Combining antipsychotics

Transcription

1 Combining antipsychotics Can it be justified? workbook P O M H U K PRESCRIBING OBSERVATORY FOR MENTAL HEALTH

2 Can it be justified? DEBIT Acknowledgements This workbook is based on the text of a workbook developed for the DEBIT study by Dr A Thompson MRCPsych, MSc (Department of Psychiatry, University of Bristol) and Dr P Rogers R.M.N., PhD, (Institute of Psychiatry, London). The DEBIT project was undertaken with a UK Department of Health grant; the lead investigator was Professor Glynn Harrison. This workbook was printed thanks to funding from Oxleas NHS Foundation Trust.

3 Introduction Thank you for taking the time to work through this workbook. The use of combinations of antipsychotics ( antipsychotic polypharmacy ) has become a major issue in clinical practice. This workbook is designed for all those involved in prescribing, dispensing or administering antipsychotic drugs, and is also relevant to all staff who discuss this medication with patients. It will to help you to review the use of combined antipsychotics in your own clinical practice, and provides an update of the latest evidence in this area. The workbook is yours to keep and we hope you will find it useful and refer to it again in the future. If you complete all of the tasks in the workbook you can receive a certificate of participation in this POMH-UK audit project. Appendix 4 contains full details of how to do this. Carol Paton and Thomas Barnes Joint Heads of POMH-UK

4 Can it be justified?

5 Contents Page Section 1: An overview Page What do clinical guidelines recommend?... 5 What happens in practice?... 7 How often are combinations of antipsychotics prescribed?... 7 Why are combinations of antipsychotics used?... 8 How good is the evidence that two antipsychotics are better than one? 9 Summary What are the potential problems with combined antipsychotics? How good is the evidence? What do patients think? Prescribing and administering of medicines Section 2: Routes to the use of combined antipsychotics Understanding combined antipsychotics; the four steps The SOMETHING that happens The INTERPRETATION The PERMISSION GIVING THOUGHTS The ACTION Section 3: Breaking the cycle Begin now Work as a team Be aware of your interpretation of events Use the alternatives (Non-pharmacological) Use the alternatives (Pharmacological) As required (PRN) medication Be aware of giving yourself permission thoughts Summary References Appendix 1: Recommended dose ranges for individual antipsychotics Appendix 2: Antipsychotic dose ready reckoner Appendix 3: Summary of the evidence supporting the use of combined antipsychotics.. 37 Appendix 4: How to obtain a certificate of your participation in this topic Your Notes... 40

6 What do guidelines recommend? Section 1: An overview Antipsychotic medication is the mainstay of treatment for psychotic disorders such as schizophrenia. NICE has produced: 1. A clinical guideline for the treatment of schizophrenia. You can find this at NICE have also produced a training package to help you understand how the guideline was developed and to take you through the main recommendations ( 2. A clinical guideline for the management of violence. You can find this at 3. A health technology appraisal for the use of atypical antipsychotics in schizophrenia (HTA 43). You can find this at 05

7 TASK A This task could be shared between the clinical team with each member looking at one guideline and sharing their findings with others. This task will take time; you can progress through the workbook while your team is still working on this task. Look at the HTA and the NICE guidelines listed opposite. What are the key recommendations for the use of antipsychotic drugs? 1. In the management of behavioural disturbance? 2. To treat an acute episode of schizophrenia? 3. In treatment resistant schizophrenia? 06

8 What happens in practice? In line with published prescribing guidelines such as those developed by NICE, most people with a psychotic illness only receive one antipsychotic at a time ( antipsychotic monotherapy ). However, the use of more than one antipsychotic medication ( combined antipsychotics ) for an individual patient is a common clinical strategy. There is a lack of good evidence for the therapeutic effectiveness of this approach, and concerns about possible harm. How often are combinations of antipsychotics prescribed? National and international surveys have consistently found that the use of more than one antipsychotic medication is common. For example, a recent UK survey by the Royal College of Psychiatrists Research Unit found that nearly half (48%) of those patients on antipsychotics were prescribed two or more (Harrington et al 2002a). There was a wide variation between Trusts in the number of patients prescribed combinations (Harrington et al, 2002b). Combined antipsychotics were more commonly used in patients who were young, male, detained under the Mental Health Act, had a diagnosis of schizophrenia and occupied a rehabilitation or forensic bed. These factors accounted for only a small proportion of the variance between services; much was unexplained. Prescribing in this way is not only seen in the UK. In a US survey, over 50% of all patients with persistent psychotic disorders in extended care units received more than one antipsychotic (Ereshefsky, 1999). Canadian research found that 27.5% of discharged patients diagnosed with schizophrenia were prescribed antipsychotic combinations (Procyshyn et al, 2001). In the US, a recent study of polypharmacy within the California Medicaid program showed that 11% of patients received two antipsychotic for more than 60 consecutive days (Stahl et al., 2002). 07

9 Why are combinations of antipsychotics used? Combinations of antipsychotics are usually used for one of the following reasons: Reasons given by clinicians 1. To manage acute behavioural disturbance (oral PRN) 2. To manage acute behavioural disturbance (IM Rapid Tranquillisation ) 3. To manage chronic behavioural disturbance 4. To manage relapse in a patient previously stabilised on a single antipsychotic 5. While switching from one drug to another 6. To speed up the onset of effect or enhance the size of the therapeutic effect 7. To target different symptoms/symptom domains 8. To reduce side effects 9. To allow administration by a different route 10. Individual patient s/carer s choice 11. Treatment resistant schizophrenia TASK B: Look through the medicine cards on your ward today. How many patients are prescribed combinations of antipsychotics (include PRN prescriptions whether they have been administered or not)? Choose one patient who is currently being prescribed multiple antipsychotics, and consider the following questions: 1. Why has more than one antipsychotic been prescribed for this patient? 2. How good do you think the evidence is to support prescribing in this way? 80

