SCHIZOPHRENIA NEW THERAPEUTIC OPTIONS Nicola Cascella MD Neuropsychiatry Program Sheppard Pratt Medical Institution Baltimore Maryland USA Schizophrenia domains of psychopathology The Case ID: 302133
Download Presentation The PPT/PDF document "TREATMENT RESISTANT" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
TREATMENT RESISTANT SCHIZOPHRENIA: NEW THERAPEUTIC OPTIONS
Nicola
Cascella
, MD
Neuropsychiatry Program
Sheppard Pratt Medical Institution
Baltimore, Maryland, USASlide2
Schizophrenia domains of psychopathologySlide3
The Case
BM is a 36-year-old female with a 17 years history of schizophrenia that is resistant to treatment. The impact of auditory hallucinations and delusions of persecution as well as first rank symptoms of thought broadcasting have been significant on her functioning. She has been unable to keep employment. She seldom leaves the house. She takes
clozapine
and
abilify
as
neuroleptics
. Because of depression she is on
fluoxetine
and
sertraline
.
Clonazepam
is used to control her anxiety and
lamotrigine
was prescribed to prevent seizures she had developed on
clozapine
in the past. More recently
famotidine
has been added to better control positive symptoms. She sees a therapist weekly. CBT has been tried but has not been helpful.
What
other treatment
options should we consider for this patient?Slide4
Physiopathology of treatment resistance
Dopamine synthesis capacity in patients with treatment-resistant schizophrenia.
(
Demjaha
A
et al.
, 2012)
Antipsychotic Treatment Resistance in Schizophrenia Associated with Elevated Glutamate Levels but Normal Dopamine Function. (
Demjaha
A
,
et al., 2013)Slide5
“Most recent” pharmacological add-on to clozapine
Lamotrigine
FamotidineSlide6Slide7
The circuit for DBS in SZ Slide8
CD-FF
Feinberg I
,
Guazzelli
M
.
Schizophrenia--a disorder of the corollary discharge systems that integrate the
motor
systems of thought with the sensory systems of consciousness.
Br J Psychiatry.
1999 Mar;174:196-204.
Thinking is our most complex motor act and as such it might conserve and utilize the computational and integrative mechanisms evolved for physical movement (H. Jackson,
Selected Writings
, (ed. J Taylor) 1958)
CD-FF in the motor system of thoughts would act to distinguish
self-produced
from externally stimulated events in consciousness.
CD would provide a neural basis for the “sensation of the intensity of
will
” as von
Helmoltz
referred to in 1925.Slide9
The Medio-dorsal nucleus of the Thalamus and Schizophrenia
Animal models
Case Reports of medial thalamic infarction in humans
Post-mortem studies in patients with schizophrenia
Structural magnetic resonance imaging (MRI)
White matter abnormalities – diffusion tensor imaging (DTI)
Functional
neuroimaging
– PET and
fMRI
Thalamus and treatment responseSlide10
Inhibition of Mediodorsal Thalamus Disrupts
Thalamofrontal
Connectivity and
Cognition (
Parnadeau
et al. 2013)Slide11
Case Reports of medial thalamic infarction in humans
McGilchrist
, I., Goldstein, L.H.,
Jadresic
, D., and Fenwick, P. 1993.
Thalamo
-frontal psychosis.
Br J Psychiatry
163:113-115.
Noda, S.,
Mizoguchi
, M., and Yamamoto, A. 1993. Thalamic experiential
hallucinosis
.
J
Neurol
Neurosurg
Psychiatry
56:1224-1226.
Santos, S.,
Alberti
, O.,
Corbalan
, T., and Cortina, M. 2009. Stroke-psychosis. Description of two cases.
Actas
Esp
Psiquiatr
37:240-242.
Yoshida, Y., Abe, K., and
Yoshizawa
, K. 2006. [A case of left
dorsomedial
thalamic infarction with unilateral schizophrenia-like auditory hallucinations].
