ANTIPSYCHOTIC GUIDELINES

ANTIPSYCHOTIC GUIDELINES TREATMENT OF SCHIZOPHRENIA AND PSYCHOSIS Page 1 of 44

Authors: Ms Diane Booth, Chief Pharmacist,. Mrs Kiran Hewitt, Lead Clinical Pharmacist, Berkshire Healthcare NHS Foundation Trust. Mrs Katie Sims, Clinical Pharmacist,. Acknowledgements: The authors would like to thank the members of the pharmacy department, Prospect Park Hospital and the Drugs & Therapeutics Committee representatives of Berkshire Healthcare NHS Foundation Trust who provided help, advice and constructive feed back during the compilation of these guidelines. Any enquiries regarding these guidelines or other medication related queries should be forwarded to the MIS (Medicines Information Service), pharmacy department, Prospect Park Hospital, on 0118 960 5075/5059, or your ward/locality pharmacist. Page 2 of 44

CONTENTS Medicines Formulary Page Treatment Choices 4 Schizophrenia Treatment Algorithm 5 Use of Atypical Antipsychotic Drugs 6 General Treatment Principles 6 Prescribing Information - Atypicals 8 Considerations Additional Information/Guidance Use of High Dose Antipsychotic Prescribing 10 Maximum & Equivalent Doses 12 Relative Side Effects 13 Important Investigations 14 Treatment of Special Patient Populations 16 Treatment Options in Patients with Co-existing 17 or Drug Induced Problems Swapping & Stopping 18 Neuroleptic Malignant Syndrome 19 Extra pyramidal Side Effects 20 Maintenance of Primary Care Patients 23 Clozapine -Initiating Treatment 24 -Plasma Level Monitoring 25 -Monitoring in the Community 25 -Management of Side Effects 26 Depot Injections 27 Appendices: Appendix 1: Guidelines for the Management of Older 29 Patients with Acutely Disturbed or Violent Behaviour Appendix 2: Guidelines for the Use of 33 Risperidone Long-Acting Injection (Risperdal Consta ) Appendix 3: Atypicals & Stroke Guidance from the Trust 35 Appendix 4: Physical Monitoring of atypicals 38 NB: For the most up-to-date Guidelines for Rapid Control/Tranquillisation of Acutely Disturbed Behaviour in Adults, see policy number CCR052 on the Trust website http://www.berkshirehealthcare.nhs.uk/policies.asp?pagenum=1&typeid=1&so rtby=1 References 44 Page 3 of 44

MEDICINES FORMULARY ANTIPSYCHOTICS FIRST LINE TREATMENT CHOICE Risperidone (oral tablets or liquid) SECOND LINE/ALTERNATIVE ATYPICALS Amisulpride Aripiprazole Olanzapine (oral tablets) Quetiapine (either immediate or modified release tablets) ALTERNATIVE TYPICALS Chlorpromazine Haloperidol Sulpiride Trifluoperazine RESTRICTED INDICATIONS need for these must be discussed with ward pharmacist prior to prescribing Olanzapine Velotabs Risperidone Quicklets Aripiprazole liquid FOR SECONDARY CARE INITIATION ONLY Depots: Flupentixol Fluphenazine Haloperidol Pipotiazine Risperdal Consta Zuclopenthixol Clozapine Sertindole Page 4 of 44

Schizophrenia Treatment Algorithm Give chosen atypical antipsychotic at lowest effective dose Adjust dose depending on response. Increase dose if necessary at two weekly intervals Assess over 6-8 weeks Ineffective (check or not tolerated compliance) Change to a different antipsychotic and follow process above (consider atypical and typical agents depending on reason for non tolerance) Ineffective or non-compliance Change to a depot Use lowest therapeutic dose at maximum allowable interval (unless practical issues demand otherwise) Adjust dose at 2-3 month intervals Assess over at least four weeks OR if Ineffective or not tolerated Change to clozapine Titrate according to licensed dosage regime Optimise treatment Assess over at least six months ineffective or partially ineffective Effective & tolerated Effective & tolerated Effective & tolerated Effective & tolerated Continue treatment at established effective dose for at least two years (five years for second or later presentations) Withdraw slowly (after careful consideration) under secondary care advice/supervision Continue treatment following process above Continue with depot therapy as sole antipsychotic for at least two years (five years for second or later presentations) Withdraw slowly (after careful consideration) under secondary care supervision Continue treatment at established effective dose for at least two years (five years for second or later presentations) Withdraw slowly (after careful consideration) under secondary care advice/supervision Page 5 of 44

1. Consider augmentation strategies: clozapine plus sulpiride, amisulpride, risperidone, lamotrigine, or omega-3 triglycerides 2. Consider alternatives to clozapine: Risperidone, high dose olanzapine, quetiapine, omega-3 triglycerides, or ECT (Patient consent must be documented in the notes) Contact ward pharmacist/mis for information Effective & tolerated If clearly measured improvement, continue and document well in patient s notes Use of Atypical Antipsychotic Drugs This policy takes account of the following facts concerning atypical antipsychotics: NICE recommends that atypical antipsychotics should be considered in the choice of first-line treatment of patients with schizophrenia newly diagnosed, relapsed or in those with unacceptable side effects from typical antipsychotics. 1 the tolerability of the atypical antipsychotics in terms of EPSE, makes them superior to conventional drugs. risperidone has been chosen as first-line treatment in our guidelines, based on consideration of atypicality, equal efficacy and cost. 2,3 one of the other atypicals should be considered when risperidone is an unsuitable choice due to intolerance, or previous non response. where there is a past history of intolerance or non-response to typical agents, an atypical antipsychotic should be used. where two atypical agents are not effective, clozapine treatment should be considered. atypical agents should be prescribed as monotherapy and never in combination with another atypical antipsychotic unless it is during a swap over period (or in combination with clozapine for a refractory illness). atypical antipsychotics should not be prescribed on a prn basis or solely for their sedative properties. Benzodiazepines are more appropriate for this indication (for short-term use only). For example, lorazepam may be useful in controlling extreme agitated behaviour and symptoms during the initial weeks (up to four generally) of atypical antipsychotic therapy. 2 General Treatment Principles if a patient is stable on a conventional antipsychotic with no significant side effects, a switch to an atypical antipsychotic should not be made 3 typical antipsychotics are associated with severe movement disorders such as tardive dyskinesia, akathisia and acute dystonic reactions patients should only be treated with ONE antipsychotic at a time (unless they are swapping treatments or being treated for a refractory illness) Page 6 of 44

