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No warranty may be created or extended by any promotional statements for this work, Neither the publisher nor the author shall be lable for any damages arising herefrom, Library of Congress Cataloging-in-Publication Data ‘Taylor, David, 1940 The Maudsley prescribing guidelines in psychiatry / David Taylor, Carol Paton, Shitij Kapur. 11th ed. percm, Prescribing guidelines in psychiatry Rev. ed. of Prescribing guidelines. 2003. Includes bibliographical references and index. ISBN 978.0-470-97948-8 (pbk. : alk. paper) |. Paton, Carol, II. Kapur, Shit, Ill. Taylor, David, 1946~ Prescribing guidelines, IV. South London and Maudsley NHS Trust, V. Title, VI. Titk: Prescribing guidelines in peychintry. IDNLM: |. Mental Disorders-drug therapy-Great Britain, 2. Psychopharmacology-methods-Great Britain. 9. Psychotropic Drugs-adminisration & dosage-Great Britain. 4, Psychotropic Drugs-therapeutic use-Great Brita WM 402], 616.89"18-de23 2011051662 AA catalogue record for thisbook is available from the British Library. Wiley also publishes its books ina variety of electronic formats. Some content that appears in print may not he available in electronic books. 8 1o/12pt Minion by Apia ® Ine, New Delhi, nda Printed in [Country only] 1 2012Chapter 1 ‘Chapter 2 Preface ‘Acknowledgements Notes on using The Maudsley Prescribing Guidelines Notes on inclusion of drugs List of abbreviations Plasma level monitoring of psychotropic drugs and anticonvulsants Interpreting sample results Schizophrenia Antipsychotic drugs Antipsychotic drugs: equivalent doses Antipsychotic drugs: minimum effective doses Antipsychotic drugs: licensed maximum doses ‘New antipsychotic drugs Antipsychotic drugs: general principles of prescribing National Institute for Health and Clinical Excellence guidelines for the treatment of schizophrenia ‘Treatment algorithms for schizophrenia Antipsychotic drugs: monitoring of metabolic effects ‘Switching antipsychotic drugs because of poor tolerability Antipsychotic response: to increase the dose, to switch, to add or just ‘wait — what is the right move? Speed and onset of antipsychotic drug action First-generation antipsychotic drugs: place in therapy Antipsychotic drugs: long-acting injections Risperidone long-acting injection Paliperidone palmitate long-acting injection Management of patients on long-term depots: dose reduction Contentsvi Contents Chapter 3 Combined antipsychotic drugs High-dose antipsychotic drugs: prescribing and monitoring Negative symptoms in schizophrenia Antipsychotic prophylaxis Refractory schizophrenia and clozapine Clozapine augmentation Refractory schizophrenia: alternatives to clozapine Clozapine: management of common adverse effects Clozapine: uncommon or unusual adverse effects Clozapine: serious haematological and cardiovascular adverse effects Clozapine, neutropenia and Clozapine and chemotherapy Clozapine-related hypersalivation Guidelines for the initiation of clozapine for patients based in the community ‘Omega-3 fatty acids (fish oils) in schizophrenia Extrapyramidal side-effects of antipsychotic drug treatment ‘Treatment of antipsychotic-induced akathisia ‘Treatment of tardive dyskinesia Neuroleptic malignant syndrome Catatonia Cardiovascular effects of antipsychotic drug treatment Antipsychotic drugs and hypertension Hyperprolactinaemia Antipsychotic-induced weight gain ‘Treatment of drug-induced weight gain Antipsychotic drugs, diabetes and impaired glucose tolerance Antipsychotic drugs and dyslipidaemia Antipsychotic drugs and sexual dysfunction Antipsychotic-associated hyponatraemia Antipsychotics and pneumonia Relative adverse effects of antipsychotic drugs: a rough guide Bipolar disorder Valproate Lithium Carbamazepine Physical monitoring of people with bipolar disorder Treatment of acute mania or hypemania Antipsychotic drugs in bipolar disorder Bipolar depression Rapid cycling bipolar disorder Prophylaxis in bipolar disorder 51 54 37 60 64 66 69 75 78 80 84 88 89 92 96 98, 103 105 110 113 5 122 123 126 128 132 138 142 148, 150 151 153 153 159 168 173 176 182 185 191 193Contents Chapter 4 Chapter 5 Chapter 6 Depression and anxiety Depression Antidepressants ‘Treatment of resistant depression ‘Treatment of psychotic depression Electroconvulsive therapy and psychotropic drugs Psychostimulants in depression ‘Treatment of depression in the elderly ‘Treatment of depression in stroke Adverse effects of antidepressants Selective serotonin reuptake inhibitors and bleeding Depression and diabetes Cardiac effects of antidepressants Antidepressants and sexual dysfunction Antidepressants and hyperprolactinaemia Antidepressants: swapping and stopping St John’s wort in the treatment of depression Drug interactions with antidepressants Alternative routes of administration for antidepressants Anxiety spectrum disorders Benzodiazepines in the treatment of psychiatric disorders Benzodiazepines and disinhibition Benzodiazepines: dependence and detoxification Insomnia Children and adolescents Principles of prescribing practice in childhood and adolescence Depression in children and adolescents Bipolar illness in children and adolescents Psychosis in children and adolescents Anxiety in children and adolescents Obsessive compulsive disorder in children and adolescents Attention deficit hyperactivity disorder Autism spectrum disorders Tics and Tourette's syndrome Melatonin in the treatment of insomnia in children and adolescents Rapid tranguillisation in children and adolescents Doses of commonly used psychotropic drugs in children and adolescents Substance misuse Alcohol dependence Opioid misuse and dependence Nicotine and smoking cessation 197 197 201 222 233 235 239 243 247 249 252 255 257 264 268 270 278 281 286 292 301 304 306 310 315 315 316 321 326 327 328 332 337 345 349 351 354 355 356 372 398,Contents Chapter 7 Chapters Stimulant drugs of dependence Benzodiazepine misuse ‘y-Butaryl-lactone and -hydroxybutyrate dependence Drugs of misuse: a summary Interactions between ‘street drugs and prescribed psychotropic drugs Use of psychotropic drugs in special patient groups Epilepsy Pregnancy Breast feeding Renal impairment Hepatic impairment Prescribing in the elderly Dementia Behavioural and psychological symptoms of dementia Parkinson's disease Multiple sclerosis Eating disorders Acutely disturbed or violent behaviour Psychotropic medications for adults with learning disabilities Borderline personality disorder Delirium Huntington's disease Psychotropic drugs and surgery Prescribing psychotropic drugs for patients with HIV infection Psychotropic drugs and cytochrome (CYP) function summary of psychiatric side-effects of non-psychotropic drugs Miscellaneous conditions and substances Psychotropic drugs in overdose Biochemical and haematological effects of psychotropic drugs Prescribing drugs outside their licensed indications Observations on the placebo effect in mental illness Drug interactions with aleohol Nicotine Smoking and psychotropic drugs Caffeine Complementary therapies Enhancing medication adherence Driving and psychotropic medicines Covert administration of medicines within food and drink Index 406 407 408 410 414 419 419 430 446 462 478 487 490 509 518 522 527 531 539 545 547 554 558 564 573 578 587 587 593 604 606 608 613 616 618 624 628 634 643 647Preface The publication of this 11th edition of The Maudsley Prescribing Guidelines marks the 18th year of its distribution. Back in 1994, the original idea behind the first edition was to provide evidence-based guidance on prescribing in common psychiatric conditions. At that time, there was almost no evidence-based guidance of any sort in this area and, partly as a consequence, treatment varied widely and prescribing practice was of somewhat variable qual- ity. Today, of course, clinicians are swamped with prescribing guidance from various sources, many of them of high repute. Our task, then, in preparing this edition is partly to find com- monality with and within other guidelines but also to provide guidance where there is none (inevitably the more obscure or arcane areas of practice). We have also tried to bring our guidelines broadly in line with those of UK NICE, notwithstanding the age of some of these publications and the small differences in opinion that are bound to arise over time. This 11th edition includes significant changes from the previous edition. All sections have been updated to include data published before the end of 2011 and several new sections have been added. We also have a new publisher, Wiley—Blackwell, who have helped considerably in the formatting of this edition, improving the organisation and navigation. As usual, thanks are due to a great many experts who have kindly contributed to The Guidelines (listed on the next page) without whom The Guidelines could not exist. We are also sincerely grateful to Joan Marsh at Wiley—Blackwell and to Maria O’Hagan who has managed the production of this and previous editions and who maintains a growing database of over 15,000 scientific references essential for the production of The Guidelines, David Taylorwledgements ‘We are deeply indebted to previous contributors and to the following contributors to the present edition of The Maudsley Prescribing Guidelines. ‘Ayesha Ali Azizah Attard Sube Banerjee James Bell Delia Bishara Tony Cleare Anne Connolly Richard Corrigall Sarah Curran Vivienne Curtis Vandana Dimri Michael Dixon Petrina Douglas-Hall Andrew Easton Sarah Elliott Emily Finch, Andrew Flynn, Russell Foster Paul Gringras Isobel Heyman Rob Howard Ann Hyatt Bimpe dow Francis Keaney Mike Kelleher Shubhra Mace Jane Marshall Gordana Milavic Ify Okonkwo Banke Olofinjana Carmine Pariante Maxine Patel Sally Porter Kylie Reed Paramala J Santosh, ‘Anna Sparshatt Argyris Stringaris Gay Sutherland Eric Taylor Helen Turner Seema Varma Eromona Whiskeyaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.of abbreviations GBL G-CSF GGT GHB Gl cit GM-CSF HDL HR IcD IM INR Vv Lal LD LDL LET LUNSERS. MAO-A MAOI MCI MHRA MI MMSE NICE NMDA NMS. NNT NRT NSAID ocD ocTT -y-butaryl-lactone granulocyte-colony stimulating factor glomerular filtr ‘y-glutamyl transferase ‘y-hydroxybutyrate gastrointestinal gastrointestinal tract granulocyte macrophage colony-stimulating factor n rate high-density lipoprotein hazard ratio International Classification of Diseases intramuscular international normalised ratio intravenous long-acting inj earning disability low-density lipoprotein liver function test Liverpool University Neuroleptic Side-Effect Ratings Scale monoamine oxidase A monoamine oxidase inhibitor mild cognitive impairment Medicines and Healthcare products Regulatory Agency myocardial infarction Mini Mental State Examination National Institute for Health and Clinical Excellence N-methyl-D-aspartate neuroleptic malignant syndrome number needed to treat nicotine replacement therapy non-steroidal anti-inflammatory drug obsessive compulsive disorder oral glucose tolerance test PANDAS PDD-Nos PEG POMH-UK prn PTSD PUFA, RCT RLAL RRBI SADQ SAWS: SGA SIADH syw SPC SPECT SSRI STARD TCA 1D TET TORDIA ucT VIE wec YMRS Paediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus pervasive developmental disorders-not otherwise specified percutaneous endoscopic gastrostomy. Prescribing Observatory for Mental Health -UK pro re nata post-traumatic stress disorder polyunsaturated fatty acid randomised controlled trial risperidone long-acting injection restricted repetitive behaviours and interests Severity of Alcohol Dependence Questionnaire Short Alcohol Withdrawal Scale second-generation antipsychotic syndrome of inappropriate secretion of antidiuretic hormone St John’s wort Summary of Product Characteristics single photon emission computed tomography selective serotonin reuptake inhibitor Sequenced Treatment Alternatives to Relieve Depression tricyclic antidepressant tardive dyskinesia thyroid function test Treatment of Resistant Depression in Adolescence UDP-glucuronosyl transferase venous thromboembolism white cell count Young Mania Rating ScaleChapter 1 Plasma level monitoring of psychotropic drugs and anticonvulsants Plasma drug concentration or plasma ‘level’ monitoring is a process surrounded by some confusion and misunderstanding. Drug level monitoring, when appropriately used, is of con- siderable help in optimising treatment and assuring adherence. However, in psychiatry, as in other areas of medicine, plasma level determinations are frequently undertaken without good cause and results acted upon inappropriately.' Conversely, in other instances, plasma concentrations are underused. Before taking blood sample for plasma level assay, check the following. ® Is there a clinically useful assay method available? Oniy a minority of drugs have available assays. The assay must be clinically validated and results available within a clinically useful timescale. Is the drug at ‘steady state’? Plasma levels are usually meaningful only when samples are taken after steady-state levels have been achieved. This takes 4-5 drug half-lives. ® Is the timing of the sample correct? Sampling time is vitally important for many but not all drugs. If the recommended sampling time is, say, 12 h post dose, then the sample should be taken 11-13 h post dose if possible; 10-14 h post dose, if absolutely necessary. For trough or ‘predose’ samples, take the blood sample immediately before the next dose is due, Do not, ander any circumstances, withhold the next dose for more then 1 or (possibly) 2 h antil a sample is taken. Withholding for longer than this will inevitably give a misleading result (it will give a lower result than ever seen in the usual, regular dosing), which may lead to an inappropriate dose increase. Sampling time is less critical with drugs with a long half-life The Maudsley Prescribing Guidelines n Peychiatry, Eleventh Ecition, David Taylor, Carol Paton and Shitij Kapur. 2012 David Taylor, Carol Paton and Shitij Kapur. Published 2012 by John Wiley & Sons, Lt.2 The Maudsley Prescribing Guidelines in Psychiatry (e.g. olanzapine) but, as an absolute minimum, prescribers should always record the time of, sampling and time of last dose. Ifa sample is not taken within 1-2 h of the required time, it has the potential to mislead rather than inform, The only exception to this is if toxicity is suspected ~ sampling at the time of suspected toxicity is obviously appropriate. ® Will the level have any inherent meaning? Is there a target range of plasma levels? If so, then plasma levels (from samples taken at the right time) will usefully guide dosing. If there is not an accepted target range, plasma levels can only indicate adherence or potential toxicity. If the sample is being used to check compliance, bear in ming that a plasma level of zero indicates only that the drug has not been taken in the past several days. Plasma levels compliance, full compliance or even long-standing non- above zero may indicate err compliance disguised by recent taking of prescribed doses. Note also that target ranges have their limitations: patients may respond to lower levels than the quoted range and tolerate levels above the range; also, ranges quoted by different laboratories sometimes vary widely without explanation. * Istherea clear reason forplasmalevel determination? Only the following reasons are valid: — to confirm compliance (but see above) ~ if toxicity is suspected ~ if pharmacokinetic drug interaction is suspected ~ if clinical response is difficult to assess directly (and where a target range of plasma levels has been established) ~ ifthe drug has a narrow therapeutic index and toxicity concerns are considerable. ‘The basic rule for sample level interpretation is to act upon assay results in conjunction with reliable clinical observation (“treat the patient, not the level’). For example, if a patient is responding adequately to a drug but has a plasma level below the accepted target range, then the dose should not normally be increased. If a patient has intolerable adverse effects but a plasma level within the target range, then a dose decrease may be appropriate. ‘Where a plasma level result is substantially different from previous results, a repeat sample is usually advised. Check dose, timing of dose and recent compliance but ensure, in particular, the correct timing of the sample. Many anomalous results are the consequence of changes in sample timing. Table 1.1 shows the target ranges for some commonly prescribed psychotropic drugs.Plasma level monitoring 3 Sample Time to Drug Target range timing steady state Comments Amisulpride 200-320 ug/l Trough 3 days See text Aripiprazole 150-210 g/l Trough 15-16days See text Carbamazepine?? >7 maf Trough 2 weeks Induces its own bipolar metabolism. Time to steady disorder state dependent on autoinduction Clozapine 350-500 yg/l Trough 2-3 days See text Upper limit of (12h target range Post. isilldefined doseif once daily) Lamotrigine*? Not Trough 5 days Some debate over utility of established Aue lamotrigine levels, but suggest induction is especially in bipolar 25-15 mail thought to. disorder. Toxicity may be ‘occur, so time increased above 15 mg/l to steady state may be longer Lithium" 0.6-1.0 12h 3-5 days Well-established target mmol/l post range (may be dose =1.0 mmol/l in mania) Olanzapine 20-40 g/l 12h 1 week See text Paliperidone'? 20-60 y.g/l Trough 2-3 days oral No obvious reeson to (9-0H 2 months suspect range should be risperidone) depot any different from . risperidone. Some practical confirmation Phenytoin® 10-20 mg Trough Variable Follows zero-order kinetics. Free levels may be useful Quetiapine Around Trough? 2-3 days oral Target range not defined. 50-100 gi? Plasma level monitoring not recommended. See text (Continued)aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.6 — The Maudsley Prescribing Guidelines in Psychiatry when the dose reached 600 mg/day. It remains unclear whether using these high doses can benefit patients with plasma levels already above the accepted threshold. Nonetheless, it is prudent to use an anticonvulsant as prophylaxis against seizures and myoclonus when plasma levels are above 500-600 g/l and certainly when levels approach 1000 g/l. Olanzapine Plasma levels of olanzapine are linearly related to daily dose, but thereis substantial variation,2> with higher levels seen in women, non-smokers” and those on enzyme-inhibiting drugs.°°°” ‘With once-daily dosing, the threshold level for response in schizophrenia has been suggested to be 9.3 ug/l (trough sample),** 23.2 yug/l (12-h postdose sample)" and 23 pg/lat a mean of 13.5 h post dose.” There is evidence to suggest that levels greater than around 40 jigi/l (12-h sampling) produce no further therapeutic benefit than lower levels.®° Severe toxicity is uncommon but may be associated with levels above 100 ug/l, and death is occasionally seen at levels above 160 pig/l®* (albeit when other drugs or physical factors are relevant). A target range for therapeutic use of 20-40 j1g/I (12-h postdose sample) has been proposed for schizophrenia; the range for mania is probably similar. Significant weight gain seems most likely to occur in those with plasma levels above 20 pg/l.®* Constipation, dry mouth and tachycardia also seem to be related to plasma level.°° In practice, the dose of olanzapine should be governed by response and tolerability. Plasma level determinations should be reserved for those suspected of non-adherence or those not responding to the maximum licensed dose (at 20 mg/day, around 20% of patients will have olanzapine levels =20 jug/l).