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Medical Management of Medical Management of Patients on Atypical Patients on Atypical
AntipsychoticsAntipsychotics
Paul Donaher, MDPaul Donaher, MDFebruary 20, 2010February 20, 2010
DisclosureDisclosure
During this presentation I will be During this presentation I will be discussing off-label uses of certain atypical discussing off-label uses of certain atypical antipsychotic medications. This discussion antipsychotic medications. This discussion is primarily to illustrate the populations of is primarily to illustrate the populations of patients in which these pharmaceuticals patients in which these pharmaceuticals are used. It should not be interpreted as are used. It should not be interpreted as an endorsement or criticisms of any such an endorsement or criticisms of any such use.use.
ObjectivesObjectives
Review of current atypical medications and their Review of current atypical medications and their indicationsindications
Review neurologic complications of Review neurologic complications of antipsychotics and discuss managementantipsychotics and discuss management
Review current guidelines on monitoring Review current guidelines on monitoring metabolic changes associated with metabolic changes associated with antipsychoticsantipsychotics
Discuss some clinical pearls in coordinating care Discuss some clinical pearls in coordinating care with mental health professionalswith mental health professionals
Survey Question #1Survey Question #1
The term “atypical antipsychotic” describes The term “atypical antipsychotic” describes how many drugs ?how many drugs ?
(2)(2) 33(3)(3) 55(4)(4) 88(5)(5) More than 10More than 10
History of Atypical AntipsychoticsHistory of Atypical Antipsychotics
1950’s Clozapine developed1950’s Clozapine developed 1970’s Clozapine introduced into general 1970’s Clozapine introduced into general
practicepractice 1994 Risperidone (Risperdal) introduced1994 Risperidone (Risperdal) introduced 1996-1997 Olanzapine (Zyprexa) and 1996-1997 Olanzapine (Zyprexa) and
Quetiapine (Seroquel) introducedQuetiapine (Seroquel) introduced 2001-2002 Ziprasadone (Geodon) and 2001-2002 Ziprasadone (Geodon) and
Aripiprazole (Abilify) introducedAripiprazole (Abilify) introduced
History of Atypical Antipsychotics History of Atypical Antipsychotics (contt)(contt)
2005 CATIE trial results published2005 CATIE trial results published 2008 First approved risperidone generics2008 First approved risperidone generics 2009 Asenapine (Saphris) and Iloperadine 2009 Asenapine (Saphris) and Iloperadine
(Fanapt) approved(Fanapt) approved 2010 Lurasidone may be approved2010 Lurasidone may be approved 2011 Olanzapine and Quetiapine 2011 Olanzapine and Quetiapine
scheduled to lose their patentscheduled to lose their patent
The Atypical The Atypical AntipsychoticsAntipsychotics
Indications and ApplicationsIndications and Applications
Clozapine (Clozaril)Clozapine (Clozaril)
Management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia
Reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder
Due to risks of agranulocytosis, Clozaril is available only through a distribution system that ensures WBC and ANC
Risperidone (Risperdol)Risperidone (Risperdol)
Treatment of schizophrenia in adultsTreatment of schizophrenia in adults Acute manic or mixed episodes of bipolar Acute manic or mixed episodes of bipolar
(alone or with lithium/valproate)(alone or with lithium/valproate) Schizophrenia in adolescentsSchizophrenia in adolescents Bipolar Mania in adolescentsBipolar Mania in adolescents Treatment of irritability of autistic children Treatment of irritability of autistic children
(5-16 y.o.)(5-16 y.o.)