oral and parenteral doses of the same drug should be prescribed separately because they can vary in bioavailability intramuscular chlorpromazine should not routinely be prescribed anticholinergic drugs should ideally be prescribed on a prn basis if and when EPSE occur. Not all patients experience these side effects. Most patients do not require them long term and withdrawal should be attempted if the patient is no longer experiencing troublesome side effects refer to anticholinergic guidelines. Page 7 of 44

Antipsychotic Guidelines Prescribing Information Atypicals Drug Available Forms Available Strengths Amisulpride Oral tablets 50mg, 100mg, 200mg, 400mg Oral solution 100mg per 1ml Aripiprazole Oral tablets 5mg, 10mg, 15mg, 30mg Orodispersible tablets 10mg, 15mg Liquid 1mg per 1ml Clozapine Oral tablets 25mg, 100mg Olanzapine Oral tablets 2.5mg, 5mg, 7.5mg, 10mg, 15mg, 20mg Velotabs (orodispersible tablets) 5mg, 10mg, 15mg Intramuscular 10mg injections Oral immediate release tablets 25mg, 100mg, 150mg, 200mg, Quetiapine The XL preparation can improve compliance, but offers no improvement in side effect profile Risperidone Oral XL (modified release) tablets Oral tablets Quicklets (orodispersible tablets) Oral liquid Long acting injection 300mg 50mg, 200mg, 300mg, 400mg 0.5mg, 1mg, 2mg, 3mg, 4mg, 6mg 1mg, 2mg 1mg per 1ml 25mg, 37.5mg, 50mg 4 Page 8 of 44

Considerations Consider the quantity of antipsychotic medication prescribed. Patients must be able to obtain their medication easily and maintain regular contact with health care professionals such as their GP or community pharmacist. Concordance. Compliance is a key issue in the management of schizophrenic patients. Keep drug regimens as simple as possible and avoid poly-pharmacy. Co-prescribing. Many drug combinations worsen side effects or can result in altered blood levels and potential toxicity. Prescribe small quantities initially and review regularly, once a week if need be. OTC medication. Examples of problematic over the counter (OTC) or herbal remedies include cold remedies containing pseudoephedrine, sedating preparations and some antihistamines. These can either cause drug interactions, be sedating and/or have an effect on the QTc interval. St John s Wort is also a major problem in terms of drug interactions with other medication. Side effects. Warn patients and their carers of the main side effects they may experience when taking antipsychotic medication. This may prevent them from discontinuing medication unnecessarily. Reassure patients about milder and transient side effects such as increased appetite, sedation or dizziness and give advice on the management of more severe side effects such as sexual dysfunction, excess weight gain or extreme movement disorders. Effects of lifestyle on medication. Alcohol acts centrally, affects dopamine and will interact with antipsychotics. The metabolism of some antipsychotics can be affected by smoking and dose adjustment may be required (usually by secondary care). Recreational abuse of drugs such as cannabis can have extreme effects on mental state and this is particularly pronounced in patients suffering from schizophrenia. Page 9 of 44

Guidance on the use of High Dose Antipsychotics (unlicensed use of antipsychotics) NB: Doses or regimes outside the manufacturers recommendations must be considered unlicensed. In 1994 the Royal College of Psychiatrists published a consensus statement on the use of high dose anti-psychotics in emergencies as well as long-term oral treatment. High doses have been associated with sudden death, cardiac toxicity, CNS toxicity, respiratory depression and seizures. This statement was reviewed and updated in 2006 and addresses the use of high dose antipsychotic medication in adult mental health services only (the full statement can be found on the Pharmacy pages of BHFTs intranet site). Identification of High Dose Antipsychotic Use High dose antipsychotic prescribing can be achieved in two ways: 1) single antipsychotic prescribed at a daily dose that is above the BNF maximum dose (high dose single drug) 2) more than one antipsychotic prescribed concurrently where the combined total percentages is above 100%. The maximum daily dose of each drug is equal to 100% (high dose combined drugs). Maximum licensed doses are shown on pages 14. BNF/SPC maximum doses of antipsychotic medication should be adhered to and not exceeded, as there is little or no evidence to support this practice in most cases. In fact, the use of high dose antipsychotics tends to increase side effects without increasing treatment response 5. High doses antipsychotics are sometimes stated as equivalent to over 1000mg of chlorpromazine in 24 hours. However, if they are to be used, the recommendations are as follows: the decision to use high doses should be discussed with the multidisciplinary team. The reasons must be discussed and explained thoroughly by the secondary care team to the patient and/or patient s relative or carer, and consent obtained where possible. This should include the reasons for initiating the unlicensed drug/dosage and details of dose, period of review, possible problems and side effects and any monitoring required the responsibility for prescribing high/unlicensed doses lies with the patient s consultant psychiatrist and so the decision should only be made by that person Supplementary prescribers should not make the decision to proceed to the use of high doses Page 10 of 44

