W11 - Schizophrenia Flashcards
What are psychotic disorders?
Major psychoses (‘madness - cancer of mental illness’)
Examples:
* Schizophrenia* Schizoaffective disorder = schizophrenia and bipolar disorder
* Delusional disorder
* Some depressive and manic illnesses
Schizophrenia is the most important of the above for the following reasons:
1. Early in onset: 18- early 20s
2. Prevalent - 1% of population
3. Disabling and chronic
* Mental state that is out of touch with reality
* Abnormalities of perception, thought & ideas
* Profound alterations in behaviour (bizarre and disturbing alienation)
What is the prevalence of Schizophrenia?
- Affects up to 1% of the population
- No significant influence of culture, ethnicity, background, socioeconomic groups
- Increased in urban areas
Difference between sexes:
Men show an earlier age at onset (18-20 yrs), higher propensity to negative symptoms, lower social functioning, and co-morbid substance abuse than that is women, whereas women display relatively late onset (30-35 yrs) of the disease with more affective symptoms eg. depression. - Before the illness can be recognised there is often a phase in late teenage years associated with social isolation, interest in fringe cults, social withdrawal
- A chronically disabling condition; responsible for a great deal of the population’s morbidity
- In the UK, the cost of treating a patient with schizophrenia through their life is about six times the cost of treating a patient with heart disease.
What are the three classes into which schizophrenia symptoms can be grouped?
Positive:
* Hallucinations (e.g. visual, auditory)
* Delusions
* Disorganised thought/speech
* Movement disorders
Negative:
* Social withdrawal
* Anhedonia - lack of pleasure
* Lack of motivation
* Poverty of speech
* Emotional flatness
Cognitive:
* Impaired working memory
* Impaired attention
* Impaired comprehension
Two or more of these symptoms must persist for at least 6 months to be classed as schizophrenia
What are hallucinations?
Perception experienced without stimulus.
(Functional Hallucination)
Most commonly auditory
Patients hears
Voices talking about them (3rd person)
Voices talking to them
Voices giving a running commentary
Voices echoing their thoughts (thought echo)
Patients may engage in a dialogue with the
voices or obey their commands.
What are delusions?
A fixed/ unshakable belief. Not
consistent with cultural/ social norms.
Often paranoid or persecutory
E.g. under control of an external influence,
thoughts known to other people because they are transmitted by radio and TV
Passivity of thoughts and actions
What Motor, volitional and behavioural disorders do schizophrenia accompany?
- Peculiar forms of motility, stupor, mutism, stereotypy, mannerism,
negativism, spontaneous automatism, impulsivity
– Stereotypies: purposeless, repetitive acts
– Bizarre postures, strange mannerisms
– Altered facial expression – grimacing
– State of catatonia – motionless, mute, expressionless, uncomfortable or contorted postures
– State of catalepsy – waxy flexible
– Bouts of extreme hyperactivity (destructiveness; walk around naked)
– Impulsive behaviour – violent acts; murder w/o reason
What is a formal thought disorder?
A disorder of conceptual thinking,
reflected in speech that is difficult to
understand and rapid shifts from one
subject to another. New words are
invented (neologisms).
What is social withdrawal?
Patients withdraw from their families and
friends and spend a lot of time on their own.
Lack of initiative or motivation
Do not want to do anything.
No longer interested in things that used to
interest them.
What are features of formal thought disorder?
- Disturbances in thinking → unintelligible speech
- Derailment of speech
- Loosening of associations; failure to follow train of though to its conclusion
- Poverty of speech (speech fails to convey sense/information)
– Manifests as distorted or illogical speech
What are cognitive deficits?
Deficits in SELECTIVE attention, problem solving
and memory
- Eg. They would be unable to differentiate between someone talking and the ticking of a clock.
Blunted affect
Decreased responsiveness to emotional issues.
Incongruous affect. Expression of affect
inappropriate to circumstances.
What are insights?
An understanding of what is wrong.
Insight lacking in schizophrenia.
Patients usually do not accept that any
thing is wrong or that treatment is necessary.
What are the 4 phases of schizophrenia?
- The Prodrome
Late teens/early twenties: often mistaken for depression or anxiety. Can be triggered by stress. - The Active/Acute Phase
Onset of positive symptoms
Differentiation of what is and isn’t real becomes difficult - Remission
Treatment -> return to ‘normality’ - Relapse
They will usually switch between Remission and Relapse.
