Antipsychotics

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 Outline
• Introduction
• First Generation Antipsychotics
• Second Generation Antipsychotics
• New generation drugs and recent
development
• Summary

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 Objectives
• By the end of this seminar, you will be able to
– Describe the dopamine pathways
– Define antipsychotics
– Distinguish between the different types of drug
classes
– Know how to identify and treat the side effects of
the major drug classes

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 Introduction
• Antipsychotics (previously called neuroleptics
or major tranquilizers) are used primarily to
treat schizophrenia, and other psychotic states.
• They are not curative and do not eliminate the
chronic psychosis or thought disorder, but
often decrease intesnity of the symtpoms, and
permit the patients to function in a supportive
environment

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 Cont’d
• Psychosis: severe psychiatric illness with
serious distortion of thought, behaviour,
capacity to recognize reality and of perception
(delusions and Hallucinations).
– Acute and Chronic organic brain syndromes
(cognititve d/os)
– Functional disorders : - Schizophrenia, paranoid
state

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 Psychosis-Affective disorders
• Mania-elation or irritable mood, reduced sleep,
hyperactivity, uncontrollable though and speech,
may be associated with reckless or violent behaviour
• Depression- sadness, loss of interest and pleasure,
worthlessness, guilt, physical and mental slowing,
melancholia, self-destructive ideation.
• When psychotic features are coupled with any of
these mood disorders, we refer to it as
psychoaffective disorder. Antipsychotics are also
important in managing these.
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 History of antipsychotic drugs
• Have been used in modern medicine for more
than 60 years
• Chlorpromazine (1952) and reserpine were
the first drugs to be used in schizophrenia
– Chlorpromazine, was developed as a surgical
anesthetic. It was first used on psychiatric patients
because of its powerful calming effect.

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• The discovery of chlorpromazine's psychoactive
effects in 1952 led to greatly reduced use of
restraint, seclusion, and sedation in the
management of agitated patients, and also led
to further research that resulted in the
development of antidepressants (1957),
anxiolytics, and the majority of other drugs now
used in the management of psychiatric
conditions.

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 Classification of Antipsychotics
• Chemical Classification : - Phenothiazines,
Butyrophenones, Thioxanthenes…
• Pharmacological classification : -
– First Generation
– Second Generation

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First Generation Anti-psychotics

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 Dopamine Pathways
• Mesolimbic
– Projects from brainstem to limbic areas
– Delusions and hallucinations, disorganized speech
and bizarre behavior
• Mesocortical
– Projects to the frontal lobes
– Maybe involved in the cognitive side effects of
antipsychotics and on the negative symptoms

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• Nigrostriatal
– Projects from the substantia nigra to the basal ganglia
• Innervates the motor and extrapyramidal system
• Side effects are called “extrapyramidal”
• Tuberoinfundibular
– Hypothalamus and projects to pituitary
– Blockade increases the level of prolactin thus leading
to galactorrhea, gynecomastia and amenorrhea

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 Mechanism of Action
• Are competitive inhibitors at a variety of
receptors, but antipsychotic effects reflect
competitive blocking of D2 dopamine
receptors.
– Acetylcholine (muscarinic), histamine and
norepinepherine

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• also called conventional, typical, or traditional
antipsychotics
• More effective against positive symptoms than
negative symptoms

• Can be classified further into low potency and

high potency antipsychotics

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• High potency typicals
– Have a high affinity to D2 receptors
– Have a higher risk for Extrapyramidal Side efffects
– Haloperidol, Pimozide, fluphenazine, thiothixine

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• Low Potency
– Less affinity for the D2 receptors but tend to
interact with nondopaminergic receptors resulting
in more cardiotoxic and anticholinergic adverse
effects including sedation, hypotension
– Chlorpromazine, thioridazine, mesoridazine

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 Therapeutic Uses
• Schizophrenia, schizoaffective disorder
• Bipolar Disorder (Manic depressive illness)
• Tourette’s syndrome
• Prevention of emesis
• Agitated patients