full documentation of the treatment plan in the patients notes; reasons for its use, previous response, outcome expectations, reasons for continuation and the patient s physical and mental state the drug charts of patient s receiving high doses of either individual drugs or as a result of combinations, will be highlighted by the use of a pharmacy high dose antipsychotic sticker not to routinely prescribe high doses by prescribing more than one drug concomitantly (even if each individual drug is within the BNF maximum dose), or by allowing extra prn medication. There may be a need to prescribe in this way in an emergency or acute situation if this case, it must be discussed with the RMO before being prescribed consideration of any complicating factors such as co-morbidity, cardiac status and history, (particularly MI, arrythmias, abnormal ECG), obesity, substance abuse, elderly consideration of potential drug interactions e.g. tricyclics, anti-histamines, diuretics, anti-hypertensives, anti-arrythmics, drugs that can prolong QTc interval, drugs that can increase antipsychotic plasma levels, OTC and herbal products (e.g. St John s Wort), alcohol obtain a baseline ECG. If QTc is prolonged (above 440ms) then review treatment and consider a cardiac assessment. If it is decided to continue treatment, the reasons must be documented in the patient s case notes continue to monitor ECG periodically (depending on baseline and clinical indication) after 1 week then every 1-3 months while the high dose treatment continues. If an ECG is not performed, the reason should be documented in the case notes gradual changes of dose, not more than once weekly baseline and regular pulse, blood pressure, temperature and electrolyte checks, and ensure adequate fluid intake regular review of progress with dose reduction to the normal range if there is no improvement after 3 months. Use validated rating scales to measure improvements in psychotic symptoms and side effects. File in patient s case notes a confirmation letter should be sent to the patient s GP to ensure continuity of care on discharge. The consultant remains responsible for the use of the unlicensed medication within the recommended regime. Problems with symptoms and side effects must be referred back to the consultant. The use of high dose antipsychotics within BHFT will be regularly audited as part of the POMH-UK initiative, details of which can be found on the Pharmacy pages of the Trusts intranet site. Although the responsibility for treating a patient with high dose antipsychotics lies with the consultant, members of the multidisciplinary team nursing, pharmacy and medical staff, are all responsible for ensuring adherence to these recommendations, highlighting patients who are prescribed high doses, whether it be planned or inadvertent, and for monitoring the patient. Page 11 of 44

Antipsychotics Maximum and Equivalent Doses Drug Consensus Equivalent Dose Possible Range of Equivalent Values in Literature (mg per day) BNF/SPC Maximum Dose (mg per day) (mg per day) Oral Chlorpromazine 100 1000 Thioridazine 100 75-100 600 (hospital pt s only) Trifluoperazine 5 2-8 None (see BNF) Flupentixol 3 2-3 18 Zuclopenthixol 25 25-60 150 Haloperidol 3 1-5 30 Pimozide 2 1-3 20 Sulpiride 200 200-270 2400 Atypicals * Clozapine 100 30-150 900 Risperidone 1.5 0.5-3 16 Amisulpride - - 1200 Olanzapine - - 20 Quetiapine - - 750 Aripiprazole - - 30 Depots Fluphenazine 5mg per week 1-12.5mg per week 50mg per week Haloperidol 15mg per week 5-25mg per week 75mg per week (4/52ly recommended) Flupentixol 10mg per week 8-20mg per week 400mg per week Pipotiazine 10mg per week 5-12.5 per week 50mg per week Zuclopenthixol 100mg per week 40-100mg per 600mg per week week Risperdal Consta - - 50mg two weekly (follow manufacturer s guidelines) 6,7,8,9 *Equivalent doses for atypical antipsychotics are not particularly useful and so manufacturers guidelines should be followed. Equivalent doses should only be used as a guide, as assessment methods used for determining equivalent doses can produce huge variations in their recommendations. 10 It is also important not to confuse antipsychotic equivalence with sedation. Page 12 of 44

Drug Antipsychotic Guidelines Antipsychotics Relative Side Effects Cardiac Anticholinergic Extrapyramidal Hypotension Typicals chlorpromazine* +++ ++ ++ +++ +++ flupentixol ++ +/- ++ + + fluphenazine** ++ ++ +++ + ++ haloperidol** + ++ +++ + + pimozide + +++ + + + pipothiazine ++ ++ ++ ++ ++ sulpiride + - + - - thioridazine* +++ +++ + +++ +++ trifluoperazine** +/- ++ +++ + + zuclopenthixol ++ + +++ + ++ Sedation Atypicals amisulpride - - + - - aripiprazole - - +/- - - clozapine +++ +++ - +++ +++ olanzapine + - - + ++ quetiapine + + - ++ ++ risperidone + - + ++ + NB: These are approximate side effect comparisons 7,8 Key: +++ high incidence/severity ++ moderate + low - very low ** high potency antipsychotics * low potency antipsychotics Page 13 of 44