10 How good is the evidence that two antipsychotics are better than one? 1. In managing acute behavioural disturbance (oral PRN)? Poor. Several studies show that some oral antipsychotics are effective in managing acute behavioural disturbance (eg Currier & Simpson, 2001). These studies recruited patients who presented when acutely unwell. The majority were not taking regular antipsychotics. The effectiveness of oral PRN in patients who are already taking a regular antipsychotic drug is very poorly studied. 2. In managing acute behavioural disturbance (IM RT )? Poor. NICE recommends IM olanzapine or IM haloperidol in patients whose behaviour is driven by psychosis. Trial evidence is in patients not receiving regular antipsychotics (eg Wright et al, 2001; Alexander et al, 2004). Patients who are acutely disturbed are at increased risk of having electrolyte disturbances (secondary to dehydration) and a prolonged QTc interval on their ECG (a risk factor for developing a cardiac arrhythmia; Hatta et al, 1999). Street drugs can precipitate acutely disturbed behaviour. These drugs are commonly used and some, such as cocaine and methadone can also increase the risk of cardiac arrhythmias. In the short term, a benzodiazepine alone may be as effective and safer than an antipsychotic. The manufacturers of IM olanzapine warn against the use of IM olanzapine in higher than recommended doses (20mg/day including oral) and in combination with benzodiazepines (see 3. In managing chronic behavioural disturbance? None. There is no evidence from systematic studies to support the use of combinations of antipsychotics. There is some evidence that clozapine alone is useful in the management of chronic aggression (eg Glazer & Dickson, 1998). 4. In managing relapse in a patient previously stabilised on a single antipsychotic? Poor. There are no studies of antipsychotic combinations. One unpublished study found that increasing the dose of an established antipsychotic in a relapsed patient is no more effective than continuing with the same dose. 5. While switching from one drug to another? Limited. The dose of some antipsychotics (eg clozapine) needs to be increased slowly and cross titration is sensible. This should be complete in 4-6 weeks. For drugs that do not require initial dosage titration (eg olanzapine and aripiprazole), a washout period or tapering of the dose is probably unnecessary when switching. 6. To speed up the onset of effect or enhance the size of the therapeutic effect? Poor. High initial doses do not produce an earlier or better response (eg Rifkin et al, 1991). There is no convincing evidence that combinations improve outcome (eg Centorrino et al, 2004). The sedation and physical slowing (parkinsonism) caused by high doses of antipsychotics are side effects that should not be confused with antipsychotic effect. 9

11 7. To target different symptoms/symptom domains? Poor. Antipsychotics have differential sedative effects but there is limited evidence to support clinically meaningful differences on positive, negative or affective symptoms. 8. To reduce side effects? Poor. In most patients it is likely that side effects will be increased (Centorrino et al, 2004). 9. To allow administration by a different route? Uncertain. Very few antipsychotics are available in short acting IM, depot or oro-dispersible formulations. Reasonable attempts should be made to choose and use one route of administration. Combinations may be useful in some clinical circumstances. 10. Individual patient s/carer s choice? Limited. Choice is not real choice unless it is informed. If the patient can understand the potential risks/side effects and benefits of combining antipsychotics and can come to a reasoned decision, this should be supported. 11. Treatment resistant schizophrenia? Equivocal. Combinations involving clozapine are better studied than combinations involving any other drug. Some studies show a modest clinical benefit from adding a second antipsychotic such as sulpiride (Shiloh et al, 1997) or risperidone (Jossiassen et al, 2005) to clozapine. Other studies have found no benefits (eg Yagcioglu et al, 1995). If other antipsychotic treatments, including clozapine and clozapine augmentation, have failed to produce any improvement, a time-limited, individual trial of combined antipsychotics may be one of very few treatment options left (Stahl 2002) TASK C: Take a few minutes to think about the strength of the evidence for combinations of antipsychotics. 1. Do you think that combinations of antipsychotics should be used as often as they are? 2. Why do you think this? 10

12 Summary What is being advised? In the UK, the BNF, the NICE guideline for the treatment of schizophrenia and the Maudsley Prescribing Guidelines (Taylor et al, 2005) all advise against the routine prescribing of more than one antipsychotic. Similar guidelines/consensus statements from three other English speaking countries (the American Psychiatric Association 1997; RANZCP 2003, working group for the Canadian Psychiatric Association and the Canadian Alliance for Research on schizophrenia 1998) provide similar advice. A summary of the evidence from which this guidance is derived can be found in Appendix 3. Are combinations ever justified? From existing guidelines and the available evidence there are three situations where antipsychotic polypharmacy may be justified:- 1. Where patients are being changed over from one antipsychotic to another. In such cases a short crossover period (of four to six weeks for example) is acceptable. 2. When giving a more sedating and/or injectable antipsychotic drug to someone who is very agitated and who is already receiving another antipsychotic drug on a regular basis ( rapid tranquillisation ). 3. In cases where the patient is receiving clozapine but has not achieved adequate symptom control. What are the potential problems with combined antipsychotics? The following problems can all occur: 1. Difficulty in attributing any benefit 2. Higher than necessary total dosage Potential problems 3. Complex regimen increasing the risk of non-adherence 4. Increased cost 5. Increased side effects (acute or longer term) 6. Drug interactions (pharmacokinetic and pharmacodynamic) 7. Increased duration of hospitalisation 8.?? Increased mortality 11

