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Graylands Hospital

DRUG BULLETIN

Pharmacy Department Brockway Road Mount Claremont WA 6010 Telephone (08) 9347 6400 Email [email protected] Fax (08) 9384 4586

Antipsychotic Monitoring

Graylands Hospital Drug Bulletin 2006 Vol. 14 No. 3 October ISSN 1323-1251

Introduction Evidence supporting what constitutes best practice in Table 1 lists suggested baseline monitoring for the monitoring of is lacking. patients starting on an drug and Monitoring patients receiving antipsychotics can be suggested ongoing monitoring. More frequent seen as having two overall goals; firstly, to identify monitoring may be indicated in certain situations; treatable pathology in a high-risk population and these are discussed under the relevant monitoring secondly, to link and track antipsychotic-induced parameter heading. adverse effects. Antipsychotics have been associated with causing a variety of cardiovascular, metabolic, Medical History hepatic, haematologic and endocrine diseases. Certain antipsychotics are contraindicated or must be used with caution in patients with other Physical health monitoring is the responsibility of the comorbidities5. Judicious selection of an patient, case manager, GP and psychiatrist. Mental antipsychotic is particularly important in patients health services should ensure that a monitoring with a history of: protocol is incorporated into the treatment plan of every patient. All monitoring protocols must include Severe cardiac, renal or hepatic disease a workable, effective call-up system and a process to Conditions that are risk factors for arrhythmia audit compliance. eg bradycardia, electrolyte imbalance

Table 1: Key Monitoring Recommendations1,2,3,4 Baseline and Early Treatment Monitoring Ongoing Monitoring

Baseline At 1-2 Monthly At 3 3-monthly 6-monthly 12-monthly weeks For 6 months months Medical history X Weight (BMI) X X X BSL X X X Fasting lipid profile X X X# X ECG X X* X* FBP X X U+E X X* LFT X X BP and pulse X X Key: BMI= Body mass index (kg/m2) ECG= Electrocardiograph U+E= Urea and electrolytes BSL= Blood sugar level (measure FBP= Full blood picture LFT= function test fasting venous glucose level) BP= Blood pressure * Suggested monitoring dependent on risk factors # For high-risk drugs for the first year, then annually There is additional, specific monitoring for ; refer to the clozapine monitoring section Graylands Hospital Drug Bulletin 2006 Vol 14 No.3 - 1 - Parkinson’s disease Aside from the recommended regular monitoring, BSL Diabetes should be measured at any time if weight loss, Closed angle glaucoma, increased intraocular polydipsia, polyuria or unexplained tiredness pressure, GI obstruction, prostatism, urinary occurs10. The following table outlines the diagnostic retention, myasthenia gravis criteria for diabetes. Epilepsy Bone marrow disorders or history of blood Blood Glucose Level10 dyscrasias Diabetes ≥7.0mmol/L (fasting) or Prolactin-dependent tumours ≥11.1mmol/L (random) Respiratory failure Must occur on two occasions, or once Phaeochromocytoma with diabetic symptoms Current pregnancy or lactation Impaired 5.5 –7.0 mmol/L (fasting) or

glucose 5.5 –11.0 mmol/L (random) Aside from a patient’s medical history, a tolerance (Diagnosis of diabetes if BSL ≥ 11.1 history including any drug allergies or adverse drug mmol/L at 2 hours following oral reactions should also be elicited. glucose tolerance test)

