Atypical Antipsychotics: A Current Review

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Atypical Antipsychotics A Current Review

• Mike Lemon, Pharm.D.
• Associate Professor
• SDSU College of Pharmacy
• VA Black Hills Health Care System, Ft Meade

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Objectives

• Define atypical antipsychotics
• Discuss pharmacologic differences of atypical
  antipsychotics
• Discuss dosing, adverse effects, patient
  monitoring, and advantages and disadvantages for
  each medication.
• Describe expected outcomes for patients.
• Discuss novel uses of atypical antipsychotics

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History of Typical Antipsychotics

• Chlorpromazine
• 1950s introduction
• Revolutionized treatment
• Limited therapeutic benefit in some patients
• High incidence of side effects
• Other typical agents followed
• Same results as before

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Typical Antipsychotics

• Chlorpromazine
• Thioridazine
• Perphenazine
• Prochlorperazine
• Fluphenazine

• Thioxthixene
• Haloperidol
• Loxapine
• Molindone
• Pimozide

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Dopaminergic System

• Positive symptoms of schizophrenia
• Auditory hallucinations
• Delusions

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Dopaminergic System

• Negative symptoms of schizophrenia
• Lack of attention
• No sense of pleasure
• Loss of will or drive
• Disorganization of thoughts and speech
• Flat affect
• Social withdrawal

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Pharmacology

• Typical agents classified by
• Chemical structure
• Potency (High or Low)
• Block D2 receptors
• Atypical agents classified by
• Chemical structure
• Atypical agents have a higher affinity for 5-HT2
  than D2

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Dopaminergic System

• Primary pathways
• Mesolimbic
• Positive symptoms
• Mesocortical
• Negative symptoms
• Nigrostriatal
• Movement disorders
• Tuberoinfundibular
• Increased prolactin levels

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Dopaminergic System

• Dopamine receptors
• D2antipsychotic action
• D1,D3,D4, D5Action unknown
• Typical antipsychotics block D2 nonspecifically
  in the brain
• Causes EPS
• Elevated Prolactin
• Possibly worsen negative symptoms

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Dopaminergic System

• Antipsychotic action occurs at a D2 receptor
  occupancy rate of 60-70
• D2 occupancy gt80 increases risk of EPS without
  increased efficacy
• Typical antipsychotics
• D2 occupancy 70-90
• Clozapine
• D2 occupancy 38-63
• Risperidone may lose atypical properties at
  higher doses

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Serotonergic System

• 5-HT2a and 5-HT2c
• Role in psychosis
• Dopamine and 5-HT relationship
• 5-HT ?dopamine levels in deficient areas
• Atypical agents have a higher affinity for 5-HT2a
  to D2 receptors
• Decreases EPS
• Improve negative symptoms

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Therapeutic and Adverse Effects and Receptors
Involved
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Atypical Antipsychotic Definition

• Antipsychotic activity in refractory patients
  (Clozapine)
• Minimal risk of EPS or TD
• Efficacy in treating negative symptoms
• Improved cognitive function
• Little effect on serum prolactin

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Atypical Antipsychotics

• 2nd Generation
• Clozapine (Clozaril)
• Risperidone (Risperdal)
• Olanzapine (Zyprexa)
• Quetiapine (Seroquel)
• Ziprasidone (Geodon)
• 3rd Generation
• Aripiprazole (Abilify)5HT-1a agonist

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Comparative Receptor Binding Profiles
Sertindole
Haloperidol
A2
H1
H1
M
A2
E972218A 2
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Atypical Antipsychotics Efficacy

• Efficacy for negative symptoms
• Difficult to measure but all atypicals claim
  improvements
• Impact on specific components under study
• Treatment resistant schizophrenia
• Clozapine

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Cost-effectiveness of Atypicals

• High acquisition costs
• AtypicalsThousands of dollars/year
• Typical agentsfew hundred dollars/year
• Study problems
• Cost reduction in one area produces savings in
  overall disease management

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Cost-effectiveness of Atypicals

• Real benefits may be in improvements in QOL
• Agents may not show cost savings but if they show
  cost neutrality and a significant benefit in less
  easily measurable areas then they offer real
  benefit
• May even increase costs due to increased
  rehabilitation and psychosocial programs

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Atypical Antipsychotics Effects on Cognition

• Neurocognitive impairment occurs frequently in
  schizophrenia (60)
• Is progressive
• May result from adjunct agents like
  anticholinergics or antiparkinson agents
• Atypical agents may prevent further cognitive
  decline
• Studies are limited

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Atypical Antipsychotics Effects on Cognition

• Clozapine, olanzapine, and risperidone can
  improve
• Verbal learning
• Executive functioning
• Differences between agents with respect to
  working memory

