Atypical Antipsychotic
Pharmacology
Using Receptor Binding Profiles to Predict
Adverse Effects
Stephanie Nichols, Pharm.D., BCPS, BCPP
Associate Professor of Pharmacy Practice
NicholsS@Husson.edu
Objectives
 Recognize atypical antipsychotics by brand
and generic name
 Understand how key pharmacological
properties of antipsychotics translate into
side effects
 Compare and contrast the pharmacology
of the atypical antipsychotics
 Predict which antipsychotics may be more,
or less, desirable in various patient
scenarios
Thioridazine
Perphenazine
Trifluoperazine
Mesoridazine
Chlorpromazine
Haloperidol
1950
Aripiprazole
Risperidone
Pimozide
1960
Clozapine
1970
1980
1990
Iloperidone
Asenapine
Quetiapine
2000
2010
Droperidol
Ziprasidone
Prochlorperazine
Lurasidone
Fluphenazine
Loxapine
Thiothixene
Paliperidone
Olanzapine
Stephanie Nichols, PharmD BCPS BCPP
2014
What defines an Antipsychotic?
 Dopamine2 post synaptic antagonism
 Reduce DA in the mesolimbic tract
 Nucleus accumbens
 Positive Symptoms
 EPS
Antagonism
Partial Agonism
Dopamine
Pathway
Function
Dopamine
Pathology in
Schizophrenia
AntiPsychotic
Efficacy
Antipsychotic
Toxicity
Nigrostriatal
Extrapyramidal
system &
movement
Mesolimbic
Emotions &
motivation
Plethora
Positive
Symptoms
Mesocortical
Cognition &
executive
function
Paucity
Negative & Akathisia
Cognitive
Symptoms
Turberoinfundibular
Regulates
prolactin release
Parkinsonism,
dystonia, &
dyskinesia
Hyperprolactinemia
http://psychopharmacologyinstitute.com/antipsychotics-videos/dopamine-pathways-antipsychotics-pharmacology/
What defines an Atypical
Antipsychotic?
 Serotonin2a post-synaptic antagonism
 5HT2a puts the brakes on DA in PFC
 Disinhibiting the inhibitor – increased mesocortical DA
 ? Improved negative and cognitive symptoms
 Reduced EPS – at what cost?
Typicals vs. Atypicals
Extra
Pyramidal
Symptoms
Metabolic
Dysregulation
Recognize
atypical
antipsychotics
by brand and
generic name
Atypical Antipsychotics in the US
Generic Availability
Brand Name Only
 Clozapine (Clozaril)
 Aripiprazole (Abilify)
 Olanzapine (Zyprexa)
 Paliperidone (Invega)
 Quetiapine (Seroquel)
 Iloperidone (Fanapt)
 Risperidone (Risperdal)
 Asenapine (Saphris)
 Ziprasidone (Geodon)
 Lurasidone (Latuda)
Understand how
key
pharmacological
properties of
antipsychotics
translate into
side effects
Receptor Antagonism &
Clinical Effect
The Good
D1
(agonism)
• ?ameliorate cognitive
deficits via DA modulation
in PFC
• ?Effects on mood
D2
DA antagonism in the
Mesolimbic Tract - ↓ positive sx
(antagonism)
The Bad
• EPS
(parkinsonism,
dystonia, dyskinesia,
akathisia),
• hyperprolactinemia
(ammenorrhea, galactorrhea,
gynecomastia)
The Good
5HT1a
(partial / full
agonism)
5HT2a
(antagonism /
inverse agonism)
• Antidepressant and/or anxiolytic ?
• Inhibit (↓) glutamate release - ↓
positive sx
DA disinhibition (↑DA) in the:
1.Nigrostriatal tract - ↓ EPS
Weight gain and
metabolic dysfunction
(antagonism /
inverse agonism)
(antagonism)
Sedation
2. Mesocortical tract - ? ↓ negative and
cognitive sx
5HT2c
5HT7
The Bad
(hyperlipidemia,
hypertriglyceridemia,
hyperglycemia)
•
•
•
Circadian rhythm
?pro-cognitive effects
?Effects on anxiety or depression
Sedation?
