Schizophrenia

Neurobiology
and aetiology
Introduction to
neuroanatomy
Schizophrenia
Schizophrenia

Organisation of the nervous system

To understand psychiatric disorders, it is important to
understand the normal structure and function of the nervous
system

The central nervous system (CNS; brain, spinal cord) and

peripheral nervous system (PNS) are composed of two main
types of neural cells:1,2

• Neurones – basic nerve cells, which transmit messages

throughout the nervous system, resulting in functions as
diverse as tasting, thinking, and moving

• Glial cells – provide structural and functional support to

neurones
• Microglia provide a phagocytic role: destroy invading
microorganisms, removing cell debris, and promoting tissue repair
• Macroglia include oligodendrocytes, Schwanm cells, astrocytes,
and ependymal cells, which have a variety of supportive functions
within the nervous system

1. Tortora & Derrickson. Principles of Anatomy and Physiology. 12th edition. 2009;
2. Martin. Neuroanatomy Text and Atlas. 3rd edition. 2003 3
Schizophrenia

Neurones
Myelin sheath
Cell body The myelin sheath is a whitish, fatty layer that wraps around
The cell body contains the cellular the axons of most neurones and serves to increase the
machinery that keeps the neurone transmission speed of an action potential along the axon 1
alive, e.g., the nucleus 1 Axons with a myelin sheath are known as ‘myelinated axons’ 2

Information flow
Axon terminals
Axon terminals are the regions at
the end of an axon that release
neurotransmitters1
Dendrites
Dendrites receive information
from other neurones1
Each neurone typically has Axon
more than one dendrite3 Nucleus Most neurones have a single axon 3
The nucleus is critical for the An axon transmits the signal generated by the
neurone’s vitality; it contains neurone (the action potential) through the
the genetic material (genes) nervous system1
needed for cell division/
development, and protein
synthesis1,4
1. Martin. Neuroanatomy Text and Atlas. 3rd edition. 2003; 2. Kandel et al. Principles of Neural Science. 4th edition. 2000;
3. Tortora & Derrickson. Principles of Anatomy and Physiology. 12th edition. 2009; 4. Oxford Concise Medical Dictionary. 2nd edition. 1998
4
Schizophrenia

Anatomical regions of the brain

Cerebrum
Diencephalon The cerebrum is known as the ‘seat of
The diencephalon is surrounded by the intelligence’.2 It is divided into two
cerebral hemispheres and includes: 1 hemispheres and is made up of three
Thalamus basic regions (see next slide)
The thalamus is a relay station for all
sensory information (except smell) C OR
P U S C A LL O S UM

from the PNS to the cerebral cortex

Hypothalamus Cerebellum
The hypothalamus is a major regulator The cerebellum is a highly folded
of internal body functions, such as structure located at the posterior of
eating, drinking, maternal behaviour, the brain. It is important in
and sleep cycles; it also plays a role in maintaining posture and for
motivation through initiating and coordinating head and eye
maintaining behaviours a person finds movements, and is also involved in
rewarding fine tuning of muscle movements
and in learning motor skills1
Brainstem
Midbrain
Located between the spinal cord
and the cerebrum, the brainstem is Pons Spinal cord
involved in involuntary functions, Medulla
such as control of blood pressure oblongata
and breathing, as well as arousal 1

1. Kandel et al. Principles of Neural Science. 4th edition. 2000; 2. Tortora & Derrickson. Principles of Anatomy and Physiology. 12th edition. 2009
5
Schizophrenia

Cerebrum Cerebral cortex

Gyri
The cerebral cortex is the main functional
The cerebrum is divided into two
unit of the cerebrum, a layer of grey matter
hemispheres that receive sensory
Sulci (neuronal cell bodies and dendrites) 2–4 mm
information from, and control the
thick on the outer surface of the brain that is
movement of, the opposite side of
essential for conscious behaviour2
the body1
The surface of the cerebral cortex is
The cerebrum is made up of three
characterised by raised ridges of tissue
main regions:1,2
called gyri, separated by shallow grooves
• The cerebral cortex called sulci1
• The underlying white matter
• Several subcortical structures,
including the basal ganglia White matter
White matter consists of glial cells and
bundles of myelinated axons that relay
Basal ganglia messages between the cerebral cortex
and other parts of the CNS3
Deep below the cerebral cortex are
interconnected nuclei, collectively
known as the ‘basal ganglia’2
Grey matter
Grey matter is made up of neuronal cell
bodies, dendrites, and axon terminals 3

1. Price & Wilson. Pathophysiology: Clinical Concepts of Disease Processes. 6th edition. 2003;
2. Tortora & Derrickson. Principles of Anatomy and Physiology. 12th edition. 2009;
3. Martin. Neuroanatomy Text and Atlas. 3rd edition. 2003 6
 Schizophrenia

