TREATMENT RESISTANT SCHIZOPHRENIA: NEW THERAPEUTIC

OPTIONSNicola Cascella, MD

Neuropsychiatry ProgramSheppard Pratt Medical Institution

Baltimore, Maryland, USA

Schizophrenia domains of psychopathology

cognition

Lack of social drive

Poverty of speech

Diminished emotional range

Hallucinations & delusions

The CaseBM 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 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.

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 DisruptsThalamofrontal 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 schizophrenia-like auditory hallucinations]. Seishin Shinkeigaku Zasshi 108:31-41.

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 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 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) .

•

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 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.

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 AffectsSchizophrenia-Like Behavior in Two Rat Models of Schizophrenia. (Klein

et al. 2013)

Midbrain Activation During Pavlovian Conditioningand Delusional Symptoms in Schizophrenia

Romaniuk et al., 2010

Impaired Prefrontal-Basal Ganglia FunctionalConnectivity 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• William 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