1. Effect of Anti-Inflammatory and Antipsychotic Treatment on
Efficacy of DBS for Treatment Resistant Depression
© 2014 Mayo Foundation for Medical Education and Research
Emma K. Brousseau,1,2 Saima Machlovi,1 Shari L. Sutor,1 Mark A. Frye,1 Susannah J. Tye PhD1,3
1Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN; 2Saint Mary’s College, Notre Dame, IN;
3Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN
A special thank you to the Mayo Clinic Translational Neuroscience
Laboratory and the Mayo Graduate School. This research project was
completed in fulfillment of the Mayo Clinic Summer Undergraduate
Research Fellowship.
Acknowledgements
Conclusions
1. Perez-Caballero L, et al. (2014) Early responses to deep brain
stimulation in depression are modulated by anti-inflammatory
drugs. Molecular Psychiatry, 19: 607-614.
2. Hamani C, et al. (2010) Antidepressant-like effects of medial
prefrontal cortex deep brain stimulation in rats. Biol. Psychiatry,
67: 117-124.
3. Nestler EJ & Hyman SE. (2010) Animal models of
neuropsychiatric disorders. Nature Neuroscience, 13(10): 1161-
1169.
References
Introduction Results
● Male albino Sprague-Dawley rats underwent
treatment as outlined in the adjacent timeline
(Figure 3).
● Control animals received daily injections of saline
(0.9% in 1 mL; i.p.). Treatment resistant
depression was induced via chronic
adrenocorticotropic hormone (ACTH;100µg/day)
injections (i.p.).
● Electrodes were implanted into the infralimic
cortex via stereotactic surgery,
● Behavior tests were completed
before and after surgery as shown
in Figure 3.
● Brain and cardiac blood collected
from each rat post-mortem.
Behavioral Tests
Figure 1.
Ventromedial
prefrontal cortex
Figure 3. Timeline of treatments and
behavioral testing
Experimental Protocol
Timeline
● Known for it’s strong predictive validity, the Porsolt Forced Swim Test (FST) is a black box method
for identifying antidepressant-like effects in rats.3
● FST involves short-term stress during which the
acutely treated rat can respond actively
(swimming, climbing) or passively (immobility).3
Figure 2. Porsolt
Forced Swim Test
set-up
● For patients with treatment-resistant depression,
deep brain stimulation (DBS) has become a
viable and effective treatment option.1
● Electrodes stimulating Brodmann areas 24/25 in
the subgenual cingulated gyrus (SCG) create an
initial antidepressant response that declines after
the first few weeks.1 A steady improvement then
occurs as the DBS treatment proceeds.1
● The early effect appears to be modulated by local
inflammation and patients taking anti-
inflammatory drugs are reported to have lower
response rates.1
● This study aims to elucidate the mechanisms
through which pharmacotherapies may impact
short term efficacy of DBS for depression.
● To achieve this, we have utilized a DBS in a
rodent model of treatment resistant depression,
targeting the infralimbic cortex in the ventromedial
prefrontal cortex (vmPFC), which corresponds to
Brodmann area 25 in the SCG.2
Aim: To investigate the role of anti-inflammatory
(Ibuprofen) and antipsychotic (Risperidone) treatments
in the early antidepressant response of infralimbic DBS.
Figure 6.
Open field
test results
for all
treatments
pre- and
post-surgery
Figure 4. Risperidone treatment efficacy in immobility scores of Forced Swim
Test pre-(blue) and post-surgery (red).
Figure 5. DBS and SHAM responses to Risperidone and Ibuprofen
treatments in immobility scores of post-surgery Forced Swim Test
A treatment-resistant depression model was created
through chronic ACTH administration, showing
increased immobility, a marker for depression-like
symptoms.
● Risperidone alone has an antidepressant-like
effect in Figure 4 with decreased immobility.
● In Figure 5, DBS treatment decreases immobility.
The addition of Risperidone decreases this
efficacy. However, when Ibuprofen is added to the
treatment, DBS has decreased immobility again.
Thus, DBS treatment with the addition of both
Risperidone and Ibuprofen has an
antidepressant-like effect.
● SHAM, however, has increased immobility
combined with both drugs in Figure 5. SHAM with
Risperidone alone also shows an increase in
immobility in Figure 4.
ACTH administration may be affecting a neural-immune
reactivity mechanism through its dysregulation of the
HPA axis. This would cause hyperactivity of
inflammatory markers. DBS, much more than SHAM,
has a therapeutic effect. The efficacy of Risperidone
may be due to its altering of cytokine production,
decreasing inflammation. And Ibuprofen may regulate
inflammatory markers as an inhibitor of the downstream
pathway. Such mechanisms should be explored further.
Figure 7.
Elevated maze
test results for
all treatments
pre- and post-
surgery
● The other behavioral tests, Open Field (OFT) and Elevated Maze (EMZ),
are used as negative controls. They are used to determine if treatments are
affecting locomotion or anxiety.