Schizophrenia Flashcards
1
Q
Negative Symptoms
A
blunted emotion
poor self-care
social withdrawal
poverty in speech
1
Q
Positive Symptoms
A
hallucinations
delusions
bizarre behavior
thought disorders
2
Q
Cognitive Symptoms
A
- decrease in cognitive function
- involves D1 receptors and glutamate receptors
3
Q
Serotonin Hypothesis of Schizophrenia
A
- LSD and mescaline were identified as 5HT agonists
- 5HT2A receptor as mediator of hallucinations
- antagonism and inverse agonism linked to antipsychotic activity
4
Q
Which receptors modulate dopamine release in cortex, limbic region, and striatum
A
5HT2A receptors
5
Q
Which receptors modulate glutamate release and NMDA receptors
A
5HT2A receptors
6
Q
Glutamate Hypothesis of Schizophrenia
A
- glutamate is major excitatory neurotransmitter
- phencyclidine and ketamine, noncompetitive inhibitors of NMDA receptors exacerbate psychosis and cognition deficits (increasing symptoms)
7
Q
Dopamine Hypothesis of Schizophrenia
A
- D2 receptor antagonists
- dopaminergic agents exacerbate symptoms of schizophrenia
- increased D2 receptor density in treated and untreated patients
-D2 receptor antagonists initially increase metabolites in the CNS and later decrease metabolites in the CNS
8
Q
Major Receptors Antagonized by Antipsychotics
A
Dopamine
D1 like = 1 and 5
D2 like = 2, 3, 4
9
Q
5HT2A Receptor Antagonists
A
clozapine
olanzapine
risperidone
10
Q
Older 5HT agents
A
chlorpromazine
haldol
thioridazine
11
Q
Norepinephrine Alpha 1 Blockade Effects
A
hypotension, sedation
12
Q
Norepinephrine Alpha 2 Blockade Effects
A
may be helpful in therapy
13
Q
Acetylcholine Effects
A
anticholinergic effects
clozapine, thioridazine
14
Q
Histamine Effects
A
H1 Receptor Antagonists
sedation, weight gain
15
Q
Correlation between binding potency and clinical effectiveness for ________ receptors, therefore more _______ drug target
A
D2; effective
16
Q
Most antipsychotics drugs are receptor _______
A
antagonists
17
Q
D2 ____ D1 receptor binding
A
>
18
Q
D2 Receptor Antagonist
A
blocks both pre and post-synaptic receptors
at first, Pre-synaptic blocked: increases the synthesis and release of dopamine
when dopamine diffuses back into the presynaptic receptor, it tells the receptor there is way too much dopamine, presynaptic receptor decreases synthesis
19
Q
Dopamine Physiology and Function: Mesolimbic
A
primary therapeutic effects
20
Q
D2 Receptor occupancy and rate of EPS as functions of plasma risperidone concentration
A
increased concentration of risperidone –> increased D2 occupancy –> increased EPS
21
Q
EPS
A
extrapyramidal symptoms
22
Q
Symptoms of EPS
A
dystonia (increased muscle tones)
pseudoparkinsonism (muscle rigidity)
tremor
akathisia (restlessness)
23
Q
When does EPS occur?
A
early, days/weeks, reversible
24
Drug Therapy for EPS
benztropine, trihexyphenidyl, akineton (anticholinergic)
diphenhydramine (antihistamine)
amantadine (dopamine release agent)
propranolol (used for akathisia)
25
Tardive Dyskinesia
occurs late, months to a year
irreversible
26
Symptoms of Tardive Dyskinesia
rhythmic involuntary movements
choreiform: irregular purposelessness
athetoid: worm like
axial hyperkinesias: to and fro movements
27
MOA of Tardive Dyskinesia
unknown
28
Monitoring of Tardive Dyskinesia
AIMS (abnormal involuntary movement scale)
check q6months
29
Treatment of Tardive Dyskinesia
prevention
1. reduce dose of current agent
2. change to a different drug
3. eliminate anticholinergic drugs
4. VMAT inhibitors
30
VMAT2 Inhibitors use
newer drug therapies for tardive dyskinesia
prevent dopamine from being packaged, decreasing dopamine release
31
Tetrabenazine
VMAT2 for Huntington's chorea
32
Valbenazine
VMAT2 for tardive diskinesia
33
Deutetrabenazine
for tardive diskinesia and huntington's chorea
34
Neuroleptic Malignant Syndrome
serious and rapid; 10% fatility
35
Symptoms of neuroleptic malignant syndrome
EPS symptoms with fever
Impaired cognition (agitation, delirium, coma)
muscle rigidity
36
Treatment of neuroleptic malignant syndrome
Restore dopamine balance
d/c drug