Olanzapine (Zyprexa)Olanzapine (Zyprexa)
Treatment of schizophrenia in adultsTreatment of schizophrenia in adults Acute manic or mixed episodes of bipolar Acute manic or mixed episodes of bipolar
(alone or with lithium/valproate)(alone or with lithium/valproate) Acute agitation associated with bipolar or Acute agitation associated with bipolar or
schizophrenia schizophrenia Depressive associated with bipolar diseaseDepressive associated with bipolar disease Treatment of refractory depressionTreatment of refractory depression
Quetiapine (Seroquel)Quetiapine (Seroquel)
Treatment of schizophrenia in adultsTreatment of schizophrenia in adults Acute manic or mixed episodes of bipolar Acute manic or mixed episodes of bipolar
(alone or with lithium/valproate)(alone or with lithium/valproate) Depressive associated with bipolar diseaseDepressive associated with bipolar disease Maintenance treatment of bipolar disease Maintenance treatment of bipolar disease
in addition to lithium/valproatein addition to lithium/valproate
Aripiprazole (Abilify)Aripiprazole (Abilify)
Treatment of schizophrenia in adultsTreatment of schizophrenia in adults Acute manic or mixed episodes of bipolar Acute manic or mixed episodes of bipolar
(alone or with lithium/valproate)(alone or with lithium/valproate) Acute agitation associated with bipolar or Acute agitation associated with bipolar or
schizophreniaschizophrenia Schizophrenia in adolescentsSchizophrenia in adolescents Bipolar Mania in adolescentsBipolar Mania in adolescents Adjunct in treatment of depressionAdjunct in treatment of depression
Ziprasadone (Geodon)Ziprasadone (Geodon)
Treatment of schizophrenia in adultsTreatment of schizophrenia in adults Acute manic or mixed episodes of bipolar Acute manic or mixed episodes of bipolar
(alone or with lithium/valproate)(alone or with lithium/valproate) Acute agitation associated with bipolar or Acute agitation associated with bipolar or
schizophreniaschizophrenia
Newer AntipysphoticsNewer Antipysphotics
Asenapine (Saphris) Approved 2009Asenapine (Saphris) Approved 2009 Iloperadine (Fanapt) Approved 2009Iloperadine (Fanapt) Approved 2009 Lurasidone Approval 2010?Lurasidone Approval 2010?
Off-label usesOff-label uses
Obsessive Compulsive DiseaseObsessive Compulsive Disease(Risperidone, Quetiapine)(Risperidone, Quetiapine)
Post Traumatic Stress DisorderPost Traumatic Stress Disorder(Olanzapine, Risperidone)(Olanzapine, Risperidone)
Personality DisordersPersonality Disorders(Olanzapine-Borderline; Risperidone-(Olanzapine-Borderline; Risperidone-Schizotypal)Schizotypal)
Tourettes SyndromeTourettes Syndrome(Risperidone)(Risperidone)
More Off-label UsesMore Off-label Uses
Sleep disordersSleep disorders Anxiety disordersAnxiety disorders Alcohol dependenceAlcohol dependence Drug use or dependenceDrug use or dependence Pervasive development disorderPervasive development disorder Anorexia nervosaAnorexia nervosa
Treatment of DementiaTreatment of Dementia Atypical antipsychotics are frequently used to Atypical antipsychotics are frequently used to
manage aggression and psychosis in patient’s manage aggression and psychosis in patient’s with dementiawith dementia
Two meta analysis studiesTwo meta analysis studies11 of antipsychotic of antipsychotic use in Alzheimers disease demonstrateduse in Alzheimers disease demonstrated- effective at improving aggression/psychosis - effective at improving aggression/psychosis - associated with increase in mortality- associated with increase in mortality
FDA issued a “black box warning” on atypical FDA issued a “black box warning” on atypical antipsychotics in 2005antipsychotics in 2005
((11Schneider 2005 , Ballard et al 2006)Schneider 2005 , Ballard et al 2006)
CATIE trialCATIE trial
Acronym for Clinical Antipsychotic Trials of Acronym for Clinical Antipsychotic Trials of Intervention Effectiveness Intervention Effectiveness
Clinical comparison of atypical Clinical comparison of atypical antipsychotics and one 1antipsychotics and one 1stst generation generation antipsychoticantipsychotic
Funded by the National institute of Mental Funded by the National institute of Mental HealthHealth
Attempted to provide a “real world” Attempted to provide a “real world” perspective to a clinical trialperspective to a clinical trial
(Lieberman et al, 2005)
CATIE DesignCATIE Design
1493 patients randomized to one of 5 1493 patients randomized to one of 5 arms in the studyarms in the study- Olanzapine (7.5-30mg/day)- Olanzapine (7.5-30mg/day)- Risperidone (1.5 – 6mg/day)- Risperidone (1.5 – 6mg/day)- Quetiapine (200-800 mg/day)- Quetiapine (200-800 mg/day)- Ziprasadone (40-160mg/day)- Ziprasadone (40-160mg/day)- Perphenazine 8-32 mg/day)- Perphenazine 8-32 mg/day)
Patients with a prior history of TD were Patients with a prior history of TD were precluded from being assigned to precluded from being assigned to perphenazineperphenazine
Survey Question #2Survey Question #2
Which number best approximates the Which number best approximates the percentage of all cause discontinuation percentage of all cause discontinuation in the CATIE trial?in the CATIE trial?