Antipsychotic Guidelines Important Investigations The healthcare professional carrying out the initial assessment of a patient (whether in primary or secondary care), is responsible for ensuring the following investigations are performed. Full blood count, including haemoglobin and red blood cell parameters - which may reveal neutropenia, anaemia, B12 and folate deficiencies. B12 and folate - deficiencies may compromise cognitive function and produce confusional states (folate deficiencies are not only implicated in the symptoms of psychosis, but can also reverse the beneficial effects of many antidepressants). Metabolic function can be investigated by checking urea and electrolyte plasma levels. Disturbances may arise due to dehydration or physical causes. (antipsychotics can cause water dysregulation including hyponatraemia). Thyroid abnormalities often lead to changes in mental state and thyroid function tests should be performed routinely, particularly during the early stages of treatment. Liver function tests, although altered by some antipsychotics, may be useful in revealing possible cases of alcohol abuse. Blood glucose level to be measured initially to provide a baseline value and because diabetes mellitus has been known to manifest itself as psychosis or delirium. It is important to continue monitoring blood glucose levels due to the increase in use of atypical agents, some of which can cause hyperglycaemia/type 2 diabetes. Body weight to be measured initially to provide a baseline value; this is increasingly important due to the increase in use of atypical agents, some of which can cause substantial weight gain. Hence, ongoing monitoring of body weight is also recommended (and can be minimised with careful diet and exercise). Blood pressure Lipids All patients should receive an initial lipid profile test. Prolactin should be checked at baseline in children and adolescents for all antipsychotics. Adult patients about to receive typical antipsychotics or risperidone should receive a baseline test. ECG an initial ECG should be performed if indicated by history or clinical picture (see trust ECG policy). Ongoing monitoring will really depend on the individual patients circumstances; baseline values of the above, co-morbidity, which antipsychotic has been prescribed and so forth. It may also be indicated when there is a change in the mental or physical health of the patient or when the treatment is modified. Blood glucose At start and at 3 months (and at 1 month if taking olanzapine); more often if there is evidence of elevated levels. Body weight see above Prolactin levels should be monitored in patients with suspected hyperprolactinaemia and in patients reporting sexual side effects. Page 14 of 44

Illicit drug use can be confirmed by urinary and/or blood drug screen. Blood pressure should be monitored during the first two weeks of treatment with antipsychotics, especially clozapine (where the monitoring should be continued if the titration period is longer). Postural hypotension is usually more common in the elderly and can be unpredictable. An ECG is essential when treating patients with high dose antipsychotics due to the cardiac side effects of these drugs (notably prolongation of the QTc interval). Lipids should be repeated after three months (or sooner if baseline level was elevated). If the levels are normal, then the level should be tested annually only in patients over 40 years old. An agreement between consultant psychiatrist and GP should be reached regarding the need for an ECG to be performed and any subsequent monitoring requirements. Page 15 of 44

Condition/ Population Pregnancy Antipsychotic Guidelines Treatment of Special Patient Populations 1 st Choice Alternative 2 nd Choice chlorpromazine trifluoperazine haloperidol sulpiridealthough limited data Avoid Comments (1) (1) Lack of data on safety of atypicals Contact MIS, Prospect Park Hospital, 01189605075/50 59 for most up to date info. Lactation sulpiride (2) (1) (1) Lack of data on safety of atypicals. (2) Choice may depend on drug used during pregnancy. Contact MIS for most up to date info. Cardio-vascular Disease Epilepsy Hepatic Impairment Renal Impairment amisulpride sulpiride olanzapine aripiprazole haloperidol sulpiride trifluoperazine amisulpride sulpiride haloperidol (4) haloperidol (5) trifluoperazine flupentixol zuclopenthixol Adolescence Atypicals: amisulpride olanzapine risperidone Old Age amisulpride (7) risperidone sulpiride quetiapine (3) risperidone haloperidol flupentixol risperidone amisulpride olanzapine flupentixol zuclopenthixol quetiapine risperidone olanzapine haloperidol chlorpromazine (6) clozapine olanzapine(7) quetiapine pimozide clozapine (3) chlorpromazine clozapine phenothiazines clozapine chlorpromazine amisulpride sulpiride Typicals (6) chlorpromazine (3) Choice depends on the specific cardiac abnormality contact MIS for specific info Start low and go slow. Consider interactions with epilepsy drugs (4) Start low and go slow contact MIS for specific info (5) Start low and go slow (doses dependent on GFR). ADR s more frequent contact MIS for specific info (6) May reduce cognition. Increased EPSE risk in this group (7) Choice is dependent on comorbidity. Start Page 16 of 44

low, go slow. More susceptible to all side effects so monitor Treatment Options in Patients with Co-existing or Drug Induced Problems Condition/ Population 1 st Choice Alternative 2 nd Choice Avoid Comments Diabetes amisulpride sulpiride risperidone quetiapine haloperidol aripiprazole clozapine (7) olanzapine (7) (7) monitor blood glucose levels regularly Obesity/ Weight problems amisulpride haloperidol trifluoperazine quetiapine aripiprazole clozapine (8) olanzapine (8) Prevention better than cure. Warn/counsel and monitor all patients Problems associated with hyperprolactinaemia clozapine quetiapine olanzapine(9) aripiprazole most typicals amisulpride risperidone sulpiride (9) may cause a transient rise in levels Aripiprazole (Abilify ) seems to have a low incidence for inducing hyperprolactinaemia, hyperglycaemia/type 2 diabetes, or weight gain. Hence, this may be an appropriate choice of antipsychotic in those patients who have developed these problems with previous medication. In addition, risperidone and olanzapine should not be used to manage behavioural symptoms in patients with dementia, due to an increased risk of cerebrovascular events. 11 Non medicinal interventions should be used to manage these patients. If this is unsuccessful, refer to the Trusts guidelines on this matter (Appendix 3). Page 17 of 44

