06_Semple_Chap06.indd 203 12/7/2012 3:30:29 PM CHAPTER 6 Schizophrenia and related psychoses 204 Box 6.4 Other SGAs (not currently listed in BNF) Zotepine (Zoleptil ) Discontinued by Healthcare Logistics from the UK market from Jan 2011 for commercial reason s. \200 High af \201 nity for D receptors, 25 \200\223100mg tds Inhibits NE re-uptake Ef fective against positive and negative symptoms of schizophrenia but controlled trial data l imited EPSEs less than FGAs Increased risk of seizures at higher doses (above 300mg) Weight gain, sedation, constipation, asthenia, dry mouth, akathisia Raised hepatic enzymes 1 and D2 receptors, also 5-HT2, 5-HT6, and 5-HT7 \200 \200 \200 \200 Sertindole (Serdolect ) Voluntarily withdrawn by Lundbeck in Dec 1998 due to concerns abou t arrhythmias associated with increase in QTc. Limited reintroduction in Jun 2002 in Europe under strict monitoring for patients in clinical trials and who are intolerant of at least one other antipsychotic. D \200 \200 \200 \200 \200 \200 2, 5-HT2, and 1 antagonist with D2 limbic selectivity Effective against positive and negative symptoms of schizophrenia 12 \200\22320mg single da ily dose (max 24mg daily) EPSEs = placebo Increase in QTc \200\224needs ECG monitoring Othe r side-effects include: nasal congestion, decreased ejaculatory volume, postural hypotensio n and dry mouth and raised liver enzymes Approximate guide to course and prognosis at 13 years \200\231 follow-up:1 \200 \200 \200 \200 \200 Approximately 15 \200\22320% of \201 rst episodes will not recur. Few people will remain in employment. 52% are without psychotic symptoms in the last two years. 52% are without ne gative symptoms. 55% show good/fair social functioning Prognostic factors Poor prognostic factors \200 \200 \200 \200 \200 \200 poor premorbid adjustment insidious onset onset in childhood or adolescence cognitive impai rment enlarged ventricles symptoms ful \201 ll more restrictive criteria (e.g. DSM-IV) Good prognostic factors \200 marked mood disturbance, especially elation, during initial presentation family history of affective disorder female sex living in a developing country \200 \200 06_Semple_Chap06.indd 204 12/7/2012 3:30:29 PM This page intentionally left blank CHAPTER 6 Schizophrenia and related psychoses 206 Antipsychotic side-effects Tolerability No single antipsychotic is substantially better tol erated than another at daily doses of <12mg haloperidol or equivalent. However, FGAs pre- s cribed above this range are less well tolerated and probably also less effective than SGA d rugs (Box 6.5). The choice of antipsychotic therefore depends substantially on the pro \201 le of side-effects and which ones are more important to avoid. \200 Sedation Avoid chlorpromazine/promazine. Prescribe high-potency antipsychotics (e.g. halope ridol) or non-sedating SGA (risperidone, amisulpride). Weight gain haloperidol, \202 uphe nazine. EPSEs Postural hypotension amisulpride, tri \202 uoperazine. Avoid phenothiazines, olanzapine and clozapine. Prescribe \200 Avoid high-dose FGAs. Prescribe SGA. Avoid phenothiazines. Prescribe haloperidol, Extra-pyramidal side-effects (EPSEs) \200 Acute dystonia sternocleidomastoid and tongue, although can be widespread (e.g. opisthoclon us); eye muscle involvement (e.g. oculogyric crisis) may occur. Virtually always distressin g and preceded by increasing agitation. Treatment Parenteral antimuscarinic (e.g. procyclid ine 10mg intravenously [IV]) \200\224see b p. 954 for more detail. Parkinsonism after admin istration. Treatment Consider dose reduction/use of oral antimuscarinic (e.g. procyclidine 5mg three times daily [tds]) \200\224 see b p. 944 for more detail. Akathisia Occurs usuall y >1mth after initiation of antipsychotic drug. Treatment Propranolol and benzodiazepines m ay be helpful. Symptoms can be notoriously dif \201 cult to treat \200\224see b p. 946 for more detail. Tardive dyskinesia (TD) (i.e. athetosis) and sudden involuntary movements, ty pically of the oral \200\223lingual region (chorea). Symptoms of TD tend to be irreversible . Treatment1 Although a consequence of antipsychotic treatment, there is little evidence th at a reduction in the dose of antipsychotic improves symptoms in the short or long term. Vi tamin E may prevent deterioration but does not improve established symptoms \200\224see b p . 950. Contraction of muscle group to maximal limit, typically Tremor, rigidity, and bradykinesia occurring >1wk Restlessness, usually of lower limbs, and a drive to move. Continuous slow writhing movements Anticholinergic side-effects Dry mouth, blurred vision, dif \201 culty passing urine, urin ary retention, con- stipation, rarely: ileus, glaucoma. Anti-adrenergic side-effects Postural hypotension, tachycardia (sometimes bradycardia), sex ual dys- function (particularly erectile dysfunction \200\224see b p. 938). 