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BY AMY, ANDRE A & S T E PHANI E

ANTIPSYCHOTICS
INTRODUCTION
What are antipsychotics?
Timeline
Mechanism of Action
The Fast Off Theory
Applications
Pediatric use
Off-label uses
Listing
Side effects
Withdrawal effects
Controversies



ANTIPSYCHOTICS
Also known as neuroleptics or major tranquilizers
Early antipsychotics are now called typical or first
generation (1960s) and newer antipsychotics are
called atypical or second generation (1990s)
Use of typicals has significantly decreased since the
advent of atypical antipsychotics
Atypicals thought to have fewer/less severe side effects
TIMELINE
Prior to 1950s treatment for schizophrenia and psychosis included:
Electroconvulsive therapy
Prefrontal lobotomy
Confinement to large institutions (non-specific sedation
and restraint for agitation)


1950: Chlorpromazine
First synthesized for use in anesthesia
Noticed it produced a calming effect and reduced
episodes of aggression in patients with schizophrenia
Was most popular throughout 1960s and 1970s
Not effective in dull, apathetic, deteriorated schizophrenic patients
Associated with Parkinson-like side effects


1958: Clozapine synthesized in Bern, Switzerland
Effective antipsychotic and not associated with extrapyramidal symptoms
Also ameliorates negative symptoms of schizophrenia
Only approved by the FDA in 1990 due to concerns it caused a potentially fatal side effect
involving reduced white blood cell counts
No longer first-line treatment but when others fail





TIMELINE CONT
1994: Risperidone approved by the FDA
Approved for childhood disorders and as result one of
most frequently prescribed
1996: Olanzapine approved by the FDA
1997: Quetiapine approved by the FDA
2001: Ziprasidone approved by the FDA
2009: Asenapine approved by the FDA
2009: Iloperidone approved by the FDA
2010: Lurasidone approved by the FDA
2013: Aripiprazole approved by the FDA

MECHANISM OF ACTION
All antipsychotics work as antagonists of dopamine D2 receptors
Typical Antipsychotics
Level of D2 blockade is directly related to antipsychotic effect (optimal
occupancy between 60%-70%)
Also act on other neurotransmitter systems besides dopamine:
Cholinergic muscarinic and alpha-1-adrenergic receptors

Atypical Antipsychotics
Also block serotonin (5-HT2A)
receptors
This regulates dopamine release in
pituitary, striatal and neocortical
regions of brain
Counteracts depletion of dopamine in areas of brain
that cause adverse effects

THE FAST OFF THEORY
Both typical and atypical antipsychotics attach to D2 receptors
Differ in how fast and how frequently they come off and on of
receptors
Atypicalsdissociate quickly from receptors
This allows endogenous dopamine to bind to same receptors
Explains how atypicals treat psychosis without extrapyramidal
symptoms
APPLICATIONS
Officially approved only for treatment of
Schizophrenia
Schizoaffective Disorder
Psychosis (including delusions and hallucinations)
Bipolar Affective Disorder (recently)
Bipolar Depression
Bipolar Mania
Used to treat both
Positive symptoms
Hallucinations, delusions
Negative Symptoms
Apathy, anhedonia, blunted cognition

PEDIATRIC USE
Generally not recommended for use in children
2006 none approved for children but prescribing for
behavioural disorders was common
Recently, quetiapine and risperidone approved
Risperidone, olanzapine, quetiapine and
aripiprazole are now indicated as useful for
treatment of schizophrenia and bipolar 1
manic/mixed episodes
For many disorders, symptoms must be severe or
other treatments failed to work
Two antipsychotics should never be used in the
same person

OFF-LABEL USES
Obsessive Compulsive Disorder
Post-traumatic Stress Disorder
Tourette Syndrome (Tics)
Autism and PDD
Aggression, irritability, impulsivity, repetitive & self-injurious
behaviour
Borderline Personality Disorder
Insomnia
Dementia
Aggressiveness
Major Depressive Disorder
Generalized Anxiety Disorder

TYPICAL/FIRST GENERATION
Haloperidol
Chlorpromazine
Loxapine
Perphenazine
Pimozide
Prochlorperazine
Promazine
Trifluoperazine

(no longer commonly prescribed)

