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Antipsychotics

Corina Freitas MS, MD, MBA, DABFM

Little bit of History

1891
o Paul Ehrlich - methylene blue (antimalarial phenothiazine): psychosis and

anti-nausea

1952
o Chlorpromazine - anesthetic, antihistaminic (anti-nausea)
o Reserpine antihypertensive (alpha blockade) with NE, DA and 5-HT

blockade, HIGHLY cholinergic not used anymore

1957-1958
o TCAs and MAOIs

1958
o Clozapine synthesized

1971
o Clozapine in practice

1972
o Lithium

1988
o Risperidone

Figure 5-1.Qualitative and semiquantitative representation of


receptor binding properties.
(Stahls Essential Psychopharm. 4 th
Ed.)

Conventional
Antipsychotics

Conventional
Antipsychotics

Low Potency
o Chlorpromazine (Thorazine)
o Prochlorperazine (Compazine)
o Thioridazine* (Mellaril)
o Mesoridazine* (Serentil)

*QTc issues

Conventional
Antipsychotics

High Potency
o Haloperidol (Haldol)
o Fluphenazine (Prolixin)
o Pimozide* (Orap)
o Thiothixene (Navane)
o Perphenazine (Trilafon)
o Trifluoperazine (Stelazine)
*QTc issues

Conventional
Antipsychotics

With atypical features


o Cyamemazine (Tercian)
o Loxapine (Loxitane)
o Sulpiride (Dolmatil)

*QTc issues

Mode of Action

Fig. 5-9 Stahls Essential Psychopharm. 4th Ed

Mode of Action

D2 blockade in the
mesolimbic pathway
reduces hyperactivity
and positive symptoms
Blockade needed for
antipsychotic effects
about 80%
If greater than 80% spillover into dorsal striatum
resulting in EPS; and in
the pituitary
hyperprolactinemia.
high cost of business
spillage in other
Fig. 5-3 Stahls Essential Psychopharm. 4th Ed
pathways (see Cost)

Mode of Action

Muscarinic M1-cholinergic receptors blockade


o dry mouth, blurred vision, constipation, and cognitive

blunting
o Protective against EPS (not TD) in Nigrostriatal pathway:
Dopamine usually block Ach release, so dopamine Blockade
increases Ach -> EPS; if M1 is blocked Ach cannot act -> no
or less EPS.
o Agents with weak M1 blockade -> higher EPS

Mode of Action

Histamine H1blockade
o weight gain and drowsiness

1-adrenergic blockade
o orthostatic hypotension and drowsiness

Cost

D2 receptors moderate positive symptoms AND


pleasure center thus blockade will lead to
neurolepsis (apathy, anhedonia, avolition,
reclusion - negative symptoms)

Paradoxically despite blocking the pleasure


reward center neurolepsis may increase drug
abuse.

Cost

Mesocortical blockade - worsen negative and


cognitive symptoms
Nigrostriatal Parkinsonism, EPS and TD (5%
young, 25% elderly), possible NMS
Tuberoinfundibular blockade hyperprolactinemia

Chlorpromazine

CNS: D2 blocker
o EPS, antiemetic, anti-psychosis
o Lowers seizure threshold because Na channel block ->

anesthesia
o Impairs hypothalamic temperature control at high doses
-> poikilothermia (body temp drops when room temp
drops)

ANS: H1, 5HT and alpha-1


o Orthostatic hypotension, reflex tachycardia, arrhythmias
o Anticholinergic sx

Weak diuretic
o Vasopressin inhibitor

Haloperidol

Blocks D2, positive symptoms of psychosis and


possibly combative, explosive, and hyperactive
behaviors
Blocks D2 in the nigrostriatal pathway, improving
tics and other symptoms in Tourettes syndrome
Addition of a mood-stabilizing anticonvulsant may
help in both schizophrenia and bipolar mania
Augmentation with lithium in bipolar mania may
be helpful
Addition of a benzodiazepine, especially shortterm for agitation

Loxapine

D2 blocker reducing (by 1/3) positive symptoms


-> plateau
Potent 5HT2a blocker at low doses ONLY
Very low weight gain
HIGH EPS

FGA SE Profile

https://www.uspharmacist.com/article/metabolic-effects-of-atypical-

Atypical
Antipsychotics

List

Aripiprazole (Abilify)
Asenapine (Saphris)
Clozapine (Clozaril FazaClo)
Iloperidone (Fanapt)
Lurasidone (Latuda)
Olanzepine (Zyprexa)
Quetiapine (Seroquel)
Paliperidone (Invega)
Risperidone (Risperdal)
Zisprasidone (Geodon)
Cariprazine (Vraylar)

What makes them atypical?