Lobes of the brain

Deep grooves, called fissures,

separate the lobes of the brain:1

• Each cerebral hemisphere has

four lobes that can be identified
on the surface of the brain2,3

• A fifth lobe, the insula, lies

deep within the brain2

1. Price & Wilson. Pathophysiology: Clinical Concepts of Disease Processes. 6th edition. 2003;
2. Tortora & Derrickson. Principles of Anatomy and Physiology. 12th edition. 2009;
3. Martin. Neuroanatomy Text and Atlas. 3rd edition. 2003 7
Neurosynaptic
transmission
Schizophrenia
Schizophrenia

Neurotransmission
Electrical neurotransmission1
Following sufficient excitatory stimulation of
the neurone, an action potential is generated
at the origin of the axon

Chemical neurotransmission1
When the action potential reaches the
axon terminal it stimulates the release of
chemical neurotransmitters

Information flow

1. Adapted from: Kandel et al. Principles of Neural Science. 4th edition. 2000
9
Schizophrenia

The synapse

• Neurones do not physically touch one

another; two neurones are separated
by a gap, known as a synaptic cleft1

• Binding of chemical signals to the

postsynaptic neuron can:
• Excite – increasing the generation of
action potentials
• Inhibit – decreasing the generation
of action potentials
• Induce other biochemical processes
1

1. Kandel et al. Principles of Neural Science. 4th edition. 2000

10
Schizophrenia

Process of chemical neurotransmission

1 An action potential reaches the axon terminal of the presynaptic

neurone1
2 Vesicles fuse with the cell membrane of the presynaptic neurone,
causing an influx of calcium ions, which causes the neurone 1
release stored neurotransmitters into the synaptic cleft 1
3 The neurotransmitters cross the synaptic cleft and bind to specific
receptors on the postsynaptic neurone 1
4 Depending upon the receptor type, when a neurotransmitter binds
to the receptor on the postsynaptic neurone it can either act by: 2
• Rapidly opening or closing an ion channel in the cell 2
membrane, thereby generating or inhibiting an action potential
• Synthesising a second messenger (e.g., cyclic AMP)
• Releasing calcium ions (Ca2+) that may interact in a wide
variety of biochemical processes 5

5 3
The neurotransmitters are cleared from the synaptic cleft by: 3,4
• Reuptake into the presynaptic neurone
• Removal by astrocytes
• Diffusion away from the synapse 4
• Breakdown by enzymes

AMP = adenosine monophosphate

1. Purves et al. Neuroscience. 4th edition. 2008;
2. Tortora & Derrickson. Principles of Anatomy and Physiology. 12th edition. 2009;
3. Kandel et al. Principles of Neural Science. 4th edition. 2000; 11
4. Sadock et al. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Vol 1–2. 2009
Neurotransmitters
Schizophrenia
Schizophrenia

Neurotransmitters and receptors

Neurotransmitter receptor subtypes1-3

Neurotransmitter Receptor subtypes

Dopamine Dopaminergic receptors (D1-5 subtypes)
Serotonin 5-HT receptors (5-HT1A-F, 5-HT2A-C, 5-HT3-7 subtypes)
Glutamate Ionotropic receptors: AMPA, kainate, NMDA receptors;
metabotropic receptors (mGluR1-8 subtypes)4
GABA GABAA-C subtypes
Noradrenaline α-adrenergic receptors (α1A-C, α2A-C subtypes);
β-adrenergic receptors (β1-3 subtypes)
Acetylcholine Cholinergic receptors: muscarinic receptors (M 1-5 subtypes);5
nicotinic receptors
Histamine Histaminic receptors (H1-4 subtypes)6

NMDA = N-methyl-D-aspartate; AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA = gamma-aminobutyric acid

1. Kandel et al. Principles of Neural Science. 4th Edition. 2000; 2. Purves et al. Neuroscience. 4th Edition. 2008;
3. Stahl. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. 2013; 4. Wierońska et al. Pharmacol Ther 2016;157:10–27;
5. Grieg et al. Recent Pat CNS Drug Discov 2013;8(2):123–141; 6. Sadek & Stark. Neuropharmacology 2016;106:56–73
13
 HO NH2
Schizophrenia

Dopamine HO

• Dopamine is produced from the

precursor molecule DOPA Nigrostriatal pathway
Mesocortical pathway
(dihydroxyphenylalanine) by Dopamine has influence
Here, dopamine influences over control of fine
DOPA decarboxylase1 perception, cognition, and movements and initiation
social behaviour2,3 of movement2,3
• Dopamine is removed from the
synapse by specialised
dopamine transporters, and is
catabolised by monoamine
oxidase (MAO) and catechol-O-
methyltransferase (COMT)1
Tuberoinfundibular pathway
• Dopamine is involved in Dopamine normally inhibits the
movement control, motivation, release of prolactin3
reward, and reinforcement; many Mesolimbic pathway
addictive substances work by Dopamine is thought to be involved in
emotion and memory, pleasurable
affecting dopaminergic sensations and reward, the euphoric
neurones1-3 effects of addictive substances, as well
as psychotic symptoms, such as
delusions and hallucinations2,3
1. Purves et al. Neuroscience. 4th edition. 2008; 2. Kandel et al. Principles of Neural Science. 4th edition. 2000;
3. Stahl. Essential Psychopharmacology. 2013
 NH2
HO
Schizophrenia
Serotonin N
H

