Remission of Major Depression Under Deep Brain
Stimulation of the Lateral Habenula in a
Therapy-Refractory Patient
To the Editor:
epression is a severe, common psychiatric illness with
limited therapeutic options. Only approximately twothirds of patients treated respond to standard antidepressants. Even with electroconvulsive therapy (ECT), a significant
fraction remains therapy refractory.
For such cases deep brain stimulation (DBS) is currently under
investigation: DBS of the subcallosal cingulate was successful in 7 of
20 patients after 6 months (1). Stimulating the ventral capsule/
ventral striatum resulted in 3 of 15 remitted patients (2).
A possible novel target is suggested by anatomical implications
of the long-standing monoamine hypothesis of depression (3): the
serotonergic, noradrenergic, and dopaminergic system each have
strong interactions and direct efferents from the lateral habenula
(LHb) (to dorsal raphe nuclei, locus coeruleus, and ventral tegmental area) that in turn receives limbic and cortical inputs (4). During
learned helplessness, an animal model of depression and anxiety
(5), susceptible rats (6) showed striking LHb hypermetabolism (7).
In humans, this area covaries with dorsal raphe nuclei activity
during the induction of depression through tryptophan depletion
(8,9), and shows selective volume reductions in brains of patients
with depression (10). Recent primate work implicated the LHb in
controlling reward through the ventral tegmental area, constituting
a “circuit of disappointment” (11). In summary, convergent evidence indicates that overactivity in the LHb is present during
depressed states, where it could drive the changes in midbrain
activity linked to depression (12,13). This suggests that the LHb
might prove to be a promising novel target for DBS in cases of
intractable major affective disorder.
We report here the results on the first patient with treatmentresistant major depression undergoing bilateral DBS of the major
afferent bundle (i.e., stria medullaris thalami) of the LHb.
Patient and Method. Our female patient with major depressive disorder (DSM-IV) was 64 years old at the time of DBS
surgery (July 2008). She suffered from major depressive episodes
(MDE) beginning at age 18 without any hypomanic or manic
episodes. No additional psychiatric diagnoses were made. At age
55, the first severe depressive episode with psychotic features was
described. Appropriate pharmacotherapeutic trials involving antidepressants and augmentation with lithium, valproate, and various
antipsychotic medications could not control the illness. At age 59,
after two suicide attempts, she received ECT. Although remission
was achieved after seven sessions, it could not be maintained. The
patient unfailingly experienced early relapse despite maximal pharmacotherapy (at least one antidepressant, one antipsychotic and
lithium), necessitating repeat ECT. We therefore started maintenance ECT (mECT), 2.5 years before surgery. However, we were
unable to prolong ECT intervals to a period of 2 weeks or longer
without relapse, despite concurrent medication including sertraline,
mirtazepine, and risperidone in the last year. During mECTs, the
patient experienced four severe relapses, rapidly developing over 2
days–3 days, reaching Hamilton Depression Scale (HAMD21) ratings
of approximately 45, with severe psychotic features (delusions of
guilt), mutism, and pronounced anxiety. With deteriorating quality
of life and increasing side effects from ECT and pharmacotherapy,
we suggested DBS surgery.
Figure 1. Clinical time course. This figure demonstrates three relapses of our
patient, quantified with the Hamilton depression scale (HAMD21). The first
relapse was treated with six electroconvulsive therapy sessions. Later on,
during full remission at week 0, deep brain stimulation (DBS) surgery was
performed. As shown in red, early stimulation was done with 5 V, and the
patient consecutively relapsed again. Stimulation was stepwise increased to
10.5 , and finally the patient reached full and stable remission (HAMD21 ⫽ 3).
The third relapse occurred a couple of days after the DBS unit was switched
off due to an incidental bicycle accident. Again the patient reached remission (HAMD21 ⫽ 0) after 12 weeks of high-voltage DBS.
After two independent psychiatrists evaluated the patient and
supported this course of action, we obtained informed consent
from the patient (during a phase of remission), her husband, and
her son for this off-label-use treatment option. After a severe
relapse 3 weeks later, another ECT course, and full remission she
received bilateral DBS surgery. The complete time course is
demonstrated in Figure 1 (see also Supplement 1).
We measured brain glucose metabolism with fluorodeoxyglucose positron emission tomography (FDG-PET) before
DBS surgery (T1) to exclude causes of organic mood disorder
and followed up with a study at week 24 (T2) during
high-parameter stimulation. At each time point the patient was
clinically remitted.