Seishin
Shinkeigaku
Zasshi
108:31-41.Slide12
Post-mortem studies in patients with schizophrenia
5 post-mortem studies in patients with schizophrenia have found a decreased number of neurons in the MD and/or a decreased volume of the MD.
5 other studies did not find any differences in the MD between patients and controls.
A post-mortem study evaluated the synaptic protein Rab3 as a marker of synaptic density and found decreased Rab3 in the thalamus which was most pronounced in the left MD and anterior nucleus (
Blennow
et al., 2000
).
Another post-mortem study examined
parvalbumin
immunoreactivity
. Decreased
parvalbumin
immunore
activity was found in the middle layers (deep III and IV) of the DLPFC, whereas more superficial layers (II and superficial III) of the cortex were spared in patients with schizophrenia compared to controls (
Lewis et al., 2001
).
This finding is consistent with the hypothesis of decreased axon terminals specifically from the MD, since MD projection neurons target layers III and IV whereas cortical inhibitory
interneurons
target all of the examined layers.
Primates treated with chronic
neuroleptics
did not have any differences in
parvalbumin
-labeled axon terminals than control animalsSlide13
Structural magnetic resonance imaging (MRI)
Konick
, L.C., and Friedman, L. 2001.
Meta-analysis of thalamic size in schizophrenia.
Biol
Psychiatry
49:28-38.
Byne
, W.,
Buchsbaum
, M.S.,
Kemether
, E.,
Hazlett
, E.A.,
Shinwari
, A.,
Mitropoulou
, V., and
Siever
, L.J. 2001.
Magnetic resonance imaging of the thalamic
mediodorsal
nucleus and
pulvinar
in schizophrenia and
schizotypal
personality disorder
.
Arch Gen Psychiatry
58:133-140.
Kemether
, E.M.,
Buchsbaum
, M.S.,
Byne
, W.,
Hazlett
, E.A.,
Haznedar
, M., Brickman, A.M.,
Platholi
, J., and Bloom, R. 2003.
Magnetic resonance imaging of
mediodorsal
,
pulvinar
, and
centromedian
nuclei of the thalamus in patients with schizophrenia
.
Arch Gen Psychiatry
60:983-991.
Portas
, C.M., Goldstein, J.M.,
Shenton
, M.E.,
Hokama
, H.H.,
Wible
, C.G., Fischer, I.,
Kikinis
, R.,
Donnino
, R.,
Jolesz
, F.A., and
McCarley
, R.W. 1998.
Volumetric evaluation of the thalamus in schizophrenic male patients using magnetic resonance imaging.
Biol
Psychiatry
43:649-659.Slide14
White matter abnormalities – diffusion tensor imaging (DTI)
Kim, D.J., Kim, J.J., Park, J.Y., Lee, S.Y., Kim, J., Kim, I.Y., Kim, S.I., and Park, H.J. 2008.
Quantification of
thalamocortical
tracts in schizophrenia on probabilistic maps.
Neuroreport
19:399-403.
Kito
, S., Jung, J., Kobayashi, T., and Koga, Y. 2009.
Fiber tracking of white matter integrity connecting the
mediodorsal
nucleus of the thalamus and the prefrontal cortex in schizophrenia: a diffusion tensor imaging study
.
Eur
Psychiatry
24:269-274.Slide15
Functional Neuroimaging
– PET
Hypometabolism
of the MD in SZ vs. controls (
Hazlett
at al., 2004;
Buchsbaum
et al., 2007
)
Hypometabolism
in the MD in SZ has also been found in drug-naïve subjects (
Lehrer et al., 2005
)
Decreased functional connectivity of the MD to other circuit areas (
Mitelman
et al., 2005; Katz et al 1996
)
Decreased D2/3 receptor binding in MD (
Kessler et al., 2009;
Talvik
, et al., 2003.;
Buchsbaum
et al., 2006.;
Yasuno
, et al., 2004
)
.