Schizophreniform positive symptoms for at least a month, but under 6 months
What is the aetiology of schizophrenia
Nature vs Nurture
Genetics:
* SCZ isn’t directly inherited, but
can ‘run in families’
* ‘Candidate’ risk genes:
* Gene deletions
* Gene mutations
Environmental Factors:
* Pregnancy/birth complications
* Stress
* Drug use
Nature AND Nurture
How do we know the Schizophrenia is caused by genetic influence?
Twin studies done in monozygotic twins.
-50% chance of developing schizophrenia if one twin diagnosed
In dizygotic twins,
~14% chance of developing
schizophrenia if one twin diagnosed
What are ‘Candidate’ Genes?
This is a polygenic disorder.
We know the exact genetic anomalies that lead to
these disorders:
Sickle-cell disease
Cystic fibrosis
Colour blindness
- COMT
- DISC1
- GRM3
Some of the ‘risk’ or
‘candidate’ genes for schizophrenia
Possessing these abnormal genes does not
mean you will definitely get schizophrenia –
similarly, some people who have schizophrenia
do not have these genetic abnormalities
What could some Pregnancy/birth complications associated with schizophrenia be? What evidence is there?
Season of birth: influenza
A Finnish study reported a spike in schizophrenia for people who were foetuses during the 1957 influenza epidemic
Pregnant women in the UK are advised to be vaccinated against seasonal flu
These are all causes of early-life stress:
Low birth weight
Premature birth
Asphyxia during birth
What is stress?
Moving country
Swedish cohort <non-refugee immigrants < refugee immigrants
Early-Life Bereavement
Cohort under 18 (Denmark & Sweden)
Loss of >1 first-degree relative further increased risk
Loss of job/home/relationship
Physical/emotional/sexual abuse
The mechanism by which stress may trigger schizophrenia is unknown
What is Drug Use?
Cannabis
Use in early life (~15 years)
Amphetamine
Cocaine
LSD
What is the Pathophysiology of Schizophrenia?
Theories:
Dopamine hypothesis
Brain structure differences
Hypofrontality
NMDA receptor hypofunction
Oxidative Stress
Neuroinflammation
What is the Dopamine Hypothesis?
Main DA pathway Involved in:
-Movement
-Cognition
-Emotions
-Motivation
-Reward
In people suffering from Schizophrenia, there is a hyperactivity in the mesolimbic dopaminergic pathway. So hyperactivity in the neurones that project from the VTA to the Ac, Hip, Am - suggested to be associated to some of the positive symptoms.
What are some theories of Neurochemistry for schizophrenia?
Theories (controversial, not sure how DA involved)
Schizophrenia caused by endogenous, DA derivative, psychotogen
Schizophrenia – overactivity of DAergic, mesolimbic pathways
Positive symptoms – hyperDAergic in mesolimbic system (increased D2 )-but D2 antagonists do the same
Negative symptoms – hypoDAergic activity in mesocortical system (decreased D1 )=>decrease cognition
D4 involved? But selective D4 antagonists not effective
What evidence is there to dopamine release?
Dopamine (pharmacological evidence)
DA release (amphetamine) produces ‘schizophrenia’ (Carlsson 2000)
Amph enhances DA release in schizophrenics more than controls which makes the disease worse
D2 agonists produce stereotyped behaviour (not D1) - repetitive movements.
Reserpine depletes DA – controls positive symptoms
Strong correlation D2 blocking activity & antipsychotic action
DA release only in mesolimbic, mesocortical NOT nigrostriatal
Evidence - psychostimulant drugs such as cocaine or amphetamine, which increases dopamine in the mesolimbic pathway - seems to induce psychotic episodes.
What is some evidence against the dopamine hypothesis of
schizophrenia?
Evidence against:
No clear change in CSF HVA concentration
No change in DA receptors in drug-free
patients (Increased D2 receptors in
samples attributed to drug treatment for schizophrenia)
What are the brain structure abnormalities found in schizophrenic patients?
Some people had looked at twins where one is schizophrenic and the other is healthy.
In schizophrenia:
-Overall brain size slightly smaller
-Reductions in grey matter
-Enlarged lateral ventricles – smaller hippocampus
*Not all people with schizophrenia have such profound structural brain differences
What is Hypofrontality? What is found so often in schizophrenic patients?
Reduced blood flow to the frontal cortex
Reduced activity in frontal cortex?
This is a very important region in decision making, judgement.
What is the NMDA receptor hypofunction theory?
Glutamate evidence:
NMDA is a receptor where the sedative neurotransmitter Glutamate binds to.