To localize changes over time, we co-registered the PET T1
and T2 images and calculated a difference image (T2 ⫺ T1). To
localize anatomical regions as well as the position of the
electrode tips, the post-operation CT image was co-registered to
a high-resolution T1 (1 mm ⫻ 1 mm ⫻ 1 mm) magnetic
resonance tomography (MRT) scan of the patient and the PET
difference images to the T1 MRT scan with the same transformation parameters. All processing steps used SPM5 (Wellcome Trust
Center for Neuroimaging, London, United Kingdom; http:// A strong bilateral increase of metabolism was found bilaterally at the electrode tips in the afferent
bundles (Figure 2).
Discussion. The DBS procedure resulted in a sustained full
remission of depressive symptoms in a patient who was therapyresistant to all standard treatments for at least 9 years and
suffered from severe major depressive disorder for 46 years.
Placebo effects, which are extremely uncommon in this patient
population (14), could be further excluded by a severe relapse
when stimulation was briefly accidentally discontinued.
We did not observe an acute antidepressive effect of DBS.
After switching to high stimulation, the interval to remission of
© 2009 Society of Biological Psychiatry
e2 BIOL PSYCHIATRY 2009;xx:xxx
Supplementary material cited in this article is available
Alexander Sartorius
Department of Psychiatry and Psychotherapy
Central Institute of Mental Health
J5, D-68159 Mannheim, Germany
[email protected]
Karl L. Kiening
Department of Neurosurgery
Division of Stereotactic Neurosurgery
University Hospital Heidelberg
Heidelberg, Germany
Peter Kirsch
Department of Psychiatry and Psychotherapy
Central Institute of Mental Health
Mannheim, Germany
Carl C. von Gall
Uwe Haberkorn
Department of Nuclear Medicine
University of Heidelberg
Heidelberg, Germany
Figure 2. Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging of metabolic effects of deep brain stimulation treatment. Cerebral standardized uptake values (SUVs) are shown. (A) The FDG-PET image at time point
T2 (post-surgery, full stimulation, full remission, week 24 in Figure 1), showing
marked metabolic increase at electrode tip sides. (B) Sagittal view shows coincidence of left electrode tip position (marked in green) with maximum metabolic increase with a difference of approximately 6 SUVs between T2 and T1
(post-surgery–pre-surgery). Thresholded positive difference images overlayed
on the magnetic resonance tomography scan are shown. (C and D) Transversal
and coronal view as indicated by yellow line in (B).
Andreas W. Unterberg
Department of Neurosurgery
University Hospital Heidelberg
Heidelberg, Germany
Fritz A. Henn
Brookhaven National Laboratory
Life Sciences
Long Island, New York
Andreas Meyer-Lindenberg
approximately 4 months corresponds to the mean time span
reported in other DBS patients stimulated at the ventral capsule/
ventral striatum or subcallosal cingulate (1,2). This convergent
experience, which is in marked contrast with the immediate
effects that DBS has in many neurological conditions, points to
induced neural plasticity in mood-regulatory circuits in recovery
from depression.
With FDG-PET, we could verify a localized metabolic increase at
the stimulation sites, as intended. Because local brain energy
consumption is driven by both inhibitory and excitatory synaptic
activity (15), the functional consequences of this afferent stimulation
on the LHb cannot be directly inferred from PET but are expected to
be inhibitory as discussed in the preceding text. No changes in LHb
metabolism were detected or expected, because convergent prior
data showed a state-dependency of LHb hyperactivity, and our
patient was in full remission during both procedures.
In conclusion, we report the first successful treatment of a severe
treatment-resistant depression with verified functional modulation
of the major afferent bundle of the LHb. Our data support a critical
role of this structure, at the juncture of brainstem monoaminergic
systems and limbic regulatory cortex, in depression. Our experience
should prompt a clinical trial of this approach.
We would like to acknowledge the excellent clinical support
of Dr. Eva Grips and Dr. Michael Fritzinger. The authors AS and
KLK are joint first authors.
The authors reported no biomedical financial interests or
potential conflicts of interest.
Department of Psychiatry and Psychotherapy
Central Institute of Mental Health
Mannheim, Germany
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Remission of major depression under deep brain stimulation of the