A Simplified Guide to Oral Antipsychotic Medications – Mechanism of Action, Side Effects and Need to Know Points
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.
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.
- Flupenthixol (depot)
- Fluphenazine (depot)
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
2. Depressed mood and secondary negative symptoms
3. Extrapyramidal side effects (EPSEs)
4. Raised Prolactin
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)
- 5HT2A antagonist actions reduce hyperprolactinaemia.
What are partial dopamine agonists?
Partial dopamine agonists are also atypical antipsychotics and are also called third-generation antipsychotics.
Aripiprazole, Brexpiprazole and Cariprazine fall under this category.
Partial dopamine agonists have a lower intrinsic activity at dopamine receptors than full agonists, allowing them to act either as a functional dopamine agonist or a functional dopamine antagonist (Goldilocks effect / Dimmer Switch Effect), depending on the surrounding levels of dopamine (full agonist).
In the absence of dopamine agonist activity, partial agonists show functional agonist activity, binding to the dopamine receptor to produce a response. In the presence of excessive dopamine agonist activity, partial agonists show functional antagonist activity.
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.
Need to know:
- Mechanism of action of olanzapine (Full product information)
- 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.
Need to know:
- Mechanism of action of Quetiapine (Full product information)
- 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.
- 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.
Need to know:
- Mechanism of action of Asenapine (Full product information)
- 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.
Need to know:
- Mechanism of action of Clozapine (Full product information)
- 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 [Learn the other mechanisms of action]
- 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.
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:
- Constipation (60% prevalence, with fatality rates of 20-30%)
- Weight gain
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
Need to know:
- Mechanism of action of Lurasidone (Full product information)
- New atypical antipsychotic with 5HT2A and D2 antagonism, high affinity for 5HT7 and 5HT2A and moderate affinity for Alpha2 and 5HT1A receptors. [View the video on Lurasidone’s mechanism of action and clinical pearls]
- 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
- 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
Need to know:
- Mechanism of action of Risperidone (Full product information)
- 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.
- Half-life is 20 hours, metabolises in three hours in extensive metabolisers.
Need to know:
- Mechanism of action of Paliperidone (Full product information)
- 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.
Need to know:
- Mechanism of action of Ziprasidone (Full product information)
- 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
Need to know:
- Mechanism of action of Aripiprazole (Full product information)
- 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 right Dopamine 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.
- 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.
- Read more detail on psychopharmacology and clinical application of Aripiprazole and Aripiprazole LAIs
Need to know:
- Mechanism of action of Brexpiprazole (Full product information)
- Brexpiprazole is chemically related to Aripiprazole. [View the video on Brexpiprazole’s mechanism of action and differences from other partial agonists]
- Dose 1 mg – 4 mg.
- 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
Need to know:
- Mechanism of action of Cariprazine (Full product information)
- Dose – 1.5 mg – 6 mg / day
- It is a dopamine D2 and D3 receptor partial agonist, with higher affinity for D3 receptors
- 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.
- More detail on psychopharmacology and clinical application of cariprazine
Need to know:
- Mechanism of action of Amisulpride (Full product information)
- D2/D3 antagonist [Read a detailed article on the psychopharmacology of amisulpride]
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
Need to know: [PI] – Not available in Australia
- D2-5HT2A antagonist at a 1:60 ratio ( compared to risperidone and olanzapine with a ratio of 12:1)
- Presynaptic D2 partial agonist and postsynaptic D2 antagonist.
- D1 receptor partial agonist: D1 receptor agonism increases activation of NMDA receptor phosphorylation, thus increasing glutamate signalling
- SERT inhibitor, which increases serotonin in the synaptic cleft.
- The steady-state level reached in 5 days after daily oral administration
- CYP3A4 metabolism, along with other enzymes
- Half-life 13 hrs with metabolites half-life 20 and 21 hrs.
- The recommended dosage of CAPLYTA is 42 mg administered orally once daily with or without food
- Indications include Schizophrenia in adults and Depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate.
A large recent meta-analysis by Leucht et al. 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.
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.
Learn more on understanding mechanisms and management of weight gain in psychiatry.
Not all antipsychotic medications are the same. While they aim to treat psychosis through dopamine (D2) receptor antagonism in most cases, there are other 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.
Stahl, S. M. (2013). Stahl’s essential psychopharmacology: neuroscientific basis and practical applications. Cambridge university press.