NMDA antagonists (ketamine (Horse tranquilliser and anaesthetic) / phencyclidine)
- Ketamine blocks the receptor and causes Psychotic symptoms – hallucinations & thought disorder
Decrease [glutamate] and glutamate receptor density in prefrontal cortex
Transgenic mice with Decreased NMDA receptor expression
Stereotyped behaviour & Decrease social interaction, responsive to antipsychotics
This shows the reduced dopaminergic neurotransmission, reduction in NMDA receptor activation is associated with positive symptoms of schizophrenia and also some negative symptoms.
What is the Serotonin (5-HT) evidence?
Serotonin (5-HT) evidence
- Lysergic acid diethylamide (LSD): partial 5HT agonist– hallucinations
- Many antipsychotics antagonise 5-HT receptors
Main current theory
-Over stimulation of mesolimbic D2 receptors
- Hypoactivity of frontal cortical D1 receptors
- Reduced prefrontal glutaminergic activity
- 5HT involved
What are some treatments for Schzophrenia?
Pharmacological
- Current
- Future therapies?
Cognitive Behavioural Therapy (CBT)
Electroconvulsive therapy (ECT)
What are Antipsychotics?
Typicals
Also known as ‘first generation’
First developed in the 1950s
Mainly antagonise D2 receptors
- Good at suppressing positive symptoms, not negative symptoms.
Atypicals
Also known as ‘second generation’
First developed in the 1980s
Mainly antagonise D2 and 5-HT2A
receptors
- Safer, less extreme side effect associated with typical side effects.
If these drugs block the D2 receptors in the striatum for example, it can lead to movement disorders.
What is a Receptor Blockade?
Antipsychotics block D2 receptors found in the mesolimbic pathway. This will supress the hyperactivity of this pathway associated with the positive symptoms of schizophrenia leading to an antipsychotic effect such as delusions and hallucinations.
D2 receptors are also found in the striatum.
-Nigro-striatal
Basal ganglia (striatum)
->Movement disorders:
Parkinsonism
Dystonia
Dyskinesia - Inability to initiate movement.
Hypokinesis - Slow movement
Tardive Dyskinesia - severe and irreversible
There are also D2 receptors found in the anterior Pituitary gland, increasing prolactin release.
Endocrine effects:
- Breast swelling - prolactin acts on mammary glands to increase breast growth
- Increases Lactation - can happen in males and females
- Impotence - sexual disfunction
There could be D2 receptors blocked in the Nucleus Accumbens, leading to decrease in pleasure (reward system)
They also block a-adrenoceptors.
-a-adrenoceptor blockade
Postural
hypotension
Nasal congestion
Hypothermia
They can also block muscarinic receptors.
Muscarinic blockade:
Beneficial for treating extrapyrimidal side effects
Dry mouth
Blurred vision
Constipation
Urinary retention
-Other
H1 receptor blockage – sedation
5-HT – weight gain
Photosensitisation
D2 receptor blockade
What is sedation?
Can occur via two different mechanisms
D2 receptor antagonism
Central H1 receptor antagonism
What are the prolactin side effects?
- Antiasychitics increase prolactin
Secretion - Gynaecomastia, milk secretion
*Menstrual irregularities, impotence, - weight gain
What can Hypotension do?
- Another ‘off-target’ effect
- α1-adrenoceptor antagonism
- These are found in the vasculature. Activation of these would cause vasoconstriction. The blockage/inhibition causes vasodilation.
-Leads to hypotension = drop of blood pressure.
What are the anticholinergic effects?
Antagonism of muscarinic acetylcholine receptors
Salivary secretions: Dry mouth
Pupillary muscles: Blurred vision
Smooth muscle contraction: Constipation and Urinary retention
Blockade of mAChRs at the neuromuscular junction: alleviates
EPSE symptoms
However, anticholinergics are thought to detrimentally impact upon
cognition
What does Muscarinic receptor activation do?
Found in the brain and periphery.
The major endogenous ligand of muscarinic receptors are acetylecholine.
Parasympathetic effects:
- Stimulation of saliva
- Slows heart beat
- Constricts bronchi
- Stimulates peristalsis and secretion
- Stimulates release of bile
- Contracts bladder.
Antimuscarinic side effects-
Sympathetic effects:
- Dilates pupils
- Inhibits flow of saliva
- Accelerates heartbeat
- Dilates bronchi
- Inhibits peristalsis and secretion
- Conversion of glycogen to glucose
- Secretion of adrenaline and noradrenaline
- Inhibition bladder contraction
