Antipsychotic Review

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Antipsychotic Review

• Jena L. Ivey, PharmD, BCPS, CPP

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Objectives

1. Review different antipsychotic agents with regard
   to efficacy and safety
2. Discuss adverse effect profiles of antipsychotic
   agents and learn how to pick the best one for
   your patient if needed

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Antipsychotic Use in Older Adults

• Decreased metabolism can lead to increased blood
  levels and increased side effects
• Decreased absorption can lead to decreased blood
  levels and reduced effectiveness
• Brain changes with aging can lead to heightened
  sensitivity to side effects (e.g. EPS) and
  reduced effectiveness
• Cognitive impairment can lead to nonadherence

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Antipsychotics

• Choice of traditional vs. new generation drugs
• Side effect profiles often direct selection
• EPS, TD, NMS less likely with newer agents
• Efficacy against negative symptoms (when
  relevant) is higher with the new drugs (probably
  related to 5HT-2 antagonism)
• 22 of Nursing home patients

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Traditional Antipsychotics

• All have tendency to produce EPS/TD
• Low potency drugs are usually highly sedating,
  highly anticholinergic and promote orthostasis
• Orthostatic hypotension is related to alpha-1
  blocking effects and correlates highly with hip
  FX
• Low cost is an advantage

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Typical Antipsychotics

• Chlorpromazine
• Prototype typical antipsychotic
• Only able to substantially improve positive
  symptoms, little effect on negative symptoms and
  many adverse effects
• Equivalent doses of other typical antipsychotics
  based on 100 mg of chlorpromazine

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Typical Antipsychotics

• Low potency
• Chlorpromazine
• Thioridazine
• Mesoridazine
• Mid potency
• Molindone
• Loxapine
• Perphenazine

• High potency
• Haloperidol
• Fluphenazine
• Thiothixene
• Trifluoperazine

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Pharmacological Profile for Haloperidol

• Affects alpha, dopamine-2 receptors
• Oral, depot formulations
• Oral
• Start 0.5 mg daily, increase to 30 mg maximum per
  day in divided doses
• Depot (haloperidol decanoate)
• Given usually once monthly
• Must been stable on oral dose first

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Why Use Depot?

• Compliance
• Once weekly dosing
• Convenience
• Side effects
• Lacks peak concentrations
• Gives lower but steady concentrations

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Perphenazine

• Mid potency typical antipsychotic
• Less EPS over high potency
• Less affinity for muscarinic, alpha, and
  histaminic receptors over low potency
• Max dose 64 mg
• Average dose in chronic schizophrenics
• 32 mg/day

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Traditional Antipschotics
Type Sedation EPS Anticholinergic Cardiovascular
Low Potency
Chlorpromazine High Mod Mod High
Mid Potency
Perphenazine Mod Mod-High Mod Low
High Potency
Haloperidol Very Low Very High Very Low Very Low
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Efficacy of Typical Antipsychotics

• Most benefit seen with positive symptoms
• Limited benefit with negative symptoms
• May worsen negative or cognitive symptoms,
  especially in high doses
• Have fallen out of favor as first-line agents

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Atypical Antipsychotics

• Improve psychotic symptoms
• Improve or not worsen negative symptoms
• May improve cognition

• Cause less or no EPS
• Cause less or no tardive dyskinesia
• Effective in refractory patients

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Decision of Antipsychotic

• Atypical agents are now accepted to be first-line
  treatment
• Considered first-line now, but anticholinergic
  effects, orthostasis and COST are important
  factors in older adults
• Treatment choice based on
• Past response or past side effects to individual
  agents and number of treatment failures
• Patient or practitioner preference
• Problems with EPS or tardive dyskinesia
• Other concomitant disease states
• Compliance issues

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Available Atypical Antipsychotics

• Clozapine
• Risperidone
• Paliperidone
• Olanzapine

• Quetiapine
• Ziprasidone
• Aripiprazole

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Clozapine

• Not a first-line agent
• Must have failed at least two other trials of
  antipsychotics
• Difficult to tolerate due to adverse drug effects
• Baseline work-up
• CBC with diff (WBC, ANC)
• Cardiac history
• EKG
• FLP
• Weight/BMI
• FPG and/or HgbA1c

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Clozapine Adverse Effects

• Black Box Warnings
• Hypotension
• Seizure
• Agranulocytosis
• Myocarditis
• Risk of death in elderly demented patients with
  psychosis
• Significant potential for metabolic
  dysregulations
• Others sedation, constipation, tachycardia

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Clozapine Agranulocytosis

• 1 incidence
• More frequently occurs early in therapy
• Monitor CBC weekly for first 6 months, every two
  weeks for next 6 months, then every 4 weeks
  thereafter
• Must be registered to receive clozapine
• Do not rechallenge if patient has experienced
  agranulocytosis to clozapine in the past
• ANClt1000

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Risperidone (Risperdal?)