Body Mass Index Most antipsychotics can cause weight gain, although If diabetes is diagnosed, once daily antidiabetic medication should be used where possible, so that the greatest mean weight gain has been associated 11 with clozapine and olanzapine6. Of the atypical treatment can be more easily supervised . Metformin is considered the preferred first-line antipsychotics, and are 11 considered the lowest risk of causing weight gain2,7. antidiabetic agent . HbA1c should be measured every 3–6 months to monitor glycaemic control. Ideal BMI should be monitored monthly for the first six 1 months or at every visit on an outpatient basis1,3. glycaemic control is represented by an HbA1c < 7% . Patients should be encouraged to maintain a BMI between 18.5-25kg/m2. Antipsychotic treatment Electrocardiograph 2 should be reviewed if BMI>30kg/m or if there is >5% QTc prolongation and resultant arrhythmia including weight gain over baseline8. Prevention of weight has been associated with a gain should be the primary objective by encouraging number of antipsychotics. A baseline ECG is behavioural modification of diet and physical recommended for all patients at the commencement 1 activity. of antipsychotic therapy . If the baseline QTc interval is >450ms, should not be prescribed5; Lipid Profile other antipsychotics should be used with caution. Antipsychotics considered a high-risk of causing hyperlipidaemia include clozapine, , The ECG should be repeated 1-2 weeks after starting and the phenothiazines2. The National treatment and at 6-monthly intervals for patients Heart Foundation recommends the following target with risk factors for arrhythmia, patients receiving lipid levels: high-dose or high-risk antipsychotics or patients receiving multiple known to prolong the 1 Target Lipid Levels9 QTc interval . Antipsychotics generally accepted as LDL-cholesterol < 2.5 mmol/L having a higher risk of causing torsades de pointes include: , droperidol, , (<2.0mmol/L for high-risk patients) 12 Total cholesterol <4.0 mmol/L pimozide and thioridazine (see www.qtdrugs.org for HDL-cholesterol > 1.0 mmol/L a complete list). Triglycerides <1.5 mmol/L Additional ECG monitoring is also recommended

when there are dose changes for high-risk drugs, or if Please note that these recommendations may differ patients experience signs of arrhythmia including from PBS criteria for eligibility for lipid lowering shortness of breath, dizziness, loss of consciousness medications. Before lipid-lowering medications are or palpitations1. commenced, secondary causes of dyslipidaemia and modifiable cardiovascular risk factors should be 9 If the QT interval is prolonged to greater than managed . c 500ms, the causative drug should be stopped, and

the patient referred to a cardiologist1. Antipsychotic Blood Glucose Level therapy should be reviewed if the QTc interval There is an increased risk of developing diabetes with becomes prolonged by greater than 60ms over certain antipsychotics, particularly olanzapine, baseline or if there is abnormal T-wave morphology1. clozapine and the . Although there is Switching to a lower-risk antipsychotic should also be a correlation between diabetes and drug-induced considered if the QTc interval is greater than 440ms weight gain, diabetes can occur independently. (men) or greater than 470ms (women) 2.

Graylands Hospital Drug Bulletin 2006 Vol 14 No.3 - 2 - careful monitoring of serum sodium is recommended. Full Blood Picture 2 Haematological abnormalities are frequently Refer to specialist medical care if Na<125mmol/L . encountered with antipsychotic therapy; however, most of these are of little clinical significance. In a Liver Function Test small minority of patients, potentially life- A baseline LFT is required to determine any hepatic threatening haematologic abnormalities including impairment. Although LFTs are a poor marker of neutropenia and agranulocytosis occur. Aside from hepatic metabolising capacity, if elevated, a lower regular monitoring, the FBP should also be monitored starting dose of highly protein-bound, hepatically if a patient develops clinical signs of infection such metabolised antipsychotics should be considered2. If as fever, sore throat or flu-like symptoms. If the a patient has severe hepatic disease, avoid 9 neutrophil count is <1.5 X 10 /L, treatment should be hepatotoxic drugs such as clozapine and 1 stopped and haematologist advice sought . phenothiazines and monitor LFTs weekly, at least initially2. If LFTs deteriorate after a new drug is introduced, consider switching to another drug. Urea and Electrolytes Antipsychotics often cause asymptomatic increases in Baseline U+E monitoring is required to assess renal aminotransferase levels. Rarely, antipsychotics can function and to make any necessary dose cause hepatotoxicity or hepatocellular cholestasis. A adjustments. Electrolyte abnormalities, particularly LFT is indicated if a patient develops jaundice, hypokalaemia, hypomagnesaemia and hypocalcaemia pruritus, dark urine, pale stools, nausea or loss of can increase the risk of QTc prolongation and appetite. arrhythmia; these should be corrected before antipsychotic therapy is commenced2. Antipsychotics have been associated with hyponatraemia caused by Blood Pressure drug-induced syndrome of inappropriate antidiuretic Monitor both recumbent and standing blood pressure hormone. U+Es should be monitored if a patient and pulse at baseline and during dose titration for develops signs of hyponatraemia including confusion, antipsychotics with alpha1-adrenergic blocking nausea, headache and lethargy. If mild activity including clozapine, , quetiapine, hyponatraemia is detected, fluid restriction with chlorpromazine and thioridazine. Additional Monitoring