The Good
Alpha2a
The Bad
?Pro-cognitive effects
(antagonism)
Alpha2c
?Pro-cognitive effects
(antagonism)
The Good
Alpha7-nicotinic
(antagonism)
?mood and cognition
The Bad
The
The Bad
Good
Alpha1
(antagonism)
H1
(antagonism)
M1
(antagonism)
M3
(antagonism)
Dizziness, orthostasis, hypotension, tachycardia,
sedation
Sedation, weight gain and metabolic dysfunction
?cognition
Anticholinergic sx/sx, memory and cognitive
deficits
?diabetes mellitus
Compare and
contrast the
pharmacology
of the atypical
antipsychotics
Addressing Negative Symptoms in Schizophrenia. CPNP University 2013
NIMH Psychoactive Drug Screening Program (PDSP) Ki Database: http://pdsp.med.unc.edu/pdsp.php
What do you think?
 Based upon Quetiapine’s
binding profile, which of
the following adverse
effects is most likely to
occur?
A. Parkinsonism
B. Antimuscarinic Effects
C. Sedation
0
+
++
5HT
2a
+
+++
+
++
+
++
++++
++
++
Olanzapine
+++
++++
0
+++
++
+++
++++
++++
+++
Quetiapine
+
(+)
+++
(++++)
0
(++)
++
(0)
+
(+)
+++
(+++)
++++
(++++)
0
(+++)
0
(+++)
Risperidone
+++
(++++)
++++
(++++)
+
(+)
+++
(++++)
+
(+++)
+++
(+++)
++ (++)
+++
(++)
0
(0)
Ziprasidone
+++
++++
+++
+++
+
++
++
+++
0
Aripiprazole
++++
(p.ag)
+++
++++
++++
+++
+++
+++
+++
0
Paliperidone
++++
++++
+
++++
+++
+++
++
++
0
++
++++
++
+++
+++
+++
+++
++++
0
Iloperidone
++++
++++
+++
+++
+++
+++
++
+++
0
Lurasidone
++++
++++
+++
++++
+++
++
0
+
0
(Norquetiapine)
(Paliperidone)
Asenapine
5HT
7
a2
a1
++++
D2
Clozapine
5HT
1a
+++
H1
5HT
2c
M1
0
+
D2
Clozapine
Olanzapine
Quetiapine
(Norquetiapine)
Risperidone
(Paliperidone)
Ziprasidone
Aripiprazole
Paliperidone
Asenapine
Iloperidone
Lurasidone
++
5HT
2a
5HT
1a
+++
5HT
7
a2
a1
++++
H1
5HT
2c
M1
Metabolic Changes
 Dyslipidemia and hypertriglyceridemia
 pancreatitis
 Hyperglycemia and insulin resistance
 diabetic ketoacidosis
 Increased body weight
 Increased adiposity
Quetiapine Metabolic Effects
low dose (<200mg/day) quetiapine
causes significant weight gain and increase in
 Even
BMI after 52 weeks
Cates ME et al. Metabolic Consequences of Using Low Dose Quetiapine for Insomnia in Psychiatric Patients.
Community Ment Health J. 2009;45:251-4.
Olanzapine in Healthy Volunteers
 10mg nightly x3 days
Albaugh VL, Singareddy R, Mauger D, Lynch CJ (2011) A Double Blind, Placebo-Controlled, Randomized Crossover Study of
the Acute Metabolic Effects of Olanzapine in Healthy Volunteers. PLoS ONE 6(8): e22662.
 15 healthy subjects given 10mg po olanzapine or placebo
(self-control)
 Results:
 decrease in glucose effectiveness, free fatty acids,
and serum cortisol
 increase in fasting glucose and prolactin
Hahn MK. et al. J Clin Psychopharmacol 2013; 33(6):740-6.
Newer Agents: Metabolic Profiles
CNS Drugs 2012. 26(9):733-59.
*
Aripiprazole Monotherapy
Aripiprazole + Low/Non-Serotonergic Antidepressant (ex. bupropion)
Aripiprazole + Highly Serotonergic Antidepressant (ex. SSRI)
4
3
2
1
0
-1
Six-Month Weight
change (lb)
Six-Month BMI
change (kg/m2)
Data from: Nguyen CT et al. Prim Care Comp CNS Disord 2012;12(5).
