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PCL200 > Drugs for Schizophrenia > Flashcards

Drugs for Schizophrenia Flashcards

1
Q

what is the ratio of men to women diagnosed

A

1:4 (women:men)

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2
Q

is the higher ratio of men diagnosed with schizophrenia due to gender

A

no there is a genetic prevalence - due to estrogen and testosterone

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3
Q

what is schizophrenia

A

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

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4
Q

when does schizophrenia get diagnosed/onset?

A

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

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5
Q

globally one of the top ___ causes of disability. _________ is a risk

A

10, urbanicity

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6
Q

what is the cause of schizophrenina

A

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

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7
Q

what is the definitions of positive (psychotic) symptoms

A

presentation of behaviours that are not normally seen in healthy people

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8
Q

what can be used to treat positive symptoms

A

can be treated by antipsychotics

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9
Q

can positive symptoms get better when treated

A

yes

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10
Q

what are examples of positive system

A

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

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11
Q

what is the definition of negative symptoms

A

the cognitive symptoms

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12
Q

examples of negative symptoms

A
  • 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
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13
Q

why do schizophrenia patients spend a lot of time at the hospital

A

episodes, may encounter law enforcement

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14
Q

through what process is schizophrenia diagnosed

A

DDx: differential diagnosis - as a physician, think of all the things that can cause what you’re seeing and rule them out

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15
Q

neurological changes of schizophrenia

A

enlarged lateral ventricles, reductions in white matter tracts, and reduced cerebral grey matter (reduced synapses, not cell number)

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16
Q

how can we tell whether a disease is genetic or is caused by environmental exposure to casual risk factors?

A

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

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17
Q

environmental risk factors for schizophrenia

A
  • 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
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18
Q

how was schizophrenia treated before the finding of antipsychotics
*therapy alone does not work for schizophrenia

A
  • lifetime institutionalisation
  • induce fever
  • induce hypoglycaemic shock
  • induce seizures with electrical stimulation
  • frontal lobotomy
  • chloral hydrate and other barbiturates
  • freudian psychotherapy (ie hypnosis)
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19
Q

how was chlorpromazine discovered as an antipsychotic

A

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

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20
Q

what are reuptake inhibitors of the dopamine system

A

cocaine (methylphenidate), amphetamine (methamphetamine)

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21
Q

what symptoms are caused by too much dopamine in the synapse (ie cocaine/methamphetamine toxicity)

A

paranoia and delusions

22
Q

what receptors are targetted by the first antipsychotics

A

d2 dopamine receptor antagonists

23
Q

what were the typical antipsychotics (first gen aps, neuroleptics)

A

chlorpromazine, haloperidol

24
Q

how were typical antipsychotics identified (in rodents)

A

ability to antagonize dopamine-mediated behaviours (eg locomotor activity)

25
Q

what are the adverse effects of typical antipsychotics (5)

A
  • 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
26
Q

do typical antipsychotics cause withdrawal

A

no <3 relapse after discontinuation (hospitalisation) 6 months

27
Q

what did pharmacologists assume for a drug to be an effective antipsychotic (had to elicit what)

A

parkinsonian adverse effects

28
Q

examples of second gen antipsychotics

A

clozapine, olanzapine, risperidone

29
Q

which drugs have dual actions on serotonin and dopamine receptors

A

olanzapine, risperidone

30
Q

describe the MOA of clozapine

A

antagonizes serotonin receptors (5HT2A) and dopamine d2 receptors (also on muscarinic, histamine receptors)

31
Q

do second gen antipsychotics cause parkinsonian motor impairments (eps) and tardive dyskinesia

A

no

32
Q

what are the adverse effects of second gen antipsychotics

A
  • 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
33
Q

what is the first line treatments of schizophrenia

A

risperidone (second gen antipsychotics)

34
Q

what are adverse drug reactions to all antipsychotics

A
  • anhedonia, flattened affect (worsening of negative symptoms)
  • sedation, somnolence
  • weight gain
35
Q

adverse drug reactions to first gen antipsychotics

A
  • 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
36
Q

what nt is most correlated to weight gain

A

histamine

37
Q

explain extrapyramidal side effects (eps)

A

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)

38
Q

what may be the cause of eps from first gen aps

A

d2 antagonism

39
Q

explain tardive dyskinesia

A

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

40
Q

how long do antipsychotics take to have full effect

A

several weeks

41
Q

what are aps effective at treating

A

positive symptoms - hallucinations, delusions, agitation, thought disorder

42
Q

does everyone benefit from aps

A

no, a substantial % of patients don’t benefit for any

43
Q

what is treatment-resistant schizophrenia best treated with

A

clozapine - not chosen first bc risk of wbc loss

44
Q

what meds can be used to improve the negative and cognitive symptoms of schizophrenia

A

none of the current ones - these are disabling and affect many aspects of daily living (mood, relationships, employment)

45
Q

what is an example of third gen aps

A

aripiprazole (abilify) - developed from structure of clozapine

46
Q

explain the moa for third gen aps and how does it differ from previous aps

A

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

47
Q

what are the new ideas abt the causes of schizophrenia

A

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

48
Q

what dose the genetics of schizophrenia tell us

A

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

49
Q

what may a genetic study on rare mutations conferring for high risk for schizophrenia tell us

A

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

50
Q

clues for schizophrenia from genetic studies

A
  • 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
51
Q

what are the ways that new treatment can be found for schizophrenia (3)

A
  1. mouse models - amphetamine, phencyclidine or ket (antagonists of nmda receptors, a type of glutamate receptor)
  2. 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
  3. clinical trials (double blind, placebo controlled) - tailor meds to specific subgroups of patients w similar genetic lesions

PCL200 (5 decks)

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