TREATMENT RESISTANT
SCHIZOPHRENIA: NEW THERAPEUTIC
OPTIONS
Nicola Cascella, MD
Neuropsychiatry Program
Sheppard Pratt Medical Institution
Baltimore, Maryland, USA
Schizophrenia domains of
psychopathology
cognition
Hallucinations &
delusions
Lack of social
drive
Poverty of
speech
Diminished
emotional range
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?
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)
“Most recent” pharmacological
add-on to clozapine
•Lamotrigine
•Famotidine
The circuit for DBS in SZ
SNr
Thalamus
MD nucleus
Cortex
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 selfproduced 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.
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 response
Inhibition of Mediodorsal Thalamus Disrupts
Thalamofrontal Connectivity and Cognition (Parnadeau et al.
2013)
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 schizophrenialike auditory hallucinations]. Seishin Shinkeigaku Zasshi
108:31-41.
Post-mortem studies in patients with schizophrenia
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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 animals
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.
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.
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 drugnaïve 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) .
•
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).
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 risperidoneresistant schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry 32:948-954.
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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.
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)
Midbrain Activation During Pavlovian Conditioning
and Delusional Symptoms in Schizophrenia
Romaniuk et al., 2010
Impaired Prefrontal-Basal Ganglia Functional
Connectivity and Substantia Nigra Hyperactivity
in Schizophrenia
Yoon et al., 2013
Anatomical location of the
substantia nigra pars reticulata
SNr in red; STN in yellow
Trajectories for Implantation of the DBS System
Electrophysiological identification of SNr during DBS Implantation
• JHU Neurosurgery
• JHU Neurology
• William Anderson
• Fred Lenz
• Stephen Grill
• JHU Dept of Psychiatry
• David Schretlen
• Akira Sawa
• McLean and Brigham
Harvard
• Lauren Moran
• Travis Tierney
• David Silbersweig