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PMCOL 412 > SCZ > Flashcards

SCZ Flashcards

1
Q

SCZ and psychotic disorders exist _____

A

along a spectrum of severity with

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2
Q

Positive symptoms meaning

A

gain of function

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3
Q

Positive symptoms examples

A 
Delusions
Hallucinations
Disorganized speech
Grossly disorganized or 
catatonic motor behaviour
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4
Q

Negative symptoms meaning

A

loss of function

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5
Q

Negative symptoms examples

A

Avolition
Social deficits
Flattened affect
Cognitive deficits

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6
Q

presence of ____ symptoms makes SCZ unique

A

Positive symptoms; most mental disorders primarily are loss of function (have negative features)

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7
Q

Spectrum of SCZ and psychosis (from least to most severe)

A

Scizotypal personality disorder –> delusional disorder –> brief psychotc disorder –> schizophreniform disorder –> SCZ –> schizoaffective disorder

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8
Q

T/F scz stays the same throughout life

A

FALSE
Schizophrenia is a persistent, progressive disorder (negative symptoms)
with periodic relapse into psychosis (positive symptoms)

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9
Q

Lifetime prevalence

A

1%

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10
Q

The societal cost of SCZ (heavy use of resources due to:)

A
  • Schizophrenic patients may account for
    up to 50% of repeat hospital
    admissions* and 25% of inpatient beds
  • Vastly overrepresented in prison and
    homeless populations
  • high suicidality
  • 50% co-morbid with substance abuse
  • psychiatric comorbidities–mood and anxiety disorders
  • decreased life expectancy (of 10-25 years)
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11
Q

Co-morbidities with SCZ

A
  • high suicidality
  • 50% co-morbid with substance abuse
  • psychiatric comorbidities–mood and anxiety disorders
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12
Q

Neuroleptic development: first antipsychotic

A

Chlorpromazine

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13
Q

Chlorpromazine

A

1at antipsychotic developed in 1950 as an anti‐histamine and sedative
◦ First synthesis Dec 1950 –> human use in 1951–> Licensed to Smith Kline & French (GSK) 1953

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14
Q

Neuroleptic drug definition

A

Drugs affecting pathological behaviour

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15
Q

Societal/medical effect of Chlorpromazine (CPZ)

A
  • Contributed directly to medicalization of mental illness
  • Recognition of mental illness as a consequence of an underlying biological
    deficit
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16
Q

Chlorpromazine actions–main systems

A

Anti‐cholinergic
Anti‐histaminergic
Anti‐adrenergic
Anti‐dopaminergic

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17
Q

Chlorpromazine side effects

A

Anticholinergic: Dry‐mouth, blurred vision,
constipation, weight gain
Anti-histaminergic: sedative, anti-emetic
ANti-adrenergic: Lowered blood pressure,
tachycardia, vertigo, incontinence,
sexual dysfunction
Anti-dopaminergic: actual antipsychotic effects (reduce positive symptoms), extrapyramidal side effects and hyperprolactinemia

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18
Q

Main effects of CPZ (bolded)

A 
Weight gain (anti-cholinergic)
Sedation (anti-histaminergic)
Antipsychotic effects (anti-DA)
Extrapyramidal effects (anti-DA)
Hyperprolactinaemia (anti-DA)
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19
Q

The Dopamine hypothesis

A

SCHIZOPHRENIA RESULTS FROM EXCESSIVE DOPAMINERGIC ACTIVITY SPECIFICALLY IN THE MESOLIMBIC PATHWAY.
this theory arose from CPZ ‘s efficacy

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20
Q

Mesolimbic dopamine is

proposed to mediate _____

A

SALIENCE
Motivational salience –addictions
Sensory salience – sensory gating

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21
Q

Too much dopamine on the mesolimbic pathway causes SCZ due to…

A

Excess dopamine activity leads the patient to perceive voices, sounds, and imagery
as inappropriately salient

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22
Q

Excess da –> ___ salience –> interpreted as ___ & ____

A

increased salience; interpreted as delusions and hallucinations
i.e. False significance assigned to internal and external stimuli are interpreted as delusions and hallucinations

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23
Q

Issues with the DA hypothesis

A

Dopamine is hyperactive in the mesolimbic but hypoactive in the cortex
◦ Presynaptic changes in dopamine synthesis
◦ Expect common changes in both mesolimbic and mesocorticolimbic pathways
◦ Postsynaptic targets of antipsychotics
Causality of dopaminergic changes is unclear!!
Lack of clear evidence for dopaminergic neuropathology in SCZ
Dopamine correlates well with positive symptoms (i.e. psychosis) BUT Poor correlation with negative symptoms

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24
Q

DA drugs have limited effects on ___ symptoms

A

Negative; which are usually the most debilitating

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25
Q

Dopamine hypothesis 2.0

A

SCHIZOPHRENIA RESULTS FROM A COMBINATION OF SUBCORTICAL DOPAMINERGIC HYPERACTIVITY AND CORTICAL DOPAMINE HYPOACTIVITY.

