Antipsychotics remain the mainstay of long-term treatment for schizophrenia. This article gives a brief overview of the commonly used antipsychotics, summarises the evidence and describes the key differences between them
Nicola Carson MPharm
Medicines Information Manager
Central and North West London NHS Foundation Trust, UK
Caroline Parker FFRPS FRPharmS FCMHP
Consultant Pharmacist, Adult Mental Health
Central and North West London NHS Foundation Trust, UK
Schizophrenia is a chronic debilitating disorder with a life time incidence of approximately 1 in 100 people. It is associated with a reduction in life expectancy and an increased risk of suicide. The main symptoms are classed as ‘positive’, which includes hallucinations such as hearing voices, delusions and muddled thoughts; and ‘negative’ symptoms such as being withdrawn, difficulty concentrating and lack of thoughts. Antipsychotics are the core treatment of schizophrenia and are used both to treat the acute positive and negative symptoms and maintain remission.
The typical or ‘first generation’ antipsychotics have been used since the 1950s when chlorpromazine was introduced. They are antagonists at the dopamine D2 receptor, which remains the target for antipsychotics to this day. The effectiveness of antagonists that target this receptor is the basis for the dopamine theory of schizophrenia, where hyperactivity of the mesolimbic dopamine pathway is hypothesised to be the cause. The typical antipsychotics are commonly associated with movement disorders called extrapyramidal side effects (EPSEs), which add to the stigma of schizophrenia. EPSEs are dose related and most occur early in treatment or after a dose change and are generally reversible. However, tardive dyskinesia is an EPSE that occurs after long-term treatment and may remain, or even worsen, if antipsychotics are stopped. Typical antipsychotics also frequently lead to raised prolactin levels which can cause problems such as breast growth in men and amenorrhoea and galactorrhoea in women.
The atypical or ‘second generation’ antipsychotics were heralded as the new era in schizophrenia treatment when they started entering the European market in the 1990s. It was hoped that they would provide more effective treatment without the troublesome EPSEs. As well as targeting the D2 receptor, most atypicals also targeted the 5-HT2A receptors and the balance between activity at D2 and 5-HT2A is now thought to be important to their mechanism of action. Although it is true that the atypical antipsychotics are much less likely to cause EPSEs, they have introduced a new problem, that of cardiometabolic side effects to an extent not seen with the typicals.1 They can cause glucose dysregulation and diabetes, weight gain and hypercholesterolaemia, with the resulting increased risk of cardiovascular disorders.
Aripiprazole is sometimes described as a third generation antipsychotic: it is a potent partial agonist at the D2 and 5-HT1A receptor and 5-HT2A antagonist. It was hoped that partial agonism of the D2 receptor might reduce the adverse effects seen with conventional antipsychotics. In contrast to the other atypicals, aripiprazole has a low risk of causing weight gain and diabetes;1,2 however it has not been shown to be more efficacious.
Although classically antipsychotics are referred to as typical and atypical it is more helpful to think of them on a continuum as many of the properties of the two groups overlap and there is not a clear distinction between them (see Figure 1).
In addition to activity at D2 and 5-HT receptors, nearly all antipsychotics additionally act at a range of other receptors. These effects do not contribute to their antipsychotic efficacy, but can cause a range of other adverse effects commonly including sedation, anticholinergic effects and cardiovascular effects.
After many years of debate it is now clear that with the exception of clozapine, the newer atypicals are no more effective than the typical antipsychotics although meaningful differences in response are seen in individual patients. A number of clinical trials and meta-analyses have shown that there is little difference in the effectiveness of antipsychotics, with the only major differences being in adverse effects.1–4 Discontinuations due to either poor efficacy or adverse effects are high among both classes. As a result, major UK guidelines do not differentiate between them in that respect.5–7
Antipsychotics therefore are a growing group of agents differentiated only by their spectrums of adverse effects.1 Excluding clozapine, the only real improvement seen in the development of the atypicals was an improvement in the treatment of negative symptoms on which the typical antipsychotics appeared to have little effect and may in fact worsen. The authors of a major trial in schizophrenia comparing atypicals to perphenazine, a typical, noted that there was no measurable difference in quality of life, compliance or efficacy.3 Lack of remission and poor tolerability was just as apparent with the atypicals as with the typicals.3,4
Onset of action
Antipsychotics work fairly quickly, so initial effects may be noticed in a week and an antipsychotic response normally seen within two weeks at an effective dose, although a full effect may take longer.8 If no response is seen after two weeks then consideration is given to either increasing the dose or switching to an alternative. Some effects, such as sedation, can be seen within a few doses and can be helpful in calming an acutely agitated patient. It is important to treat the patient quickly; those left untreated for long periods are often slower to respond and more difficult to treat and generally have a poorer prognosis than those who get effective treatment quickly.9 As schizophrenia is a chronic illness, long-term treatment is required after recovery to prevent relapse.