Fig. 5-12 Stahls Essential Psychopharm. 4th Ed

5-HT production

Fig. 5-13 Stahls Essential Psychopharm. 4th Ed.

5-HT destruction

g. 5-14 Stahls Essential Psychopharm. 4th Ed.

Link to
Depressio
n

5HT2A functions
Cortical neurons
(1)Serotonin is released in the
cortex and binds to
5HT2Areceptors on
glutamatergic pyramidal
neurons, causing activation of
those neurons.
(2)Activation of glutamatergic
pyramidal neurons leads to
glutamate release in the
brainstem, which in turn
stimulates GABA release.
(3)GABA binds to dopaminergic
neurons projecting from the
substantia nigra to the
striatum, inhibiting dopamine
release (indicated by the
Figure 5-15 Stahls Essential
dotted outline of the
Psychopharm. 4th ED.

5HT2A
(1) In the striatum, serotonergic
projections synapse directly with
dopaminergic neurons and indirectly
via GABAergic neurons. At GABAergic
neurons, serotonin binding to
5HT2Areceptors disinhibits GABA
release, which in turn decreases
release of dopamine (indicated by
the dotted outline of the
dopaminergic neuron). Similarly,
when serotonin binds to
5HT2Areceptors directly on dopamine
neurons, this causes a decrease in
dopamine release.
(2) Serotonin can also decrease
dopamine release in the striatum via
5HT2Abinding in the brainstem. That
is, serotonin released in the raphe
nucleus binds to 5HT2Areceptors on
GABAergic interneurons. This causes
GABA to be released onto

Understanding 5HT2A

Post-synaptic neurons, EXCITATORY


o Cause downstream glutamate release, which in turn

causes downstream dopamine is inhibited


o Blocking 5-HT2A -> increase in dopamine -> low EPS
as this dopamine competes with D2 receptors and
decrease blockade to about 60% enough to reduce EPS
and hyperprolactinemia, this creates therapeutic
window.

Understanding 5HT1A

Post-synaptic cortical and pre-synaptic raphe


nuclei neurons INHIBITORY
o Activating 5HT1A results in glutamate inhibition in turn

dopamine is released.
o Blocking 5HT1A -> decreases dopamine

5HT1Areceptorstimulationis functionally
analogous to cortical 5HT2Areceptorblockade

antipsychotics

Figure 5-24.5HT2Abinding by atypical


antipsychotics

Figure 5-26.5HT1Abinding by atypical

Binding profiles

Other 5HT receptors

5HT1B/D presynaptic, autoreceptors, decrease 5HT


o iloperidone, ziprasidone andasenapine -> may have

antidepressant benefits
o Weak - olanzapine, quetiapine, and aripiprazole

5HT2C postsynaptic suppress DA and NE release


o Suppresses DA mesolimbic > nigrostriatal (NO EPS??!!!!)
o Vabacaserin abandoned in trials
o Lorcaserin obesity medication
o TCAs block it
o Quetiapine and Olanzepine
o Fluoxetine
o Asenapine (weak)

Other 5HT receptors

5HT3postsynaptic and release inhibitory GABA ->


blocking 5HT, Ach, NE, DA, and HT.
o CTZ -> nausea and vomiting
o Peripherally in the gut regulate bowel motility
o Clozapine (very strong)

5HT6postsynaptic may regulator Ach release


o clozapine,olanzapine, asenapine (strong)

5HT7postsynaptic autoreceptors (raphe and in the


prefrontal cortex). When blocked, serotonin is
released.
o TCAs and many atypicals

Other receptor profiles

D2 partial agonism

Partial agonists have the ability to bind receptors


so that causes release to be in between full
output and no output
In the process
Aripiprazole 1st attempt
Cariprazine (Vraylar) 2015

Side effect profile of common


atypicals

From St. Elizabeths Medication Guidelines 2013

Clozapine an atypical atypical

modest affinity
D1,D2 &D3, D5
High for D4
affinity for 5HT2A&H1
M1, H1, alpha1
Few EPS, no TD and
no hyperprolactin
Decreases suicide
Therapeutic: 300-450
Max dose: 900/day

