A Simplified Guide to Oral
Antipsychotic Medications –
Mechanism of Action, Side Effects
and Need to Know Points
Author: Dr. Sanil Rege MBBS, MRCPsych, FRANZCP
April 29, 2018
Antipsychotic medications were discovered serendipitously in the 1950’s, when
Chlorpromazine, which has antihistaminic properties was also observed to have
antipsychotic effects when prescribed in patients with schizophrenia.
Antipsychotic medications were predominantly used in the treatment of
schizophrenia, however, nowadays they are used in a range of disorders and are
evidence-based in the treatment of bipolar disorder, schizoaffective disorder and are
used off-label for other disorders, such as post-traumatic stress disorder and eating
disorders.
Antipsychotic medications are broadly divided into typical and atypical
antipsychotics although this distinction does not necessarily take into account the
individuality in receptor profiles of the individual antipsychotic medications.
In this particular summary, we focus on the commonly used oral atypical
antipsychotic medications that are used in schizophrenia and highlight the key
receptor profiles. It is important to note there may be several other receptors
involved. However, we focus on the most important ones that are responsible for
efficacy and tolerability.
Each antipsychotic has a link to the full product information from the Therapeutic
Goods Administration (TGA) for products available in Australia and FDA for
Cariprazine.
CONVENTIONAL OR TYPICAL OR FIRST GENERATION
ANTIPSYCHOTIC
A conventional, typical or first-generation antipsychotic is defined by the ability to
block dopamine (D2) receptors.
They also have in, varying degrees, M1, Alpha-1 and H1 receptor blockade.
Typical antipsychotics:
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Chlorpromazine
Flupenthixol (depot)
Fluphenazine (depot)
Haloperidol
Sulpiride
Trifluoperazine
How does dopamine blockade treat psychosis?
Blocking Dopamine receptors in the mesolimbic area treats psychotic symptoms.
However, because the mesolimbic pathway is also a reward pathway, D2
antagonism can result in patients having apathy, anhedonia, and amotivation.
Why does D2 blockade result in side effects?
When a typical antipsychotic which is a dopamine antagonist is prescribed, it cannot
selectively block the D2 in the mesolimbic area while sparing the D2 receptors in
other areas.
Therefore, prescription of a D2 antagonist can block Dopamine receptors in other
areas, resulting in side effects.
1.Cognitive Side Effects
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2. Depressed mood and secondary negative symptoms
3. Extrapyramidal side effects (EPSEs)
4. Raised Prolactin
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UNCONVENTIONAL OR ATYPICAL OR SECOND GENERATION
ANTIPSYCHOTICS
The atypicality of the atypical antipsychotics has been attributed to the combination
of the D2 antagonism with the 5HT2A antagonism.
There are other antipsychotics that derive their atypicality from other receptor
mechanisms which we outline below.
How does the 5HT2A receptor make the antipsychotic atypical?
The 5HT2A receptor can be considered to be a break on the Dopamine release, i.e.,
if the 5HT2A receptor is activated it blocks Dopamine release.
Thus, 5HT2A antagonism stimulates Dopamine release in a range of pathways, thus
reducing the side effects that a typical Dopamine blocker would cause.
5HT2A antagonism reduces EPSE by increasing Dopamine in the nigrostriatal areas.
5HT2A antagonism reduces negative symptoms by improving Dopamine in the
prefrontal cortex.
5HT2A antagonism has antidepressant effects by increasing dopamine in the
ventromedial prefrontal cortex. (This is one of the mechanisms of actions of mirtazapine
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– see: https://psychscenehub.com/psychinsights/summary-21-antidepressants-network-
metaanalysis/).
5HT2A antagonist actions reduce hyperprolactinaemia.
How are atypical antipsychotics classified?
The atypical antipsychotics can be divided into the dones, the pines, two pips and
a rip.
Below we cover the main receptor profiles of the different antipsychotics that are
relevant to clinical practice as opposed to outlining every single receptor binding.
THE PINES
OLANZAPINE
Need to know:
Mechanism of action of olanzapine (Full product information
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=
CP-2011-PI-02804-3&d=2018050116114622483)
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Dose – 5 – 20 mg per day (Higher doses have been prescribed)
D2 – 5HT2A antagonist with anti-H1 and anti-muscarinic properties
Significant weight gain due to antihistaminergic and antimuscarinic blockade
Greatest cardiometabolic risk along with Quetiapine
Half life – 21 – 54 hours
Metabolised by CYP1A2 and CYP2D6. Therefore inhibitors of CYP1A2 (Fluvoxamine
and Ciprofloxacin) and CYP2D6 (Paroxetine) can increase levels. Smoking is a
CYP1A2 inducer and can decrease levels.
