Session Five (Schizophrenia)

Question 1

Describe the stigma around schizophrenia in UK society?

Answer 1

• Surveys have found most Brits think of Sz patients as dangerous, unpredictable and impossible to treat.
• Significant issues around finding and keeping work.
• These issues are fueled by popular media who paint people with Sz as “Schizos”?

Question 2

Briefly describe some of the historical perspectives of Sz?

Answer 2

• Historical treatment; Long term institutionalisation, restraint, sedation, anything to calm the patients to make them easier to manage
• Kraepelin described 2 debilitating and untreatable neurological disorders with no obvious causes; Manic depressive insanity, Dementia praecox (marked by hallucinations, delusions, incoherent speech, blunted emotions, lack of insight. Early Sz diagnosis)
• Bleuler coined the term Sz, and described it as a loosening of the associations between the different functions of the mind; thoughts, emotions, co-ordination, cognitions become separate and fight for control.
• Schneider revolutionised the field by focusing not on the contents of the delusions but on the CONVICTIONS with which they were held. Described 1st rank symptoms, which if present he said could distinguish Sz from psychosis

Question 3

What are Schneider’s 1st rank symptoms?

Answer 3

• Thought broadcasting
• Thought insertion
• Thought withdrawal
• Third person hallucinations
• Running commentary
• Thought echo (think a thing, hear that thought back a couple of seconds later)
• Made feelings and impulses (I’m not unhappy, they are projecting unhappiness into my brain)
• Delusions of control
• Delusional perception

Question 4

What are the positive symptoms of psychosis?

Answer 4

• Delusions (paranoid delusions, beliefs that comments on the tv or radio are directed at the self)
• Perceptual Abnormalities (distortions or exaggerations of perception in any of the senses, auditory or visual are most common)
• Thought disorder (key aspect, tangential speech, lack of association, incoherent)
• Disorganised behaviour (agitation, social inhibition, odd behaviours, difficulty with goal-directed behaviour, purposelessness)

Question 5

What are the negative symptoms of Sz?

Answer 5

AAA:

• Affective flattening (reduction in range and intensity of emotional expression, tone of voice, eye contact, body language)
• Alogia (poverty of language, reduction in fluency and productivity of language. reflects thought slowing or blocking)
• Avolition (reduction, difficulty or inability to initiate and persist in goal-directed behaviours e.g. loss of interest in social activities)

Question 6

What scoring system is used for Schizophrenia?

Answer 6

PANSS (Positive and Negative Syndrome Scale)

Scores based on 30 items on a 7 point scale. Items divided into:

• Positive (delusions, hallucinations, excitement, conceptual disorganisation..)
• Negative (blunted affect, withdrawal, poor rapport, lack of spontaneity)
• General (anxiety, guilt feelings, tension, depression, motor retardation, unusual thought content…)

Question 7

Why can it sometimes be difficulty to diagnose Sz properly?

Answer 7

• “Psychosis” refers to the presence of hallucinations, delusions and odd behaviour
• These are viewed as classic of Schizophrenia, but all can also be caused by organic conditions, substance abuse disorders, depression, bipolarism.
• Further confusing this is the fact many schizophrenics have co-morbidities that include depression and substance abuse disorders
• Furthermore, most diagnostic models fall victim to issues relating to cultural bias (misinterpretation of normal behaviour as abnormal) or pathologising of behaviour that is just unusual (e.g. eccentricity)

Question 8

What are some benefits of both the ICD and DSM diagnostic manuals for Sz?

Answer 8

• ICD makes a distinction between first onset Schizophrenia and multiple episode Schizophrenia. This emphasises how different these presentations are and allows them to be treated more effectively.
• DSM uses a multi-axial approach that allows us to gain a greater picture of the patient as a whole.
  (Ax1 = The actual disorder, Ax2 = Personality disorder and mental retardation, Ax3 = General medical condition, Ax4 = Psychosocial and environmental factors surrounding the patient, Ax5 = Global assessment of function). This approach allows view the patients condition as a whole.

Question 9

What are the broad similarities between the DSM and ICD definitions

Answer 9

Both use a:
- At least one of...
- Or two of....
- For a duration of...
- With an absence of...
Criteria

Question 10

What are some of the subtler symptoms of Sz worth bearing in mind?