13 How good is the evidence? 1. Difficulty in attributing any benefit Not knowing which antipsychotic has helped in the short term may lead to the patient continuing to receive a combination/high dose unnecessarily in the long term. 2. Higher than necessary total dosage There is no evidence that high doses of antipsychotics are more effective than standard doses (Lehman et al, 1998). The major cause of high dose prescribing is combinations of antipsychotics (Harrington et al, 2002a). Appendix 1 shows the maximum dose of commonly used antipsychotic drugs and how using more than one antipsychotic can lead to the use of a high dose. TASK D: Use the ready reckoner in Appendix 2 to calculate the total dose of antipsychotic prescribed for a patient on combined antipsychotics. A sample calculation can be found in Appendix Complex regimen increasing the risk of non-adherence In the general population, simple medication regimens involving a small number of tablets are more likely to be taken than complex regimens (Chen, 1991). This is particularly likely to be true in patients with schizophrenia, who may be disorganised, lack motivation and have cognitive deficits. Poor adherence to medication is a major cause of relapse and hospitalisation. 4. Increased cost An average NHS Trust spends about 3% of its total income on medicines and this spend is currently rising by 10-12% a year. Atypical antipsychotics are expensive; most cost for a month s treatment. 5. Increased side effects (acute or longer term) All antipsychotics have side effects. Profiles differ. One study shows that patients who receive combinations have 50% more side effects than those who receive only one drug (Centorrino et al, 2004). 6. Drug interactions (pharmacokinetic and pharmacodynamic) The safety of combinations of antipsychotics has not been studied systematically but there are many published case reports of serious side effects such as cardiac arrhythmias (Chong et al, 1997) and neuroleptic malignant syndrome (Kontaxakis et al, 2002). Interactions may be pharmacokinetic (where one drug interferes with the absorption, metabolism or excretion of another drug) or pharmacodynamic (where two drugs have opposing or additive effects on physiological functioning). For example, there are case reports of risperidone causing a significant rise in clozapine serum levels (a pharmacokinetic interaction; eg Koreen et al, 1995) and a combination of haloperidol and olanzapine causing severe parkinsonian symptoms (a pharmacodynamic interaction; Gomberg, 1999). 12

14 7. Increased duration of hospitalisation One study found that the average length of hospital stay was more than 50% longer in patients who were prescribed combinations of antipsychotics (Centorrino et al, 1994). 8.?? Increased mortality One study found that patients who were prescribed combinations were twice as likely to die over a 10 year period as those who took one antipsychotic (Waddington et al, 1998). A summary of the potential problems associated with combined antipsychotics can be found in Appendix 3. What do patients think? Service user groups and national service user bodies have expressed concerns regarding the side effects of medication and antipsychotic polypharmacy. The National Schizophrenia Fellowship document A Question of Choice (2000) surveyed patients views on medication and other interventions for mental illness. They found that over 16% of respondents with schizophrenia were prescribed two or more antipsychotics. They found, as expected, that side effects were widely experienced and that almost half the respondents said that; The side effects of their medication affected their ability to live their everyday life They had stopped their medication due to side-effects. TASK E: Identify a patient currently on the ward who is prescribed a complex medication regimen. 1. How many tablets does the patient have to take each day? 2. How many times a day is medication prescribed? 3. If you were prescribed these medications, how would you make sure that you remembered to take them all, at the right time each day? 13

15 Prescribing and administration of medicines All professionals are responsible for their own actions irrespective of what others say or do, or the pressure on services. It should be standard practice for prescribers to document the rationale for using combined antipsychotics in clinical notes along with a clear account of any benefits and side effects. For nurses, The Nursing and Midwifery Council Guidelines for the Administration of Medicines states that: As a registered nurse you must maintain your professional knowledge and competence and that You are personally accountable for your practice. This means that you are answerable for your actions and omissions, regardless of advice or directions from another professional The administration of medicines is an important aspect of the professional practice of persons whose names are on the Council s register. It is not solely a mechanistic task to be performed in strict compliance with the written prescription of a medical practitioner. It requires thought and professional judgement.. In exercising your professional accountability in the best interests of your patient you must: Know the therapeutic uses of the medicine to be administered, its normal dosage, side effects, precautions and contra-indications Have considered the dosage, method of administration, route and timing of the administration in the context of the condition of the patient and co-existing therapies. 14

16 TASK F: Patients should receive only one antipsychotic drug unless they meet one of the three exceptions. Can you remember what the three exceptions are? Can you think of any other reasonable exceptions? TASK G: Look at the medicine cards of all patients currently on the ward. Do all patients who are prescribed combined antipsychotics meet one of the three exceptions? 15

17 Section 2: Routes to the use of combined antipsychotics A study conducted by the University of Bristol identified four factors that clinicians (nurses and doctors) felt were important in moulding their practice; 1. The individual clinician s acquired knowledge and learning 2. The individual clinician s interpretation of that knowledge and learning 3. The individual clinician s own past experiences 4. The influence of the social and clinical context in which the individual clinician practices. 1. Acquired knowledge and learning ( What I have been told ) This theme relates to personal prescribing and administration habits that have been shaped over the years from accumulated knowledge gathered from various sources (eg medical and nursing training, opinions of respected colleagues, journals, internet, conferences etc). 2. Interpreted knowledge ( What I make of what I have been told ) This theme relates to how individual clinicians interpret their acquired knowledge. Two clinicians can interpret similar information in two entirely different ways. When discussing a case where two separate antipsychotic medications were being administered, one consultant psychiatrist reported the following interpretation: Conventional clinical wisdom is that you try another compound as different as possible to the first compound, and if the first compound is a compound that targets D2 receptors, then it seems to me to make sense that the second compound should be a compound that has fairly low potency for D2 receptors However, another consultant psychiatrist reported the following interpretation: It [combining antipsychotics] really does not make a lot of pharmacological sense to me 3. Individual past experiences ( What I have learnt from my personal experiences ) This theme relates to how clinical decisions are often guided by an individual clinician s own personal experiences. This leads to drug preferences. These drug preferences can outweigh the evidence base. One consultant psychiatrist reported: I have only used clozapine on a total of three occasions. I had a very bad experience; the first ever patient I put on it ended up in ICU so I was obviously unlucky with that but it stayed in my mind so that has made me reluctant to go down the clozapine line 16