Compliance and depot antipsychotics
Patient compliance, or adherence, with prescribed medicines is notoriously a problem across all patient groups, including those with chronic and severe physical and mental health illnesses such as schizophrenia. Non-compliance is associated with relapse, and repeated or long relapses are thought to be the cause of loss of brain function and cognitive decline that is seen in some patients.
Some antipsychotics are formulated as depots (long-acting injections). These are commonly used for patients where oral formulations are not suitable, such as those who struggle to remember to take medicines every day. There are currently four atypical and five typical antipsychotic depots available in the UK, although pipotiazine has recently been discontinued. They are administered between every week to every five weeks. There is very little difference in efficacy between the depots and side effects are similar to their oral equivalents. The main differences are related to their pharmaceutical formulations and kinetics.
Up to one in three patients with schizophrenia are ‘treatment resistant’, that is, they have failed to respond to at least two antipsychotics given at an adequate dose for an adequate length of time. Clozapine, the first atypical antipsychotic, is the only antipsychotic that has been shown to be effective in treatment resistance and more effective than other antipsychotics. The use of clozapine is restricted by serious haematological side effects, neutropenia and agranulocytosis, necessitating frequent blood monitoring. Compliance, either with the associated regime for blood monitoring as well as with the tablets themselves, are its major limiting factors. Clozapine can be used in patients who have failed to respond to at least two antipsychotics, although in practice its use is often delayed and in many cases it is inappropriately considered to be the treatment of last resort. Stopping clozapine suddenly can cause distressing rebound psychoses. As it is only available orally, clozapine does not provide an option for the many treatment resistant patients who struggle with compliance of oral medications. Clozapine is not associated with EPSEs but can cause significant weight gain and is high risk for precipitating diabetes and high cholesterol. Its prescribing is restricted to psychiatrists.
Lurasidone, a dopamine D2 receptor and serotonin 5-HT2A/7 receptor antagonist, is the newest antipsychotic to enter the European market for the treatment of schizophrenia.10 It has provided another option for patients for whom metabolic side effects are a problem. However, EPSEs may be more problematic than with other atypicals.2,9 No evidence suggests it has any advantage over other antipsychotics in terms of efficacy. Other recent antipsychotics include asenapine, however this is currently only licenced for the treatment of moderate to severe manic episodes associated, with bipolar I disorder; and loxapine, a typical antipsychotic, which is now licensed as a breath-actuated device for the rapid control of mild to moderate agitation.
There are currently only four antipsychotics in the pipeline and a handful of augmenting agents aimed at treatment resistive cases as adjuncts. The new antipsychotics still focus heavily on antagonising the D2 receptor, as well as looking to improve treatment of specific symptoms (for example, cognitive deficit) or minimising adverse effects (for example, metabolic adverse effects). None are likely to provide major advances in treatment and are at best refining current treatments.
The treatment of schizophrenia has not seen any major breakthroughs in development of medications since the introduction of the first antipsychotics and treatment remains inadequate for many patients. Side effects are a significant burden for many patients making it difficult to achieve an acceptable balance of effect and adverse effects. Major advances in treatment are needed.
- Clozapine, the first atypical antipsychotic, is the only antipsychotic that has shown to be effective in treatment resistance.
- All other antipsychotics have been shown to be equally effective although significant individual patient differences in response are seen.
- Side effects between antipsychotics are significantly different and this should be used to tailor drug choice to the individual patient.
- Adherence to long-term treatment is important to prevent relapse and poorer long-term prognosis.
- Chronic side effects of antipsychotics can be distressing and cause discontinuation; they need to be recognised and managed effectively.
- Leucht S et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013;382:951–62.
- Leucht S et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009;373:31–41.
- Lieberman JA et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209–23.
- Jones PB et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006;63:1079–87.
- Barnes TRE et al. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2011;25:567–620.
- National Institute for Health and Care Excellence (NICE). Clinical Guideline: CG178 Psychosis and schizophrenia in adults: treatment and management. February 2014.www.nice.org.uk/guidance/cg178.
- Scottish Intercollegiate Guidelines Network (SIGN). Management of Schizophrenia: SIGN publication number 131. March 2013. www.sign.ac.uk/guidelines/fulltext/131/.
- Agid O, Seeman P, Kapur S. The ‘delayed onset’ of antipsychotic action – an idea whose time has come and gone. J Psychiatry Neurosci 2006;31:93–100.
- Marshall M et al. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch Gen Psychiatry 2005;62:975–83.
- Citrome L et al. Long-term safety and tolerability of lurasidone in schizophrenia: a 12-month, double-blind, active-controlled study. Int Clin Psychopharmacol 2012;27:165–76.
- NICE guidelines on Psychosis and schizophrenia in adults: treatment and management: www.nice.org.uk/guidance/cg178.
- British Association of Psychopharmacology evidence based guidelines for the pharmacological treatment of schizophrenia: www.bap.org.uk/pdfs/Schizophrenia_Consensus_Guideline_Document.pdf.
- Royal College of Psychiatry www.rcpsych.ac.uk/.
- Mind: www.mind.org.uk/.