Physical Effects of Antipsychotics

Transcription

1 Physical Effects of Antipsychotics C L A U D I N E L A N G - H O D G E P H A R M D, B C P P C L I N I C A L P H A R M A C I S T A L B E R T A C H I L D R E N S H O S P I T A L S E P T 1 0, C L A U D I N E. L A N G - H O D G A H S. C A

2 Disclosures I have no current or past relationships with commercial entities Speaking Fees for current program: I have received a complimentary registration for today s conference

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5 Objectives Review of antipsychotic pharmacology/uses Discuss metabolic side effects of APs Discuss movement side effects of APs Highlight emergency reactions to APs Determine monitoring/treatment for side effects

6 Antipsychotics: 1 st Generation Also known as Typical Antipsychotics Introduced between Haldol (haloperidol) Loxapac (loxapine) Clopixol (zuclopenthixol) Orap (pimozide) Fluanxol (flupenthixol decanoate) Modecate (fluphenazine decanoate) Piportil (pipotiazine palmitate) Largactil (chlorpromazine) Nozinan (methotrimeprazine)

7 Antipsychotics: 2 nd Generation Also called Atypical Antipsychotics Newer, only available since Clozaril (clozapine) - Riperdal (risperidone) - Zyprexa (olanzapine) - Seroquel (quetiapine) - Invega (paliperidone) - Zeldox (ziprasidone) - Saphris (asenapine) - Latuda (lurasidone) 3 rd generation - Abilify (aripiprazole)

8 (NIMH) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) To the extent that antipsychotics differ, it is more in their side effects than therapeutic effects. LIEBERM, J.A, STROUP, T..S.; Commentary :Am J Psychiatry 168:8, August 2011

9 Schizophrenia Schizoaffective d/o Bipolar mania Depression Acute agitation/aggression Sleep Anxiety Dementia Eating disorders Tics Antipsychotic Uses

10 Neurotransmitter Pathways Review

11 Dopamine Hypothesis of Schizophrenia Schizophr Bull, image, viewed May2016 <

12 Medication Overview: Antipsychotics Excessive dopamine in specific areas of the brain causes psychoses Antipsychotics: block various dopamine receptors in the brain Attempt to regulate: Positive symptoms Negative symptoms Mood

13 Mechanism of Action of Antipsychotics Exact mechanisms of action are unknown The primary actions have been attributed to D2 dopamine blocking 3 rd generation (aripiprazole) acts as partial agonist The different actions at the neurotransmitters account for the different efficacy and side effect profiles

14 Aripiprazole: 3 rd Generation AP: Partial Agonist Third generation antipsychotic drugs: partial agonism or receptor functional selectivity?; image, viewed May 2016 <

15 Pharmacological Effects of APs on Neurotransmitters/Receptors Dopamine Blockade D2 in mesolimbic =antipsychotic effect (controlling positive symptoms of schizophrenia) in nigrostriatal tract=eps and TD in tuberoinfundibular area= prolactin elevation Histamine Blockade Sedation, drowsiness, hypotension, weight gain, antiemetic Acetylcholine Blockade Dry mouth, blurred vision, constipation, urinary retention, anticholinergic delirium Serotonin Blockade May decrease negative symptoms of schizophrenia, anxiolytic, antidepressant, modulate EPS, hypotension, sedation, weight gain Alpha Blockade Hypotension, reflex tachycardia, sedation, hypersalivation, sexual disturbance

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17 Lieberman, Jeffrey Effectiveness of Antipsychotic Drugs in Patients With Chronic Schizophrenia: Efficacy and Safety Outcomes of the CATIE Trial, image, viewed May 2016 <

18 Organ Systems Affected by Antipsychotics Endocrine system Central nervous system CNS Effects EPS Neuroleptic Malignant Syndrome Seizures Cardiovascular system Hepatic system Dermatologic system Hematologic system Genitourinary system

19 Organ Systems Affected by Antipsychotics Endocrine system Central nervous system CNS Effects EPS Neuroleptic Malignant Syndrome Seizures Cardiovascular system Hepatic system Dermatologic system Hematologic system Genitourinary system

20 Endocrine System Effects Metabolic Effects Prolactin Effects

21 Metabolic Effects of APs Weight gain Increased blood pressure Increased lipids Increased total cholesterol Increased LDL Increased triglycerides Decreased HDL Increased fasting glucose Increased risk for insulin resistance, type 2 DM Increased prolactin

