Balancing the benefits and harms of antipsychotic therapy
Published in MedicineWise News
Date published: About this date
- Assess benefits and harms of antipsychotic therapy
- Engage patients and carers in recognising and managing adverse effects
- Reinforce the importance of adherence to antipsychotics when prescribed
- Review ongoing need for antipsychotics for behavioural symptoms of dementia and trial withdrawal
Assess benefits and harms of antipsychotic therapy
Most clinical data for antipsychotics are from trials in schizophrenia and bipolar I disorder. Adverse effect data reported in these conditions are also useful for clinical decision-making in other psychotic disorders for which there is less evidence.
Antipsychotic choice in schizophrenia requires individual tailoring
Drug safety profiles and patient risk factors for adverse effects should guide antipsychotic choice. Weigh up the potential to cause metabolic side effects (e.g. weight gain), extrapyramidal side effects (including tardive dyskinesia) and other common problems such as sedation or anticholinergic effects (see Table 1).1,2
On average, the trade-off between efficacy and adverse effects does not favour any particular antipsychotic.2 The newer “atypical” antipsychotics are most frequently prescribed, but recent trials challenge the view that they are more effective overall than older “conventional” antipsychotics.3
Antipsychotic maintenance therapy prevents relapse of hallucinations, delusions and abnormal behaviours in schizophrenia; however, achieving an acceptable outcome involves trial and error. Lack of clinical response or poor tolerability can occur with any antipsychotic. Assess regularly and, if necessary, review choice of antipsychotic and dose.1
Table 1: Selected common and serious adverse effects of oral antipsychotics1,10
Antipsychotics are one of several options in bipolar disorder
Antipsychotics, lithium, antidepressants and anticonvulsants all have a place in treating bipolar disorder.1,4,5 The likelihood of short- and long-term adverse effects, patient preferences and individual risk factors will influence the choice of treatment. Diagnosis and treatment selection for people with bipolar disorder requires specialist expertise and, as in schizophrenia, multiple therapeutic trials may be necessary.
Consider adjunctive psychotherapy for people who are relatively stable but have mild to moderate affective symptoms. Psychotherapy can improve symptoms and reduce relapse rates.4,6
There is some evidence for using antipsychotics in all phases of bipolar disorder. However, the relative effectiveness of antipsychotics versus other drugs such as lithium is uncertain. Only a few antipsychotics have been adequately assessed in randomised controlled trials for relapse prevention or bipolar depression, and evidence supporting use of antipsychotics for people with bipolar II disorder (i.e. who do not experience full-blown mania) is limited.1,4,5 (See table of antipsychotic approved indications and PBS listings.)
Non-pharmacological approaches are first line for behavioural symptoms of dementia
Rule out physical causes of distress or delirium, medicines that can impair cognition, environmental factors and diagnoses such as depression before considering other treatment.1
Ensure carers have access to advice and training in behaviour management techniques (see list of programs and resources for carers and consumers).
A variety of psychosocial and other non-drug therapies can reduce agitation and aggression associated with dementia, with a low risk of adverse effects.7 An individually tailored non-pharmacological approach is first line, given that antipsychotics have limited efficacy and can cause serious or intolerable adverse effects.
Use an antipsychotic only if aggression, agitation or psychotic symptoms of dementia cause severe distress or an immediate risk of harm
Risperidone has the most evidence for efficacy in managing behavioural symptoms of dementia and is the preferred antipsychotic. Olanzapine is an alternative, but is not PBS listed for this indication. Other antipsychotics may be efficacious; however, there is less evidence to support their use. Continue non-pharmacological approaches during antipsychotic treatment.1
Discuss the proposed treatment with the patient, family or carer. Contact the State or Territory Adult Guardian, Public Guardian or Public Advocate’s office for information about the legislation on substitute consent.