ATYPICAL/SECOND GENERATION
Aripiprazole
Asenapine
Clozapine
Iloperidone
Lurasidone
Olanzapine
Palperidone
Quetiapine
Risperidone
Ziprasidone
SIDE EFFECTS
One of the primary reasons why people stop
taking antipsychotics is due in part to the adverse
effects


Common 1-50% incidence for
most antipsychotic drugs
include:

Weight gain
Sedation
Headaches
Dizziness
Diarrhea
Anxiety
Orthostatic Hypotension
SIDE EFFECTS
Adverse Effects continued . . .
Extrapyramidal side effects
- Akathisia - Parkinsonism
- Dystonia - Tremor

Hyperprolactinaemia
- Galactorrhoea - Sexual Dysfunction (in both sexes)
- Gynaecomastia - Osteoporosis

Anticholinergic side effects
- Amnesia - Constipation
- Blurrred vision - Dry mouth (also hyper salivation)
- Reduced perspiration

Tardive Dyskinesia
SIDE EFFECTS
Rare/Uncommon (<1% incidence for most antipsychotic drugs)

Metabolic problems (Type II Diabetes)
Neuroleptic malignant syndrome
Pancreatitis
Seizures
Myocardial infarction
Stroke

*Some studies have found decreased life expectancies associated with
the use of antipsychotics. Also increases the risk of early death in
individuals with dementia

*Chronic treatment with antipsychotics may reduce amounts of brain
tissue and potentially cause some of the symptoms believed to be due
to schizophrenia
SIDE EFFECTS
There have been 117,414 Adverse Drug Reactions in connection with
antipsychotics that have been reported to the FDAs Adverse Event
Reporting System (MedWatch), between 2004 and 2012.
The FDA estimates
that less than 1% of
all serious events are
ever reported to it,
so the actual
number of side
effects occurring
are most certainly
higher.

WITHDRAWAL EFFECTS
Physical dependence can result in withdrawal
effects especially on abrupt discontinuation of
the antipsychotic after prolonged use
Factors which increase effects: length, dose,
speed of cessation
During withdrawal recurrence of psychotic
symptoms may occur, can be confused with a
relapse
WITHDRAWAL EFFECTS
Most withdrawal effects are relatively mild and resolve
spontaneously
Withdrawal of an antipsychotic after long-term therapy
should be gradual and closely monitored to avoid the
risk of acute withdrawal syndromes or relapse
CONTROVERSIES
Dementia
90% of people with dementia
exhibit aggression, agitation, loss
of inhibitions and psychosis
(delusions and hallucinations).
Drugs used can make patients
calmer and more compliant
2/3 of these of these prescriptions
are inappropriate.
Johnson & Johnson allegedly payed kickbacks to
Omnicare to promote Risperidone in nursing homes
CONTROVERSIES
Medicating the Young
Second-generation antipsychotics, or SGAs, are being
prescribed to two- and three-year-olds for aggression,
attention deficit/hyperactivity disorder, conduct disorders,
frustration intolerance and even poor sleep.
Elevated blood fats and abnormal blood sugar levels
Across Canada, from 2005 to 2009,
antipsychotic drug prescriptions
for children and youth increased
114 per cent.
Prescribing is being done not by
psychiatrists, but by family
doctors, often with little training
CONTROVERSIES
Drug Studies
In 54% of studies, duration was less that 6 weeks
Mean number of patients was 65
Only 41% showed therapeutic response to medication,
compared to 24% on placebo
Evidence flawed as they didnt take into account that meds
sensitize the brain and provoke psychosis if discontinued
Not approved for pediatric pops.

The constantly poor quality of reporting
is likely to have resulted in an
overoptimistic estimation of the effects
of treatment.

CONTROVERSIES
Pharmaceutical Companies
For example, Johnson & Johnson has agreed to pay $2.2
billion misbranded the atypical antipsychotic drug Risperdal
for uses not approved as safe and effective by the Food and
Drug Administration
Company combined negative data with other studies to
make it appear that there was an overall lower risk for adverse
events.
Antipsychotic drugs are now the
top-selling class of pharmaceuticals in
America
Every major company selling the drugs have been involved in
legal claims involving including Medicare fraud, off label
promotion, and inadequate manufacturing practices.
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