• Serotonin (also known as 5-HT)

is a neurotransmitter that is found Cerebral cortex
throughout the body.1 High Within the forebrain,
concentrations are found in the serotonin is thought to
CNS, platelets, and certain cells regulate sleep and
wakefulness2
in the gastrointestinal tract1

• There are many receptor

subtypes for serotonin; the roles
of these receptor subtypes are
not fully elucidated

• Serotonergic neurones project

widely throughout the brain from Raphe nuclei
their origin in the raphe nuclei of
the brainstem2,3
Spinal cord
Serotonergic projections to the
spinal cord may regulate pain 3
CNS = central nervous system
1. Brunton et al. Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 11th edition. 2006;
2. Purves et al. Neuroscience. 4th edition. 2008; 15
3. Stahl. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. 2013
Schizophrenia

The dopamine D1, D2, and serotonin 5-HT2A and 5-HT6 receptors are distributed across a variety of locations in the brain
Neocortex D1 5-HT2A
Septum D2 5-HT6

Striatum Substantia nigra

pars reticula

Olfactory
tubercle
Ventral tegmental
area
Nucleus
accumbens
Hypothalamus
Hippocampus
Amygdala

Adapted from: Ayano. J Ment Disord Treat 2016;2:1–4; Cadet et al. CNS Neurol Disord Drug Targets 2010;9:526–538;
Jaber et al. Neuropharmacology 1996;35:1503–1519; López-Giménez et al. Eur J Neurosci 1999;11(10):3761–3765;
Charnay & Léger. Dialogues Clin Neurosci 2010;12:471–487; Mansour & Watson. Psychopharmacology: The Fourth Generation of Progress. 1995; 16
Zhang & Stackman. Front Pharmacol 2015;6:1–17; Ramírez. Alzheimers Res Ther 2013;5(2):15; Upton et al. Neurotherapeutics 2008;5(3):458–469
Schizophrenia

The dopamine D1, D2, and serotonin 5-HT2A and 5-HT6 receptors are distributed across a variety of locations in the brain
D1 5-HT2A
Septum D2 5-HT6

Striatum Substantia nigra

pars reticula

Olfactory
tubercle
Ventral tegmental
area
Nucleus
accumbens
Hypothalamus
Hippocampus
Amygdala

Adapted from: Ayano. J Ment Disord Treat 2016;2:1–4; Cadet et al. CNS Neurol Disord Drug Targets 2010;9:526–538;
Jaber et al. Neuropharmacology 1996;35:1503–1519; López-Giménez et al. Eur J Neurosci 1999;11(10):3761–3765;
Charnay & Léger. Dialogues Clin Neurosci 2010;12:471–487; Mansour & Watson. Psychopharmacology: The Fourth Generation of Progress. 1995; 17
Zhang & Stackman. Front Pharmacol 2015;6:1–17; Ramírez. Alzheimers Res Ther 2013;5(2):15; Upton et al. Neurotherapeutics 2008;5(3):458–469
Schizophrenia

The dopamine D1, D2, and serotonin 5-HT2A and 5-HT6 receptors are distributed across a variety of locations in the brain
Neocortex D1 5-HT2A
D2 5-HT6

Striatum

Olfactory
tubercle

Nucleus
accumbens
Hypothalamus
Hippocampus
Amygdala

Adapted from: Ayano. J Ment Disord Treat 2016;2:1–4; Cadet et al. CNS Neurol Disord Drug Targets 2010;9:526–538;
Jaber et al. Neuropharmacology 1996;35:1503–1519; López-Giménez et al. Eur J Neurosci 1999;11(10):3761–3765;
Charnay & Léger. Dialogues Clin Neurosci 2010;12:471–487; Mansour & Watson. Psychopharmacology: The Fourth Generation of Progress. 1995; 18
Zhang & Stackman. Front Pharmacol 2015;6:1–17; Ramírez. Alzheimers Res Ther 2013;5(2):15; Upton et al. Neurotherapeutics 2008;5(3):458–469
Schizophrenia

The dopamine D1, D2, and serotonin 5-HT2A and 5-HT6 receptors are distributed across a variety of locations in the brain
Neocortex D1 5-HT2A
D2 5-HT6