22 Monitoring for Metabolic Effects Baseline monitoring: before start of medication or as soon as possible This includes Personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease Weight and height (so that BMI can be calculated) Waist circumference (at the level of the umbilicus) Blood pressure Fasting plasma glucose Fasting lipid profile +/- Prolactin level (depending on medication)

23 Follow up Monitoring Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Every 5 years Personal/ Family History X X Weight (BMI) X X X X X Waist Circumference X X Blood Pressure Fasting Plasma Glucose X X X X X X Fasting Lipid Profile X X X

24 Pediatric/Adolescent Metabolic Monitoring CAMESA Guidelines Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children CAMESA is led by Dr. Tamara Pringsheim, neurologist and clinical epidemiologist at the University of Calgary

25 Metabolic Monitoring Form Example: Risperidone

26 Parameter Pre-Treatment Baseline 1 Month 2 Month 3 Month 6 Month 9 Month 12 Month General Information: Assessment Date (YYYY/MM/DD): Patient Age at Assessment: Daily Dose of risperidone: mg mg mg mg mg mg mg Physical Examination Maneuvers: Height (cm) Height percentile 1 Round to nearest 5, 10, 25, 50, 75, 90, or 95 %ile Weight (kg) Weight percentile 1 Round to nearest 5, 10, 25, 50, 75, 90, or 95 %ile BMI (kg/m 2 ) 1 #DIV/0! #DIV/0! #DIV/0! #DIV/0! #DIV/0! #DIV/0! #DIV/0! BMI percentile 1 Use CDC calculator to calculate value 1 Waist Circumference (at level of umbilicus) (cm) Waist Circumference percentile 2 Systolic Blood Pressure (mm Hg) >90, or round to nearest 10, 25, 50, 75, or 90 %ile Systolic Blood Pressure percentile 3 Provide range (<50, 50-90, 90-95, 95-99, or 99) Diastolic Blood Pressure (mm Hg) Diastolic Blood Pressure percentile 3 Provide range (<50, 50-90, 90-95, 95-99, or 99) Neurological Examination: Neurological Exam completed? 4 Neurological Exam Normal or Abnormal? Laboratory Evaluations: Test Normal Values Fasting Plasma Glucose mmol/l 5 5 5,8 5,7 Fasting Insulin 6, pmol/l 6 6 6,8 6, 7 Fasting Total Cholesterol 7, 8 < 5.2 mmol/l 8 7 Fasting LDL-C 7, 8 < 3.35 mmol/l 8 7 Fasting HDL-C 7, mmol/l 8 7 Fasting Triglycerides 7, 8 < 1.5 mmol/l 8 7 AST ALT Prolactin 9, Amylase Other (e.g. A1C, OGTT, etc.); Please List

27 Prolactin Effects D2 blockade in tuberoinfundibular area in brain risp=pali>fga>olanz>zipr>quet cloz>arip In women can lead to: galactorrhea, amenorrhea, irregular menses, anovulation, osteoporosis In men: impotence and azoospermia, and gynecomastia with or without lactation

28 Prolactin Elevation If asymptomatic, typically watch and wait No intervention If symptomatic, preferred treatment is to switch to another antipsychotic agent with reduced riskcaution with relapse potential Other options: Add aripiprazole D2 partial agonist Add other dopamine agonists: bromocriptine, cabergoline

29 Organ Systems Affected by Antipsychotics Endocrine system Central nervous system CNS Effects EPS Neuroleptic Malignant Syndrome Seizures Cardiovascular system Hepatic system Dermatologic system Hematologic system Genitourinary system

30 CNS Effects of Antipsychotics CNS Effects Drowsiness, sedation Insomnia, agitation Movement Disorders Extrapyramidal symptoms Neuroleptic Malignant Syndrome (NMS) Seizures All APs lower the seizure threshold, use with caution in patients with seizure disorder (typically dose related) Higher risk with chlorpromazine and clozapine

31 CNS Effects of Antipsychotics CNS Effects Drowsiness, sedation Insomnia, agitation Movement Disorders Extrapyramidal symptoms Neuroleptic Malignant Syndrome (NMS) Seizures All APs lower the seizure threshold, use with caution in patients with seizure disorder (typically dose related) Higher risk with chlorpromazine and clozapine

32 Movement Disorders Associated with Antipsychotics (EPS) D2 Blockade in nigrostriatal tract leads to extrapyramidal symptoms