Antipsychotics - Swapping and Stopping When switching from one antipsychotic to another, abrupt withdrawal of the first drug should be avoided, in order to prevent problems such as: -relapse or destabilisation of illness/symptoms -cholinergic rebound (nausea, vomiting, restlessness, anxiety, insomnia, fatigue, - myalgia, headaches) -withdrawal EPSE -combined side effects and drug interactions (from 1 st and 2 nd drug) However, where a severe, acute adverse effect has occurred (e.g. clozapine red blood result), immediate discontinuation may be necessary. No specific regimes for swapping antipsychotics are available. When selecting an appropriate regimen, a number of factors must be taken into consideration: speed how quickly the swap over needs to be carried out (taking into consideration how unwell the patient is) individual susceptibility and patient tolerability current dose of the first drug and its half life individual drugs and their effects Cross tapering is usually the preferred option, where the dose of the first drug is slowly reduced (over anything up to 8 weeks), whilst the new agent is being introduced. 12 Contact the Medicines Information Service (MIS), pharmacy department, Prospect Park Hospital (or your ward pharmacist), on 0118 960 5075/5059, for advice on specific swapping regimes. Discontinuation Discontinuation symptoms have a number of characteristics: they usually start within 48 hours of stopping the drug they are resolved within 24 hours of restarting the drug symptoms usually persist for 7-14 days, and could be longer they include tardive dyskinesias, psychosis, cholinergic rebound headache diarrhoea, vomiting and restlessness Reducing the rate of drug withdrawal can reduce the incidence of discontinuation syndrome and relapse of symptoms dramatically. Page 18 of 44

Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS) is a sudden loss in control of body temperature during drug therapy. It occurs in up to 1% of patients receiving antipsychotic medication and has also been seen in patients treated with antidepressants, lithium, carbamazepine, metoclopramide and on sudden discontinuation of levodopa therapy. It may be due to sudden changes in dopaminergic function upsetting thermoregulatory centres in the brain. NMS can be fatal due to renal and respiratory failure. The incidence of fatalities is around 20% although higher figures have been quoted in patients receiving depot antipsychotics. 5, 8 Onset of NMS is variable; it may be as early as 45 minutes or as late as 65 days after initiation of the antipsychotic. 13 Main Symptoms hyperthermia or fever within 24 72 hours (not always seen e.g. if concomitant carbamazepine is being given ) usually to over 38.5 0 c severe muscle rigidity and tremor mental state changes - confusion, agitation, altered (reduced) level of consciousness, irritability, mutism sweating, dehydration dysphagia hypertension, fluctuating blood pressure and tachycardia incontinence, urinary retention, obstruction raised creatinine phosphokinase (CPK) levels - over 1000iu in 1L raised white cell count Risk Factors being young being male dehydration having an affective disorder being on a MAOI Being on fluphenazine depot Treatment immediate withdrawal of all antipsychotic, antidepressant and lithium treatment transfer to medical or ICU ward, for general supportive medical intervention supportive treatment to correct dehydration and hyper-pyrexia use diazepam for sedation and as a muscle relaxant bromocriptine 2.5 to 20mg TDS or IV dantrolene monitor blood pressure, rigidity and muscle tone, and temperature every four hours Page 19 of 44

Antipsychotic Guidelines monitor white cell count, U&E, and liver function tests daily. Rechallenge with antipsychotics review diagnosis of NMS to ensure key features were present and review diagnosis to confirm the need for antipsychotic medication consider alternative strategies where possible, e.g. ECT, benzodiazepines etc a minimum of 5 14 days should elapse post recovery before restarting the antipsychotic depot medication must never be used for rechallenge, choose a drug from a different class from the one which caused NMS, or select a low potency drug (e.g. chlorpromazine) or an agent with low D2 receptor blockade (e.g. quetiapine, clozapine) use low starting dose and increase slowly perform alternate day CPK levels and monitor pulse, temperature and muscle tone daily until stable inform patients and carers of the risks and how to recognise the syndrome in the future Extra Pyramidal Side Effects (EPSE) Akathisia, pseudoparkinsonism, dyskinesias and dystonias have all been associated either acutely or chronically with antipsychotic drugs and are thought to be due to non-selective dopamine (D2) receptor blockade. 14 They are generally dose related, more likely to occur with typical antipsychotics (high potency ones) but uncommon with most atypicals. 7 Pseudoparkinsonism Pseudoparkinsonism has been estimated to occur in 15-50% of patients. It is more common in elderly females. 15 Symptoms usually appear within one month of onset of treatment or dose increase. Characteristics muscle rigidity tremor excess salivation decreased/slow physical and/or mental activity shuffling gait lack of facial expression slow monotonous speech Treatment reduce dose of antipsychotic prescribe antimuscarinic drug - e.g. procyclidine 5mg when required, up to three times a day (see antimuscarinic prescribing guidelines) Page 20 of 44

switch to an antipsychotic less likely to produce parkinsonian symptoms e.g. atypicals or sulpiride The condition should resolve itself upon termination of treatment with the antipsychotic, but may take several weeks to disappear depending on the individual patient. Acute Dystonia and Dyskinesia Dystonic reactions have been estimated to affect 2-10% of patients. 14 It is more common in young males (especially antipsychotic naive males) given high potency drugs. Acute dystonia can occur within hours of commencing treatment with oral antipsychotics. Characteristics uncontrolled muscle spasms torticollis involuntary tongue protrusion oculogyric crisis Treatment reduce dose of antipsychotic prescribe antimuscarinic/cholinergic drug - e.g. procyclidine 5mg when required up to three times a day see antimuscarinic prescribing guidelines switch to an antipsychotic less likely to produce parkinsonian symptoms e.g. atypicals or sulpiride Akathisia Akathisia is estimated to be a problem in 20-30% of patients taking antipsychotics. It can occur within a few weeks of commencing treatment with antipsychotics or increasing the dose. Characteristics motor restlessness/compulsion to move/inability to stay still - rocking, foot stamping and tapping, pacing mental unease irritability, agitation and aggression (often mistaken for worsening of the patient s symptoms or behavioural problems) Treatment reduce dose of antipsychotic switch to lower potency or atypical antipsychotic prescribe propranolol (30-160mg/day in divided doses) unlicensed indication prescribe clonazepam (up to 1.5mg daily in divided doses) unlicensed indication Page 21 of 44