18 One nurse also gave an example of the influence of experience when discussing a hypothetical admission: I do not prescribe or diagnose, my job is to nurse and I am very aware of that but I have got experience enough to know what does and does not work 4. The social and clinical context ( What are the other pressures I face in the real world ) This theme relates to what clinicians described as the difference between the ideal and the real world of patient care. Many factors are at play such as inherited cases with established treatment patterns, patients requiring rapid tranquillisation, and practical issues relating to time and other resources affecting prescribing decisions. One consultant psychiatrist gave an example of this: - It is not the way I would want to ideally treat them [prescribing more than one antipsychotic] but it is very difficult when patients you have inherited have been on that long term Understanding combined antipsychotics: The four steps Given that most clinicians understand that there is no good evidence to support the increased efficacy of combined antipsychotics and that prescribing in this way increases the risk of an adverse event, it should be a general rule in psychiatric clinical practice that antipsychotic polypharmacy (apart from the three exceptions noted) should not occur. However, although this is the general rule, in certain cases, this general rule is broken or over-ridden and combined antipsychotics are used OUTSIDE of the three exceptions. A chain of events is necessary to influence the prescribing and administration of antipsychotic combinations. This pathway is illustrated below in its simplest form. Something happens Interpretation Permission-giving thoughts Action 17

19 The SOMETHING that happens The something can be viewed as the trigger. This trigger invariably acts as a catalyst and begins a sequence of events. It does not always result in the use of more than one antipsychotic but often does. There are many examples of the something from clinical practice, obvious ones include: - A patient displaying agitated behaviour A self-harming incident A request from carers or staff to improve symptoms A violent incident An incident of damage to property An absconding incident A refusal to take medication A verbal outburst A known violent patient being newly admitted TASK H: List up to three somethings that have happened while you have been on duty over the last four weeks: 18

20 The INTERPRETATION The interpretation of the something is crucial. The interpretation will often determine whether the next stage of the pathway is reached. Clinicians can interpret the same occurrences differently. Often these interpretations are personal in their content. However, for individuals these interpretations can be consistent and, with some personal effort be predictable. Possible interpretations that occur following violence, agitated behaviour and a carer s request to improve acute symptoms are shown below. Common interpretations by ward staff of a violent incident. The Trigger A violent incident Common interpretations It was preventable. I should have... His medication is not working I have failed my team It was my fault If I do nothing and this happens again then it will be my fault He will really hurt someone next time The other patient s will not be able to cope with this We have not got the staff to manage this These interpretations can lead to a range of feelings including a sense of not being in control, fear, anxiety, anger, apprehension, guilt, etc. Common interpretations of a patient displaying agitated behaviour. The Trigger A patient displaying agitated behaviour Common interpretations If I do not do anything he/she will become violent If I do not do anything someone will get hurt Lorazepam will only disinhibit him/her further 19

21 Common interpretations of a carer asking you to improve the patient s symptoms quicker. The Trigger Carers requests something to improve voices more rapidly Common interpretations If I do not do anything then I will lose the trust of the carer If I do nothing and he/she fail s to improve I will look bad in front of peers/carer I am not making a difference, we are failing Again, these interpretations can lead to a range of feelings including a sense of not being in control, fear, anxiety, anger, apprehension, guilt, etc. The way that these interpretations and feelings are managed will also to a large extent determine what is done next. In the recent Bristol study, one nurse gave an example of this: I was really concerned that his voices would go from being good voices to bad voices and he could hit out because he did have a history of it. Now if I thought he was escalating I would start giving PRN medication, anything A consultant psychiatrist was quoted as saying: The patient is coming to you and saying I am no better; what do you do? If you try and educate a patient who is distressed and is not responding to treatment about the dangers of polypharmacy the patient might consider that you are uncaring and you are denying treatment These interpretations lead us to move onto the next stage of the pathway giving ourselves permission. TASK I: Think about a recent situation where a patient refused to take oral medication, and write a brief summary of how you interpreted this. 20

22 The PERMISSION-GIVING THOUGHTS Giving ourselves permission is crucial in the chain of events leading to prescribing combined antipsychotics. It allows a clinician to break the general rule that two antipsychotics should not be prescribed at the same time. Giving ourselves permission allows us to justify to others and ourselves this course of action. The ACTION The action is the prescribing and administration of more than one antipsychotic medication (outside the three exceptions), even if for just one day. 21

23 Section 3: Breaking the cycle This section will provide six simple steps to breaking the cycle of using combinations of antipsychotics. 1. Begin now The longer you over-ride the general rule of not using more than one antipsychotic, the harder it will be to change your practice. Make an effort to re-examine those patients who are currently prescribed combinations of antipsychotics. Think about the evidence base. Do all patients meet one of the three exceptions? If not, could anything different be done to avoid using combinations of antipsychotics? Determine a plan (both medical and non-medical) with your clinical colleagues for future cases. This means developing a new general rule. Using the guidance available in this booklet, it may be possible to develop an agreed team plan for managing and caring for new cases. TASK J: 1. Write down three things you could do to reduce the use of combined antipsychotics on your ward. 2. Write down three obstacles you might face. 3. Identify how you would manage these obstacles if and when they occurred. 4. Identify a specific start date for trying to change your practice in this way. 22