QUETIAPINE
Need to know:
Mechanism of action of Quetiapine (Full product information
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=
CP-2010-PI-07764-3)
D2 – 5HT2A antagonism.
Its metabolite norquetiapine has 5HT7, 5HT2C and Alpha2 antagonism with 5HT1A
agonism and is also a Noradrenaline Reuptake Inhibitor (NRI) all of which mediate
antidepressant effects.
Dose 25 mg – 800 mg per day.
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Available in immediate release (IR) and extended release (XR). The IR formulation has
a rapid onset and short duration of action and hence suitable as a hypnotic but not as
an antipsychotics. The reverse holds true for the XR version as the peak effect is
delayed and thus the patient can experience residual sedation during the day. The
antipsychotic action is of longer duration (more extended D2 receptor occupancy) and
hence can be used as an antipsychotic.
Triple effect– sedative at 50 mg XR, antidepressant at 300 mg XR, antipsychotic at 800
mg XR. The extended release (XR) is the preferred option for depression due to day-
long receptor occupancy of 5HT2C and Noradrenaline transporters. There is minimal
EPSE and is the preferred antipsychotic in patients with Parkinson’s disease and
psychosis.
Predominantly metabolised by CYP3A4, therefore can be induced significantly by the
Carbamazepine
Half life – 7 hours ; Norquetiapine 12 hours.
ASENAPINE
Need to know:
Mechanism of action of Asenapine (Full product information
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=
CP-2011-PI-03052-3&d=2018050116114622483)
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Dose 10-20 mg wafer sublingual due to very low oral bioavailability. Avoid eating or
drinking 10 minutes before or after as absorption is decreased.
Metabolised by CYP1A2 and direct glucuronidation by UGT1A4
Half-life – 24 hours
D2 – 5HT2A antagonism, along with pharmacological properties similar to Mirtazapine –
5HT2A, 5HT2C, and Alpha 2 antagonism, along with antihistaminergic effects.
Generally administered twice per day.
Can result in oral hypoaesthesia.
Antidepressant properties are due to 5HT2A, 5HT2C, 5HT7, 5HT1B/D, Alpha2 receptor
antagonism plus 5HT1A agonism.
CLOZAPINE
Need to know:
Mechanism of action of Clozapine (Full product information
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=
CP-2009-PI-00043-3)
Clozapine is indicated in treatment-resistant schizophrenia.
‘Hit and Run’ mechanism – rapidly dissociates from D2 receptors hence mitigates
EPSEs, cognitive and negative symptoms and raised prolactin
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12.5 mg initiation, gradually increased to a maximum of 900 mg per day.
Aim for a plasma level of 350 mcg/L – 500 mcg/L.
We have covered the efficacy of Clozapine in a previous article. At
https://psychscenehub.com/psychinsights/clozapine-in-schizophrenia/.
Patients have been known to experience an awakening characterised by near
normal level of cognitive, interpersonal and vocational functions, not just significant
improvement in positive symptoms.
Clozapine has anti-suicidal effects.
Clozapine reduces tardive dyskinesia.
It is metabolised by CYP1A2, which is induced by smoking and inhibited by caffeine.
Ciprofloxacin, fluvoxamine, and caffeine are inhibitors and can increase levels of
clozapine.
It is also metabolised by CYP3A4 to a lesser extent- Inducers like carbamazepine can
reduce levels.
Its elimination is biphasic with a mean terminal half-life of 12 hours (range: 4-66 hours)
Common side effects:
Sedation
Hypersalivation
Constipation (60% prevalence, with fatality rates of 20-30%)
Hypertension
Tachycardia
Weight gain
Fever
Serious side effects:
Seizures can occur with doses >600 mg or with levels >500 mcg/L.
Neutropenia (2.7%) and agranulocytosis (0.8%). Deaths from agranulocytosis occur in
less than 1:10000.
Thromboembolism 1:2000 – 1:6000
Myocarditis – Incidence in Australia is up to 1%, UK is 0.02%, in USA 1:67000, Canada
1:12000
Cardiomyopathy – 1:5000 – 1:10000
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THE DONES
LURASIDONE
Need to know:
Mechanism of action of Lurasidone (Full product information
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=
CP-2014-PI-01715-1)
New atypical antipsychotic with 5HT2A and D2 antagonism, high affinity for 5HT7 and
5HT2A and moderate affinity for Alpha2 and 5HT1A receptors.