Striatum

Olfactory
tubercle

Nucleus
accumbens

Hippocampus

Adapted from: Ayano. J Ment Disord Treat 2016;2:1–4; Cadet et al. CNS Neurol Disord Drug Targets 2010;9:526–538;
Jaber et al. Neuropharmacology 1996;35:1503–1519; López-Giménez et al. Eur J Neurosci 1999;11(10):3761–3765;
Charnay & Léger. Dialogues Clin Neurosci 2010;12:471–487; Mansour & Watson. Psychopharmacology: The Fourth Generation of Progress. 1995; 19
Zhang & Stackman. Front Pharmacol 2015;6:1–17; Ramírez. Alzheimers Res Ther 2013;5(2):15; Upton et al. Neurotherapeutics 2008;5(3):458–469

Schizophrenia
Glutamate
• Glutamate is the principal
excitatory neurotransmitter
in the CNS1
• Glutamate is an amino acid
that is produced from
glutamine1
• Glutamate is removed from
the synapse by
transporters on glial cells,
metabolised to glutamine,
then resupplied to the
relevant neurone terminals1
CNS = central nervous system
1. Purves et al. Neuroscience. 4th edition. 2008; 2. Stahl. Stahl’s Essential Psychopharmacology. 2013
O O
HO OH
Thalamo–cortical glutamate
NH2 pathways2
Cortico–thalamic This pathway innervates pyramidal
glutamate pathways 2 neurones in the cortex
Cortico–cortical
glutamate pathways2
These can be direct,
or indirect via GABA
neurones
Cortico–striatal
glutamate pathway 2
Cortico–brainstem
glutamate projection2
Regulates neurotransmitter Hippocampal–striatal
release from the brainstem glutamate pathway2
20
 O
Schizophrenia H2N
GABA OH

• GABA is found throughout the brain, rather than being localised to specific areas or
• Most inhibitory neurones pathways1
in the brain use GABA or
glycine – as many as a • There are three types of GABA receptor, which although varied can typically be separated
third of the inhibitory as follows:1
synapses in the brain use • GABAA – ionotropic chloride channel
GABA1
• GABAB – metabotropic G-protein coupled receptor
• The predominant • GABAC – ionotropic chloride channel
precursor for GABA is
glutamate1 • Glycine, the other major inhibitory neurotransmitter, has a more localised distribution
(about half of the inhibitory synapses in the spinal cord use glycine);
• GABA is removed from it is used as a co-transmitter on NMDA receptors 1,2
the synapse by specific
transporters1

GABA = gamma-aminobutyric acid

1. Purves et al. Neuroscience. 4th edition. 2008;
2. Stahl. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. 2013 21
 OH

Schizophrenia
HO NH2
Noradrenaline Prefrontal cortex
HO Some noradrenergic projections to
the frontal cortex are thought to
help regulate mood; others are
• Noradrenaline (also thought to mediate attention 1
called norepinephrine) is The noradrenergic projection to the
limbic cortex is thought to mediate
a neurotransmitter of emotions, energy, fatigue, and
neurones in the locus psychomotor agitation/retardation 1
coeruleus1,2

• The principal function of Cerebellum

the locus coeruleus is to The noradrenergic projections
prioritise competing to the cerebellum is thought to
mediate motor movements,
incoming stimuli, whether
especially tremor1
external (e.g., a threat
from the environment) or
internal (e.g., pain), and
to focus attention1

Spinal cord
The noradrenergic projection to the
brainstem controls blood pressure 1
1. Stahl. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 2nd edition. 2000;
2. Purves et al. Neuroscience. 4th edition. 2008; 3. Dunn & Swiergiel. Eur J Pharmacol 2008;583:186–193
Locus coeruleus
Noradrenergic projections from the locus
coeruleus project to the back of the brain,
and are important in arousal and attention 1-3
22
The pathophysiology of
schizophrenia
Schizophrenia
Schizophrenia

The positive symptoms of schizophrenia

• The positive symptoms of schizophrenia are
thought to be caused by an excess of Mesolimbic
pathway
dopamine in the mesolimbic pathway,
although the reasons for this increase are not
known

• Positive symptoms include hallucinations and

delusions

• Theoretically, decreasing dopamine in this

pathway would be therapeutic

Adapted from: Stahl. Stahl’s Essential Psychopharmacology. 2013; Owen et al. Lancet 2016;388(10039):86–97
24
Schizophrenia

The negative and cognitive symptoms of schizophrenia

Mesolimbic
Mesocortical pathway
pathway

• The negative and cognitive symptoms of

schizophrenia are thought to be caused by a
shortage of dopamine in the mesocortical pathway
• Theoretically, increasing dopamine in this pathway
would be therapeutic

Adapted from: Stahl. Stahl’s Essential Psychopharmacology. 2013; Owen et al. Lancet 2016;388(10039):86–97
25
Schizophrenia

Major dopamine pathways and the symptoms of schizophrenia

Mesolimbic pathway
Mesocortical pathway Regulation of emotional
Cognition and behaviour
executive function

Negative symptoms Positive symptoms

(hypodopaminergic): (hyperdopaminergic):
• Alogia • Delusions
• Affective flattening • Hallucinations
• Avolition • Disorganised thought,
speech, behaviour

