Pathophysiology and Evolving

Theories in Schizophrenia

Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.

©Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD April 2017 MRC2.CORP.D.00244

1 The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice
or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
 This program was developed with the support of
Otsuka Pharmaceutical Development &
Commercialization, Inc. and Lundbeck, LLC.
The speakers are either employees or
paid contractors of Otsuka Pharmaceutical
Development & Commercialization, Inc.

The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice
2 or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
 Brain Regions Implicated in
Schizophrenia's Phenotypic Makeup1-3
Delusions Euphoria Motor
Pleasure Reward Relay site from PFC
Interests Motivation
Libido Hallucinations A=amygdala
Fatigue ACC=anterior cingulate
cortex
Executive function BF=basal forebrain
Attention C=cerebellum
Concentration H=hippocampus
Emotions Hy=hypothalamus
S NA=nucleus accumbens
Negative symptoms PFC T
Ruminations AC PFC=prefrontal cortex
NA S=striatum
Suicidality C SC=spinal cord
BF Hy T=thalamus

Pain
A Sensory relay
C Alertness
Memory H
Alertness Fear
Anxiety Motor
Panic Sleep
Memory Pain SC Appetite
Re-experiencing Endocrine

1. Stahl SM, Mignon L. Chapter 1. In: Stahl's Illustrated Antipsychotics: Treating Psychosis, Mania, and Depression; 2010:1-30. 2. Stahl SM. Chapter 4. In: Stahl SM, ed. Stahl's
Essential Psychopharmacology: Neuroscientific Basis and Practical Application. 4th ed; 2013:79-128. 3. Turner JA, et al. Neuroinformatics. 2006;4(1):21-49.

3 The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Many Neurotransmitters Are Implicated
in Schizophrenia
Dopamine (DA) • Depending on pathway affected, may mediate1
– Positive symptoms
– Negative symptoms
– Affective symptoms
– Cognitive dysfunction
Serotonin (5-HT) • May mediate negative symptoms1
• May ameliorate D2-induced EPS1
Norepinephrine (NE) • May mediate arousal, attention, and cognitive shifts2,3

Glutamate • Implicated in a wide range of positive, negative, and

and GABA cognitive symptoms4-7

• It is important to recognize that these systems are interconnected and likely

modulate each other’s activity; their roles in schizophrenia should be hypothesized
within this context
D2, dopamine receptor D2; EPS, extrapyramidal symptoms; GABA, gamma-aminobutyric acid.
1. Meltzer HY, et al. Chapter 16. Schizophrenia. In: Ebert MH, et al, eds. Current Diagnosis & Treatment: Psychiatry, 2e; 2008. 2. Yamamoto K, Hornykiewicz O. Prog
Neuropsychopharmacol Biol Psychiatry. 2004;28(5):913-922.3. Sara SJ. Nat Rev Neurosci. 2009;10(3):211-223. 4. Stahl SM. Chapter 4. In: Stahl SM, ed. Stahl's Essential
Psychopharmacology: Neuroscientific Basis and Practical Application. 4th ed; 2013:79-128. 5. Marek GJ, et al. Mol Pharmacol. 2010;77(3):317-326. 6. Taylor SF, et al.
Neuropsychopharmacology. 2014;39(4):1000-1008. 7. Stan A, Lewis DA. Curr Pharm Biotechnol. 2012;13(8):1557-1562.

