Antipsychotics: New agents and

new perspectives on older agents

Ted D. Williams
PharmD, PGY1 Resident
Syracuse VAMC
June 9, 2010
 Outline
 Psychotic Disorders
 Pathophysiology & Pharmacology
 Typical vs. Atypical Antipsychotics
 Side Effect Management
 Therapy Management
 A closer look at select agents
 Psychosis vs. Neurosis
 Psychosis
› Inappropriate processing of sensory information
› Disturbed views of reality and self
› Not recognized by sufferer
 Neurosis
› Abnormal reactions
› Recognized by sufferer by abnormal
 Disorders with Psychotic Symptoms
Possible
 Big Three
› Schizophrenia
› Bipolar Disorder
› Delirium in Dementia
 Other Causes
› Depression
 Major Depressive Disorder
 Secondary Depression
› Post Traumatic Stress Disorder
› Drug Induced
 Schizophrenia Symptoms
 Positive Symptoms
› Disordered thoughts
› Delusions
› Paranoia
› Hallucinations
› Loose ideation
 Negative Symptoms
› Flat Affect
› Anhedonia
 loss of emotional response
 Models of Psychosis

 Current models suggest psychotic symptoms to

be a disregulation in dopaminergic pathways
 These models primary built on efficacy of
dopamine antagonist in schizophrenia
 Dopamine Receptor Response
EPS
 D2 receptor occupancy of 65%–
70% correlates with maximal Optimal
antipsychotic efficacy Response
› unclear if this 65%–70%
occupancy has to be continuously
maintained or intermittently
achieved (tight versus loose D2
receptor binding)
 prolactin elevation appearing
beyond 72% D2 occupancy Ineffective
 Extrapyramidal Symptoms (EPS)
appear beyond 78% D2
occupancy without any increase
in benefits at higher rates of
occupancy

• Nasrallah, HA, Dandon, R.Textbook of Psychopharmacology:Chapter 27. Classic Antipsychotic Medications

 Dopaminergic Pathways
 Mesolimbic
› Project from Ventral tegmental area to the cerebral cortex,
including the Nucleus Accumbens (reward pathways)
 Mesocortical
› Project from Ventral tegmental area to the limbic
structures
 Tuberoinfundibular
› D2 receptors in the Hypothalamus inhibit Prolactin
secretion
 Nigrostriatal pathway
› Associated with Parkinsonian Symptoms
 Pathology of Schizophrenia
 Mesolimbic
› Overactivity of mesolimbic pathway produce positive symptoms
 Mesocortical
› Underactivity of mesocortical pathways produces negative symptoms
 Tuberoinfundibular and Nigrostriatal pathways unaffected by Schizophrenia

MesolImbic Tuberoin-
Nigrostriatal
Meso-cortical fundibular
 Typical vs. Atypical
 Typical or First Generation Antipsychotics (FGA)
have
› High affinity for dopamine receptors
› Low/no affinity for serotonin receptors
 Atypical or Second Generation Antipsychotics
(SGA) have
› Moderate affinity for dopamine receptors
› Increased affinity for serotonin Receptors
 Rich Pharmacology is beneficial
 FGA provide a strong
dopama-lytic™response
 SGA with 5-HT2
antagonism blocks normal
vesicular release inhibition,
promoting dopamine
release into the synapse
 This increased dopamine
signal is believed to prevent
downstream remodeling
and development of EPS
 Pharmacologic treatment of Schizophrenia
 Dopamine blockade correct mesolimbic positive symptoms
 Serotonin corrects mesocortical negative symptoms
 Too much dopamine blockade causes
› EPS via nigrostriatal
› Lactation via Tuberoinfundibular
 The models don’t entirely match clinical observations
› Serotonin modeled to prevent tuberinfundibular and nigrostriatal symptoms
› Clinical trial show FGA haloperidol to be more effective in improving negative symptoms than quetiapine