° In the latter case, dose may then be adjusted to give 12-h plasma levels of 20-40 pg/l. Quetiapine (IR) Dose of quetiapine is weakly related to trough plasma concentration.7- Mean levels reported within the dose range 150 mg/day to 800 mg/day range from 27 pgil to 387 g/l,’ although the highest and lowest levels are not necessarily found at the lowest and highest doses. Age, gender and co-medication may contribute to the significant interindividual vari- ance observed in therapeutic drug monitoring studies, with female gender,’”? older age”"”* and CYP3A4-inhibiting drugs®*7*-”* likely to increase quetiapine concentration. Reports of these effects are conflicting” and not sufficient to support the routine use of plasma level monitoring based on these factors alone. Thresholds for clinical response have been proposed as 77 pg/l””” and 50-100 .g/l;”* EPS has been observed in females with levels in excess of 210 pig/l.’7” Despite the substantial variation in plasma levels at each dose, there is insufficient evidence to suggest a target therapeutic range, so plasma level monitoring has little value. Most current reports of quetiapine concentrations are from trough samples. Because of the short half-life of quetiapine, trough levels tend to drop to within a relatively smal] range regardless of dose and previous peak level. Thus peak plasma levels may be more closely related to dose and clinical response’ although monitoring of such is not currently justified in the absence of an established peak plasma target range. Quetiapine has an establishedPlasma level monitoring 7 dose-response relationship and appears to be well tolerated at doses well beyond the licensed dose range.” In practice, dose adjustment should be based on patient response and tolerability. Risperidone Risperidone plasma levels are rarely measured in the UK and very few laboratories have devel- oped assay methods for its determination, Plasma level monitoring is probably unproductive (dose-response is well described) except where compliance is in doubt and in such cases, measurement of prolactin will give some idea of compliance. The therapeutic range for risperidone is generally agreed to be 20-60 ug/l of the ac- tive moiety (risperidone + 9-OH risperidone)™*' although other ranges (25-150 jug/l and 25-80 j1g/l) have been proposed.*? Plasma levels of 20-60 j1g/l are usually afforded by oral doses of between 3 mg and 6 mg a day.*”* ** Occupancy of striatal dopamine D2 receptors has been shown to be around 65% (the minimum required for therapeutic effect) at plasma levels of approximately 20 jag/I.*! Risperidone long-acting injection (25 mg/2 weeks) appears to result in plasma levels aver- aging between 4.4 and 22.7 pg/L! Dopamine D; occupancies at this dose have been variously estimated at between 25% and 71%.°"**7 There is considerable interindividual variation around these mean values, with a substantial minority of patients with plasma levels above those shown. Nonetheless, these data do cast doubt on the efficacy of a dose of 25 mg/2 weeks™ although it is noteworthy that there is some evidence that long-acting preparations are effective despite apparently subtherapeutic plasma levels and dopamine occupancies."* References 1. 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Clin Paychopharmacol 1993; 13:383-59, 42, Potkin 5G etal. Plas clozapine comentrations pred lin (Suppl 8133-136 43, Perry PI. Therapeutic drug monitoring of anipsychotis. Psychopharmacol Ball 200; 3519-2 14, let PM ah tfscivencs af closapine in netclptic-restant chinoprenie:lniclvenpone il plain douceaatoe J Obie Newrose2002;27:30-37. 45. xiang YQ al. Serum concentrations elczapine and norSozapine inthe prediction of elapse of patents With schiophvenlaSchizophe Res 2006;88:201-210 46, Stctfenhofer Veta. Clozapine plasms level montoring for predicion of ehesptalzation schizophrenic outpatients Pharmacopsychitry 47. Khan AY tl, Examining concentraion-dependent toxicity of clozapine: mle of therspevtic drug monitoring, }Peychistr Pract 20055, 1299-301, 48, Varma St al. Clovapine-rdated EEG changes and seizures dose and plasma-evelredatoeships. Ther Adv Psychopharmacol 201: 147-66 coacentvation inte paints, lin Deycinry 1961; 625-28, 1 espouse in rcatenent-ristantshizophrenia.| lia Psychiatry 1994538, 49. Greenwood Saith Cet al Serum clozapine levels review oftheir clinical wiity | Paychopharnsacel 2003; 17234-238Plasma level monitoring 9 50, Yusuf B ea. Prevalence and narute of side effects during clozapine maintenance weatment andthe relationship with clompine doseand plasn concentration. Int Clin Pychopharmacol2007;22:238-243, 31, Volpell $A etal Deerminatin of eloapine, worlompine and clozapine N-oxide in serum by liga chromaiography- ia Chem 1993 39:1656-1959, 52. Guiton Cet Clozspine snd metabatite concentrations dusing teatment ofpatieats with chronic chizophresia.} Clin Pharmacol 1999; 58, Palego Let al. Clozapine, torelazapine plasma level, their sum and cto in $0 psjehote patients: iafuence of pateatedated variables, Prog Neurpsychopharmacol Bil Psychiat 2002263175410, SA. WangCY eal The dterenial elects of steady sate fuvoxamine othe pharmcokineticsof olanzapine and lompinein heathy volunteers, J Clin Pharmacel 2008, 44785-792, 3B Areosist M fl, Plone level eneibhiing SY sop ia pltaie Wb shopivnks Senin Gj Wiadrpiemnnee chromatography with electrochemical detection, Ther Dag Monit 1997519:3¢7-313, 56, Gex Fabry Metal Therpeatic drug monitringf olanzapine: the combined effect of age, gender, siokig, and comediaton. Ther Drug Monit 2008; 29:65, 57. Bergemana N eal, Olanzapine plat concentition, sverige daly dove nd interaction with ca-mediction in sckinophrenic patients Pharmacepsychiatry 2004;57:63-08, 58, Perr P eal: Clanzapine plasm concentrations and dinical esponse in acuely il schimphrenic patients, } Chin Psychopharmacol 1997; 6472-477, 59, Fallows Lt ah went 25:612-699, (60. Mauri MC el linia outcome and olanzapine plas lees in ste chivophrenia. Eur Psychiatry 2005; 2055-60 G1. Rao MLctal [Olanzapine: pharmacology, pharmacokintis and therapeutic deus monitoring] Portadhe Neurol Pyehitr 200 69810-517 62. Robertson MD ata. Olanzapine concentrations in 1 Forensic Si 2000; 4:418-421. 663. Bech st sl, Olanzapine plasms evel ie relation toantimanic effect theacut therapy of manic state, Nox} Psychiatry 2006; 6081-182 (4, Perry Petal. The association of weight gain and olanzapine plasma concentrations J Cli Psyehophuemacol 2005; 28250-254 (65, Kelly DL at al Plena concentrations of high-doce slanzpine in a doubled creeaver stay. Hum Paychopharacol 2006; 21 (0 Patel MX et a, Plasma olanzapine in relation te preseribes dose and other factors. Usta fom a therapeutic drug monitoring servic, 1999-2008, Pychopharmacology 2011; 311-7. 67. Gerlich M etd. Therapeutic deug monitoring of quetipine in adolescents with psychotic disorders, Phatmacopaychiatry 2007; 40: (68. Hasselstrom J etal. Quetinpine serum concentzations in pryhistec patients the in uence of comedization. Ther Drug Menit 2108, 26:446-191 69, Sparhat Atal Relationship henecen daily dose rem concentetions.dapamine receptor ocupancy. a linia sponte to avenge: a review. Clin Poyciatry 20115 7211081123 mer Het al steacy-sttepharmacckinet safety and toleabily profes of quetapine, norguetiapine, and other quetiapine metabolites in pediatric and adult patients wh prchotc disorders. | Chid Adbles Peychopharmacst 200% 1881-88. 71. Li KY etl, Maltiple dose pharmacolinetiss of quetiapine and some of ite metabolite in Chinese aufering from schinphenia, Acta Pharmac Sn 2004; 26-396-304 72, McConville Be al. Pharmacokineticy, tolerability and linia efectiveres of quetiapine fumarate: an open-label tr in aoescents with psyehotcdsonéers. lin Psychatry 2000; 61:252-200 73, Castherg Let a. Quctiapine and drug interactions: evidence fom a routine therapeutic drug monitoring serie, JC (68:1540-1545, 74. Aichtorn W ta: Influence of age gence body weight sad valprone comediation on quetiapine plana comcntetions, Int Clin Peyshopharmacsl 2006; 2181-8. 75, MauriMCetal. Two week quetiapine eaten forschiophreni, drug induced psychosrand bordeline personality disorder naturalistic ion of urge plorma concentration fet relationships for olansapine in ehizorheenia. The Drog Monit 200%; inal serum and postmortem blood specimens - when doestherpeutic beccme tx? yehistry 20075, std with drm levels. Expert Opin Pharmacahes 76, Deagicevc A, Mulle MI, Sachs J, Harter 8, Hiemke C. Therapeutic drug monioring (TDM) of quetapine. Lecture presented a the symposium of he AGNE, October 8-100h 2003, Nun 177. Dragicevie A, Sichse}, Hatter 5, Hiembe C, Muller MI. Sum concentrations of quetiapine and clinic effets. Iaterational Meeting fon Fharmacovigilanc: in Fsychistey, Therapeutic Drug Mositoring and Pharmacogenetics of Psychotropic Drugs, September 1-3 2005, Lavminne Switerand 78, Dragicevi Ay ThotzauerD, Hiembe C, Muller M). Gender andage eects on quetiapine serum concentatons in patien's wth schizophrenia or schiznalfectve dvorders Leste presented atthe 2th Syimposiam ofthe AGNP, October 56th 2003, Munich 79, Sparshatt eta. Oustiapine:dove-respanse relationship in shizophreia. CNS Drugs 2008; 23:49-68, (Olesen OV etal Serum concentrations ands ffcts in psychiatric patients during esperifone therapy. Ther DrugMonit 1938;20:380-38410 The Maudsley Prescribing Guidelines in Psychiatry 41, Remington G eal. APET study evaluating dopamine D2 eceptoroccupancy for long-acting injectable riperidone. Am | Psyciatey 2006; 163396-01 12, Seto K e a. Riperidone inschimphreni: ie there a role for therapeutic drug non ng? Ther Drag Monit 2091; 33273-289. 43, Lane HY etal. Risperidone in actly exacerbated schizophrenia: dosingytateges and plasma evel} Clin Pyshiatry 2000; 61:209-214 14, Taylor D. Risperidone long acting inketionin prictce- more questions than answers? Acta PaychintrSeand 2006; 1141-2. 15, Nyberg Stel Singmteinial fftve dann oftepridone bane on PET: re patients. Am Psychiatry 1999; 186:869-875, 1M, Modori Ret al, Pasa antipsychotic concentration and receptor occupancy, with speci focus om risperidone long acting inetable, Eur Newopsychoplarmacol 2006; 16238-240 7, GefsertO ct al Pharmacokinetics and D2 ceptor occupancy of ngactng injectable rsperitone (Risperdal Consts™) in patient with sed D2and SHTIA rerptoreceupnney itches shop, Int J Newropryshophermacol 2005; 827-36. [88, NybergS tal, D2 dopamine receptor occupancy dringlow ose restment wi haloperidol decane, Am J Psychiatry 199515217: 78aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Schizophrenia 13 8. Davis IM etal A metu-anaisis ofthe efficacy of second generation antpsychetics. Arch Gen Paychstry 2003 6053-564 9. Leucht Se a. Scone: generation versus firs generation antipsychotic drugs for schizophrenia meta-analysis Lancet 200%; 373:31-. 10, Parker € etal Anipschotis drug and rik of venous thromboembolism: nese cave-contol study. BM) 2010; 3411243 11, Pope A etal. Anessent of adverse fect in clic ses of antipsychotic mediation: survey of methods sed. Br} Prychistry 2010; 9797-72, 12, Falak P. Limistiont af surest therapies why do patients etch therapies? ur Newropeychopharmacol 2008; 18(Suppl 3}:S135 si3s, 1 Yusuf 8 @ ab Prevalence and nature of sie eects during clozapine maintenance treatment and the relationship with clompine dose and plasma concentaton Int Clin Pychopharmacol2007;22:288-243. 14, Day IC etal, A comparison of pater’ and prescribers’ baits about neuroleptic side-ffcs: prevalence, distress and cavston, Acta Papen Sand 1998,97.93-97. 15, Waddell Leta A new seating sale for detecting sypical or second-generation antipsychotic side eet. | Psychopharmacol 2008; 16, DayiC ots. A selfrting sale for meaning neuroleptic side-eets,Valiatin ina group of chinophrenic patients Br Fychistry 199; 166350-653 17, Zhatsetal Time to dscontinuaton ofdepor and oral ist generation amipsycotis in the usu cateorsebtzphyenia Psychiatr Ser 2008; 5935-3 18, Adams CE et al Systematic meta teview of depot antipsychotic dogs fox people with schophenia Br] Bychitry 2001; 179299-298, 19, Schooler NR, Relapse and mhowitalizntion: comp 20, Tihonen | a Effectiveness of antipsychotic trestmests ina natonwite cohort of patients ia communty cate after first hospitalisation «deo sch-ophrenia and shiaafleciredivorder-observational follow-up study. BM} 2016; 333224 21, Lect C et al. Oral versus depet antipsychotic due for schizophrenia ~ a crite systemati review and meta-analysis of randomised. long term tralsSchitophe Res 29115 127.85-92. 22. Kane et al. Clrapize forthe tatment-roitant schisopheenic. A double-blind comparison with chlorpromazine. Arch Gea Paychitey 1988, 45:789-79 28, McBioy [Pet al Effectiveness ofclozapine versus olanzapine quetiapine, and speridone inpatients with eheonic schizophrenia who did rot espond to prior type aptipaychtictestment. Am I Beyeintry 2906; 168:60)-610 agora ond depot ontpeychotis J Clin Pochiaty 2003 (Suppl 1614.27. 24, Lewin SW etal Randomined controlled tril oF eect of prescription of clozapine ern ther second: generation antipsychotic drags in resistant schizophrenia. Schizophr Bul 2006, 32:715-723 25, Stone JM etal. Review: the biological kas antipsychotic response in schizophrenia} Psychopharmacol 2010;24:938.964 26, Agid O et al. Aa algorithm based approach to fist-episodeschizphenia: esponse rates over 3 prospective antipsychotic tris with a stecpectve dat alysis) Clin Payehiatey2011)72(01)1409- 1444 Antipsychotic drugs vary greatly in potency (not the same as efficacy) and this is usually expressed as differences in ‘neuroleptic’ or ‘chlorpromazine’ ‘equivalents. Some ofthe estimates relating to neuroleptic equivalents are based on early dopamine binding studies and some largely on clinical experience or even inspired guesswork. British National Formulary (BNE) maximum doses for antipsychotic drugs bear litte relationship to their ‘neuroleptic equivalents” Table 2.1 gives some approximate equivalent doses for conventional drugs.'? Values given should be seen asa rough guide when transferring from one conventional drug to another. An early review of progress is essential. It is inappropriate to convert second-generation antipsychotic doses into ‘equivalents’ since the dose-response relationship is usually well defined for these drugs. Dosage guidelines are discussed under each individual drug. Those readers desperate to find chlorpromazine equivalents for the newer drugs are directed to the published articles listing such data"14 The Maudsley Prescribing Guidelines in Psychiatry Equivalent dose Range of values in Antipsychotic (consensus) literature Chlorpromazine 100 mg/day - Flupentixol 3 mg/day 2-3 mg/day Flupentixol depot 10 mgweek 10-20 mg/week Fluphenazine 2 mg/day 2-5 mg/day Fluphenazine depot 5 mgMweek 1-12.5 mg/week Haloperidol 3 mg/day 1.5-5 mg/day Haloperidol depot 15 mg/week 5-25 mg/week Perphenazine 10 mg/day 10 mg/day Pimozide 2 mg/day 2 mg/day Pipotiazine depot 10 mg/week 10-12.5 mg/week Sulpiride 200 mg/day 200-270 mg/day Trifluoperazine 5 mg/day 2.5-5 mg/day Zuclopenthixol 25 mg/day 25-60 mg/day Zuclopenthixol depot 100 mg/week 40-100 mgiweek References 1. Foster. Neueoepticequivaence,Phatm J 19895 21831432, 2, Atkias M, Burgess A, Bottomley C, Rico M Psyeiat Bull 1997; 2124-226 3, Woods SW, Chlerpromazineequraln! dose forthe newer atypical antipsychotics | Clin Paycisty 20034 64662- 67, 4. Gardner DM, MurphyAL,O”Donnell H, Cenorrino P, Baldessarini]. International consetsus suc of antipsychotic desing. Am JPsychistry 2010; 1673486695, lospromazineequivlents a consensus of opinion for bath dlnialand esearch implications Table 2.2 suggests the minimum dose of antipsychotic likely to be effective in schizophrenia (first episode or relapse). At least some patients will respond to the dose suggested, although others may require higher doses. Given the variation in individual response, all doses should be considered approximate. Primary references are provided where available, but consensus opinion has also been used (as have standard texts such as the BNF and Summaries of Product Characteristics). Only oral treatment with commonly used drugs is covered,Schizophrenia 15 First episode Relapse/exacerbation Antipsychotic Dose (mg) Dose (mg) First-generation antipsychotics Chlorpromazine 200° 300 Haloperidol'> 2 ~4 Sulpiride® 400° 800 Trifluoperazine” 10° 15 Second-generation antipsychotics Amisulpride®"" 400° 800 Aripiprazole'?'5 10° 10 Asenapine’® 10° 10 lloperidone” + a Olanzapine®'®'? 5 10 Quetiapine?25 150° 300 Risperidone**7* 2 3 Sertindole?’ Not appropriate 12 Ziprasidone?>* 80° 80 “Estimate ~ too few data available References Oosthize Petal Determining the optimal ose of haloperidol in frst episode psychosis | Prchopharmacol 2001; 15:251-255. MeGarry PD. Recommended haloper Wanich PS eta, Halperidl doe forthe acute phase of schizophrenia. Cochrane Databste Spt Rev 2002;CD001951 Schooler N etal Rsperidoae and Raloperdol sn st-epsode psychosis long-term: randomized ted. Am] Psychiatr 2005; 162947959. . Keefe RS eal. Longterm neurocogative eects of olanzapine ot low dose haloperidol in fistepsode psychosis. Biol Paychistry 2006; 9397-105, Sone BGt al Sulpirie fr schizophrenia, Cochrane atabuee St Rev 2000, CDEOI162 7. Aementers JL al Antipsychotics in erly onset schiaphreni: systematic review and meta-analysis Eur Child AdclesePychistry 2008; Is41-18, 5. Mots NE « al. Amisupride for schizophrenia. Cochrane Databae Syst Rey 2012: CDO01357, 9. Puech A etal. Amiaulprid, and atypical antipsychotic, in the teainent of acute episodes of schizophrenia: a dove-ranging study vs 1 and risperidone doesn first-epnode psychosis Clin Payhintry 1999; 60704-7095, halo 10, Moller Hf etal. improvement of acute exacerbations of chizopheeia with amisulpide: a comparison with haloperidol, PROD-ASLP Study Group. Psychopharmcology 1997; 132:396-401 1. Spamhatt A et a. Amitulpnde doce, platma consentntion, occupancy and reponse: mplictione ior thrapeatic dng monitcing. Acta Payhiat Scand 2008;120:416-128 12, Taylor D.Aripiprazoleareiew of ts pharmacology antic uty, Int | Clin Pract 2005; 5749-4 13, Cutler Al tal The efficacy and fey flower doves ofa CNS Specie 2005; 11:591-702. iol The Amini Study Group. Asta Paychiste Sad 1988; ravle forthe treatment of rtients wits acue exacerbation ofschimphrena 15, Sparhatt A etd A systemic sevew of apiprezole - dose, plana concentration, receptor accupancy and respase: implications for therapeutic drug mositoring J Clin Psjchiatry 2010; 17447-1456. 16, Cittomet.Role af suhtingialacnapine in testment of schimph rena, Neuropyshite Dis Test 2011: 7:3 17, Crabtree Bet al Hoperidone forthe management of adults with schizophrenia. Clin Ther 201); 38:3016 The Maudsley Prescribing Guidelines in Psychiatry 18, Sanger TM etal Olarzapie vers hloperitol ueatment infest episode psychosis Am | Poyhiatry 1998: 18679 19, Kasper Risperidone and olanzpine-optimal desing fr eficacy and tolerability inpatients wth schizophrenia. Int lin Prychopharmacol 20, Smal JG ct sl. Quetiapine in patents with schizophrenia, A high- and low-dose double blind comparison with placebo, Seroquel Siady Group. Ach Gen Payhiatry 1997; 5449-557. 21, Poukene| ot a compariton of quetispineand dhlorpromatine inthe treatment of chinophreis, ets Prychine Scand 1975 06268-273, 22, Aevinitis LA etal. Multiple fixed doses of Seroquel” (quetiapine) in patents with sete xacerbation of sthizopheena: comparison with haloperidol an placebo. tol Psychiatry 197; 42253-246, 23, Kopala LC etal. Treattent ofa fist epiode efpsjchotcllaes with quetiapine: an aalysisof2 year outcomes Schizophe Res2006;81:29-39, 20, Sparshatt At a. Quetiapine: daxe-rsponse relationship in schizophrenia, CNS Drugs 2008; 2249-58, 25. Spenhelt A cal Relaionnkip biweendaly done plae concentrations dopeminereecplor oneupancys at sinval spon qutig a review.) Clin Peychiatry 20115721 108-1123, 26, Lane HY etl Risperdonein actely exacerbated schiaphreni: dosing strategies and ples evls.