(2)(2) 5%5%(3)(3) 25%25%(4)(4) 50%50%(5)(5) 75%75%(6)(6) 95%95%
CATIE ResultsCATIE Results
82%Quetiapine (seroquel)
79%Ziprasidone (Geodon)
75%Perphenazine
74%Risperidone (Risperdal)
64%Olanzapine (Zyprexa)
Discontinuation Rate
Drug
CATIE OutcomesCATIE Outcomes
Primary OutcomePrimary OutcomeAll cause discontinuation after 18 monthsAll cause discontinuation after 18 months
Secondary OutcomesSecondary Outcomes-Neurological side effects-Neurological side effects-Weight gain (> 7%)-Weight gain (> 7%)-Change in blood sugar-Change in blood sugar-Change in lipid profile-Change in lipid profile-Change in prolactin-Change in prolactin-PANSS and CGI scores-PANSS and CGI scores
CATIE ResultsCATIE Results
1.1
-1.6
-2.0
0.8
9.4
Average Weight Gain (lbs)
6.8/0.0516%Quetiapine
2.3/-0.107%Ziprasadone
5.2/0.1012%Perphenazine
6.7/0.0814%Risperidone
15.0/0.4130%Olanzapine
Fasting Blood Sugar (mg/dl)/HgbA1c (%)Change
Weight Gain >7%
Drug
Neurologic Side EffectsNeurologic Side Effects
13%Quetiapine (Seroquel)
14%Ziprasidone (Geodon)
17%Perphenazine
16%Risperidone (Risperdal)
14%Olanzapine (Zyprexa)
FrequencyDrug
Catie ResultsCatie Results
5.3
-9.2
0.5-2.1
9.7
ChangeIn TotalCholesterol (mg/dl)
-9.319.2Quetiapine
-5.6-18.1Ziprasadone
-1.28.3Perphenazine13.8-2.6Risperidone
-6.142.9Olanzapine
Change in Prolactin(mg/dl)
Change in TG(mg/dl)
Drug
CATIE criticismsCATIE criticisms
Dosages were not consistent with current Dosages were not consistent with current dosing guidelinesdosing guidelines
Duration of study was too short to Duration of study was too short to evaluate for neurological side effectsevaluate for neurological side effects
Potential bias in TD patients who were not Potential bias in TD patients who were not randomized to perphenazinerandomized to perphenazine
(Dettling et al, 2006)
Common Medical Issues Associated Common Medical Issues Associated with Atypical Antipsychoticswith Atypical Antipsychotics
Neurological DisordersNeurological Disorders Metabolic SyndromeMetabolic Syndrome ProlactinemiaProlactinemia
Extrapyramidal Extrapyramidal SymptomsSymptoms
Description and ManagementDescription and Management
Akathesia / DystoniaAkathesia / Dystonia
AkathesiaAkathesia- feeling of restlessness, desire to move - feeling of restlessness, desire to move legs or walklegs or walk
DystoniaDystonia-slow sustained contractions or spasms -slow sustained contractions or spasms that result in involuntary movementthat result in involuntary movement
Drug Induced ParkinsonismDrug Induced Parkinsonism
Muscle stiffness/ CogwheelingMuscle stiffness/ Cogwheeling Shuffling gaitShuffling gait Stooped postureStooped posture Masked faciesMasked facies TremorTremor
Management of Management of Akathesia/Dystonia/Drug Induced Akathesia/Dystonia/Drug Induced
ParkinsonismParkinsonism AkathesiaAkathesia
- Symptoms usually abate with reduction of dose - Symptoms usually abate with reduction of dose or discontinuation of the medicationor discontinuation of the medication- Addition of anxiolytic or b-blocker may be - Addition of anxiolytic or b-blocker may be helpfulhelpful
Dystonia / Drug Induced ParkinsonismDystonia / Drug Induced Parkinsonism-require immediate intervention-require immediate intervention-administration of anticholinergic or -administration of anticholinergic or antiparkinson medication antiparkinson medication-reduce dose or change medication-reduce dose or change medication
Tardive DyskinesiaTardive Dyskinesia
Repetitive rhythmic involuntary movementsRepetitive rhythmic involuntary movements
ExamplesExamples-Tongue thrusting-Tongue thrusting-Lip smacking-Lip smacking-Chewing movements-Chewing movements-Grunting/Humming-Grunting/Humming
Mangement of Tardive DyskinesiaMangement of Tardive Dyskinesia
Prevention is the keyPrevention is the key Screening recommended every 3 to 6 Screening recommended every 3 to 6
months using tools such as the Abnormal months using tools such as the Abnormal Involuntary Movement Scale (AIMS)Involuntary Movement Scale (AIMS)
When identified, reduce or eliminate the When identified, reduce or eliminate the causative agentcausative agent