anticholinergic drugs e.g. procyclidine may be effective if parkinsonism is also present, but are not very useful for the relief of akathisia Upon discontinuation of the antipsychotic, akathisia symptoms generally resolve within 7 days, but may take several weeks to disappear. Tardive Dyskinesia The prevalence of tardive dyskinesia (TD) has been estimated at around 10-20% (may be up to 40% in long term patients). It is more common in elderly females, those with an affective illness, negative symptomology and those who have had acute EPSE. 16 It usually occurs after months to years of treatment. Characteristics abnormal, involuntary orofacial movements lip smacking, chewing, tongue protrusion pin rolling pelvic thrusting TD is potentially irreversible in 50% of cases. After antipsychotic withdrawal, symptoms may improve or worsen within several weeks, but this is usually followed by a long slow recovery over the next months or years. Treatment withdraw all antimuscarinics (which can exacerbate symptoms) reduce dose of, or discontinue antipsychotic consider change to clozapine, olanzapine or quetiapine 17 withdraw other drugs which may exacerbate TD e.g. metoclopramide, antidepressants, antimuscarinics, and antiparkinson drugs consider use of tetrabenazine 12.5-200mg/day * consider other treatments- clonazepam (1-4mg/day in divided doses) ** buspirone ** vitamin E (400iu increasing to 1600 iu/day) ** calcium-channel blockers ** * only licensed treatment of TD in the UK ** unlicensed treatment options contact MIS for specific information Page 22 of 44

Maintenance of Primary Care Patients Where possible, patients maintained in the community on continuation therapy should be stable and free from side effects of their medication. These patients should be maintained on treatment for at least two years (five years for second or recurrent episode presentations). Unfortunately, few patients fall into this category and secondary care advice may be required for a number of reasons. Reasons for acute deterioration in mental state should be investigated, such as:- substance misuse (including alcohol) non-concordance with medication drug induced side effects depression Secondary care specialists should be consulted when the cause or source of the problem is not obvious and will be happy to give advice concerning their patients Advice should be sought as soon as possible in the following circumstances: Patients suffering from rapid weight gain in the first 3 months (steady weight gain over a long period may be managed with diet and exercise) Patients suffering from movement disorders such as EPSE, akathisia and tardive dyskinesia Patients suffering from sexual dysfunction or hyperprolactinaemia related problems Patients suffering from significant deterioration in renal or hepatic function or ECG changes Patients suffering from excessive and prolonged sedation (lasting more than 4 8 weeks) Patients receiving an unlicensed drug or dose should have all their problems referred Patients who remain partially resistant to treatment Patients receiving depot medication. If the patient remains without symptoms for 5 years, consult with secondary care Patient receiving poly-pharmacy. Refer those who are unstable and receiving multiple psychotropics and/or have coexisting medical conditions NB: Clozapine doses must not be altered without secondary care advice. Page 23 of 44

Clozapine Initiating Treatment Clozapine can only be initiated under a consultant psychiatrist s supervision/advice. Each patient, doctor prescribing and pharmacist dispensing, has to be registered with the manufacturing company and blood testing is a mandatory part of treatment. This takes place weekly for the first 18 weeks, then fortnightly for the next 32 weeks and monthly thereafter. Slow initiation of clozapine is essential to minimise common side-effects such as hypotension and sedation, which are dose-dependent and more frequent at the beginning of treatment. Blood pressure (lying and standing) and pulse checks should be carried out twice a day during the titration period. The initial dose should be 12.5mg, given at night (to avoid the need for blood pressure checks over the first few hours). Doses are increased slowly (see table below), given twice daily, until a daily dose of 450mg daily is achieved (if tolerated). Response should be observed over several weeks at this dose before increasing further, in increments of 50-100mg/week. If a dose is not tolerated, decrease to a dose which was tolerated and increase more slowly if need be. If the patient has not taken clozapine for more than 48 hours, it should be recommenced at the starting dose but the increasing regime can be done more quickly. Day Morning Dose (mg) Evening Dose (mg) 1-12.5 2 12.5 12.5 3 25 25 4 25 25 5 25 50 6 25 50 7 50 50 8 50 75 9 75 75 10 75 100 11 100 100 12 100 125 13 100 150 14 125 150 15 150 150 18 150 200 21 200 200 28 200 250 Page 24 of 44

Clozapine Plasma Level Monitoring Studies suggest that efficacy in treatment-resistant schizophrenia may be associated with trough clozapine concentrations of 0.35mg/L or above. 18 Although clozapine dosage adjustment is normally made according to clinical response and tolerance, a clozapine plasma level may be useful in the following situations: Poor responders after 3-6 months at over 400mg/day - if the level is less than 0.35mg/L, dosage adjustment can be made until the level exceeds this and then reviewed again Suspected non-concordance with medication total or erratic non-concordance is predictable from clozapine plasma levels Managing drug-interactions (e.g. concurrent SSRIs or enzyme-inducing drugs, which could result in an unexpectedly high or low level of clozapine). A level will assist decisions on dose changes. Dose related adverse-effects can also be easily diagnosed particularly where clozapine clearance may be reduced, e.g. hepatic impairment. Investigating clozapine overdose Metabolic differences between individuals can lead to large variations in values. A level is only useful after the titration period has elapsed and if the clozapine dose has been stable within the last week. The blood sample should ideally be taken 6-8 hours after a dose, but a trough sample (immediately before the next dose) can be taken if more convenient. Please make requests for plasma levels prior to the patient s next routine blood test and send to the pharmacy clozapine service, so that blood for a plasma level can be taken at the same time (to avoid patients having to have additional blood tests). The pharmacy clozapine service will arrange samples to be sent to the appropriate place (Medical Toxicology Unit, Kings College Hospital, London); do not send blood samples yourself. Clozapine Monitoring in the Community Once a patient has been receiving clozapine for 52 weeks with no haematological problems, blood sampling is carried out every four weeks and prescriptions can be dispensed monthly. If appropriate, prescribing and management of the sampling can be transferred to the patient s GP. Transfer of prescribing responsibility needs to be agreed between the consultant, the GP, the pharmacy supplying the clozapine (which needs to be registered with the company) and the pharmaceutical company. The patient must be advised that the timings for blood sampling and supply of medication differ in the community. The patient must visit the GP for a blood test two weeks prior to the next supply of clozapine being due. If the result is green, a supply Page 25 of 44

