Anti-psychotics
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Mainstay of pharmacological treatment for
schizophrenia and related disorders
Diminish positive symptoms such as
hallucinations, delusions, thought disorder
Some impact on negative symptoms such
as lack of motivation, blunted affect,
cognitive impairment
Important as a part of relapse prevention
Anti-psychotics
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Antagonise dopamine receptors,
resulting in anti-psychotic effects
Indications-schizophrenia, acute
mania, psychotic depression,
Conventional and atypical
Both of equivalent efficacy when
taken at recommended dosages
Atypicals have lower incidence of
EPSE
Dopamine Theory
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The dopamine hypothesis
of psychosis – overactivity
of dopamine neurons in
the mesolimbic pathway of
the brain may mediate the
positive symptoms of
psychosis
Mesolimbic pathway
responsible for pleasure,
effects of drugs and
alcohol and hallucinations
and delusions
Blockade Of D2 Receptors?
D2
ANTAGONIST
Nigrostriatal pathway
extrapyramidal side effects
(EPS) and tardive dyskinesia
Mesocortical pathway
enhanced negative and
cognitive psychotic
symptoms
Mesolimbic pathway
dramatic therapeutic action
on positive psychotic
symptoms
Tuberoinfundibular pathway
hyperprolactinemia (lactation,
Dopamine Receptors
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Five subtypes – D2 most important
in terms of psychosis
Blockade of mesolimbic receptors
leads to reduced psychotic symptoms
Blockade of the mesocortical
pathway leads to increased negative
symptoms
Dopamine Receptors
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Dopamine and acetylcholine have a
reciprocal relationship• Blockade of dopamine receptors
increases the activity of acetylcholine
• Over activity of acetylcholine causes
EPSE
• Blockade of dopamine causes
movement disorders in the nigostriatal
pathway
• Long tem blockade causes
“upregulation” and leads to Tardive
Dyskinesia
Conventional or typical
Antipsychotics
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Have four actions –
blockade of:
• Dopamine 2
• Muscarinic/choliner
gc
• Alpha adrenergic
• Histamine
Serotonin and Dopamine
Interactions
The Dopamine Receptor
Antagonist Hypothesis of
Antipsychotic drug Action
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Blockade of post
synaptic dopamine
receptors in the
mesolimbic
pathway is thought
to mediate the
efficacy of the drug
and its ability to
diminish positive
symptoms
Receptor Affinity
Low Affinity (loosely bound)
- Quetiapine, Olanzapine, Amisulpride,
Clozapine
High Affinity (tightly bound)
- Chlorpromazine, Haloperidol,
Flupenthixol, Fluphenazine
Tightly bound drugs lead to increased
sensitivity to dopamine blockade so
more likely to cause EPSE
Atypical Antipsychotics
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Pharmacologic
Properties
• 5HT2A and D2
antagonism (as
opposed to
conventional drugs
which are D2
without 5HT2A
antagonism)
• Atypicals –
blockade of D2 and
5HT2A
Dopamine and Serotonin
Receptors
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Dopamine and
serotonin have a
reciprocal
relationship
Serotonin opposes
the release of
dopamine in the
nigrostriatal and
tuberofundibular
pathways
Dopamine and Serotonin
Receptors
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Action of atypicals – firstly binds to
the D2 receptor
Secondly, binds to the 5HT2A
receptor
The second action reverses the first
– reverses the blockade of D2
Blocking 5HT2A disinhibits the
dopamine neuron causing dopamine
to pour out
Dopamine and Serotonin
Receptors
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The dopamine and serotonin then
compete with the drug for the D2
receptor
Increased dopamine in the
mesocortical pathway
Reduction in movement
disorders/EPSE for atypical
antipsychotics
Atypicals
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In reality – not simple
serotonin-dopamine
antagonists
Most complex
pharmacological
properties
Act on multiple
serotonin and
dopamine receptors,
histamine, alpha
adrenergic &
cholinergic
Atypicals versus conventional
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All equal efficacy (except Clozapine)
Consideration for:
• Merits of high versus low affinity drugs
• Cerebral selectivity of the drugs
• Adverse effect profile
• Dose necessary to achieve optimal D2
blockade