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 Haloperidol

• a typical butyrophenone type antipsychotic

that exhibits high affinity dopamine D2 receptor
antagonism
• Given that antagonism of D2 receptors is more
beneficial on the positive symptoms of
schizophrenia, this characteristic underlies
haloperidol's greater effect on delusions,
hallucinations and other manifestations of
psychosis
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• Preparation
– Oral tablets (not to exceed 30mg/day)
– Lactate injectable solution (IV or IM, not to exceed
20mg day)
– Decanoate injectable (only IM)
• Drug interactions
– Tricyclic antidepressants
– Lithium,
– Anti-arrhythmic drugs (amiodarone)
• It is metabolized in the liver and has a
bioavailability of 60% after PO
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• Side effects
– EPS
– NMS
– Hypotension
– Arrythmia
• Category C for use in pregnancy
• Contraindication
– Preexisting coma, acute stroke
– Severe intoxication with alcohol
– Known cardiac illness
– Known allergy
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 Chlorpromazine
• one of the phenothiazine. Its mechanism of
action is not entirely clear but believed to be
related to its ability as a dopamine antagonist.
It also has antiserotonergic and anti-
histaminergic properties.

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• Preparation : - Tablet and injectable solution
• Metabolised by the liver

• Has bio availability of 20% (due to 1st pass

metabolism)

• Onset 30-60 minutes

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• Drug interactions
– Food and alcohol ingestion simulatenously with
CPZ can reduce its absorption
– Lithium and chronic barbiturates use can cause
increased clearance
– Tricyclic antidepressants can decrease clearance
and hence increase exposure
• Category C for use in pregnancy
• Contraindicated : - in liver disease, coma, drug
intoxication

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 Thioridazine
• typical antipsychotic drug belonging to the
phenothiazine drug group
• previously widely used in the treatment of
schizophrenia and psychosis
• was withdrawn worldwide in 2005 because it
caused severe cardiac arrhythmias (sometimes
still used in our setup)

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• It has a higher side effect profile than other
typical antipsychotics
– Degenerative retinopathy
– Hypotension and cardiotoxicity
– Causes QT prolongation in a dose dependent
manner (even malignant arrhythmia)
• Category C for use in pregnancy

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 Side Effects of
Typical Antipsychotics
• Sedation • Anticholinergic SE
• Headaches • Tardive dyskinesia
• Dizziness • Neuroleptic Malignant
• Diarrhea Syndrome
• Anxiety • QT interval
• Extrapyramidal side prolongation
effects • Seizure
• Weight gain • Thromboembolism

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 Extrapyramidal Side Effects (EPS)
• The inhibitory effects of dopaminergicc neurons
are normally balanced by the excitatory actions
of cholinergic neurons in the striatum. Blocking
dopamine receptors alters this balance, causing
a relative excess of cholinergic influence, which
results in extrapyramidal motor effects
• Akathisia, Dystonia (10%), muscle rigidity,
Pakinson-like symptoms and tardive dyskinesia
(10-20%)
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• Ususally occur within weeks to months of
initiating treatment.
• Most commonly associated with haloperidol
and fluphenazine

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 Treatment
• decreasing the dose of the antipsychotic
• Switching  to an atypical antipsychotics
• Acute dystonia : - Anticholinergic
(diphenhydramine, 50 mg), or artane (1-4 mg
PO BID)
• Akathisia :- Propranolol, 20-40mg TID
• Parkinsonian-like symptoms- artane 2-5mg , 2-
4 times a day
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 NMS
• Life threatening complication that occur at any time
during the course of therapy with dopamine antagonists

• Prevalence 0.02%
• Men are commonly affected than women ; Young
patients than the elderly

• Usually evolve over 24 to72 hours and lasts 10-14days if

untreated

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Clinical manifestation:
• Muscular rigidity, dystonia, akinesia, mutism
obtundation and agitation
• hyperpyrexia, sweating and increase pulse and
blood pressure
Lab finding:
• Increased WBC count, creatinine phosphokinase,
liver enzymes, plasma myoglobulin, myoglobinuria
occasionally associated with renal failure