Nigrostriatal pathway
Motor control
Tuberoinfundibular pathway
Regulation of prolactin secretion

Adapted from: Stahl. Stahl’s Essential Psychopharmacology. 2013

26
Schizophrenia

The conundrum of treating schizophrenia – i

In the ‘normal’ brain

• Dopamine levels within both the mesolimbic and the mesocortical dopamine pathways are at
normal levels, therefore no symptoms of schizophrenia are experienced

‘Normal’ dopamine level

Mesolimbic pathway Mesocortical pathway

(Normal levels: (Normal levels:
no positive symptoms) no negative symptoms)

Adapted from: Stahl. Stahl’s Essential Psychopharmacology. 2013

27
Schizophrenia

The conundrum of treating schizophrenia – ii

In the schizophrenia brain

• Dopamine levels in the mesolimbic pathway are increased, causing the positive symptoms of
schizophrenia

• Simultaneously, the dopamine levels in the mesocortical pathway are decreased, leading to
negative and cognitive symptoms

Sch
izop
Mesolimbic pathway hre
n ia
(High levels: dop
ami
positive symptoms) ne l
eve
l

Mesocortical pathway
(Low levels:
negative symptoms)

Adapted from: Stahl. Stahl’s Essential Psychopharmacology. 2013

28
Schizophrenia

The conundrum of treating schizophrenia – iii

Schizophrenia treated with D2 antagonist antipsychotic

• Treating a patient with schizophrenia with a dopamine antagonist can successfully treat their
positive symptoms by reducing dopamine signalling in the mesolimbic pathway

• However, the dopamine antagonist also reduces signalling in the mesocortical pathway, meaning
that the negative and cognitive symptoms are not addressed, and in some cases can be
worsened

antagonist

antagonist
D2

D2

antagonist

antagonist
D2

D2
Dopam
ine level
Mesolimbic pathway
(Normal levels:
no positive symptoms)
Mesocortical pathway
(Low levels:
negative symptoms)

Adapted from: Stahl. Stahl’s Essential Psychopharmacology. 2013

29
Schizophrenia

The conundrum of treating schizophrenia – iv

Schizophrenia treated with an atypical, D2 partial agonist antipsychotic

• A dopamine partial agonist works to reduce the excess dopamine in the mesolimbic pathway,
treating the positive symptoms of schizophrenia

• Simultaneously, within the mesocortical pathway a dopamine partial agonist will act to enhance
dopamine signalling, meaning that the negative and cognitive symptoms of schizophrenia could
be improved as well

D2 partial
agonist
Dopamine level

Mesolimbic pathway Mesocortical pathway

D2 partial
agonist
(Normal levels: (Normal levels:
no positive symptoms) no negative symptoms)

Adapted from: Stahl. Stahl’s Essential Psychopharmacology. 2013

30
Schizophrenia

Antipsychotic drugs and the dopamine pathways of the brain

The therapeutic actions of typical
antipsychotic drugs are due to
antagonism of D2 receptors, Mesolimbic
Mesocortical pathway
specifically in the mesolimbic pathway
dopamine pathway. This has the D2 receptor
D2 receptor
effect of reducing the excess antagonism by
antagonism by
release of dopamine in this antipsychotic drugs
typical
reduces positive
pathway that is thought to cause antipsychotics can
symptoms
the positive symptoms of psychosis cause or worsen
negative and
cognitive symptoms
However, typical antipsychotics
block D2 receptors throughout the D2 receptor
antagonism by
brain and not just those in the antipsychotic drugs
mesolimbic dopamine pathway; D2 receptor antagonism by typical can result in EPS
this extensive blockade of D2 antipsychotics can increase prolactin
receptors is responsible for many levels Nigrostriatal
pathway
undesirable adverse effects. Tuberoinfundibular pathway
Atypical antipsychotics are more
discriminating

EPS = extrapyramidal symptoms

Adapted from: Stahl. Stahl’s Essential Psychopharmacology. 2013 31
Schizophrenia

The role of glutamate in the pathology of schizophrenia

• It seems clear that changes in dopamine signalling in the Interactions between glutamatergic and dopaminergic
brains of patients with schizophrenia underlie the pathways1
symptoms of psychosis, but what causes these changes?
Reduced NMDA receptor availability/
functioning on GABAergic interneurones
The glutamate hypothesis

• The predominant ‘go’ neurotransmitter in the brain is

glutamate1,2 Disinhibition of glutamatergic projections onto
midbrain dopamine neurones
• There are many lines of evidence implicating glutamate
NMDA receptors in schizophrenia:1
• Post mortem changes in NMDA receptors in the brains
Increased glutamate release
of patients with schizophrenia
• NMDA-receptor antagonists can cause psychotic
symptoms in humans
• Some glutamatergic drugs have shown promise in Increased activation of dopaminergic neurones
treating schizophrenia