Prolactin Thyroid Function Test A prolactin level is indicated if a patient reports Changes in thyroid function may occur in patients signs and symptoms of hyperprolactinaemia such as taking quetiapine. A baseline thyroid function test sexual dysfunction, galactorrhoea, amenorrhoea or and follow up at one month may be advisable for gynaecomastia. If prolactin-related adverse patients at risk of hypothyroidism1. reactions are intolerable, consider reducing the dose of medication or switching to a prolactin-sparing 3 Clozapine Monitoring antipsychotic . For clozapine, monitoring of FBP is required weekly for the first 18 weeks of therapy and then monthly Creatine Kinase thereafter. Stop clozapine if neutrophils <1.5 X Monitor creatine kinase (CK) as well as FBP (for 109/L; total leukocyte count <3.0 X 109/L; or if leukocytosis) if a patient presents with fever, eosinophils >3.0 X 109/L13. rigidity and diaphoresis to rule out neuroleptic malignant syndrome. Raised CK (>1000IU/L) may The manufacturers of clozapine recommend indicate possible neuroleptic malignant syndrome2. monitoring baseline markers of myocardial damage using troponin I or T assay and serum creatinine as well as an ECG. The baseline cardiac enzymes and Electroencephalograph ECG should be repeated on days 7 and 14 of Most antipsychotics produce a dose related treatment to detect any early signs of acute reduction in seizure threshold. Monitor EEG if myocarditis. Stop clozapine if ECG shows significant myoclonus or seizures occur. If EEG changes occur, changes13. consider switching to a drug with a low proconvulsive effect or adding an anticonvulsant. After 6 months of treatment, it is advised that patients undergo echocardiography to test for the Eye Examination development of chronic cardiac adverse effects as Phenothiazines may induce cataracts or pigmentary well as to provide a baseline reading against which 13 retinopathy, which is dependent on both the dose future events may be measured . and duration of treatment. Ocular examinations More frequent haematological and cardiac should be performed annually or if changes in vision monitoring may be indicated in certain cases; refer are reported3. to the manufacturer published clozapine protocol. Graylands Hospital Drug Bulletin 2006 Vol 14 No.3 - 3 - Therapeutic Drug Monitoring (TDM) of Psychotropics

Table 2: Interpretation of Sample Results2,5,14,15,16 Drug Target Sampling Time to Comments Therapeutic Time Steady Range State Clozapine 350-600 µg/L Trough 2-3 days Plasma levels generally lower in males, younger patients and smokers. Lithium 0.5-1.2 mmol/L 12 hours 5 days Aim for the upper end in acute mania and lower end in post –dose maintenance therapy. Valproate 50-100 mg/L Trough 2-3 days Clinical value in bipolar disorder is controversial; dosing should be guided by clinical response and tolerability Carbamazepine 6-12 mg/L Trough 2 weeks Time to steady state depends on its auto-induction. Lamotrigine 1-14 mg/L Trough 5 days Recommended for compliance monitoring only Olanzapine 20-80 µg/L 12 hours 1 week Dosing should be guided by response and tolerability post –dose and TDM reserved for compliance monitoring and lack Risperidone + 20-60 µg/L Trough 1 day of response at maximum dosage. 9-0H risperidone Quetiapine 70-170 µg/L Trough 2 days Amisulpride 100-400 µg/L Trough 2-3 days