• Patient tolerability, preference, response
Anti-psychotics
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Conventional – eg chlorpromazine,
haloperidol, stelazine, depots such as
flupenthixol, zuclopenthixol,
fluphenazine
Atypical – eg olanzapine, risperidone,
quetiapine, amisulpride, clozapine,
risperdal consta intramuscular
injection, aripiprazole, paliperidone,
ziprasidone
Also have effects on acetylcholine,
histamine,serotonin receptors –
Atypical antipsychotics
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The ‘newer” antipsychotics
Effectively treat psychotic symptoms
Lower incidence of extra pyramidal
side effects than conventional agents
Have effects on dopamine, serotonin,
histamine and muscarinic receptors
Atypical antipsychotics
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Current atypicals in use in Australia are:
Amisulpride
Aripiprazole
Quetiapine
Olanzapine
Risperidone
Clozapine
Ziprasidone
Paliperidone
Therapeutic effects on
symptoms
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Agitation, sleep and appetite often
respond in the first 1-2 weeks
Personal hygiene and basic interpersonal
socialisation may take 2-3 weeks and
psychotic symptoms can gradually
decrease over 2-6 weeks
An effective trial should be at least 6-8
weeks at doses that are within the
prescribed range
How long should antipsychotics be
taken for?
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At least 6 months after an acute
episode reduces relapse rates
If the person experiences another
episode they may need antipsychotic
medication for 2-5 years before
ceasing use
For those with multiple episodes,
they may need medication for much
of their life
Adverse Effects
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Sedation
Postural hypotension
Anticholinergic effects – dry mouth,
blurred vision, constipation, urinary
hesitancy
Weight gain-clozapine, olanzapine
Metabolic effects-increased serum
lipids, impaired glucose toleranceclozapine, olanzapine, quetiapine
Adverse Effects
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Hyperprolactinaemia-leads to
galactorrhoea, amenorrhoea, decreased
libido
Sexual dysfunction
QTc prolongation-leads to cardiac
arrhythmias
EPSE-extrapyramidal side effects
• Acute dystonias -laryngeal spasm,
oculogyric crises
• Akathisia-severe sense of agitation, inner
restlessness in the limbs, especially the
legs
Adverse Effects
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Akathesia – a severe sense of
psychomotor agitation
Parkinsonism -poverty of movement,
tremor, rigidity, drooling, hypersalivation
Tardive dyskinesia-involuntary
hyperkinetic movements, affects the
mouth, lips, tongue, jaws with smacking,
tongue writhing, sucking,chewing and tic
like movements,limbs and trunk can be
affected
Adverse Effects
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Irreversible in some patients
Neuroleptic malignant syndrome-rare
but potentially fatal – high temp,
muscle rigidity, altered
consciousness, raised creatinine
kinase –cease medication
Can happen at anytime during
treatment
30% patients will develop syndrome
again on rechallenge
Depot Anti-psychotics
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Used when concerns around
compliance
Conventional-zuclopenthixol(useful
for agitated,aggressive,disturbed
behaviour) flupenthixol (may have
mood elevating effects) fluphenazine
-EPSE common
Typical-Risperdal Consta – onset of
action 3 weeks, need oral
Risperidone to supplement until peak
Comparative Information for
Anti-Psychotics
Chlorpromazine, Pericyazine
Most sedating, most potent
anticholinergic effects, least
likely to cause EPSE, most likely
to cause orthostatic
hypotension. Low potency
antipsychotics
Trifluperazine, Fluphenazine
Moderately sedating,
intermediate propensity to cause
EPSE, some potential to cause
orthostatic hypotension
Haloperidol, Droperidol,
Thiothixene, Pimozide
Least sedating, almost no
anticholinergic effects, most
likely to cause EPSE, least likely
to cause orthostatic
hypotension, sometimes referred
to as ‘high potency’
antipsychotics
Atypical antipsychotics
Amisulpride
Less potential for weight gain
and sedation
Aripiprazole
May cause insomnia, less
potential for
hyperprolactinaemia
Clozapine
Effective treatment-resistant
patients but has serious sideeffects (blood dyscrasias,
seizures, cardiomyopathy,
myocarditis, orthostatic
hypotension, sedation,
weight gain).
