Antipsychotics Flashcards
what is schizophrenia ?
major CNS disorder
its debilitating
progressive illness with serious consequences
what is another name for antipsychotics?
neuroleptics
why has schizophrenia been called the most devastating disease to affect mankind?
because it is not just a single disease but a spectrum of disorders
- its symptoms can change over time
when is its peak onset?
it strikes young people with little warning
- in males peak onset is 15-25 years
- in females peak onset is 25-35 years and often another peak post menopause
each gender is affected equally
what is the prevalence of schizophrenia ?
1.3%
about 40-50% of hospitalised psychiatric patients suffer from schizophrenia
what influences schizophrenia ?
genetic element is polygenic- in twin studies, if one twin has it then then other twin has a 50% chance of developing it
large environmental component
what are the different symptom category groups in schizophrenia ?
positive symptoms negative symptoms cognitive symptoms mood symptoms - range of symptoms which often occur at the same time
what are the positive symptoms ?
delusions
hallucinations
disorganised speech
- these are symptoms added onto normal behaviours
what are the negative symptoms ?
decreased emotion decreased motivation decrease in interests decreased thoughts and speech decreased pleasure
what are the cognitive symptoms ?
attention
working and verbal memory
executive function
- it is NOT an intellectual impairment
what are the mood symptoms ?
depression/anxiety- they tend to just stare at a space on the floor and dont really interact with people
hostility
aggression
suicide
- these symptoms are often part of the negative symptoms
- patients cant hold eye contact, they have less flashes of eyes and less smiles
what are the 2 main neurotransmitter systems affected in schizophrenia?
dopamine and glutamate - these were discovered by accident
serotonin is also thought to be involved
what is dopamine hypothesis ?
- dysregulation of dopamine neurotransmission - abuse of stimulants leads to schizophrenic like pyschosis via release of dopamine e.g chronic cannabis - this is probably more prevalent in individuals which have a predisposition to schizophrenia
- animal models have shown that dopamine release produces specific stereotypy seen in schizophrenia
- dopamine2 receptor agonists such as bromocriptine and apomorphine produces similar stereotypy and exacerbates schizo symptoms
what is difficult to determine about the dopamine hypothesis ?
it is difficult to know if it is a cause of schizophrenia or a symptoms of it but it is more likely to be a symptoms
what do antipyschotic drugs that block dopamine 2 receptors do and what do drugs that block neuronal dopamine storage do ?
e,g, reserpine
they are able to control the positive symptoms
DA2 receptor antagonists reduce positive symptoms
what do dopamine 2 receptor anatagonists have a strong correlation with ?
strong correlation between clinical antipsychotic potency and dopamine receptor blocking activity
- as the clinical antipsychotic potency increases the dopamine receptor blocking activity increases
how much of the dopamine 2 receptors have to be occupied to induce clinical efficacy ?
from imaging studies it is thought that it requires about 80% occupancy
what is schizophrenia linked to ?
a hyperactive dopamine system- dopamine mesolimbic pathway= positive and dopamine mesocortical pathway= negative
when were antipsychotics discovered ?
by accident in the 1950s
where have all the antipsychotics shown clinical effectiveness?
all of them have been dopamine antagonists
what does high dopamine 2 receptor occupancy cause ?
side effects
what do dopamine 2 antagonists have little effect upon ?
limited or no effect on negative and cognitive symptoms
how many patients dont respond to antipyschotic drugs nd what is the compliance in out patients ?
> 30% of patients are poor responders
50% of patients are non compliant in out patients which indicates that the drugs are either not that effective or they have side effects
why do antipyschotics have many side effects ?
because of their promiscuous receptor profile
what have PM and PET studies shown ?
these studies have not been consistent with the dopamine hypothesis
- controversy as to whether there are abnormal levels of dopamine 2 receptors in untreated schizophrenics - could antipsychotics be increasing the receptors
- thought that there is a genetic based aetiology for dopamine dysfunction
- there are other neurochemical dysfunctions such as glutamate and in the phasic/tonic hypothesis this neurochemical dsyfunction was demonstrated but there were no changes in dopamine receptor number
why is glutamate being the main transmitter for pyramidal cells an important factor ?