GABA = gamma-aminobutyric acid; NMDA=N-methyl-D-aspartic acid

1. Howes et al. J Psychopharmacol 2015;29(2):97–115; 2. Purves. Neuroscience. 2008 32
Schizophrenia

The pathophysiology of treatment-resistant schizophrenia

Schizophrenia versus TRS Brain structure1,2

• Evidence suggests that treatment-resistant • Studies using brain imaging techniques have
schizophrenia (TRS – schizophrenia that does not highlighted differences between patients with TRS
respond to antipsychotic treatment) may represent and those with treatment-responsive schizophrenia,
a distinct pathophysiological entity1 such as widespread grey matter volume reductions
in several lobes of the brain
• One study used meta-analysis techniques to
examine TRS, and from 19 original research Brain connectivity3,4
publications tentatively concluded that TRS may be
a categorically distinct disorder1 • Patients with TRS show reduced connectivity in
certain key brain regions, and a reduced total
TRS may be a distinct pathophysiological entity, density of dopaminergic synapses, compared to
but more research is needed treatment-responsive/non-refractory schizophrenia
with larger sample sizes1-4 and to the control population

TRS = treatment-resistant schizophrenia

1. Gillespie et al. BMC Psychiatry 2017;17:12; 2. Anderson et al. Int J Neuropsychopharmacol 2015;18:pyv016;
3. White et al. Neuropsychopharmacology 2016;41:1274–1285; 4. Roberts et al. Synapse 2009;63:520–530 33
Hypotheses for the underlying
causes of schizophrenia
Schizophrenia
Schizophrenia

The neurodevelopmental model of schizophrenia

• Normal cortical development involves proliferation, migration of cells, dendritic arborisation (circuit
formation), and myelination, with the first two processes occurring mostly during prenatal life and
the latter two continuing through the first two post-natal decades 1

• A progressive reduction of grey-matter volume with age is observed with longitudinal

neuroimaging.1,2 The combined effects of pruning of the neuronal arbor and myelin deposition are
thought to account for this1

• Psychosis nearly always emerges in late adolescence or early adulthood, with a peak between the
ages of 18 and 25, when the prefrontal cortex is still developing 1

• The neurodevelopmental trajectory in children developing schizophrenia could include reduced

elaboration of inhibitory pathways, and excessive pruning of excitatory pathways, leading to altered
excitatory–inhibitory balance in the prefrontal cortex 1

1. Insel. Nature 2010;468(7321):187–193; 2. Paus et al. Nat Rev Neurosci 2008;9(12):947–957

35
Schizophrenia

Socio–developmental–cognitive models of schizophrenia

• There have been attempts to explain schizophrenia using Cognitive models of schizophrenia1,2
cognitive models1,2
Anomalies of Social
• Cognitive models of schizophrenia suggest that the Stress
conscious experience adversity
interpretation of social adversity (e.g., child abuse)
through biased cognitive schema and appraisal
processes, results in the individual judging the adversities
Search for meaning
as being externally driven, giving rise to paranoid
delusions1,2 Biased cognitive Unbiased cognitive
schema schema
• Attempts have been made to integrate these cognitive Experiences are externally Rationalisation and
models with the known pathophysiology of schizophrenia, driven and uncontrollable understanding
postulating that genetic predisposition and
neurodevelopmental insults disrupt the dopamine system,
alongside social adversity leading to biased cognitive
schema – these forces act in concert to hardwire the Paranoia
individual in favour of the psychotic interpretation of the
world around them1

1. Howes & Murray. Lancet 2014;383(9929):1677–1687;

2. Bentall et al. Arch Gen Psychiatry 2009;66(3):236–247 36
Schizophrenia

Neurotransmitters and schizophrenia

Evidence for involvement in the pathophysiology of schizophrenia
• Patients with schizophrenia show
Receptor Evidence
abnormal synaptic communication
Dopamine • Drugs that prevent the activity of dopamine in the brain, by between neurones in the brain1
blocking D2 receptors, can reduce positive symptoms 1
• Amphetamines, which increase the levels of dopamine in the • These abnormalities occur in several
brain, can increase psychotic symptoms 1
neurotransmitter systems; disruption
Glutamate • NMDA receptor antagonists, such as phencyclidine and of one system results in compensatory
ketamine, produce psychosis-like features indistinct from
mechanisms by other systems1
schizophrenia1
GABA • Reduced synthesis and reuptake of GABA has been
demonstrated in the prefrontal cortex in patients with
schizophrenia1
Acetylcholine • Decreased levels of cholinergic receptors are observed in the
hippocampus, thalamus, and striatum in patients with
schizophrenia1
Serotonin • Prefrontal 5-HT2A receptors have been linked to the
pathogenesis of schizophrenia2,3
• Activation of 5-HT2A receptors induces a schizophrenia-like
psychosis in humans2,3

5-HT = serotonin; GABA = gamma-aminobutyric acid; NMDA = N-methyl-D-aspartic acid