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 Treatment
• Discontinue the AP
• Supportive mgt (fluid & electrolyte,
antipyretics, monitor vitals closely)
• Dantrolene 10mg/day in divided doses or
Bromocriptine 20-30 mg/day in divided doses
• Wait for at least 2wks and switch to low
potency typical or to the atypical APs

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 TD
• Delayed effect of antipsychotics /usually 6
months/

• Women > men and ; patients over 50 ; and in

those with brain damage
• Common are perioral movements and include
darting, twisting and protruding movements
of the tongue, lip smacking, puckering

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Treatment
• Discontinue, Reduce the dose or change to
atypical (e.g. clozapine)
• vitamin B6 and vitamin E

• Screening for tardive dyskinesia is strongly

recommended at least every 3 to 6 months
• Using antipsychotics when clearly indicated and
using it with the minimum effective dose

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Second Generation/Atypical Antipsychotics

• Also called serotonin-dopamine antagonists (SDAs)

• They’re called atypical because of their improved
side effect profile
– Esp. their lower risk of extrapyramidal side effects (EPS),
• These drugs are used mainly for schizophrenia and
bipolar disorder
– Some can also be used for major depressive disorder

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FDA approved Atypical APs include
 Aripiprazole  Olanzapine
 Asenapine  Paliperidone
 Clozapine  Quetiapine
 Iloperidone  Risperidone
 Lurasidone  Ziprasidone

The common ones in our setting are highlighted in red.

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 • Dopamine = Serotonin
• Dopamine + Psychosis >>
Serotonin
• Dopamine + Psychosis <<<
Serotonin + Dopamine
antagonist
A B • Dopamine + Psychosis +
Serotonin antagonist <
Serotonin + Dopamine
antagonist
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 Mechanism of Action of Atypical APs
Weak Post-synaptic blockade of Dopamine D2
receptors
 Reducing the dopaminergic activity in the Mesolimbic
pathway results in Anhedonic effect. /Decreased
pleasure, motivation and salience of one’s life
experiences./
 In the Mesocortical pathway ; cognitive, affective and
negative symptoms of schizophrenia.
 Nigrostriatal pathway ; extrapyramidal side effects
 Tuberoinfundibular pathway ; hyperprolactinemia
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Potent Serotonin 5HT2 receptor blockade

• Minimizes the effects the weak D2 receptor

blockade symptoms.

• But all Atypical APs have unique receptor

affinity and interaction

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 Clozapine

• The first Atypical agent

• Is an antagonist of 5-HT2A, D1, D3, D4, and a
(especially a1) receptors. It has relatively low potency
as a D2 receptor antagonist.

• Metabolized by Cytochrome P450 enzyme

• Peak plasma level achieved with in 2hrs, and half life
of 12 hrs.
• 25 mg dosage --) not exceeding 900 mg/day
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 Uses
• Psychotic patients with severe EPS
• Treatment resistant mania
• Severe psychotic depression
• Persistent negative symptoms
• Idiopathic Parkinson's disease,
• Huntington's disease, and
• Suicidal patients with schizophrenia or
schizoaffective disorder.
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 ADR
• Agranulocytosis
• Hypersalivation
• Sedation
• Seizure
• Tachycardia
• Hypotension
• Weight gain & DM precipitation

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 Olanzapine
• Resembles Clozapine,
• Blockage of D2, 5HT2, a1 and a2 receptors

• Metabolized by CYP1A2 & glucuronyl

transferase enzyme,
• Peaks at 5hrs, half life of ~30 hrs
• Usually 5mg as initial dose, preferred not to
exceed 20 mg/day
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 Uses
• Both positive & negative symptoms of
Schizophrenia
• Schizoaffective disorders
• Acute tx of manic or mixed episodes of Bipolar
I disorder
• Treatment resistant depression with fluoxetine

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 ADR
• Increased risk of stroke
• Dose related increase in EPS
• Weight gain and rise in blood sugar level
• Elevated transaminase level
• Somnolence
• Dyspepsia
• Dry mouth and constipation

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 Risperidone
• An antagonist of the serotonin 5-HT2A,
dopamine D2, a1-adrenergic and a2-
adrenergic receptors
• More potent D2 blockage than Clozapine, has
dose adjusted safety.