because these are the sources of efferent and interconnecting pathways of cerebral cortex and limbic system which are regions implicated in schizophrenia
how is glutamate thought to be implicated in schizophrenia ?
thought to be less glutamate transmission
- genetic factors thought to affect the signalling of ion channel receptors and GPCRs - leading to hypofunction of glutamate- this is relevant for the negative symptoms
what do glutamate receptor antagonists (ketamine and phencyclidine) cause ?
cause the positive and negative symptoms
ketamine is directly implicated in schizophrenia and it could induce it if you have a predisposition to schizophrenia
why is it thought that serotonin may be implicated in schizophrenia ?
based on the fact that LSD produces schizophrenic like symptoms - this is a theory
also effective antipyschotics seem to act as serotonin receptor antagonists because serotonin has a modulatory effect on dopamine pathways
- particularly serotonin 2a is a feature of newer antipsychotics which confer fewer side effects
why do antipsychotic drugs need to be classified ?
due to the large number of drugs > 20 different ones are available
how are antipsychotics classified ?
typical and atypical drugs - old and new
there is not a great deal of differences between these 2 types but the newer ones have fewer side effects but they still have serious side effects - however the newer ones are less effective
what is main difference between the typical and atypical drugs ?
the atypical ones have fewer incidence of motor disturbances
describe the typical antipsychotics :
selective for dopamine 2/3 receptors treat positive symptoms no effect on negative symptoms no effect on cognitive symptoms serious side effects
describe the atypical antipyschotics ?
dopamine 2/3 antagonists and other affinities
treat positive symptoms
limited effect on negative symptoms - virtually none for majority
limited effect on cognitive symptoms
serious side effects
what are some examples of current antipsychotics ?
olanzapine risperidone quetiapine aripiprazole global market value for antipyschotics is about £10billion
what are some examples of typical antipsychotics ?
PHENOTHIAZINES
- chlorpromazine, thioridazine- most commonly used in UK
THIOXANTHENES
- flupenthixol- similar to above
BUTYROPHENONES
- haloperidol- chemically different but long established
what are some examples of atypical antipsychotics?
sulpriride, pimozide, remoxipride
- all D2 receptor antagonists, less side effects but less effective
clozapine
- non-selective D1/D2 antagonist but has affinity for D4
- effective for negative and positive symptoms
- current gold standard antipsychotic but its not great
what is a major problem with the treatments for schizophrenia ?
there is no cure the drugs are just trying to control the symptoms
- the best drug for each individual is bases upon a balance between the beneficial relief of symptoms vs the adverse effects caused
where has the evidence for blockade of dopamine receptors for antipyschotics come from ?
- receptor binding, functional assays
- correlation of assays with clinical potency- however this is really just focussing on the positive symptoms
- amphetamine in man
what are the effects of a single dose, single high dose and chronic abuse of amphetamine in man ?
single dose causes CNS excitation
single high dose causes manic behaviour
chronic abuse causes paranoia, delusions
what is a problem with the evidence for dopamines involvment in schizophrenia ?
its indirect evidence
what is a problem when you start taking antipsychotics ?
they have a therapeutic delay like antidepressants
- 2-3 weeks of treatment dopamine receptors are up regulated
how is dopamine synthesis increased ?
tyrosine hydroxylase activity increases
metabolites increase
what happens to the nigrostriatal and mesolimbic dopaminergic neurons ?
their firing rate increases then declines and this leads to the clinical effects but also the adverse effects
what pathway is the major one associated with the main unwanted side effects ?
nigrostriatial pathway
clozapine has less effect on this pathway
how does haloperidol effect dopaminergic pathways ?
after initially taking it it peaks in both the nigrostriatal and mesolimbic pathways
- it then decreases in both pathways as the weeks of treatment continue and it appears to plateau
- the decrease seems to cause some sort of clinical effects
- the decrease is greater in the mesolimbic pathway compared to the nigrostriatal
what are the antipyschotic behavioural effects in man ?
neuroleptic syndrome:
- sedation
- decreased aggression
- apathy
- affective indifference- no reactions
- no impairment of intellect
what are the antipyschotic effects in animals ?