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26
Q

Dopamine hypothesis 3.0

A

Schizophrenia results from combined genetic and environmental insult resulting in altered neurodevelopment, including subcortical dopaminergic hyperactivity and psychosis.

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27
Q

1st generation antipsychotics AKA ____ antipsychotics are characterized by ____

A

‘ TYPICAL’ ANTIPSYCHOTICS

CHARACTERISED BY ANTAGONISM OF THE DOPAMINE D2 RECEPTOR

28
Q

Phenothiazines examples

A

1st gen

Clorpromazine; thoridazine, Trifluoperazine, Perphenazine

29
Q

Phenothiazines–defintion

A 
1st gen; Low potency antipsychotics have 
increased anticholinergic side effects 
(dry mouth, constipation, weight gain) 
and decreased extrapyramidal side 
effects
30
Q

Thioxanthenes

A

Modified ring structure from
phenothiazines ( N –> C)
Piperazine derivatives are potent antipsychotics

31
Q

Thioxanthenes

A

1st gen
Modified ring structure from
phenothiazines ( N –> C)
Piperazine derivatives are potent antipsychotics

32
Q

Butyrophenones and diphenylbutylpiperidines

A 
1st gen
Butyrophenones (haloperidol) are high potency antipsychotics – common ‘front line’ antipsychotics
• BUT High risk of extrapyramidal 
side effects 
Diphenylbutylpiperidines
(pimozide) – derived from 
butyrophenones – have longer 
duration of action
33
Q

Which is has a longer duration of action Butyrophenones or diphenylbutylpiperidines

A

diphenylbutylpiperidines (a derivative of Butyrophenones)

34
Q

Which is has a longer duration of action Butyrophenones or diphenylbutylpiperidines

A

diphenylbutylpiperidines (a derivative of Butyrophenones)

35
Q

Extrapyramidal side effects (EPS)

A

Akinesia – inability to initiate movement
Akathisia – inability to remain motionless
Acute dystonia – sustained muscle contraction, twisting and repetitive movements
Pseudoparkinsonism – fixed (non‐progressive) Parkinsonism without degeneration of dopaminergic neurons
Tardive dyskinesia – involuntary, repetitive motor disorder that persists after discontinuation of antipsychotic therapy

36
Q

Akinesia

A

EPS

inability to initiate movement

37
Q

Akathisia

A

EPS

inability to remain motionless

38
Q

Acute dystonia

A

EPS

sustained muscle contraction, twisting and repetitive movements

39
Q

Pseudoparkinsonism

A 
EPS
fixed (non‐progressive) Parkinsonism without degeneration of dopaminergic neurons
40
Q

Tardive dyskinesia

A

EPS

involuntary, repetitive motor disorder that persists after discontinuation of antipsychotic therapy

41
Q

Degeneration of dopaminergic neurons in the
______ is central to the pathophysiology of
Parkinson’s disease, with symptoms including…

A

nigrostriatal system

causing tremors, rigidity, forward‐flexed posture and shuffling steps, bradykinesia (slowed movement)

42
Q

Antipsychotic blockade of __ receptors in the ____ is responsible for extrapyramidal side‐effects

A

D2; in the striatum

43
Q

DA in the _____ pathway suppresses the release of _____ from the pituitary; antipsychotic antagonism of D2 causes ____

A

tuberoinfundibular pathway; prolactin; Hyperprolactinemia can result from antipsychotic
treatment: causes Amenorrhea (♀), infertility(♂/♀), sexual dysfunction (♂/♀), hypogonadism (♂), spontaneous lactation (♂/♀)

44
Q

@nd gen antipsychotics aka ___ are characterized by

A

‘ATYPICAL’ ANTIPSYCHOTICS

CHARACTERIZED BY ANTAGONISM OF THE 5HT2A RECEPTOR AND D2R

45
Q

[Tri/tetra]cyclics`

A 
2nd gen 
Dibenzodiazepine antipsychotics
Effects on 5HT2AR proposed to explain 
efficacy against negative symptoms
CLozapine, N‐desmethylclozapine (active metabolite with affinity for D2R) and Olanzepine (5HT2A and D2R affinity – high rate of weight gain and diabetes)
46
Q

CLozapine

A 
the first atypical AP; a Dibenzodiazepine antipsychotics
• High affinity antagonism of 5HT2AR
• Low affinity for D2R
• Possible effects on D‐serine 
(NMDAR co‐agonist) and GABABR
• Risk of agranulocytosis and cardiac 
toxicity
47
Q

WHy do [Tri/tetra]cyclics work better on negative symptoms

A

Due to effects on 5HT2AR
• N‐desmethylclozapine – active metabolite with affinity for D2R
• Olanzepine – 5HT2A and D2R affinity – high rate of weight gain and diabetes