Negligible histaminergic and muscarinic antagonism.
Dose – 40 mg – 160 mg /day.
Effective antipsychotic without sedation, with little or no weight gain and dyslipidaemia
Side effects of weight gain and dyslipidaemia may also reverse after the changeover
from antipsychotic which is associated with weight gain
Absorption of Lurasidone is greater when taken with 350 calories of food
No QTc prolongation
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Robust efficacy in bipolar depression and mixed depression due to 5HT1A, 5HT7, and
Alpha 2 antagonism
Metabolised by CYP3A4. Lurasidone is contraindicated with strong CYP3A4 inhibitors
(e.g., ketoconazole, clarithromycin, ritonavir, and voriconazole) and strong CYP3A4
inducers (e.g., rifampin, St. John’s wort, phenytoin, and carbamazepine)
Grapefruit and grapefruit juice should be avoided in patients taking Lurasidone, as these
may inhibit CYP3A4.
Half-life of 18 hours
RISPERIDONE
Need to know:
Mechanism of action of Risperidone (Full product information
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=
CP-2010-PI-01616-3)
D2 – 5HT2A antagonist
Predominant D2 blocker at higher doses and low dose can be used in agitation and
psychosis in dementia.
Can increase Prolactin even at low doses.
2 mg – 16 mg per day.
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Half-life is 20 hours, metabolises in three hours in extensive metabolisers.
PALIPERIDONE
Need to know:
Mechanism of action of Paliperidone (Full product information
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=
CP-2013-PI-01421-1)
Paliperidone is the active metabolite of Risperidone; 9-hydroxyrisperidone.
The D2 – 5HT2A affinity ratio for paliperidone is higher than risperidone.
The presence of an OH group at position 9 in paliperidone’s molecular structure makes
it cross the blood-brain barrier (BBB) at a lower extent than risperidone.
Paliperidone is not hepatically metabolised, and it has few drug interactions.
Less sedation.
3 mg – 12 mg /day.
Half life – 21 hours in extensive metabolisers and 30 hours in poor metabolisers.
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ZIPRASIDONE
Need to know:
Mechanism of action of Ziprasidone (Full product information
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=
CP-2010-PI-05917-3)
Dose – 80 mg – 160 mg /day. Administered in a twice-daily dose as half-life is around 7
hours.
Little or no metabolic dysfunction.
Needs to be taken with at least 500 cals of food as bioavailability is increased
Previously thought to lead to prolonged QTc but these concerns are now considered to
be unjustified
No significant interactions with medications. One third metabolised by CYP3A4 and rest
by aldehyde oxidase
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THE PIPS
ARIPIPRAZOLE
Need to know:
Mechanism of action of Aripiprazole (Full product information
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=
CP-2010-PI-03820-3)
Dopamine (D2) partial agonist.
Aripiprazole is known to have a Goldilocks effect, where it is described as not being too
hot, or not too cold at the Dopamine receptor, resulting in just the rightDopamine
agonism/antagonism to treat psychotic symptoms
Dose 10 – 30 mg per day.
When switching to Aripiprazole, it is important to start at the middle dose of Aripiprazole
by building up the Aripiprazole dose over 3 – 7 days and then tapering the other pill.
Lacks sedative properties as no M1 or H1 antagonism. Therefore the absence of the
histamine and muscarinic antagonism also results in little or no propensity for weight
gain.
Low association with insulin resistance, dyslipidaemia and/or fasting triglycerides.
Evidence-based in the treatment of schizophrenia, mania, and bipolar depression.
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Also used as an antidepressant for augmenting SNRI/SSRI’s in treatment-resistant
major depression.
Very long half-life of 75 – 100 hours (chief metabolite)
Metabolised by CYP3A4 and CYP2D6.
CYP3A4 inhibitors are clarithromycin, ketoconazole, and nefazodone. CYP3A4
inducers is Carbamazepine.
CYP2D6 inhibitors are Paroxetine, Fluoxetine, which can increase the dose of
Aripiprazole.
BREXPIPRAZOLE
Need to know:
Mechanism of action of Brexpiprazole (Full product information
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=
CP-2017-PI-01863-1)
Brexpiprazole is chemically related to Aripiprazole.
Dose 1 mg – 4 mg.
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Greater D2 antagonism than Aripiprazole. More potent 5HT2A antagonism, 5HT1A
partial agonism and Alpha1 antagonism relative to D2 partial agonism.