Answer 10

Poor rapport with therapist/interviewer and difficulty in holding a regular conversation due to tangental nature of speech are actually very common signs of the condition.

Question 11

What is the Psychosis Continuum?

Answer 11

• Theory outlined by John et al in 2004
• Looked into how common vaguely psychotic symptoms are
• Found that 5.5% of people suffered one or more items associated with Sz without having a psychotic disorder
• True subclinical psychotic experiences prevalence = 8%
• Half of which are associated with a degree of distress.
• Suggests behaviours we brand as abnormal may just be severe versions of actually normal behaviour.
• A meta-analysis by van Os et al supports this

Question 12

What evidence is there that Schizophrenia may not even exist?

Answer 12

• John et al found that minor psychotic symptoms are prevalent in the general population.
• These minor symptoms are correlated with things like Low IQ, Low education, Living in cities, Cannabis dependence, Life events, Neuroticism and Being an ethnic minority
• All of which are notable risk factors for Sz
• Provides further support for the idea that Sz may not be a condition in and off itself but a more severe version of very common psychotic symptoms.
• Therefore perhaps not a CATEGORICAL illness, rather a continuum.
• However there are issues of cause and effect here, to what extent are low IQ, education, etc caused by Sz rather than the other way around.

Question 13

Schizophrenia may not be a distinct condition but an extreme form of a normal variant. What might this imply about diagnosis?

Answer 13

• Suggests Sz may not be a categorical definition but rather one that exists on a continuum
• Also suggests diagnosis may not be necessary.
• Avoiding diagnosing someone with Sz is a good way of avoiding stigma
• BUT diagnosis is still necessary for effective treatment.
• A categorical division between healthy and unhealthy should only be made at the point it seems useful to initiate treatment.

Question 14

What is the Psychosis Prodrome?

Answer 14

• Period characterised by mental state features that represent a change from a person’s premorbid functioning
• For Sz, the age to look for this in is 18-35

3 Broad features to look out for:

• Attenuated psychosis syndrome
• Brief limited intermittent psychosis (<7 days)
• Family history of psychosis and a decline in global functioning (general health)

MRI studies have managed to identify grey matter volume alterations prior to the onset of psychosis. 31% transitioned to psychosis (Pantelis et al 2003)

Question 15

Who is more at risk of developing Sz?

Answer 15

• Men (also have earlier onset)
• People of low SE group
• People in urban areas
• Homeless people

Question 16

What is the impact of Sz on a person’s life expectancy?

Answer 16

• Reduces it by 20-25 years

- 5-10% die by suicide

Question 17

What causes Sz?

Answer 17

• Brief answer, no idea.
• Sz is an etiologically complex disorder arising from the interaction of a range of factors acting at various stages of life.
• Some genetic elements, as evidenced by MZ twin studies

Question 18

What does genetic evidence suggest about Sz?

Answer 18

• Twin, adoption and family studies all suggest a genetic component
• Heritability of about 80% in twins
• However, no single gene has been found to be responsible for SCZ
• And people carrying risk genes do not necessarily express the disease

SCZ HAS A MULTIFACTORIAL, POLYGENETIC MODE OF TRANSMISSION (i.e. likely requires multiple genes and environmental exposures)

Question 19

What have linkage and association studies and genome wide association studies told us about Sz?

Answer 19

• Both have implicated several common risk alleles.

O’Donovan (2014):

• Largest ever study in mental illness has found 128 gene variants in 108 distinct locations associated with Sz.
• Patients with Sz have an increased number of Copy Number Variants (CNVs) (microscopic deletions and duplications of segments of DNA)

Owen (2007/2010):

• Identified a few candidate genes
• Candidate genes involve COMT (enzyme related to dopamine), NRG1 (involved in neurodevelopment somehow) and other factors.
• Also DISC1, Dysbindin, BDNF

Question 20

What is an Endophenotype?

Answer 20

• An endophenotype = a highly heritable neurophysiological, biochemical, endocrinological etc feature of a disorder.
• Quantitative, can be assessed using lab methods.
• Thought to be closer to genetic variation than symptomatic variation, therefore linked to heritability.

Question 21

What has endophenotypic research informed us about Sz?