Side effects

agranulocytosis, in 0.52% of patients


increased risk of seizures (dose dependent, need
Depakote above 450mg/day)
very sedating (M1, H1, and 1)
excessive salivation (profound muscarinic block)
Ileus (muscarinic block)
Myocarditis
Greatest degree of weight gain (unknown
mechanism)

Example Titration
Schedule

Doses can be increased with daily


dosage increments of 25 to 50
mg/day, if well tolerated, to
achieve a target dose of 300 to
450 mg/day by the end of 2
weeks.
After Week 2, subsequent dosage
increments should be made no
more than once or twice weekly,
in increments not to exceed
100 mg.
Cautious titration and a divided
dosage schedule are necessary to
minimize the risks of hypotension,
seizure, and sedation.
If skipped dose >24hr restart
Source: Teva Clozapine Package
Insert.

St. Elizabeths Medication


Guidelines, 2013

Olanzapine

oral disintegrating
tablet
acute intramuscular
injection
long-acting 4-week
intramuscular depot

Olanzapine
(Zyprexa)

Chemically related to clozapine but more potent


5HT2A and D2
Little EPS
Sedation, weight gain - M1, H1and 1
No increase in prolactin
Cardiac effects
Used:
o Schizophrenia
o Bipolar
o Resistant Depression (with fluoxetine) likely due to 5HT 2C,

5HT7and 2antagonism

Quetiapine
(Seroquel)

Atypical receptors
(weak D2) + active
metabolite,
Norquetiapine
o NE reuptake

inhibitor
o 5HT7, 5HT2C, and
2antagonism
o 5HT1Apartial

agonist

PO tab: IR and XR
No EPS or incr. PRL

Quetiapine
(Seroquel)

IR: great hypnotic not


antipsychotic
o Short half life occupies 60% of D2

receptors at 300mg but falls off


quick; at 800mg ok for 12 hours.
o Sedating at peak delivery, take at
night, best 50mg

XR: good antipsychotic not


hypnotic
o Slow peak but fast D2 occupancy

at 60% full effect for 24 hours,


best at 800mg
o Not as sedating, but hangover,
take in the am.
o Good antidepressant bipolar and
unipolar at 300mg (5HT 2C and NE)
because of metabolite

Asenapine

Similar to
Mirtazipine but no
antidepressant
properties
Sublingual -> oral
numbness, cannot
drink for 10min
Acute sx
Needs more
studies

Risperidone

Typical at high doses


Approved for children
o irritability in autism (ages

516),
o Bipolar aggression towards
others, self-injury,
tantrums, rapid-cycle (ages
1017)
o schizophrenia (ages 1317)

Depot, PO, ODT, Liquid


PRL
Metabolite: Paliperidone
(renal only), start higher
SR, Depo

Zisprasidone
(Geodon)

Needs 500 cal. Meal


otherwise lower
absorption and
inconsistent effect

Potential
antidepressant
o 5HT2C, 5HT7, 5HT1B/D,

2ant., 5HT1Apartial
agonism, and weak
NE & 5HT reuptake
blockade

Iloperidone

Newer
Orthostasis
Low EPS and
weight
Potential antidepressant

Lurasidone (Latuda)

high affinity D4, 5HT7&5HT2A


Mod. affinity 5HT1A&2
Min. affinity H1 & M1
Effective, no sedation
Min. weight issue
Mod. EPS, if qhs
Needs 500cal meal
GREAT bipolar
antidepressant (5HT7,
5HT1A, & 2)

Aripriprazole (Abilify)

High D2 &D3 partial


Lacks M1 and H1
PO, ODT, IM, Depo x2, Liq
Schizophrenia, Mania,
Schizophrenia (age 13+);
acute mania/mixed mania
(age 10+), & autism
irritability (ages 617)
Augments antidepressants
5HT2B cardioprotective,
less known, MDMA site
Activating -> akathisia

Cariprazine (Vraylar)

D3, 5HT2B, D2, &


5HT1A

Schizophrenia
Acute mania/mixed
of Bipolar I
PO (1.5mg to 6mg)

Side effect profile of common


atypicals

From St. Elizabeths Medication Guidelines 2013