33 Extrapyramidal Symptoms (EPS) Drug induced movement disorders that include acute and tardive symptoms Dystonia continuous spasms and muscle contractions Akathisia state of excessive restlessness Pseudoparkinsonism rigidity, bradykinesia, tremor Tardive dyskinesia abnormal involuntary movement The Extrapyramidal Symptom Rating Scale (ESRS) to assess four types of drug-induced movement disorders FGA> risp=pali>olan=zipr=arip>quet>cloz Chouinard, G, Margolese HC: Manual for the Extrapyramidal Symptom Rating Scale (ESRS); Schizophr Res,2005 Jul 15;76(2-3): Epub 2005 Apr 18

34 Extrapyramidal Symptoms (EPS)- Dystonia Dystonia (10-30%) Rapid onset 1 or 4 days of start or increase of antipsychotics Prolonged muscle spasms / contractions - Oculogyric crisis rotating of eyeballs - Opisthotonus- tension in neck, spine, arching - Tongue spasms or protrusion - Torticollis twisted neck - Trismus-unable to open mouth (forced jaw opening) - Pharyngeal-laryngeal spasm

35 Extrapyramidal Symptoms (EPS)-Dystonia Treatment/ Recommendation for Acute Dystonia Anticholinergics: - Benztropine (PO,IM,IV) - Procyclidine (PO) - Trihexyphenidyl (PO) Diphenhydramine (PO,IM,IV) Reduce dose of antipsychotics Symptoms will resolve within minutes with IV therapy

36 Extrapyramidal Symptoms (EPS)-Akathisia Akathisia (20-40%) Usually in first 10 days of start or increase of antipsychotics Restlessness, pacing, fidgeting, subjective jitteriness, associated with suicide Most common: Movements affecting the legs May describe vague sensations of internal restlessness, discomfort, or anxiety Resembles psychotic agitation, agitated depression

37 Extrapyramidal Symptoms (EPS)- Akathisia Treatment / Recommendations for Akathisia Lower antipsychotic dose if possible - Greater risk with high dose vs. lower dose Change to different drug (atypical antipsychotic) - Higher risk with FGA - Quetiapine, clozapine less EPS Beta-blocker (propranolol) Benzodiazepines

38 Extrapyramidal Symptoms (EPS) Pseudoparkinsonism Pseudoparkinsonism (15-35%) Onset may be as late as 30 days after initiation/increase Represents symptoms of Parkinson s disease: akinesia, bradykinesia, decreased movement initiation, shuffling gait micrographia, decreased arm swing, masklike faces postural abnormalities

39 Extrapyramidal Symptoms (EPS) - Pseudoparkinsonism Treatment /Recommendation for Pseudoparkinsonism Lower antipsychotic dose if possible - SGA Change to different drugs - Low risk with SGAs and TGA Antiparkinsonian medications (anticholinergics) Benztropine, trihexphenidyl, or procyclidine

40 Extrapyramidal Symptoms (EPS)-Tardive Dyskinesia Tardive Dyskinesia (5%) Late onset: after 3 or more months of treatment Abnormal involuntary movements: - Often begins with tongue or fingers > face -> limbs -> gait -> trunk -> posture - Tongue thrusting, fly catching, lateral jaw movement, abnormal hand movement - Can interfere with eating/swallowing Major risk factors: -High doses, long duration of treatment, increased age, history of parkinsonian side effects -

41 Extrapyramidal Symptoms (EPS)-Tardive Dyskinesia Treatment / Recommendation for Tardive Dyskinesia Remission: likely with prompt discontinuation of antipsychotic therapy No treatment with proven efficacy - suggestion: switch to an SGA or TGA - clozapine? Discontinue anticholinergic med if pt is taking concurrently (benztropine, trihexphenidyl, or procyclidine)

42 CNS Effects of Antipsychotics CNS Effects Drowsiness, sedation Insomnia, agitation Movement Disorders Extrapyramidal symptoms Neuroleptic Malignant Syndrome (NMS) Seizures All APs lower the seizure threshold, use with caution in patients with seizure disorder (typically dose related) Higher risk with chlorpromazine and clozapine

43 Neuroleptic Malignant Syndrome Life threatening neurologic emergency associated with a class of medications that block dopamine transmission Characterized by fever, severe muscle rigidity, and autonomic and mental status changes Incidence of % of pts treated with antipsychotics Mortality estimated 10-20% (was 76% in 1960s)