• Mixed serotonin-dopamine antagonist activity
• Also antagonizes alpha-2, histamine receptors
• Baseline work-up
• Cardiac history
• EKG
• FLP
• Weight/BMI
• FPG and/or HgbA1c
• Black Box
• risk of death in elderly demented patients with
  psychosis

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Risperidone Adverse Effects

• Lower EPS than with typical antipsychotics like
  haloperidol
• Risk of EPS higher with doses greater than 6
  mg/day
• Prolactin elevation
• Orthostasis
• Tachycardia

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Risperidone Decanoate

• Only long-acting atypical antipsychotic injection
• Compliance
• Gluteal injection
• Polymeric microspheres
• Main release at 3 weeks
• Single dose maintained for 4-6 weeks

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Paliperidone (Invega?)

• Major metabolite (9-OH) of risperidone
• Innovative delivery system
• Delivers smooth plasma levels over 24 hrs
• Baseline work-up
• Similar to Risperidone
• Black Box
• risk of death in elderly demented patients with
  psychosis

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Paliperidone

• Comparison to risperidone
• Less peak/trough fluctuations, possibly less side
  effects due to fluctuations
• Once-daily dosing
• No CYP 2D6 interactions (e.g. paroxetine,
  fluoxetine, poor metabolizers)
• Better choice for patients w/liver dysfunction
• Phase II metabolism

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Olanzapine (Zyprexa?)

• Potent antagonist of several serotonin receptors,
  dopaminergic, muscarinic, histaminergic, and
  alpha
• Baseline work-up
• Similar to risperidone PLUS
• LFTS
• Black Box
• risk of death in elderly demented patients with
  psychosis

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Olanzapine Adverse Effects

• Significant potential for metabolic
  dysregulations
• Sedation
• Anticholinergic effects
• Tachycardia
• EPS less than with risperidone
• monitor for akathisia at higher doses (gt15mg)

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Olanzapine IM

• For control of acute agitation in schizophrenic
  and bipolar patients
• Calming without oversedation
• Can give Q 2-4 hours
• Risk of bradycardia and orthostasis
• Do not give within 1 hour of IM/IV lorazepam

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Quetiapine (Seroquel?)

• Antagonist of serotonin, dopamine receptors, some
  effect on histamine/alpha receptors
• Baseline work-up
• Similar to risperidone PLUS
• CBC in pre-existing low WBC or h/o drug-induced
  neutropenia
• Black Box
• Risk of death in elderly demented patients with
  psychosis

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Quetiapine Adverse Effects

• EPS appears to be less due to less effect on
  dopamine (loose and transient binding to dopamine
  receptors)
• Sedation/fatigue
• Orthostasis
• Anticholinergic effects at doses gt300-400mg
• Tachycardia
• Increased LFTs (transient)

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Ziprasidone (Geodon?)

• High affinity for serotonin receptors, moderate
  dopamine/histamine, no affinity for alpha/beta
• Baseline work-up
• Similar to risperidone PLUS
• Electrolytes
• Black Box
• Risk of death in elderly demented patients with
  psychosis
• Contraindicated
• H/O arrhythmias or QTc prolongation
• Uncompensated heart failure
• Acute or recent myocardial infarction

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Ziprasidone Adverse Effects

• EPS versus activation
• Minimal effects on metabolic profile
• EKG changes
• QTc prolongation

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Ziprasidone Intramuscular

• For acute psychotic agitation
• Calming without oversedation
• Can give Q 2-4 hours
• Can give with IM/IV lorazepam

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Aripiprazole (Abilify?)

