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PMCOL 412 > SCZ > Flashcards

SCZ Flashcards

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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
Dopamine hypothesis 2.0
SCHIZOPHRENIA RESULTS FROM A COMBINATION OF SUBCORTICAL DOPAMINERGIC HYPERACTIVITY AND CORTICAL DOPAMINE HYPOACTIVITY.
26
Dopamine hypothesis 3.0
Schizophrenia results from combined genetic and environmental insult resulting in altered neurodevelopment, including subcortical dopaminergic hyperactivity and psychosis.
27
1st generation antipsychotics AKA ____ antipsychotics are characterized by ____
‘ TYPICAL’ ANTIPSYCHOTICS | CHARACTERISED BY ANTAGONISM OF THE DOPAMINE D2 RECEPTOR
28
Phenothiazines examples
1st gen | Clorpromazine; thoridazine, Trifluoperazine, Perphenazine
29
Phenothiazines--defintion
``` 1st gen; Low potency antipsychotics have increased anticholinergic side effects (dry mouth, constipation, weight gain) and decreased extrapyramidal side effects ```
30
Thioxanthenes
Modified ring structure from phenothiazines ( N --> C) Piperazine derivatives are potent antipsychotics
31
Thioxanthenes
1st gen Modified ring structure from phenothiazines ( N --> C) Piperazine derivatives are potent antipsychotics
32
Butyrophenones and diphenylbutylpiperidines
``` 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
Which is has a longer duration of action Butyrophenones or diphenylbutylpiperidines
diphenylbutylpiperidines (a derivative of Butyrophenones)
34
Which is has a longer duration of action Butyrophenones or diphenylbutylpiperidines
diphenylbutylpiperidines (a derivative of Butyrophenones)
35
Extrapyramidal side effects (EPS)
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
Akinesia
EPS | inability to initiate movement
37
Akathisia
EPS | inability to remain motionless
38
Acute dystonia
EPS | sustained muscle contraction, twisting and repetitive movements
39
Pseudoparkinsonism
``` EPS fixed (non‐progressive) Parkinsonism without degeneration of dopaminergic neurons ```
40
Tardive dyskinesia
EPS | involuntary, repetitive motor disorder that persists after discontinuation of antipsychotic therapy
41
Degeneration of dopaminergic neurons in the ______ is central to the pathophysiology of Parkinson’s disease, with symptoms including...
nigrostriatal system | causing tremors, rigidity, forward‐flexed posture and shuffling steps, bradykinesia (slowed movement)
42
Antipsychotic blockade of __ receptors in the ____ is responsible for extrapyramidal side‐effects
D2; in the striatum
43
DA in the _____ pathway suppresses the release of _____ from the pituitary; antipsychotic antagonism of D2 causes ____
tuberoinfundibular pathway; prolactin; Hyperprolactinemia can result from antipsychotic treatment: causes Amenorrhea (♀), infertility(♂/♀), sexual dysfunction (♂/♀), hypogonadism (♂), spontaneous lactation (♂/♀)
44
@nd gen antipsychotics aka ___ are characterized by
‘ATYPICAL’ ANTIPSYCHOTICS | CHARACTERIZED BY ANTAGONISM OF THE 5HT2A RECEPTOR AND D2R
45
[Tri/tetra]cyclics`
``` 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
CLozapine
``` 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
WHy do [Tri/tetra]cyclics work better on negative symptoms
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
Quetiapine
2nd gen; [Tri/tetra]cyclics Quetiapine – 5HT2A and moderate D2 antagonist • Norquetiapine – active metabolite – D2 affinity and norepinephrine reuptake inhibitor
49
Asenapine
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
Benzisoxazoles--exmaples
Risperidone, Paliperidone (palmitate), Ziprasidone, Lurasidone, Iloperidone
51
Risperidone
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
Other Benzisoxazoles
``` 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
Aripiprazole
``` 2nd gen (but other) partial agonist at D2 and 5HT1A, weak partial agonist at 5HT2A (functional antagonist) • Minimal sedation and metabolic side effects ```
54
Relative efficacy of antipsychotics
With the exception of clozapine, most atypical and typical antipsychotics have comparable performance. Previous assertions that atypical antipsychotics are superior have been questioned.
55
Are atypical psychotics better?
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
Tolerability of antipsychotics
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
___ has the highest rates of discontinuation largely due to ___ side effects
Haloperidol; EPS Potent D2 antagonists (haloperidol, risperidone) have highest rates of hyperprolactinaemia
58
Glutamate hypothesis--why?
- 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
Evidence increasing glutamate may be helpful
- 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
D-serine
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
Immune function in SCZ--why we could target it
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
Immuned cells of CNS regulate...
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
Anti‐inflammatory minocycline
reported efficacy as an adjunctive treatment | support immune function
64
Cannabidiol
Antipsychotic effects of cannabidiol are suggested to involve neuroinflammation
65
Neurochemistry of SCZ
◦ Dopamine hypothesis ◦ Glutamate and GABA (NMDA or E/I imbalance) ◦ Immune hypothesis
66
Typical vs Atypical
Typical’ (1st generation) antipsychotics ◦ Potent D2 antagonists ◦ Effective against positive symptoms Atypical’ (2nd generation) antipsychotics ◦ 5HT2A antagonists ◦ Some efficacy against negative symptoms

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