Drugs for Schizophrenia Flashcards
what is the ratio of men to women diagnosed
1:4 (women:men)
is the higher ratio of men diagnosed with schizophrenia due to gender
no there is a genetic prevalence - due to estrogen and testosterone
what is schizophrenia
a brain disorder that affects thought and perception, difficult to discern what is real. frequent symptoms are hallucinations and delusions, but changes in social interactions, motivation, mood, impaired cognitive functions are the most disabling and difficult to treat
when does schizophrenia get diagnosed/onset?
onset in early adulthood, men 18-25 and women 21-30 - there is a prodomal period of 2-5 years before diagnosis, with subclinical behavioural changes noted in by friends and family
globally one of the top ___ causes of disability. _________ is a risk
10, urbanicity
what is the cause of schizophrenina
the precise cause is unknown. both genes and environment play an important role, with genetic risk factors contributing 80% of overall risk, many environmental factors are associated with prenatal development and early childhood
Complex interactions by many genes - rare and powerful mutation events or collection of different variants in genes
what is the definitions of positive (psychotic) symptoms
presentation of behaviours that are not normally seen in healthy people
what can be used to treat positive symptoms
can be treated by antipsychotics
can positive symptoms get better when treated
yes
what are examples of positive system
hallucinations (auditory, visual, olfactory, tactile), delusions (paranoia, grandeur, control (they make me have thoughts)), illogical disturbances in the flow/order/content of thought, neologism (making up words), nonsensical rhymes
what is the definition of negative symptoms
the cognitive symptoms
examples of negative symptoms
- lack of behaviours that are normally present in healthy people
- avolition (decreased motivation)
- anhedonia (decreassed ability to experience pleasure of identify activities as being pleasurable)
- flattened affect - lack of emotion or expression of emotion
- poverty of speech (small vocab)
- social withdrawal
why do schizophrenia patients spend a lot of time at the hospital
episodes, may encounter law enforcement
through what process is schizophrenia diagnosed
DDx: differential diagnosis - as a physician, think of all the things that can cause what you’re seeing and rule them out
neurological changes of schizophrenia
enlarged lateral ventricles, reductions in white matter tracts, and reduced cerebral grey matter (reduced synapses, not cell number)
how can we tell whether a disease is genetic or is caused by environmental exposure to casual risk factors?
twin studies - monozygotic twins (identical twins) have the same genetic code and experience in the same prenatal environment, vs dizygotic twins (fraternal) genetically they have the same similarity as siblings but they did experience the same prenatal environment
freq of schizophrenia amongst relatives:
18% for fraternal, 50-70% for identical
environmental risk factors for schizophrenia
- maternal infection in 2nd trimester
- maternal starvation
- infection with plasmodium gondii (cat feces)
- obstetric complications
- physical or psychological abuse/trauma
- low socioeconomic status
- urbanicity
- drug exposure (amphetamine, cannabis, phencyclidine)
- hypoxia during birth
how was schizophrenia treated before the finding of antipsychotics
*therapy alone does not work for schizophrenia
- lifetime institutionalisation
- induce fever
- induce hypoglycaemic shock
- induce seizures with electrical stimulation
- frontal lobotomy
- chloral hydrate and other barbiturates
- freudian psychotherapy (ie hypnosis)
how was chlorpromazine discovered as an antipsychotic
tldr: give the animal (rodents) amphetamine and then the test drugs - as the amphetamine increases dopamine = all the drugs had in common was blocking dopamine D2 type receptor = decrease dopamine levels
henri laborit (french surgeon) tried to develop new anesthetics (sedative, narcotic, hypnotic) and used a compound by rhone-poulenc that lowered body temperature w reduced antihistamine and enhanced sedative properties –> chlorpromazine was developed in 1950 and given to patients to generate a chemical lobotomy, other antipsychotics were developed based on the chem structure of this - they looked for drugs that block locomotor activity == we didn’t know mech of action so we just copied
what are reuptake inhibitors of the dopamine system
cocaine (methylphenidate), amphetamine (methamphetamine)
what symptoms are caused by too much dopamine in the synapse (ie cocaine/methamphetamine toxicity)
paranoia and delusions
what receptors are targetted by the first antipsychotics
d2 dopamine receptor antagonists
what were the typical antipsychotics (first gen aps, neuroleptics)
chlorpromazine, haloperidol
how were typical antipsychotics identified (in rodents)
ability to antagonize dopamine-mediated behaviours (eg locomotor activity)
what are the adverse effects of typical antipsychotics (5)
- induces serious motor impairments at or near therapeutic dose (due to d2r antagonism) –> similar to parkinson’s disease symptoms (muscle rigidity, slow movement, dystonia)
- cause anhedonia (due to d2r antagonism) –> non-compliance lading to relapse