06_Semple_Chap06.indd 206 12/7/2012 3:30:30 PM ANTIPSYCHOTIC SIDE-EFFECTS 207 Antihistaminic side-effects Sedation, weight gain (although precise mechanism unclear \200 \224see b p. 930). Idiosyncratic Cholestatic jaundice, altered glucose tolerance, hypersensitivity reac- tions , skin photosensitivity (sun block important in sunny weather), yellow pigmentation to skin (chlorpromazine), neuroleptic malignant syndrome (rigidity, \202 uctuating consciousness , and pyrexia) \200\224may be fatal, requires immediate transfer to general medical care an d usually ICU/anesthetic support/dantrolene may be helpful \200\224see b p. 956 for more de tail. Box 6.5 SGAs vs. FGAs? Recent effectiveness studies such as the Clinical Antipsychotic Trials of Intervention Effe ctiveness (CATIE),1 the Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Stu dy (CUtLASS),2 and the European First-Episode Schizophrenia Trial (EUFEST)3 have been inter - preted as showing no differences between FGAs and SGAs (with the possible exception of cl ozapine and perhaps olanzapine). Although this may be true in terms of overall effectivenes s, most clinicians (and patients) would agree there are many real differences among drugs, particularly when it comes to side-effects. Whilst guidelines from NICE or the BAP may prov ide helpful frameworks for rational prescribing, treatment ought to be individualized throu gh a shared decision-making process. Tolerability is a huge factor in adherence (see b p. 9 24) and it ought to be remembered that the best antipsychotic in the world will not work if the patient does not actually take it. 1 Lieberman JA, Stroup TS, McEvoy JP, et al. (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. NEJM 353: 1209 \200\2231223. 2 Jones PB, Barnes TRE, Davies L, et al. (2006) Randomized controlled trial of the effect on quality of life of sec ond- vs. \201 rst-generation antipsychotic drugs in schizophrenia: Cost Utility of the La test Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 63: 1079 \200\22387. 3 Kahn RS, Fleischhacker WW, Boter H, et al. (2008) Effectiveness of antipsycho tic drugs in \201 rst-episode schizophrenia and schizophreniform disorder: an open random ized clinical trial. Lancet 371: 1085 \200\22397. 1 Soares-Weiser KV and Joy C (2003) Miscellaneous treatments for neuroleptic-induced tardiv e dyskinesia. Cochrane Database Syst Rev 3: CD000208. 06_Semple_Chap06.indd 207 12/7/2012 3:30:30 PM CHAPTER 6 Schizophrenia and related psychoses 208 An approach to treatment-resistant schizophrenia (TRS) De \201 nition Treatment resistance is the failure to respond to two or more antipsy- chotic medications given in therapeutic doses for 6wks or more. Patients with refractory symptoms generally have more severe functi onal impair- ments and are more likely to have abnormalities of cerebral structure and neur opsychology. See Box 6.6 for guidelines. Prevalence Approximately 30% of patients respond poorly to antipsychotic medica- tion, and the number of people who show \200\230total non-response \200\231 is 77%. Etiology The etiology is uncertain. However, the following factors may be important: \200 Neurodevelopmental factors: soft signs, history of obstetric complications, cognitive impai rment. Drug non-compliance. Lack of adequate treatment: poor drug administration/absorption . However, over-treatment (>12mg haloperidol or equivalent) may also lead to poor tolerabil ity/response. Aggravating factors alcohol misuse, anticholinergic effects of anti-Parkinson ian medication or antidepressants. \200 despite adequate treatment: concurrent drug or Management \200 Clarify diagnosis re-inspected to ensure the correct diagnosis has been reached. Address co morbidity Comorbid substance misuse is common in schizophrenia and worsens outcome. Non-com pliance compliance therapy, or family therapy to improve compliance with prescribed medicat ion. Pharmacological interventions strongly supported by the evidence, and there is evidenc e that depot antipsychotic medication may convey a small advantage over an oral dose. Cloza pine resistance Switching from clozapine to a previously untried SGA (e.g. olanzapine, risp eridone, quetiapine) might be of bene \201 t in partial treatment resistance. In more dif \201 cult cases, augmentation of clozapine with benzamides (sulpiride, amisulpride) and an ti-epileptics (lamotrigine) shows some success1. Rehabilitation Consider the role of NHS /n on-NHS rehab facilities in maximizing function, maintaining quality of life, and supporting those who remain symptomatic despite treatment \200\224best evidence supports combination of medication with psychosocial treatments. The clinical history and presentation should