Mental Health Pharmacology Schizophrenia Flashcards
Which neurochemicals are imbalanced in the brain in SZ?
DA
* Glu (glutamate)
Ach, 5HT, GABA
What are the positive symptoms of SZ?
Hallucinations (auditory, visual), delusions, thought insertion, disorganised thought processes, disorganised speech, disorganised behaviour, agitation, catatonia (non response to stim)
What are negative symptoms of SZ?
Flattening of emotional responses, low mood, loss of motivation, lack of energy, social withdrawl, anhedonia (loss of pleasurable activities), speech and language deficits, poor self care
What are cognitive symptoms of SZ?
Impaired working memory, loss of attention, impaired decision making
Describe the epidemiology of SZ:
Prevalence 0.3-0.7%
Incidence 0.3 in 1000 so lifetime risk is 1%
Typical onset of +ve symptoms is late adolescence/ early adulthood (15-25)
Same incidence rates in male to female, but typically there is later onset in females
What is the mortality like in SZ?
50% increased mortality
Life expectancy decreased by 20-30 years
Increases CV risk, lifestyle, suicide
Describe the aetiology of SZ:
Genetic (70-80%) and environmental (20-30%)
What are the risk factors for SZ?
Family history
Developmental
Environment
Describe how family history can be a risk factor for SZ:
50% concordance in identical twins
20% in non identical
10% siblings
15% parent
Describe how developmental factors can be a risk factor for SZ:
Pre-natal (before birth) factors e.g maternal stress- viral infection, birth trauma
Neurodevelopmental abnormalities
Describe how the environment can be a risk factor for SZ:
Stressful life events
Urban environment
How can genetics be a link to SZ?
Many SZ susceptibility genes have been identified
Involved in neuronal development, synaptic organisation and function- neurotransmission:
-receptors
-TFs
-protein turnover
-ion channels
-structural proteins
-epigenetics
Describe the pathophysiology of SZ:
Increase in size of ventricles
Loss of grey matter (thinning of cortex)
Decreased white matter volume
Altered activity in dorsolateral pre-frontal cortex, ventromedial pre-frontal cortex, amygdala and hippocampus
Change in neurotransmitters
Describe the loss of grey matter in the pathophysiology of SZ:
Nº neurons unchanged (not neurodegenerative disease)
Synaptic connections- size of dendritic tree so less connections:
-increase dendritic pruning, means less connections
-many susceptibility genes involved in synaptic maintenance
Describe a decreased white matter volume in the pathophysiology of SZ:
Decrease in number of oligodendrocytes (cells which make myelin sheath)
What is the function of the dorsolateral pre-frontal cortex?
Decision making, motivational drive
What is the function of the ventromedial prefrontal cortex?
Emotional function
Describe pharmacological evidence for the dopamine hypothesis:
Drugs that cause DA release/ increase in synaptic conc (e.g amphetamine, cocaine) can cause psychosis
Drugs that deplete DA (e.g reserpine) decreases psychosis
D2 agonists (e.g bromocriptine) exacerbate sz
A SE of dopaminergic drugs is hallucinations
What receptors do all antipsychotics block and what does this mean?
All block D2 receptors
Decrease psychotic (+ve) symptoms
Correlation between clinical potency and affinity of antipsychotic drugs for the D2 receptors
What is psychosis in sz due to?
Over activity of dopaminergic neurons in the mesolimbic pathway causing the +ve symptoms of sz
Describe the dopamine hypothesis:
Increase conc of dopamine have been found in the presynaptic terminals of DA neurons in the mesolimbic pathway
Increase release of DA from dopaminergic neurons in mesolimbic pathway
Release of DA is greater during periods of psychosis compared to periods of remission
What is the cause of the -ve symptoms of sz according to the dopamine hypothesis?
Decreased activity in the mesocortical pathway, which contributes to the -ve symptoms
Name the dopamine pathways:
Mesolimbic pathway
Mesocortical pathway
Nigrostriatial pathway
Tuberohypophyseal
Describe the mesolimbic pathway:
VTA (ventral tegmental area) to limbic areas, notably to nucleus accumbens (hippocampus, amygdala)
Behavioural- reward pathways (addiction problems)
Describe the mesocortical pathway:
VTA to frontal cortex
Cognition and thought
Describe the nigrostriatial pathway:
Cell bodies in substantia nigra (midbrain) projecting
Control of movement
Describe the tuberohypophseal pathway:
Hypothalamus to pituitary
Control of secretion
DA inhibits prolactin secretion
What is the glutamate hypothesis?
Due to decreased activity of glutamatetgic synapse in pyramidal neurones in the prefrontal cortex, decreased signalling via NMDAr
Can explain all types of symptoms of SZ
Can explain the changes in DA that occur in the mesolimbic and mesocortical pathways
How can the glutamate hypothesis explain the changes in DA that occur?