use DA agonists, diazepam, or dantrolene
37
Intractable Hiccupts
chlorpromazine
38
Alcohol withdrawal (hallucinations)
haloperidol
39
nausea and vomiting
metoclopramide
promethazine
40
potentiation of opiates and sedatives
droperidol
41
Behavioral effects of antipsychotic drugs
unpleasant in normal subjects or reversal of signs and symptoms of psychosis in affected individuals
42
neuroleptic syndrome of antipsychotic drugs
suppress emotions
reduce initiative and interest
affect
may resemble negative syndromes
43
Loss of accomodation, dry mouth, difficulty urinating, constipation
muscarinic cholinoceptor blockade
44
orthostatic hypotension, impotence, failure to ejaculate
alpha adrenoceptor blockade
45
PD, akathasia, dystonias
dopamine receptor blockade
46
tardive dyskinesia cause
supersensitivity of dopamine receptors
47
toxic-confusal state
muscarinic blockade
48
sedation
histamine receptor blockade
49
amenorrhea-galactorrhea, infertility, impotence
dopamine receptor blockade resulting in hyperprolactinemia
50
weight gain
possibly combined H1 and 5HT2c blockade
51
precautions and contraindications of antipsychotics
CV
PD
epilepsy (clozapine will lower seizure threshold)
diabetes (for newer agents)
52
Aliphathic Phenothiazines
chlorpromazine (no longer 1st line therapy)
53
Chlorpromazine Structure
R2: important for potency
R10: requires 3 atom chain (allows nitrogen to bind receptor)
2 atom chain = antihistamine
54
Aliphatic Phenothiazines used for H1 antagonist properties
promethazine
(also for N/V)
55
piperidine phenothiazines
thioridazine (sedation, hypotension, anticholinergic, many SE)
56
piperazine phenothiazines
fluphenazine (EPS)
prochlorperazine (antiemetic)
perphenazine (CATIE studies: combo with anticholinergic)
57
Thioxanthines
thiothixene: modest EPS
58
Butyrophenones
haloperidol (EPS)
strong D2 block
59
molindone
moderate EPS
60
pimozide
tourette's disease
tics, vocalizaitons
61
Atypical/Second Gen Antipsychotics overview
more metabolic problems
reduced EPS
62
Clozapine
1st atypical antipsychotic
very effective
63
Agranulocytosis in Clozapine
occurs in 1-2% within 6 months
(weekly blood monitoring)
2nd or 3rd line therapy
64
Side Effects of Clozapine
anticholinergic, antihistamine
reduced D2 potency = decreased movement disorders
risk of diabetes
65
Olanzapine
- weight gain
- less likely to cause N/V
- less likely to cause movement disorders
- risk of diabetes
66
Loxapine
- older agent
- metabolite= amoxipine
- inhibits NET --> antidepressant
67
Quetiapine
- metabolite w/ antidepressant activity
- 5HT2a and D2
- low EPS
- low antimuscarinic
- hypotension (alpha 1)
- sedation (h2)
- risk of diabetes
68
Risperidone MOA
5HT2A and D3 receptor antagonist
69
Risperidone Pearls
relatively low EPS < 8 mg/day
weight gain, sedation
70
Paliperidone (Invega)
9-hydroxyrisperidone
71
Iloperidone
structurally related to risperidone
very potent at alpha 1 receptors
72
Ziprasidone MOA
5HT2A, D2, Alpha 1 affinity
73
Ziprasidone Pearls
prolongs QT interval
long acting formulation under study
74
Asenapine
5HT2A and D2
75
Lurasidone MOA
5HT2A and D2
76
Lurasidone Pearls
- less weight gain and metabolic effects
- fast onset (days without titration)
- low doses similar effectiveness to high doses
77
Pimavanserin
inverse agonist 5HT2A
PD psychosis
78
Aripiprazole MOA
high affinity for 5HT2 and D2
partial agonist at 5HT1A receptors (used in depression)
moderate affinity for D4, alpha, and histamine
79
Side Effects of Aripiprazole
weight gain
low risk for D2 effects
80
When is aripiprazole lauroxil given
q4-8 weeks
prodrug
81
Brexpiprazole MOA
D2/D3 partial agonist with less akathisia
82
Cariprazine MOA
D2/D3 partial agonist with greater affinity for D3
weak partial agonist activity at 5-HT1A
akathisia is high
83
Lumateperone MOA
partial D2 agonist presynaptic receptors/antagonists at postsynpatic receptors (5HT2A antagonist)
84
Key features that define psychotic disorders
delusions: fixed false beliefs that are not amendable to change even with confliction evidence
hallucinations
disorganized thinking and speech