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Adverse Effects Extrapyramidal symptoms (EPS)

• Dystonia
• Akathisia
• Pseudoparkinsonism
• Tardive Dyskinesia

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Adverse Effects EPS

• Typical agents often cause EPS at normal doses
• Atypical agents
• Clozapine
• Negligible risk
• Mild akathisia
• Risperidone
• Moderate risk
• ? 6mg/day similar to placebo

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Adverse Effects EPS

• Atypical agents
• Olanzapine
• Moderate risk
• Dose related reports of akathisia
• ? rates of akathisia with doses higher than
  recommended
• Quetiapine
• Negligible risk

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Adverse Effects EPS

• Aripiprazole
• Low risk
• Ziprasidone
• Moderate risk

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Adverse Effects Tardive Dyskinesia

• Atypical agents have the potential to lower the
  risk of TD
• Clozapine has demonstrated efficacy in treating
  severe TD
• May take 1-3 years to resolve
• Use other atypicals for mild TD symptoms
• Risperidone induced TD usually with doses
  ?6mg/day
• Current data in TX of TD is limited

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Adverse Effects Neuroleptic Malignant Syndrome
(NMS)

• Rare but potentially lethal complication of
  antipsychotic use
• Idiosyncratic reaction
• Fever
• Muscular rigidity
• Altered mental status
• Autonomic dysfunction.
• Lab changes CK, WBC, LDH, BUN, Cr

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Adverse Effects NMS

• D2 blockade thought to be the cause
• Hypothalamus Temp control
• Nigrostriatal EPS and rigidity
• Other mechanisms
• Serotonergic
• Mediate dopamine hypoactivity
• Cholinergic hyperactivity

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Adverse Effects NMS

• All atypicals have been implicated
• Combinations with lithium, fluoxetine, or typical
  antipsychotics increase risk

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Adverse Effects Hyperprolactinemia

• Blockade of D2 receptors
• Serum prolactin gt60ng/ml
• Amenorrhea
• Galactorrhea
• Gynecomastia
• Sexual dysfunction
• Anovulation
• Osteoporosis

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Adverse Effects Hyperprolactinemia

• Atypical agents have a decreased incidence
• due to higher 5-HT2 to D2 binding
• Clozapine and Quetiapine
• Little or no change in prolactin
• Olanzapine
• Small, transient, dose dependent increase

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Adverse Effects Hyperprolactinemia

• Risperidone
• Greatest changes in prolactin
• Dose-dependent elevation in prolactin levels
• Switching from typical to atypical agent
• Return of sexual function and fertility
• Warn regarding pregnancy

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Adverse Effects Weight Gain

• Occurs in up to 40 of patients treated with
  antipsychotics
• May pose a long term health risk
• Cardiovascular events
• Factor in noncompliance
• Mechanism poorly understood
• Concomitant lithium or valproic acid use increase
  risk of significant weight gain

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Atypical Antipsychotics Weight Gain

• Causes
• Antihistamine effects
• Antimuscarinic effects
• 5-HT2c blockade
• Dietary factors
• Activity levels
• Concomitant medications

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Adverse Effects Weight Gain

• Clozapine
• 10 or greater weight gain occurs in 80 of
  patients
• 13 had a 40 or greater weight gain

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Adverse Effects Weight Gain

• Olanzapine also associated with significant
  weight gain
• Risperidone and Quetiapine cause weight gain but
  to a lesser extent
• Ziprasidone and aripiprazole have negligible
  weight gain

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Atypical Antipsychotics Weight Gain
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Adverse Effects Diabetes Mellitus (DM)

• All atypical antipsychotics had a warning added
  in 2004
• Warning regarding hyperglycemia and DM
• Higher prevalence of type II DM in schizophrenic
  patients
• Weight gain
• Impaired glucose tolerance and increased insulin
  secretion

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Adverse Effects DM

• Monitoring suggested for those at risk when
  starting therapy for
• Obese patients
• Family history of DM
• Monitor all patients for symptoms of hyperglycemia

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Adverse Effects Lipids

• Atypicals may increase
• Triglycerides
• Cholesterol
• Metabolic syndrome (Syndrome X)
• Weight gain
• Diabetes
• Lipid abnormalities

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Atypical Antipsychotics Stroke Risk

• April 2005 FDA added new warnings to atypical
  antipsychotics regarding stroke risk
• Cerebrovascular adverse events (e.g., stroke,
  transient ischemic attack) including fatalities

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Atypical Antipsychotics Stroke Risk

• 15/17 trials showed increased mortality in
  treatment group vs. placebo
• Included 5106 patients
• 1.6-1.7 fold increase in mortality

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Atypical Antipsychotics Stroke Risk

