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Anti-psychotics

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

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

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

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

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

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
Blockade of post
Action
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

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

Dopamine and
serotonin have a
reciprocal relationship
Serotonin opposes
the release of
dopamine in the
nigrostriatal and
tuberofundibular
pathways

Dopamine and Serotonin


Receptors

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

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

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

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

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 varying
adverse effects

Atypical antipsychotics

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

Current atypicals in use in Australia are:


Amisulpride
Aripiprazole
Quetiapine
Olanzapine
Risperidone
Clozapine
Ziprasidone
Paliperidone

Therapeutic effects on
symptoms

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?

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

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

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

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

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

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 plasma reached

Comparative Information for


Anti-Psychotics
Chlorpromazine, Pericyazine
Most sedating, most potent

Trifluperazine, Fluphenazine

Haloperidol, Droperidol,
Thiothixene, Pimozide

anticholinergic effects, least


likely to cause EPSE, most likely
to cause orthostatic
hypotension. Low potency
antipsychotics
Moderately sedating,
intermediate propensity to cause
EPSE, some potential to cause
orthostatic hypotension
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
Effective treatment-resistant
patients but has serious sideeffects (blood dyscrasias,
seizures, cardiomyopathy,
myocarditis, orthostatic
hypotension, sedation,
weight gain).

Clozapine

Atypical antipsychotics
Olanzapine

Quetiapine

Risperidone, Paliperidone

Ziprasidone

Related to Clozapine may


cause sedation, weight gain,
peripheral oedema; increased
risk of stroke and related
mortality in elderly dementia
patients
Sedating and vasoactive, less
potential for
hyperprolactinaemia
Orthostatic hypotension and
hyperprolactinaemia, may be
a problem; increased risk of
stroke and related mortality
in elderly dementia patients
Less potential for weight gain

Drug Interactions

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

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

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

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

Avoid antipsychotics if possible


Use the lowest effective dose
Neonatal adverse effects observed
include generalised hypertonicity and
dystonic reactions

Pregnancy & lactation

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

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:

Psychological therapies

Exclude organic illness as a cause of mental health symptoms

Address any alcohol and/or illicit substance abuse

Assess the social situation

General lifestyle measures: adequate rest/sleep, balanced diet,


exercise
The decision to treat should be made on an individual case basis

Conclusion

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

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