| Clin Pryhiatry 2000; 61:209-214 27, Wilians 8. Optima dosing with rgpridone: updated recommendations, I Clin Pjchiaty 206; 62242-288 28, EzewutieN etl Establishing a dose-response relationship fororalisperitonein relapsed chiopheni. | Tsychepharmacol2006;20:85-90, 29, Lincstrom Eta, Setindcle ethcacy and sfety in chizophtena, Expet Opla Pharmacither2006;7:1825-1834 30, Bagaall At al. Ziprasdone for schizophrenia and severe meatal ilness. Cochrane Databse Syst Rey 2000, CDOD1 948, 31, Taylor D, Ziprasidone ~an typist antipsychotic, Pham | 2001 266:395-401 52, Joyer AT eal Elect of inl sprasidone dove om lengih of therapy in shizopheenin. Schizopby Res 2006; 88:85. 28 Further reading Datie JM el Dore erponse and dove equivalence ofontpeyhotice | lin Paychapharmacol 2004 26192 208 ts the UK licensed maximum doses of antipsychotics. Antipsychotic Maximum dose (mg) First-generation antipsychotics - oral Daily Chlorpromazine 1000 Flupentixol 18 Haloperidol 30 (see BNF) Levomepromazine 1000 Pericyazine 300 Perphenazine 24 Pimozide 20 Sulpiride 2400 Trifluoperazine None (suggest 30) Zuclopenthixol 150Schizophrenia 17 Antipsychotic Maximum dose (mg) Second-generation antipsychotics - oral___Daily Amisulpride 1200 Aripiprazole 30 Asenapine 20 Clozapine 900 Olanzapine 20 Paliperidone 12 Quetiapine 750/800 (see BNF) Risperidone 16 (see BNF) Sertindole 24 Ziprasidone™ 160 Depots Weekly Flupentixol 400 Fluphenazine 50 Haloperidol 300 mg every 4 weeks (see BNF) Paliperidone 150mg per month Pipotiazine 50 Risperidone 25 Zucopenthixol 600 Doses above these maxima should be used only in extreme circumstances: there is no evidence for improved efficacy. “Not available in the UK at time of publication, European labelling used. BNF, British National Formulary. Asenapine ‘Asenapine has affinity for D), SHT2, 5HT3¢ and a,/a9-adrenergic receptors, along with relatively low affinity for Hy and ACh receptors. At a dose of 5 mg twice daily, asenapine has been demonstrated to be more effective than placebo in acute treatment of schizophrenia and more effective than risperidone in the treatment of negative symptoms, perhaps through selective affinity for different dopamine pathways, most notably in the prefrontal cortex. In the longer term, at a modal dose of 10 mg twice daily, asenapine reduces relapse rates in schizophrenia! and bipolar disorders Itis also effectivein mania.” Asenapine has less potential to raise prolactin than risperidone and may be associated with a lower risk of weight gain. It is, it seems, metabolically neutral and shows considerable advantage over olanzapine in this, regard.’ Widespread use may be inhibited by the fact that asenapine is absorbed sublinguelly and not absorbed if swallowed."" Licensed uses vary from country to country.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.20 The Maudsley Prescribing Guidelines in Psychiatry New antipsychotic drugs: costs Newer antipsychotics are relatively expensive medicines, although their benefits may make them cost-effective in practice. Table 2.5 gives the cost a6 of November 2011 of atypicals at their estimated lowest effective dose, their approximate average clinical dose and their licensed maximum dose. The table allows comparison of different doses of the same drug and of different drugs at any of the three doses. It is hoped that the table will encourage the use of, lower doses of less expensive drugs, given equality in other respects and allowing for clinical requirements, Approximat Minimum effective average clinical Maximum dose Antipsychotic dose cost dose cost cost Amisulpride* 400 mg/day 800 mg/day"* 1200 mg/day" £13.92 £107.41 £121.33 Aripiprazole 10 mg/day 20 mg/day 30 mg/day £102.57 £205.14 £205.14 Olanzapine (oral") 10 mg/day 15 mg/day 20 mg/day £3.64 £4.88 £6.32 Olanzapine pamoate 300. mg/4 weeks 405 mg/4 weeks 300 mg/2 weeks £222.64 £285.52 £445.28/28 days Paliperidone 3 mg/day 6 mg/day 12 mg/day £104,23 £104.23 £208.46 Paliperidone palmitate 50 mg/month 100 mg/month 150 mg/month £183.92 £314.07 £392.59 Quetiapine IR 300 mg/day 500 mg/day 750 mg/day £113.10 £141.55 £226.55 Quetiapine XL 300 mg/day 600 mg/day 800 mg/day £85.00 £170.00 £226.20 Risperidone (oral’) Amg/day 6 mg/day™* 16 mg/day" £1.87 £27.81 £57.49 Risperidone (injection) 25 mg/2weeks 37.5 mg/weeks 50 mg/2weeks £159.38/28 days £222.64/28 days £285.52/28 days Sertindole 12 mg/day 20 mg/day 24 mofday POA POA POA Costs for UK adults (30 days), MIMS, November 2011. Average clinical doses for inpatients receiving maintenance therapy Clozapine costs not included because it has different indications. “Generic versions available, costs vary. “Lower costs possible using different dosage forms. POA, price on application.Schizophrenia 21 © Thelowest possible dose should be used. For each patient, the dose should be titrated to the lowest known to be effective (see section on ‘Antipsychotic drugs: minimum effective doses’ in this chapter); dose increases should then take place only after 2 weeks of assessment during which the patient is clearly showing poor or no response. With depot medication, plasma levels rise for 6-12 weeks after initiation, even without a change in dose. Dose increases during this time are therefore inappropriate. = For the large majority of patients, the use of a single antipsychotic (with or without addi- tional mood stabiliser or sedatives) is recommended (seesectionon ‘Combined antipsychotic drugs’ in this chapter). Apart from exceptional circumstances (e.g. clozapine augmentation), antipsychotic polypharmacy should be avoided because of the risks associated with OT pro- longation and sudden cardiac death.! ® Combinations of antipsychotics should be used only where response toa singleantipsychotic (including clozapine) has been clearly demonstrated to be inadequate. In such cases, the effect of the combination against target symptoms and the side-effects should be carefully evaluated and documented. Where there is no clear benefit, treatment should revert to single antipsychotic therapy. = In general, antipsychotics should not be used as prn sedatives. Short courses of benzodi- azepines or general sedatives (e.g. promethazine) are recommended. = Responses to antipsychotic drug treatment should beassessed using recognised rating scales and be documented in patients’ records. = Those receiving antipsychotics should undergo close monitoring of physical health (includ- ing blood pressure, pulse, electrocardiogram [ECG], plasma glucose and plasma lipids) (see section on ‘Antipsychotic drugs: monitoring of metabolic effects’ in this chapter). References 1. Ray WA etal Atpical antipsychotic drugs and the sk of sudden cardiac death N Eng J Med 2009; 360:225-235, Further reading Pharmacovgiince Working any. Pubic atesrentreporton neuroleptics and cardiac safety, in particular QT probongation ardiacarhyth ‘nits, ventrcular uchyeardia and torsades de pointe. 200, wvovmbra gov22 The Maudsley Prescribing Guidelines in Psychiatry ‘The 2009 NICE guidelines differ importantly from previous guidelines (see summary in Box 2.1). There is no longer an imperative to prescribe an ‘atypical’ as first-line treatment and it is now recommended only that clozapine be ‘offered? (rather than prescribed) after the prior failure of two antipsychotics. Much emphasis is placed on involving patients and their carers in prescribing decisions. There is some evidence that this is rarely done? but that it can be done.? = For people with newly diagnosed schizophrenia, offer oral antipsychotic medication. Provide informetion and discuss the benefits end side-effect profile of each drug with the service user. The choice of drug should be made by the service user and healthcare professional together, considering: ~ the relative potential of individual antipsychotic drugs to cause extrapyramidal side-effects (including akathisia), metabolic side-effects (including weight gain) and other side-effects (including unpleasant subjective experiences) — the views of the carer where the service user agrees. = Before starting antipsychotic medication, offer the person with schizophrenia an electrocardiogram (ECG) if: specified in the Summary of Product Characteristics (SPC) a physical examination has identified specific cardiovascular risk (such as high blood pressure) ~ there is personal history of cardiovascular disease, or the service user is being admitted as an inpatient. = Treatment with antipsychotic medication should be considered an explicit individual therapeutic trial. For each patient: ~ record the indications and expected benefits and risks of oral antipsychotic med- ication, and the expected time for a change in symptoms and appearance of side-effects ~ start with a dose at the lower end of the licensed range and slowly titrate upwards within the dose range given in the British National Formulary (BNF) or SPC justify and record reasons for dosages outside the range given in the BNF or SPC. = Monitor and record the following regularly and systematically throughout treat- ment, but especially during titration: efficacy, including changes in symptoms and behaviour ~ side-effects of treatment, taking into account overlap between certain side-effects and clinical features of schizophrenia, for example the overlap between akathisia and agitation or anxiety — adherence ~ physical health the rationale for continuing, changing or stopping medication, and the effects of such changes.Schizophrenia 23 ® Carry out a trial of the medication at optimum dosage for 4-6 weeks (although half of this period is probably sufficient if no effect at all is seen). = Do not use 2 loading dose of antipsychotic medication (often referred to as ‘rapid neuroleptisation’) (this does not apply to loading doses of depot forms of olanzapine and paliperidone). ® Do not initiate regular combined antipsychotic medication, except for short periods (for example, when changing medication). = If prescribing chlorpromazine, warn of its potential to cause skin photosensitivity. Advise using sunscreen if necessary. ® Consider offering depot/long-acting injectable antipsychotic medication to people with schizophrenia: — who would prefer such treatment after an acute episode ~ where avoiding covert non-adherence (either intentional or unintentional) to antipsychotic medication is a clinical priority within the treatment plan. = Offer clozapine to people with schizophrenia whose illness has not responded ad- equately to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs. At least one of the drugs should be a non- clozapine second-generation antipsychotic (see section on Treatment algorithms for schizophrenia’ in this chapter; we recommend that one of the drugs should be olanzapine). = For people with schizophrenia whose illness has not responded adequately to clozap- ine at an optimised dose, healthcare professionals should establish prior compliance with optimised antipsychotic treatment (including measuring drug levels) and en- gegement with psychological treatment before adding e second antipsychotic to augment treatment with clozapine. An adequate trial of such an augmentation may need to be up to 8-10 weeks (recent data suggest 6 weeks may be enough’). Choose a drug that does not compound the common side-effects of clozapine. References 1. National niu fr Melt nd Clinic Elen. Sekiophreni core interventions nthe teataeat al management of schisnphrci sds in primary and seenday cat (update), 2009, wen aiccorguh OlofisanaB ta. Antipaychotic crags - information and choice: patient sarey. Psychiatr Bul 2005; 29:359-371, 3 Whishey Ea Evaluation of an atipschotc information sheet for patients Int J Payshistry Chin Pst 20055 9:264-27. Taylor D etal. Augmentation of clozapine wih second antipsychotic. A meta anal, Aca Peychat Scand 2011; ep ahend of printaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Schizophrenia 25 == Acute drug treatment required —— Figure 2.2 Treatment of relapse or acute exacerbation of schizophrenia (full adherence to medication confirmed). Poorly tolerated treatment “Compliance ads (a9, Medidese sjsem) aro not asubsitute for patent education The utimate ain _shoul bef promote independent vin, perhaps with patients ilrg ther own compliance ai, having fitstbeen give support and taining, Compliance ais ae of ie use uness the paints ceary Motisecie shee e preted teen. lea me modi ae rel sai x sagen Lack of insight or pport Figure 2.3. Treatment of relapse or acute exacerbation of schizophrenia (adherence doubtful or known to be poor).aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.30 The Maudsley Prescribing Guidelines in Psychiatry References 1 Burckar Gy el. Neutropenia allowing acute chlorpromazine ingestion. Clie Toxicol 1981; 18797-801, 2. Grohmann Rctal Aganulocytvis an signfcantleucopeniswith neuroleptic drugs rsuks fom the AMUP program. Peychopharmacology 1998; 99(uppleS108-S112 Esposito Det al Ropetidone-induced morring preaoneutmpenia, A} Prybiatry 2005; 162397 Moatgomery |. Ziprasidone-rlted spranulocytoris folowing olarzapie-indaced neutrpenis. Gen Hor Psychiatry 2006, 2885-85, Cowan Ct al Leukopeniaand neutropenia induced by quetiapine. Prog Neuropsyshopharmacol Bil Psychiatry 2008; 31101107, Buchman et Olnzapine induced lekopenis with human leukacye antigen profiling. Int Chin Pychopharmacol 2001: 1655.57 Marder Skt Physical health montoringof patients with shizephretia. An] Ppchstry 2004 161:1334-134. Fenton WS etal Mecteatcn-sncced weight gain and Usipdemns i paint Wit schizophrenia, Am | Tsyehstry 2000; 18821971704 ‘Weisman EM eal Lip monitoring in patients wit schizophresia prescribed second genention antipsychotics. [Clin Psychiatry 2006; e7an23-1326, 10, Cohn TA et al Metabolic monitoring for patient trated with antipeyshoticmediseions, Cam | Pychiatry 2006, 81:402-501 11, Paton € «al, Obes, dyspidaemias and smoking in an inpatient population treated with antipsychotic drugs Acta Peyhiate Scand 20045 110299-.05. 12, Taylor D ea. Undiagnored impaired ating sense ard disetes mellitus amon inpatients eceiving antipeychotic drug. | Pichopha smacol 2005; 19182-186, rome Leal Inchlence prevalence, and srveltancefor diabetes in New York State pyshiatric owt, 1997-2004. Paychat ery 2006; 57:1132-1139, 14, Novotny T etal Mositoring of QT intervals patients eatel with psychotropic drags. fat | Candiol 2007; 117(3}828- 332, 15. RaylWA eal. Atypical antipaychotic dag and the rak of wudden cndiac death N Engl J Med 2009; 360:25-25, 16, Hummer M et. Hepatotexcity of elzapite J Clin Pychopharmacol 1997; [7314-317 17, Bedogan A etal. Management of marked lner enzyme incresse during clozapine treatment a case port and review ofthe iterture. nt Psychintry Med 20083348389, 18, Regs! RE tal. Phenothazine induced cholestaticaundice. Clin Phare 1987;6:787.794 ing treatment with pial end atypical antipsycotin- Am) Paget 2002; 159:109- 19. Cenlorsine Peta EEG abnormalities 20, Grom A etal. Clorapine induced QEEG changes corel wih clinical epee in ehizophrenkpaiens:. promectiv, longitudinal tidy. Pharmacepsyehiatry 2004;372119-121 21, Tastes BR et a. The safety of quetiapine: sls of « post-earketingsurveilance study on 1728 patent in England. J Paychopharmacl 20075 21392-399 22, Kelly BL eal. Thyroid function in teatanet-restant achizophreaa patients tested with quatapine, risperidone, or fupenssne Chia Peychiatry 2005 669-88aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.34 The Maudsley Prescribing Guidelines in Psychiatry and prolactin). These more recent studies are in accord with older studies involving fixed-doses ofhaloperidol.® However, itis important to keep in mind that these doses are extracted from group evidence where patients are assigned to different doses, which is a different question from the clinical one where one considers increasing a dose only in those who have failed an initial dose. To our knowledge, only one study has systematically addressed this question in its clinically relevant dimension. Kinon et al” examined patients who failed to respond to the (then) standard dose of fluphenazine (20 mg) and tested three strategies: increasing dose to 80 mg, switching to haloperidol or watchful waiting (on the original dose). All three strategies were equivalent in terms of efficacy. Thus, it seems that at a group level (as opposed to an individual level), there is little cvidence to support treatment beyond the recommended doses. Plasma level variations Group level evidence cannot completely determine individual decisions. There is significant interindividual variation in plasma levels in patients treated with antipsychotics. One can ofien encounter a patient who when at the higher end of the dose range, say 6 mg of risperidone or 20 mg of olanzapine, would have plasma levels that are well below the range expected for 2 mg risperidone or 10 mg of olanzapine, respectively. In such patients, onc can make a rational case for increasing the dose, provided the patient is informed and the side-effects are tolerable, to bring the plasma levels to the median optimal range for the particular medication. More details on plasma levels and their interpretation are provided in Chapter I. However, one often encounters an unresponsive compliant patient, whose dose has reached the ceiling and plasma levels are also sufficient — what next? Treatment choices ‘Thereareessentially three options here: clozapine, switch to another drugor add another (non- clozapine) drug. If the patient meets the criteria for clozapine, it is undoubtedly the preferred option. However, many patients either do not meet criteria or do not like the idea of regular blood testing and the regular appointments required to receive clozapine. For these patients, the choice is to switch to another medication or to add another antipsychotic. The data on switching are sparse. While almost every clinical trial in patients with chronic schizophrenia has entailed the patient switching from one antipsychotic to another, there are no rigorous studies of preferred switch combinations (e.g. if risperidone fails, what next? Olanzapine, quetiapine, aripiprazole or ziprasidone2). If one looks at only the switching trials which have been sponsored by the drug companies, it leads to a rather confusing picture, with the results being very closely linked to the sponsors’ interest (see Heres et al*). CATIE, a major US-based publicly funded comparative trial, examined patients who had failed their first atypical antipsychotic and were then randomly assigned to a different sec- ond one®: patients switched to olanzapine and risperidone did better than those switched to quetiapine and ziprasidone. This greater effectiveness is supported by a recent meta-analysis,aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.38 The Maudsley Prescribing Guidelines in Psychiatry observation (as expressed in the CGI scale). It is now understood that one requires a 15-20 point change in PANSS before an average clinician can identify ‘minimal improvement’ by subjective impression.’ Thus, one can see how even though the onset of improvement israther early, it does not reach the threshold of 15~20% change till the end of the second week on average, giving an impression of a liter onset. The findings have three important clinical implications. * First, they emphasize the critical role of the first few days after initiating antipsychotics. The first 2 weeks on a new antipsychotic or dose are not dormant periods but probably the period of maximum change.! This should be communicated to patients and clinicians need to be particularly attentive to changes early on ® Secondly, the data highlight the value of using structured scales in daily clinical practice and should encourage clinicians to consider the routine use of scales. ™ Finally, the data revive the question of how long one should wait if a medication is not effective. Should one switch after 2, 4 of 6 weeks? While most algorithms currently would suggest waiting between 4 and 6 weeks on a given drug and dose, the early onset idea, the empirical evidence and clinical imperative suggest that it may be appropriate to switch earlier, say after 2 weeks, in patients in whom a combination of drug and dose has made no clinical improvement at all and where viable other alternatives exist. Controlled clinical trials comparing clinical strategies which rely on early onset (ie. use an early cut-off point to determine switching) versus more conservative strategies (wait 4-6 weeks) are now required. The first of these are appearing. Kinon et al!” treated a large number of patients with risperidone for 2 weeks, then continued those who had shown 20% response on their current dose of risperidone, while they randomised those who showed no response to continuc their risperidone or to switch to olanzapine. The most striking result was that those who showed the early response (at 2 weeks) did substantially better at 12 weeks than the early non-responders. Amongst the early non-responders, those who switched did marginally better than those who continued. This study provides the first indication of the potential clinical relevance of the findings on early onset of action, Another interesting question is whether this ‘early onset’ is restricted to clinical symptoms (ie. delusions, hallucinations and general symptoms of psychosis) or whether one can ob- serve early change in functional outcomes (quality of life, objective functioning and subjective wellness). Despite the general assumption that functional improvement must take longer, a controlled trial of 628 patients! showed that improvement across multiple outcome dimen- sions was not delayed relative to improvement in psychiatric symptoms. In summary, antipsychotics start the improvement of psychotic symptoms as well as func- tional improvement fast, often within the first week, for most patients for whom they are going to eventually work. These data have several implications, though it would be premature to make restrictive recommendations. Clinicians should make their decisions about timing of dose escalation and switching based on the evidence provided above (summarised in Box 2.3) and their clinical judgement in individual cases.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.46 The Maudsley Prescri ing Guidelines in Psychiatry Switching Recommended method of from switching comments No treatment Start risperidone oral at 2 mg/day Use oral risperidone before giving (new patient and titrate to effective dose. If injection to assure good or recently tolerated, prescribe equivalent tolerability. Those stabilised on non- dose of RLAI. Continue with oral 2 mg/day start on 25 mg/2 weeks. compliant) risperidone for at least 3 weeks Those on higher doses, start on then taper over 1-2 weeks. Be _37.5mg/2 weeks and be prepared prepared to continue oral to use 50 mg/2weeks risperidone for longer Oral Prescribe equivalent dose of RLAI See above risperidone Oral Either: Dose assessment is difficult in antipsychotics (not risperidone) Depot antipsychotic Antipsychotic polyphar- macy depot a. Switch to oral risperidone and titrate to effective dose. If tolerated, prescribe equivalent dose of RLAI. Continue with oral risperidone for at least 3 weeks then taper over 1-2 weeks. Be prepared to continue oral risperidone for longer Or: b. Give RLAI then slowly discontinue oral antipsychotics after 3-4 weeks. Be prepared to continue oral antipsychotics for longer Give RLAI 1 week before the last depot injection is given Give RLAI 1 week before the last depot injection is given. Slowly taper oral antipsychotics 3-4 weeks later. Be prepared to continue oral antipsychotics for longer those switching from another antipsychotic. Broadly speaking, those on low oral doses should be switched to 25 mg/2 weeks. ‘Low’ in this context means towards the lower end of the licensed dose range or around the minimum dose known to be effective. Those on higher oral doses should receive 37.5 mg or 50 mg every 2.weeks. The continued need for oral antipsychotics after 3-4 weeks may indicate that higher doses of RLAI are required Dose of RLAI difficult to predict. For those on low doses (see above), start at 25 mg/2 weeks and then adjust as necessary. Start RLAI at 37.5 mg/2 weeks in those previously maintained on doses in the middle or upper range of licensed doses. Be prepared to increase to 50 mg/2 weeks Aim to treat patient with RLAI as the sole antipsychotic. As before, RLAI dose should be dictated, as far as possible, by the total dose of oral and injectable antipsychoticaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.50 The Maudsley Prescribing Guidelines in Psychiatry References 1, Janssen Pharmaceuticals INVEGA® SUSTENNA® (paliperidone palmitate) Extended-Raeas Injectubl Suspension for intamuscularuse Fall Preserhing Informatio, 2011. wow janssencas.com/sustenna-prescibing infomation, 2, ansen-Citg LU Summary of Product Characteristics. XEPLION 50 mg, 75 mg. 100 mg and 150 mg prolonged eelease suspension for ineetion, 2011, wrranclicines ong h/EMChnekine/24403/SPC(KEPLION 450} mgisde+75¢mghi2e+100}+-mpp-end1504-mp4 prolonged ees suspension or tnjection. 3, Tonssen-Cilg Led, Summary of Product Characteristics Risperdal ables liquits and quicklt 2011, wwe medicines. og.ubleme! “4 Hane 1g 1M. Summary of Product Charscterstie. INVEGA 1.5 mg. 5 mg. 6 mg. © mg. 11 mg prolonged telenwe tablets 2011 swore medisines arg ulEMCimedicine!1 9826/SPCINVEGA-+1.5+mgiite+ H+mggk2e+s+msd2c+9+ mghi2e+ 12+mgsprolenged All patients receiving long-term treatment with antipsychotic medication should be seen by their responsible psychiatrist at least once a year (ideally more frequently) in order to review their progress and treatment. A systematic assessment of side-effects should constitute part of this review. There is no simple formula for deciding when to reduce the dose of maintenance antipsychotic treatment; therefore, a risk/benefit analysis must be done for every patient. The prompts listed in Box 2.5 may be helpful. ® Is the patient symptom free and if so for how long? Leng-standing, non-distressing symptoms which have not previously been responsive to medication may be ex- cluded = What is the severity of the side-effects (EPS, tardive dyskinesia, obesity, etc.)? = What is the previous pattern of illness? Consider the speed of onset, duration and severity of episodes and any danger posed to self or others. © Has dosage reduction been attempted before? If so, what was the outcome? = What are the patient's current social circumstances? Is it a period of relative stability or are stressful life events anticipated? = What js the social cost of relapse (e.g. is the patient the sole breadwinner for a family)? * Is the patient able to monitor his/her own symptoms? if so, will he/she seek help? If after consideration of the above, the decision is taken to reduce medication dose, the patient's family should be involved and a clear explanation given of what should be done if symptoms return/worsen. It would then be reasonable to proceed in the manner shown in Box 2.6.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.54 The Maudsley Prescribing Guidelines in Psychiatry 31, Thompsoa A etal. The DESIT tial: anintewention to reduc antisychotcpolyphuemacy prescribing in adult psychiatry wards a ster sandomized controll rl Psychol Med 2008; 38705-715. 52, Tucker WM When lr move: reducing the IncHence of antipsychotic polypharmacy. J Psychiatr Pract 2007; 19:202-204 53, Fleichhacker WW etal. Effects of adjunctive treatment wih aripprsane on bodr weight ard clnial cacy in schizophrenia patente treated wih loapine a randomized, double lied, plcebo contd ra. Int] Neuropsychopharmacol 2000; 13:1115-1125. 4, Shin JC ato: Ajinetioe tetra wth adopemnine port joni wephpremle fo atlnychaic induced hyperprolitinei« tbs controlled tial Am | Pyehitey 2007; 1641404-1410, 435, Shiloh et al Sulpinide augmentation in people with ichizphenia partially responsivetoclzapine. A double-blind, placcho-contolled study. Be] Poehitey 1997; 171:569-573, 36, Josiseen RC eta, Clozapine augmented with xperidone inthe trestment of shizophtent:a randomized, double-blind, placcbo-contrlled tri Am | Pyshiatry 2005, 16290-1386 37, Paton C tal. Agmentaton with second antiprchoic in patient with schimprenia who pactilly respond toclozaine:a mets-anabsi 1 Clin Pychopharmacal2007;27198-208, arbui Cet a. Does the adtion of second antipsych ph Bll 2000; 95:458-468 ‘Taylor DM eta Augmentation of clouapine witha second astipeychtic- a meta analysi of randomized, placebo-coatolled studies, Acta rug improve slomipinetreatnent? Sch ge Psychiat Seune 2009, 11911925, Further reading “High dose’ can result from the prescription of either: = a single antipsychotic in a dose that is above the recommended maximum, or ® two or more antipsychotics that, when expressedas a percentage of their respective maximum recommended doses and added together, result in a cumulative dose af 100%. Efficacy ‘There is no firm evidence that high doses of antipsychotics are any more effective than standard doses. This holds true for the use of antipsychotics in rapid tranquillisation, the management of acute psychotic episodes, chronic aggression and relapse prevention. Approximately a quarter to a third of hospitalised patients are prescribed high-dose antipsychotics, the vast major- ity through the cumulative effect of combinations;!? the common practice of prescribing antipsychotic drugs on a prn basis makes a major contribution. Reviews of the dose-response effects of a variety of antipsychotics have revealed no evidence whatever for increasing doses above accepted licensed ranges." Effect appears to be optimal at low doses: 4 mg/day risperidone,® 300 mg/day quetiapine,° 10 mg/day olanzapine,’ ete. A small number of RCTs have examined the efficacy of high versus standard doses in patients with treatment-resistant schizophrenia.” Some demonstrated benefit"? but the majority of these studies are old, the number of patients randomised is small and study design is poor by current standards. Some studies used doses equivalent to more than 10 gchlorpromazine. One small (n = 12) open-label study of high-dose quetiapine (up to 1400 mg/day) found modestaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.58 The Maudsley Prescril ing Guidelines in Psychiatry Pharmacological management of negative symptoms in schizophrenia Several drugs that modulate glutamate pathways have been tested. There are negative RCTS of glycine!® and modafanil”’ augmentation of antipsychotics, and of LY2140023 monotherapy?! (an agonist at mGlu 2/3 receptors) and small preliminary positive RCTs of pregnenolone”? and ocycline."> With respect to decreasing glutamate transmission, there is a positive meta- analysis of lamotrigine augmentation of clozapine’! and a negative RCT of memantine? A Cochrane review of antidepressant (mainly selective serotonin reuptake inhibitors [SSRIs]) augmentation of an antipsychotic to reduce affective flattening, alogia and avolition concluded that this may he an effective strategy”* whereas a meta-analysis of SSRI augmen- tation of an antipsychotic was less positive” A more recent meta-analysis that included available data for all antidepressants was cautiously optimistic” but the authors noted that their findings were not definitive. ‘A meta-analysis supports the efficacy of augmentation of an antipsychotic with Ginkgo biloba? while small RCTs have demonstrated some benefit for selegiline.»°" testosterone (applied topically)? and ondansetron.” Data for repetitive transcranial magnetic stimulation are mixed. A large (n = 250) RCT in adults” anda smaller RCT in elderly patients each found no benefit for donepezil and there isa further negative RCT of galantamine.”” Patients who misuse psychoactive substances experience fewer negative symptoms than patients who do not." It is not clear if this is cause or effect. Recommendations for the management of negative symptoms of schizophrenia are shown, in Box 2.10. = Psychotic illness should be identified and treated as early as possible as this may offer some protection against the development of negative symptoms ® For any given patient, the antipsychotic that gives the best balance between overall efficacy and side-effects should be used. Where negative symptoms persist beyond an acute episode of psychosis: ® ensure EPS (specifically bradykinesia) and depression are detected and treated if present, and consider the contribution of the environment to negative symptoms (e.g. institutionalisation, lack of stimulation) ® consider augmentation of antipsychotic treatment with an antidepressant such es an SSRI, ensuring that choice is based on minimising the potential for compounding side-effects through pharmacokinetic or pharmacodynamic drug interactions ® if clozapine is prescribed, consider augmenting with lamotrigine or a suitable second antipsychotic = there are insufficient data to make recommendations about other pharmacological strategies, but pregnenolone, minocycline, selegiline, Gingko biloba, testosterone and ondansetron may have potential. EPS, extrapyramidal side-effects; SSRI, selective serotonin reuptake inhibitor. Source: Barnes."aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.62 The Maudsley Prescribing Guidelines in Psychiatry Adherence to antipsychotic treatment Amongst people with schizophrenia, non-adherence with antipsychotic treatment is highs only 10 days after discharge from hospital, up to 25% are partially or non-adherent, rising to 50% at 1 year and 75% at 2 years.”? Not only does non-adherence increase the risk of relapse, it may also increase the severity of relapse and the duration of hospitalisation? The risk of suicide attempts also increases four-fold? Dose for prophylaxis Many patients probably receive higher doses than necessary (particularly of the older drugs) when acutely psychotic." In the longer term, a balance needs to be struck between effec tiveness and side-effects. Lower doses of the older drugs (8 mg haloperidol/day or equivalent) are, when compared with higher doses, associated with less severe side-effects,” better sub- jective state and better community adjustment.” Very low doses increase the risk of psychotic relapse.” There are no data to support the use of lower than standard doses of the newer drugs as prophylaxis. Doses that are acutely effective should generally be continued as prophy- laxis.5° How and when to stop?” The decision to stop antipsychotic drugs requires a thorough risk/benefit analysis for each patient (see Box 2.5). Withdrawal of antipsychotic drugs after long-term treatment should be gradual and closely monitored. The relapse rate in the first 6 months after abrupt withdrawal is double that seen after gradual withdrawal (defined as slow taper down over at least 3 weeks for oral antipsychotics or abrupt withdrawal of depot preparations).** Abrupt withdrawal may also lead to discontinuation symptoms (e.g. headache, nausea, insomnia) in some patients.” As with first-episode patients, patients, carers and key workers should be aware of the early signs of relapse and how to access help. Be aware that targeted relapse treatment is much less effective than continuous prophylaxis.!” Those with a history of aggressive behaviour or serious suicide attempts and those with residual psychotic symptoms should be considered for life-long treatment. Box 2.11 highlights the key facts that patients and carers should know. References 1, Grow 1} e al The Northwick Park study of ist episodes of schtophreni Il, A randomised contoled til of prophylactic neuroleptic treatment. Be J Paychistry 1986; 48:120-127 Nucchterkin KH eta. The eny course of scitophrenia and long tem maintenance neusleptictheapy. Arch Gen Psychiatry 1995; 3, Davis [Met a Depot antipsychotic dmgs. Place ia therapy. Drugs 1994:47:741-778 44. Shetman BB etal. The evaiation and treatment offs cpsode prychoris. Schizophr Bull 197; 28553-<61 5. American Peychintric Assocation, Practice guneine fr the trentment of patients with schizophrenia. ArT Paychstry 1997: 1S4¢Sappt svtaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Schizophren 83 References 1, Waller AM ea Moriyin cent nd rere i apne Eyeing 997 871-677 2. Mun eal Actine monitoring 2760 apie recent in he UK an lad Br Poetry 199917857650 3. Thule Closapne and ranlocyns 206, Personal omonniation 4. Palo CA Evang thermos btoeen vpn sven homeo Ans Hah yt Pharm 208; 68:1025-160. 5. Lacia rl Pulmonary enbolospoubly socited with covapine esimen (Leer, Can achat 199944396997 6. Hage Ss Asotin ofvenoas thrmbcembalom cheapie. Lancet 200539: 155-1150 7 Drv Seta Aniphopha antbotesnocinted wth doapinerexment. Arm] Hemata 994; 6165-167 8. Atsloon Set In vi fet ofantiychtic on human ple adhesion an agen aud plan congton lin xp Pharmacol Physio 2007; 342775-780, 9, Liperoti Ret al. Venous thromboembalsm mong eldey patents treated with atypical and cosventinalenipsychoti agents. Ach Ingeen Med 2005, 165326972682 87-850 11, Bors Lal. Pulmonary thromboembolism associated with olanaapineand risperidone. Emerg Med 2008; 35:159-16t. 12. Maly Reta. Four casr of reno thrombocmbolsm asosied with olanzapine. Prchairy Clin Neurosci 2009; 63:1 16-116 13, HaggS etal. Asocations betwee venous thrombormbolis and antipychote. A sty ofthe WHO database of adverse drug reactions Drug Saf 2008; 91:688-094, 14, Lacut K eal, Association between astpsychoic rus, anideprestant drug and venous thromboembolisn: results from the EDITH cave controls, Fundam Clin Pharmacol 2007; 21:63 65 15. Zink otal. A ete ofpulmonarythrombocebolian an shabdomolytied 20065673855, 16, Maly K etal. Assessment of isk of venous thromboembolism and is possible prevention in psychiatric patients Psychiatry Clin Newosct 20085 62:36 17 Kills JGet al. Myocarditis and cardiomyopathy ssocited with clozapine. Lancet 1999; 354:1841 1645. 18. Hill GR eal. Cleapine and myoerin: «ene series from the New Zealand Inensine Medicines Monitoring Programme: N Z Me} 2008, 1218-75, 19, La Grenade Lot al. Myocarditis and cardiomyopathy associated with dozapine use inthe United States (Letter). N Engl} Med 2001; sas204-05, 20, Warner Be al. Clozapine and sulden death, Lancet 2000; 3853842, 21, Keinders Jet al Clozpine tated myeeandiss and cardiomyopathy in ap Austallan metropolitan pstchiavi servic. AUSEN ZI Bsyehitey 2004 38915922 22, Has 5) eal Clozapine-awocsid myocanlitiss a review of 116 cases of pected myncantis amociated wth the wre of clerapine in ‘Aunclia during 1993-2001, Drug Saf2007;30:47 57, 23. Marler SE et al Physcl halth monitoring of patents with chiaphrenia Am | Pechisey 2064; 16113-1308. 24. Angumraj etal Fay eecogaiton of clozapine induced syocaeitis.JClinPaychopharmacol 2007; 2779-483, 25, WehmeierPM etal Chart rview for potental features of myocarditis, pericarditis, nd cadiomyopalhy in children and adolescents treated with clozapine. | Chik Adolesc Psychophaemacol 2004; 4267-27, 26, Romapno ct ab Bete block Psyehatry 2008 30:200-283, 27 Floran eal. Successful challenge with clozapine llowing development of clozapine induced cardiomyopathy, Aust N ZI Psychiatry 2008 42:707-768, 28. Roh Set a. Carkiomyopathy astociated with lorapine. Exp Clin Pyshopharmacol 2006; 1494-98 29, Matopust| el al Repeated securtenee of elosapine induced myocatdits na patent with schizoufeetne dorderand comorbid Parkinson's disease. Neuro Endocrinol Let 2009; 3019-21, 80. Hassun al. Monitoring in osapine challenge after myocadits. Austealas Psyehatey 2011; 19:3 51. BrayA ed: Sucesflcloapinerechulenge after acute myocarditis, Aut NZ] Pychatey 2011; 45:0. 