MesolImbic Meso-
Meso- Tuberoin-
MesolImbic Nigrostriatal
cortical
cortical fundibular
 Other Receptor Affinities
 Alpha 1 Antagonism
› Hypotension / Reflex Tachycardia
› Sedation
 Muscarinic Antagonists
› Anticholinergic Effects
 H1 Antagonism
› Sedation
› Weight Gain (Appetite)
 Compilation of Receptor Affinities
 FGA have high D2 affinity and low 5HT affinity
 Newer SGA have balanced D2 and 5HT affinities
 Pharmacology & Pathophysiology
Summary
 Dopamine antagonism is the primary proposed
mechanism of psychosis
 Multiple CNS pathways mediate symptoms and
ADRs of agents
 Synaptic dopamine levels appear to be modulated
by serotonin
 Achieving the correct level of synaptic dopamine
is the key to therapeutic response without ADRs
 Clinical Outcomes
 Efficacy vs. Tolerability?
› Both lack of efficacy and
intolerability contribute
significantly to very high
discontinuation rates
 Efficacy Measures
› Psychiatric Scores
 (e.g. PANSS, CGI)
› Activities of Daily Living
› Independent Living
› Employment status
 Tolerability
› Weight Gain
› EPS
› Sedation

• Lieberman, JA et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. NEJM 2005;353:1209-23.
 Controversies
 First vs. Second Generation Antipsychotics
 Metabolic Side Effects
 First vs. Second Generation
 Leucht, S, Wahlbeck,K, Hamann,J, Kissling, W. New generation
antipsychotics versus low-potency conventional antipsychotics: a
systematic review and meta-analysis. The Lancet, 2003:361;1581-
1589
› Mean doses less than 600 mg/day of chlorpromazine or its equivalent had
no higher risk of EPS than new generation drugs
 Rosenheck, R, Perlick, D, Bingham, S. et al. Effectiveness and Cost
of olanzapine and haloperidol in the treatment of schizophrenia: A
randomized controlled trial. JAMA 2003;290:2693-2702.
› n=309, 12 months, VA Study
› Flexible dose olanzapine+benzotropine vs. flexible dose haloperidol
› No significant differences in quality of life, symptoms, or ADR.
› Olanzapine associated with significant metabolic syndrome and
significantly higher costs $3,000-9,000 annually
› Haloperidol associated with significant akathesia and reduced memory
 First vs. Second Generation
 Jones, PB, et al. Randomized controlled trial of the
effect on quality of life of second vs. first generation
antipsychotic drugs in schizophrenia. Archives of
General Psychiatry 2006;63:1079-1087
› CUtLASS 1 trial.
› n=275, 52 weeks randomized to FGA or SGA for patient
who failed antipsychotic therapy (ineffective or ADR)
› Quality of Life Scale and psychotic symptom scores not
significantly different between groups
 The debate rages on, but the pendulum appears to be
swinging back towards the re-introductions of FGA
 Metabolic side effects
 Metabolic Alterations
› Weight
› Glucose
› Lipids
 Lipid panel required every 6 months for all antipsychotics
per VA/DoD Guidelines
 Proposed Mechanisms
› H1, serotonin, and alpha-1 antagonism have all been suggested
› Appetite stimulation
› Insulin resistance
 Clinical Comparison of Weight
Gain
 CATIE Trial
› Greater than 7% increase
in body weight
› (p < 0.001)
› Olanzapine 30%
› Quetiapine 16%
› Risperidone 14%
› Perphenazine 12%
› Ziprasidone 7%
 Treatment of Metabolic Syndrome
 Exercise!!!!
› Increase insulin sensitivity
› Controls weight
 Diet
› Weight gain partially due to appetite stimulation
 Metformin
› Increase insulin sensitivity
› Reduces appetite (GI ADRs)
 Topiramate
› Taste perversion
 HealthBuddy™?
• Ellinger, LK, Ipema, HJ, Stachnik,JM. Efficacy of Metformin and Topiramate in Prevention and Treatment of Second-
Generation Antipsychotic–Induced Weight Gain. Annals of Pharmacotherapy 2010;44:668-79.
• Bushe, CJ, Bradley, AJ, Doshi, S, Karagianis, J. Changes in weight and metabolic parameters during treatment with
antipsychotics and metformin: do thedata inform as to potential guideline development? A systematic review of clinical
studies. The International Journal of Clinical Practice. 2009
• Wong, R-R, et al. Metformin addition attenuates olanzapine-induced weight gain in drug-naïve first-episode schizophrenia
aptients: A double-blind, placebo-controlled study. American Journal of Psychiatry 2008; 165:352–358
 Monitoring of Metabolic Side
Effects of Antipsychotics