24 2. Work as a team Although it is usually the doctor who prescribes, the medication regimen of an inpatient should be regularly reviewed by the clinical team, and this usually occurs at the ward round. Psychiatry is one of the few specialties in medicine where multidisciplinary decisions are the norm. Prescribing decisions should be, and are, influenced by all team members. Each professional should also have a defined role in the process. For example, if a doctor prescribes a combination of antipsychotics and the patient suffers from intolerable side-effects, the ward staff have a key role in influencing the decision to alter the prescription. Conversely, the doctor must not feel pressured into prescribing when he/she is reluctant, and when the patient could be managed without resorting to combinations of antipsychotics, or other medication. On acute adult psychiatry wards there will undoubtedly be pressure on bed resources and therefore pressure to improve symptoms quickly. This can lead to combinations of antipsychotics being prescribed. Evidence also shows that high doses of medication do not speed up the remission of symptoms. Staffing difficulties can lead to problems or worries about disturbed behaviour from patients. Doctors and nursing staff feel these pressures but in different ways. Doctors may feel pressured into prescribing, or to try to do something ; nurses may feel they need to have medication at hand just in case or to protect other patients. However, the patient may suffer most in terms of side effects. There are times when prescribing more than one antipsychotic is unavoidable (such as acute disturbance leading to rapid tranquillisation) but the number of these occasions can be reduced with the techniques discussed below. The decision to start someone on more than one antipsychotic should NEVER be taken lightly and it is best if the whole treating team are involved in that decision. 3. Be aware of your interpretations of events Be aware of how events are interpreted. A common example is the interpretation of behavioural disturbances. It is rare for a single cause to lead to a single event. However, often you will come across situations where medication is seen as the only answer to behavioural disturbances. This all or nothing thinking often can introduce cognitive bias as it ignores the grey areas. Such thinking also has a tendency to ignore alternative ways of looking at a problem and therefore new solutions. A person may be agitated, aggressive or violent towards others. However, even with the more classically considered violence-inducing psychotic symptoms (eg command hallucinations) a direct cause and response should not be assumed. For example, it is possible that the person was agitated and feeling stressed, which in turn increased the urgency of the command hallucinations and that these two things combined led to the violence? Even if the patient had heard command hallucinations instructing violence, why did they comply? It is important to gain a full as possible understanding of the psychotic symptoms and how emotional states (eg anger) and the environment (eg high noise levels) influence these psychotic symptoms. The Royal College of Psychiatrists (Wing et al 1998) guidelines on the management of imminent violence highlight environmental factors, overcrowding (or an inability to find somewhere that is private), lack of privacy, lack of activities and long waiting times to see staff as important precipitants of violence. 23

25 Social factors, such as poor communication between patients and staff, and weak clinical leadership, may contribute to feelings of frustration and tension among all parties. Dealing with these issues in advance may reduce the risk of violence and aggression (Wing et al 1998). NICE have developed a treatment guideline for the management of violence. The importance of de-escalation skills are emphasised. As mentioned before, there are other important somethings that happen. The cross-over period when switching from one antipsychotic drug to another deserves special mention. Patients often get caught in the cross-over trap and left on two antipsychotic medications if they improve during the cross-over period. A common interpretation is that it is the combination that has benefited them and polypharmacy continues. Alternative interpretations could be that the improvement is due to monotherapy alone (a time effect) or a relative dose increase has occurred due to drug-drug interactions which improves the efficacy of the initial drug. 4. Using the alternatives (non-pharmacological) Coping strategies Assist the patient to identify simple but effective coping strategies when their symptoms become distressing. This involves two stages: 1. Checking all the strategies that the patient has previously tried and then rating these strategies on a 0-8 scale of how effective they have been (0 = no effect up to 8 = complete cessation of symptoms) 2. Having identified the effective coping strategies, work out together how the patient can use these in future situations. This can be a challenge when patients are in an acute inpatient setting as the environment may in fact provide its own constraints (eg long walks may not be possible). However, if you examine the core characteristics of the successful coping strategy then you may be able to try a similar approach. Example Although not always possible, long walks may allow the patient to have time alone, without interruption or demands on their attention. In addition, they may allow time away from a negative environment, or the exercise may divert their attention. By examining the core characteristics of successful coping strategies it should be possible to come up with coping strategies that have a similar effect and a jointly agreed plan for the future. For example, the intervention could involve going to a guaranteed quiet area, where the patient is free from any interruption and where they can do some gentle exercise. 24

26 Alternative strategies Other approached which can be clinically useful, are: The use of noise reducing earplugs. The use of loud music with headphones so as not to disturb others. Many patients report that loud music helps drown out distressing voices and that it can divert their attention. However, loud music can often be a source of conflict between staff and patients as it disturbs other residents, especially at night. It may help to have some relatively cheap personal music players with headphones available for ward issue. It is helpful to ask patients to experiment with different types of music. Many patients report that although loud music can divert their attention, the type of music can also influence their mood and agitation. For example, heavy bass music with aggressive and provocative lyrics can cause further agitation. It is often helpful to give patients a selection of music tapes and ask them to try out different types of music the next time they are hallucinating. The patient is then helped to determine what noise level and type of music has the best effect for them. Access to and support in listening to a relaxing tape, somewhere quiet and away from disruption. Access to and support in engaging in non-aggressive physical exercise. The key to successful coping strategies is that the patient has several to choose from. Therefore, it is helpful to equip patients with at least three options, so if one fails, they have something else that they can try. The more strategies available, the more in control and the less distressed they will feel. Early warning signs for future behavioural disturbances This involves using the previous or last episode of behavioural disturbance as a means of identifying the early signs that something is wrong. In effect, you can use previous behavioural disturbances to try and reduce the chances of further episodes. Identifying first signs This involves the doctor or nurse sitting down with the patient to try and understand from the PATIENT S PERSPECTIVE how and why the last behavioural disturbance occurred. What was the first sign to the patient that something was wrong? Is this a consistent first sign? Is this a usual first sign? In future, what could they use as their FIRST SIGN? Remember, first signs can be many things. For example, feelings of frustration, clenched fists, something a voice says, a certain thought that starts their paranoia, the way someone talks to them, having a request turned down that was important to them, the way other patients treat them, etc. 25

27 Having identified this first sign, then establish what the patient tends to do when they notice it. Do they tend to react impulsively? Do they try to suppress it and, if so, how long can they manage to do that before acting? This information provides both the patient and you with an idea of the window of opportunity that you have between first sign recognition and action. For patients who report impulsive action, you may be limited in the interventions that you can try. Agreeing future responses to the appearance of first signs After identifying the first signs, and time available to intervene, the next stage is asking the patient to consider what they could do themselves immediately they notice their first signs to try and avoid the situation deteriorating. What can they try to do the next time this happens? If that fails, what else might be worth trying? What would the patient prefer the clinician s role to be when they are doing this? Should they actively engage with the patient, or merely observe from a distance? It is useful to have medication as a part of this plan, and to agree at what stage the patient should ask for it or the nurse should suggest it. It is also useful to consider the previous section on coping strategies when designing interventions to break the cycle between first signs and behavioural disturbance. When medication is used, NICE recommends that patients should be encouraged to record their account of the incident in their clinical notes. This account may give staff valuable insight into precipitants and useful management strategies. Reviewing progress Remember that it is very important to regularly review with the patient how well an intervention has worked. Formally evaluate it at least weekly in the early stages. Try and build into the intervention the expectation that the patient will inform staff whenever they have used the agreed plans so that they can be supported and helped further. If the intervention that a patient chooses to break their cycle is self-initiated then it may be that they are successfully doing this three times a day but no one else knows about it. When evaluating whether an intervention is successful or not, try to see what could be done next time to improve it further. Interventions that are known to be helpful should be recorded in the patient s clinical notes. Consideration should be given to including this information in advance directives. 26

