Schizophrenia

Question 1

Typical symptoms of a psychotic episode

Answer 1

Hallucinations: perceptions disconnected from external stimuli. Seeing or hearing things.

Illusions: severly distorted perceptions or misinterpretations of stimuli. Seeing an object pulsating.

Delusions: fixed and false beliefs that are not shared by others in culture.

Ideas of reference: beliefs that ordinary objects such as licence plates contain specific messages for individual.

Thought insertion/deletion: belief that outside agency has removed or added thoughts to brain

Individual will appear to have lost touch with reality.

Question 2

What conditions can result in psychosis?

Answer 2

Schizophrenia, mood disorders (mania or severe depression), schizoaffective disorder if chronic schizo symptoms persist.

Schizophreniform disorder: individuals develop acute and transient schizo syndromes followed by full recovery.

may result from abusing drugs

Question 3

Define schizophrenia

Answer 3

split mind

Question 4

What are the three symptomatic clusters in schizophrenia?

Answer 4

Positive: delusions, hallucinations, disorganised speech, erratic/catatonic behaviour.

Negative: reduced emotional expression, speech poverty, social withdrawal.

Cognitive: impaired executive function, reduced working memory and difficulty initiating goal-direction behaviour

Question 5

Describe onset of schizophrenia

Answer 5

Age: manifests in late teens or early 20s.

Early symptoms: difficulties at school or work, socially isolated and eccentric.

Some individuals become intermittently belligerent whereas others develop negative symptoms.

Question 6

Genetic risk of developing schizophrenia

Answer 6

Highly influenced by genes
Monozygotic twin (100% shared DNA) have 48% lifetime risk of developing schizophrenia whereas general population just 1%.
(but twin most probable same environment…)

Relatives of individuals may have symptoms
such as suspiciousness, social isolation, eccentric beliefs and cognitive deficits — but not psychotic symptoms. This condition
is currently classified as schizotypal personality disorder.

Question 7

Dysbindin gene

Answer 7

May affect dopamine D2 receptor levels and glutamate and GABA transmission

Question 8

Neureglin 1

Answer 8

Involved in synaptic plasticity and myelination

Question 9

DISC1

Answer 9

Associated with neurodevelopment and also signalling in corticolimbic areas

Question 10

COMT (catechol-O –methyltransferase):

Answer 10

Linked to dopaminergic transmission

Question 11

DAOA (D-amino acid oxidase activator):

Answer 11

Linked to glutamatergic transmission

Question 12

BDNF (brain derived neurotrophic factor):

Answer 12

neurogenesis

Question 13

Genetic vulnerabilities vs genes affecting phenotype

Answer 13

vulnerable: developmental pathogenesis

Pheno: neuromodulation

Question 14

Brain changes in schizo?

Answer 14

Characterised loss of grey matter in frontal and temporal regions of the cerebral cortex (unaffected first degree relatives have similar but milder grey matter thinning).

Grey matter loss starts in adolescence: Significant progressive loss occurs in schizophrenia in parietal, motor, supplementary motor and superior frontal
cortices. Progressive loss of up to 5% per year.

Changes observed are similar in brains of male and female teenagers:

Question 15

Changes to neural cells in schizophrenia

Answer 15

Reduced spine volume and number: reduction of dendrites and axons (neuropil).

No evidence of cell loss or gliosis.

Question 16

Environmental risk factors

Answer 16

complications during pregnancy or at birth, an older father, immune system activation, excessive use of cannabis.

Question 17

Link between schizophrenia and neuroinflammation

Answer 17

Prenatal infection, increased levels of cytokines during pregnancy = increase risk in offspring

Proinflamm cytokines elevated in PFC of schizo and increased loss of grey matter in patients with high levels.

Activated microglia present in schizo within few years of disease onset.
NB: astrocytes and microglia maintain and prune dendritic spines and influenced by inflammatory mechanisms.

Question 18

Ventricles of schizophrenics?

Answer 18

Schizophrenics have enlarged ventricles: third and lateral ventricles normally accompanies loss of grey matter in PFC and temporal cortex.

Question 19

What do antipsychotic drugs treat?

Answer 19

Schizophrenia, acute mania, schizoaffective disorders and psychosis associated with depression or drug intoxication.

NB: antipsychotic not anti-schizophrenic

Question 20

Issues with current antipsychotics?