Atypical antipsychotics
Olanzapine
Related to Clozapine may
cause sedation, weight gain,
peripheral oedema; increased
risk of stroke and related
mortality in elderly dementia
patients
Quetiapine
Sedating and vasoactive, less
potential for
hyperprolactinaemia
Risperidone, Paliperidone
Orthostatic hypotension and
hyperprolactinaemia, may be
a problem; increased risk of
stroke and related mortality
in elderly dementia patients
Ziprasidone
Less potential for weight gain
Drug Interactions
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Cytochrome P450 isoenzymes are
significant in psychotropic drug
interactions
Inducers or inhibitors of this pathway
may produce clinically important
drug interactions
May lead to increase or decrease of
medications due to interactions
Cytochrome P450
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Examples
• Fluvoxamine inhibits olanzapine and
clozapine metabolism
• Smoking induces Olanzapine
metabolism
• SSRIs inhibit most antipsychotics and
therefore increase serum concentrations
• Phenytoin reduces serum concentration
of Quetiapine
• Others – grapefruit juice, Antibiotics,
Clozapine
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Used when previously unresponsive to
other antipsychotics
Serious adverse effect profile
Strict guidelines relating to
commencement and monitoring
Significant risk of agranulocytosis
Trial at least 2 different standard
antipsychotics at an adequate dose and
for an adequate duration prior to
commencing Clozapine
Use of antipsychotics with older
persons
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Various disorders treated with
antipsychotics in the elderly – psychosis,
bipolar affective disorder, delirium &
dementia
Use extreme caution because of side
effect profile
‘Start low & go slow’ (Malone et al 2007)
& titrate over longer periods of time to
reach the required dose
Avoid polypharmacy wherever possible
Pregnancy & lactation
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Avoid antipsychotics if possible
Use the lowest effective dose
Neonatal adverse effects observed
include generalised hypertonicity and
dystonic reactions
Pregnancy & lactation
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The safety of atypical agents is yet to
be established but preliminary
reports there to be no deleterious
effects to the foetus
Isolated cases of congenital
abnormalities with the use of
Clozapine
Pregnancy & Lactation
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No increased risk has emerged with
the use of Olanzapine
The conventional agents are
generally preferred
Supervised dose reduction and
cessation 7-10 days prior to delivery
should be considered
What other treatments are
available?
Remember that antidepressant medication is only part of the
treatment for antenatal depression and anxiety. Also consider:
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Psychological therapies
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Exclude organic illness as a cause of mental health symptoms
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Address any alcohol and/or illicit substance abuse
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Assess the social situation
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General lifestyle measures: adequate rest/sleep, balanced diet,
exercise
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The decision to treat should be made on an individual case basis
Conclusion
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Conventional and atypical antipsychotics are used
as the foundation for pharmacological
management of schizophrenia and related
psychosis
All have equal efficacy, exception Clozapine
Atypicals generally better tolerated & have less
EPSE
Atypicals first line treatment
Start lowest effective possible dose & titrate
upwards
Ongoing monitoring & management of adverse
effects
Caution numerous drug interaction & potential for
neuroleptic malignant syndrome
Resources
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Therapeutic Guidelines – Psychotropic
Version 5
www.tg.com.au 9329 1566
Australian Medicines Handbook
www.amh.net.au 08 8303 6977
MIMS online
http://www.ppmis.org.au Perinatal
Psychotropic Medicine Information
Service