of clozapine can be prescribed and collected from the nominated pharmacy in two weeks time. For further advice please contact the pharmacy clozapine service, Prospect Park Hospital on 0118 960 5296. Management of Clozapine-Induced Side-Effects Side-Effect Likely Time Frame Management Suggestions Sedation First 4 weeks. May be persistent, but tolerance should develop Give larger proportion at night. May need single night-time dose. Decrease Hypersalivation Tachycardia First 4 weeks, but may persist. Common at night First 4 weeks. May persist. Often dose-related dose if necessary Use a towel to cover pillow. If distressing, try antimuscarinic agent, e.g. hyoscine 300mcg sucked and swallowed at night. Discuss alternative agents with pharmacy Slow down dose escalation. Reduce dose. Consider small dose of beta-blocker Constipation Any time. Usually persists High fibre diet. Bulk forming/stimulant laxatives. Check for/encourage adequate fluid intake Hypotension First 4 weeks Take care when standing up. Reduce dose or slow down rate of increase. Give largest dose at bedtime. Consult pharmacy if severe. Hypertension First 4 weeks, sometimes longer Monitor closely and slow down dose increases if necessary. Hypotensive therapy is rarely necessary. Weight Gain First year or at anytime. Dietary counselling before and during treatment. Monitor weight. Exercise. Fever First 3 weeks Give antipyretic but check FBC. Not usually related to blood dyscrasias. Seizures Any time. More frequent at doses over 600mg/day (and/or plasma levels above 0.6 micrograms per litre) Avoid rapid dose increases. After a fit, withhold dose for 1 day & resume at half dose. Consider EEG/neurology referral and valproate prophylaxis. Page 26 of 44

Nausea First 6 weeks. Try an anti-emetic e.g. domperidone. Avoid metoclopramide and prochlorperazine (which can cause EPSE) Nocturnal Enuresis Any time Avoid night-time doses (last dose before 6pm) and fluids before bedtime. Consider desmopressin. Neutropenia/agranulocytosis First 18 weeks usually Stop clozapine. Admit General Guidance Depot Injections The main advantage and general indication for giving antipsychotic medication in depot form is that compliance with therapy can be assured. Disadvantages include a suspected higher incidence of extra-pyramidal side effects (EPSE), local complications due to the administration of an intramuscular injection and other side effects associated with antipsychotic medication (see previous). These are more common in elderly patients and when using high doses. always give a test dose when initiating treatment - to minimise potential side effects of the drug and adverse reactions to the oil. It should be noted that some EPSE occur only after several doses of the depot (see BNF or contact MIC for manufacturers recommended test doses) continue with the lowest therapeutic dose - low doses are better tolerated, less expensive and may also be at least as effective as higher doses. 7 administer at the longest possible licensed interval - all depots can be safely administered at their maximum licensed dosing interval - there is no evidence to suggest shortening the dose interval improves efficacy and less frequent administration is less stressful (injections are painful). administer the smallest volume of depot possible (injections are painful). adjust doses only after an adequate period of assessment - peak plasma levels and achievement of steady state are delayed with depot injections so should be increased only after careful assessment over at least one month. Page 27 of 44

Points to Remember at the start of therapy, plasma levels of antipsychotic released from a depot increase over several weeks, without increasing the given dose depot preparations take at least two months to achieve steady plasma levels true relapse seems only to occur three to six months after withdrawing depot therapy injections should be given into the buttock as a large muscle is needed for steady absorption of the drug Page 28 of 44

Appendix 1 GUIDELINES FOR THE MANAGEMENT OF OLDER PATIENTS WITH ACUTELY DISTURBED OR VIOLENT BEHAVIOUR (GUIDELINES FOR RAPID TRANQUILLISATION) Acute behavioural disturbance can occur in the setting of delirium, psychiatric illness, dementia or/and alcohol misuse. Causes of delirium, for example infection, hypoxia, stroke, metabolic disturbance, dehydration and physical illness, need to be assessed. Agree and document management plans and risk assessment prior to the implementation of these guidelines. The practice of rapid tranquillisation in older people is ONLY to be used when appropriate psychological and behavioural approaches have failed and where all attempt has been made to correct the underlying physical causes. The aims of rapid tranquillisation are: 1. To reduce suffering for the patient. 2. To reduce the risk of harm to others by maintaining a safe environment. 3. To do no harm (by prescribing in a safe way and to monitor physical health.) This protocol must be reviewed at 24 hours and if the patient is not settling within 24-48 hours, a senior colleague should be consulted. Prior to rapid tranquillisation: Ensure adequate numbers of staff who are trained in Control and Restraint, and life support training. Try to calm patient in a reassuring and confident manner. Try non-pharmacological approaches such as talking, distraction, timeout, and environment. Make a careful assessment of any medication previously received and their response to it. Check for any physical factors, which may be a contra-indication to rapid tranquillisation, for example, avoid use of lorazepam in respiratory depression. Check that all clinically relevant information is available and reviewed by a senior clinician where appropriate. Check that the management plan is clearly documented. If not, then document it. Try to obtain consent to accept medication/treatment and document response. If patient unable to give verbal consent, the emergency situation then applies. Page 29 of 44