Neuroleptic Malignant SyndromeNeuroleptic Malignant Syndrome
High FeverHigh Fever Muscle RigidityMuscle Rigidity Change in Mental StatusChange in Mental Status Autonomic InstabilityAutonomic Instability Profuse DiaphoresisProfuse Diaphoresis Fatality rate of 10-30%Fatality rate of 10-30%
Management of Malignant Management of Malignant Neuroleptic SyndromeNeuroleptic Syndrome
Hospital transferHospital transfer Withhold neuroleptic medicationWithhold neuroleptic medication Hydration to correct fluid losses and hypotensionHydration to correct fluid losses and hypotension Benzodiazepines and physical restraints as Benzodiazepines and physical restraints as
neededneeded Cooling with antipyretics, cooling blanketsCooling with antipyretics, cooling blankets Dopamine agonists (Bromocriptine, amatadine)Dopamine agonists (Bromocriptine, amatadine) Avoid DantroleneAvoid Dantrolene Psychiatry, neurology, and renal consults as Psychiatry, neurology, and renal consults as
appropriateappropriate
(Benzor 2009)
HyperprolactinemiaHyperprolactinemia
Symptoms and managementSymptoms and management
Hyperprolactinemia SymptomsHyperprolactinemia Symptoms
OsteoporosisOsteoporosis
DyspareuniaErectile Dysfunction
InfertilityInfertility
Acne/HirsutismDecreased libido
Amenorrhea/OligomennorrheaGynecomastia
GalactorrheaGalactorrhea
WomenMen
Hyperprolactinemia ManagementHyperprolactinemia Management
Do not check prolactin levels in asymptomatic Do not check prolactin levels in asymptomatic patientspatients
In symptomatic patients, evaluate other In symptomatic patients, evaluate other potential causes of symptoms (thyroid disease, potential causes of symptoms (thyroid disease, pregnancy, low testosterone)pregnancy, low testosterone)
Consider an MRI in patients whose history may Consider an MRI in patients whose history may suggest a pituitary lesion or not well explained suggest a pituitary lesion or not well explained by the drug in questionby the drug in question
Consider endocrinology referralConsider endocrinology referral Consider discontinuing drug in consultation with Consider discontinuing drug in consultation with
patient and psychiatristpatient and psychiatrist
(Miller 2004)
Metabolic SyndromeMetabolic Syndrome
Monitoring and ManagementMonitoring and Management
Metabolic SyndromeMetabolic Syndrome
In 2004, FDA issued a black box warning In 2004, FDA issued a black box warning on hyperglycemia and diabetes associated on hyperglycemia and diabetes associated with atypical antipsychoticswith atypical antipsychotics
The American Diabetic Association The American Diabetic Association published a consensus statement in published a consensus statement in conjuction with the American Psychiatric conjuction with the American Psychiatric Association, the American College of Association, the American College of Endocrinology outlining management of Endocrinology outlining management of metabolic sequelae of antipsychotic usemetabolic sequelae of antipsychotic use
(ADA, Diabetes Care 2004)
Baseline MonitoringBaseline Monitoring
Document any Personal/Family History of Document any Personal/Family History of Obesity, Diabetes, Hyperlipidemia, or Obesity, Diabetes, Hyperlipidemia, or Heart DiseaseHeart Disease
Weight and Height Measurements (BMI)Weight and Height Measurements (BMI) Waist CircumferenceWaist Circumference Fasting Plasma GlucoseFasting Plasma Glucose Fasting Lipid ProfileFasting Lipid Profile
Baseline MonitoringBaseline Monitoring Initiate standard treatment for any Initiate standard treatment for any
patients found to be hypertensive, patients found to be hypertensive, diabetic, or with elevated lipidsdiabetic, or with elevated lipids
Nutritional and physical activity counseling Nutritional and physical activity counseling for patients who are overweight or obesefor patients who are overweight or obese
Patients and family should be informed of Patients and family should be informed of the risks of weight gain and diabetes.the risks of weight gain and diabetes.