4 The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Alterations in Glutamate and GABA

Glutamate – Major Excitatory Neurotransmitter1 Cerebral Cortex

• Strong evidence for reduced glutamate signaling in
schizophrenia, especially at the NMDA receptor2
• Signaling components altered in individuals with
schizophrenia2 S
• Genes associated with increased schizophrenia
risk are involved in glutamate signaling3 ACC T
PFC
GABA – Major Inhibitory Neurotransmitter4 Hy
• GABA biosynthesis is tightly coupled to
glutamate via GAD enzyme, which is reduced in A
patients with schizophrenia5,6 C
H
• Neuroimaging studies suggest:
• Reduced GABA-mediated cortical inhibition in
schizophrenia7
• Negative affect in schizophrenia associated Glutamate
(directly or indirectly) with GABAergic function8 GABA
A, amygdala; ACC, anterior cingulate cortex; C, cerebellum; GABA, gamma-aminobutyric acid; GAD, glutamic
acid decarboxylase; H, hippocampus; Hy, hypothalamus; NMDA, N-methyl-D-aspartate; PFC, prefrontal cortex; Illustration adapted from: Carlsson A. Int Clin Psychopharmacol.
S, septum, T, thalamus.
1995;10(Suppl 3):21-28 and Paul SM. In: Bloom FE, et al., eds.
1. Boulland JL, et al. J Comp Neurol. 2004;480(3):264-80. 2. Marsman A, et al. Schizophr Bull. 2013;39(1):120-9. Psychopharmacology: the Fourth Generation of Progress. 1995:87-
3. Owen MJ, et al. Mol Psychiatry. 2004;9(1):14-27. 4. D'Hulst C, et al. Drug Discov Today. 2009;14(17-18):866-
75. 5. Choudary PV, et al. Proc Natl Acad Sci USA. 2005;102(43):15653-8. 6. Addington AM, et al. Mol
94.
Psychiatry. 2005;10(6):581-8. 7. Rogasch NC, et al. Schizophr Bull. 2014;40(3):685-96. 8. Taylor SF, et al.
Neuropsychopharmacology. 2014;39(4):1000-8.

5 The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Nicotinic Modulation of DA, GABA &
Glutamate
• Acetylcholinergic system: a7
a4b2
• Muscarinic and nicotinic PFC
glu neuron
receptors (nAChRs) are GABA
PPT/LDT
widespread throughout the brain1 ACh neuron glu
ACh
• May be involved in cognitive Nicotine
Nicotine
directly
and attentional processing1 desensitizes activates
Nicotine indirectly DA
activates DA
DA release
release
• Deficits in acetylcholinergic
functioning have been
demonstrated in schizophrenia VTA
and the nAChR has emerged GABA DA neuron
interneuron
as a putative target to improve
cognitive deficits1

• Modulation of DA release through nicotinic receptor

activation is achieved through various interactions
with GABA and glutamatergic cells2
a7, a7 nicotinic acetylcholine receptor; a4b2, a4b2 nicotinic acetylcholine receptor; ACh, acetylcholine; DA, dopamine; GABA, gamma-aminobutyric acid; Glu, glutamate;
PPT/LDT, pedunculopontine and laterodorsal tegmental; nAChR, nicotinic acetylcholine receptor; VTA, ventral tegmental area.
1. Rowe AR, et al. J Psychopharmacol. 2015;29(2):197-211.
2. Opler LA, et al. CNS Spectr. 2014;19(2):142-156.

6 The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Additional Hypotheses
Hypothesis Details/Evidence
• Family, twin, and adoption studies suggest hereditary
Genetics component1
• Multiple genes implicated1

• Neuroinflammation, microglial activation, cytokine production,

Neuroinflammation
and other immune processes observed in disease2,3

Plasticity / Connectivity • Possible structural changes at the cellular level and/or functional
Changes changes through changes at the synaptic level4

• Neuroimaging studies reveal changes in the morphology and

White Matter integrity of white matter tracts are present from the earliest
Alterations disease stages5
• Alterations in white matter can be found in multiple brain regions6
1. Sun et al. PLoS One. 2010;5(6):e11351. 4. Stephan KE et al. Biol Psychiatry. 2006;59(10):929-939.
2. Girgis et al. Biol Psychiatry. 2014;75(4):292-299. 5. Connor CM, et al. Int J Dev Neurosci. 2011;29(3):325-34.
3. Monji A. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:115-121. 6. Kubicki M, et al. Neuroimage. 2005;26(4):1109-18.