always be Consider interventions such as psychoeducation, Clozapine is the intervention most 06_Semple_Chap06.indd 208 12/7/2012 3:30:30 PM AN APPROACH TO TREATMENT-RESISTANT SCHIZOPHRENIA 209 Box 6.6 Guidelines for the use of high-dose antipsychotics Where a patient has failed to respond to, or has only partially responded to, antipsychotic medication, some practitioners advocate high-dose prescribing. High-dose prescribing refer s either to the prescription of a single antipsychotic at doses greater than the BNF maximu m, or the prescription of two or more antipsychotics with a combined chlorpromazine equival ent dose of >1g daily (see the table on b p. 201). Although there may be a therapeutic resp onse to this approach in some individual patients there is no evidence that high-dose presc ribing confers any therapeutic advantage. The Royal College of Psychiatrists1 suggest the f ollowing guidelines for high-dose prescribing: \200 High-dose antipsychotic prescribing (>1g chlorpromazine or equivalent) should be avoided wh erever possible. Consider alternative approaches including adjuvant therapy and newer or SG A antipsychotics such as clozapine. Bear in mind risk factors, including obesity \200\224pa rticular caution is indicated in older patients, especially those over 70. Consider potenti al for drug interactions. Where patients receive one or more antipsychotics at high dose, r egular physical examination, ECG, LFTs, U&Es, FBC should be performed. Carry out ECG to exc lude abnormalities such as prolonged QT interval; repeat ECG periodically and reduce dose i f prolonged QT interval or other adverse abnormality develops. Increase dose slowly and not more often than weekly. Carry out regular pulse, blood pressure, and temperature checks; e nsure that patient maintains adequate \202 uid intake. Consider high-dose therapy to be f or a limited period and review regularly; abandon if no improvement after 3 months (return to standard dosage). A local protocol should exist for the purpose of informing good medica l practice. \200 \200 1 Royal College of Psychiatrists London, Council Report CR138 (May 2006) Consensus statemen t on high-dose antipsychotic medication. M http://www.rcpsych.ac.uk/ \201 les/pdfversion/ CR138.pdf 1 Kerwin, RW and Bolonna, A (2005) Management of clozapine-resistant schizophrenia. Adv Psy chiat Treat 11: 101 \200\2236 . 06_Semple_Chap06.indd 209 12/7/2012 3:30:30 PM CHAPTER 6 Schizophrenia and related psychoses 210 Clozapine 1: general guidelines Clozapine, an SGA antipsychotic, is a dibenzodiazepine deri vative. Shortly after its introduction to clinical practice in the mid-1970s it was withdra wn from use because of several episodes of fatal agranulocytosis in patients on treatment. It was thought to have special ef \201 cacy in treatment-resistant schizophrenia, and this clinical belief was supported by an important trial by Kane et al. (1988), leading to its reintroduction in psychiatric practice, albeit with strict limitations to its prescription. Patients on clozapine and doctors prescribing the drug must be registered with a central m onitoring agency and have regular, initially weekly, full blood counts with discontinu- ati on of the drug where there is evidence of neutropenia. Evidence from a Cochrane systematic review1 has shown clozapine to be more effective than F GA medication in the management of acute schiz- ophrenia (NNT 6) in both the short- and lon g-term and of even greater bene \201 t in those patients resistant to FGAs (NNT 5). Clozap ine is also more acceptable in long-term treatment than FGA antipsychotic drugs (usually ha loperidol or chlorpromazine: NNT 6). In the CATIE trial (McEvoy et al. 2006),2 clozapine was demonstrated to be superior in both treatment response (positive and negative symptoms) and compliance for patients who failed to improve on an SGA and who were randomized to receive either another SGA or clozapine. NICE guideline3 (CG82 Schizophrenia (update) Mar 2009) NICE recommends: \200\230Offer cloz apine to people with schizophrenia whose ill- ness has not responded adequately to treatmen t despite the sequential use of adequate doses of at least two different antipsychotic drug s. At least one of the drugs should be a non-clozapine second-generation antipsychotic. \200\231 Mode of action Clozapine mainly blocks D1 and D4 receptors; its effects on D2 receptors are relatively less than traditional FGAs. The lower af \201 nity of clozapine for D2 recepto rs may partially explain its lack of EPSEs and hyperprolactin- aemia. Clozapine does have s igni \201 cant anticholinergic, antihistaminergic, and anti-adrenergic activity, which acc ounts for its common side-effects (see p. 214). The superior ef \201 cacy of clozapine in treating resistant schizophrenic