• Control of agitation and aggression in elderly is
  off label use
• Patient population already at risk for stroke
• Vascular dementia

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Atypical Antipsychotics Stroke Risk

• Recommend careful documentation of risk vs.
  benefit with patient when starting in at risk
  population
• Consider other agents
• Typical antipsychotics may get warning also

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Adverse Effects Anticholinergic

• Dry mouth
• Xerolube, ice chips, sugarless gum
• Constipation
• Fluid, dietary fiber, exercise
• Tachycardia
• Blurred vision
• Urinary retention
• Impaired memory
• Clozapine and Olanzapine worst

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Adverse Effects Cataracts

• Quetiapine
• Recommend routine eye exams at the start of
  therapy and every 6 months thereafter
• No evidence of formation in humans but occurred
  in dogs
• Phenothiazine antipsychotics have been associated
  with cataracts also

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Adverse Effects Seizures

• All antipsychotics lower the seizure threshold
• Worst atypical is Clozapine

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Adverse Effects ECG Changes

• Prolongation of QT and PR intervals
• Usually not clinically significant
• However may cause problems in
• Elderly
• Patients with underlying cardiac disease
• Multiple antipsychotics

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Adverse Effects Hematologic Complications

• Clozapine
• Agranulocytosis rate 0.38 in US
• Only 0.012 patients died
• Highest risk during 1st 6 months
• Risk peaks during 1st 3 months

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Adverse Effects Hematologic Complications

• Clozapine Monitoring
• WBC weekly for first 6 months
• If stable then may monitor WBC every 2 weeks for
  6 months
• Stable defined as
• WBC 3500/mm3
• ANC2000/mm3
• If stable then may monitor WBC every 4 weeks
• Monitor for 4 weeks upon DC

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Adverse Effects Clozapine

• Withdrawal symptoms may occur upon abrupt DC
• Withdraw over 1 to 2 weeks but 3 to 6 weeks may
  be needed
• Use anticholinergics to prevent or alleviate
  symptoms if abrupt withdrawal is needed

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Clozapine Levels

• Concentrations gt350 ng/ml linked to greater
  response rates
• Concentrations gt1000 ng/ml are associated with
  increased risk of delirium, anticholinergic
  toxicity, and seizures
• Agranulocytosis not related to serum
  concentrations
• Use for compliance, toxicity, DI, and response

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CATIE Trial Info

• NEJM 20053531209-23
• 1493 patients
• Compared
• Olanzapine 7.5-30 mg qd
• Perphenazine 8-32 mg qd
• Quetiapine 200-800 mg qd
• Risperidone 1.5-6 mg qd
• End pointTime to discontinuation of medication

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CATIE Trial Info

• 74 of patients DC study med before 18 months
• 64 in the Olanzapine group
• 75 in the Perphenazine group
• 82 in the Quetiapine group
• 74 in the Risperidone group
• 79 in the Ziprasidone group

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CATIE Trial Info

• Olanzapine had best time to discontinuation
• Olanzapine had the most weight gain and metabolic
  effects
• Perphenazine efficacy appeared similar to
  quetiapine, risperidone, and ziprasidone

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Recommended Dosages
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Dosage Forms

• All available in oral form
• Oral liquids
• Risperidone liquid dosage form
• Orally disintegrating tablets
• Olanzapine, Risperidone
• Injectable
• Olanzapine, Ziprasidone
• Long-acting injection
• Risperidone consta

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Novel Uses of Atypical Antipsychotics

• Management of aggression
• Management of mania
• Acute symptoms
• Maintenance therapy

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Novel Uses of Atypical Antipsychotics

• Antidepressant properties
• 5-HT2c receptor antagonism
• Clozapine and olanzapine inhibit norepinephrine
  reuptake
• Efficacy demonstrated for clozapine, risperidone,
  and olanzapine

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Novel Uses of Atypical Antipsychotics

• Management of treatment resistant or psychotic
  depression
• Potential indications
• Obsessive compulsive disorder
• Parkinsons (psychosis, tremor)
• Tardive dyskinesia
• Tourettes syndrome

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Monitoring Patient Outcomes

• Treatment of target symptoms
• Reasonable time course for response
• Monitor for side effects
• Avoid unwanted side effects

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Monitoring Patient Outcomes

• AIMS
• Weight
• Lipid profile
• Blood Glucose/HbA1c
• ECG monitoring in high risk patients
• Use minimum effective dose

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Conclusion

• Considered first line agents for schizophrenia
• Promising in the treatment of other psychiatric
  or neurologic conditions
• Better side effect profiles but have problems
  with
• Diabetes and Metabolic Effects
• Further pharmacoeconomic data is needed

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THE END Questions