Answer 20

Treat psychosis and extend period between relapses, good at treating positive symptoms only
Do not abolish relapses
Poor cognitive symptom response
Harsh side effects: increased plasma levels of prolactin and extrapyramidal symptoms (EPS)

EPS: drug induced movement disorder that include dystonia, akathisia (motor restlessness), parkinsonism (characteristic tremors) and tardive dyskinesia (irregular, jerky movements).

Prolactin: tuberoinfundibular pathway transmits DA from hypothalamus to pituitary. Block of D2-like receptors increases prolactin.
Breast swelling, lactation in both sexes and pain.

Question 21

Difference between typical and atypical antipsychotics?

Answer 21

Typical (Chlorpromazine): first generation.

Atypical (Clozapine): second generation.

Question 22

What did the treatment of schizophrenia with chlorpromazine and reserpine do?

Answer 22

First antipsychotic drugs: reduced number of patients in state mental hospitals.

Question 23

Outline the dopamine hypothesis

Answer 23

Dysfunctional midbrain DA system thought to play role (too much DA).

FOR:
Most antipsychotics block DA receptors to diff degrees.
Amphetamine and cocaine abuse can lead to pschosis and both increase DA levels.
Parkinson’s patients taking L-DOPA sometimes show psychosis.
Correlation between D2 antagonist affinity and therapeutic potency.
Dopamine metabolism gene expression (COMT) is altered in schizophrenics.

AGAINST:
Some patients have full DAr blockade with antipsychotics and no reduction in psychotic symptoms.
DA block is rapid but antipsychotics take weeks to take effect.
Atypical antipsychotics have lower affinity for DA receptors but are often more effective.
Many antipsychotics target multiple receptor systems (‘dirty’) .

Question 24

Outline amphetamine psychosis

Answer 24

Amphetamine psychosis: delirium, panic, hallucination. Difficult to distinguish from acute schizophrenia.

Amp is transported into presynaptic nerve terminals via the dopamine transporter.
In terminal it disrupts vesicular storage of monoamine transmitters (DA).
Monoamines (DA) are pumped out into nerve terminal via reverse action of dopamine transporter.

Increased DA = associate with stereotypies (movement disorders), cognitive inflexibility, impulsivity etc.

Question 25

Explain goldilocks effect of dopamine and noradrenaline on the brain and cognition.

Answer 25

Too little: ADHD symptoms (distracted, impaired working memory), poor cognition.

Cognition increases as levels lise

Just right: Peak performance reached

Levels of transmitter continue to rise past optimal point and cognition becomes increasingly impaired.

Too much : poor cognition, inattentive, hyperactive etc.

Question 26

Where are dopaminergic neurons found and associated pathways?

Answer 26

1) substantia nigra: nigrostriatal pathway involved in motor control.
* substantia nigra to striatum (more local)

2) ventral tegmental area: mesocorticolimbic pathway involved in reward, reinforcement.
* VTA to frontal lobe

Question 27

What DA pathways thought to give rise to different symptoms?

Answer 27

Both from mesocorticolimbic but diff aspects.

Overactive mesolimbic: positive symptoms.

Dysfunction of mesocortical: negative and cognitive symptoms.

Question 28

Briefly describe diff DA receptors

Answer 28

There are 5 and all 5 are metabotropic.

Divided into 2 groups

D1-like: stimulate adenylyl cyclase.
D2-like: inhibiit adenylyl cyclase

Question 29

Why does antidepressant therapeutic effacy take weeks?

Answer 29

Possibly due to long-term neural adaptations that are required to experience symptom relief.

Question 30

Mechanism of action of flupentixol, haloperidol and chlorpromazine

Answer 30

All typical and competitively antagonise D2 receptors in mesocorticolimbic pathway.

Question 31

Mechanism of action of atypical anti?

Answer 31

Weaker antagonism of D2-like and bind to other receptors.
NB: LSD causes hallucinations as acts as partial agonist at 5HT-2A. Block of 5HT is part of how atypical work. Others include, muscarinic cholinergic, and adrenergic receptors.

This weaker antag means reduced EPS and hormonal side effects but also introduce new side effects = antimuscarinic actions such as constipation, hypotension

Question 32

Outline the glutamate hypothesis of schizophrenia

Answer 32

FOR:
PCP (NMDAR antag - binds inside channel pore) psychosis is clinically indistinguishable from schizophrenia.
Ketamine (NMDAR antagonist) exacerbates psychosis in schizo.
Anti-NMDAR encephalitis has schizo like symptoms (ab against extracellular NMDAR domain)
6.5% of patients at first schizo diagnosis have anti-NMDAR antibodies
EEG markers for schizo are mimicked by ketamine.
Mutations in NMDA subunit GRIN2 associated with schizo

Question 33

How do novel drugs enhance glutamate function?