Answer 21

Various endophenotypes across various forms of research have been associated with increased risk of Sz:

• Neurocognitive; VS, working and verbal memory all implicated, as well as executive function.
• Neurophysiology; Oculomotor function, sensory motor gating, EEG signal alterations
• MRI; Ventricular volume, superior temporal gyrus volume

However, no endophenotype has been confirmed in a large sample of at risk individuals.

Question 22

What are some known environmental risk factors for Schizophrenia?

Answer 22

• Abnormalities in pregnancy and delivery
• Winter birth
• Foetal malnutrition/infection
• Urban birth or rearing
• Childhood motor, social, cognitive dysfunction
• Low social class (cause and effect)
• Immigration (only 1st or 2nd generation weirdly)
• Substance abuse (especially cannabis)

But none are more important than STRESS, both in the sense of stressful life events and high expressed emotion

Question 23

Briefly describe the Stress-Vulnerability model of psychosis risk?

Answer 23

• Some sort of vulnerability (be it genetic or environmental) leads to a decreased ability to cope with stress
• As well as an increased baseline levels of cortisol, the stress hormone
• Prolonged elevations in cortisol can change certain brain structures
• Which creates a positive feedback loop eventually causing significant changes in brain function down the line, for instance in the dopamine system.

Question 24

What did the AESOP study reveal about Sz?

Answer 24

• Sz 9x higher in Afro-Caribbean populations
• 6x higher in African populations
• Urbanicity had a significant impact on the chances of developing Sz
• Social disadvantage cumulatively increases risk of developing psychosis

Question 25

Summarise the gene-environment interactions in medicine?

Answer 25

- The effects of the environment will affect us differently depending on our genetic make-up - Ou genetic make-up will make us prone to expose ourselves to certain environmental risk factors

Question 26

Give an example of evidence suggesting a gene-environment causality to Sz?

Answer 26

Caps (2005) - Adolescents with a particular variant of the gene coding for COMT (a dopamine enzyme) were found to be more likely to develop psychosis on cannabis use. - Carriers of the variant were more likely to develop Sz if they had used cannabis as a teenager

Question 27

What factors did Modinos' 2013 meta-analysis suggest as environmental triggers of Sz in an individual at an increased genetic risk?

Answer 27

- Cannabis - Winter birth - Stress - Childhood abuse - Obstetric complications

Question 28

What are some issues common to gene-environment relationship studies?

Answer 28

- Often use small sample sizes - Achieving precise and reliable measures of environmental exposure is often difficult - Methodological issues and inconsistencies across studies - Low probability of a true association between a disorder and any one among many thousands of genetic polymorphisms.

Question 29

Describe the course and prognosis of Sz?

Answer 29

- Can be acute, can be chronic - Within chronic, can be relapsing and remitting or consistent Rule of thirds: - 1/3rd recover fully - 1/3rd have a number of future relapses - 1/3rd go into a chronic form with multiple relapses

Question 30

What drugs are available for the treatment of Sz?

Answer 30

- Typical antipsychotics e..g Haloperidol, Chlorpromazine | - Atypical antipsychotics e.g. Olanzapine, Risperidone, Clozapine

Question 31

What are the pros and cons of pharmacological treatment of Sz?

Answer 31

PROS: - Can mostly treat symptoms CONS: - Risk of wrong medication or dosage is high, often have to try various options before finding something that sticks - Potent side effect profile - Stigma around being on anti-psychotics

Question 32

Outline some of the post-mortem findings in the brains of people with Sz?

Answer 32

- Altered neuronal density and abnormal cytoarchitecture (e.g. location and clustering of neurones). Especially true in limbic, temporal and frontal regions. - Minimal evidence of neuronal loss. - No evidence of gliosis, the process by which brain tissue responds to progressive brain disease, infection or brain lesions. No gliosis in a structurally abnormal brain suggests a fixed prenatal or genetic pathology leading to a developmental change over the lifetime of the person

Question 33

What do structural MRI studies tell us about Sz?

Answer 33

- Shenton et al (2001) - Found 80% of patients had ventricular enlargement - 74% had bilateral medial temporal lobe reductions - 74% had superior temporal guys reduction - 68% had abnormalities in either the basal ganglia or the corpus callosum - Other studies that have followed up patients over a 20 year period have found these changes to be progressive over the course of the life span. Also found a reduction in overall brain size. - From this data we can conclude that there is strong evidence for progressive ventricular enlargement and brain matter loss in specific areas over the life of an Sz patient.