With any antipsychotic, adverse effects such as parkinsonism, sedation, confusion and falls offset reductions in symptoms. In one large trial, failure to respond or intolerable adverse effects caused most patients to discontinue treatment.8
Other pharmacological treatments do not have established efficacy in managing behavioural symptoms.9
Engage patients and carers in recognising and managing adverse effects
Use multiple methods to assess side effects
Ask about adverse effects as part of routine patient review; it may also help to provide written information about antipsychotics so that patients are aware of what to expect (see Box 1). Most people with a psychotic illness experience one or more troublesome adverse effects day to day.11 While these effects reduce quality of life and may cause poor adherence, relatively few report them to their GP or psychiatrist without prompting.12
Manage according to patient needs and relapse risk
Adverse effects may subside a few weeks after starting or altering treatment, or may be manageable with non-drug approaches. When unacceptable adverse effects persist, a change in regimen is preferable to non-adherence. If symptoms are well controlled, assess if the dose can be reduced without risk of relapse.1
Switching to an antipsychotic with a different adverse effect profile is often necessary, for example in case of rapid weight gain or metabolic abnormalities. The protocol for tapering from the old drug to the new one should be worked out with a psychiatrist. Engage patients and carers, informing them about the risk of relapse or temporary exacerbation of adverse effects during the changeover period, as well as the potential benefits.1
Box 1: Information for patients and carers about mental health and antipsychotic treatment
- Antipsychotic medicine brochure. Includes information on how to take antipsychotics, precautions to take and common side effects.
- SANE Australia, for information on schizophrenia and bipolar disorder, as well as on antipsychotic treatment.
Beyond Blue and the Black Dog Institute for information on bipolar disorder
- Alzheimer’s Australia for information about behavioural symptoms of dementia and advice about non-pharmacological treatments and support for carers.
Regularly monitor the physical health of people receiving antipsychotics long term
Monitor for cardiometabolic risk factors, burdensome adverse effects such as extrapyramidal symptoms or symptoms of hyperprolactinaemia (e.g. sexual disturbances, amenorrhoea or gynaecomastia).1 Australian survey data indicate a high prevalence of cardiovascular and metabolic risk factors.13 Prompt management can forestall serious long-term adverse effects of antipsychotic treatment. A checklist of suggested items for review along with a template for monitoring results is available for download.
Additional monitoring may need to be negotiated with other members of the mental health team, depending on risk factors or for people on particular drugs.
GPs have a leading role in managing the physical health of people taking antipsychotics and GP visits may be the only opportunity to receive lifestyle assessment and support, allied health referrals or preventive health screening. People with serious mental illness often have poor physical health, which can be a consequence of the adverse effects of antipsychotics, poor diet, a lack of physical activity, and alcohol and illicit drug use.
There is also evidence that limited access to healthcare adds to the problem.14
Monitor symptoms intensively in people with dementia receiving an antipsychotic
When starting antipsychotic therapy for agitated or aggressive behaviour in dementia:
- assess the targeted behaviour weekly
- measure blood pressure at baseline and within the first 7 days of treatment
- check body weight and blood glucose at baseline
- observe closely for signs of sedation, postural hypotension, extrapyramidal symptoms (e.g. abnormal movements of the face, arms, legs or trunk) or anticholinergic effects (e.g. dry mouth, constipation, urinary hesitancy or delirium).1,15
Reinforce the importance of adherence to antipsychotics when prescribed
Poor adherence is strongly associated with relapse of psychotic illness
Assess adherence to antipsychotic therapy regularly and systematically.2 As well as asking about side effects, ask about attitudes to and problems taking medicines.16 Simple measures can help adherence, especially addressing troublesome adverse effects (see Box 2).1 Risk factors for non-adherence include alcohol and illicit drug use, lack of family involvement, poor clinician–patient relationship and a negative attitude towards treatment.17 In one study, people with recent-onset schizophrenia were several times more likely to relapse if they had poor adherence (odds ratio 14.6, 95% confidence interval 3.3 to 64.0).18
Box 2: Practical measures to promote adherence1
- Provide and discuss written information and personalised instructions
- Prescribe the simplest dosing regimen possible
- Give positive feedback for treatment adherence
- Assess and address adverse effects
- Involve family, carers or friends when appropriate
- Suggest daily routines as prompts to remind patients to take their medicines
- Monitor use, e.g. consider medication review
- Enquire about patients’ preference for using any particular dosage form
Review ongoing need for antipsychotics for behavioural symptoms of dementia and trial withdrawal
Discontinue antipsychotic use if there is no improvement in the targeted behaviour
Response usually occurs in 1–2 weeks19; discontinue if there is no improvement within 12 weeks and reassess. An alternative antipsychotic may be tried. The incremental benefit of antipsychotics over placebo is small, for example in 3 randomised controlled trials of 12 weeks, an average of 46% of participants treated with risperidone responded, compared with 33% of participants treated with placebo (odds ratio 1.8, 95% confidence interval 1.4 to 2.3).19
Cease antipsychotics gradually—taper the dose by 50% every 2 weeks and continue for 2 weeks on the minimum dose before stopping.