Patients and families should be advised on Patients and families should be advised on how to recognize the signs and symptoms how to recognize the signs and symptoms of diabetes.of diabetes.
Weight measurementsWeight measurements
Weight should be monitored monthly for Weight should be monitored monthly for the 1the 1stst 3 months 3 months
For patients who have gained > 5%; For patients who have gained > 5%; consider changing agentconsider changing agent
Rapid discontinuation of medication should Rapid discontinuation of medication should be avoidedbe avoided
3 Months3 Months
WeightWeight Fasting plasma glucoseFasting plasma glucose Lipid profileLipid profile Blood PressureBlood Pressure
Patients who develop worsening blood Patients who develop worsening blood sugar or lipids should consider switching sugar or lipids should consider switching agentsagents
Annual AssessmentsAnnual Assessments
Family / Personal historyFamily / Personal history WeightWeight Blood pressureBlood pressure Fasting Plasma LevelsFasting Plasma Levels Waist CircumferenceWaist Circumference
Lipids (may be done every 5 years)Lipids (may be done every 5 years)
Monitoring ScheduleMonitoring Schedule
xxxLipid Profile
xxxFasting glucose
xxxBlood Pressure
xxWaist
xxxxxxWeight
xxPersonal/ Family history
Every 5 years
EveryYear
Every 3 Months
12weeks
8 weeks
4 weeks
Baseline
EpilogueEpilogue
Morrato et al examined the testing of fasting Morrato et al examined the testing of fasting glucose and lipids in patients receiving atypical glucose and lipids in patients receiving atypical antipsychotic medicationsantipsychotic medications
Laboratory claims for 18, 876 US patients Laboratory claims for 18, 876 US patients enrolled in a commercial health plan receiving enrolled in a commercial health plan receiving antipsychotic medications from 2001 through antipsychotic medications from 2001 through 20062006
Comparisons before and after the FDA letter Comparisons before and after the FDA letter campaign and ADA consensus statementcampaign and ADA consensus statement
Survey Question #3Survey Question #3
Which of the following best describes the Which of the following best describes the percentage of patients on antipsychotic percentage of patients on antipsychotic medication who had an annual fasting glucose medication who had an annual fasting glucose in study by Morrato et al ?in study by Morrato et al ?
(2)(2) 20%20%(3)(3) 40%40%(4)(4) 60%60%(5)(5) 80%80%(6)(6) 95%95%
Effect of ADA and FDA on Annual Effect of ADA and FDA on Annual Glucose ScreeningGlucose Screening
Effect of ADA and FDA on Baseline Effect of ADA and FDA on Baseline Glucose ScreeningGlucose Screening
SummarySummary
Educate patients about possible side Educate patients about possible side effects of medications prior to initiating effects of medications prior to initiating therapytherapy
Monitor patients for EPS after starting Monitor patients for EPS after starting therapy therapy
Follow weight, glucose, and lipid levelsFollow weight, glucose, and lipid levels Coordinate care with mental health care Coordinate care with mental health care
providersproviders
Points to ConsiderPoints to Consider
Many patients on antipsychotic Many patients on antipsychotic medications have cognitive limitationsmedications have cognitive limitations
Primary care physicians are asked to see Primary care physicians are asked to see more and more patients per hourmore and more patients per hour
Community mental health services are Community mental health services are sometimes limited in availability of staffsometimes limited in availability of staff
Points to ConsiderPoints to Consider
Allow more time in the schedule for Allow more time in the schedule for appointmentsappointments
Try to have a trusted caregiver accompany Try to have a trusted caregiver accompany the patient to the appointmentthe patient to the appointment
Identify the patient’s mental health Identify the patient’s mental health provider and coordinate careprovider and coordinate care
Develop a network of trusted psychiatric Develop a network of trusted psychiatric care providerscare providers