To explain pathogenesis of Schizophrenia To classify antipsychotic drugs To describe mechanism of action of antipsychotics To enlist side effects of antipsychotic drugs. Atypical antipsychotics have mixtures of pharmacological properties. Beyond antagonism of 5HT2A and D2 receptors, they interact with multiple other receptor subtypes for both dopamine and serotonin, and have effects on other neurotransmitter systems as well. Some of these multiple pharmacological properties can contribute to the therapeutic effects of atypical antipsychotics (e.g., antidepressant, antimanic, and anxiolytic effects), whereas others can contribute to their side effects (e.g,. sedative-hypnotic and cardiometabolic effects). No two atypical antipsychotics have identical binding properties, which probably helps to explain why they all have distinctive clinical properties.

1. 3rd Year
Neurosciences II
Antipsychotics
Fazaia Ruth Pfau Medical College
Department of Pharmacology 1

2. Objectives:
 To explain pathogenesis of Schizophrenia
 To classify antipsychotic drugs
 To describe mechanism of action of antipsychotics
 To enlist side effects of antipsychotic drugs.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 2

3. Antipsychotic
drugs
Typical
PHENOTHIAZINES
BUTYROPHENONE
Atypical
Diabenzodiazipine:
CLOZAPINE
Theinobenzodiazipine:
OLANZAPINE
Diabenzothiazipine:
QUETIAPINE
Benzisoxazole:
RESPERIDONE
Dihydroindolone:
ZIPRASIDONE
Dihydrocarbostyril:
ARIPIPRAZOLE
Fazaia Ruth Pfau Medical College
Department of Pharmacology
3
Classification

4. Typical & Atypical antipsychotics and D2 & 5HT2A
receptors
Atypical antipsychotic
drugs are effective at lower
occupancy of 30-50% -
because of concurrent high
occupancy of striatal 5HT2A
receptors.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 4
EPS when
occupancy of
striatal D2
receptors reach
80% or more.
Typical Antipsychotics are
COMPETITIVE antagonists
D2 dopamine receptor
Typical antipsychotic
drugs must be given in
sufficient doses to
achieve 60% occupancy
of striatal D2 receptors.

5. Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 5

6. D2 partial agonism render an
antipsychotic atypical - may stabilize
dopamine neurotransmission in a state
between silent antagonism and full
stimulation.
Partial agonists have the intrinsic ability
to bind receptors in a manner that
causes signal transduction from the
receptor to be intermediate between full
output and no output.
Thus, many degrees of partial agonism
are possible between two extremes.
Full agonists, antagonists, and partial
agonists may cause different changes
in receptor conformation.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 6
Typical VS Atypical and diversity in Atypical

7. Atypical antipsychotics have mixtures of
pharmacological properties.
Beyond antagonism of 5HT2A and D2 receptors, they
interact with multiple other receptor subtypes for
both dopamine and serotonin, and have effects on
other neurotransmitter systems as well.
Some of these multiple pharmacological properties
can contribute to the therapeutic effects of atypical
antipsychotics (e.g., antidepressant, antimanic, and
anxiolytic effects), whereas others can contribute to
their side effects (e.g,. sedative-hypnotic and
cardiometabolic effects).
No two atypical antipsychotics have identical
binding properties, which probably helps to explain
why they all have distinctive clinical properties.
Atypical antipsychotic binding properties.
Serotonin and/or
norepinephrine reuptake
inhibition – quetiapine
has potency greater
than its D2 binding
Atypical antipsychotics
(aripiprazole & cariprazine) have
greater efficacy for nonpsychotic
mania.
Potent antihistamine actions
Clozapine, Quetiapine,
Olanzapine Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 7

8. Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 8
(3) Nigrostriatal pathway - Substantia Niagra to corpus
striatum, coordination of voluntary movements ,
accounts for 75% of Dopamine in brain, + D2 receptor blockade
is responsible for extra pyramidal symptoms. This pathway is
involved in movement regulation. Remember that
dopamine suppresses acetylcholine activity.
Dopamine hypoactivity can cause Parkinsonian
movements i.e. rigidity, bradykinesia, tremors),
akathisia and dystonia.
(1) Mesolimbic – Ventral tegmental
area to nucleus accumbens.
Increased activity in this pathway may
cause delusions, hallucinations, and
other so-called positive symptoms of
schizophrenia. Problem here in a
psychotic patient is there is too much
dopamine.
(2) Mesocortical pathway -
Ventral tegmental area to
cortex. Decreased activity in
can cause apathy,
withdrawal, lack of
motivation and pleasure,
and other so-called negative
symptoms of schizophrenia.
Mesocortical dysfunction also
disinhibits the mesolimbic
pathway. Problem here for a
psychotic patient, is too
little dopamine.
(4) Tuberoinfundibular system
- hypothalamus to pituitary
gland, inhibits prolactin secretion
from anterior pituitary.
Area postrema (to vomit centre in
reticular formation)
Incertohypothalamic pathway -
descending pathways originating in
hypothalamus

9. Fazaia Ruth
Pfau Medical
College
9
Administration of D2 antagonist - conventional
antipsychotic, blocks dopamine, which reduces
hyperactivity in this pathway and thereby reduces
positive symptoms.
SCHIZOPHRENIA
UNTREATED
TREATED
Mesolimbic dopamine pathway and D2 antagonists.
In untreated schizophrenia, mesolimbic
dopamine pathway is hyperactive.
This leads to positive symptoms such as
delusions and hallucinations.
Department of Pharmacology

10. If D2 receptors in mesolimbic
system are blocked, then it also
block reward mechanisms,
leaving patients apathetic,
anhedonic, lacking motivation,
interest, and joy from social
interactions, like negative
symptoms of schizophrenia.
Antipsychotics also block D2
receptors in meso-cortical DA
pathway where it is already
deficient in schizophrenia
This worsen negative and
cognitive symptoms.
Typical antipsychotics can cause
“neuroleptic induced deficit
syndrome” as it is like negative
symptoms produced by
schizophrenia.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 10

11. In untreated schizophrenia, the mesocortical dopamine pathways to DLPFC and to VMPFC
are hypoactive resulting in cognitive symptoms of DLPFC, affective symptoms of VMPFC
AND negative symptoms due to both.
Administration of a D2 antagonist could further reduce activity in this pathway and thus
potentially worsen them.
Mesocortical dopamine pathway and D2 antagonists.
Dorsolateral prefrontal cortex Ventromedial prefrontal cortex
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 11

12. Fazaia Ruth Pfau Medical College
Department of Pharmacology
12
Blockade of D2 receptors with a conventional antipsychotic, prevents
dopamine from binding there and can cause motor side effects that
are often collectively termed extrapyramidal symptoms (EPS).
Nigrostriatal dopamine pathway and D2 antagonists.
This pathway is unaffected in untreated schizophrenia.
Long-term blockade of D2 receptors in
nigrostriatal dopamine pathway cause
upregulation of receptors, which lead
to a hyperkinetic motor condition -
tardive dyskinesia tongue
protrusions, facial grimaces, chewing
as well as quick, jerky limb
movements.
Tardive dyskinesia.