- decreased spontaneous movement
- suppression of conditioned avoidance response
- large doses= catalepsy- pharmacological assay in which it produces a state in animals where they dont move, they are not sedated they just dont move- waxy rigidity
- antagonism of amphetamine effects
what are the effects on antipsychotics on positive symptoms (type1)?
good response but delayed by 2-3 weeks before insight returns
what are the effects of antipsychotics on the negative symptoms (type2)?
poor responses to most
clozapine reportedly effective
what are the difficulties with treatment with antipsychotics ?
- delayed effects means its difficult to decide effective dose
- individual variation to different drugs- therefore you need to find the best one
- psychotherapy is still important
what is psychotherapy useful for and what is it not useful for ?
its useful for helping to cope, educating them and the family
it is not useful for gaining insight, they still dont see that anything is wrong with them
when were antipsychotics first implemted and what effect did this have ?
1956
it caused a decline in resident patients so there were less patients in hospitals
what are the side effects of antipsychotics ?
most are related to dopamine antagonism
- extrapyramidal syndrome- parkinson like symptoms, akathisia
- these effects are dose dependent and reversible
what can be used to treat the side effects of dopamine block ?
use of atropinic drugs which affect muscarinic receptors
cant use levodopa
what is tardive dyskinesia ?
it is a big problem
- develops after months/years in 20-40% of patients treated with typical drugs, there is less incidence with atypicals
- chorea type symptoms- loss of neurons
- oral symptoms are common
- symptoms change with activity
- not usually reversible and may be worsened by drug withdrawal
what are the endocrine effects caused by antipyschotics ?
increase prolactin release because dopamine in the hypothalaus acts as release inhibiting factor for prolactin
- this causes galactorrhea, infertility, gynacomastia in men (moobs)
dopamine controls other hormones and therefore aps cause a decrease in growth hormone
what are the 4 main side effects of antipsychotics not related to dopamine ?
blockade of muscarinic receptors
blockade of adrenoreceptors
hypothermia and weight gain
idiosyncratic/hypersensitivity reactions
what are the side effects caused by blockade of muscarinic receptors ?
- dry mouth, blurred vision
- often subject to tolerance
- may be beneficial in extrapyramidal syndrome as less disturbance of balance between excitation (ach)/inhibition (da)
e.g. thioridazine- effective atropinic, causes little eps
whereas in comparison haloperidol is very selective for dopamine receptors and causes severe eps
what are the effects caused by blockade of adrenoreceptors ?
- leads to hypotension particularly orthostatic
- this occurs less with selective dopamine blockers
e.g. butyrophenones, thioxanthenes
this is more severe with typical chlorpromazine- blocks adrenoreceptors, dopamine, serotonin and muscarinic receptors
what are the effects caused by hypothermia and weight gain ?
- hypothermia due to actions in the hypothalamus
- weight gain is associated with serotonin antagonism in atypical drugs- patients put on a lot of weight and this is often an element for poor compliance
what are the idiosyncratic/hypersensitivity effects ?
- jaundice- especially with chlorpromazine
- leucopenia= reduced number of leucocytes, agranulocytosis=reduced PMN leucocytes - this occurs especially with clozapine , have to monitor blood, the levels are recovered if clozapine admin is stopeed
- antipsychotic malignant syndrome- muscle rigidity, hyperthermia, confusion– fatal in 10-20% (renal/CVS failure)
what are other difficulties with antipsychotics ?
- compliance- 50% of patients fail to take medication due to the unwanted side effects - often use intramuscular depot injection which lasts 2-4 weeks because it slowly releases the drug
- only effective in about 70% of patients , others are pharmacoresistant
- most only control the positive symptoms, only clozapine has some effect on the negative symptoms
- the receptor specificity and functional and therapeutic effects are not understood
why is dopamine considered a symptom, not a cause of schizophrenia ?
because dopamine antagonism is not effective in everyone and their effects are limited