disorgaanized or abnormal motor behavior
negative symptoms
85
Disease course in schizophrenia
onset late adolescence to early adulthood
men: late teens, early 20s
women: late 20s, early 30s
86
Smoking and Antipsychotics
smoking is associated with induction of 1A2 due to hydrocarbons produced and inhaled
decreases the serum concentration of 1A2 substrate antipsychotics (olanzapine, asenapine, clozapine, loxapine)
87
Which 3 medications can hasten the onset of schizophrenia, exacerbate symptoms, and reduce time to relapse
marijuana, cocaine, amphetamine
88
Must consider when prescribing antipsychotics
doses per day
side effects
previous drug therapy
cost of drug therapy
concomitant drug therapy
need for monitoring
89
First line for Schizophrenia
oral antipsychotic drug therapy is generally considered first-line, unless patient presents reasons to consider IM depot drug therapy first
90
Typical Antipsychotics MOA
D2 receptor antagonist
efficacy for positive symptoms is similar to atypical antipsychotics
91
Most commonly used typical antipsych
haloperidol: routine and prn
92
EPS in typical antipsych
more eps with higher potency
93
typical antipsych effect on positive, negative, cognitive symptoms
positive: effective
negative may worsen
cognitive: may worsen
94
Atypical Antipsychotics MOA
D2 antagonism + 5HT2A antagonist
95
Atypical EPS compared to Typical
less EPS, more metabolic side effects
96
Partial Agonists
stabilize dopamine transmission (not too much, not too little)
associated with more akathisia than other antipsychotics
approved for adjunct treatment of depression (have boxed warning for suicidal thoughts/behavior)
97
Aripiprazole MOA
partial agonist
98
Aripiprazole CYP P450
2D6 and 3A4 substrate
99
Aripiprazole akathisia
moderate
100
Aripiprazole weight gain
low
101
Brexpiprazole MOA
partial agonist
102
Brexpiprazole CYP P450
2D6 and 3A4 substrate
103
Brexpiprazole akathisia
moderate
104
Brexpiprazole weight gain
low-moderate weight gain
105
Cariprazine MOA
partial agonist
106
Cariprazine CYP P450
3A4 substrate
107
Cariprazine akathisia
moderate
108
Cariprazine weight gain
low-moderate
109
-Pines
less D2 antagonism, more 5HT2A antagonism
significantly less EPS
higher weight gain
110
Asenapine
sublingual and patch
QTc prolongation
111
Clozapine
boxed warnings for neutropenia, orthostaisis, bradycardia, syncope, seizures, myocarditis, cardiomyopathy
side effects: sedation, weight gain, constipation, hypersalivation, dry mouth, GI hypomotility with obstructive risk
QTc
112
Olanzapine
signficant weight gain and sedation
high risk metabolic syndrome
DRESS warning
113
1A2 Substrates
asenapine
clozapine
olanzapine
114
Quetiapine
3A4 substrate
QTc prolongation
weight gaine an sedation
boxed warning for suicidal ideation
115
Secuado (Asenapine) Patch Warning
QTc prolongation
116
Secuado (Asenapine) Patch Interactions
UGT and 1A2 substrate
reduce dose of patch if given with strong 1A2 inhibitor (fluvoxamine)
117
Clozapine REMS (ON EXAM)
monitoring timelines weekly x6months, biweekly x 6months, then every 4 weeks
118
Olanzapine/Samidorphan (Lybalvi)
Samidorphan is an opioid antagonist with preferential activity at the mu opioid receptor
119
the dones
D2 and 5HT2A antagonists
variable EPS and metabolic side effects
120
Iloperidone warning
high risk for othostasis and syncope
QTc prolongation
121
Iloperidone CYP interaction
2D6 substrate
122
Lurasidone CYP interaction
3A4 substrate
123
Lurasidone Warnings
suicidal thoughts
higher risk for akathisia
take with food to incrase bioavailability
124
Ziprasidone warnings
QTc prolongation (contraindication)
DRESS warning
take with food to increase absorption and bioavailabiltiy
125
Ziprasidone CYP interaction
3A4 and aldehyde oxidase
126
Risperidone and Paliperidone
highest D2 blockade for atypicals
highest EPS, moderate metabolic side effects
127
Risperidone CYP interaction
2D6 substrate (minor 3A4)
128
Risperidone SEs
EPS
hyperprolactinemia
weight gain
sedation
orthostatis
129
Paliperidone
renally eliminated
QTc prolongation
130
Lumateperone