13. D2 antagonists reduce activity in
this pathway.
This causes prolactin levels to
rise, which is associated with
side effects such as
galactorrhea & irregular
menstrual periods.
Tuberoinfundibular dopamine pathway and D2 antagonists.
This pathway projects from
hypothalamus to pituitary
gland, is “normal” in
untreated schizophrenia.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 13

14. Reciprocal relationship of Dopamine and Acetylcholine in the nigrostriatal dopamine pathway
Dopamine neurons make postsynaptic connections
with the dendrite of a cholinergic neuron.
Normally, dopamine suppresses acetylcholine
activity.
Antagonism of D2 receptors on the cholinergic
dendrite, results in acetylcholine excess.
This produces extrapyramidal symptoms (EPS) due
to relative dopamine deficiency and a relative
acetylcholine excess.
D2 antagonism and anticholinergic agents: Anticholinergics
overcome excess acetylcholine activity caused by removal of
dopamine inhibition when dopamine receptors are blocked by
conventional antipsychotics and reduces extrapyramidal symptoms
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 14

15. (1) Serotonin is released in the cortex and binds
to 5HT2A receptors 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. GABA
binds to dopaminergic neurons projecting
from the substantia nigra to the striatum,
inhibiting dopamine release.
Cortical 5HT2A receptors decrease dopamine release.
Their blocking will ↑ dopamine release
from substantia nigra into striatum.
5HT2A are located in many brain regions and are postsynaptic.
On cortical pyramidal neurons, they are excitatory & ↑
downstream glutamate release.
5HT2A receptors are the key to understand atypical antipsychotics.
5HT2A receptors are brakes on dopamine release in the Striatum. 5HT2A antagonism cuts this brake cable.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 15

16. Nigral and striatal 5HT2A receptor stimulation decreases dopamine release
Blocking nigral and striatal 5HT2A
receptors increases dopamine
release.
5HT2A receptor stimulation by
serotonin at either end of
substantia nigra neurons
hypothetically blocks dopamine
release in the striatum
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 16

17. Cortical 5HT1A receptor stimulation
↑ dopamine release.
5HT projections from raphe nucleus to cortex
also make axoaxonic connections with
glutamatergic pyramidal neurons.
(1) Serotonin released at these synapses
can bind to 5HT1A receptors, which
causes inhibition of the glutamatergic
neuron.
(2) If glutamate is not released from
glutamatergic pyramidal neurons into
brainstem, then GABA release is not
stimulated and in turn cannot inhibit
dopamine release from substantia nigra
into striatum.
Cortical 5HT1A receptor stimulation is
functionally analogous to cortical 5HT2A
receptor blockade, in that both lead to
increased dopamine release in the
striatum.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 17

18. Serotonin binding to 5HT1A receptors in
the raphe nucleus inhibits serotonin
release.
(1) In the striatum, reduced serotonin
release means that 5HT2A receptors on
GABAergic & dopaminergic neurons are
not stimulated, which in turn means that
dopamine release is not inhibited.
(2) Similarly, in the brainstem, reduced
serotonin release means that 5HT2A
receptors on GABAergic interneurons
are not stimulated and therefore GABA is
not released. Thus, dopamine can be
released into striatum.
Raphe 5HT1A receptor stimulation increases dopamine release.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 18

19. Normally, 5HT inhibits DA release
Antagonist of 5HT2A receptor disinhibits
dopamine neuron, causing dopamine
release.
Thus dopamine compete with SDA for D2
receptor & reverse inhibition there. As D2
blockade is thereby reversed, SDAs cause
little or no extrapyramidal symptoms (EPS)
or tardive dyskinesia
5HT2A receptor antagonism
makes an antipsychotic
atypical: low EPS
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 19

20. Dopamine inhibits prolactin
release from pituitary gland when it
binds to D2 receptors (red circle).
Serotonin (5HT) stimulates prolactin
release from pituitary gland when it binds to
5HT2A receptors (red circle).
Conventional antipsychotic drugs are D2
antagonists and thus oppose dopamine’s
inhibitory role on prolactin secretion
As dopamine and serotonin have reciprocal
regulatory roles in the control of prolactin
secretion, one cancels the other. Thus,
stimulating 5HT2A receptors reverses the effects
of stimulating D2 receptors.
5HT2A receptor
antagonism makes
an atypical
antipsychotic : low
hyperprolactinemia
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 20

