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Neuropharmacology > Ch 19: Schizophrenia And The Antipsychotics > Flashcards

Ch 19: Schizophrenia And The Antipsychotics Flashcards

1
Q

Schizophrenia

A
  • is a neurodevelopemental disorder
  • gene x environment interaction
  • abnormal development of PFC and hippocampus
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2
Q

First-line treatments

A

Largely target the dopamine system

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3
Q

Positive Symptoms of Schizophrenia

A

*behavioral excesses

  • incoherent speech, loose associations
  • delusions
  • hallucinations
    • tactile hallucination are often electrical, inkling, or burning sensations
  • predominantly positive: tend to be older when experience sudden onset of symptoms
  • respond to antipsychotic medications that block dopamine receptors (D2)
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4
Q

Negative Symptoms of Schizophrenia

A

*behavioral deficits

  • inappropriate or flat affect
  • inattention to self-care
  • social withdrawal
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5
Q

Cognitive Symptoms of Schizophrenia

A
  • resemble PFC dysfunction
  • working memory deficits
  • poorer functioning in community and greater isolation
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6
Q

Schizophrenia is a neurodevelopment disorder : gene x environment interactions

A
  • genetic predisposition
    • synapse structure, function, plasticity
  • environmental stressors
    • perinatal/ immunological factors confer risk

*Two- hit model

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7
Q

Two-hit model

A
  1. Genetic brain development

2. Environment at adolescence

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8
Q

Schizophrenia is a neurodevelopment disorder: alter the developmental trajectory of PFC

A
  • anatomical and functional deficits
  • symptoms that resemble abnormal PFC function (reduced function)
  • less activation in left DLPFC. ACC, and thalamus
  • greater control in VLPFC, amygdala, and insula
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9
Q

Neurodevelopmental Model

A
  1. Negative symptoms

2. Positive symptoms

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10
Q

Reduced brain regions occur because:

A
  • small soma
  • reduced dendritic trees
  • reduced dendritic spine density
  • increased cell packing
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11
Q

[…] cells are more disorganized and selected […] layers are atrophied

A

Hippocampal cells are more disorganized and selected cotical layers are atrophied

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12
Q

DISC1 gene mutations

A

Increase probability of developing schizophrenia

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13
Q

2 times are much cortical gray matter loss than normal patients

A

Starts in parietal lobes —> temporal lobes —> DLPFC —> frontal eye field

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14
Q

Amphetamine-induced stereotypy

A

Animal model for schizophrenia

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15
Q

Hypoglutamate Model

A

Acute reduction fo Glu NT

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16
Q

Prepulse Inhibition of Startle (PPI)

A

Used to study sensory-filtering deficits

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17
Q

Two main families of antipsychotic medications

A
  • typical antipsychotics (neuroleptic; FGA)
  • atypical antipsychotics (SGA)
    • fewer abnormal movement side effects
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18
Q

Primary targets of antipsychotics are

A
  • Dopamine (DA) receptors

- Serotonin (5-HT) receptors

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19
Q

Neuroleptic Drugs

A

Phenothiazine

- chlorpromazine (aliphatic) (Thorazine)
- thioridazine (piperidine)
- fluphenzine (piperazine)

Butyrophenone
- haloperidol (Haldol)

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20
Q

Neuroleptics

A
  • are potent D2 receptor antagonists
    • pre-synaptic, post-synaptic, and autoreceptors
    • can reduce symptoms at low doses because of high affinity
  • are effective anitopsychotics
  • have significant side-effects
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21
Q

Neuroleptic are potent D2 receptor antagonists

A

Left: binding to D2 receptors is correlated with clinical efficacy

Right: antipsychotics displace [11C]raclopride from D2 receptors

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22
Q

Clinical Efficacy of Neuroleptics

A

Of neuroleptics has been shown in 100’s of double-blind RCTs

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23
Q

Symptoms of Neuroleptics

A
  • more effective in treating the positive symptoms

- negative and cognitive symptoms are difficult

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24
Q

Maintenance of Neuroleptics

A
  • after treating acute psychosis, antipsychotic drugs are prescribed for maintenance
  • discontinuation is often not attempted
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25
Q

Neuroleptics are effect antipsychotics

A
  • 1/3 respond well, have a meaningful and productive life
  • 1/3 show improvement but will relapse, often requiring hospitalization
  • 1/3 fail to respond, chronically ill, highest rate of suicide
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26
Q

Neuroleptics are potent […]

