Neurobiology of Schizophrenia
Schizophrenia
• Features
o Schizophrenia affects the most basic human processes of perception, emotion, judgement
o Heterogenous syndrome
o No single defining symptom or sign
o Currently cannot be identified with a diagnostic laboratory test
o Diagnosis:
▪ Psychotic phenomena – hallucinations, delusion and thought disorder – after other causes of
psychosis have been excluded
• Symptoms
o Positive symptoms – characterised by abnormal thoughts, perceptions, language and behaviour
▪ Include
• Delusions
o False beliefs or thoughts with no basis in reality
• Hallucinations
o Disturbances of sensory perception – e.g. seeing, hearing, feeling things that
are not there
o Auditory and visual hallucinations
• Disorganised thinking / speech
o Jumping from topic to topic, slipping off topic, responding to questions with
unrelated answers, speaking incoherently
• Disorganised behaviour
o Problems performing goal directed daily activities like meal planning and
maintaining personal hygiene, child-like actions, unprovoked agitation
• Lack of insight
o Individuals unaware that their delusions or hallucinations aren’t real –
distressing
▪ Positive symptoms can also be characterised as symptoms of psychosis
• Symptoms of psychosis
o Delusions
o Hallucinations
o Disorganised thinking/ speech
o Disorganised behaviour
o Lack of insight
• Causes of psychosis
o Schizophrenia – more likely to have persecutory delusions
o Bipolar disorder – during episodes of mania + more likely to have grandiose
delusions
o Severe stress/anxiety
o Severe depression
o Postnatal psychosis – 1:1000
o Lack of sleep
o Encephalitis
o Substance misuse
o Can also occur in several medical conditions – AD, PD, malaria,
hypoglycaemia, MS, brain tumour
o Negative symptoms – characterised by restrictions in range and intensity of emotional expression,
communication, body language and interest in normal activities
▪ Blunted (flat) effects
,Neurobiology of Schizophrenia
• Decreased emotional expressiveness, unresponsive immobile facial appearance,
reduced eye contact and body language
▪ Alogia
• Reduced speech, responses are curt and detached, speech may be less fluid
▪ Avolition
• Lacking motivation, spontaneity, initiative
o E.g. sitting for length periods or ceasing to participate in work or daily
activities
▪ Anhedonia
• Lacking pleasure or interest in activities that were once enjoyable
o Cognitive symptoms
▪ Subtle cognitive problems are increasingly recognised as central to the disease
▪ Include
• Impairments in attention, working memory, learning, verbal fluency, motor speed,
executive functions
o Poor working memory
▪ Linked to dysfunction of the dorsolateral prefrontal cortex
▪ Even patients with good performance are inefficient in their use of
prefrontal networks
▪ Cognitive deficits are relatively stable + already apparent in first-episode patients
▪ Leads to impairment of skills and diminished functional capacity
▪ Also found in biological relatives of subjects
• Suggesting that the aspect of cognitive impairment in SCZ – may be under genetic
control
▪ Cognitive tests could be used in clinical trials and genetic testing
• Diagnosing schizophrenia
o Criteria for schizophrenia – from the diagnostic and statistical manual of mental disorders 5th edition
(DSM5)
▪ A
• 2 or more of the following symptoms for >1 month unless treated successfully –
include:
o Delusions, hallucinations, disorganised speech, disorganised or catatonic
behaviour, + negative symptoms – such as affective flattening or loss of
initiative
▪ B
• Level of functioning is significantly decreased in work, personal relationships, and/or
personal care
▪ C
• Symptoms of the disorder last >6 months
▪ D
• Exclusion of schizo-affective disorder, unipolar and bipolar effective disorder
▪ E
• Symptoms cannot be attributed to the use of drugs or medication, or to a somatic
disorder
▪ F
• In the case of pre-existing autism spectrum disorder – at least 1 month with
prominent hallucinations or delusions
• Treating schizophrenia (psychosis) by targeting the dopamine pathway
o Dopamine hypothesis of SCZ
▪ Derived in part from the discovery of anti-psychotics in the 50s
▪ D2 dopamine receptor is the main target of antipsychotics
,Neurobiology of Schizophrenia
o First generation anti-psychotics (1950s)
▪ Include
• Chlorpromazine
• Haloperidol
• Perphenazine
▪ Extrapyramidal side effects include – tremor, rigidity, dystonia, tardive dyskinesia –
nigrostriatal DA system