Both downstream of the pyramidal neurons in the pre-frontal cortex
Decrease signalling via NMDAr causes downstream increased activity in the mesolimbic pathway, but decreased activity in the mesocortical pathway
Therefore fundamental NT imbalance is glutamate rather than dopamine
Describe the evidence for the glutamate hypothesis:
NMDA antagonists (e.g phencyclidine, ketamine) are psychomimetic, also mimic -ve and cog symptoms of sz
Observed structural changes to the glutmainreigc pyramidal neurons in the pre frontal cortex- size and complexity of dendritic fields are decreased
Changes in all glutamate r and VGLUT1 have been reported in post mortem sz pts, but results are inconsistent in expression
Genes related to glutamergic transmission are associated with risk of sz
What are the susceptibility genes for sz involved in?
Neuronal development
Synaptic formation, maintenance, structure and function
Name examples of susceptibility genes for sz:
GRIN2A (NMDAr subunit) and GRIA3 (AMPAr subunit)
DAAO and DAoA (D a.a oxidise/ activator)- D serine important mod at NMDAr
CACNA1G (VGCa channel a subunit-sig at glutamaterigc synapse)
Name the two classes of antipsychotics:
First gen (FGA’s) aka typical or conventional
Second gen (SGA’s) aka atypical or non-conventional
Name examples of first gen antipsychotics:
Chlorpromazine (a phenothiazine) and haloperidol
Name examples of second gen antipsychotics:
Clozapine
Risperidone
Olanzapine
Quetipaine
Describe the pharmacology of antipsychotics:
Activity is primarily due to blocking D2r in the mesolimbic pathway
Clinical efficacy at 80% occupancy of D2r in this pathway (although there are exceptions e.g clozapine)
Also block dopamine receptors in other dopaminergic synapses which lead to SEs
Describe the effects antipsychotics have for blocking the nigrostriatial pathway:
Motor effects- leads to extrapyramidal SEs- affects basal ganglia
Acute- soon after starting treatment:
Pseudo Parkinsonism
Involuntary movement
-repetitive movement
-spasm esp in face and neck (dystonias)
Later:
Tardive dyskinesias (involuntary movement in face and limbs)
Describe the effects antipsychotics have for blocking the tuberoinfundibulnar pathway:
Increase prolactin secretion (hyperprolactinamiea) as DA normally inhibits secretion via D2r:
-breast development/ enlargement/ lactation/pain
-amenorrhoea/ decreased fertility in women
-loss of libido/ sexual dysfunction
Describe the effects antipsychotics have for blocking the mesocortical pathway:
Blocking an already deficient pathway so can worsen -ve symptoms
Describe the effects antipsychotics have for blocking the mesolimbic pathway:
Inhibition of reward pathways so can worsen negative symptoms
How did SGA’s aim to improve clinical efficacy and SE profile?
Antagonist activity at 5HT2Ar e.g clozapine, olanzapine
Improving selectivity for D2 over D1r e.g risperidone
Improving selectivity for D2r over all receptors e.g sulpuride
Rapid dissociation from D2r e.g quetiapine
Partial agonist at D2r e.g aripirazole
Action at muscarinic receptors
What is the SGA’s having antagonistic activity at the 5HT2Ar?
Increase release of DA in striatum
5HT increases prolactin secretion so therefor antagonist inhibits secretion
Also proposed to increase glutamate release in the cortical pyramidal cells- help all symptoms
What is the effect of SGA’s having rapid dissociation from the D2r?
Antagonism not be enough for EPSE’s- downstream effects
What is the effect of SGA’s being a partial agonist at D2r?
Stim D2r at much lower level than agonist
So antagonist activity so not totally shutting down pathway- fine balance
What is the effect of SGA’s action at muscarinic receptors?
Ach unopposed if decreased DA so PD symptoms
What side effects will antipsychotics cause if they have a1 antagonism?
Causes post hypotension, plus DA antagonism causes hypotension
What side effects will antipsychotics cause if they have H1 antagonism?
Contributes to sedation caused by these drugs
Name other SEs of antipsychotics:
Some 1st gen- neuroleptic malignant syndrome (rare but fatal)- muscle rigidity, confusion, high temp
Metabolic syndrome
Prolongued QT interval- arrhythmia
Neurotpenia and agranulocytosis (clozapine- must monitor WBC)
Describe the metabolic syndrome SE of antipsychotics:
Weight gain (can be 2kg in 2 weeks)
Insulin resistance
Hyperlipidaemia
Can lead to T2D (also more common in pts with sz) and increased risk of CVD
Mechanism unknown (5HTr?, H1r?) but more frequent with SGA’s
Name some potential antipsychotic targets:
NMDA and AMPA allosteric modulators- enhance activity
mGLUr
mGlur/5HT2r heterodimer
Describe how NMDA and AMPA allosteric modulators would work:
Agonists at the NMDA glycine site could enhance activity
GlyT inhibitors were not found to be effective in clinical trials