- cause sedation and somnolence (due to h1 histamine receptor antagonism) esp chlopromazine
- anti-emetic properties (treat vomiting)
- cause weight gain
do typical antipsychotics cause withdrawal
no <3 relapse after discontinuation (hospitalisation) 6 months
what did pharmacologists assume for a drug to be an effective antipsychotic (had to elicit what)
parkinsonian adverse effects
examples of second gen antipsychotics
clozapine, olanzapine, risperidone
which drugs have dual actions on serotonin and dopamine receptors
olanzapine, risperidone
describe the MOA of clozapine
antagonizes serotonin receptors (5HT2A) and dopamine d2 receptors (also on muscarinic, histamine receptors)
do second gen antipsychotics cause parkinsonian motor impairments (eps) and tardive dyskinesia
no
what are the adverse effects of second gen antipsychotics
- extreme weight gain (olanzapine can cause 20-40 lbs gained in 1 month)
- increase in appetite
- metabolic syndrome: weight gain, unhealthy plasma lipid levels, type 2 diabetes, increased risk of cvd
- blood disease - agranulocytosis from clozapine
what is the first line treatments of schizophrenia
risperidone (second gen antipsychotics)
what are adverse drug reactions to all antipsychotics
- anhedonia, flattened affect (worsening of negative symptoms)
- sedation, somnolence
- weight gain
adverse drug reactions to first gen antipsychotics
- extrapyramidal side effects (parkinsonian effects)
- tardive dyskinesia
- hyperprolactinemia - elevated prolactin hormone causes breast development in men and women, lactation in women, impotence in men, disruptions to women’s menstrual cycle
what nt is most correlated to weight gain
histamine
explain extrapyramidal side effects (eps)
typical or first gen aps can cause immobility and muscle rigidity similar to parkinson’s disease at or near their therapeutic dose - they can also cause dystonia or akathisia (restlessness)
what may be the cause of eps from first gen aps
d2 antagonism
explain tardive dyskinesia
occasionally occurs after long term treatment w typical aps (first gen), symptoms persist even after discontinued, patients have involuntary twitches of facial muscles predominantly but also hands and legs
how long do antipsychotics take to have full effect
several weeks
what are aps effective at treating
positive symptoms - hallucinations, delusions, agitation, thought disorder
does everyone benefit from aps
no, a substantial % of patients don’t benefit for any
what is treatment-resistant schizophrenia best treated with
clozapine - not chosen first bc risk of wbc loss
what meds can be used to improve the negative and cognitive symptoms of schizophrenia
none of the current ones - these are disabling and affect many aspects of daily living (mood, relationships, employment)
what is an example of third gen aps
aripiprazole (abilify) - developed from structure of clozapine
explain the moa for third gen aps and how does it differ from previous aps
it is a weak or partial agonist of d2 dopamine receptors instead of being an antagonist
the maximum effect is still less. the drug slips into the same spot as dopamine, instead of the receptor receiving a certain amount of dopamine, it receives aripiprazole instead = less activation signal
in brain regions where dopamine is too low, it activates the receptors to a lower degree, but in regions where its too high, it competes with dopamine
–> drug that normalizes dopamine receptor activity
what are the new ideas abt the causes of schizophrenia
current: schizophrenia can be caused by a:
1) a rare de novo mutation in one of hungreds of genes that can lead to schizophrenia
2) combo of several risk genes plus environmental stressors
- recent gwas studies identified 145 genetic areas where variants in DNA sequence increase risk for schizophrenia - these variants alone are only likely to have a minor effect
what dose the genetics of schizophrenia tell us
no one gene or nt that is changed in all patients with the diagnosis - this is likely an umbrella diagnosis that is applied to many different disorders
what may a genetic study on rare mutations conferring for high risk for schizophrenia tell us
Now you can tell what a normal variation is - eg different regions.
Not seen = nature selects against this
If many people w a variant is not healthy = can tell that the schizophrenia stems from here = can tell that the genes for schizo are in the 100s
The high ones are the ones with they are most confident cause the disease
clues for schizophrenia from genetic studies
- focus on genes for glutamate receptors, dopamine receptors, proteins for synaptic signaling, and neuron excitability
- genes for immune function are some of the risk genes
- overlap with risk genes for neurodevelopmental disorders, autism and bpd
what are the ways that new treatment can be found for schizophrenia (3)
- mouse models - amphetamine, phencyclidine or ket (antagonists of nmda receptors, a type of glutamate receptor)
- induced pluripotent stem cells (IPSCs) from patients - take wbc or skin cells, convert to stem, differentiate into neurons (anything diff from healthy neurons), test drugs in a dish
- clinical trials (double blind, placebo controlled) - tailor meds to specific subgroups of patients w similar genetic lesions