1. Sadock et al. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 2009;
2. Vollenweider et al. Neuroreport 1998;9(17):3897–3902; 3. Santini et al. J Neurosci Res 2013;91(5):634–641 37
Schizophrenia

Inflammation and schizophrenia

• The immune system is linked to the pathology of Microglial activity measured with PET in patients
schizophrenia, with evidence including elevated with schizophrenia and matched controls1
cytokines and microglial activation1,2

Mean [11C]PBR28 distribution

• PET imaging has been used to examine immune *** ** ***

volume ratio (SD)

system activity in patients with schizophrenia1

• One study found elevated microglial activity in

unmedicated patients with sub-clinical symptoms
who were at ultra high risk of psychosis, and found
a significant positive correlation with symptom
Total grey matter Frontal lobe Temporal lobe
severity1
Healthy controls (n=14)
• These data indicate that neuroinflammation is linked Patients with schizophrenia (n=14)
to the risk of psychosis and related disorders, and
the expression of sub-clinical symptoms1

**p < 0.01, ***p ≤ 0.001

PET = positron emission tomography; SD = standard deviation
1. Bloomfield et al. Am J Psychiatry 2016;173(1):44–52; 2. Melborne et al. Curr Treat Options Psychiatry 2017;4(2):139–151 38
Schizophrenia

The microbiome and schizophrenia

• The makeup and function of the gut microbiota is
increasingly being linked to the pathology of neurological
disorders, including schizophrenia, depression, and
bipolar disorder1-3

• The normal flora of the gut is made up of several species

of bacteria, and also of viruses and fungi, which colonise
the gut at birth4

• In a comparison of 16 patients with schizophrenia and 16

controls, differences in oropharynx flora were: 5
• Patients with schizophrenia were dominated by a greater
number of microbiome species
• Patients with schizophrenia had greater abundance of lactic
acid bacteria
• There were differences in the metabolic pathways controlling
glutamate and B12 transport (increased in schizophrenia) and
carbohydrate and lipid metabolism (decreased in
schizophrenia)

5-HT = serotonin
1. Nguyen et al. J Psychiatr Res 2018;99:50–61; 2. Chrobak et al. Arch Psychiatr Psychother 2016;2:5–11;
4. Rodrigues-Amorim et al. World J Biol Psychiatry 2018;19(8):571–585; 5. Castro-Nallar et al. PeerJ 2015;3:e1140 39
Environmental factors
Schizophrenia
Schizophrenia

The environment and schizophrenia

• Factors pre- and post-natal have been linked to an increased risk of schizophrenia 1,2

• Epidemiological studies and twin studies have identified many environmental factors that are linked
to the development of schizophrenia, for example: 1,2
• Prenatal exposure to viral infections
• Poor pre-natal nutrition
• Adverse obstetric events
• Cannabis smoking during adolescence

1. Sadock et al. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 2009;

2. Lakhan & Vieira. Ann Gen Psychiatry 2009;8:12 41
Schizophrenia

Environmental factors and schizophrenia

Comparison of a set of relatively well-established risk factors for schizophrenia 1
The general impact of some
8
of the factors listed here is
7
uncertain, however many
6
environmental factors
5
Odds ratio

contribute to a risk of
4 developing schizophrenia1
3
2
1
0
Urban

Rubella
Influenza

Polio virus

Famine

Flood

Unwantedness
Bereavement
Respiratory

Rh incompatibility
Winter

CNS

Hypoxia

CNS damage

Pre-eclampsia
Low birth weight
Maternal depression
Birth Infection Prenatal Obstetric

CNS = central nervous system; Rh=rhesus

1. Sullivan. PLoS Med 2005;2(7):e212 42
Schizophrenia

Cannabis as a risk factor for developing psychosis

Meta-analysis of prospective observational studies
Odds ratio for studies supporting a positive association reporting an association between use of cannabis
between cannabis and schizophrenia-like psychosis 1 and risk of schizophrenia2
Study Odds ratio (95% CI) Study Odds ratio (95% CI)

Andreasson 1987 2.41 (1.76, 3.30) Swedish cohort

1.50 (1.10, 2.00)
– schizophrenia
Rolfe 1993 4.36 (2.65, 7.15) Dunedin
– schizophreniform 1.42 (0.54, 3.74)
Grech 1998 2.25 (1.22, 4.14) disorder
Grech 1998 4.36 (0.44, 43.33) ECA
1.30 (0.98, 1.74)
– psychotic experience
Arsenault 2002 3.71 (1.04, 13.20)
NEMESIS
2.11 (0.78, 5.71)
Farrell 2002 3.27 (1.61, 6.61) – psychotic symptom
EDSP
Van Os 2002 3.25 (1.48, 7.15) 1.53 (1.13, 2.07)
– psychotic symptom
Overall 2.93 (2.36, 3.64) Overall 1.43 (1.19, 1.67)

0.02 1 50
0.5 1.0 2.0 3.0 6.0

Cannabis use has been identified as a risk factor for developing schizophrenia,
and is suggested to increase the chance of psychosis by up to 3 times 1,2