patients may be due to its additional blockade of 5HT2 receptors. Antipsychotic activity also may be due t o an increased turnover of GABA in the nucleus accumbens, which inhibits dopaminergic neuro ns. Pharmacokinetics Rapidly absorbed when taken orally (unaffected by food). Extensive \201 rst- pass metabolism means only 27 \200\22350% of a dose reaches the systemic cir- culation unchanged, with wide interindividual variations in the resulting plasma concentrations (in \202 uenced by factors such as smoking, hepatic metabolism, gastric absorption, age, and possibly gender). Steady-state plasma concentrations take 7 \200\22310 days of treatment. M ean terminal elimi- nation half-life ranges from 6 \200\22333hrs. Onset of antipsychotic ef fect may take several weeks, but maximal effects can require several months (and improvemen t may continue for up to 2yrs). 06_Semple_Chap06.indd 210 12/7/2012 3:30:30 PM CLOZAPINE 1: GENERAL GUIDELINES 211 Interactions (see Table 6.4 for summary) \200 Lithium can increase the risk of developing seizures, confusion, dyskinesia, and possibly n euroleptic malignant syndrome (NMS). May interfere with the action of AChEIs (e.g. donepezi l and tacrine). Smoking cigarettes increases the clearance of clozapine and may result in a substantial reduction in clozapine plasma concentrations. Plasma concentrations of clozapi ne are increased by caffeine (caffeinism is surprisingly common in this population), hence dose changes will be necessary when there is a change in caffeine-drinking habits. \200 Contraindications Previous/current neutropenia or other blood dyscrasias; previous myocar- ditis, pericarditis and cardiomyopathy; severe renal or cardiac disorders; active or progre ssive liver disease/hepatic failure. (See BNF for a complete list.) Table 6.4 Clozapine interactions Effect Examples Ethanol, H1-blockers, opiate agonists, anxiolytics, sedatives/hypnotics, tramadol, and TCAs Increased drowsiness, sedation, dizziness, and the possibility of respiratory depression Increased possibility of developing myelosuppressive effects Use of clozapine with other drugs known to cause bone marrow depression (e.g. chemotherapy agents) Drugs known to induce CYP1A2 activity may reduce ef \201 cacy Carbamazepine, phenobarbital, phenytoin, rifabutin, and rifampicin Drugs known to inhibit the activity of CYP1A2 may increase clozapine serum levels Cimetidine, clarithromycin, cipro \202 oxacin, diltiazem, enoxacin, erythromycin, or \202 uvoxamine Drugs known to inhibit the activity of CYP2D6 may increase clozapine serum levels Amiodarone, cimetidine, clomipramine, desipramine, \202 uoxetine, \202 uphenazine, halo peridol, paroxetine, quinidine, ritonavir, sertraline, and thioridazine Highly protein-bound drugs (may increase serum concentrations) Digoxin, heparin, phenytoin, or warfarin Worsening of anticholinergic effects H1-blockers; phenothiazines; TCAs; and other drugs with antimuscarinic properties Increased risk of hypotension Antihypertensive agents 1 Wahlbeck K, Cheine M and Essali MA (2003) Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev 3: CD000059. 2 McEvoy JP, Lieberman JA, Stro up TS, et al., and CATIE Investigators (2006) Effectiveness of cloza- pine versus olanzapin e, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond t o prior atypical antipsychotic treatment. Am J Psychiat 163: 600 \200\22310. 3 M http://gui dance.nice.org.uk/CG82/NICEGuidance/pdf/English. 06_Semple_Chap06.indd 211 12/7/2012 3:30:30 PM CHAPTER 6 Schizophrenia and related psychoses 212 Clozapine 2: starting and stopping Initiation of treatment and monitoring This is best done as either an inpatient or where appropriate facilities exist for monitoring (e.g. at a day -patient facility). All patients must be registered with a monitoring service (see Table 6. 5). A normal leukocyte (WBC > 3500/mm3, neutrophils > 2000/mm3) count must precede treat- m ent initiation. FBCs must be repeated (and sent to monitoring service) at weekly intervals for 18wks and then fortnightly until 1 year. Blood monitoring should continue monthly inde \201 nitely thereafter. If there are concerns about compliance, serum blood levels may als o be checked (see b p. 928 for reference range). Table 6.5 Clozapine monitoring services Brand (manufacturer) Formulation Monitoring Clozaril (Novartis) Clozaril Patient Monitoring Service (CPMS) Login: https://www.clozaril.co.uk/ T: 25mg (scored), 100mg Denzapine (Merz) T: 25mg (scored), 50mg, 100mg Denzapine Monitoring Service (DMS) Login: https://www.denzapine.co.uk/ S: 50mg/mL Support: http://www. denzapinesupport.co.uk/ T: 25mg (scored), 100mg Zaponex Treatment Access System (ZTAS) Login: http://www.ztas.co.uk/ Zaponex (TEVA UK) Key: T=tablets; S=suspension Dose (see Table 6.6) \200 Starting regime: 12.5mg