Antipsychotic drugs Flashcards
Schizophrenia prevalence, comorbidities and outcomes
- affects 1% of population worldwide
- onset in early adulthood –> earlier in men than women
- women experience a second onset at menopause
increased mortality due to:
- increased morbidity (2-3x more illnesses) such as heart disease, liver disease, diabetes, drug use
- suicide - 4.9% of people with schizophrenia die this way
- 1/2 of peoplee have co-occuring mental or behavioural health disorders
positive symptoms of schizophrenia
higher than usual in population - helped by antipsychotics
- psychotic symptoms
- hallucinations
- delusions
- illogical disturbances in flow order and content of thought
- disorganized speech
- absence of goal oriented behaviour
negative symptoms of schizophrenia
lack of behaviour seen in healthy people
- generally worsened by antipsychotics
- abolition (decreased motivation)
- anhedonia
- flattered effect - lack of emotion and expression
- poverty of speech
- social withdrawal
cognitive symptoms of schizophrenia
- can be worsened by antipsychotics
- IQ decrease
- neurocognitive effects: working memory impairment, attention, executive function
- difficulties understanding nuances of interpersonal cues
- encoding verbal information
mood symptoms of schizophrenia
can be cheerful or sad
often depressed
causes of schizophrenia
- monozygotic twins were likely to have schizophrenia if their twin did, the effect is seen slightly less in dizygotic twins but still present
- landmark paper identified over 200 single nucleotide polymorphisms in genome that have a high risk of developping schizophrenia
- the most significant one is a locus associated with inflammation
- but they all have low prevalence and not one is enough to cause it on its own
chlorpromazine as a first antipsychotic
- D2 antagonist
- based on methylene blue which was initially intended to fight malaria drug
- developed in 1950 as an anesthetic with reduced antihistamine and enhanced sedative properties
- induced somnolescence - was given to calm down patients and showed to decrease positive symptoms
- in 1952 given to schizophrenia patients after it was reported to generate chemical lobotomy in patients
chlorpromazine and haloperidol MOA
MOA
- bind to D2 dopamine receptor
- direct correlation between clinical potency and D2 receptor affinity –> led to the belief that schizophrenia was due to excess DA
Typical antipsychotics - First generation APS
chlorpromazine, haloperidol
- D2 antagonists
- antagonized dopamine mediated locomotor activity in rodents
- good at reducing positive symptoms
- induced serious motor impairments at or near therapeutic dose due to D2 antagonism ex. tar dive dyskinesia
- causes anhedonia which leads to noncompliance
- causes sedation/somnolescence (antagonism as H1 histamine receptor)
- anti emetic properties
- does not cause withdrawal symptoms
- does not cure illness but alleviates it
dopamine hypothesis
schizophrenia due to too much DA in brain - APS are effective because they block D2
support
- APS block D2
- amphetime induces psychosis in normal individuals by releasing too much DA, people with schizophrenia release more DA from basal ganglia when given amphetamines
against
- APS don’t treat or worsen negative and cognitive symptoms
- amphetamine doesn’t induce negative or cognitive symptoms and can actually improve them
- diminished DA in cortex and hippocampus –> may be disrteghulation of DA rather than too much
- NMDA receptor antagonists (phencyclidine) causes positive, negative and cognitive symptoms in healthy people
- genetic susceptibility genes point to NT systems in DA, 5HT, GLU and GABA and neurodevelopment process
extrapyramidal side effects
- immobility and muscle rigidity similar to PD
- restlessness
- due to D2 antagonism
- helped by muscorinic antagonists
tardive dyskinesia
- occurs with longterm treatment of typical APS
- persist event after APS dyscontinued
- involuntary twitches in facial muscles and arms and legs
- thought to reflect DA receptor sensitivity
- also seen in L Dopa treatment of PD
- both of these treatmemts have fluctuations of high and low DA tone
hyperprolactinemia
- endocrine effects of APS
- DA neurons in hypothalamus project to pituitary and release DA which reduces prolactin secretion
- when D2 is blocked –> increased prolactin secretion
- leads to milk production and GnRH supression
- disrupts menstrual cycle and causes ED and infertility in males
first generation of typical APS/second generation atypical APS
- pharmacologists believed that APS had to induce extrapyramidal side effect to be effective
- but with clozapine in 1960s this changed - effective and did not induce catalepsy
- less affinity for D2
- more effective for depressive and negative and cognitive symptoms
- better tolerated
- antagonists of D2 and 5HT at equal affinity
atypical antipsychotics and most common side effect
resperidone - weight gain
aripiprazole - weight gain, elevated cholesterol, insomnia
ziprasidone - possible heart effects due to long QT interval
clozapine - weight gain, rare fatal blood disorder
olanzapine - weight gain, diabetes
quetiapine - weight gain, elevated cholesterol, somnolescence