 Morrato, EH et al. Metabolic screening after the American Diabetes Association’s consensus statement on antipsychotic drugs and diabetes. Diabetes
Care 2009;32:1037-1042
 EPS
 Extra Pyramidal Side Effects
› Generated by extra pyramidal cells in the nigrostriatal pathway
› Range from lip smacking to gross tremors
 Abnormal Involuntary Movements Scale (AIMS)
› 12 item clincician administered test
 Four questions on orofacial movments
 Three questions on extremity and truncal dyskinesia
 3 questions on global severity, both patient and clinician perspectives
 Two questions about possible dental confounders
› Should be re-administered at least every 6 months for antipsychotics to be re-approved
› Available for download at http://www.cqaimh.org/pdf/tool_aims.pdf
 Treatment/Prevention
› Anticholinergics
 Diphenhydramine
 Benztropine
 ADR Management Summary
 Antipsychotic therapy has a very high failure rate
due to both intolerance and lack of efficacy
 EPS have classically been associated with FGA,
but that may have been a dose-response effect
 Metabolic side effects are know, but not typically
well managed in the community
 Nothing but opportunity for pharmacist to help
manage therapy
Therapy Management
 Polypharmacy: Is it good policy?
1. Rational
› No studies have been performed demonstrating multiple antipsychotics to be more
effective than monotherapy
2. Clinically Appropriate
› Antipsychotics have a high discontinuation rate
› There is a documented efficacy hierarchy, with Olanzapine and Clozapine having
been demonstrated to be the most efficacious in refractory schizophrenia
3. Safe
› Current models of schizophrenia as a D2 mediated disorder suggest that multiple
agents with the same MOA is essentially administering supra-maximal doses
4. Cost Effective

• Principles of a Sound Drug Formulary System.  October 2000

• Lieberman, JA et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. NEJM
2005;353:1209-23
 Cross Tapering – When
polypharmacy make sense
 Comparison of three switching strategies
 RR of early discontinuation was 0.77 (CI 0.61–0.99)
 Can discontinuation of previous antipsychotic be part of the non-formulary
approval process?

• Ganguli, R. et al. Assessment of strategies for switching patients from olanzapine to risperidone: A randomized, open-label,
rater-blinded study. Medicine 2008, 6:17
 Formulary Recommendations
Risperidone
Quetiapine
 Each agent should
undergo a 6 week Aripiprazole
Ziprasidone
trial for efficacy
 AIMS testing and
Candidate
No
lipid screening is for
Clozapine
required with ALL
SGA at initiation Yes
and every 6 Clozapine Olanzapine
months.
Paliperidone
 Equipotent Dosing
Medication Chlorpromazine Typical dosage VA cost based on
100mg/day range (mg) maximum daily
equivalents (mg) dose
Clozapine 50 250-500 $3
Quetiapine 75 300-800 $6
Olanzapine 5 15-30 $22
Ziprasidone 60 80-160 $8
Risperidone 2 2-6 $1
Aripiprazole 7.5 10-30 $6
Haloperidol 3* ~15 $0.37