• Usually started at 1mg/day dose, up to 4mg

but can go up.

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 Uses
• Acute and maintenance treatment of
schizophrenia in adults
• Schizophrenia in adolescents.
• Short-term treatment of acute manic or mixed
episodes associated with bipolar I disorder.
• Irritability associated with autistic spectrum
disorder in young children and adolescents.

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 ADR
• EPS,
• Dizziness,
• Hyperkinesias,
• Somnolence,
• Nausea.
• Marked elevation of prolactin

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 ADVERSE EFFECTS
• The SDAs share a similar spectrum of
adverse reactions, but differ considerably
in terms of frequency or severity of their
occurrence.

• There are also specific side effects that are

unique to a specific drug.

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Most common side effects
include Rare but serious side effects

– weight gain and related • tardive dyskinesia

metabolic effects • neuroleptic malignant
– hypotension syndrome
– sedation
• seizures
– anticholinergic symptoms
• agranulocytosis
– hyperprolactinemia
– extrapyramidal symptoms
• hypersensitivity reactions
(EPS) and
– cardiac effects • an increased risk of mortality
– cardiomyopathies from all causes, especially in
– cataracts older adult patients with
– sexual dysfunction dementia-related psychosis

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 Metabolic syndrome
• Common offenders
are Olanzapine, Quetiapine, and Clozapine
• Dx:
– Weight gain
– Hyperlipidemia
– Hyperglycemia
– Hypertension

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 Management

• Monitoring
• Switching the offending drug
• Behavioral weight loss interventions
• Treating each condition
– Antihypertensive
– Statins
– Metformin

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 Hyperprolactinemia
• Commonly seen in  Risperidone
and Paliperidone.
• can lead to galactorrhea and menstrual
disturbances in women as well as sexual
dysfunction and gynecomastia in men.
• Management
– Changing to an antipsychotic with a lower
likelihood of causing prolactin
elevation (Quetiapine and Aripiprazole)
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 Anti-cholinergic symptoms
• Include
– dry mouth
– urinary hesitancy
– constipation
– visual disturbance
– cognitive impairment

• These effects tend to be worse in older patients.

• Seen with clozapine, olanzapine, and,

– to a lesser extent, with Quetiapine, Iloperidone, and loxapine

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 Sedation
•  severe sedation is most common Clozapine
and Quetiapine.

• Most severe during the first weeks of treatment

– often require gradual titration of the antipsychotic.

• Sedating medications may be best tolerated at

bed time.

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 Leukopenia, Granulocytopenia,
Agranulocytosis
• Seen in patients taking Clozapine.
• Contraindicated in patients with
– white blood cell (WBC) count below 3,500 cells per mm3
– A Previous bone marrow disorder
– A history of agranulocytosis during clozapine treatment or
– the use of another drug that is known to suppress the bone
marrow, such as carbamazepine.
• Management is to monitor and discontinue the drug if
– the WBC count < 3,000 cells per mm3 or
– the granulocyte count < 1,500 per mm3

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 Third generation
antipsychotics and new
developments

partial agonists or something more?

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Auto- and presynaptic dopamine receptors as
antipsychotic candidates
• “dopamine hypothesis of schizophrenia”
• antagonism of D2 receptors has been
accepted as a way of controlling positive
symptoms of schizophrenia

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• a novel hypothesis was developed in the late 1970's

• Dopamine autoreceptors
– now known to be composed of high densities of D2 and
low densities of D3 receptors
– When activated, they cause a decrease in both synthesis
and release of dopamine, and a decrease in the firing of
dopamine neurons
– higher potency at these autoreceptors versus what are
regarded as postsynaptic D2 functions

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 2. Aripiprazole as the third generation
antipsychotic prototype
• Aripiprazole is a relatively new approved
antipsychotic drug
– A high affinity, low intrinsic activity partial D2
agonist
– the first “dopamine stabilizer”
– “functionally selective”

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3. Functional selectivity and the notion of
intrinsic efficacy

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Summary…

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 References
• UpToDate, 2018
• Synopsis, 11th edition
• Katzung’s Basic and Clinical pharmacology

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