense (DARPA) to explore how TMS can modulate
the brain circuits involved in thinking and memory. Specifically, this
work is geared to identify with functional Magnetic Resonance Imaging
(fMRI) the networks that are responsible for impaired thinking following
sleep deprivation and to determine how TMS can tune these circuits to
reverse the cognitive abnormalities. Other work has focused on the nature
of the backward masking deficit in patients with schizophrenia. When two
visual stimuli follow each other closely in time, second stimulus may
obliterate perception of the first. This is the backward masking effect
and it is well established that patients with schizophrenia are subject
to masking at prolonged intervals between the two visual stimuli. Backward
masking can also be achieved by presenting a visual stimulus followed
by a single magnetic pulse delivered to primary visual cortex (e.g., area
18). Led by Drs. Luber, Lisanby and Sackeim, the TMS research has shown
that the backward masking “deficit” is largely an artifact
of chance level performance on the part of some patients with schizophrenia.
In turn, this finding will lead to a new interpretation of a vast literature.
In the past year, Drs. Burt, Lisanby, and Sackeim published a meta-analysis
of the therapeutic effects of (non-convulsive) TMS in the treatment of
major depression in the International Journal of Neuropsychopharmacology.
A multi-site study involving NYSPI and Harvard University was completed
involving a sham-controlled comparison of two different forms of TMS (left-sided
high frequency and right-sided low frequency stimulation), with Dr. Sackeim
serving as Study Chair and Dr. Lisanby directing the research at NYSPI.
Another trial of non-convulsive TMS was completed in patients with bipolar
major depression. This work was supported by another award from the Stanley
Foundation. Finally, in the past year, Dr. Sackeim has served as Study
Chair developing a national, multi-site investigation of the antidepressant
potential of non-convulsive TMS.
Other Research Efforts
There was a large number of diverse research accomplishments in the past
year. These efforts included completion of the first trial of Vagus Nerve
Stimulation (VNS) in the treatment of major depression, with the key report
appearing in 2001 in Neuropsychopharmacology, and supervision of a large
national study of VNS. The Brain Imaging Division of the Department of
Biological Psychiatry was especially active. This group, led by Drs. Mensh,
Moeller, and Yu and using PET, identified mismatches between blood flow
and cerebral metabolism in patients with late-onset major depression and
the brain circuits involved in therapeutic response to antidepressant
medications. Dr. Nobler completed a study in healthy volunteers of the
circuits involved in memory of recent and remote autobiographical events,
as well as semantic memory. This and related work has led to a new NIMH-supported
study, using PET, to identify the brain abnormalities involved in retrograde
amnesia. In a similar vein, Dr. Kinnunen established a new paradigm, using
fMRI, to investigate the circuitry involved the anterograde amnesia produced
by ECT. Dr. Pelton completed a study, using PET measurement of cerebral
blood flow, on the alterations in regional brain activity that accompany
an immunological challenge in healthy volunteers. In addition, in collaboration
with Dr. Fallon in the Department of Therapeutics, the first evidence
was presented for abnormal blood flow and cerebral metabolism in individuals
with persistent and treatment-resistant Lyme disease.
The Neuropsychiatry Clinics, comprising the Memory Disorders Center, Huntington’s
Disease Society of America Center of Excellence, Late-Life Depression
Clinic, and the Brain-Behavior Clinic all continued to be among the most
active clinical research facilities at NYSPI. During the past year, a
variety of new projects were initiated in these facilities, including
work on the treatment of cognitive impairment in patients with major depression
(Drs. Pelton and Devanand) and several new research grants were obtained.
In particular, Drs. Burt, Pelton, and Seidman received K-awards for research
conducted in these clinics.