Ensure that all emergency resuscitation equipment is available before treatment is commenced. In an emergency situation: N.B. Treatment in an emergency is given under common law but must take account of a person s rights under the Human Rights Act 98. This is particularly important in any use of restraint, which must always be a final resort. The emergency situation applies when it is in the best interests of the patients i.e. to save life, relieve serious suffering, prevent deterioration in an emergency situation or represents minimum interference necessary to prevent the patient from behaving violently and being a danger to others or themselves. Page 30 of 44

STEP INTERVENTION 1. Distraction, time out, environment etc. If unsuccessful, go to step 2: 2. Offer oral treatment as below (take into account patient s size and physical status) DRUG DOSE MAX DOSE IN 24 HOURS Lorazepam 0.5 1mg 4mg Or Trazodone 50 75mg 150 200mg 3. If unsuccessful or patient showing signs of, or known to be disinhibited, consider the following antipsychotics orally: DRUG DOSE MAX DOSE IN 24 HOURS Quetiapine 25 50mg 100 150mg Haloperidol 0.25 0.5mg 2mg Risperidone Quicklets 1mg 2mg Caution in dementia, CVA and cerebrovascular risk factors Olanzapine Velotabs Caution in dementia, CVA and cerebrovascular risk factors 5mg 20mg 4. If oral medication refused, consider the following I/M: DRUG DOSE INSTRUCTION MAX DOSE IN 24HRS I/M Lorazepam If Lorazepam is contra-indicated (i.e. respiratory depression) or unsuccessful, consider: Or I/M Olanzapine Especially if Parkinsons Disease or disinhibition. Caution in dementia, CVA and cerebrovascular risk factors 0.5-1mg 2.5mg 5mg Repeat in 1 hour if not settled. Repeat 3-4 hourly Repeat after 2 hours. Max 3 injections in 24 hours. Monitor for sedation and cardio-respiratory depression if patient has had I/M benzodiazepine. Avoid giving olanzapine I/M and lorazepam I/M within an hour of each other. Or I/M Haloperidol 0.5mg Repeat 1-2 hourly 2mg OBSERVATIONS and further management: Monitor pulse and respiratory rate every 10 minutes for 1 hour after IM injection Monitor BP 30 and 60 minutes after Ensure availability of anticholinergics such as Procyclidine 2.5mg 5mg IM in case of acute dystonic reactions Ensure availability of Flumazenil to reverse the effects of Lorazepam. Flumazenil must be given by a doctor if the respiratory rate drops below 10/min after lorazepam has been used. If this happens during standard working hours, contact a doctor on the ward or within the hospital ASAP and consider calling 999. Outside standard working hours, contact the on-call doctor AND call 999. 2-4mg 20mg Page 31 of 44

Consider use of Mental Health Act in patients where repeated enforced medication is required. N.B. THE MENTAL HEALTH ACT HAS NO REMIT TO TREAT PATIENTS FOR PHYSICAL ILLNESS. References Working group for Faculty of Old Age Psychiatry RCPsych, RCGP, BGS and Alzheimers Soc March 2004 www.rcpsych.ax.uk/college/faculty/oap/professional/guidance - summary.htm#notes Committee on Safety of Medicines www.mca.gov.uk.aboutagency/refframework/csm/csmframe.htm Howard R, Ballard C. O Brien J, Burns A. Guidelines for the management of agitation in dementia. International Journal of Geriatric Psychiatry 2001; 16:714-717 BNF September 2004 NICE guidelines HRA 98 articles 3,5,8. Page 32 of 44

Appendix 2 Guidelines for the Use of Risperidone Long-Acting Injection (Risperdal Consta ): SUMMARY Risperdal Consta is indicated for the treatment of schizophrenia and other psychotic conditions in which positive symptoms and/or negative symptoms are prominent. It should be considered for: 1. Patients who have responded to treatment with an oral atypical antipsychotic, but who are non-compliant, or 2. Patients who have responded well to a depot preparation of a typical antipsychotic, but are suffering from side effects. Risperdal Consta should not be used as first line treatment or for patients who have a history of treatment resistance to atypical antipsychotic agents. Treatment Guidelines Risperdal Consta releases risperidone via sustained release biospheres. Only small amounts of risperidone are released during the first three weeks. The main drug release starts in week three and peaks in weeks 5-6. As a result, alternative antipsychotic cover (ideally oral risperidone) will be needed for the first three weeks of treatment. Risperdal Consta should only be initiated by or following consultation with a consultant psychiatrist Risperidone naive patients should undergo a trial of oral risperidone to identify intolerance to the drug. Oral risperidone should be given for at least three weeks patients taking 4mg of risperidone orally (or equivalent dose of another antipsychotic) should be started on the 25mg dose administered every two weeks Patients taking higher doses of oral antipsychotic can be stared on 37.5mg every two weeks any existing antipsychotic medication should ideally be reduced and discontinued three weeks after the first Risperdal Consta injection at least three 25mg doses of Risperdal Consta should be given at two weekly intervals prior to increasing the dose, to allow blood levels to peak. where necessary, (e.g. patients receiving the equivalent or more than 4mg per day of risperidone), the dose of Risperdal Consta may then be increased to 50mg if oral supplementation is deemed necessary, consider low dose benzodiazepines (short term) Switching regimes may vary depending on the individual patient and current drug regime. Contact the Medicines Information Service, pharmacy department, Prospect Park Hospital, on 0118 960 5075/5059 for specific information. Storage and General Information Page 33 of 44