32, Rosenfeld A etal Successflclowapine tril afte suspected myocarditis. Am] Psychiatry 2010; 167:350-351 33, Ronddson KI etal. Cincaleourse and analysis often fal eas of clozapine induced myocardts and comparison wil 66 surviving ass, Schizophr Res 2011512816116. {44 Ronson KI e al. A new montoring protocol fr clozapine indaced ayocaditis based on a analyse of 75 cases and 94 controls. Aust IN Z| Paenitey 20115 495138-40. 5, Pastor CA et al. Masked clovapine-induced cardiomyopathy | Am Soaed Fam Med 2008;21:70-74 36, Sagi R etal. Clorapine-induced cardiomyopathy preseatingas panic attacks, | Pychite Pract 2008; 14:18 137, Mousil eta. Sudden deathin paints receiving dosupineestmentsaprliminary investigation. lia Paythophurmacol 2000, 2025-527, ud venous thrombsembslis Clin Ady Hematol Oxcol 2008, sstherapy with mirtazapine snd pera. Ilia eychiatry 1a angotensin-convertng eye inhibior may lint certain caine advene cet ofclozapine. Gea Hop maa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Schizophrenia 87 receive clozapine-lithium combinations develop neurological symptoms typical of lithium toxicity despite lithium levels being maintained well within the therapeutic range. ‘The use of lithium to elevate WCC in patients with clear prior clozapine-induced neutropenia is not recommended. Lithium should only be used to elevate WCC where it is strongly felt that prior neutropenic episodes were unrelated to lozapine. ‘The patient's individual clinical circumstances should be considered. In particular, patients in whom the first dyscrasia: = was inconsistent with previous WCCs (i.e. not part of a pattern of repeated low WCCs) = occurred within the first 18 weeks of treatment ® was severe (neutrophils < 0.5 x 10°/1), and = was prolonged should be considered to be very high risk if rechallenged with clozapine. Generally re-exposure to clozapine should not be attempted. ‘Management of patients with either of the conditions below should be treated as outlined in Figure 2.6: ®™ lowinitial WCC (<4 x 10°/1) or neutrophils (<2.5 x 10°/1), or ® clozapine-associated leucopenia (WCC <3 x 10°/l) or neutropenia (neutrophils <1.5 x 10/1) thought to be linked to benign ethnic neutropenia. Such patients will be of African or Middle Eastern descent, have no history of susceptibility to infection and have morphologi- cally normal white blood cells. References 1. Minto et al Active monitoring oF 12760 chrapine repens in the UK and Ireland, Be) Pychstry1990;178:576- S40. Whiskey Beta. Restartng ocapine ster nutropeni:evaluling the pesbilties nd practicalites.CNS Drug 200721: ‘Dunk LK eal. Rechalenge with dozapie lowing leucopenia oF aetzopenis during previoustherapy Bt] Psychiatey 2006 188255-269. Abramson N eta, Leakocyosis:basic of clinical assessment. Amt Fam Physician 2000; 62053-2060 Laplere Geta: Lithiam carbons an leuocytoss,Am J Hosp Pharm 1980;37:1525-1528 {Carmen et al The fete ith therapy om leukocytes « L-yese fllow-up std. J Not Med Avsnc 19934 85.901-203, Palominae A etal. Leakoeyosi str Ithium and clozapine combination therapy. Ann Clin Psychiatry 2010; 22205-206 Smal JG ea. Tlerbilty an etiacyof clozapine combined with ithiuin in schizophrenia and schizvaflesive disorder | Clin Pechophar- ‘macol 2003; 23223-228 9. BlierP eta Lithium and clrapin induced neutropenia agranulocytosis nt lin aychephareacol 1998, 13:37-14, 10. Ondemie MA etal Linn induced hematulogicchanges in patients wit bipolar affetine diced. Bil Inychney 19945 38: Johake RB eta. Accelerated marsow recovery following total-body ieadiarion afer tea inesistnelithiam. [tJ Cal Cloning 1991;9:78-88 12. Greco BA otal Effect of Ithiue carbonate om the neutropenia caused by chemthenspy: a preliminary cliial wal, Oncology 1977: 34153155 13, Ridgway D etal: Enhanced Iymphocye response to PHA among leukopenia patients taking oa lthium carbonate, Cancer aves 19865, 4515-517. 14, Aditanjee A. Modification of clzapize-indaced leukopenia and neutropenia with thin carbonate. Am] Pychatey 1995, 152648-649. at with vinrisine, lithium oF combined 16, Hoshes RA eta. Inittion of clowapine therapy ina patient with preexisting leukopenia: a discussion ofthe ratinnae of current testenent options Ann Clin Psychiatry 2001; 13233-2197 17. Papett Fetal. Weatmentofclompine induced gramuloytopenia wit lithium (two observations), Encephale 2004: 30:578-S82. 18, Kutsher BC etl Clezapin-induced leukopenia suecesflly treated wit lithium. Am | Health Syst Pharm 2007; 642027-2031,aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.96 The Maudsley Pres 19 Guidelines in Psychiatry Fish oils contain the omega-3 fatty acids, eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), also known as polyunsaturated fatty acids (PUFAs). These compounds are thought to be involved in maintaining neuronal membrane structure, in the modulation of membrane proteins and in the production of prostaglandins and leukotrienes.' High intake of PUFAs seems to protect against psychosis? and antipsychotic treatment may normalise PUFA deficits.” They have been suggested as treatments fora variety of psychiatricillnesses*® but most research relates to their use in schizophrenia, where case reports, case series? and prospective trials suggest useful efficacy (Table 2.22). On balance, evidence suggests that EPA (2-3 g daily) is a worthwhile option in schizophrenia when added to standard treatment, particularly clozapine.!*!! However, doubt remains over the true extent of the beneficial effect derived from fish oils, and research in this area has dwindled in the last few years." "? Fish oils are relatively cheap, well tolerated (mild gastroin- testinal symptoms may occur) and benefit physical health.'*"” "© In addition, a seminal study of 700 mg EPA + 480 mg DHA in adolescents and young adults at high risk of psychosis showed that such treatment greatly reduced the emergence of psychotic symptoms compared with placebo.” Fish oils are tentatively recommended for the treatment of residual symptoms of schizophre- nia but particularly in patients responding poorly to clozapine (Box 2.14). Careful assessment of response is importantand fish oils may be withdrawn ifno effect is observed after 3 months” treatment, unless required for their beneficial metabolic effects. In younger people at risk of psychosis, there seems to be no reason not to give fish oils, Omacor (450 mg EPA) 5 capsules daily or Maxepa (170 mg EPA) 10 capsules daily For prevention of first-episode psychos (2 Omacor capsules or 5 Maxepa capsules), in high-risk young people, the dose is 700 mg EPAaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.ing Guidelines in Psychiatry The Maudsley Presci 100 cuei2lguuanas ase sase> 40 %05 frorewxorddy sieah 0} syLUOW 58DOp annuBo20INIU unum parerosse oq Kew aL queued. ul uo Auea $q3 a3nze ey aney oy asour mw ‘soul |ANDaE YIM 250U3 w uswom Auap/> mw :u! oUNLHO? 3101 zy ansodxe 2noy2Asdnue 4O.ueah sad squaned Jo % umespyyim uaag aney sonoypAsdiyue seye asisiad ue> pue dojonap 01 1060} soyer elsupeye enipieL “asop aun bulseas>u Jo snoypfsdrue Bunseys 40 S{aam 0} sunoy UIYRIAN sunzp0 esiyzeye e1my {,2uidezo)> pue auidenanb ‘auidezue|o ‘suopyiedsu ‘ajozeididue uapio Sulseanap Uy steaidAye yum 559) on'96S2 Alaxewxosdy poseasou! 51 atop ays J0 powers ‘ave sBnup snoy>ksdrue saye 9j2am 03 shea (ow ‘axons ‘Auntui peau) a6ewep je2!5ojosnau Sunsixe-ad yim asoun a sajewias ALs2pi> Ul UOUsWO9 210u1 ang ,%02 Ajsewixody quowneon shoysAsdrue yo sveaf 0} syyuow Jaye sanao0 e1uoasép anlpseL (pasn s1 81n01 AI 40 WI ay Ji sannut) spowksdnue anap0 ued euoastp aino¥ ‘Auapie aun ut ues ave suonzees 1U05Kq, (iopuadojey ‘6) snap (ousiod-yBIy Yum w aneu-sndajounau ayy sajew Bunoh uowuio> 10 3g ,%OL AsreuiKoiddy dojanep or oye) uth (s6rup apie aim) spuajenetd (@uuienowi jeunouge) | Gsoussopsey) eIsMpeY (99 owen) wusiwosupyied-opnasa (uiseds sejmsnut poyjonuosun) e1ucrsXaaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Schizophrenia 107 Treatment: other possible options The large number of proposed treatments for TD undoubtedly reflects the semewhat lim- ited effectiveness of standard remedies. Table 2.25 lists some of these putative treatments in alphabetical order. Drug Comments Amantadine®5* Amino acids Botulinum toxin? > Calcium antagonists” DonepezilS*# Fish oils®" © Gebapentin® Levetiracetam***” Melatonin®* Naltrexone”? Ondansetron”"* Pyridoxine”? Quercetin”® Sodium oxybate’> Transcranial magnetic stimulation’® Rarely used but apparently effective at 100-300 mg a day Use is supported by a small randomised, placebo-controlled trial. Low risk of toxicity Case reports of success for localised dyskinesia. Probably now treatment of choice for focal symptoms A few published studies but not widely used. Cochrane is dismissive Supported by a single open study and case series. One neg RCT (n = 12). Dose is 10 mg/day Very limited support for use of EPA at dose of 2 g/day Data derived almost entirely from a single research group. Adds weight to theory that GABAergic mechanisms improve TD. Dost 900-1200 mg/day Three published case studies. One RCT. Dose up to 3000 mg/day Use is supported by a well-conducted trial. Usually well tolerated. Dose is 10 mg/day. Some evidence that melatonin receptor genotype determines risk of TD® May be effective when added to benzodiazepines. Well tolerated. Dose is 200 mg/day Limited evidence but low toxicity. Dose is up to 12 mg/day Supported by a well-conducted trial. Dose is up to 400 mg/day Plant compound which is thought to be an antioxidant. No human studies in TD but widely used in other conditions One case report. Dose was 8 g/day Single case report EPA, eicosapentanoic acid; GABA, y-aminobutyric aci dyskinesia RCT, randomised controlled trial; TD, tardiveaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.122 The Maudsley Prescribing Guidelines in Psychiatry 49, Priori SG etal. Low penetrance in theong-OT syadrone clinical impact. Ciculation 1999; 99:528-533 50, FrasatiD et al Hiden cardiac lesions and peychoteopic drugs as a posible cause of sudden death in pschiaec patent: a report of 14 avo and teview of the Ierature Can] Psychiatr 2004 49:100-165. Further reading [Ablelmans Not al Sudden candve death and antipsychotic. Pat 1: Risk factors and mechanisms. Adv Pychite Tut 2006; 12:35-4, ryt antilepretant and anipashotic drugs. Expeet Opin Dru Sf 2008; 7181-194, “Tier K cal. Atypical antipsychotics from potissium channels o torsade de poates and sullen death, Drug Saf 2005, 28:35-51, There are two ways in which antipsychotic drugs may be associated with the development or worsening of hypertension. 1 Slow steady rise in blood pressure over time. This may be associated with weight gains being overweight increases the risk of developing hypertension. The magnitude of the effect has been modelled using the Framingham data; for every 30 people who gain 4 kg, one will develop hypertension over the next 10 years.' Note that thisis a very modest weight gain; the majority of patients treated with some antipsychotics gain more than this, increasing further the risk of developing hypertension. © Unpredictable rapid sharp increase in blood pressure on startinga new drugor increasing the dose. Increases in blood pressure occur shortly after starting, ranging from within hours of the first doseto amonth, The information below relates to the pharmacological mechanism behind this and the antipsychotic drugs that are most implicated. Postural hypotension is commonly associated with antipsychotic drugs that are antagonists at postsynaptic adrenergic « receptors: examples include clozapine, chlorpromazine, queti- apine and risperidone. Some antipsychotics are also antagonists at presynaptic a) adrenergic receptors; this can lead to increased release of norepinephrine, increased vagal activity and vasoconstriction. Asall antipsychotics that are antagonists at a. receptors are also antagonists ata receptors, the end result for any given patient canbe difficult to predict but for avery small number, the result can be hypertension. Some antipsychotics are more commonly implicated than others, but individual patient factors are undoubtedly also important. Receptor binding studies have demonstrated that clozapine, olanzapine and risperidone have the highest affinity for «, adrenergic receptors? so it might be predicted that these drugs would be most likely to cause hypertension. Most case reports implicate clozapine, with some clearly describing normal blood pressure before clozapine was introduced, a sharp rise during treatment and return to normal when clozapine was discontinued. Blood pressure has. also been reported to rise again on rechallenge and increased plasma catecholamines have been noted in some cases. Case reports also implicate aripiprazole,'*"? sulpiride,'* risperidone,® quetiapine® and ziprasidone." Data available through the Committee on Safety of Medicines yellow card system in the UK indicate that clozapine is the antipsychotic drug most associated with hypertension. There are a small number of reports on aripiprazole, olanzapine, quetiapine and risperidone.!®aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.130 The Maudsley Prescribing Guidelines in Psychiatry References 1. Marler Si etal Physical health monitoring patients with chizphetia. Ast | Psychaey 2004; 161-334-1339 2, Paton Cea Obesity dyspidacmias and smoking in sn inptient population treated with antipsychotic drugs. Acta Psychiat Scand 2004; 110399-205, 2. Kom 1S tal Weight schizoafetvedsotdr: a 12-weck rasdomized controled clinica rial Clin Payhistry 2006, 67:547-553, 4 Littl KH et a. The fet ofan educational intervention on antipsychotic indeed weight gin. Nurs Scholarh 2003; 35:257-261 5. Mauri M eal. fect fn educational intervention om wight gn in pater teste with antipsychotics. Clin Pjchopharmacal 2006 26:452-406 6. Alvarez jmener M eta. Altenuation of amipsyeotic induced weight gain with extly behavioral intervention in deug-naie Hn eplode psychosis patients:asandomizedcontolled tral] Clin Psychiatry 2006;67:1388-1260, Stroup TSet al A randostized tal examining the ffeivense oft witching fromm olanzapine, quetiapine, or riperidane to aripipeanle to ‘reduce metabolic isk: Comparizon of Anipyshctics for Metabolic Protlems(CAMP), Am J Prychisry 29115 1683947-956 18. Casey DE t al Switching patients to aripiprazole fom other antipychotic agents:a multienier randomized sy, Paychopharmacology 2003; 166,391-599, 9, Delert Metal A cme series: evaluation ofthe metabolic sty of aripiprazole. Schizophr Bl 2007; 3:523-820. 10, Lin SK etal, Reversal of antipsychotic induced byperprolainemi, weight gain, and dslipidemia by aripiprazole a ase report. Jl sgctaent progtam for treament-emergent weight gsin in olaneapine-teated patients wih schizophrenia oF Payehlatry 2006,6721307 11, Newcomer JW tal. A muienter, andomzed,double-blin study ofthe effects of aripiprazole in overweight subjects wi schizophrenia lor schizoalfectivednorderswitchd fem olaneapineJ lin aychnty 2008 «91041056. 12. Kim SH eal. Metabolic impact f witching antipeychatic Nevspy to atpiprzole ster weight gina plot tay 1 Clin Pachopharmacol 2007; 27:365-358 13, sukundan A c a. Antipschotic switching for people with schizophrenia who hove nearoleptic-induced weight oF metabolic problems. Cochrane Database Sst Rev 2010; CD006628, 14, Weiden Pj eta. Improvement inindize of helthstatur in outpatient with schizophrenia switched to tiprsidone.) Clin Paychopharmacl 15, Moste JM et a Improvement a antipsychotic lated metabolic disturbances in patents with schinphresia switched to dprasdone Prog Neuropsychopharmacol Bil Psychiatry 2007; 31:383-38, 16, Kanal ON etl Switching ror quetiapine to prasidonesa scteen-week,apen-Ibel, mulicenter study evaluating the efectnenese and safey of iprasfone in outpatient subjects wth schizophrenia or shizoffecte disorder J Psychiat Prac 201 1700-19, 17, Gupta $e al, Weight decline in patients switching from olanzapine to quetiapine. Sehizopht Res 2004; 7057-4 18, Ried LD at al. Weight change after an typi antpsyctic switch. Ana Pharmacother 2003; 37:1381-1386, 19, Englisch Set a.Combined antpiychotc retmentinvolvingclozapine and aripiprazole. Prog Neuropsyshopharmacol Biol Psychiatry 20085 20. Schott SG etal A 12-mouth follow-up stu of teeating overweight schizophrenic patients wih arpprszle. Acta Pychiste Scand 2008; 119246-250 21, Fleichhacker WW etal. Weight change on sipiprazole- clozapine combination in schizophrenic patients with veight gain and suboptenal sesponse on clozapine 16-eck double-blind study. Eur Psychiatry 2008; 28(Suppl2):S114-SH15, 22, Hemlerson DC ctl Aripipranoe edd overweight and ebsa slanzapine-teatl shicophreni patie.) Clin Pychopbermcol 2009; 29:155-109, 23, Werncke U etal. Behwioural management of antipsychotic induced weight gun: review. Asta Peyshiatr Sand 2003, 1082 Se al. Weight gain with risperidone among patients with mental retalaton: effect of ealovie restriction lin Psychiatry 200 erie 25, Smith H et al Low ghreaemic index det inpatients precribed clozapine: pot study Paya Bl 2004; 28:292-294. 26. Ball MP etal. Aprogram fr tretng clanzspine-relatl weight gain. Psychiat Serv 2001;52:967-969. 27. Pendlebusy | etal. Evaluation ofa behavioural weght uanagement programe forpatients With severe mental les: 3 yee rests. Hum Psychopharmacol 206 28, Vredand 8 ea. A program for managing weight gain sociated with apical antipsychotics. syehatr Serv 2003; $4115 29, Ohlen Ret al: A dedicated nurs Jed service for antiprychovi-induced weight gat: an eraluaton, Psychiat Bull 204; 28164-166, 9. Chen CK etal. fects of 3 10-week weight contol program on obese patients with schizophrenia ar chioafectvedivrder: 3 12-month follow wp. Psychiatry Clin Neurosci 2008; 6:17-22, 51. Flora eal. fect ofamantadine on weight gain ring olanzapine treatment ar Neuropsychopharmicol 2001; 1:181-182. 52, Gracious BL etal. Amantadine teatment of psychotepic-iaduced weight gin in chilren and adolescents ase series | Cid Adolese Psychopharmacol 2002;12249-257aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.150 The Maudsley Prescribing Guidelines in Psychiatry References 1 De Leon je a Polyipsia and water intoxication in psychiatric patients a review ofthe epidemiological iterstue. Bil Psychiatry 1994; 3540-419, 2, Pate IK. Polydpsa, hyponatremia nd water intoxication among sychistricpatiats, Hosp Comman Petchiatry 1994; 51073-1074 ‘say in long-term payed wnt, Ear Ach Psychiatry Clin Neurons 2003 253:37-99, 3: Deteon h Pulp 4, Sigil AT et al. Primary and drug-induced disorders of water homeostasis in eychintic patients: principles of diagnosis and management. Harv Rey Bsyehiatry 1998;6:190-200 5. Sieger Fle al Risk Sctor for he development of hypomatmimi in psychiatic npatens. Arc Intern Med 1985; 15:953-957 66. Machusondansn § «al. yponatraemia srocsted with pyshotropie mediations. A review ofthe Ieature and spontaneous reports Adverse Dug eat Toxicol Re 2002;21217-28 2. Bachu K etal. ripipazole induced syndrome ofinappropriate aeidiuttic hormone secretion (SIADH). Am | Ther 2006:18:370-872, [8 Duceja 5} et al. Olanapine induced hyponatraemia. Uster Med J 2010;79:101-105 ° cas syst eve ofthe published evidence Deg Saf 2010;38:101-114 Meuendike Deal Antipsychotic induced hyponat 10. MannesseCK otal lyporatraemia a an adverse drug reacion of antipsychotic drug case-comrl study in Vigiase, Drog Saf 2105, 33356 11, Sarma al. Severe hyponatracmia svocisted with desmopressin nas spray to teat dovapine induced nociurnal enuresis. st NZ. Psychiatry 2005 39:90 12, Zaid AN-Rhabdomyolysinafercorvetion of hyponatremia in pychogriepolyipss possibly complicated by ziprasidone, Ann Pharma ‘other 2005; 381726-1731, 13, Camaso CM etal. Clozapine esores naterbalance in chicpheenic patents with plydipsia Ayposatremia syndrome. J Nesropeychiatry Clin Neos! 1900; 16-00. 