once or twice on \201 rst day, then 25 \200\22350mg on second day , then increased gradually (if well tolerated) in steps of 25 \200\22350mg daily over 14 \200\22321 days up to 300mg daily in divided doses (larger dose at night; up to 200mg daily may be taken as a single dose at bedtime). May be further increased in steps of 50 \200 \223100mg once or twice weekly. Usual dose 200 \200\223450mg daily (max 900mg daily). Note \200 \200 : increase in seizure frequency occurs above 600mg/day. \200\230Traf \201 c light \200\231 noti \201 cation Telephone (urgent action) \200 No sample received local hematology laboratory so that the next supply of medication may be dispensed. Sample non-suitable for analysis Abnormal hematological results the blood count or STOP clozapine with advice regarding further monitoring (i.e. Red light situation \200 \224see Written reports, b p. 213). Send another sample to CPMS/DMS/ZTAS and the \200 As for \200\230no sample received \200\231. (e.g. neutrophil count). Either repeat 06_Semple_Chap06.indd 212 12/7/2012 3:30:30 PM CLOZAPINE 2: STARTING AND STOPPING 213 Written reports \200 Normal \200\224clozapine may be administered to the patient. Green l ight \200 Amber light Caution \200\224further sampling advised. If either WCC falls to 30 00 \200\2233500/mm3 or the absolute neutrophil count falls to 1500 \200\2232000/ mm3, blood monitoring must be performed at least twice weekly until the WCC and absolute neutrophil c ount stabilize within the range 3000 \200\2233500/mm3 and 1500 \200\2232000/mm3, respective ly, or higher. STOP clozapine immediately. If the WCC < 3000/mm3 or Red light the absolute neutrophil count < 1500/mm3, discontinue treatment with clozapine. Take blood samples daily until abnormality is resolved. Seek specialist advice from a hematologist. Monitor patient s closely for symptoms suggestive of infection. Do not administer other antipsychotic drugs . Discontinuation Abrupt discontinuation of clozapine is not recommended, unless required by the patient \200\231s medical condition (e.g. leukopenia). Gradually discontinue over 1 \200\2232wks (like the initiation schedule in reverse). Patients should be carefully observ ed for the recurrence of psychotic symptoms during drug discontinuation. Symptoms related t o cholinergic rebound, such as pro- fuse sweating, headache, nausea, vomiting, and diarrhea may also occur. Table 6.6 Clozapine dosing guidelines Day Morning dose (mg) Night-time dose (mg) 1 \200\223 12.5 25 25 25 25 50 50 75 75 100 100 125 125 150 150 200 12.5 12.5 25 25 50 50 50 75 75 100 100 125 125 150 150 200 200 2 3 4 5 6 7 8 9 10 11 12 13 14 15 18 21 200 250 28 Note: Gradually increase by 50 \200\223100 mg/week (max dose should not exceed 900 mg/day). Routine blood level monitoring is not recommended; however, increasing dose until a plasma level of 350mcg/L is achieved is sometimes recommended. If adverse effects are noted, redu ce dose until side-effects settle, then increase again more slowly. Lower doses may be requ ired for elderly, female, or non-smoking patients, and if the patient is on other medicatio n that may affect the metabolism of clozapine. Where there has been a break in treatment of more than 48 hr, treatment should be re-initiated with 12.5mg once or twice on the \201 rst day, and re-escalated. 06_Semple_Chap06.indd 213 12/7/2012 3:30:30 PM CHAPTER 6 Schizophrenia and related psychoses 214 Clozapine 3: side-effects (See Table 6.7 for management) Common side-effects \200 Anticholinergic urine. Anti-adrenergic Other fatigue, hypersalivation, tachycardia, hyperte nsion, drowsiness, dizziness. Constipation, dry mouth, blurred vision, dif \201 culty passing \200 Hypotension, sexual dysfunction. Sedation, weight gain, nausea, vomiting, ECG changes, headache, Less common \200 Fainting spells. \200 Gastric discomfort. \200 Small involuntary mus cle contractions. \200 Periodic catalepsy (reduced responsiveness and prolonged lack of m ovement). Enuresis. Rarer or potentially life-threatening \200 Impaired temperature regulation, fever, hepatitis, cholestatic jaundice, pancreatitis. Agra nulocytosis: fatal agranulocytosis1 is estimated to be 1:4250 patients treated.) Thrombocyt openia (discontinuation of clozapine is recommended if platelet count falls below 50 000/mm 3). Dysphagia. Circulatory collapse, arrhythmias, myocarditis, cardiomyopathy, pericarditis , pericardial effusion, thromboembolism. Discontinue if persistent tachycardia occurs in th e \201 rst 2mths of treatment. Note: The risk of fatal myocarditis or cardiomyopathy is e stimated to be up to 1:1300 patients treated, although there is wide variation in data (e.g . USA \200\2241:67 000 patients treated). Pulmonary embolism ( estimated to be 1:4500 patie nts treated.) Confusion, delirium, restlessness, agitation. Diabetes mellitus, hypertriglyc eridaemia, intestinal obstruction, paralytic ileus, enlarged parotid gland, fulminant hepat ic necrosis. Interstitial nephritis, priapism, skin reactions. Neuroleptic malignant syndro me. leukopenia, eosinophilia, leukocytosis. (Note: the risk of \200 Note: The risk of fatal pulmonary embolism is \200 \200 Of note: clozapine actually reduces mortality in schizophrenia, mainly due to a lower risk of suicide. 