monitoring. Canadian journal of Psychiatry. 2005;50(9):555-562. TDM 5 eMims Online. Donahoo E, editor: Health Communication Network; 2006 TDM is a valuable tool when used appropriately for 6 Allison D, Mentore J, Heo M, Chandler L, Cappelleri J, Infante M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. optimising drug therapy in clinical psychiatry. Table American Journal of Psychiatry 1999;156:1686-1696. 2 outlines practical issues of TDM for a number of 7 Taylor D, McAskill R. Atypical antipsychotics and weight gain — a systematic review. Acta Psychiatrica Scandinavica. 2000;101:6 41. psychotropic drugs. 8 Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2):596-601. 9 National Heart Foundation of Australia and the Cardiac Society of Sampling Australia and New Zealand. Position statement on lipid management- 2005. Before sampling, steady state plasma concentrations [homepage on the internet] 2005. Available from: www.heartfoundation.com.au/downloads/Lipids_HLCPosStatementFINAL_2 should be reached in order to prevent 005.pdf. misinterpretation of drug concentrations. In 10 Lambert T, Chapman L (on behalf of the Consensus Working Group). Diabetes, psychotic disorders and antipsychotic therapy: a consensus practice, sampling for most psychotropic drugs is statement. MJA 2004; 181(10):544-548. carried out one week after chronic daily dosing 11 Proietto J. Diabetes and antipsychotic drugs. Australian Prescriber. 2004;27(5):118-119. either 12 hours post-dose or immediately before the 12 ArizonaCert Center for education and Research on Therapeutics. Drugs 14 next dose depending on the drug . In both cases, that prolong the qt Interval and/or induce torsades de pointes ventricular samples taken more than 1-2 hours before or after arrhythmia. Arizona: The university of Arizona [homepage on the internet] c2006 [updated June 15 2006]. Available from http://www.qtdrugs.org/. the scheduled time are likely to lead to falsely low 13 Clopine ConnectTM Protocol. Parkville, Victoria: Mayne Pharma Pty Ltd; or high readings15. 2006 Available from www.clopineconnect.com.au. 14 Micromedex® Healthcare Series [intranet database]. Version 5.1. Greenwood Village, Colo: Thomson Micromedex. 15 Baumann P, Hlemke C, Ulrich S, Eckermann G, Gaertner I, Kuss H et al. Interpretation of Results The AGNP-TDM expert group consensus guidelines: therapeutic drug If the drug concentration is within therapeutic monitoring in psychiatry. Pharmacopsychiatry. 2004;37:243-265. 16 PathWest Laboratory Medicine WA. Laboratory Reference Ranges. range, modification of dosage is recommended only November 2003. Available from http://www.pathwest.com.au/. when justified by clinical reasons such as adverse effects or lack of clinical response. When plasma concentrations are unusually low, a repeat level is Acknowledgement: recommended; this may help to determine irregular compliance, or presence of environmental or genetic Antipsychotic Monitoring was written by Karolinka Golebiewski factors leading to rapid metabolism of the particular and Therapeutic Drug Monitoring was written by Jung Kim. 14,15 drug . This bulletin was reviewed by members of the Pharmacy References: 1 Western Australian Psychotropic Drugs Committee. Antipsychotic drug Department and Dr Nathan Gibson. guidelines. Version 3. Western Australian Psychotropic Drugs Committee; 2006 Available from www.watag.org.au. 2 Taylor D, Paton C, Kerwin R. The Maudsley 2005-2006 prescribing guidelines. 8th ed. London: Taylor and Francis; 2005. Comments are welcome at the email address: 3 Marder S, Essock S, Miller A, Buchanan R, Casey D, Davis J et al. Physical health monitoring of patients with schizophrenia. American Journal of [email protected] Psychiatry. 2004;161(8):1334-1348. 4 Poulin M, Cortese L, Williams R, Wine N, McIntyre R. Atypical antipsychotics in psychiatric practice: practical implications for clinical Graylands Hospital Drug Bulletin 2006 Vol 14 No.3 - 4 -