14. Speirs NM et al Clozapine treatment in plydipia and intermittent hyponatemi.| Clin Poyhitey 1996, 37:123-128 15, Lituell KH et ab Etfeas of olanzapine on pelyipsia an intermittent hyponatremia. Cli Psyhiatry 1997; 98549, 16, Kawai N etal Rsperidre fied to improve polydisia-typonstremia ofthe shizophrenc paints Pyshitry Clin Neurosci 20025 17, Montgomery Ile al. Adjuntive quetiapine treatment of the ply dpa intermitentyponateoiasand paychon spades acne report 1 Clin Psychiatry 2003 64:339-31, 1, Canaso CM etal: Docs minimizing neuroleptic dosage influence byponstremiatPochiatry Res 1996; 63:227-229. 19, Josie RC et Tolan ew tol forthe efectvetretmentofhypenatrea in pychotcdsoxders. Exper Opin Phatmaccther 2010 1637-108, 20, Deeux Getal. Now: peptide arginine vasopressin antagoniss: the vaptans. Lancet 2008; 371 ‘After it became clear that the ase of antipsychotics increased mortality in elderly patients, researchers began to look for the reasons for this. A Dutch database study published in 2008! found that current use of antipsychotics was associated with a 60% increased risk of pneumonia in an elderly population. Risk was highest in the first week of treatment and an increased risk ‘was seen with SGAs but not FGAs. Another study” found a higher rate of chest infection in people taking SGAs. Two further studies found a dose-related increased risk of pneamonia in older people taking both FGAs and SGAs.™4 The risk was again noted to be highest in the first week(s) of treatment, Schizophrenia itself seems to afford a higher risk of complications (e.g. admission to intensive care) in people diagnosed with pneumonia. ‘The mechanism by which antipsychotics increase the risk of pneumonia is not known. Pos: s include sedation (risk seems to be highest with drugs that show greatest H;, antagonism? }; dry mouth causing poor bolus transport thereby increasing therisk of aspiration; and perhaps some ill-defined effect on immune response.!s* An increased risk of pneumonia should be assumed for all patients (regardless of age) taking any antipsychotic for any period. All patients should be very carefully monitored for signs of chest infection and effective treatment started promptly. Early referral to general medicalaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Bipolardisorder 157 The teratogenic potential of valproate is not widely appreciated and many women of child- bearing age are not advised of the need for contraception or prophylactic folate."**” Valproate may also cause impaired cognitive function in children exposed to valproate in utero."* Interactions with other drugs Valproate is highly protein bound and can be displaced by other protein-bound drugs, such as aspirin, leading to toxicity. Aspirin also inhibits the metabolism of valproate; a dose of at least 300 mg aspirin is required.” Other, less strongly protein-bound drugs, such as warfarin, can be displaced by valproate, leading to higher free levels and toxicity. Valproate is hepatically metabolised; drugs that inhibit CYP enzymes can increase valproate levels (e.g. erythromycin, fluoxetine and cimetidine). Valproate can increase the plasma levels of some drugs, possibly by inhibition/competitive inhibition of their metabolism. Examples include tricyclic antidepressants (TCA) (particularly clomipramine™ ), lamotrigine," quetiap- ine,®* warfarin® and phenobarbital. Valproate may also significantly lower plasma olanzapine concentrations; the mechanism is unknown.>* Pharmacodynamic interactions also occur. The anticonvulsant effect of valproate is antag- onised by drugs that lower the seizure threshold (e.g. antipsychotics). Weight gain can be exacerbated by other drugs such as clozapine and olanzapine. ‘The prescribing and monitoring of valproate are summarised in Table 3.1. Indications Mania, hypomania, bipolar depression (with an antidepressant) Prophylaxis of bipolar affective disorder May reduce aggression in a range of psychiatric disorders (data weak) Note sodium valproate is licensed only for epilepsy and semi-sodium valproate only for acute mania Pre-valproate FBC and LFTs work-up Baseline measure of weight desirable Prescribing Titrate dose upwards egainst response and side-effects. Loading doses can be used and are generally well tolerated Note that controlled-release sodium valproate (Epilim Chrono) can be given once daily. All other formulations must be administered at least twice daily Plasma levels can be used to ensure adequate dosing and treatment compliance. Blood should be taken immediately before the next dose Monitoring ‘As a minimum, FBC and LFTs after 6 months Weight (or BMI) Stopping Reduce slowly over at least 1 month BMI, Body Mass Index; FBC, full blood count; LFT, liver function test.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.70, Mazza M etal Beneficial acute antidepresunt effects of aripiprazole as an adjunctive treatment or monotherapy in bipolar patients ‘unresponsive tomood stabilizers result rom a 1-week open-label rial: Expet Opin Pharmacother 2008 9:3185-3149, 71. Gras etal Eficacy of medern antiprychoties in placcb controled tris bipolar depression: teta-anaya. lot] Newoprychophar smacol 2010; 135-14 72, Wang PW etl Gabapentin augmentation therapy in bipolar depresion Bipolar Dixon 2002; 296-301 7. Ashton Hat al. GABA ergic ray ont tge lf enter sage right. | Papchophermaca 200% 17474178 74. Cheagapps KNet al. [most as an add-on weatment fr bipolar depression. Bipols: Disord 2000; 247-55 7S, Diazgranatos N et al A randomined add-on trial of at N-methy-D-ssparate antagonist in teatment-sstact bipolar depression. Arch Gen Pychitey2010;67:798-802 76, Shakani Ret al Ketamine assocated ulcerative cpttis:a new clinical entity, Urology 2007; 69:810-812, 77. Frye MA et al A placbo: 1o4i242-120. 78. Calabrese Ret al Adjuncive armodsinil for major deprenive epider associated with bipolar I ditonler:a randomized, muticester, nioled elution of adjunctive medafii in the treatment of bipolar depression. Amy J Dhychistry 20073 Aouble- bland placebo- which suggest a combination of lithium and valproate as first-line treatment. Adding an antipsychotic with proven activity in bipolar disorder and/or rapid cycling should be the next step (see Table 3.12).aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Depression and anxiety 199 ots to Figure 4 ' Tools such asthe Montgomery-Asberg Depression Rating Scale (MADRS) ani the Hamiton Dapression Fatng Scale [MAM-0) are used ‘na to assess arug ete The HAW-U Is now Somewhat anacrronisue ang few ciclans are Tamllar win the MAORS (anraugh 5 sobably the bestscalete measure severity and changel The PHOS" is simple to use ands recommendeé for assessing sypton change ‘a depression alttoughit beter measures trequency rather then sevety ef symptoms) ' ‘switting between drug lasses in cases of por tlerablity isnot clearly supported by published studs but hasa strong theoretical basis Inpractce, any patients who carnotelerate one SSA wil rediy aerate ancther. 1» In cases of son-response, there is some evidence hat switching within a drug cassis effective! hut switching between classes 6, in sactice, the most comnon tion andi supportedby some analyses. The National Insite fr Health and Clinical Excelence (ICE) and 1 There's minmal evidence to suppert increasing the dose af most SSH in depression" Slightly better evidence suggests th ‘ose of venlataxee, esealopram and uieyohes may be heptu ‘switch trearnents eal (e.g after week or wo) if adverse etfcts ee inlerate oif no improvement a ais seen byS~ weeks Opinions ‘on when to switch vary somewhat butts clear that antidepressants have a faly prompt onset of acon" and thatnon-esporse at 2-6 wasksis a good preictor of everalinon-respanse. Tha absence ef any mpravement at lat 3-4 weoks should normally pravokea change intreament(Brtsh Associaton for Psychoptarmacology guidelines suggest 4weeks'). Ithereis sane improvenent at tis time, continue fad asses fora farther 2-2 weeks, increasing the Principles of prescribing in depression * Discuss with the patient choice of drug and utility/availability of other, non-pharmacological treatments. ® Discuss with the patient likely outcomes, such as gradual relief from depressive symptoms over several weeks. ® Prescribe a dose of antidepressant (after titration, ifnecessary) that is likely to be effective. = Fora single episode, continue treatment for at least 6-9 months after resolution of symptoms (multiple episodes may require longer). © Withdraw antidepressants gradually; always inform patients of the risk and nature of dis- continuation symptoms. ‘The drug treatment of depression is summarised in Figure 4.1. References 1, American Pychiatric Association Pracice Guideline forthe Treatment of Patients with Mawr Deresve Disarder, rd. eda 2010. Wathingon, DC: American Feyehisteic Assocation: 2010, 2 AndersonIM tal. Bvidenceased guidelines for testing depresive dsorlers vith atideprestats a eirion of the 2000 Brish Avocaion {or Pychopharmacologygeielines J Psychopharmacol 2008; 2243-35 3. Crismon ML eta. Th Texas Meicaton Algorithm Project: eport ofthe Teas Consensis Conference Panel on Medication Treat Majer Depressine Disorder] lia Psychiatry 1999; 60:142-156, fat of 4. Kocsis if etal. Maintenance therapy for chronic depresion, Acontulled clinical trialof desipramine. Arch Gen Poychisey1996;33769-74 5, Dekder etal. The use of antidepressants ae recvery fom depression, Eur} Pyshatey2000;14:207-212, 6, Nelson IC. Treatment ofatidepressat nonresponders: augaentaton or swith? | Clin Pychstry 198; (Suppl 15): 35-4 7, Joffe RY. Sabetiton therapy in patient wth maior depreaion CNS Drage 199; 1175-180 5. Montgomery SA et lA new depression scale designed oe sensitive to change, Be Paychisty 1979; 134382289, 9, Hamilton M. Developmentofatingscae for primary depresvellness. Br | Soc Chin Psychol 1967; 6278-296 10. Kroenke K etal. The PHQ:9: validity of brief depression severity measre | Gen Intern Med 2001; 1606-613 11, Thase ME etal. Citalopram treatment of fuoxetine nosresponders. J lia Psychiatry 2001; 6283-687. 12 Rash Ale XR afer fie f SSRs for depremion-N Fg] Med 20065 3541231-1212 13, Rube HG etal. Switching atidepresiate ater a fit selective serotonin ruptae inhibitorin major depresve diorder a sytematic review. 1 Clin Psychiatr 2006 67218361855, 14, Bren etal Switching to nother SSRI orto ventafane with or without copnitive behavioral therapy for adolescents with SRT-rsiant Aepression: the TORDIA randomized contilled til JAMA 2008; 299:91-915,aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.The Maudsley Prescribing Guidelines in Psychiatry 206 soviqiyu axexdno4 U9320,049 Yonpodd Jo ALowUUNS “Dds “JOpsosIp s59:9¢ HEWINE 360d ‘aSLd 1194 ‘anisinduioo anissasqo ‘a0 ‘Snip Kuoyewule|pul-Aue [eplo194s-UOU ‘IYSN “JOUgIWU! asepixo suIWeOUOUL '|OYWN “(Aep e adm) a/p UI Sq ‘pq ‘/ueinuso4 /eUOReN YSU ay PUe LOReWIOJUI szasm>eJNUELI ayy OF 49}94 s}eI9P |} 104 Aep/6w 002-Sz sid 90M L Jo seasayut ie Bu 05 0 sdais U! paseauout aq Kew Aep/Sw 00¢-0S uA LieL uyeysen fop/Sus 0s-sz sueydordiay/saivsN Bhi (sunpe), ou yBnouze) Aep/6u 002-05 4apun) a0. Joyooje :uorne> 4apiosip Aep/6w ooz-se —_Aie|xue [e105 joydesoBe F Aep/6w 002-2 42ps0sip 21Ued Aarxue ‘aUOS Jo sjana] ¥ uoissaidap ewse(d sseo.0uy 200d 49 gnuauin2es ayjoqeiaw “Ukep/6w sasop 104614 Jo asde|au (fen Kew aouid anne gore ses0p: 404 249P!49~ 49 uonjuana.d ouob) yeom eseH ye Alou) asow) 6w ooL-0s esn pue Aaixue siaiger wi 001/90°0 9@~ — SGZdAD SNAIL wesdojeyD 104 5y —Kep/Wo0z-05 = UoIssaidoq —ouNeRDS @)3809 (4) eyrsreq Suomperaiuy sHey2 (pepnpursou UOREIpy]__ajqeHeAe areuiyxoiddy sofew asianpe we —_sasop Auapie) pasuar — suo) ‘Iss sasop pasuarryaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Depression and anxiety 217 Next-step treatments Approximately one-third of patients do not respond to the first antidepressant that is pre- scribed. Options in this group include dose escalation, switching to a different drug and various augmentation strategies. The lessons from the Sequenced Treatment Alternatives to Relieve Depression (STAR-D) programme are that a small proportion of non-responders will respond with each treatment change, but that effect sizes are modest and there is no clear difference in ef- fectiveness between strategies. See section on “Treatment of resistant depression’ in this chapter. Use of antidepressants in anxiety spectrum disorders Antidepressants are first-line treatments in a number of anxiety spectrum disorders. See section on ‘Anxiety spectrum disorders’ in this chapter. References 1. NatisnalInttte for Heal and Clinical Excellence Depressions the testment and management of depression in alts update) 200%. srrwaice org. 2. Kirsch Ital. nil severity and unidepresunt benefits:a ma-aniyssf data submittedto th Food and Drug Adminstration. PLoS Med 5. Fouimier IC eal. Antidepressant drugeffects and depression sevetiy: a atien-levd mete anal. JAMA 2010;303:17-5. 4 AndersonIM etal: Bvidenceased guidelines for treating depresivedsorsers vith atidepresrants a einion ofthe 2000 Binh Avocsion for Fychepharmacology guidelines. Psychopharmacol 2008, 22:43-35. 5. Khan A etal, Why hos the antidepresint-pacebe difference in antidepres linea tras diminished over the pas thre decals? CNS [Newosc Thee 2010; 16:217-220 6. Taylor MJ etal Early onset of selective serotonin reuptake inhibitor amtilepresant action systematic review and meta analysis. Arch Gen Payehatry 2006 63:1217-1223 Aepressivedisoner. Clin Psychopharmacol 2006 26:5+-60, 8. Szeged Act al. arly improvement in the fst 2 weeks as a predictor of treatment outcome in patients with major depresive ssorder: a ‘mets-analysis including 6562 patients. Clin Paychitry 2008, 70:344-353, eel cuaained seeponee rates between sotidepretnnts snd place for the tontnent of jo 9. National Insite for Heahh and Clinical Excellence, Depresion (amended) mansgement of depression in primary and condary cre 10, Cipriani A eta Comparaineeffcacy and acceptability of 12 new generstion atideprenants + mpl treatments meta-anlysit Lancet 2009; 373748-758 11. GarlehnerG etal Comparative Benefits and harms ofsecond- generation antidepressants background paper forthe America College of Physicians Anntntern Med 2008, 149734 12 Fanngan R).Foal ont f deus use in psychistey Hum Psychophaemacol 2008, 29(Suppl 1549-51 13, KellyCM etal. Selective serotonin reuptake inhibitors and brat cancer mortality in women recivingtamerifen:a population based cobort stodr BMI 2016; 340693, 14, Stone M oo Bik of esiality in linia rae of atiteprosants in adultes analy of proprntary data wibmitted > US Food and Dig -Administntion. BM 2009;339:2880, 15, Schneewebs § eal. Variation inthe rik of sukide attempts ard completa suicides by antidepresaet agent in adults a propessity score adjusted analysis of yeas data Arch Gen Psychitey 1010; 67487-506, 16, Isesion G etal The incresed use af antidepressants has enteibated i the worldwide reduction in susie mts. Be J Daychisty 2010; 17, acon Get al, Amtidepresant mediation prevents suicide depression, Acta Pyshiat Scand 2010; 122454160, 18 Simon GEet al Suit ris during antidepressant treatment. Am | Psychiatry 2006; 1631-47, 19. Mulder RT et al Antideprewant feniment is acocinted witha reduction in suicidal Menton and ssicide attempts, Acta Psychiatr Scand 2008 18116122, 20, Ton Lt. aed stats during atideprestant treatment in 789 Sardinian patients with major afetine diced. Acta Pychate Scand 2008 118:106-115, 21, Hayson Ket al Toxiety antidepressants: ates ofsuicil relative to preeribingand on fatal overdse. Br] Payehitey 2016 196354388aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Depression and anxiety 225 Treatment Advantages Disadvantages Refs Add quetiapine Good evidence base Dry mouth, sedation, (150 mg or 300mg a —_—Usually well tolerated constipation can be day) to SSRVSNRI Plausible explanation Provlematic for antidepressant Weight gain risk in the effect longer term Possibly more effective than lithium Add risperidone Developing evidence Hypotension Bea (0.5-3 mg/day) to antidepressant base Usually well tolerated Hyperprolactinaemia Add aripiprazole (5-20 mg/day) to antidepressant Good evidence base Usually well tolerated and safe Akathisia and “0 restlessness common (10-20% of patients) SSRI + bupropion Up to 400 mg/day Supported by STAR-D Well tolerated Not licensed for 1251-55 depression in the UK ‘SSRI or venlafaxine + mianserin. (30 mg/day) or mirtazapine (30-45 mg/day) Recommended by NICE Usually well tolerated Excellent literature support Widely used Always consider non-drug approaches (e.g. CBT) ‘Theoretical risk of Ae ae serotonin syndrome (inform patient) Risk of blood dyscré with mianserin Weight gain with mirtazapine CBT, cognitive behavioural therapy; ECG, electrocardiogram; ECT, electroconvulsive therapy; NICE, National Institute for Health and Clinical Excellence; SNRI, serotonin and noradrenaline rouptake inhibitor; SSRI, selective serotonin reuptake inhibitor; STAR-D, Sequonced Treatment Alternatives to Relieve Depression; TCA, tricyclic antidepressant; TFT, thyroid function test; UE, urea and electrolytes. References 1. Dunaer Dl a Prospective long-term, multicenter study ofthe naturalistic outcomes of patients with eaten sistant depression. J 13192-103, Wooderion SC etal. Prospective evuation of specsist inpatient treatment for reftictory affective disorders. J Affect Disotd 2011 3, Fela A tal. What happens to patients with tearment-esizant depression? systematic review of mem to agterm outcome ste. 1 Affi Disord 2009; 1164-11aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Depression and anxiety 235 19, Navatto V etal Costinuaton/maintenance treatment with nortpeyiae vesus combined nortriptyline and ECT in latte psychotic depression «two-year randomized stay, Am | Geriat Pyshatry 2008;16:498-505. 0. BelanfF IK eal An open label ial of C1073 (mifeprntone) for psychetic major deprenion. Bil Paychiary 2002; 92:386-392, 1. Rubin RT.De Rubin pie (Letter). Am J Prychisry 2004; 1611722 2. Blasey CM et al A multisite trial of mifepritone fr the treatment of pjehotc depression ste by treatment ineration. Ci “vik 2008; 30288-28, 23. Huaag CC et a. Adunetie use of methyphenidate in the teeatment of psythotic unipolar depression, Cin Newopharmscal 208; sini enap Clin Further reading Keler J etal: Curren! sus inthe lsitcation of psyctie major depression, Schizph: Bull 2007;33:877-885, TIyrka ARt al. Peychotic major depression: heneit-rsk avesement ftrestment options Drug Saf 200629491508 Psychotropics are often continued during ECT and some agents (particularly anti- depressants’) enhance its efficacy. Table 4.9 summarises the effect of various psychotropics on seizure duration during ECT. Note that there are few well-controlled studies in this area and so recommendations should be viewed with this in mind. Note also that choice of anaesthetic agent profoundly affects seizure duration,?* post-ictal confusion and ECT efficacy? Effect on ECT seizure Drug duration Comments'*"* Benzodiazepines Reduced All may raise seizure threshold and so should be avoided where possible. Many are long-acting and may need to be discontinued some days before ECT. Benzodiazepines may also complicate anaesthesia and may reduce efficacy of ECT If sedation is required, consider hydroxyzine. If benzodiazepine use is very long term and essential, continue and use higher stimulus SSRIs? 