Atypical antipsychotics in schizophrenia

Atypical antipsychotics are often the medications of choice compared to the other antipsychotics in the treatment of schizophrenia; however, there are important differences between them that can be relevant for patients.

In 1988, a paper was published that changed the way we treated schizophrenia.¹ Clozapine was shown to have improved efficacy over existing treatments. The hunt was on for medication with similar pharmacology.

The drugs that were developed were termed atypical or second generation antipsychotics and promised improved side effect profiles, particularly reduced extrapyramidal side effects (EPSEs) and better efficacy for negative symptoms and low mood.

Since then, more and more data have emerged suggesting that the atypical antipsychotics were not quite the miracle drugs that they were thought to be. In 2006 in the UK, and in 2007 in the USA, two non-commercial clinical trials were published.^2,3 They compared typical and atypical antipsychotics and surprised the authors with the results. Overall, the newer drugs were no more effective or better tolerated than the older drugs.

The final frontier for choosing atypical over typical antipsychotics would be the risk of tardive dyskinesia; a repetitive and involuntary dyskinesia that may be irreversible and is socially stigmatising. A systematic review has shown that for studies of medication given for at least a year, atypical antipsychotics have a reduced risk for tardive dyskinesia.⁴

The atypical antipsychotics currently available in the UK for treatment of schizophrenia are amisulpride, aripiprazole, clozapine, lurasidone, olanzapine, paliperidone (a metabolite of risperidone), quetiapine, and risperidone.⁵

Although how exactly to define atypicality is still being debated, it is generally accepted that the clinically relevant differences between these agents and typical antipsychotics are as follows:^6,7

• May have efficacy against negative psychotic symptoms such as lack of motivation and social withdrawal as well as positive symptoms such as delusions and hallucinations
• Cause no, or at worst only weak, EPSEs at therapeutic doses, with the exception of higher doses of risperidone and amisulpride
• Do not cause sustained elevation of prolactin levels at therapeutic doses, with the exception of higher doses of risperidone and amisulpride
• May be associated with a lower risk of tardive dyskinesia during long-term treatment.

Pharmacology

All the antipsychotics block dopamine to a greater or lesser extent, usually at dopamine D2 receptors. Most of the atypicals also affect 5-HT2A receptors. This attenuates the dopamine blockade in the pathways of the brain associated with dopamine-related adverse effects and is thought to contribute to how atypicals differ to typical antipsychotics.⁶

Efficacy

All antipsychotics, typical or atypical, are as effective as one another for the treatment of schizophrenia.^3,4 This does not negate the fact that not everyone taking a given medication will respond to it, and currently there is no robust manner to predict this.

More recently, a meta analysis of trials of typical and atypical antipsychotics has confirmed they are not homogenous as a group, with small differences being seen in efficacy, but marked differences being seen in tolerability.¹⁶

A significant minority of people with schizophrenia fail to respond to antipsychotics; in these people, whose schizophrenia is deemed to be ‘treatment-resistant’, clozapine is more effective than other antipsychotics^1,18 and in fact would seem to be associated with substantially lower mortality than other antipsychotics.¹⁹

Tolerability

All else being equal, the main difference between the atypical antipsychotics is their adverse effect profiles.¹⁶

All antipsychotics act on multiple neurotransmitter and receptor systems. The adverse effects of antipsychotics can generally be divided into two different types of effects due to the agent acting on:

• Dopamine receptors other than those involved in psychosis – usually EPSEs and prolactin elevation.
• Receptor/hormone systems other than dopamine. These can include:
• • Effects on histamine, leading to sedation
  • Anticholinergic effects such as constipation, dry mouth and blurred vision
  • Alpha adrenergic effects such as postural hypotension
  • Weight gain caused by sedation (histamine blockade), dry mouth (cholinergic blockade) and effects on appetite (via affecting leptin secretion).⁶

Many of these often wear off with time or can be overcome by suitable dose titration (starting at a low dose and increasing the dose every couple of days for postural hypotension) or deliberate dose timing (giving sedating agents at night).