Decreased dopamine binding in MD is correlated with positive symptoms (
Buchsbaum
et al., 2006.;
Yasuno
, et al., 2004
).
Dopaminergic
innervation
to MD has been identified in the MD as well as the midline and
intralaminar
thalamic nuclei (
Deicken
et al., 2002;
Rieck
et al., 2004
) .
Slide16
Functional Neuroimaging – fMRI
SZ subjects show decreased activation of MD compared with controls in working memory tasks (
Andrews et al., 2006
)
A meta-analysis of 41
fMRI
studies of executive function in SZ demonstrated decreased activation in the left DLPFC, anterior
cingulate
and MD across a variety of different tasks used to test executive function (
Minzenberg
et al., 2006
). Slide17
Thalamus and treatment response
Molina Rodriguez, V.,
Montz
Andree, R., Perez
Castejon
, M.J.,
Capdevila
Garcia, E., Carreras Delgado, J.L., and
Rubia
Vila, F.J. 1996.
SPECT study of regional cerebral perfusion in
neuroleptic
-resistant schizophrenic patients who responded or did not respond to
clozapine
.
Am J Psychiatry
153:1343-1346.
Holcomb, H.H.,
Cascella
, N.G.,
Thaker
, G.K.,
Medoff
, D.R.,
Dannals
, R.F., and
Tamminga
, C.A. 1996.
Functional sites of
neuroleptic
drug action in the human brain: PET/FDG studies with and without haloperidol
.
Am J Psychiatry
153:41-49.
Molina, V., Tamayo, P., Montes, C., De
Luxan
, A., Martin, C., Rivas, N.,
Sancho
, C., and Dominguez-Gil, A. 2008.
Clozapine
may partially compensate for task-related brain perfusion abnormalities in
risperidone
-resistant schizophrenia patients
.
Prog
Neuropsychopharmacol
Biol
Psychiatry
32:948-954.
Strungas
, S., Christensen, J.D., Holcomb, J.M., and
Garver
, D.L. 2003.
State-related thalamic changes during antipsychotic treatment in schizophrenia: preliminary observations
.
Psychiatry Res
124:121-124.
Cohen, B.M., and
Yurgelun
-Todd, D. 2001.
Alterations of thalamic activity in schizophrenia and in response to antipsychotic drugs: studies in the legacy of Seymour S.
Kety
.
Neuropsychopharmacology
25:305-312.
Lavin, A., and Grace, A.A. 1998.
Response of the ventral
pallidal
/
mediodorsal
thalamic system to antipsychotic drug administration: involvement of the prefrontal cortex.
Neuropsychopharmacology
18:352-363.Slide18
DBS in Preclinical Models of Schizophrenia
1. Opposite effects of
ketamine
and DBS on rat
thalmo
-cortical information processing. (
Kulikova
et al. 2012)
2. DBS of the
mediodorsal
thalamic nucleus yields increases in the expression of
zif-268
but not
c-
fos
. (
Ewing et al. 2013)
3. Mapping
Brain Regions in Which Deep Brain Stimulation Affects
Schizophrenia-Like Behavior in Two Rat Models of
Schizophrenia. (
Klein et al. 2013
)Slide19
Midbrain Activation During Pavlovian Conditioning
and Delusional Symptoms in Schizophrenia
Romaniuk
et al., 2010Slide20
Impaired Prefrontal-Basal Ganglia FunctionalConnectivity and Substantia
Nigra
Hyperactivity
in Schizophrenia
Yoon et al., 2013Slide21
Anatomical location of the substantia
nigra
pars
reticulata
SNr
in red; STN in yellowSlide22
Trajectories for Implantation of the DBS SystemSlide23
Electrophysiological identification of
SNr
during DBS ImplantationSlide24
JHU NeurosurgeryWilliam Anderson
Fred Lenz
JHU Dept of Psychiatry
David
Schretlen
Akira
Sawa
JHU Neurology
Stephen Grill
McLean and Brigham Harvard
Lauren Moran
Travis Tierney
David
Silbersweig