Metabolic Changes
• clozapine
• olanzapine
•
•
iloperidone
quetiapine
• asenapine
• paliperidone
• aripiprazole*
• lurasidone
• ziprasidone
•
risperidone
0
+
D2
Clozapine
Olanzapine
Quetiapine
(Norquetiapine)
Risperidone
(Paliperidone)
Ziprasidone
Aripiprazole
Paliperidone
Asenapine
Iloperidone
Lurasidone
++
5HT
2a
5HT
1a
+++
5HT
7
a2
a1
++++
H1
5HT
2c
M1
Extra Pyramidal Symptoms (EPS)
DA
 Dystonia
 Parkinsonism
 Tardive Dyskinesia
ACh/5HT
_______________________________________________
DA
 Akathisia
NE/5HT
Parkinsonism
• risperidone
• paliperidone
• olanzapine
• ziprasidone
• lurasidone
• asenapine
• iloperidone
• aripiprazole
• quetiapine
• clozapine
Akathisia
• ziprasidone
• lurasidone
• asenapine
• aripiprazole
• risperidone
• paliperidone
• iloperidone
• olanzapine
• quetiapine
• clozapine
Poyurovsky M. BJP 2010;196:89-91.
0
+
D2
Clozapine
Olanzapine
Quetiapine
(Norquetiapine)
Risperidone
(Paliperidone)
Ziprasidone
Aripiprazole
Paliperidone
Asenapine
Iloperidone
Lurasidone
++
5HT
2a
5HT
1a
+++
5HT
7
a2
a1
++++
H1
5HT
2c
M1
Hyperprolactinemia
 Gynecomastia
 Amenorrhea
 Breast tenderness
 Sexual dysfunction
 Galactorrhea
Hyperprolactinemia
• risperidone
• paliperidone
• lurasidone
• olanzapine
• ziprasidone
• quetiapine
• iloperidone
• asenapine
• clozapine
• aripiprazole
Peuskens J et al. CNS Drugs 2014. PMID 24677189
0
+
D2
Clozapine
Olanzapine
Quetiapine
(Norquetiapine)
Risperidone
(Paliperidone)
Ziprasidone
Aripiprazole
Paliperidone
Asenapine
Iloperidone
Lurasidone
++
5HT
2a
5HT
1a
+++
5HT
7
a2
a1
++++
H1
5HT
2c
M1
Sedation
• clozapine
• quetiapine
• olanzapine
• asenapine
• iloperidone
• risperidone
• aripiprazole
• ziprasidone
• paliperidone
• lurasidone
0
+
D2
Clozapine
Olanzapine
Quetiapine
(Norquetiapine)
Risperidone
(Paliperidone)
Ziprasidone
Aripiprazole
Paliperidone
Asenapine
Iloperidone
Lurasidone
++
5HT
2a
5HT
1a
+++
5HT
7
a2
a1
++++
H1
5HT
2c
M1
What do you think?
 Based upon receptor binding, which agent may be
expected to be associated with constipation, urinary
retention, and blurred vision?
 Clozapine
D2
 Asenapine
 Ziprasidone
 Iloperidone
Clozapine
Olanzapine
Quetiapine
(Norquetiapine)
Risperidone
(Paliperidone)
Ziprasidone
Aripiprazole
Paliperidone
Asenapine
Iloperidone
Lurasidone
5HT
2a
5HT
1a
5HT
7
a2
a1
H1
5HT
2c
M1
Anticholinergic Effects
 Urinary retention
 Constipation
 Tachycardia
 Blurred vision
 Dry mucous membranes
 Flushing
 Confusion and delirium
 Blind as a bat
 Dry as a bone
 Red as a beet
 Mad as a hatter
Anticholinergic Effects
• clozapine
• olanzapine
• quetiapine
•
•
•
•
risperidone
paliperidone
asenapine
lurasidone
•
•
•
iloperidone
ziprasidone
aripiprazole
Orthostasis and Dizziness
 Reduces sympathetic tone and decreases peripheral
vascular resistance
 Especially in elderly patients and those on diuretics
Orthostatic Hypotension and
Dizziness
• clozapine
• quetiapine
• iloperidone
• risperidone
• paliperidone
• asenapine
• olanzapine
• ziprasidone
• lurasidone
• aripiprazole
QTc Prolongation
Torsades de Pointes
Beach et al. Psychosomatics 2013:54:1–13
Neilsen et al. CNS Drugs 2011;25(6):473-90.