▪ Rapid onset of action
▪ Dose-dependency
• Leads to parkinsonian side effects at high doses
▪ Primary mechanism of action is D2 dopamine receptor blockade
• Dopamine receptors in the brain are GPCRs
o D2 dopamine receptor
▪ Coupled to inhibitory G-protein Gi = inhibits an enzyme adenylate
cyclase
o Potency of first-generation antipsychotics in treating positive symptoms =
strongly correlated with their affinity for D2 dopamine receptors
o Second generation anti-psychotics – atypical anti-psychotics
▪ Risperidone
• Less likely to cause EPS + tend to also act on serotonin receptors as well
▪ Clozapine
• Also act on serotonin (target 5HT2A)
• Can be used in treatment resistant individuals
• Less side EPS – but other serious side effects
• Dysregulated neurotransmitter systems in schizophrenia
o Dopamine
▪ Importance neurotransmitter involved in:
• Movement, emotional regulation, reward, cognition
▪ 5 dopaminergic pathways in humans
• Nigrostriatal, mesolimbic, mesocortical, tuberinfundibular, thalamic
o Mesolimbic and mesocortical dopaminergic pathways = most relevant to the
pathophysiology of schizophrenia
▪ Mesolimbic pathway
• Originate in dopamine-producing cells in the central
tegmental area (VTA) in the midbrain → dopaminergic
neurons second afferents to the striatum, hippocampus,
amygdala
• Increased dopaminergic activity in the mesolimbic pathway
= accounts for the positive symptoms
▪ Mesocortical pathway
• Originates in the VTA → projects throughout the cortex –
including the PFC
• Decreased dopaminergic activity in the mesocortical
pathway = may account for the negative symptoms and
cognitive impairments
▪ Dopamine receptors
• GPCRs
• 5 subtypes of the dopamine receptor
o D2 and D4 are most relevant to schizophrenia
• Primary mechanism of therapeutic action of antipsychotics = blockade of D2
receptors
, Neurobiology of Schizophrenia
• Blockade of D2 receptors in the mesolimbic pathway → produces antipsychotic
effects
• Blockade of D2 receptors in the nigrostriatal pathway → produces extrapyramidal
symptoms
▪ Atypical antipsychotics still block D2 receptors → producing antipsychotic effect
• But also block other receptors – 5HT2A receptors → attenuateing the neurological
side effects
o Antagonist at 5HT2A receptors → enhances striatal dopamine release = may
confer some antipsychotic effects
▪ Models of schizophrenia using animals with dysregulated dopaminergic neurotransmission
• After release from presynaptic terminals – dopamine is cleared from the extracellular
space by a membrane-spanning dopamine transpoter (DAT) – which plays a critical
role in the regulation of dopamine levels
o DAT knockout mice → have increased brain dopamine levels, hyperactivity,
deficits in sensory gating
▪ Amphetamine or L-DOPA administration can mimic symptoms of schizophrenia
▪ Antipsychotic drugs alleviate some of the symptoms of amphetamine psychosis
▪ Excess dopamine release occurs in schizophrenics
▪ Increased dopamine receptor binding – specifically D2 receptors in patients brains and scans
o Glutamate
▪ Dissociative anaesthetics – phencyclidine (PCP), ketamine = non-competitive antagonist at
the NMDA subtype of glutamate receptors
• Can produce psychotic + cognitive abnormalities reminiscent of SCZ in humans
o NMDA receptor hypofunction – may contribute to the cognitive symptoms of
SCZ
• Decreased neurotransmission at NMDA receptors in SCZ
• May be a loss of synaptic connectivity in SCZ
o Glutamate receptors are enriched on the postsynaptic side on dendritic
spines (protrusions from the dendrite)
▪ There may be a loss of dendritic spines in SCZ
• Seen in postmortem studies
o Overall decrease in density of postsynaptic elements
– particularly in cortical areas
• Seen in living patients – decreased synaptic connectivity
o Loss of excitatory synapses in individuals with SCZ
▪ Synaptophysin is a marker of synapse
• Its mRNA expression is reduced in the hippocampus,
superior temporal gyrus (STG), visual cortex – from
individuals with schizophrenia
▪ Vesicular glutamate transpoter-1 (VGLUT1) is a synaptic protein –
concentrates glutamate into synaptic vesicles
• Its mRNA expression is reduced in the hippocampus and
DLPFC
▪ Data indicates that a loss of glutamatergic synapses occurs in
multiple brain areas in SCZ
• Changes in brain structure
o Changes in brain volume in schizophrenia
▪ Ventricular enlargement
• Lateral and third ventricular enlargement
▪ Medial temporal lobe (hippocampal formation, subiculum, parahippocampal gyrus) volume