28 TASK K: 1. Identify a patient who has recently been troubled and distressed by psychotic symptoms. 2. Write down any strategies you can think of, other than medication, that may have helped. 3. Write down any barriers or obstacles you can think of that could stop you trying these alternative strategies. 4. Write down what steps you could take to manage these barriers if and when they occur. 5. Make a plan to implement these strategies with that patient (including a specific time frame to carry it out). 27

29 Using the alternatives (pharmacological) 1. Avoid as required (PRN) prescription of antipsychotic medication for sedation in psychotic patients who are on established medication doses (including depot medication) and who are no longer in the acute phase of illness. (Using this strategy alone would half the number of patients receiving combined antipsychotics). If PRN sedation is required, a benzodiazepine or promethazine are effective alternatives. 2. Make sure you do not forget to stop the first antipsychotic drug after cross-tapering to a new one. Do not assume that improvement during cross-tapering is due to combination treatment. 3. Consider other reasons for poor response with monotherapy (eg non-adherence, side effects, drug interactions, continued drug/alcohol or other substance use). Antipsychotics have limited therapeutic effects in many patients. Do not assume that high doses or combinations will lead to greater improvement. If combinations are used, always document the symptoms targeted, and document the side effects before and after starting the combination to ensure that unsuccessful treatments are not continued. 4. Consider longer trials of monotherapy or the use of clozapine in treatment resistant cases. As required medication (PRN) 1. Consider all non-pharmacological interventions. 2. If PRN (as required medication) is required in a patient with active psychosis who is receiving a regular antipsychotic, use a benzodiazepine (eg lorazepam) or the same antipsychotic for both regular and PRN. Make sure the PRN prescription is time limited and the indication is clearly written on the drug chart. 3. If PRN is required for a patient where there is no diagnosis of psychosis, first consider a benzodiazepine (eg lorazepam). Make sure the PRN prescription is time limited. 4. In cases when PRN medication is required for rapid tranquillisation, first consider lorazepam. In the rare cases where lorazepam is not indicated, consider haloperidol or olanzapine (see NICE clinical guideline, 2002). Make sure the PRN prescription is time limited. 28

30 5. Being aware of giving yourself permission thoughts Giving ourselves permission to break the rule of antipsychotic monotherapy can, if we are not challenged by anyone about it, become easier each time we do it and become a habit. The problem with such habits is that fewer and fewer permission giving thoughts are required each time. Hence, the exception may slowly but surely become a rule. Perhaps the general rule of no more than one antipsychotic at a time (apart from the exceptions) has lost some of its authority. Given how commonly combinations are used, this will continue until one of two things happens: 1. The lack of evidence for the effectiveness of combined antipsychotics persuades clinicians to make a concerted effort to re-introduce the rule (prescribe antipsychotic monotherapy). 2. Serious adverse consequences of antipsychotic polypharmacy occur which reinforce the need for the general rule. TASK L: 1. Identify the last patient to whom you administered an antipsychotic combination (outside of the three exceptions). 2. How or why did you over-ride the rule not to prescribe or administer antipsychotic polypharmacy (outside of the three exceptions)? 3. Work out two ways in which you can manage these permission-giving thoughts when they occur in future. 29

31 Summary This workbook has been provided for you to reconsider your own clinical practice as it relates to combining antipsychotics. It provides you with an update about the latest evidence on the prescribing and administering of antipsychotic medication. Although it may feel like it is not the most important area of your practice that needs reviewing, putting it off further will only lead to a short term avoidance of the problem, and in the long term may increase the likelihood that combining antipsychotics will occur. This workbook offers some simple steps that can be taken. It will not be possible to implement this guidance overnight. However, by beginning to discuss the issues in clinical team meetings, by thinking about current cases that could be reviewed, and by examining the alternatives you may well find that, slowly but surely, practice is changing for the better. 30

32 References: Alexander J, Tharyan P, Adams C et al, Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting. British Journal of Psychiatry 185, Centorrino F, Goren JL, Hennen J et al., Multiple versus single antipsychotic for hospitalised psychiatric patients ; case-control study of risks versus benefits. American Journal of Psychiatry 161, Chen, A., Noncompliance in community psychiatry: a review of clinical interventions. Hospital and Community Psychiatry 42, Chong SA, Tan CH, Lee HS., Atrial ectopics with clozapine-risperidone combination. Journal of Clinical Psychopharmacology 17, Currier GW & Simpson GM., Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. Journal of Clinical Psychiatry 62, Ereshefsky, L., Pharmacologic and pharmacokinetic considerations in choosing an antipsychotic. Journal of Clinical Psychiatry 60, Freudenreich, O. & Goff, D. C., Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatrica Scandinavica 106, Glazer WM & Dickson RA, Clozapine reduces violence and persistent aggression in schizophrenia. Journal of Clinical Psychiatry 59 (Suppl.3), Gomberg, R.F., Interaction between olanzapine and haloperidol (letter). Journal of Clinical Psychopharmacology 19, Harrington, M., Lelliott, P., Paton, C., et al, 2002a. The results of a multi-centre audit of the prescribing of antipsychotic drugs for inpatients in the UK. Psychiatric Bulletin 26, Harrington, M. & Lelliott, P., 2002b. Variation between services in polypharmacy and combined high dose of antipsychotic drugs prescribed for inpatients. Psychiatric Bulletin 26, Hatta K, Takahashi T, Nakamura H et al., Laboratory findings in acute schizophrenia. Relevance to medical management on emergency admission. General Hospital Psychiatry 21, Josiassen RC, Ashok J, Kohegyi E et al., Clozapine augmented with risperidone in the treatment of schizophrenia : a randomized, double-blind, placebo-controlled trial. American Journal of Psychiatry 162, Koreen, A. R., Lieberman, J. A., Kronig, M. & Cooper, T. B., Cross-tapering clozapine and risperidone. American Journal of Psychiatry 152, Kontaxakis VP, Havaki-Kontaxi BJ, Stamouli SS et al., Toxic interaction between risperidone and clozapine: a case report. Progress in Neuropsychopharmacology and Biological Psychiatry 26, Lehman AF, Steinwachs DM, and co-investigators of the PORT project, Translating research into practice: The schizophrenia patient research outcome team (PORT) treatment recommendations. Schizophrenia Bulletin 24,1-10. National Institute for Clinical Excellence (NICE), Guidance on the use of newer (atypical) antipsychotic drugs for the treatment of schizophrenia. London: NICE. 31