44 Neuroleptic Malignant Syndrome Pathophysiological mechanism Antipsychotic-induced dopamine blockade likely plays a pivotal triggering role in the condition - central dopamine receptor blockade in the hypothalamus = hyperthermia and other signs of dysautonomia - Interference with nigrostriatal D 2 blockade = rigidity, tremor

45 Neuroleptic Malignant Syndrome Associated Medications Neuroleptic agents - Greater risk: High potency FGA (haloperidol, fluphenazine) Other drugs with anti-dopaminergic activity - eg, Antiemetic drugs metoclopramide, promethazine, domperidone Withdrawal of L-dopa or dopamine agonist therapy

46 Neuroleptic Malignant Syndrome Onset of symptoms Within first two weeks of initiation or change in dose of neuroleptics Predisposing factors Increased use of higher doses, rapid dose escalation, a greater number of IM injections (long acting) However, NMS usually occurs within the therapeutic dosage range of antipsychotics

47 Neuroleptic Malignant Syndrome Tetrad of distinctive Clinical Features: (DSM-V Diagnostic Features) ever utonomic Instability Severe Muscle igidity ental status changes o Analysis of 340 Cases: 70% of patients followed the symptoms below in order: Mental status changes Rigidity Hyperthermia Autonomic dysfunction

48 Neuroleptic Malignant Syndrome Differential diagnosis Prime importance because NMS is a diagnosis of exclusion Lab abnormalities Elevated serum CK >1000IU/L Leukocytosis: WBC count 10,000 to 40,000/mm Mild elevations of lactate dehydrogenase, alkaline phosphatase, liver transaminases Electrolytes abnormalities: hypocalcemia, hypomagnesemia, hypernatremia, hyperkalemia, metabolic acidosis Myoglobinuric acute renal failure resulting from rhabdomyolysis Low serum iron conc

49 Differential Diagnosis- NMS Stawn, J. Keck, Jr, P. and Caroff, S. Neuroleptic Malignant Syndrome. Am J Psychiatry 164:6, June 2007

50 Neuroleptic Malignant Syndrome Treatment Discontinue antipsychotic drug (do not taper) Supportive Care/Hydration - eg. control of fever, intravenous fluid support, correction of electrolyte abnormalities Use benzodiazepines to control agitation, if necessary Specific pharmacotherapy: - Dopaminergic agents bromocriptine amantadine dantrolene (especially, for patients with extreme temperature elevations and rigidity) ECT

51 Neuroleptic Malignant Syndrome Drug Treatment for NMS Bromocriptine start with 1 or 2.5mg doses. If ineffective, increase to 15-20mg TID or QID Amantadine 100mg once daily to TID Dantrolene 4-8mg/day IV divided QID or mg/day PO Once patients respond to drug treatment it should be continued for 1-2 weeks.

52 NMS- Prognosis Most episodes resolve within two weeks Reported mean recovery time 7-11 days Cases persisting for 6 months with residual catatonia and motor signs are reported Risk factors for a prolonged course: depot antipsychotic use and concomitant structural brain disease Most patients recover without neurologic sequelae except severe hypoxia or grossly elevated temperatures for long duration

53 NMS- Restarting Antipsychotics Minimize risk by: Waiting for at least 2 weeks before restarting therapy Using low-potency rather than high-potency drugs Starting with low doses and titrating upward slowly Avoiding concomitant lithium Avoiding dehydration Carefully monitoring for symptoms of NMS

54 CNS Effects of Antipsychotics CNS Effects Drowsiness, sedation Insomnia, agitation Movement Disorders Extrapyramidal symptoms Neuroleptic Malignant Syndrome (NMS) Seizures All APs lower the seizure threshold, use with caution in patients with seizure disorder (typically dose related) Higher risk with chlorpromazine and clozapine

55 Seizures Most agents lower seizure threshold and may produce seizures Predisposing factors for antipsychotic induced seizures: Pre-existing seizure disorder Abnormal EEG without a history of seizure Pre-existing CNS pathology Rapid increases in antipsychotic dosage Clozapine greatest risk of 2 nd gen AP (dose dependent)

56 Organ Systems Affected by Antipsychotics Endocrine system Central nervous system CNS Effects EPS Neuroleptic Malignant Syndrome Seizures Cardiovascular system Hepatic system Dermatologic system Hematologic system Genitourinary system