reduction
Schizophrenia
• Features
o Schizophrenia affects the most basic human processes of perception, emotion, judgement
o Heterogenous syndrome
o No single defining symptom or sign
o Currently cannot be identified with a diagnostic laboratory test
o Diagnosis:
▪ Psychotic phenomena – hallucinations, delusion and thought disorder – after other causes of
psychosis have been excluded
• Symptoms
o Positive symptoms – characterised by abnormal thoughts, perceptions, language and behaviour
▪ Include
• Delusions
o False beliefs or thoughts with no basis in reality
• Hallucinations
o Disturbances of sensory perception – e.g. seeing, hearing, feeling things that
are not there
o Auditory and visual hallucinations
• Disorganised thinking / speech
o Jumping from topic to topic, slipping off topic, responding to questions with
unrelated answers, speaking incoherently
• Disorganised behaviour
o Problems performing goal directed daily activities like meal planning and
maintaining personal hygiene, child-like actions, unprovoked agitation
• Lack of insight
o Individuals unaware that their delusions or hallucinations aren’t real –
distressing
▪ Positive symptoms can also be characterised as symptoms of psychosis
• Symptoms of psychosis
o Delusions
o Hallucinations
o Disorganised thinking/ speech
o Disorganised behaviour
o Lack of insight
• Causes of psychosis
o Schizophrenia – more likely to have persecutory delusions
o Bipolar disorder – during episodes of mania + more likely to have grandiose
delusions
o Severe stress/anxiety
o Severe depression
o Postnatal psychosis – 1:1000
o Lack of sleep
o Encephalitis
o Substance misuse
o Can also occur in several medical conditions – AD, PD, malaria,
hypoglycaemia, MS, brain tumour
o Negative symptoms – characterised by restrictions in range and intensity of emotional expression,
communication, body language and interest in normal activities
▪ Blunted (flat) effects
,Neurobiology of Schizophrenia
• Decreased emotional expressiveness, unresponsive immobile facial appearance,
reduced eye contact and body language
▪ Alogia
• Reduced speech, responses are curt and detached, speech may be less fluid
▪ Avolition
• Lacking motivation, spontaneity, initiative
o E.g. sitting for length periods or ceasing to participate in work or daily
activities
▪ Anhedonia
• Lacking pleasure or interest in activities that were once enjoyable
o Cognitive symptoms
▪ Subtle cognitive problems are increasingly recognised as central to the disease
▪ Include
• Impairments in attention, working memory, learning, verbal fluency, motor speed,
executive functions
o Poor working memory
▪ Linked to dysfunction of the dorsolateral prefrontal cortex
▪ Even patients with good performance are inefficient in their use of
prefrontal networks
▪ Cognitive deficits are relatively stable + already apparent in first-episode patients
▪ Leads to impairment of skills and diminished functional capacity
▪ Also found in biological relatives of subjects
• Suggesting that the aspect of cognitive impairment in SCZ – may be under genetic
control
▪ Cognitive tests could be used in clinical trials and genetic testing
• Diagnosing schizophrenia
o Criteria for schizophrenia – from the diagnostic and statistical manual of mental disorders 5th edition
(DSM5)
▪ A
• 2 or more of the following symptoms for >1 month unless treated successfully –
include:
o Delusions, hallucinations, disorganised speech, disorganised or catatonic
behaviour, + negative symptoms – such as affective flattening or loss of
initiative
▪ B
• Level of functioning is significantly decreased in work, personal relationships, and/or
personal care
▪ C
• Symptoms of the disorder last >6 months
▪ D
• Exclusion of schizo-affective disorder, unipolar and bipolar effective disorder
▪ E
• Symptoms cannot be attributed to the use of drugs or medication, or to a somatic
disorder
▪ F
• In the case of pre-existing autism spectrum disorder – at least 1 month with
prominent hallucinations or delusions
• Treating schizophrenia (psychosis) by targeting the dopamine pathway
o Dopamine hypothesis of SCZ
▪ Derived in part from the discovery of anti-psychotics in the 50s
▪ D2 dopamine receptor is the main target of antipsychotics
,Neurobiology of Schizophrenia
o First generation anti-psychotics (1950s)
▪ Include
• Chlorpromazine
• Haloperidol
• Perphenazine
▪ Extrapyramidal side effects include – tremor, rigidity, dystonia, tardive dyskinesia –
nigrostriatal DA system
▪ Rapid onset of action