• Dopamine-2 partial agonist, partial serotonin-1A
  agonist
• Baseline work-up
• Similar to risperidone
• Black Box
• Risk of death in elderly demented patients with
  psychosis
• Risk of increased suicidal behavior similar to
  antidepressants labeling
• FDA approval for adjunct therapy in MDD

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Aripiprazole Adverse Effects

• EPS initially presumed minimal
• Akathisia versus anxiety, restlessness
• Minimal effects on metabolic profile
• Nausea
• Headache

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Aripiprazole IM

• For acute agitation in patients with
  schizophrenia or bipolar d/o
• Calming without oversedation
• Can give Q 2 hours
• Can give with IV/IM lorazepam

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Dosing
Drug Initial Doses in Dementia Pts Usual Ranges for Psychotic D/O
Clozapine 25mg Initial dosing BID-TID minimizes side effects 300-450mg Max 900mg
Olanzapine Oral 2.5-5mg (start Qday dosing at HS) Oral 10-30mg Max 20mg IM (short-acting) 5-10mg Max 30mg/24 hrs
Quetiapine 12.5-25mg (start Qday dosing at HS) 300-800mg Max 800mg
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Dosing
Drug Initial Doses in Dementia Pts Usual Ranges for Psychotic D/O
Risperidone Oral 0.25-0.5mg IM (long-acting) 12.5-25mg Oral 2-6mg Max 16mg IM (long-acting) 25-50mg Max 50mg Administer q 2 weeks
Paliperidone 3mg Absorption increased with high fat meal 6-12mg Max 12mg
Max dose per Product Labeling risk of EPS
higher with doses gt 6mg
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Dosing
Drug Initial Doses in Dementia Pts Usual Ranges for Psychotic D/O
Aripiprazole Oral 2-5mg Oral 10-20mg Max 30mg IM (short-acting) 9.75mg Max 30mg/24hrs
Ziprasidone Oral 20mg Absorption increased with food Oral 120-200mg Max 200mg IM (short-acting) 10-20mg Max 40 mg/24hrs
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Antipsychotic Adverse Effects
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Orthostatic Hypotension

• Vulnerability in older adults is increased
  because of decreased sensitivity of
  baroreceptors in the carotid and BP regulatory
  centers in the hypothalamus PLUS decreased
  alpha-1 adrenergic receptors
• 30 of institutionalized older adults display
  symptomatic orthostatic hypotension
• Drugs cause this primarily by blocking alpha-1
  receptors
• TCAs, MAOIs, antipsychotics (including many of
  the new generation drugs) and lithium are all
  offenders
• Benzodiazepines can cause falls by producing
  dysequilibrium rather than orthostasis

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Falls/Hip Fractures

• 250,000 yearly
• Most occur in women over age 65
• 90 are due to a fall from standing height!
• 50-60 of FXs in this age group require Nursing
  Home placement and about 1/2 never leave
• Mortality rate at the end of 1 year is 20
• Most falls are due to a combination of
  orthostasis, dizziness, EPS, sedation, decreased
  vision and dysequilibrium all of which can be
  caused or exacerbated by psychotropics

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Tardive Dyskinesia

• Risk much higher in older adults
• Incidence may be as high as 25 per year (versus
  5 per year in younger patients)
• Older adults have increased severity and lower
  spontaneous remission rates
• Risk factors AGE, FgtM, early-onset EPS, length
  of neuroleptic exposure
• TX empiric. ?branched-chain amino acids,
  vitamin E, benzos

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Antipsychotic Comparison
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(No Transcript)
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Atypicals and Weight Gain

• Lots of ways to look at this issue (total average
  wt gain, number of patients with gt10 initial
  body weight gain, length of weight gain, types of
  weight gain)
• Risk of significant weight gain
• Clozapine, olanzapine and quetiapine, high
• Risperidone, moderate
• Ziprasidone, aripiprazole, low
• Generally, thinner people gain more weight
  (lower BMI)
• weight gain seems to plateau at 3 yrs or so, but
  average weight gain is in the 15 lb range
• weight gain may be less of a problem in the
  elderly
• However, even in low risk drugs like ziprasidone
  and aripiprazole, certain individuals gained
  large amounts of weight according to package
  insert date (7-8)

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How Do Atypicals Cause Weight Gain?