57 Cardiovascular Effects of APs QTc prolongation Tachycardia Orthostatic hypotension Cardiomyopathy (reported with clozapine)

58 QT prolongation Sudden Arrythmia Death Syndromes Foundation, image viewed May 2016 <

59 Normal QTc intervals Mean daily variation is approximately 75msec Males: Prolonged if >440msec Female: Prolonged if >450msec Or any increase of >40ms from baseline for either gender If >500ms, at increased risk for Torsade de pointes (4x greater risk)

60 Risk Factors for QTc prolongation Hypokalemia Hypomagnesemia Age Female sex Advanced heart disease Congenital and acquired long-qt syndromes Family history of sudden death Anorexia Bradycardia

61 Examples of QTc Prolongation Associated With Select Antipsychotics Antipsychotic Aripiprazole -1 to -4 Clozapine 10 Haloperidol 7 to 15 Olanzapine 2 to 6.5 Paliperidone 2 to 4 Pimozide 19 Quetiapine 6 to 15 Risperidone 3.5 to 10 Thioridazine 33 to 41 Ziprasidone 16 to 21 Approximate QTc interval prolongation in milliseconds b a List is not comprehensive. Other antipsychotics may be associated with QTc prolongation b QTc prolongation interval may depend on the route of administration <

62 Monitoring for QTc Prolongation Obtain history for congenital or acquired long QT syndromes Identify other QT prolonging medications (crediblemeds.org) Obtain baseline ECG If borderline prolongation or combining with other QT prolonging agents, obtain second ECG after initiation Usually wait for steady state (3-5 days) before repeating If concern, can repeat sooner

63 Crediblemeds.org Example

64 Recap: Objectives Review of antipsychotic pharmacology/uses Discuss metabolic side effects of APs Discuss movement side effects of APs Highlight emergency reactions to APs Determine monitoring/treatment for side effects

65 References 1. Alvarez PA, Pahissa J. QT alterations in psychopharmacology: proven candidates and suspects. Curr Drug Saf. 2010;5(1): American Psychiatric Association. Desk Reference to the Diagnostic Criteria from DSM-5 TM. London: American Psychiatric Publishing; Bezchlibnyk-Butler KZ, Virani AS. Clinical Handbook of Psychotropic Drugs for Children and Adolescents. 3 rd ed. Ashland: Hogrefe & Buber Publishers 4. Boyer EW, Shannon M. The Serotonin Syndrome. N Engl J Med 2005;352: Boyer EW. Serotonin Syndrome UpToDate [cited 2015 Sep 14] 6. Chouinard, G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS); Schizophr Res,2005 Jul 15;76(2-3): Epub 2005 Apr Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care February 2004vol. 27 no Elbe, Dean et al. Clinical Handbook of Psychotropic Drugs for Children and Adolescents, 3 rd edition, 2015 Hogrefe Publishing 9. Leucht S et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Vol 382; September 14, Lieberman JA. Managing Anticholinergic Side Effects. Prim Care Companion J Clin Psychiatry. 2004; 6(suppl 2): Muench J, Hamer AM. Adverse Effects of Antipsychotic Medications. American Family Physician. March 1, Volume 81, No Nielsen J, Graff C, Kanters JK, et al. Assessing QT interval prolongation and its associated risks with antipsychotics. CNS Drugs. 2011;25(6): Pringsheim T. Extrapyramidal Symptoms Associated with Second Generation Antipsychotic Use 14. Strawn JR, Keck PE, Caroff SN. Neuroleptic Malignant Syndrome. AM J Psychiatry 164:6, June Taylor DM. Antipsychotics and QT prolongation. Acta Psychiatr Scand. 2003;107(2): Vieweg WV. New generation antipsychotic drugs and QTc interval prolongation. Prim Care Companion J Clin Psychiatry. 2003;5(5): Weiden PJ. EPS Profiles: The Atypical Antipsychotics Are Not All the Same. Journal of Psychiatric Practice Vol. 13, No. 1. January Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of torsade de pointes. Dtsch Arztebl Int. 2011;108(41): Wijdicks E. Neuroleptic malignant syndrome UpToDate [cited 2015 Sep 14] 20. Yatham, LN et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and international Society of CANMAT guidelines for the management of patients with bipolar disoder: update Bipolar Disorders 2013: 15:1-44

66 Questions?