low risk for weight gain or metabolic side effects
low risk for eps or akathisia
3A4 substrate
131
Pimavanserin
treatment of hallucinations or delusions in PD
inverse agonist and antagonist at the serotonin 5HT2A
3A4 inhibitor
132
Warnings for all Antipsychotics
- boxed warning for increased risk of death in elderly patients treated with antipsychotics for dementia with related behaviors
- metabolic adverse effects
- eps
- risk of somnolence, hypotension, increases risk for falls and fractures
133
Haloperidol Decanoate
given every 4 weeks
loading dose: 20x oral dose
maintenance: 10x oral dose
134
Risperdal Consta
must supplement with oral risperidone (or another oral antipsychotic) for the first few weeks of treatment (until 3rd injection)
135
Perseris (risperidone)
abdominal subq injection
34A inducers, use 120 mg dose or may need oral supplementation
136
Rykindo (risperidone)
every 2 week IM injection
oral dose overlap is shorter than risperdal Consta ( 7 days vs 21 days)
137
Uzedy (risperidone)
abdominal or upper arm subq injection
given once monthly or every 2 months
138
Invega Sustenna (paliperidone)
loading dose, then booster q4 weeks starting 5 weeks after loading injection
inital loading and booster must be given in deltoid
if loading, no need for oral overlap
may require dose adjustment in moderate to severe renal impairment
139
Invega Trinza (paliperidone)
may be initiated for a patient who has been on stable monthly (q4week) IM injection of Invega Sustenna at least four stable doses
recommended to be given in deltoid
not recommended if CrCl<50 mL/min
q3months
140
Invega Hafyera (paliperidone)
may be initiated after stable invega sustenna for 4 months or stable invega trniza after one 3 month dose
gluteal injection only
q6month
141
Zyprexa Relprevv (olanzapine)
PDSS - post dose delirium sedation syndrome
REMS
142
Abilify Maintena
must overlap with oral aripiprazole for at least 14 days after first injection
deltoid or gluteal
143
Dose Adjustments for P450 Interactiosn: Abilify Maintena
if taking 2D6 or 3A4 inhibitors or 3A4 inducers for more than 14 days as concomitant therapy
avoid 3A4 inducers use
144
Abilify Asimtufii (aripiprazole)
every 2 month dosing
gluteal injection only
continue oral aripiprazole for 2 weeks after first injection
145
Aristada (aripiprazole lauroxil)
overalap with oral aripiprazole for 3 weeks after first injection
146
Aristada Initio (aripiprazole lauroxil)
developed to avoid 21 day oral overlap of antipsychotic
avoid in patients who are 2D6 poor metabolizers or with strong 3A4 or 2D6 inhibitors
147
Commonly used immediate release antipsychotic injections
haloperidol, chlorpromazine, fluphenazine
148
Olanzapine IM and benzodiazepine IM
cannot be given at the same time, boxed warning for respiratory depression
149
Loxapine for inhalation
not commonly used for emergencies due to REMS
150
Treatment of Acutre Dystonia
IM anticholinergic now dose (benztropine 2 mg, diphenhydramine 50 mg)
151
Treatment of Drug Induced PD
oral anticholinergic
(trihexyphenidyl, diphenhydramien)
152
Treatment of Akathisia
beta blocker (propranolol)
benzodiazepine (lorazepam)
153
Treatment of Tardive Dyskinesia
VMAT inhibitors
154
Valbenzine CYP interacgtion
2D6/3A4 substrate
QTc prolongation
155
Duetetrabenazine CYP Interaction
2D6 substrate
QTc prolongation
156
Neuroleptic Malignant Syndrome
life threatening, medical emergency
hyperpyrexia, tachycardia, labile bp
muscle rigidity
treatment is suspportive
future antipsychotic use is not contraindicated
157
metabolic adverse effects
hyper glycemia, hyperlipidemia, hypertension
clozapine = olanzapine >
quetiapine = risperidone = paliperidone = asenapine = iloperidone = cariprazine = brexpiprazole >
ziprasidone = lurasidone = aripiprazone
158
personal family hx monitoring
baseline
yearly
159
weight (BMI) metabolic monitoring
baseline
4 weeks
8 weeks
12 weeks
every 3 months
160
waist circumference monitoring
baseline
yearly
161
BP/A1C monitoring
baseline
12 weeks
yearly
162
fasting lipids monitoring
baseline
12 weeks
every 5 years