Potkin et al. J Clin Psychopharmacol 2013;33: 3Y10
Watanabe et al. J Clin Psychopharmacol 2012;32: 18Y22
QTc Prolongation
• ziprasidone
• iloperidone
• paliperidone
•
•
•
asenapine
clozapine
olanzapine
• aripiprazole
•
•
•
lurasidone
quetiapine
risperidone
Predict which
antipsychotics
may be more, or
less, desirable in
various patient
scenarios
Diabetes, Obesity or Metabolic
Syndrome
Usually Weight Neutral
 Aripiprazole
(except with 5HT antidepressants)
 Lurasidone
 Ziprasidone
Most Weight Gain
 Clozapine
 Olanzapine
 Quetiapine
Parkinson’s Disease or History of
Extra Pyramidal Symptoms (EPS)
Less likely to
cause EPS
 Clozapine
 Quetiapine
More EPS
 Parkinsonism and
Dystonia
 Risperidone
 Paliperidone
 Akathisia
 Aripiprazole
 Lurasidone
 Asenapine
 Ziprasidone
Orthostatic Hypotension, Dizziness,
or Recurrent Falls
Highest Risk
Lower Risk
 Clozapine
 Aripiprazole
 Risperidone
 Lurasidone
 Iloperidone
 Ziprasidone
 Quetiapine
Insomnia
More Sedating
Less Sedating
 Quetiapine
 Aripiprazole
 Clozapine
 Ziprasidone
History of Hyperprolactinemia or
Concerns About it’s Occurrence
More
Hyperprolactinemia
Less
Hyperprolactinemia
 Risperidone
 Clozapine
 Paliperidone
 Aripiprazole
 Iloperidone
 Asenapine
 Quetiapine
History of Ventricular Arrhythmias
More likely to
prolong QTc
Less likely to
prolong QTc
 Ziprasidone
 Aripiprazole
 Iloperidone
 ?Lurasidone
Will adjusting the dose fix the
problem?
Dose related
effects
 EPS
 Sedation
 Amenorrhea
 Agitation
 Activation
Non-dose related
effects
 Weight gain
 Metabolic changes
Sedation
Weight
gain
Parkisonism
Akathisia
QTc
prolongation
Hyperprolacti
nemia
Orthostatic
hypotension
Anticholinergic
effects
Aripiprazole
+
+ (+++)
++
+++++
+
+
+
+
Asenapine
++++
++
++
+++++
+++
++
+++
+
Clozapine
+++++
+++++
+
+
+++
+
+++++
+++++
Iloperidone
++
+++
++
++
+++++
++
+++++
+
Lurasidone
+++
+
++++
+++++
++
+++
+
+
Olanzapine
++++
+++++
+++
++
++
+++
+++
+++
Paliperidone
++
+++
+++++
+++
++++
+++++
++++
+
Quetiapine
+++++
+++
+
+
+++
++
+++++
+++
Risperidone
++
+++
+++++
++++
+++
+++++
++++
+
Ziprasidone
+++
+
+++
+++++
+++++
+++
+
+
Take Home Points
 D2 antagonism = ↓ positive symptoms
 EPS (ex. parkinsonism, dystonia) = high D2 antagonism
 Risperidone, paliperidone
 5HT2a antagonism = ↓ EPS
 may help with (or not exacerbate) negative and cognitive symptoms
 Histamine1, alpha1, and muscarinic antagonism = side effects
 Quetiapine, clozapine, and olanzapine
 5HT2c + H1 antagonism = metabolic dysregulation & weight gain
 Olanzapine, clozapine
 Effects of binding 5HT1a, 5HT7, alpha2a, and alpha2c are still not
fully understood but felt to contribute to efficacy
Thank you!!