21. The mesolimbic and mesocortical pathways, which are
responsible for positive and negative symptoms, may
be involved in aggression and violence. Agents
targeting much more than 60% D2 receptor occupancy
in these pathways could reduce these symptoms.
Orbitofrontal cortex and amygdala play a role in
impulsive aggression, which could be relieved by
targeting much more than 60% D2 receptor occupancy.
Affective symptoms may contribute to violent behavior
are mediated by ventromedial prefrontal cortex and
could potentially be treated with mood stabilizers.
Finally, instrumental aggression and violent sociopathy
may be mediated by dorsolateral prefrontal cortex, and
may best be managed with behavioral strategies,
including seclusion and incarceration.
Psychopharmacologic targeting of circuits associated with violence.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 21

22. NMDA receptors require presence of both
glutamate and a coagonist at glycine site in
order to be fully active. Hence agonists at
glycine coagonist site may enhance NMDA
functioning.
The glycine transporter 1 terminates actions of glycine at
NMDA receptors in glutamate synapse by transporting
glycine back up into glial cells as a reuptake pump.
Inhibitors at GlyT1 would increase availability of
synaptic glycine, enhancing activity at NMDA receptors.
Schizophrenia is linked to hypoactive NMDA receptors.
Glycine agonists OR GlyT1 inhibition may thus be promising future treatments for
negative and cognitive symptoms of schizophrenia without worsening positive symptoms.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 22

23. Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 23
AT FIRST anti
psychotic drugs
cause an
increase in
dopamine
synthesis,
release, and
metabolism.
A response to
acute blockade
of postsynaptic
dopamine
receptors.
Over time, continued
dopamine receptor
blockade leads to
inactivation of
dopaminergic neurons
which results in
reduced dopamine
release from
mesolimbic &
nigrostriatal neurons
and alleviate the
positive symptoms of
schizophrenia while
causing EPSs.
Lastly the reduction
in dopamine release
caused by
depolarization
blockade leads to
dopamine receptor
up-regulation and to
dopamine agonists.
This super sensitivity
may contribute to the
development of a
delayed type of EPS
called tardive
dyskinesia.
Whereas these receptors are blocked immediately when antipsychotic
drugs are first administered, therapeutic effects usually require
several weeks to fully develop.
This is because antipsychotic drugs produce three time-dependent
changes in dopamine neurotransmission.
Pharmacologic Effects

24. Mechanisms Responsible for the Therapeutic and Adverse Effects of Antipsychotic Drugs
* .
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 24
MECHANISM THERAPEUTIC EFFECTS ADVERSE EFFECTS
Blockade of α1 -adrenoceptors — Dizziness, orthostatic hypotension, and
reflex tachycardia
Blockade of dopamine D2 receptors Alleviation of positive symptoms of
schizophrenia
Extrapyramidal effects (akathisia,
dystonia, and pseudoparkinsonism) and
elevated serum prolactin levels
Blockade of dopamine D4 receptors Alleviation of negative symptoms of
schizophrenia and decrease in the
incidence of extrapyramidal side
effects
—
Blockade of histamine H1 receptors Sedation may be considered a
therapeutic effect with a typical
antipsychotic administered for acute
psychosis
Drowsiness and increase in appetite
and weight
Blockade of muscarinic receptors — Blurred vision, constipation, dry
mouth, and urinary retention
Blockade of serotonin 5-
HT2 receptors
Alleviation of negative symptoms of
schizophrenia and decrease in the
incidence of extrapyramidal side
effects
Anxiety and insomnia

25. Antipsychotic adverse effects
 Tardive Dyskinesia (TD)-involuntary muscle movements that may not resolve
with drug discontinuation- risk approx. 5% per year
 Neuroleptic Malignant Syndrome (NMS): Characterized by severe muscle
rigidity, fever, altered mental status, autonomic instability, elevated WBC,
CPK and fits. Potentially fatal.
 Extrapyramidal side effects (EPS): Acute dystonia, Parkinson syndrome,
Akathisia
Effects due to
 alpha adrenoceptors blockade.
 muscuranic cholinoceptor blockade
 endocrine & metabolic disturbances: galactorrhea, loss of libido &
gynaecomastia
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 25