48
Q

Quetiapine

A

2nd gen; [Tri/tetra]cyclics
Quetiapine – 5HT2A and moderate D2 antagonist
• Norquetiapine – active metabolite – D2 affinity and
norepinephrine reuptake inhibitor

49
Q

Asenapine

A

2nd gen; [Tri/tetra]cyclics
extremely high (sub‐nM) affinity for 5HT2A, strong D2
antagonist – low weight gain
Risk of death in dementia patients

50
Q

Benzisoxazoles–exmaples

A

Risperidone, Paliperidone (palmitate), Ziprasidone, Lurasidone, Iloperidone

51
Q

Risperidone

A

Risperidone – strong 5HT2A inverse agonist, D2 antagonist
• High risk of metabolic and prolactin side effects, high EPS relative to other atypicals
• Paliperidone (palmitate) – active metabolite marketed as an antipsychotic – palmitate ester allows long‐release injectable formulation (monthly)

52
Q

Other Benzisoxazoles

A 
Ziprasidone – low weight gain, high cardio side effects
Lurasidone – low cognitive side effects
Iloperidone – low weight gain, moderate EPS
AND paliperidone (palmitate) – active metabolite of risperidone marketed as an antipsychotic – palmitate ester allows long‐release injectable formulation (monthly)
53
Q

Aripiprazole

A 
2nd gen (but other)
partial agonist at D2 and 5HT1A, weak partial agonist at 5HT2A (functional antagonist)
• Minimal sedation and metabolic side effects
54
Q

Relative efficacy of antipsychotics

A

With the exception of clozapine, most atypical and typical antipsychotics have comparable performance.

Previous assertions that atypical antipsychotics are superior have been questioned.

55
Q

Are atypical psychotics better?

A

Not necessarily
Previous assertions that atypical antipsychotics are superior have been questioned.
• 5HT2A affinity does not necessarily correlate with
efficacy
ex. Asenapine – extremely high 5HT2A affinity has moderate efficacy

56
Q

Tolerability of antipsychotics

A

Haloperidol (typ) has the highest rate of EPS and highest
overall discontinuation
Potent D2 antagonists (haloperidol, risperidone) have
highest rates of hyperprolactinaemia
Olanzepine (atyp) has the highest rate of weight gain

57
Q

___ has the highest rates of discontinuation largely due to ___ side effects

A

Haloperidol; EPS
Potent D2 antagonists (haloperidol, risperidone) have
highest rates of hyperprolactinaemia

58
Q

Glutamate hypothesis–why?

A
  • role of NMDA receptor in SCZ
  • Multiple genetic risks associated with excitatory synaptic function & plasticity
  • NMDAR hypofunction in SCZ; current drugs increase - — NMDAR-antags cause positive and negative symptoms
59
Q

Evidence increasing glutamate may be helpful

A
  • NMDA antagonists (ketamine, phencyclidine [PCP]) produce positive and negative symptoms
  • Haloperidol (1st gen antipsychotic) increases NMDA receptor density and extracellular glutamate concentrations
  • Elevated glutamate levels are reported in patients taking antipsychotics
  • Oral administration of glycine (NMDA receptor co‐agonist) reported improving negative symptoms in patients
60
Q

D-serine

A

Potential future drug
◦ Potent co‐agonist at the NMDAR glycine site
◦ Improves negative, positive, and cognitive symptoms as an adjunctive therapy
◦ Clozapine shown to increase release of D‐serine from astrocytes
◦ D‐amino acid oxidase (DAAO) activity has been reported to be elevated in SCZ
◦ Risperidone is an antagonist at DAAO

61
Q

Immune function in SCZ–why we could target it

A

Numerous genetic and environmental risks converge on immune function
◦ Polymorphisms in Major Histocompatibility Complex
◦ Pre‐ and peri‐natal risks such as maternal infection,
stress, nutrition, and delivery complications

62
Q

Immuned cells of CNS regulate…

A

development and plasticity
◦ Critical for establishing E/I balance (that is messed up in SCZ)
◦ Regulate synaptic turnover of glutamate, GABA,
and D‐serine

63
Q

Anti‐inflammatory minocycline

A

reported efficacy as an adjunctive treatment

support immune function

64
Q

Cannabidiol

A

Antipsychotic effects of cannabidiol are suggested to involve neuroinflammation

65
Q

Neurochemistry of SCZ

A

◦ Dopamine hypothesis
◦ Glutamate and GABA (NMDA or E/I imbalance)
◦ Immune hypothesis

66
Q

Typical vs Atypical

A

Typical’ (1st generation) antipsychotics
◦ Potent D2 antagonists
◦ Effective against positive symptoms
Atypical’ (2nd generation) antipsychotics
◦ 5HT2A antagonists
◦ Some efficacy against negative symptoms

PMCOL 412 (35 decks)

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