Answer 33

Activate mGluRs.
1) activity of mGluRs enhances NMDAR function.
2) presynaptic mGluRs increase glutamate release.
3) mGluR activation on glial cells can regulate removal of glutamate on synaptic cleft.

Question 34

Aetiology of schizo?

Answer 34

Likely different for different individuals, psychosis thought to be final common path for processes affecting brain function.

Question 35

What do EEGs detect?

Answer 35

Firing of neuronal populations.

1) glu relased at synapse and postsynaptic cation channels open. Positive ions enter cell and extracellular fluid becomes more negative.
2) positive current flows down dendrite, some leaks out of mem. Causes extracellular fluid to be more positive.
3) each electrode detects activity from thousands of neurons.

Inputs active in irregular pattern= low amp EEG
Inputs active in synchronous= large amp, these produce oscillations and oscillations linked to differing behavioural states.

Question 36

What does it mean if diff brain structures are oscillating in synchrony?

Answer 36

Information transfer is facilitated

Question 36

Describe how to produce event related potentials (ERPs)

Answer 36

1) presentation of stimulus such as tone.
2) brain activity recorded.
3) stim is repeated and recorded.
4) evoked responses are averaged to uncover characteristic patterns of responses.

ERP: pattern of brain activity evoked by specific stimulus.

Question 37

Outline how neural synchrony is altered in schizo.

Answer 37

Schixo show lower power to stim at 40Hz than control subjects (no diff at lower freq).

Ability of diff brain regions to phase lock with one another is attenuated in schizo.

Question 38

Diagnostic criteria

Answer 38

Need at minimun 1 v clear symptom and two less clear to occur for over 1 month (6 months in DSM-V).

Thought disorder
Catatonic behaviour (rigidity, erratic movements, echolalia).
Delusions
Negative symptoms (less motoivation, social withdrawal)
Behavioural changes
3rd person hallucinations
impaired cognition (attention, verbal memory etc).

Question 39

Recent advances in classification

Answer 39

Moving towards use of biomarkers instead of symptoms.
No reliable for schizo yet.

Question 40

Course of schizo

Answer 40

Difficult to generalize (differing ways of diagnosis, patient follow up and identification of recovery)
UK AESOP study : 10 year follow up for first episode of psychosis showed 23% had unremitting illness and 45% were free of symptoms for at least 2 years. (Morgan et al, 2014)
Bleuler’s 20 year follow up after hospital admission : 20% complete remission, 25% good social adjustment, 24% severely disabled (M.Bleuler, 1974)
Higher mortality rates (especially with comorbid alcohol and substance use) : Men with schizophrenia die 20 years prematurely, and for women 15 years. (Saha et al, 2007)
60% of excess mortality is accounted by unnatural causes (suicide and accidents) , 40% related to physical health co-morbidities eg cardiovascular disease (Shier et al, 2015)

Question 41

What factors linked to poor outcome of schizo?

Answer 41

Demographic: male, single, younger onset, comorbid substance abuse.

Clinial: insidious onset (gradual with no symptoms at first), untreated.

Other: high expressed emotion in family, poor adherence with treatment.

Question 42

Melatonin and schizophrenia

Answer 42

Secreted in response to light and shown to be both inc and dec. Stimulates antioxidants…

Marker: lower levels at night compared to neurotypical. Chlorpromazine increases levels…

Tardive dyskinesia (abnormal haw movement)is side effect of antipsychotics due to oxidative stress.
- high dose melatonin can ameliorate this

Question 43

Treatment resistant

Answer 43

Failure of 2+
- earlier onset, more heritable, greater reduction in grey matter vol.
Thought to be either new subtype or more severe.

Novel treatments
-TMS: dlpfc 10hz, decrease in negative symptoms
-DBS: nac showed 60% reduction in positive and 30% reduction of negative

Question 44

Drug induced model

Answer 44

Repeat admin of amphetamine: hyperactivity (no negative or cognitive symptoms)

Question 45

Genetic model

Answer 45

DISC1: disrupted in schizo 1, synaptic involved in perinatal development.

Mice show reduced cortical thickness and brain volume. Reduced PV+ neurons

Males- hyperactivity
Females- reduced spatial memory

Question 46

Developmental model

Answer 46

MAM (methylazomethanol): antimitotic that methylates DNA.

Decreased mPFC, increased DA activity and decreased social interaction