26. Haloperidol
 High potency & widely used.
 Highly lipid soluble & protein bound (92-
99%). They have large volume of
distribution(usually more than 7 L/kg).
 Extensively metabolized by liver -
bioavailability of about 65% after an oral
dose and excreted in urine.
 Has longer clinical duration of action as is
evident from plasma half life.
 It has fewer autonomic effects but greater
extra pyramidal effects
Clozapine (Clozaril)
 First of the new generation of
antipsychotics. (Atypical)
 Decreased risk of extra pyramidal effects &
effective for negative symptoms of
Schizophrenia.
 Associated with agranulocytosis (0.5-2%)
and therefore requires weekly blood draws
x 6 months)
 Associated with the most sedation, weight
gain and Increased liver enzymes
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 26

27. Risperidone (Risperdal)
 Available in regular tabs, IM depot forms
and rapidly dissolving tablet
 Functions more like atypical
antipsychotic.
 Increased extrapyramidal side effects
(dose dependent)
 Weight gain, less sedation & orthostatic
hypotension.
 Most likely atypical to induce
hyperprolactinemia
 It also lengthens QT interval and
predispose patients to cardiac
arrhythmias.
Quetiapine (Seroquel)
 Available in a regular tablet form
only
 May cause Increased level of liver
enzymes - 6% of all patients.
 May be associated with weight gain,
though less than seen with
olanzapine
 May cause hypertriglyceridemia,
hypercholesterolemia, hyperglycemia
(even without weight gain), however
less than olanzapine
 Most likely to cause orthostatic
hypotension
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 27

28. Aripiprazole’s unique binding profile.
Aripiprazole differs from most other
antipsychotics in that it is a partial
agonist at D2 receptors rather than an
antagonist. Additionally it is 5HT2A
antagonist actions, 5HT1A partial agonist
actions, and 5HT7 antagonist actions.
Aripiprazole has weak binding
potency at receptors associated with
sedation & also lack associated with
weight gain and increased
cardiometabolic risk, such as
increasing fasting plasma
triglyceride levels or increasing
insulin resistance.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 28

29. Monitoring on the metabolic highway.
First, increased appetite and weight gain can lead to
elevated body mass index (BMI) and ultimately
obesity.
Second, atypical antipsychotics can cause insulin
resistance by an unknown mechanism; this can be
detected by measuring fasting plasma triglyceride
levels.
Finally, atypical antipsychotics can cause sudden
onset of diabetic ketoacidosis (DKA) or
hyperglycemic hyperosmolar syndrome (HHS) by
unknown mechanisms, possibly including blockade
of M3-cholinergic receptors. This can be detected by
informing patients of the symptoms of DKA/HHS and
by measuring fasting glucose levels.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 29

30. Take home points
 Be clear on the diagnosis you are treating
and any comorbid diagnoses when you are
selecting an agent to treat- often can get 2
birds with 1 stone!
 Select the agent based on patients history,
current symptom profile and the side effect
profile of the medication- there is no one
correct answer in most cases.
 Monitor for efficacy and tolerance and
adjust as indicated.
 If the patient does not improve step back,
rethink your diagnosis and treatment plan!
 Keep an eye on drug-drug interactions
Sulaiman
AlRajhi
Colleges
Department of Pharmacology 30
1. Basic & Clinical Pharmacology by Katzung 13th
edition.
2. Rang & Dale Pharmacology 8th edition.
3. Pharmacology by Brenner 3rd edition.
4. Board review series Pharmacology 5th edition.
5. Netters Pharmacology.
6. Stahl’s Psychopharmacology 4th edition.