CI = confidence interval; OR = odds ratio

1. 1. Semple et al. J Psychopharmacol 2005;19(2):187–194; 2. Vaucher et al. Mol Psychiatry 2018;23(5):1287–1292 43
Genetic factors
Schizophrenia
Schizophrenia

The heritability of schizophrenia – twin and adoption studies

• Numerous studies have shown that the risk of developing schizophrenia is greater in the relatives of
patients with schizophrenia1-3

• Data from twin studies and adoption studies support the significant role of genetic factors in
schizophrenia1

• Research conducted more recently has identified susceptibility genes that may result in an
increased risk of developing schizophrenia 2,4,5

1. Sadock et al. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 2009; 2. Gejman et al. Psychiatr Clin North Am 2010;33(1):35–66;
3. McGue & Gottesman. Schizophr Bull 1989;15(3):453–464; 4. Keshavan et al. Schizophr Res 2011;127(1–3):3–13;
5. Lakhan & Vieira. Ann Gen Psychiatry 2009;8:12–19 45
Schizophrenia

The genetics of schizophrenia

• An ambitious genome-wide association study (GWAS) was conducted by the Schizophrenia Working
Group of the Psychiatric Genomics Consortium, analysing genetic data from >35,000 individuals with
schizophrenia and >110,000 controls1

• This GWAS analysis identified 108 distinct loci – 83 of which had not been previously implicated in
schizophrenia1

• Noteworthy gene locations included:1

• The dopamine receptor D2 gene – highlighting the known importance of dopamine neurotransmission in the
pathology of schizophrenia
• Several genes encoding proteins involved in glutamatergic neurotransmission, and several voltage-gated calcium
channel component proteins – providing an aetiologically relevant foundation for treatment development
• Genes expressed in tissues with important roles in immunity – supporting the hypothesised link between
schizophrenia and the immune system

• In an analysis of data from several different GWAS studies, attempting to integrate the data, six crucial
genes have been identified as being linked to an increased risk of developing schizophrenia – five of
which are related to neurodevelopment2

GWAS = genome-wide association study

1. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Nature 2014;511(7510):421–427;
2. Ma et al. Transl Psychiatry 2018;8(1):67 46
Schizophrenia

Results from a large-scale twin study

• A study following pairs of twins (>30,000 pairs) to see • The analysis also looked for factors that were
which developed schizophrenia was, at the time of associated with increased risk within twin pairs 1
publishing in 2017/18, the largest concordance study
• It was found that early age of schizophrenia onset in
ever undertaken1,2 the first twin was a risk factor for the second twin
developing schizophrenia – this suggests that
• The concordance rates of schizophrenia were:2
early-onset schizophrenia may have a stronger
• 33% in monozygotic twins (identical twins) genetic component of risk than other subtypes
• 7% in dizygotic twins (non-identical twins) of schizophrenia1
• The concordance rates of schizophrenia spectrum
• These results demonstrate that there is a high
disorder were:2
genetic component to the risk of developing
• 32% in monozygotic twins schizophrenia, however, vulnerability to the illness
• 9% in dizygotic twins is not solely genetic1,2

The genetic heritability of schizophrenia was

estimated to be 79%2

1. Hilker et al. EBioMedicine 2017;18:320–326; 2. Hilker et al. Biol Psychiatry 2018;83(6):492–498

47
Schizophrenia

The future of genetic research in schizophrenia

1. What more can be learned from GWAS in 4. Can we evaluate the role of rare copy number
schizophrenia? variants in schizophrenia?
Larger and larger datasets are required to zero-in Larger datasets are required to provide power to
on rarer alleles and variations assay rare genetic events, but they could contain
useful clues about the pathology of schizophrenia
2. What more can we learn from genetic risk
scores (GRS)? 5. Can we perform well-powered studies of rare
Can all the GWAS data be brought together to sequence variation?
produce a weighted score that represents an Rare mutations in genes implicated in the original
individual’s risk? And is this useful? GWAS (e.g., voltage-gated calcium channel
signalling) will be studied
3. What can we learn about the relationships
between brain disorders? 6. What can we learn from densely affected
Genomic study may uncover similarities between pedigrees?
brain disorders, including MDD, bipolar disorder, Analysing the clustering of risk factors within a
and schizophrenia family may be useful

GRS = genetic risk score; GWAS = genome-wide association study; MDD = major depressive disorder
1. Corvin & Sullivan. Schizophr Bull 2016;42(3):538–541 48
Success for [Psychiatric Genomics Consortium 3]
will be measured by the evaluation of the biological
significance of common and rare genomic findings
and their relevance to the aetiology, diagnosis or
treatment of schizophrenia. If successful this will help
to guide and focus the search for those core
molecular aetiological mechanisms most likely to
improve patient care
Corvin & Sullivan. Schizophr Bull. 2016;42(3):538–541

49