33 National Institute for Clinical Excellence (NICE), Schizophrenia: core interventions in the treatment and management of schizophrenia in primary and secondary care. Clinical Guideline 1, NICE. National Schizophrenia Fellowship, A Question of Choice. London: NSF. Procyshyn, R.M., Kennedy, N.B., Tse, T. & Thompson, B., Antipsychotic polypharmacy: A survey of discharge prescriptions from a tertiary care psychiatric institution. Canadian Journal of Psychiatry 46, Rifkin A, Doddi S, Karajgi B et al, Dosage of haloperidol for schizophrenia. Archives of General Psychiatry 48, Royal College of Psychiatrists, Consensus Statement on the Use of High Dose Antipsychotic Medication. Council Report CR26. London: Royal College of Psychiatrists. Shiloh, R., Zemishlany, Z., Aizenberg, D., et al., Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. British Journal of Psychiatry, 171, Taylor D, Paton C, Kerwin R, The Maudsley Prescribing Guidelines. 8th Edition. Martin Dunitz, London. Stahl, S.M., Antipsychotic polypharmacy: evidence based or eminence based? Acta Psychiatrica Scandinavica, 106, Tyson, S. C., Devane, C. L. & Risch, S. C., Pharmacokinetic interaction between risperidone and clozapine. American Journal of Psychiatry, 152, Waddington, J.L., Youssef, H.A. & Kinsella, A., Mortality in schizophrenia: antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. British Journal of Psychiatry, 173, Wing, J.K., Marriott, S., Palmer, C. & Thomas, V., The Management of Imminent Violence: Clinical Practice Guidelines to Support Mental Health Services. Occasional Paper OP41. London: Royal College of Psychiatrists. Wright P, Birkett M, avid SR et al, Double-blind, placebo controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. American Journal of Psychiatry 158, Yagcioglu AEA, Akdede BBK, Turgut TI et al, A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. Journal of Clinical Psychiatry 66,

34 Appendix 1 Understanding Maximum Doses of Antipsychotics Every drug has a recommended dosage range. This recommended range is determined after careful consideration of the efficacy and toxicity data for each drug. Doses below the recommended range are unlikely to be effective. Doses above the recommended range have not been demonstrated to have greater efficacy and are generally associated with an unacceptably high burden of side effects. The recommended dosage range for each drug is reflected in the summary of product characteristics (SPC) for that drug. All SPCs are available at Recommended dosage ranges can also be found in the BNF. The table below shows the maximum recommended dose for commonly used antipsychotic drugs. Oral Antipsychotics Maximum BNF daily dose (mg) Short acting intramuscular injections Maximum BNF daily dose (mg) Amisulpride 1,200 Chlorpromazine 200 Aripiprazole 30 Haloperidol 18 Chlorpromazine 1,000 Olanzapine 20 Clozapine 900 Flupentixol 18 Intermediate acting intramuscular injections Fluphenazine 20 Zuclopenthixol ( acuphase ) 150mg Haloperidol 15 Olanzapine 20 Long acting intramuscular injections Maximum BNF weekly dose (mg) Quetiapine 750 Flupentixol 400 Quetiapine (mania) 800 Fluphenazine 50 Risperidone 16 Haloperidol 75 Sulpiride 2,400 Pipotiazine 50 Trifluoperazine 50 Risperidone 25 Zuclopenthixol 150 Zuclopenthixol

35 It is possible for a patient to receive a high (above maximum) dose in two ways: 1. A single drug prescribed in a dose above the BNF maximum eg olanzapine 30mg. 2. A combination of antipsychotic drugs when: a. The dose of each drug is converted to a percentage of the maximum dose for that drug b. And the percentages are added together c. Giving a value above 100%. For example amisulpride 800mg plus risperidone 8mg each day. The maximum dose of amisulpride is 1200mg, so 800mg is 67% of the maximum. The maximum dose of risperidone is 16mg, so 8mg is 50%. When 67% and 50% are added together, the total dose of 117% is considered to be a high dose. 34

36 Appendix 2 ANTIPSYCHOTIC DOSAGE READY RECKONER Commonly used antipsychotics Oral/IM: dose in mg/day Depot: dose in mg/week Amisulpride Oral Aripiprazole Oral Chlorpromazine Oral Clozapine Oral Haloperidol Oral Olanzapine Oral Quetiapine Oral Risperidone Oral Sulpiride Oral Trifluoperazine Oral Zuclopenthixol Oral Chlorpromazine IM Haloperidol IM Olanzapine IM Flupentixol Depot Fluphenazine Depot Haloperidol Depot Pipotiazine Depot Risperidone Long acting Zuclopenthixol Depot Percentage of BNF maximum adult daily dosage % (83%) (17%) (44%) (17%) (84%) (37.5%) * 2 (12.5%) 4 6 (37.5%) (17%) ** 20 (13%) (12.5%) (28%) 10 (56%) 15 (84%) (17%) (83%) 600 *750mg/day maximum for schizophrenia, 800mg/day maximum for mania: % given are for schizophrenia treatment. **There is no maximum dose for trifluoperazine stated in the BNF or SPC; 50mg is used by convention. 35