7 The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Genetic Risk in Schizophrenia1

1. Kahn RS, et al. Nat Rev Dis Primers. 2015;1:15067.

8 The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Neuroinflammation in Schizophrenia
• Several studies have reported increased
blood concentrations of inflammatory
cytokines in patients with schizophrenia1
• Blood cytokine abnormalities have been
associated with:
– Cognitive function decline1
– Negative symptoms1
– Decreased CNS volume1,2
• Additional inflammatory abnormalities in
schizophrenia include increased levels of:
– Autoantibodies1
– C-reactive protein1
– Circulating lymphocytes1
– Monocytes3
– Activated microglial cells3
– Macrophages3
• Evidence of increased risk of schizophrenia
in offspring arising from gestational infection Image from: Miller et al. 20094
and enhanced maternal cytokine levels3
5-HT, serotonin; BDNF, brain-derived neurotrophic factor; GLU, glutamate; IDO, indolamine 2,3 dioxygenase; IFN, interferon; IL, interleukin; NMDA, N-methyl-D-aspartate;
QUIN, quinolinic acid; RNS, reactive nitrogen species; ROS, reactive oxygen species; TNF, tumor necrosis factor; TRP, tryptophan.
1. Kirkpatrick B, et al. Schizophrenia bulletin. 2013;39(6):1174-9. 3. Donev R (ed). Advances in Protein Chemistry and Structural Biology (Vol. 88). Academic Press; 2012.
2. Müller N, et al. Front Neurosci. 2015;9:372. 4. Miller AH et al. Biol Psychiatry. 2009;65(9):732-741.

9 The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Alterations in Plasticity

• Plasticity — complex
structural/functional changes in the
nervous system underlying
learning/memory1-3 + Synaptic
Activity
• “Dysconnection hypothesis”
states core pathology in - Synaptic
schizophrenia due to Activity

abnormal glutamate receptor

regulation by other neuro-
transmitters (eg, DA, 5-HT,
acetylcholine)4
• Anatomical changes Synaptic plasticity6: ongoing, adaptable structural changes involving glutamate
over time suggest receptors and underlying learning, memory, and cognitive changes 1-3
possible brain remodeling3
• Clinical success with targeted
cognitive training suggest benefits
of restoring plasticity5
5-HT, serotonin; DA, dopamine. 3. Lesch & Waider. Neuron. 2012;76(1):175-191.
4. Stephan KE, et al. Biol Psychiatry. 2006;59(10):929-939.
1. Purves D et al (eds). Neuroscience. 2nd Edition. Sinauer Associates, 2001.
5. Fisher M, et al. Schizophr Bull. 2010;36(4):869-879.
2. Bermúdez Rattoni F (ed). Neural Plasticity and Memory: From Genes to Brain
6. Image: Vitureira N, Goda Y. J Cell Biol. 2013;203(2):175-186.
Imaging. Boca Raton (FL): CRC Press; 2007.

10 The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 White Matter Alterations
• White matter alterations have been found in high risk individuals
prior to disease onset1
• Postmortem studies reveal alterations in frontal, temporal, and
parietal lobe white matter1
• Increased or decreased white matter volumes have been
observed2
– Whole brain white matter volume decreased by 1% in patients with
schizophrenia3
– Study suggests cerebellar vermis white matter volume greater in
patients with schizophrenia (n=30)4
• Correlated with:
– Severity of positive symptoms and thought disorder
– Impairment in verbal logical memory
1. Connor CM, et al. Int J Dev Neurosci. 2011;29(3):325-34.
2. Paillère-Martinot M, et al. Schizophr Res. 2001;50(1-2):19-26.
3. Di X, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(8):1390-4.
4. Levitt JJ, et al. Am J Psychiatry. 1999;156(7):1105-7.

11 The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Pathophysiology and Evolving
Theories in Schizophrenia

Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.

©Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD April 2017 MRC2.CORP.D.00244

12 The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice
or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.