5HT1A partial agonism and 5HT7A antagonism may be responsible for antidepressant
properties.
Low incidence of EPSE and akathisia.
Metabolised by CYP3A4 and CYP2D6.
The terminal elimination half-life of brexpiprazole and its major metabolite, DM-3411, is
91.4 hours and 85.7 hours, respectively
THE RIP
CARIPRAZINE
Need to know:
Mechanism of action of Cariprazine (Full product information
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204370lbl.pdf)
Dose – 1.5 mg – 6 mg / day
It is a dopamine D2 and D3 receptor partial agonist, with higher affinity for D3 receptors
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Partial agonism of 5HT1A receptors might enhance dopaminergic neurotransmission in
mesocortical pathways leading to improvement of negative and depressive
symptomatology.
The 5HT2A antagonism may promote dopaminergic neurotransmission in the
nigrostriatal circuitry, providing further explanation of lower risk of motor side effects in
the course of treatment with cariprazine.
It undergoes extensive hepatic metabolism by cytochrome P450 (CYP), mainly the
highly variable 3A4, with the formation of active metabolites
However, the parent compound – particularly its active didesmethyl derivative – is
cleared very slowly, with elimination half-lives in schizophrenic patients ranging from 2–
5 days for cariprazine to 2–3 weeks for didesmethyl-cariprazine.
Cariprazine is associated with a higher incidence of akathisia and extrapyramidal side
effects than placebo.
It has a lower propensity for weight gain, metabolic abnormalities, prolactin increase, or
corrected QT prolongation.
OTHERS
AMISULPRIDE
Need to know:
Mechanism of action of Amisulpride (Full product information
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=
CP-2010-PI-01659-3)
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D2/D3 antagonist
It preferentially blocks pre-synaptic D2/D3 dopamine receptors, producing dopamine
release responsible for its disinhibitory effects. This atypical pharmacological profile
may explain amisulpride’s antipsychotic effect at higher doses through post-synaptic
dopamine receptor blockade located in the limbic areas and its efficacy against negative
symptoms, at lower doses, through presynaptic dopamine receptor blockade.
In addition, the reduced tendency of amisulpride to produce extrapyramidal side effects
may be related to its preferential limbic activity
Dose 400 mg – 1200mg / day
Dose dependant QTc prolongation
Prolactin elevation and EPSEs due to post-synaptic dopamine blockade
Minimal hepatic metabolism
Half life 12 hours
CLINICAL PEARLS
A large recent meta-analysis by Leucht et al. (see:
https://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.2017.16121358) showed
that there are small differences in efficacy between antipsychotics however they
differ substantially in regard to side effects.
This is relevant clinically as an understanding of receptor profiles can help choose
antipsychotics with a lower propensity for side effects which in turn enhances
compliance.
How do I minimise metabolic side effects with antipsychotic medications?
5HT2C, M3 and H1 antagonism mediate metabolic side effects. Another unknown
receptor X may be involved.
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Olanzapine, Quetiapine, and Clozapine have greater cardiometabolic risks due to a
strong affinity with the above receptors.
On the other hand, Lurasidone, Aripiprazole, and Brexpiprazole have lower
cardiometabolic risks due to low binding to the above receptors.
How do I maximise efficacy and minimise side effects?
Antipsychotic medications like Aripiprazole, Lurasidone, and Brexpiprazole have
antidepressant effects due to 5HT7 and 5HT1A partial agonism and hence may be a
better choice to treat depressive symptoms in schizophrenia.
If sedation is required, then Quetiapine and Olanzapine have higher H1 antagonism
which needs to be balanced against the risk of weight gain as the same receptor
mediates both actions.
CONCLUSION
Not all antipsychotic medications are the same. While they aim to treat psychosis
through dopamine (D2) receptor antagonism in most cases, there are other
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antipsychotics with atypical modes of action. This atypicality informs efficacy and
side effects.
Clinicians should be familiar with the different receptor profiles which will enable
them in individualising the choice of antipsychotic.
References
1. Stahl, S. M. (2013). Stahl’s essential psychopharmacology: neuroscientific basis and practical
applications. Cambridge university press.
2. Leucht, S., Leucht, C., Huhn, M., Chaimani, A., Mavridis, D., Helfer, B., … & Geddes, J. R. (2017).
Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review,
bayesian meta-analysis, and meta-regression of efficacy predictors. American journal of
psychiatry, 174(10), 927-942.
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