Question 34

What brain changes are apparent in childhood onset Sz?

Answer 34

- In normal cortical development, a process of pruning occurs - Neuronal connections are severed as the brain makes itself more efficient and gets rid of useless connections - In childhood onset Sz, you see an exaggerated form of this process - Excessive pruning of grey matter, sweeping from parietal to prefrontal regions

Question 35

Summarise what MRI studies have shown about the neuro-anatomical undermining of Sz?

Answer 35

- Grey matter loss in a number of regions (namely the prefrontal and temporal) and ventricular enlargement are associated with Sz. - Grey matter volume changes are present in the prodromal phase, and occur mostly in the areas mentioned above - Progressive cortical loss, greater loss of volume after the first episode. - Exaggeration of normal cortical development pattern seen in early onset Sz.

Question 36

What has research into neurochemistry told us about SZ?

Answer 36

- PET scans have shown excess activity at dopaminergic synapses in certain areas of the brain

Question 37

What are some issues with the use of imaging studies in Sz? How can we work around these issues?

Answer 37

- Most of these patients have been on medication their whole life, how can we know the changes we're seeing are caused by the CONDITION not the MEDICATION. - Similarly, how can we distinguish the acute effects of an Sz episode vs the chronic changes we know are present in Sz patients? - One way of working around this issue is by studying patients in the prodromal phase, before medication or the condition becoming chronic.

Question 38

What have prodromal studies into the neurochemistry of Sz revealed?

Answer 38

- Increased pre-synaptic dopamine storage and synthesis predates the onset of Sz in people with ARMS (at risk mental state) - DA overactivity is predominantly localised in the associative striatum, this makes sense in the context of the severity of symptoms and neuro-cognitive dysfunction - Increased pre-synaptic dopamine in ARMS is predictive of transition and increases post transition

Question 39

The main neurotransmitter associated with Schizophrenia is Dopamine, but what others have been linked?

Answer 39

- GABA - Glutamate However no antipsychotic active on these systems has shown any sort of clinical efficacy.

Question 40

Outline Versions 1 and 2 of the neurobiological theories of Sz

Answer 40

- Main Theory (version 1) focuses on Hyperdopaminergia - DA = The wind of psychotic fire. - One of dopamine's roles in healthy individuals is to mediate the salience to ideas and objects - When individuals are acutely psychotic, they show an excessive release of DA1 - This heightened transmission leads to aberrant assignment of salience to both external and internal stimuli - Delusions are actually attempts to explain this abnormal salience - Version 2 expands on this Hyper-D theory by adding Hypo-D in other areas as a result - States Prefrontal region becomes depleted of Dopamine due to increased activity elsewhere in the brain - Both theories criticised for over focusing on dopamine in isolation, and for ignoring recent genetic/imaging findings.

Question 41

What is Version 3 of the Dopaminergic theory of Sz?

Answer 41

- The Final Common Pathway - Framework that links RFs (e.g. obstetric complications, stress and trauma, drug use...) to increased presynaptic dopaminergic activity in the striatum. - Aims to explain how such a complex array of structural or functional abnormalities, as well as cognitive impairments, can converge neuro-chemically to cause psychosis through this abnormal saliency.

Question 42

Outline the Neurodevelopmental theory of Sz?

Answer 42

Sz very distinctly develops in the second decade of life, surely theres a reason for this? - Genetic cause, or early environmental insult, leads to Sz - There is a "risk window" post birth where environmental insults have most impact (on people with an existing predisposition) - This theory conceptualises Sz as a process of abnormal neurodevelopment across the life span In brief, there is a genetic predisposition to abnormal neurodevelopment which interacts with many environmental factors to produce psychosis.

Question 43

Outline the MAM model of Sz?

Answer 43

1) Genetic predisposition and environmental risk leads to... 2) Abnormal emotion and stress regulation leads to... 3) Hyperactive amygdala driving Hippocampal overdrive (this may be amplified by Glutamate GABA activity) leads to... 4) Abnormal inputs from hippocampus to striatum and midbrain leads to... 5) Dopamine dysfunction in striatum leads to... 6) Abnormal salience leads to... 7) Psychosis!