06_Semple_Chap06.indd 214 12/7/2012 3:30:30 PM CLOZAPINE 3: SIDE-EFFECTS 215 Table 6.7 Dealing with clozapine side-effects Problem Possible solution Constipation Encourage high- \201 bre diet, adequate \202 uid intake, use of aperients if persistent Fever Symptomatic relief, check FBC and look for sources of infection Hypersalivation Consider use of hyoscine hydrobromide (up to 300 micrograms tds) Hypertension Monitor closely, slow rate or halt dose increase, if persistent consider use of hypotensive agent (e.g. atenolol) Hypotension Advise caution when getting up quickly, monitor closely, slow or halt dose increase Nausea Consider use of anti-emetic (avoid metoclopramide and prochlorperazine if previous problems with EPSEs) Neutropenia/ agranulocytosis Stop clozapine, if outpatient admit to hospital Nocturnal enuresis Avoid \202 uids in the evening, alter dose scheduling, if severe consider use of desmopre ssin Sedation Reschedule dosing to give smaller morning or total dose Seizures Withhold clozapine for 24 hr, recommence at lower dose, consider prophylactic anticonvulsan t (e.g. valproate) Weight gain Dietary and exercise counseling (see b p. 930) 1 A report of data from the Clozaril National Registry revealed that agranulocytosis occu rred in 400 (0.6%) of 67 600 patients during the period of 1990 \200\22395. 12 of these 400 patients died; 340 of these 400 developed agranulocytosis in the \201 rst 6mths of thera py. The incidence rate of 0.6% is similar to earlier data published in 1993. The risk of de veloping agranulocytosis increased with age and was higher in women. 06_Semple_Chap06.indd 215 12/7/2012 3:30:31 PM CHAPTER 6 Schizophrenia and related psychoses 216 Antipsychotic depot injections Antipsychotics may be given as a long-acting depot injection (the active drug in an oily suspension) injected into a large muscle (usually gluteus maxi mus), allowing for sustained release over 1 \200\2234wks. Previously, only FGAs were availa ble, but now a number of SGA preparations have been developed and are \201 nding their pl ace in clinical practice. Dose for dose, the ef \201 cacy of these preparations is not gre ater than oral medication, but they do increase likelihood of compliance. Indications Poor compliance with oral treatment, failure to respond to oral medication, memory problems or o ther factors interfering with ability to take medication regularly, clinical need to ensure patient compliance (e.g. due to treatment order for patients detained on MHA). Administrat ion (see Table 6.8 Dosing schedules, and dose equivalents b p. 201) Test dose: as undesirab le side-effects can be prolonged. Not more than 2 \200\2233mL of oily injection should be a dministered at any one site. Correct injection technique (including the use of z-track tech nique) and rotation of injection sites are essential. If the dose needs to be reduced to al leviate side-effects, remember plasma-drug concentration may not fall for some time after r educing the dose and it may be many weeks before side-effects subside. Speci \201 c side-e ffects Pain/swelling at injection site, rarely abscesses, nerve palsies. Side-effects as fo r oral medication but may take 2 \200\2233 days to emerge and persist for weeks after disco ntinuation. May be more likely to cause EPSEs than oral preparations (good evidence is lack ing). 1Post-injection syndrome Depot olanzapine pamoate carries an unpredictable risk (1.4% of patients or 1:1500 injections) of idiosyncratic excessive sedative akin to olanzapine o verdose between 1 \200\2236hrs post- injection. It is recommended that after injection the patient should be observed for at least 3hrs for any signs of this syndrome (e.g. sedation, acute confusion/aggression, EPSEs, dysarthria/ataxia, or seizure, see Box 6.7). Box 6.7 Depot dosing Olanzapine \200 Olanzapine 10mg/day (oral): start 210mg/2 weeks or 405mg/4 weeks, maintenance after 2 month s treatment, 150 mg/2 weeks or 300 mg/4 weeks. Olanzapine 15mg/day (oral): start 300mg/2 we eks, maintenance after 2 months, 210mg every 2 weeks or 405mg every 4 weeks. Olanzapine 20m g/day (oral): start 300mg/2 weeks, maintenance after 2mths, 300mg/2 weeks. Adjust dose acco rding to response; max 300mg every 2 weeks. Risperidone depot dosing \200 \200 \200 Risperidone up to 4mg/day (oral), start 25mg/2 weeks. Over 4mg/day risperidone (oral), star t 37.5mg/2 weeks. Dose adjusted at intervals of at least 4 weeks in steps of 12.5mg to max 50mg/2 weeks. During initiation oral risperidone should be continued for 4 \200\2236 weeks; oral dosing may also be used during dose adjustment of depot. 