▪ Dose-dependency
• Leads to parkinsonian side effects at high doses
▪ Primary mechanism of action is D2 dopamine receptor blockade
• Dopamine receptors in the brain are GPCRs
o D2 dopamine receptor
▪ Coupled to inhibitory G-protein Gi = inhibits an enzyme adenylate
cyclase
o Potency of first-generation antipsychotics in treating positive symptoms =
strongly correlated with their affinity for D2 dopamine receptors
o Second generation anti-psychotics – atypical anti-psychotics
▪ Risperidone
• Less likely to cause EPS + tend to also act on serotonin receptors as well
▪ Clozapine
• Also act on serotonin (target 5HT2A)
• Can be used in treatment resistant individuals
• Less side EPS – but other serious side effects
• Dysregulated neurotransmitter systems in schizophrenia
o Dopamine
▪ Importance neurotransmitter involved in:
• Movement, emotional regulation, reward, cognition
▪ 5 dopaminergic pathways in humans
• Nigrostriatal, mesolimbic, mesocortical, tuberinfundibular, thalamic
o Mesolimbic and mesocortical dopaminergic pathways = most relevant to the
pathophysiology of schizophrenia
▪ Mesolimbic pathway
• Originate in dopamine-producing cells in the central
tegmental area (VTA) in the midbrain → dopaminergic
neurons second afferents to the striatum, hippocampus,
amygdala
• Increased dopaminergic activity in the mesolimbic pathway
= accounts for the positive symptoms
▪ Mesocortical pathway
• Originates in the VTA → projects throughout the cortex –
including the PFC
• Decreased dopaminergic activity in the mesocortical
pathway = may account for the negative symptoms and
cognitive impairments
▪ Dopamine receptors
• GPCRs
• 5 subtypes of the dopamine receptor
o D2 and D4 are most relevant to schizophrenia
• Primary mechanism of therapeutic action of antipsychotics = blockade of D2
receptors
, Neurobiology of Schizophrenia
• Blockade of D2 receptors in the mesolimbic pathway → produces antipsychotic
effects
• Blockade of D2 receptors in the nigrostriatal pathway → produces extrapyramidal
symptoms
▪ Atypical antipsychotics still block D2 receptors → producing antipsychotic effect
• But also block other receptors – 5HT2A receptors → attenuateing the neurological
side effects
o Antagonist at 5HT2A receptors → enhances striatal dopamine release = may
confer some antipsychotic effects
▪ Models of schizophrenia using animals with dysregulated dopaminergic neurotransmission
• After release from presynaptic terminals – dopamine is cleared from the extracellular
space by a membrane-spanning dopamine transpoter (DAT) – which plays a critical
role in the regulation of dopamine levels
o DAT knockout mice → have increased brain dopamine levels, hyperactivity,
deficits in sensory gating
▪ Amphetamine or L-DOPA administration can mimic symptoms of schizophrenia
▪ Antipsychotic drugs alleviate some of the symptoms of amphetamine psychosis
▪ Excess dopamine release occurs in schizophrenics
▪ Increased dopamine receptor binding – specifically D2 receptors in patients brains and scans
o Glutamate
▪ Dissociative anaesthetics – phencyclidine (PCP), ketamine = non-competitive antagonist at
the NMDA subtype of glutamate receptors
• Can produce psychotic + cognitive abnormalities reminiscent of SCZ in humans
o NMDA receptor hypofunction – may contribute to the cognitive symptoms of
SCZ
• Decreased neurotransmission at NMDA receptors in SCZ
• May be a loss of synaptic connectivity in SCZ
o Glutamate receptors are enriched on the postsynaptic side on dendritic
spines (protrusions from the dendrite)
▪ There may be a loss of dendritic spines in SCZ
• Seen in postmortem studies
o Overall decrease in density of postsynaptic elements
– particularly in cortical areas
• Seen in living patients – decreased synaptic connectivity
o Loss of excitatory synapses in individuals with SCZ
▪ Synaptophysin is a marker of synapse
• Its mRNA expression is reduced in the hippocampus,
superior temporal gyrus (STG), visual cortex – from
individuals with schizophrenia
▪ Vesicular glutamate transpoter-1 (VGLUT1) is a synaptic protein –
concentrates glutamate into synaptic vesicles
• Its mRNA expression is reduced in the hippocampus and
DLPFC
▪ Data indicates that a loss of glutamatergic synapses occurs in
multiple brain areas in SCZ
• Changes in brain structure
o Changes in brain volume in schizophrenia
▪ Ventricular enlargement
• Lateral and third ventricular enlargement
▪ Medial temporal lobe (hippocampal formation, subiculum, parahippocampal gyrus) volume
reduction