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Others, such as EPSEs and raised prolactin can be persistent, and if the patient finds them debilitating then swapping to an agent with less propensity to cause these adverse effects may be preferable.¹⁷

National guidance regarding use

National Institute for Health and Care Excellence guidance²⁰ states that the patient and health professional should make the decision about which antipsychotic to use bearing in mind likely adverse effects, with the carer(s) also involved if the patient agrees.

No recommendations are made regarding which antipsychotic(s) or class of antipsychotic(s) should be regarded as first-line. In line with the licencing of the drug, clozapine is recommended as soon as adequate trials of two other antipsychotics have failed.^10,20

The British Association for Psychopharmacology guidelines concur with these recommendations and in addition recommend that factors such as relevant medical history and current comorbidities are also considered.²¹

Availability and pragmatic considerations

When choosing the appropriate antipsychotic, the licenced indication for each agent will be relevant (for example, clozapine may only be used in certain situations).¹⁰ Individuals who are unable or unwilling to swallow tablets may be able to tolerate liquids or dispersible dose forms.

There are now four long-acting injectable (LAI) forms of atypical antipsychotics available, which allow choice for individuals that struggle to adhere to oral dose forms. Aripiprazole cannot be loaded and is only licenced for administration via the gluteal route, plus it needs to be given monthly;²² this may cause logistical issues in community settings when administration falls due on weekends.

Interestingly, only one dose of aripiprazole LAI is used, irrespective of the oral dose of aripiprazole used prior.²² Olanzapine LAI can be loaded to achieve steady state and therefore onset of effect more quickly, and is given either every fortnight or every four weeks.²³

It is only licenced via the gluteal route and tolerability issues if the injection is advertently administered directly into the bloodstream confer the need for close monitoring in the first few hours after administration.²³

Paliperidone LAI may be loaded to achieve steady state relatively quickly, and can be given via the deltoid or gluteal routes, but like aripiprazole it needs to be administered monthly.²⁴

Risperidone LAI needs to be given fortnightly, cannot be loaded and requires refrigerated storage, although it can be given via the deltoid or gluteal routes.²⁵

Whereas oral forms of all atypicals except lurasidone are now available as generic forms, all the LAIs are branded so their acquisition costs are comparatively high. The individual’s preference regarding which adverse effects they would prefer to avoid should be taken into account, as should any pre-existing comorbidities.²⁰

The clinical context may mean certain agents are favoured, everything else being equal. For example, in an acute inpatient situation where an individual is exhibiting agitation, aggression or acute behavioural disturbance, an agent such as olanzapine that is sedating, has injectable and dispersible forms, and does not need dose titration may be the first choice.

In a community setting where an individual may wish to avoid sedation, risperidone may be more useful. Quetiapine may be chosen in an older adult due to the flexibility of the dosages available and the possibility of using very small initiation doses. In someone with pre-existing diabetes, aripiprazole or lurasidone may well be good options.

Conclusions

• All antipsychotics have the same level of efficacy with the exception of clozapine. Clozapine is the only treatment available for treatment-resistant schizophrenia
• Patient preference is paramount
• Each atypical has a different set of side effects. Knowledge of those will help to decide the tolerability on an individual patient basis
• The frequency of dosing and dosage form are also an important factor to take into account.

Key points

• Atypical antipsychotics are essentially identical from an efficacy perspective; the differences between them are predominantly in their tolerability profiles.
• Knowledge of the pharmacology of the different agents allows prediction of many of the adverse effects experienced.
• Pragmatic considerations such as once-daily dosing and flexibility of available dosage forms are important.
• Patient preference is paramount with respect to choice of agent used.

Authors

Nikki Holmes MPharm MRPharmS MCMHP DipPsychPharm NMP
Head of Pharmacy – Forensic Directorate, Nottinghamshire Healthcare NHS Foundation Trust
Vice President, College of Mental Health Pharmacy
Email: [email protected]

Juliet Shepherd BPharm MRPharmS CertPsychPharm
Mental Health Lead Pharmacist, Wye Valley NHS Trust
Honorary Secretary, College of Mental Health Pharmacy

References

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