37 Less commonly used antipsychotics Percentage of BNF maximum adult daily dosage Oral/IM dose in mg/day % Benperidol Oral Flupentixol Oral Fluphenazine Oral Levomepromazine Oral 2.5 (12.5%) 3 (17%) (37.5%) (62.5%) Pericyazine Oral Perphenazine Oral 4 (17%) Pimozide Oral Promazine Oral Sertindole Oral (18.5%) 300 (37.5%) (17%) Zotepine Oral Levomepromazine IM Promazine IM 50 (17%) (12.5%) (12.5%) To calculate the total antipsychotic percentage dose prescribed for an individual, use the table to determine the percentage of BNF maximum dosage for each antipsychotic that is prescribed, and then sum the percentages. For example, for a person prescribed clozapine 400mg a day and oral haloperidol 5mg PRN up to 3 times a day, the respective percentages would be 44% and 50%, giving a total antipsychotic prescribed dosage of 94%. 36

38 Combining Antipsychotics? Appendix 3 Why? How good is the evidence that two antipsychotics are better than one? To manage acute behavioural disturbance (oral PRN) To manage acute behavioural disturbance (IM RT ) To manage chronic behavioural disturbance To manage relapse in a patient previously stabilised on a single antipsychotic While switching from one drug to another Poor Poor None Poor Limited Some studies show that some oral antipsychotics are effective in managing behavioural disturbance. See caveats under IM below. NICE recommends IM olanzapine or haloperidol in patients whose behaviour is driven by psychosis. Trial evidence is in patients not receiving regular antipsychotics. A benzodiazepine alone may be as effective and safer. Some evidence supports the use of clozapine (monotherapy) in managing chronic aggression. One study has shown that increasing the dose of an established antipsychotic in a relapsed patient is no more effective than continuing the same dose. Combinations have not been systematically studied. The dose of some antipsychotics (eg clozapine) needs to be increased slowly and cross titration is sensible. This should be complete in four to six weeks. To speed up the onset of effect or enhance the size of the therapeutic effect To target different symptoms/symptom domain Poor Poor Response takes time. High initial doses do not speed up the onset of response. Combinations have not been studied. There is no evidence that combinations improve outcome. Antipsychotics have differential effects on sleep but there is limited evidence to support clinically meaningful differences on core psychotic symptoms. To reduce side effects Poor In most patients it is likely that side effects will be increased. To allow administration by a different route Individual patient s/carer s choice Uncertain Limited Very few antipsychotics are available in short acting IM, depot or orodispersible formulations. Reasonable attempts should be made to choose and use one route of administration. Combinations may be useful in some clinical circumstances. Choice is not real choice unless it is informed. If a patient can understand the potential benefits and risks of antipsychotic combinations and come to a reasoned decision, this should be supported. Treatment resistance Equivocal Combinations of clozapine should be considered before those involving other antipsychotic drugs. Overall there is a lack of evidence supporting benefit 37

39 What are the potential problems? Difficulty determining cause and effect Higher than necessary total dosage Complex regimen increasing the risk of non-adherence How good is the evidence for this? Not knowing which antipsychotic has helped in the short term may lead to the patient receiving a higher than necessary dose (and more side effects) in the longer term. There is no good evidence that high doses of antipsychotics are more effective than standard doses. The major cause of high dose prescribing is combinations of antipsychotics. In the general population, simple medication regimens involving a small number of tablets are more likely to be taken than complex regimens. This is particularly likely to be true in patients with schizophrenia who may be disorganised, lack motivation and have cognitive deficits. Increased cost Some antipsychotics are expensive ( /month). Two cost more than one. Increased side effects (acute or long term) Drug interactions (pharmacokinetic and pharmacodynamic) Increased duration of hospitalisation All antipsychotics have side effects. Profiles differ. One study showed that patients who received combinations had 50% more side effects than those who received one antipsychotic drug. The safety of combinations of antipsychotics has not been studied systematically but there are many published case reports of serious side effects such as cardiac arrhythmias and neuroleptic malignant syndrome. One study found that the average duration of hospital stay was more than 50% longer in patients who were prescribed combinations of antipsychotics.?? Increased mortality One study found that patients who were prescribed combinations were twice as likely to die over a 10 year period than those who took one antipsychotic. 38

40 Appendix 4 If you would like to receive a certificate of participation in this POMH-UK topic: 1. Complete tasks A-L. 2. Complete your name and address below Name:.. Address: Send your completed booklet, along with a stamped (A4) self addressed envelope to: Prescribing Observatory for Mental Health, Royal College of Psychiatrists Research Unit, Standen House, 21 Mansell Street, London E1 8AA Your completed booklet and certificate of participation will be returned to you. 39

41 0

42 Can it be justified? Your notes 40

43 Your notes 41

44 Can it be justified? 42

45 POMH-UK The Prescribing Observatory for Mental Health (POMH-UK) is a national quality improvement programme open to all specialist mental health services in the UK. POMH-UK works with mental health services to help improve prescribing practice in discrete areas ('Topics') of prescribing practice. Each Topic involves an audit cycle. Participating teams collect data for a baseline audit of their practice. This is followed by teams engaging in a number of quality improvement interventions and the audit cycle is completed with a follow-up audit of practice. This workbook is one of the quality improvement interventions that have been made available for Topic 1; Prescribing of high dose and combination antipsychotics for patients on adult acute and psychiatric intensive care wards. POMH-UK is based at the Royal College of Psychiatrists Centre for Quality Improvement, 4th Floor, Standon House, 21 Mansell Street, London, E1 8AA. Tel: Fax: P O M H U K PRESCRIBING OBSERVATORY FOR MENTAL HEALTH