Review at least every 3 months
If symptoms are stable, try a gradual dose reduction and withdrawal. Review the targeted behaviour, changes in function and treatment-related adverse effects every 3 months or according to clinical need.1 Behavioural symptoms can fluctuate significantly or resolve within 12 weeks, as reflected in the high placebo response rates in clinical trials. People with dementia whose behavioural symptoms are under control often show no worsening when they stop antipsychotics.20-22
Antipsychotic use in dementia is associated with serious adverse effects
Trial data show an excess of approximately 1 death for each 100 people with dementia treated with risperidone, olanzapine, quetiapine or aripiprazole for 10–12 weeks.23 Deaths appeared to be cardiovascular or infectious (e.g. pneumonia) in nature.24 This risk appears to extend to all antipsychotics.25
Expert reviewersProfessor Brian Draper MBBS MD FRANZCP Professor (Conjoint), School of Psychiatry, University of NSW
Dr Bill Lyndon MBBS FRACGP FRANZCP Director, Mood Disorders Unit, Northside Clinic Clinical Senior Lecturer, Department of Psychological Medicine, University of Sydney
- Therapeutic Guidelines: Psychotropic. 6th ed, 2008.
- National Institute for Health and Clinical Excellence. Schizophrenia. Core interventions in the treatment and management of schizophrenia in adults in primary and secondary care (updated edition). Clinical Guideline No. 82. 2009. (accessed 29 April 2011).
- Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009;373:31–41.
- National Institute for Health and Clinical Excellence. Bipolar disorder. The management of bipolar disorder in adults, children and adolescents, in primary and secondary care. Clinical Guideline No. 38. 2006. (accessed 9 June 2011).
- Yatham LN, Kennedy SH, Schaffer A, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar disorders 2009;11:225-55.
- Miklowitz DJ. Adjunctive psychotherapy for bipolar disorder: state of the evidence. Am J Psychiatry 2008;165:1408-19.
- O'Connor DW, Ames D, Gardner B, et al. Psychosocial treatments of behavior symptoms in dementia: a systematic review of reports meeting quality standards. Int Psychogeriat 2009;21:225–40.
- Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med 2006;355:1525-38.
- Ballard C, Gauthier S, Corbett A, et al. Alzheimer's disease. Lancet 2011;377:1019-31.
- Haddad PM, Sharma SG. Adverse effects of atypical antipsychotics : differential risk and clinical implications. CNS Drugs 2007;21:911-36.
- Castle D, Morgan V, Jablensky A. Antipsychotic use in Australia: the patients' perspective. Aust N Z J Psychiatry 2002;36:633–41.
- Cascade E, Kalali AH, Mehra S, et al. Real-world data on atypical antipsychotic medication side effects. Psychiatry 2010;7:9-12.
- John AP, Koloth R, Dragovic M, et al. Prevalence of metabolic syndrome among Australians with severe mental illness. Med J Aust 2009;190:176–9.
- Lawrence D, Kisely S. Inequalities in healthcare provision for people with severe mental illness. J Psychopharmacol 2010;24:61-8.
- Ruby C, Kennedy D. Psychopharmacologic medication use in nursing home care. Clinics Fam Pract 2001;3:577-98.
- Velligan DI, Weiden PJ, Sajatovic M, et al. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry 2009;70 Suppl 4:1-46.
- Masand PS, Narasimhan M. Improving adherence to antipsychotic pharmacotherapy. Current Clin Pharmacol 2006;1:47-56.
- Morken G, Widen JH, Grawe RW. Non-adherence to antipsychotic medication, relapse and rehospitalisation in recent-onset schizophrenia. BMC Psychiatry 2008;8:32.
- Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry 2006;14:191–210.
- Ballard C, Lana MM, Theodoulou M, et al. A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Med 2008;5:e76.
- Ballard CG, Thomas A, Fossey J, et al. A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: the neuropsychiatric inventory median cutoff is a predictor of clinical outcome. J Clin Psychiatry 2004;65:114-9.
- Fossey J, Ballard C, Juszczak E, et al. Effect of enhanced psychosocial care on antipsychotic use in nursing home residents with severe dementia: cluster randomised trial. BMJ 2006;332:756-61.
- Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005;294:1934–43.
- US Food and Drug Administration. FDA Public Health Advisory. Deaths with antipsychotics in elderly patients with behavioral disturbances. 2005. (accessed 17 June 2011).
- Mittal V, Kurup L, Williamson D, et al. Review: Risk of cerebrovascular adverse events and death in elderly patients with dementia when treated with antipsychotic medications: A literature review of evidence. Am J Alzheimers Dis Other Demen 2011;26:10–28.