Antipsychotic dose : from research to clinical practice

A case note study of antipsychotic prescribing In an inner London hospital showed that although doses of individual drugs were below the British National Formulary limits, polypharmacy occurred in a third of cases. Multiple regression analysis showed high doses were associated with a current risk to the self or others and increasing number of previous admissions In patients with mania and treatment non-responsiveness


The study
All patients in the acute wards of Springfield psychiatric hospital, London, who were receiving regular antipsychotic medication were studied during a one month period in 1994.Case notes were examined to obtain data on sociodemographic details, diagnoses and history.This was supplemented, where necessary, by a brief dis cussion with the nurse in charge or the junior psychiatrist.Ward staff had no opportunity to modify prescribing.The current daily antipsychotic dose in mg/day chlorpromazine equivalents was calculated according to the method of Foster (1989).Six patients receiving only risperidone, for which there is no data on chlorpromazine equivalent dosage, were excluded from the analysis.
A psychiatric diagnosis was made from the information available in the case notes.Three diagnostic groups were formed: schizophrenia (including schizoaffectlve disorder, paranoid psy chosis and other non-affective psychoses), mania (including mixed affective disorder), and 'other'.The broad classification of schizophrenia was used for comparison with studies of optimum antipsychotic dose.
Other psychotropic drugs additionally pre scribed regularly to the sample included benzodiazepines (10 patients), lithium (19 patients), anticonvulsants (seven patients) and antidepressants (13 patients).Those with schizophrenia or mania who were additionally prescribed lithium or an anticonvulsant received a median dose of 1000 mg chlorpromazine equivalents and the three patients prescribed benzodiazepines re ceived a median dose of 1900 mg.
Using multiple regression analysis, the doses in chlorpromazine equivalents prescribed to men (median 847 mg/day) and women (median 666 mg/day) were not significantly different.Patients with schizophrenia (median dose of 848 mg, 50% interquartile range 500-1250 mg) and those with mania (median dose 800 mg, 50% interquartile range 550-1200 mg), received strik ingly similar doses but those with other diagnoses (most frequently depressive disorder) received a significantly lower dose (median 300 mg).
Within each diagnostic group an attempt was made using multiple regression analysis to model the variation of the antipsychotic dose In chlorpromazine equivalent with a range of sociodemographic and clinical factors.The multiple regression models proposed were of the form: antipsychotic dose=a+.T/?1Xi where X, represented the variables age, gender, ethnicity, history of violence, risk of self-harm, risk of harm to others, Mental Health Act status, drug or alcohol history, acute disturbance, treatment unresponsiveness and number of previous admissions.In those with schizophre nia, the only variable with which higher antipsychotic dose was significantly associated at the 5% level was a history of treatment unrespon siveness.In those with mania, higher antipsycho tic dose was significantly associated with a current risk to the self or others, and increasing numbers of previous admissions.
High dose antipsychotic was defined as >1000mg chlorpromazine equivalent per day and was prescribed to 34 (41%) patients with schizophrenia, 6 (37.5%) patients with mania but to none of those with other diagnoses.Only one patient was prescribed a single drug at higher dose than recommended by the British National Formulary (BNF; British Medical Association and Royal Pharmaceutical Society of Great Britain, 1993).A separate univariate analysis was used to examine the characteristics of the patients with schizophrenia receiving high dose antipsychotics.This was strongly associated with a history of violence (x2=8.41,d.f.= l.P=0.004), and a mental state characterised by a risk of self-harm, harm to others or severe disturbance (x2=4.91,d.f.=l, P=0.027).

Comments
This study shows that the guidelines in the Royal College Consensus Statement are being adhered to with regard to the use of individual antipsychotic drug doses within the maximum limits set by the BNF.However, antipsychotic polypharmacy occurred in nearly a third of all patients, and as a result high doses (>1000 mg chlorpromazine equivalents) were prescribed to 40% of patients with diagnoses of schizophrenia and mania.
The factors that predicted high dose prescribing can be divided into two groups.First, those that were prescribed for their sedative effects in patients suffering from schizophrenia with acute disturbance or a history of violence, and in patients with mania at risk of harming them selves or others.This suggests they are used in preference to benzodiazepines which were only regularly prescribed to 10% of the sample.Additionally, this cross-sectional data suggests that the use of other agents (e.g.mood stabilisers The other important indicator of high dose prescription was illness with a poor outcome.Measures of chronicity in patients with mania (increasing number of admissions) and treatment resistance in patients with schizophrenia were associated with increased prescribed dose.Alter native strategies for the management of treat ment resistance (Royal College of Psychiatrists, 1994) include review of diagnosis and compli ance, dose reduction, clozapine (only used in 3% of our sample despite 27% being treatment resistant), augmentation with mood stabilising drugs where appropriate, and re-evaluation of environmental Stressors.
This study has addressed the patient charac teristics associated with the receipt of high dose antipsychotic drugs but is of limited value in explaining the therapeutic rationale behind such decisions.Further studies are needed to investi gate the attitudes of psychiatrists to the use of high dose antipsychotics and polypharmacy.

Conclusion
Patients are frequently prescribed higher doses of antipsychotics than supported by research find ings, even though keeping within safe BNF limits.High dose treatment arises from polypharmacy and carries increased risk of toxic effects, for example Parkinsonism and akathisia, with sub sequent risk of non-compliance and limited evidence of therapeutic advantage.It is recom mended that psychiatrists reduce polypharmacy, consider alternative options for treatment refrac tory patients, attempt careful dose reductions in patients receiving high doses and locally audit their antipsychotic prescribing practices.

Second Edition
Edited by Dinesh Bhugra and Alistair Burns Since the last edition rapid changes in the NHS have meant that clinicians have had even less time to manage change and keep up to date with health reforms.For this new edition, all the existing material has been extensively revised.In addition, eight new chapters have been added, including a section on changes and conflicts covering large areas of potential difficulty that clinicians may have to deal with.As before, the emphasis is on how to get the best for and from services.Practical advice is given on management.Negotiation techniques and time and stress management are also covered.

Table 1 .
Patient characteristics and antipsychotic drug prescriptions