A

Neuroleptics are potent D2 receptor antagonists

*best predictor of antopsychotic efficacy is potency of D2-R antagonism

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27
Q

Parkinsonism symptoms

A

Side effects that include tremors, akinesia (slowing/ loss of voluntary movement), muscle rigidity, akathisia (constant walking), and loss of facial expression

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28
Q

DA cell groups and pathway: Nigrostriatal (A9)

A
  • activation, motivation, and cognition
  • motor side effects
  • EPS side effects
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29
Q

DA cell groups and pathway: Mesolimbic (A10)

A
  • behavioral arousal and reward learning
  • delusions and hallucinations
  • antipsychotic efficacy
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30
Q

DA cell groups and pathway: Mesocortical (A10)

A
  • attention and working memory

* cognitive effects and negative symptoms

31
Q

DA cell groups and pathway: Tuberohypophyseal (A12)

A
  • prolactin release
  • neuroendocrine side effects
  • endocrine side effects
32
Q

EPS side effects

A

Blocking D2 receptors in the nigro-striatal pathway can cause

- dystopia, parkinsonism 
- tardive dyskinesia
33
Q

Endocrine side effects

A

D2 blockade increases the release of prolactin

- males: gynecomastia, delayed ejaculation
- females: galactorrhea, amenorrhea, decreased libido
34
Q

Additional Side Effects of Neuroleptics

A

Histamine H1 antagonist

- sedation
- weight gain

Alpha1 NE antagonist
- postural hypotension

MACh antagonist
- dry mouth, pupil dilation/ blurred vision, cognitive impairment, constipation, tachycardia

35
Q

Schizophrenia: Serotonin

A
  • the hallucinogenic drug LSD exerts it’s effects by activating 5-HT2A receptors
  • atypical antipsychotics have less affinity for D2, and greater affinity for 5-HT2 receptors
36
Q

“Atypical “ Antipsychotics (SGA)

A 
Clozaril (clozapine)
Zyprexa (olanzapine)
Seroquel (quetiapine)
Risperdal (risperidone)
Geodon (ziprasidone)
Latuda (lurasidone)
Abilify (aripiprazole)
Rexulti (brexpiprazole)
Vraylar (cariprazine)
37
Q

SGA and bipolar disorder

A 
Zyprexa (olanzapine)
Seroquel (quetiapine)
Risperdal (risperidone)
Geodon (ziprasidone)
Latuda (lurasidone)
Abilify (aripiprazole)
Vraylar (cariprazine)
38
Q

SGA and MDD add-on therapy

A

Zyprexa (olanzapine)

Rexulti (brexpiprazole)

39
Q

Severe side effects limit the clinical use of clozapine

A

Agranulocytosis

- loss of white blood cells in 1-2% of users
- reversible, but potentially fatal
- requires frequent blood monitoring (increased expense)

Substantial weight gain is also problematic
- increased risk for metabolic syndrome (pre-diabetes) and ensuing cardiovascular disease

Reduction in seizure threshold

40
Q

Clozapine has some advantages over neuroleptics

A

Effective in about 1/3 of neuroleptics non-responders
EPS (Parkinsonism) side-effects less severe
Reduces suicide risk in schizophrenia and schizoaffective disorder

41
Q

Atypical Antipsychotic: Receptor Affinity

A
  • Low affinity D2 antagonist

- High affinity 5-HT2A antagonist (or 5-HT1A partial agonist or D2 partial agonist)

42
Q

Atypical Antipsychotic: DA-Eric side effect profile

A
  • EPS (Parkinsonism) less severe

- endocrine side-effects (hyperprolactemia) less severe

43
Q

Atypical antipsychotics are low-affinity dopamine D2 antagonists

A
  • 5-HT2A antagonism increases DA output

- 60% D2 receptor accupancy

44
Q

Selective D2 Receptor Antagonists

A

Sulpiride and amisulpride

45
Q

Dopamine System Stabilizers

A

Aripiprazole (Abilify)

- DA partial agonist

46
Q

Broad- Spectrum Antipsychotics

A

Clozapine

- weak affinities for D1 and D2

47
Q

Pharmacological Action of Atypical Antipsychotics

A

Nigrostriatal pathway

2A antagonists decrease cortical excitation

Decrease GABA inhibition
Increased DA release

Increase motor output
Mitigate EPS

48
Q

5-HT2A regulation of dopamine release is not the same everywhere

A

No effect on mesolimbic or mesocortical areas (don’t have 5-HT2A receptors)

  • Nigrostriatal: decreased EPS side effects
  • Tuberohypophyseal: decreased endocrine side effects
49
Q

5- HT1A and D2 partial agonist contributes to antipsychotics and AD efficacy

A

“Peens” and “dones”: high affinity 5-HT2A antagonists

“2 pips and a rip”:

- lower affinity for 5-HT2A receptors
- 5-HT1A partial agonist
- D2 partial agonist
50
Q

Similar to 5-HT2A antagonism, […] also increase DA release selectively in […] pathway and […]

A

Similar to 5-HT2A antagonism, 5-HT1A partial agonism also increase DA release selectively in nigrostriatal pathway and pituitary

51
Q

[…] “stabilizes” DA

A

D2 partial agonist “stabilizes” DA

52
Q

“Peens” and “dones”

A

5-HT1A partial agonist

Depressive episodes in BD

- Seroquel (quetiapine)
- Latuda (lurasidone)
53
Q

“2 pips and a rip”

A

D2 partial agonist
5-HT1A partial agonist

Adjunct in MDD

- Abilify (apiprazole )
- Rexulti (brexipiprazole)
54
Q

General side effects of atypical antipsychotics: Sedation

A
  • H1, ACh, a1 antagonism
  • Clozaril
  • Zyprexa
  • Seroquel
55
Q

General side effects of atypical antipsychotics: Cardiometabolic

A
  • High
    • Clozaril
    • Zyprexa- very high weight gain
  • Moderate
    • Risperdal, Seroquel, Fanapt
56
Q

The Cardiometabolic Effects of Atypical Antipsychotics

A
  1. Increased appetite
  2. Weight gain
  3. Elevated triglycerides
  4. Insulin resistance
  5. Diabetes
    • increased risk of type 2
  6. Cardiovascular events
57
Q

Acute psychosis

A
  • Neuroleptics- alone or in combo with BDZ and/ or anticholinergic (eg. Benztropine)
  • Zyprexa (short- acting IM/ ODT) or Geodon (short-acting IM)
58
Q

First episode psychosis

A
  • Atypicals often used used due to more favorable side-effect profile
  • start with low dose, titration slowly
59
Q

Switching for Adverse Effects: EPS

A

1st Alternative: Clozaril; Zyprexa
Other: Seroquel; Abilify
Worst: Haldol; Thorazine

60
Q

Switching for Adverse Effects: Sedation

A

1st Alternative: Invega; Fanapt
Other: Abilify; Latuda
Worst: Clozaril; Thorazine

61
Q

Switching for Adverse Effects: Weight gain

A

1st Alternative: Haldol; Geodon
Other: Abilify; Seroquel
Worst: Zyprexa; Clozaril

62
Q

Switching for Adverse Effects: Hyperprolactinemia

A

1st Alternative: Abilify; Seroquel
Other: Saphris; Zyprexa
Worst: Invega; Risperdal

63
Q

Switching for Adverse Effects: Long QTc

A

1st Alternative: Latuda; Abilify
Other: Invega; Haldol
Worst: Serlect; Geodon

64
Q

Atypical antipsychotics carry a box warning

A

Increased mortality in elderly patients with dementia-related psychosis:

- 2x increase in death in patients with dementia- related psychosis 
- cardiovascular (heart failure, sudden death) or infectious

Equivocal evidence of therapeutic efficacy for behavioral and psychological symptoms of dementia

- agitation, aggression, noncompliance with care, disturbed sleep
- CMS requires documentation of medical necessity
65
Q

Should Clozapine be a first-line medication?

A

Should not be reserved as a treatment of last-resort

66
Q

Antipsychotics in Children: Schizophrenia

A

Abilify
Fanapt
Seroquel
Risperdal

67
Q

Antipsychotics in Children: Bipolar

A

Abilify
Fanapt
Seroquel
Risperdal

68
Q

Antipsychotics in Children: Irritaibility/ Autism

A

Abilify

Risperdal

69
Q

Hippocampal activity is pathologically enhanced

A

Antipsychotics work at D2 receptors

The pathology is at the hippocampus

70
Q

Neuroscience of Schizophrenia

A

Negative Symptoms: excessive pruning in PFC

Positive Symptoms: loss of top-down control over brain stem DA neurons

71
Q

Depot injections: atypical antipsychotics

A 
Olonzapine pamoate (Zyprexa Relprevv)
Apiprazole lauroxil (Aristada)
Palperidone palmitate (Invega Trinza)
72
Q

Depot Injection Advantages

A
  • avoids first-pass metabolism
  • improved adherence
  • reduced relapse and rehospitalization
73
Q

Depot Injection Disadvantage

A
  • less flexibility of dose adjustment
  • tolerance to side-effects are delayed
  • frequent travel to outpatient clinics

Neuropharmacology (15 decks)

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