06_Semple_Chap06.indd 216 12/7/2012 3:30:31 PM 0 6 _ S e m p l e _ C h a p 0 6 . i n d d Table 6.8 Dosing schedules for depot antipsychotics 2 1 7 Generic name Brand name t Peak dose Time to Test dose Test to Starting dose Dose interval Max. dose steady state treatment interval Depixol Flupentixol decanoate 8d (sd); 17d (md) 3 \200\2237d 10 \200\22312wks 20mg 7d 20 \200\22340mg 2 \200\2234wks 400mg/wk Modecate Fluphenazine decanoate 6 \200\22310d (sd); 14 \200\223100d (md) 6 \200\22348h 6 \200\22312wks 12.5mg 4 \200\2237d 12.5 \200\223 100mg 14 \200\22335d A N T Haldol Haloperidol decanoate 18 \200\22321d 3 \200\2239d 10 \200\22312wks 50mg 4wks 50mg 4wks 300mg/4wks I P S Y C H O T C See b p. 216. For patients taking oral olanzapine; risk of post- injection syndrome. ZypAdhera Olanzapine pamoate 23 \200\22342d 2 \200\2234d 12wks Xeplion Paliperidone 25 \200\22349d 13d 10 \200\22316wks 150mg 8d 100mg 4wks 150mg/4wks I Piportil Pipotiazine palmitate 14 \200\22321d 9 \200\22310d 8 \200\22312wks 25mg 4 \200\2237d 25 \200\22350mg 4wks 200mg/4wks D E P O T See b p. 216. Release of drug starts 3wks after injection and subsides by 7wk. Risperidone Risperdal Consta 3 \200\2236d 4 \200\2236wks 6 \200\2238wks I N E C T O N S Clopixol Zuclopenthixol decanoate 17 \200\22321d 4 \200\2239d 10 \200\22312wks 100mg 7d 200 \200\223500mg 1 \200\2234wks 600mg/wk J I t = elimination half-life; d = days; h(s) = hour(s); wk(s) = week(s); sd=single dose; md= multiple dose; supp = supplementation 1 2 / 7 2 1 7 / 2 0 1 2 3 : 3 0 : 3 1 P M CHAPTER 6 Schizophrenia and related psychoses 218 Disorders related to schizophrenia Both ICD-10 and DSM-IV describe a number of disorders wh ich show signi \201 cant symptomatic overlap with schizophrenia. It is currently unclear w hether these disorders represent distinct disorders, or (as seems more likely) they share s ome degree of common etiology with schizophrenia. Schizoaffective disorder This disorder has features of both affective disorder and schizoph renia which are present in approximately equal proportion. Its nosological status is uncert ain since some believe it to be a variant of schizophre- nia; others, bipolar disorder; and some believe it represents a point on a continuum of \200\230unitary psychosis \200\231 l ying between schizophrenia and mood disorders.1 Lifetime prevalence is 0.5 \200\2230.8% wit h limited data available on gender and age differences. ICD-10 criteria \200 Schizophrenic and affective symptoms simultaneously present and both are equally prominent. Excludes patients with separate episodes of schizophrenia and affective disorders and when episodes are in the context of substance use or other medical disorder. DSM-IV criteria \200 Major depressive, manic, or mixed episode concurrent with symptoms that meet criterion A fo r schizophrenia. \211 \200 2wks of delusions and/or hallucinations without prominent mood symptoms. Symptoms meeting criteria for a mood episode are present for a substantial portio n of the active and residual periods. The disturbance is not due to the direct physiologica l effects of a drug of abuse or medication or a general medical condition. Treatment As for schizophrenia but treat manic or depressive symptoms as outlined in bipola r disorder (see b pp. 326 \200\22331). Prognosis Depressive symptoms are more likely to sig nal a chronic course com- pared to manic presentations. Good/poor prognostic factors are th e same as for schizophrenia. Overall, prognosis is better than schizophrenia (as there is u sually a non-deteriorating course) and worse than primary mood disorder. Schizotypal disorder Schizotypal disorder is classi \201 ed along with schizophrenia and r elated dis- orders in ICD-10, but along with cluster A/ \200\230odd-eccentric \200\231 pers onality dis- orders in DSM-IV. It shares some of the clinical features of schizophrenia, bu t not the delusions or hallucinations. It is seen in approximately 3% of the general popula tion and approximately 4.1% of psychiatric inpatients. The disorder tends to run a stable c ourse. It is currently viewed as representing \200\230partial expression \200\231 of the schiz- o phrenia phenotype \200\224although the underlying mechanism for this is 06_Semple_Chap06.indd 218 12/7/2012 3:30:31 PM DISORDERS RELATED TO SCHIZOPHRENIA 219 unclear. Evidence for this view includes the fact that monozygotic (MZ) twin studies have s hown an increased risk of schizotypy in the unaffected relative, that schizotypy is more co mmon in the other \201 