1"? Minimal effect; Generally considered safe to use during ECT. small increase Beware complex pharmacokinetic interactions possible with anaesthetic agents (Continued)aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Depression and anxiety 239 35, Pralash I etal. Therspeutic and prophylactic uty ofthe memory-eshancing drug donepeil hdeochloride on cogiton of patents ng letraconvulsietherapy:a randomized controlled til. | ECT 2006; 22:163-168, 36, Leng M eal. retcsiers with buprofento prevent slecroconvalsivetherapy- induced headache | Chin Paychatry 2003;64:351-253, 57, Markowit J etal Intanasl sumatriptan is post ECT headache results of a open-label. ECT 20015 17280-23, vende Further reading National Initite for Hlth and Clinica Excellence, The dni effectiveness and com effctivenees of elacroconvulaive therapy (ECT) for Aepreviv illness, chiraphreria catatonia and mans. Technology Appaiel 59. London: National lnstitte for Health and Clinieal Eeelence, 2003. Pata KK etal. Implication of herbal alterative medicine fr elestoconvulsve therapy.) ECT 2004; 20:186-164. Psychostimulants reduce fatigue, promote wakefulnessand aremood elevating (as distinct from antidepressant). Amfetamines have been used as treatments for depression since the 1930s! and more recently modafinil has been evaluated as an adjunct to standard antidepressants.? ‘Amfetamines are now rarely used in depression because of their propensity for the devel- opment of tolerance and dependence. Prolonged use of high doses is associated with paranoid psychosis.’ Methylphenidate is now more widely used but may have similar shortcomings. Modafinil seems not to induce tolerance, dependence or psychosis but lacks the euphoric ef- fects of amfetamines. Armodafinil, the longer-acting isomer of modafinil, is available in some countries. Psychostimulants differ importantly from standard antidepressants in that their effects are usually seen within a few hours. Amfetamines and methylphenidate may thus be useful where a prompt effect is required and where dependence would not be problematic (eg. in depres~ sion associated with terminal illness). Their use might also be justified in severe, prolonged depression unresponsive to standard treatments (e.g. in those considered for psychosurgery). Modafinil might justifiably be used as an adjunct to antidepressants ina wider range of patients and asa specific treatment for hypersomnia and fatigue. ‘Table 4.10 outlines support (or the absence of it) for the use of psychostimulants in various clinical situations. Generally speaking, data relating to stimulants in depression are poor and inconclusive.4> Careful consideration should be given to any use of any psychostimulant in depression since their short- and long-term safety have not been clearly established. Inclusion of individual drugs in the table below should not in itself be considered a recommendation for their use.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Depression and anxiety 243 56, Lazarus LW eta Efficacy and side eet of methriphenidate for poststoke depression. [Clin Psychiatry 1992: 88:447-449. 37, Lingam VR et a Metaylphenidate in treating poststroke depression) Cin Pyshiaty 1985; 49:15, 38. Sugsen SG et al Modfiil monetherapy in poststroke depresionPaychosomates 2004; 45:80-81 38. Rosenberg PB etl. Methylohenidate in depressed medially patients. | Clin Pyshiatry 1991;32:263-267, 40. Woods SW etal Psyehostimulant treatment of depressive dsoners secoadaryto medical nest | Clin Pspehiaty 1986; 4722-15 AL, Koulmann MW at a. The vw of amphetamine in medically ill depressed paints | Clie Peycintry 1982; 49463 16 42, Wagser Gl etal Desamphetamine as trestmens for depression and low energy i AIDS patients a plot stuly. | Tsychesom Res 1997: 07-41 43, Wagner Gi etal. Effects ofdextecamphetatnine on depression and fatigue in men with HIV: a double lin, placho-conteled tial} lia Psychiatry 2000, 61:836-40, Further reading Hanly SE Methylphenidate forthe tnatment of depreive symptoms including ftp nnd apathy. medical il oer sdulbaand terminally ‘Hadas. Am] Geriatr Pharmacother 2009; 734-59, The prevalence of most physical illnesses increases with age. Many physical problems such as cardiovascular disease, chronic pain, diabetes and Parkinson’s disease are associated with a high risk of depressive illness.'"? The morbidity and mortality associated with depression are increased in the elderly as they are more likely to be physically frail and therefore vulnerable to serious consequences from self-neglect (e.g, life-threatening dehydration or hypothermia) and immobility (e.g. venous stasis). Almost 20% of completed suicides occur in the elderly.* In common with placebo-controlled studies in younger adults, at least some adequately powered studies in elderly patients have failed to find ‘active’ antidepressants to be more effective than placebo,” although it is commonly perceived that the elderly may take longer to respond to antidepressants than younger adults.® Even in the elderly, it may still be possible to identify non-responders as early as 4 weeks into treatment.’ ‘Two studies have found that among elderly people who had recovered from an episode of depression and had received antidepressants for 2 years, 60% relapsed within 2 years if antidepressant treatment was withdrawn." This finding held true for first-episode patients. Lower doses of antidepressants may be effective as. prophylaxis. Dothiepin (dosulepin) 75 mg/day has been shown to be effective in this regard.!? Note that NICE recommends that dosulepin should not be used, as itis particularly cardiotoxic in overdose.'® There is no evidence to suggest that the response to antidepressants is reduced in the physically ill! although outcome in the elderly in general is often suboptimal.!56 Antidepressants may not work at all in dementia.!” ‘There is no ideal antidepressant: all are associated with problems (Table 4.11). SSRIs are generally better tolerated than TCAs;!® they do, however, increase the risk of gastrointestinal bleeds, particularly in the very elderly and those with established risk factors such asa history of bleeds or treatment with a NSAID, steroid or warfarin. The risk of other types of bleed such. as haemorrhagic stroke may also be increased" (see ‘SSRIs and bleeding’ in this chapter). The elderly are also particularly prone to develop hyponatraemia with SSRIs (see ‘Antidepressant induced hyponatraemia’ in this chapter), as well as postural hypotension and falls (the clinical consequences of which may be increased by SSRI-induced osteopenia”®), Ultimately, choice isaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Depression and anxiety 251 escitalopram!*!5 and duloxetine.’ Noradrenergic antidepressants are clearly linked to hypona- traemia,'! there a notably few reporis for MAOIs”? and none for agomelatine, CYP2D6 poor metabolisers may be at increased risk” of antidepressant-induced hyponatraemia, Managing hyponatraemia”® It may be possible to manage mild hyponatraemia with fluid restriction.’ Some suggest in- creasing sodium intake’ although this is likely to be impractical. If symptoms persist, the antidepressant should be discontinued. = The normal range for serum sodium is 136-145 mmol/l. © If serum sodium is >125 mmol/l, monitor sodium daily until normal. Symptoms include headache, nausea, vomiting, muscle cramps, restlessness, lethargy, confusion and disorien- tation. Consider withdrawing the offending antidepressant. = Ifserum sodium is <125 mmol/l, refer to specialist medical care. Thereis an increased risk of life-threatening symptoms such as seizures, coma and respiratory arrest. ‘The antidepressant should be discontinued immediately. (Note risk of discontinuation symptoms which may complicate the clinical picture.) Note also that rapid correction of hyponatraemia may be harmful. Restarting treatment with an antidepressant ® For those who develop hyponatraemia with an SSRI, there are many case reports of recurrent hyponatraemia on rechallenge with the same or a different SSRI, and relatively fewer reports of recurrence with an antidepressant from another class.!"? There are also case reports of successful rechallenge.! ® Prescribe a drug from a different class. Consider noradrenergic drugs such as nortriptyline and lofepramine or an MAOI such as moclobemide. Begin with a low dose, increase slowly, and monitor closely. If hyponatraemia recurs and continued antidepressant use is essential, consider water restriction and/or careful use of demeclocycline (see BNF) * Consider ECT. Other prescribed drugs Carbamazepine has a well-known association with SIADH. Note also that antipsychotic use has been linked to hyponatraemia*’*? (see section on ‘Antipsychotics and hyponatraemia’ in Chapter 2). Other commonly prescribed drugs such as thiazide diuretics, NSAIDs, tramadol, omeprazole and trimethoprim can also cause hyponatraemia 2* References 2. Lams Gel veviw of drug-induced hyponatiemia. m Kidsey Dis 200, 82:144-13 3. Kruger Stal. Duloxetine and hyponatremia report’ cie. | Clin ychophaemacol 2007527101104 4. Avinzon ZH etl. Delayed recurrent SIADH associated with SSRIS. Ann Pharmacother 2002; 3641751177 5, Fabin Tt al Paontine ded hyponatremia in older alse 12-neck pronpstive dy. Arch tera Med 2004 1642792aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.260 The Maudsley Prescribing Guidelines in Psychiatry References 1. Honig A etal. Treatment of pst-myocanial infiretion depretsive donde: & randomized, placbo-ceatroled til wih mirtazapine Paychosom Med 2007; 6906-613, 2, Sauer WH et a Selective serotonin reaptakeinhibitorsand myocardial infarction, Circulstion 2001; 104:1894-1898 3. Sauer WH ota: Elect of entidepremants and their ative alsty forthe serotnin transporter om he risk of myocardial infarction, Circulation 2003; 108:32-% 4, Davies Seta. Teatment of ansiety and depressive disorders in patients wit caiowasuardicase, BMY 2004;328:939-943, 5. Taylr Det a. Pharmacologica interventions fer people with depression and chronic physical hath problems: estematic review and a of Payhinry 20115 198178185. ts D eal The rl ofthe telectiveserotoni s-uplae ihibitor sertraline in nondepettive patients with chronic tehemic heat failure: preininay study. Pacing Clin Electrophysiol 2010;38:1217-1223. CChen $ etal. Serotonin and catecholaninergc polymorphic ventricular tachycardia ponble therapeutic role for SSR? Candiovse | Aft 4, Berman P eta. Eft oftreating depreson ad low perceived seca sipport om dic events after myocar nfrstionthe Enhancing Recovery in Coronary Heat Disease Patients (ENKICHD) Randonized Til, JAMA 200); 289 3106-3116, 8. Dalton $0 et al Us of sletive serotonin ptake inhibitors and risk of upper xatroimestinsl tae bleding:a population-bared cohort study. Arch Inten Med 2003 168:59-54 10, Warrington 5) «tal, The cardiovascular effets of anidepresants aychl Med Monogr Suppl 19895 165-40 11, Hippisley-Cox etal. Antidepressants isk ctor for ischaemic heat disease case conto study in primary cae. BN] 2001; 328666-669, 12, Whyte IM etal Relate toxicity f venlafaxine and selective serotosin reuptake nhibitorsin overdose compared to trieglic antidepressants QIN 2003; 96-69-14, 13, van NC etal, Pychotropic drug associated with correted QT interval prolongation. | Clin Psychopharmacol 2009; 299-15, 14, Stern H etal Candionasculrees of single doses ofthe antidepressants amiriptyine and ltepramine in healhy subjects. Phasmacopsy shitry 19855 18272-277 15. Waring WS etl. Acute myocarditis afer massive henlvineoverdose ar} Clin Pharmacol 2007; 68:1007- 100 16, Fhch . ee of fact om the lestrvcandiog-am] Clin Paysiatry 1985 4612-4. 1, Ellison JN et al Fluocetine induced badyesria and syncope i to patents J Clin Psychiatry 1990;51:385-888, 1, Roore SP etal. Candnvasclar elects of lunctine in depressed patients with heart disease, An Pychiatxy 1998; 1S8:660-665. 19, Stel I etal Efcacy and safety of fluxetne in he weatment of patiens with major depression afer Fist myeeanil infrction: ingings from a double-Hind,placebo-contrlld tril Peychosom Med 2000; 6273-789. 20, Kus Ht etal, Candiowasculir effects of paroxetine Peyeaopharmacslogy 1990;102:379-382 21, Roose SP ct al Comparison of paroxetine asd noxriptyline in depressed patients with ischemic hea disewse. JAMA 1998; 279:217-291 22. Shapiro PA etal. An open-label preliminary tril of sertraline for treatment of major depresion after acute myacindal infarction (the rts-analyss of safety and efcacy. The Brtsh Jo SADHAP Trial}. Serine Anti Depretnnt Heat Attack Tih Arm Heat | 1999513731 100-1166, 23, Glassman AH eal. Sertraline treatment of major depression in patents with scute MI orunstable angina. JAMA 200%; 288701709, 24, Winkler D etal Trazodone induced cudiaearehythmias:a repo of two ease. Hum Poydhopharmacol 206; 2:61-42 25, Fang W eal. Safety and efficacy of sertraline far depreson ia patients with CHF |SADHART-CHF): a randomized, double-blind, plcsho- controled tril ofsertelne for major depression wi congestine heat fire, Am Hart} 2008156417444 26, Rasmunsen Stal: Candis safety of cielopram:prowpstive 27, Catdao G et al. QTc intewval prolongation assocated with citalopram overdose: acse eport and erature review. Clin Newropharmacol 20015 24158-182, 28; Lerperance Fetal, Eft ofclapratr dd interpeional ppchotherpy on depresion in pllets wil cobain rtérydionectheCanadion CCandse Randomiaed Evaluation of Antidepresart and Psychotherapy Eicacy (CREATE) trish JAMA 207; 297:367-379. 28, Asim Lilja C etal. Drug induced torsades de pointes:a review ofthe Swed pharmacovigience databae. Pharmacoep emia Drug Saf 80, Stk I} etal. Cardiac side-efecs of wo sdectve serotonin eupiake inhibitors ia middle-aged and eldeey depressed patient. tnt Clin Paychophermacol 1998 19.263-267 31, Stirnimann G etal. Bragads syndrome ECG provcked by the elective serotonin reuptake ihibito luroxamine, Europace 2010; 2282-283. 32, Wyeth Phirmaceutias,Efoor XL, Sunmarr of PrductCharateritis. 1011. mi atedicinesorguklEM Cimediine/2210/SPC/Bfexnr} XL 33, Khaya IS etal Cariowasclarefectsof weletive serotonin reuptake inhibitor andother novel antigepremants- Hear Dis 2003:5153-160, sana stonpsstis alas, Clin Pryhopharmasl 19995 1907-15, 3. Lets K etal. QT interval prolongation asscited with venfaxine administration, Int Cando] 20t5; 19:116-117 35. TaybrD etal. Yote bee oa venlfanite-resons an rfetions | Paychopharmacel 2000; 2087-01 46, ColuciV etal Heat failure worsening and exacerbation afer vealafaxine and duloxetine therapy. Ann Pharmacother 2008; 42882 37. Sharma Act al. Pharmacokinetic anda of ulotetin, a 7 serotonin aed norepinephrine reuptake inhibior} lin Pharmacol 2000;aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.266 The Maudsley Prescribing Guidelines in Psychiatry Not all of the sexual side-effects of antidepressants are undesirable;! serotonergic antide- pressants including clomipramine are effective in the treatment of premature ejaculation" and may also be beneficial in paraphilias. Sexual side-effects can be minimised by careful selection of the antidepressant drug — see Table 4.16. Treatment A thorough assessment is essential to exclude physical causes such as diabetes and cardiovas- cular disease, and psychological and relationship difficulties. Spontaneous remission occurs in approximately 10% of cases and partial remission in a further 11%.’ If this does not happen, the dose may be reduced or the antidepressant discontinued where appropriate. Drug ‘holidays’ or delayed dosing may be used*” or dose reduction. This approach is prob- lematic as the patient may relapse or experience antidepressant discontinuation symptoms. More logical is a switch to a different drug that is less likely to cause the specific sexual prob- lem experienced (see Table 4.16). Note that agomelatine™"and amfebutamone (bupropion ~not licensed for depression in UK)"®"" have probably the lowest risk of sexual dysfunction. Bupropion is widely used in the USA as a first-line antidepressant with minimal risk of sexual je-effects, and as an adjunct (antidote) in patients with SSRI-induced sexual dysfunction. Preliminary data support the reduction of sexual side-effects in patients treated with duloxe- tine or SSRIs when mirtazapine is added."**" Trazodone may have similar effects."° Selegiline transdermal patches (licensed for the treatment of depression in the USA) seem to beassociated with a low risk of sexual side-effects."® Adjunctive or ‘antidote’ drugs may also be used (see section on ‘Sexual dysfunction’ in Chapter 2 for further information), Sildenafil is more effective than placebo at improving erectile function in men‘? and in improving sexual function in women taking SSRIs.* A small RCT supports the efficacy of maca root.” A Cochrane review of the ‘swategies for managing sexual dysfunction induced by antide- pressant medication’ found that the addition of sildenafil, tadalafil or bupropion may improve sexual function but that other augmentation strategies did not.” References 1, Baldwin DS et Efets ofantdepresantdeugs om sens function. fot] Psychiatr Clin Pract 197, 147-58 2. Pollack MH et. Genitousinaryand ecual adver elect ofpaychotropic medication Ie J Pechiney Med 1982; 2205-127 3 Lappino FS etal. Overweight, obesity. and €epresion:asysemat: review and meta-analysis f longitudinal stidies Arch Gen Peychistry 2016;67:20-4 4. Kivimaki M et Arvidepressant medicatin use weight gain, and risk of type 2 siahetr a population based study Dishetes Care 20105 Spanish Woekng Group forthe Study of Psychotopic Related Sexual Dysfunction. } Clin Psychiatry 2001; 62(Suppl 10-2 6, Soguves RT, Effects of psychotzepic drugs on human erection and ejaculation. Arch Gen Psychiatry 1989; 46:275-284 Kennedy SH etal. Sen drefuntion before amtiepresant therapy in majo 48 Cheng ¥ etal, eprasive ympiomatalogyand male seal functions in lat fe | Affect Disord 2007; 104225-228, lpreion. 1 fet Disord 1999; $6201-208aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.270 ‘The Maudsley Prescribing Guidelines in Psychiatry 21, Schule C tal. Reboxetin cuter stimulates contol, ACTH, growth hormone and prolactin secretion in healthy malesubjts: Prychoaeu: roendocrinology 200; 29:183-2, Laskmane G et al fects of minazapine on growih hormone, prolacin, and cortnl secretion in healthy male subjects. Poycheneursen Aoctinolagy 199%; 2479-784, 28, Laskmana G etal. Mirtazspinean inhbitr of eetisel secretion that doesnot influence growth hormone and prolactin secretion. | Peychophermaco! 2000; 26101-103, 24, Schule C etal. The ialuence of mirtaapine om asterior pituitary hormone secretion ia Healthy mal subjects, Foychopharacobgy (Bee) 2002; 16895-101 25, Whitemaa PD etal. Bupropion fils affect plasma pnlactia and growth hormone in normalsubjets. Be J Cla Pharmacol 1982; 1828. Further reading Gober # tal Antidepressant-induceéhyperproluctinzembaiacidence, mechanisms and management. CNS Daags 2010; 24:563-574. ® All antidepressants have the potential to cause withdrawal phenomena.' When taken con- tinuously for 6 weeks or longer, antidepressants should not be stopped abruptly unless a serious adverse event has occurred (e.g. cardiac arrhythmia with a tricyclic) (see section on ‘Antidepressant discontinuation symptoms’ in this chapter). ® Although abrupt cessation is generally not recommended, slow tapering may not reduce the incidence or severity of discontinuation reactions. Some patients may therefore prefer abrupt cessation and a shorter discontinuation syndrome. = When changing from one antidepressant to another, abrupt withdrawal should usually be avoided, Cross-tapering is preferred, in which the dose of the ineffective or poorly tolerated drugis slowly reduced while the new drugis slowly introduced. See Table 4.18 for an example. See Table 4.19 for a summary of all classes of antidepressants. ® The speed of cross-tapering is best judged by monitoring patient tolerability. Few studies have been done, so caution is required. * Note that the co-administration of some antidepressants, even when ctoss-tapering, is abso- lutely contraindicated (see Table 4.19). In other cases, theoretical risks or lack of experience preclude recommending cross-tapering. # In some cases cross-tapering may notbe considered necessary. An example is when switching from one SSRI to another: their effects are so similar that administration of the second drug Drug Week 1 Week 2 Week 3 Week 4 Withdrawing 40mg 20 mg 10mg 5mg Nil citalopram od od od od Introducing Nil 15mg 30 mg 30mg 45mg mirtazapine od od od od (if required) 06, once daily.