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Neuropharmacology > Ch 19: Schizophrenia And The Antipsychotics > Flashcards

Ch 19: Schizophrenia And The Antipsychotics Flashcards

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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
Neuroleptics are effect antipsychotics
- 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
26
Neuroleptics are potent […]
Neuroleptics are potent D2 receptor antagonists *best predictor of antopsychotic efficacy is potency of D2-R antagonism
27
Parkinsonism symptoms
Side effects that include tremors, akinesia (slowing/ loss of voluntary movement), muscle rigidity, akathisia (constant walking), and loss of facial expression
28
DA cell groups and pathway: Nigrostriatal (A9)
- activation, motivation, and cognition * motor side effects * EPS side effects
29
DA cell groups and pathway: Mesolimbic (A10)
- behavioral arousal and reward learning * delusions and hallucinations * antipsychotic efficacy
30
DA cell groups and pathway: Mesocortical (A10)
- attention and working memory | * cognitive effects and negative symptoms
31
DA cell groups and pathway: Tuberohypophyseal (A12)
- prolactin release * neuroendocrine side effects * endocrine side effects
32
EPS side effects
Blocking D2 receptors in the nigro-striatal pathway can cause - dystopia, parkinsonism - tardive dyskinesia
33
Endocrine side effects
D2 blockade increases the release of prolactin - males: gynecomastia, delayed ejaculation - females: galactorrhea, amenorrhea, decreased libido
34
Additional Side Effects of Neuroleptics
Histamine H1 antagonist - sedation - weight gain Alpha1 NE antagonist - postural hypotension MACh antagonist - dry mouth, pupil dilation/ blurred vision, cognitive impairment, constipation, tachycardia
35
Schizophrenia: Serotonin
- 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
“Atypical “ Antipsychotics (SGA)
``` Clozaril (clozapine) Zyprexa (olanzapine) Seroquel (quetiapine) Risperdal (risperidone) Geodon (ziprasidone) Latuda (lurasidone) Abilify (aripiprazole) Rexulti (brexpiprazole) Vraylar (cariprazine) ```
37
SGA and bipolar disorder
``` Zyprexa (olanzapine) Seroquel (quetiapine) Risperdal (risperidone) Geodon (ziprasidone) Latuda (lurasidone) Abilify (aripiprazole) Vraylar (cariprazine) ```
38
SGA and MDD add-on therapy
Zyprexa (olanzapine) | Rexulti (brexpiprazole)
39
Severe side effects limit the clinical use of clozapine
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
Clozapine has some advantages over neuroleptics
Effective in about 1/3 of neuroleptics non-responders EPS (Parkinsonism) side-effects less severe Reduces suicide risk in schizophrenia and schizoaffective disorder
41
Atypical Antipsychotic: Receptor Affinity
- Low affinity D2 antagonist | - High affinity 5-HT2A antagonist (or 5-HT1A partial agonist or D2 partial agonist)
42
Atypical Antipsychotic: DA-Eric side effect profile
- EPS (Parkinsonism) less severe | - endocrine side-effects (hyperprolactemia) less severe
43
Atypical antipsychotics are low-affinity dopamine D2 antagonists
- 5-HT2A antagonism increases DA output | - 60% D2 receptor accupancy
44
Selective D2 Receptor Antagonists
Sulpiride and amisulpride
45
Dopamine System Stabilizers
Aripiprazole (Abilify) | - DA partial agonist
46
Broad- Spectrum Antipsychotics
Clozapine | - weak affinities for D1 and D2
47
Pharmacological Action of Atypical Antipsychotics
Nigrostriatal pathway 2A antagonists decrease cortical excitation Decrease GABA inhibition Increased DA release Increase motor output Mitigate EPS
48
5-HT2A regulation of dopamine release is not the same everywhere
No effect on mesolimbic or mesocortical areas (don’t have 5-HT2A receptors) - Nigrostriatal: decreased EPS side effects - Tuberohypophyseal: decreased endocrine side effects
49
5- HT1A and D2 partial agonist contributes to antipsychotics and AD efficacy
“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
Similar to 5-HT2A antagonism, […] also increase DA release selectively in […] pathway and […]
Similar to 5-HT2A antagonism, 5-HT1A partial agonism also increase DA release selectively in nigrostriatal pathway and pituitary
51
[…] “stabilizes” DA
D2 partial agonist “stabilizes” DA
52
“Peens” and “dones”
5-HT1A partial agonist Depressive episodes in BD - Seroquel (quetiapine) - Latuda (lurasidone)
53
“2 pips and a rip”
D2 partial agonist 5-HT1A partial agonist Adjunct in MDD - Abilify (apiprazole ) - Rexulti (brexipiprazole)
54
General side effects of atypical antipsychotics: Sedation
- H1, ACh, a1 antagonism - Clozaril - Zyprexa - Seroquel
55
General side effects of atypical antipsychotics: Cardiometabolic
- High - Clozaril - Zyprexa- very high weight gain - Moderate - Risperdal, Seroquel, Fanapt
56
The Cardiometabolic Effects of Atypical Antipsychotics
1. Increased appetite 2. Weight gain 3. Elevated triglycerides 4. Insulin resistance 5. Diabetes - increased risk of type 2 6. Cardiovascular events
57
Acute psychosis
- Neuroleptics- alone or in combo with BDZ and/ or anticholinergic (eg. Benztropine) - Zyprexa (short- acting IM/ ODT) or Geodon (short-acting IM)
58
First episode psychosis
- Atypicals often used used due to more favorable side-effect profile - start with low dose, titration slowly
59
Switching for Adverse Effects: EPS
1st Alternative: Clozaril; Zyprexa Other: Seroquel; Abilify Worst: Haldol; Thorazine
60
Switching for Adverse Effects: Sedation
1st Alternative: Invega; Fanapt Other: Abilify; Latuda Worst: Clozaril; Thorazine
61
Switching for Adverse Effects: Weight gain
1st Alternative: Haldol; Geodon Other: Abilify; Seroquel Worst: Zyprexa; Clozaril
62
Switching for Adverse Effects: Hyperprolactinemia
1st Alternative: Abilify; Seroquel Other: Saphris; Zyprexa Worst: Invega; Risperdal
63
Switching for Adverse Effects: Long QTc
1st Alternative: Latuda; Abilify Other: Invega; Haldol Worst: Serlect; Geodon
64
Atypical antipsychotics carry a box warning
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
Should Clozapine be a first-line medication?
Should not be reserved as a treatment of last-resort
66
Antipsychotics in Children: Schizophrenia
Abilify Fanapt Seroquel Risperdal
67
Antipsychotics in Children: Bipolar
Abilify Fanapt Seroquel Risperdal
68
Antipsychotics in Children: Irritaibility/ Autism
Abilify | Risperdal
69
Hippocampal activity is pathologically enhanced
Antipsychotics work at D2 receptors | The pathology is at the hippocampus
70
Neuroscience of Schizophrenia
Negative Symptoms: excessive pruning in PFC Positive Symptoms: loss of top-down control over brain stem DA neurons
71
Depot injections: atypical antipsychotics
``` Olonzapine pamoate (Zyprexa Relprevv) Apiprazole lauroxil (Aristada) Palperidone palmitate (Invega Trinza) ```
72
Depot Injection Advantages
- avoids first-pass metabolism - improved adherence - reduced relapse and rehospitalization
73
Depot Injection Disadvantage
- less flexibility of dose adjustment - tolerance to side-effects are delayed - frequent travel to outpatient clinics

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