• Antihistamine effects (H1) clozapine,
  olanzapine, quetiapine are strong inhibitors
• 5HT2c blocking effects Mice with this receptor
  knocked out are all obese all atypicals are
  5HT2c blockers except aripiprazole
• Endocrine effects such as hyperprolactinemia may
  contribute
• Genetic susceptibility (receptor polymorphisms)

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Atypical Antipsychotics Hyperglycemia

• Hyperglycemia has been seen with olanzapine
  clozapine
• Good prospective studies are lacking DM in
  schizophrenics increased dramatically after
  neuroleptics introduced in 1950s
• Schizophrenics may have impaired glucose
  tolerance
• Insulin resistance may be the mechanism
• Monitor Hgb A1c every 3 months Chol TGs every
  6 months

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Monitoring Protocolab
Variable Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually
Weight (BMI) x x x x x
Waist circumfer. x x
Blood Pressure x x x
Fasting Glucose x x x
Fasting Lipids x x

aBased on American Diabetes Association Consensus
statetment bMore frequent assessments may be
necessary based on clinical status
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Managing Side Effects

• Anticholinergic Effects
• fluids, sugarless gum, bowel regimen
• EPS
• lower dose of drug (esp. risperidone)
• drug holiday
• Hypotension
• rise slowly from bed, divide doses, increase salt
  intake, TED hose, fludrocortisone in refractory
  cases
• Sedation lower dose, modafanil (Provigil),
  methylphenidate (Ritalin)

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Prolongation of QTc interval

• QTc interval is time it takes the heart to
  repolarize, corrected for heart rate
• 440 msec upper limits of nomal gt480 definitely
  prolonged
• Tricyclics widen QRS QTc intervals
• Drugs which may significantly prolong QTc
  include thioridazine , mesoridazine,
  ziprasidone, droperidol, pimozide ketoconozole
  - often metabolized by P450-3A4
• Drugs which interfere with metabolism of these
  QTc prolongers such as Nefazodone (SERZONE),
  fluvoxamine (LUVOX), cimetidine, erythromycin,
  ketoconazole, norfluoxetine can cause problems

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QTc Prolongation In Antipsychotics

• 2 Pimozide, Mesoridazine, Thioridazine,
  Droperidol
• 1 Ziprasidone, Clozapine, Loxapine,
  Thiothixene, ...Chlorpromazine,
  Trifluoperazine, Risperidone,
• ...Quetiapine
• /- Olanzapine, Haloperidol, Fluphenazine
• RISK FACTORS
• Female sex
• Congenital Long QT
• Ischemic heart disease

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QTc Prolongation by Other Drugs

• Antidepressants
• Fluoxetine, Sertraline, Citalopram, Doxepin,
  Desipramine, Amitriptyline, Maprotiline
• Non-psychiatric
• Amiodarone, Ibutilide, Procainamide,
  Inadapamide,Clarithromycin, Erythromycin,
  Cisapride
• partial list

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QTc Recommendations

• Do not use thioridazine, mesoridazine or pimozide
  for patients with known heart disease, hx of
  syncope, FH of sudden death or congenital
  prolonged QT.
• If ziprasidone is used for any of these patients,
  a baseline ECG should be obtained before
  beginning treatment. A subsequent ECG is
  indicated for symptoms suggestive of a prolonged
  QT interval (e.g. syncope)
• AJP, August 2004, pg 1334. (These are recs for
  patients with schizophrenia)

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Stroke Risk - Antipsychotics

• Some evidence to suggest increased risk of
  cerebrovascular events and death seen in older
  patients treated with antipsychotics for
  behavioral and psychological symptoms of dementia
  
• Risperidone, olanzapine studied the most
• Similar risk noted with atypical and typical
  agents
• Studies are retrospective and the groups
  receiving and not receiving antipsychotics may
  not be comparable for the question being asked

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Stroke Risk - Antipsychotics

• Try non-drug modalities first
• Educate family/patient on risks associated with
  use
• Must weigh benefits of use with potential harms
  on case-by-case basis
• Pharmacologic choices are limited in this
  population and there is no evidence one way or
  the other whether other pharmacologic agents used
  for these same purposes are any safer

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Selecting Atypical Antipsychotics
Specific Side Effect Best Medication Choices to Avoid Specific Side Effects
Sedation ziprasidone, aripiprazole, risperidone/paliperidone
Weight gain/metabolic side effects aripiprazole, ziprasidone
EPS/tardive dyskinesia clozapinegtquetiapinegtziprasidone/aripiprazolegt olanzapine
Sexual/reproductive All except risperidone/paliperidone
Anticholinergic effects risperidonegtziprasidonegtaripiprazole, quetiapine (at low to medium doses)
J Clinical Psychiatry 1999603-80