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Depression and anxiety 303 antipsychotics and benzodiazepines, either by showing a very marked antipsychotic response or by allowing the use of lower-dose antipsychotic regimens. Side-effects Headaches, confusion, ataxia, dysarthria, blurred vision, gastrointestinal disturbances, jaun- dice and paradoxical excitement are all possible side-effects. A high incidence of reversible psychiatric side-effects, specifically loss of memory and depression, led to the withdrawal of triazolam..” The use of benzodiazepines has been associated with at least 2 50% increase in the risk of hip fracture in the elderiy.'®"” ‘The risk is greatest in the first few days and after 1 month of continuous use. High doses are particularly problematic, This would seem to be a class effect (the risk is not reduced by using short-half- life drugs). Benzodiazepines can cause anterograde amnesia?” and can adversely affect driving performance.”! ‘They can also cause disinhibition; this seems to be more common with short-acting drugs. Respiratory depression is rare with oral therapy but is possible when the IV route is used. A specific benzodiazepine antagonist, flumazenil, is available, Flumazenil has a much shorter half-life than diazepam, making close observation of the patient essential for several hours afier administration. Intravenous injections can be painful and lead to thrombophlebitis, because of the low water solubility of benzodiazepines; therefore it is necessary to use solvents in the preparation of injectable forms. Diazepam is available in emulsion form (Diazemuls) to overcome these problems. Drug interactions Benzodiazepines do not induce microsomal enzymes and so do not frequently precipitate pharmacokinetic interactions with any other drugs. Most benzodiazepines are metabolised by CYP3A4, which is inhibited by erythromycin, several SSRIs and ketoconazole. It is theo- retically possible that co-administration of these drugs will result in higher scrum levels of benzodiazepines, Pharmacodynamic interactions (usually increased sedation) can occur. Ben- zodiazepines are associated with an important interaction with methadone (see section on ‘Methadone’ in Chapter 6). References 1. emyttentere Ket a Clini factors influencing he precrigtion af antideprteants and bensoiazepne: real fom the Furpean sty ofthe epidemiology of mental disorders (ESEMeb). fet Disord 2008; 1084-33, 2 Manin Jet a. Benzodiazepines in generalized ansiety disorder: heterogeneity of outcomes based ona systematic review and meta-analysis cof cna trials. JPrychopharmacol 2007; 21:774-782. 3. Davilsoa R etal A paychopharracolgical reatrent algorithm for generalised anxiety dsorde (GAD). | Poychopharmacel 2010; 24:3-26, a lorgtudinal and prospective study. Ae J GevatPsyeiaty 2008 16: 13 5 Hidalgo RB ct a. An ect-size analysis of pharmacologic teatmen's or genciized anxiety disorder Pychopharmacol 2097; 2864-472. 6. National Istie for Health and Clirical Excellence. Genenlised anvety disorder and panic dsonter (vith of without agoraphobia in dul Clinical Guidline 6113, 2011 wer nice ong klaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.308 The Maudsley Prescribing Guidelines in Psychiatry Approximate dose (mg) equivalent Benzodiazepine to 10 mg diazepam Chlordiazepoxide 25mg Clonazepam 1-2 mg Lorazepam 11mg Lormetazepam 1mg Nitrazepam 10mg ‘Oxazepam 30mg Temazepam 20mg schedule; some patients may tolerate more rapid reduction and others may require a slower taper. ® Reduce by 10 mg/day every 1-2 weeks, down to a daily dose of SO mg ® Reduce by 5 mg/day every 1-2 weeks, down to a daily dose of 30mg ® Reduce by 2 mg/day every 1-2 weeks, down to a daily dose of 20mg = Reduce by 1 mg/day every 1-2 weeks until stopped Usually, no more than one week's supply (exact number of tablets) should be issued at any one time. Gradual dose reduction accompanied by psychological interventions (relaxation, CBT) is more likely to be successful than dose reduction alone.” Anticipating problems'> '° Problematic withdrawal can be anticipated if previous attempts have been unsuccessful the patient lacks social support, there isa history of alcohol/polydrug abuse or withdrawal seizures, the patient is elderly, or there is concomitant severe physical/psychiatric disorder or person- ality disorder. The acceptable rate of withdrawal may inevitably be slower in these patients. Some may never succeed. Risk/benefit analysis may conclude that maintenance treatment with benzodiazepines is appropriate, and there is support from an RCT examining the benefits and risks of this strategy.' Some patients may need interventions for underlying disorders masked bybenzodiazepine dependence. If the patient is indifferent to withdrawal (ie. is not motivated to stop), success is unlikely. ‘Too rapid withdrawal may be risky; a case report describes a fatal outcome.!?aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Children and adolescents 323 Medication Comment Oxcarbazepine Olanzapine Risperidone Quetiapine Aripiprazole A double-blind placebo-controlled study did not show significant differences between placebo and oxcarbazepine (mean dose 1515 mg/day) in reducing mania rating?? A double-blind, placebo-controlled study” showed olanzapine (5-20 mg/day) to be significantly more effective than placebo in YMRS mean score reduction over 3 weeks. There was higher weight gain in the treatment group (3.7 kg for olanzapine versus 0.3 kg for placebo) and associated significantly increased fasting glucose, total cholesterol, AST, ALT and uric acid A double-blind, placebo-controlled study showed risperidone (at doses 0.5-2.5 or 3-6 mg) to be significantly more effective than placebo in YMRS mean score reduction in a 3-week follow-up.’ The lower dose seems to lead to the same benefits at a lower side-effects risk. Sleepiness and fatigue were common in the treatment arms. Mean weight increase in treatment groups was 1.7 kg for the low and 1.4 for the high dose arm versus 0.7 kg for placebo. A double-blind, placebo-controlled study* showed quetiapine (at doses of 400 mg/d or 600 mg/d) to be significantly better than placebo in reducing mean YMRS scores. The most common side-effects included somnolence and sedation. Weight gain was 1.7 kg in the quetiapine group versus 0.4 kg for placebo Quetiapine is effective as an adjunct to valproate compared with placebo”? and was equally effective as valproate in a double-blind trial” A double-blind placebo-controlled study” showed aripiprazole (at doses 10 mg/d or 30 mg/d) to be significantly better than placebo in reducing mean YMRS scores and inducing response (reduction of at least 50% in YMRS score). Note the significantly higher incidence of extrapyramidal side-effects in the treatment groups (especially the higher dose). No significant differences in weight gain between the three groups were observed ALT, alanine transaminase; AST, aspartate aminotransferase; ER, extended release; IR, immediate release; NICE, National Institute of Health and Clinical Excellence; YMRS, Young Mania Rating Scale.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.330 The Maudsley Prescribing Guidelines in Psychiatry Consider guided self help support > and information for family/carers inetfectve or refused Offer CBT (+ERP); involve famiy/carers (individual or group formats) 4 Ineffective or refused Considor an SSRI (with caroful monitoring) J ‘Muttidisciptinary review J ‘SSAl + ongoing CBT (including ERP}: Consider use in 8-11 year age group Offer to 12-18 year age group Carefully monitor for acverse events, especialy at tartof treatment t ther (especialy i previous goot Different SSRI Clomipramine Consid fesponse to) Figure 5.1 Treatment options for children and young people with OCD. CBT, cognitive behaviour therapy; ERP, exposure and response prevention; SSRI, selective serotonin re- uptake inhibitor. Adapted from NICE guidance® Reproduced from Heyman et al." with permission from BMJ Publishing Group Ltd. The summary treatment algorithm from the NICE guideline is shown in Figure 5.1. Cognitive behaviour therapy and medication in the treatment of childhood obsessive compulsive disorder Medication has occasionally been used as initial treatment where there is no availability of CBY or if the child is unable or unwilling to engage in CBT. Though medication should not bewithheld from the child who needs treatment for their OCD, parents and clinicians should be aware of NICE recommendations that all young people with OCD should be offered CBT: Medication may also be indicated in those whose capacity to access CBT. ited by learning disabilities, although every attempt should be made to modify CBT protocols for such children. ‘The only study that directly compares the efficacy of CBT, sertraline, and their combination, in children and adolescents concluded that children with OCD should begin treatment with CBT alone ot CBT plus an SSRI?aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.338 ‘The Maudsley Prescribing Guidelines in Psychiatry neurodevelopmental, medical and psychiatric disorders that may complicate the symptom profile, These include mental retardation, ADHD, epilepsy, anxiety, obsessive compulsive and mood disorders, sleep disturbance, self-harm, irritability and aggression towards others. Pharmacotherapies are commonly used in individuals with ASD asadjuncts to psychological interventions. There are now several published reports describing controlled and open-label, clinical trials. These are used to guide current clinical practice. The bulk of the evidence to date is for the efficacy of risperidone, methylphenidate and some selective reuptake in- hibitors in the treatment of problem behaviours in ASD. Preliminary controlled trials of sodium valproate, atomoxetine and aripiprazole are promising. ‘There is a potential role for a-2 agonists, cholinergic agents, glutamatergic agents and oxytocin and these require further investigation, Currently, there is no single medication for ASD thatalleviates symptoms inall three domains simultaneously. Targeting pharmacological interventions by identifying problem behaviours and the level of impairment these cause is essential. The efficacy and adverse effects associated with pharmacotherapy should be systematically monitored, bearing in ming that individuals with ASD often have impaired communicati Standardised behaviour ratings scales and adverse effect checklists are an essential tool in monitoring progress.! A very wide range of pharmacological interventions have been studied in autism (both allopathic and ‘alternative’) but few are well supported? Pharmacological treatment of core symptoms of autism spectrum disorders Restricted repetitive behaviours and interests domain ‘These are an important intervention target to improve overall outcomes in ASD. There is high demand for treatment of this distressing and disruptive core symptom domain. Serotonin reuptake inhibitors have become the most widely prescribed medication to treat restricted repetitive behaviours and interests (RBIs) in paediatric ASD populations. The evidence supporting the effectiveness of SSRIs in ameliorating these symptoms remains limited, with the bulk of reports being from single case studies and open-label trials, with only a few RCTS published to date. The SSRIs that have been studied include fluoxetine, fluvoxamine, sertraline, citalopram and escitalopram. While side-effects have generally been considered to be mild, increased activation and agitation occurred in some subjects. The current available literature reports inconsistent benefit from SSRIs and there remains uncertainty about the optimal dose regimen, which may be lower than those used for treatment of depression in typically developing individuals” The mean dose of fluoxetine has been approximately 10 mg per day, starting with 2.5 mg (see Box 5.4). A recent Cochrane review found ‘no evidence of effect of SSRIs in children and emerging evidence of harm’* Other potential pharmacological treatments include second-generation antipsychotics,’ an- ticonvulsants!” and the neuropeptide oxytocin.'! Research on risperidone indicates that it is effective in reducing repetitive behaviours in children who have high levels of irritability or aggression"? although reductions in core repetitive behaviours have been reported.*!*"*aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.346 The Maudsley Prescribing Guidelines in Psychiatry Adrenergic «-2 agonists Clonidine has been shown in open studies to reduce the severity and frequeney of ties but in one study this effect did not seem to be convincingly larger than placebo.” Other studies have shown more substantial reductions in tics.*!! Guanfacine (also an adrenergic a-2 agonist) has been shown to lead to a 30% reduction in tic rating scale scores.” In the UK, only clonidine is readily available. Therapeutic doses of clonidine are in the order of 3-5 g/kg, and the dose should be built up gradually. Main side-effects are sedation, postural hypotension and depression. Patients and their families should be informed not to stop clonidine suddenly because of the risk of rebound hypertension. Antipsychotics Adverse effects of antipsychotics may outweigh beneficial effects in the treatment of tics and so it is recommended that clonidine is tried first. Antipsychotics may, however, be more effective than clonidine in alleviating tics in some individuals. There have been few trials of atypical antipsychotics, but in practice these newer drugs are now more widely used than older medications such as haloperidol or pimozide. A 24-week, double-blind, placebo-controlled double cross-over study of 22 children and adolescents found pimozide (mean dose 3.4 mg/day) to be statistically superior to placebo in controlling ties." Outcome in the haloperidol arm of this study (mean dose 3.5 mg) was numerically superior to placebo but did not reach statistical significance. Although this study is widely quoted as being positive for pimozide and negative for haloperidol, the absolute difference in response between the two active treatment arms was small. A recent Cochrane review of pimozide has demonstrated robust efficacy in a meta- analysis of six trials.'* ECG monitoring is essential for pimozide and haloperidol. Haloperidol is often poorly tolerated. Risperidone has been shown to be more effective than placebo in a small (N = 34), ran- domised study.!5 Fatigue and increased appetite were problematic in the risperidone arm and a mean weight gain of 2.8 kg over 8 weeks was reported. Although there is a suggestion that risperidone!® and olanzapine'” may be more effective than pimozide, weight gain may be more pronounced in children and adolescents than in adults and this may limit the use of atypical antipsychotics in young people. One small randomised, controlled trial found risperidone and clonidine to be equally effective.'* Overall, metabolic side-effects and weight gain are common so benefit/risk ratios need careful discussi Sulpiride has been shown to be effective and relatively well tolerated," as has ziprasidone.” Open studies support the efficacy of quetiapine’! and olanzapine.” Case series suggest aripiprazole is effective and well tolerated”*"*® (also in tics”). One very small cross-over study (N= 7) found no effect for clozapine. Other drugs Asmall (N = 10), double-blind, placebo-controlled, cross-over trial of baclofen was suggestive of beneficial effects in overall impairment rather than a specific effect on tics.’® The numericalaa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.aa You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.350 The Maudsley Prescribing Guidelines in Psychiatry Side-effects Many of the children who have received melatonin in RCTs and published case series had developmental problems and/or sensory deficits. The scope for detecting subtle adverse effects in this population is limited. Screening for side-effects was not routine in all studies. Early reports included a very small case series where melatonin was reported to worsen seizures!” and exacerbate asthma"*''® in the short term. Other reported side-effects include headache, depression, restlessness, confusion, nausea, tachycardia and pruritus." In the largest placebo- controlled study to date (as yet unpublished), involving children with learning difficulty, autism and epilepsy, there were no adverse effects in the treatment groups in particular, seizures were not worsened. Dose ‘The cut-off point between physiological and pharmacological doses in children is less than 500 tig. Physiological doses of melatonin may result in very high receptor occupancy. The doses used in RCTs and published case series vary hugely, between 500 1g and 5 mg being the most common, although much lower and higher doses have been used. The optimal dose is unknown and there is no evidence to support a direct relationship between dose and response.!* Increasing doses above 5 mg is likely to involve the sedative effects of melatonin, rather than its sleep phase shifting properties. This might be necessary and helpful for some children with severe and bilateral brain injury. The use of salivary melatonin measurements is likely to become important in identifying those children with the most delayed sleep phase (likely to have the best response to exogenous melatonin) and those children who are slow metabolisers of melatonin in whom serum levels accumulate (particularly on higher doses). References Gringras?, When to use drags to help sleep. Arch Dis Child 2008;93:975-961 “Macchi MM tal, Heman pines physology and fnetinal ignifcance of melatonin. Pont Neuroendocrinol 2004; 2:177-195, [Arend | «al. Melatonin and its agoninte an update. Be Psychiatry 2005; 193:267- 268 Buscemi N etd. The effccy and sat of exogenous melatonin fr primary sleep disorder. A meta-analysh. J Gen Intern Med 2005; 5. BuscemiN et al Etficcy and say of exogenous melatonin fr secondary sleep dsoxters an sleep dsordem accompanying deep restriction meta-analysis. BM] 2006; 382:35-395, (6. Van der Heiden KB et al. fect of melatorin om alee, behavion and cognition ip ADHD and chronic deep-oneetincomnia. | Am head (Chil Adolesc Feychintry 20075 46233-241. 7. Wastell MB etal, A andomizes,placcho-cntrled tril of contoled relents melatonin treatment of delayed sleep phase syndrome and iis] Pineal Res 2008 4437-54, 4, Braamn W etal. Melatonin treatment in individuals with intellectual disability and chronic insomnit:aandemize placeho-contled study Jmpsired sleep maintenance in children with newodevelopmental tect Daal Res 2008, 5.256268 9. Gupta M et a. Add-on mdatonin improves seep bchevioe in chillen with epitepry: randomized, double-blind, placcho-contilled ta Child Neurol 2005; 20:12-115, 10, Coppola G etal. Melatonin in wakesteep disorders in children wdokicents and young aduks with mental rtadaton with or without epilepsy: double-blind coss-ve,placebe-contolle tral. Brain Dev 2004;26:373-37