rst-degree rela- tives of schizophrenic subjects than in the gener al population, and that relatives of schizotypal subjects have an increased risk of schizop hrenia. Symptoms (DSM-IV criteria) Ideas of reference. Excessive social anxiety. Odd beliefs or mag ical think- ing. Unusual perceptions (e.g. illusions). Odd/eccentric behavior or appearance . No close friends/con \201 dants. Odd speech. Inappropriate or constricted affect. Suspic iousness or paranoid ideas. Differential diagnosis Autism, Asperger syndrome, expressive/mixed receptive \200\223expres sive lan- guage disorder, chronic substance misuse, other personality disorders (especially borderline, schizoid, and paranoid). Treatment Risperidone ( \211 2mg/day)2 has some support from an RCT. Other antip- sychotics may also be helpful. There is little evidence in support of other interventions but highly structured supportive CBT may be best. Schizophreniform disorder (Included under \200\230other schizophrenia \200\231 in ICD-10) The original term referred to patients with schizophrenic symptoms with a good prognosis3 a nd now refers to a schizophrenia-like psychosis that fails to ful \201 l duration criterio n for schizophrenia in DSM-IV. The treatment is the same as for an acute episode of schizop hrenia. It is most common in adolescence and young adults and is much less common than schi zophre- nia with a lifetime prevalence of 0.2%. DSM-IV \200 \200 Criteria A, D, and E of schizophrenia are met. An episode of the disorder (including prodro mal, active, and residual phases) lasts at least 1mth but less than 6mths. Speci \201 ed a s with good prognostic features (as evidenced by 2+ of: onset of prominent psychotic sympto ms within 4wks of the \201 rst noticeable change in usual behavior or functioning; confus ion or perplexity at the height of the psychotic episode; good premorbid social and occupat ional functioning; no evidence of premorbid personality disorder; absence of blunted or \202 at affect). Course and prognosis Psychosis lasting for more than 1mth but less than 6mths. Patients ret urn to baseline functioning once the disorder has resolved. Progression to schizophrenia is estimated to be between 60 \200\22380%. Some patients have 2 or 3 recurrent episodes. Treatment Antipsychotics a mood stabilizer and psychotherapy. 1 Mellor C (2007) Schizoaffective, paranoid and other psychoses. In: Stein G and Wilkinson G, eds, Seminars in general adult psychiatry, 2nd rev edn, pp. 187 \200\223201. London: Rcp ssych Publications. 2 Koenigsberg HW, Reynolds D, Goodman M, et al. (2003) Risperidone in t he treatment of schizo- typal personality disorder. J Clin Psychiat 64: 628 \200\22334. 3 L angfeldt G (1982) De \201 nition of \200\230schizophreniform psychoses \200\231. Am J Psy chol 139: 703. 06_Semple_Chap06.indd 219 12/7/2012 3:30:31 PM CHAPTER 6 Schizophrenia and related psychoses 220 Delusional disorder 1: clinical features Essence Delusional disorder is an uncommon conditi on in which patients present with circumscribed symptoms of non-bizarre delusions, but with absence of prominent hallucinations and no thought disorder, mood disor- der, or signi \201 cant \202 attening of affect. Symptoms should have been present for at least 1mth (D SM-IV). ICD-10 speci \201 es at least 3mths for delusional disorder but, if it is less tha n this, allows diagnosis under other persistent delusional disorder. DSM-IV speci \201 es particular subtypes (see Box 6.8). Points to note \200 Patients rarely present directly to psychiatrists. More often they may be seen by other phy sicians due to somatic complaints, lawyers due to paranoid ideas, or the police when they a ct on or complain about their delusions. Careful assessment and diagnosis is vital, because delusions are the \201 nal common pathway of many illnesses (see b p. 222). When delusio nal disorder is discovered, treatment can be fraught with dif \201 culty because of the re ticent nature of such patients. With persistence, a combination of biopsychosocial treatmen ts can be effective. Diagnosing pathological delusions \200\224key points1 Clinical judgment is necessary to dis tinguish delusions from over-valued ideas, particularly when the ideas expressed are not ne cessarily bizarre or culturally abnormal (and may actually have some basis in reality). Suc h judgements may be informed by: \200 The degree of plausibility. \200 Evidence of syst emization, complexity, and persistence. \200 The impact of the beliefs on behavior. \200 Allowing for the possibility that they might be culturally sanctioned beliefs different f rom one \200\231s own. Observation of associated characteristics, including hallucinations. History of \200\230morbid change \200\231. Evidence of other risk factors (see \200 \200 Risk factors, b p. 221).