*Haloperidol equivalent dose is 3 mg at<20 mg/d and 5 mg at >20 mg/d

• Woods, Chlorpromazine equivalent doses for the newer atypical antipsychotics.Journal of Clinical Psychiatry. 2003;64:663-667
• Atkins, M, Burgess, A, Bottmley, C, Riccio, M. Chlorpromazine equivalents: a consensus of opinion for both clinical and research
applications. Psychiatric Bulletin 1997;21:224-226
• Pricing from VISN 2 CPRS. Retrieved 6/8/2010
 Clozapine
 Widely regarded as the most effective SGA
 Avoided because of agranulocytosis
› Occurs in less than 2% of patients
› Typically within the first 6 months
› Requires weekly monitoring
 WBC >2000/mm3
 ANC >1000/mm3
 Also has significant, dose-response weight
gain, approximately one pound per week
 Providers at the Syracuse VA recognize it
can be tremendously effective, but are
reluctant to use it due to intensive
monitoring and workload constraints
› What a great opportunity for pharmacy!!!

• Agid, O. et al. Early Use of Clozapine for Poorly Responding First-Episode Psychosis Journal of Clinical Psychopharmacology 2007;27:369-373
• Clozapine Underutilization and Discontinuation in African Americans Due to Leucopenia Schizophrenia Bulletin 2007;33:1221–1224
• deLeon, J. et al. Weight Gain During a Double-Blind Multidosage Clozapine Study Journal of Clinical Psychopharmacology 2007;27:22-27
• McEvoy et al. Effectiveness of Clozapine Versus Olanzapine,Quetiapine, and Risperidone in Patients With Chronic Schizophrenia Who Did Not Respond to Prior
Atypical\Antipsychotic Treatment Am J Psychiatry 2006; 163:600–610
• Alvir, JMJ, et al. Clozapine-Induced Agranulocytosis -- Incidence and Risk Factors in the United States. NEJM 1993’;329:162-167
 Non-Traditional Uses
 PTSD
› Olanzapine and Risperidone have been demonstrated no more effective than placebo in controlling
symptoms
 Depression
› Antipsychotics as add on therapy, not as monotherapy in PSYCHOTIC depression vs. Major Depressive
Disorder may be appropriate.
› Monotherapy is less effective than SSRI based therapy
 Insomnia
› Primarily due to anticholinergic effects
 Can you say hydroxyzine?
› Per VISN 2 formulary: Please try to deter providers from using low-dose quetiapine 25mg QHS for sleep.
 Agitation
› Some have FDA indication for this use
 Olanzapine IM
 Aripiprazole IM
 Ziprasidone IM

• Stein, DJ, Ipser, JC, Seedat, S. Pharmacotherapy for post traumatic stress disorder (PTSD). The Cochrane Collaborative. 2009
• Wijkstra, J, Lijmer, J, Blak, F, Geeddes, J, Nlen, WA. Pharmacological treatment for psychotic depression. The Cochrane Collaborative. 2009
 Agitation & Behavioral
Emergencies
 The Expert Consensus Guideline Series. Treatment of
Behavioral Emergencies 2005. J Psychiatr Pract. 2005;11 Suppl
1:5-108
› No SGA emerges as a non-specific replacement for haloperidol.
 If using haloperidol, use with benzodiazepines
› For oral treatment for agitation related to schizophrenia or mania first
line is
 Haloperidol plus Benzodiazepines
 Risperidone +/- Benzodiazepines
 Olanzapine +/- Benzodiazepines
› Second line therapy
 Ziprasidone
 Quetiapine
 New Agents
 Asenapine (Saphris®)
› Dibenzamine, similar to olanzapine and clozapine
› Low Muscarinic receptor affinity
› High Dopamine and serotonin affinities
› Available only as a sublingual formulation
 Iloperidone(Fanapt®)
› Structurally similar to risperidone and aripiprazole
› Low muscarinic receptor affinity
› High affinity for dopamine and serotonin receptors
› Also as norepinephrine receptor affinity
› Available as standard tablets
 No significantly compelling reasons to add to the
formulary
• Descriptive information from Clinical Pharmacology Online Database
• Structures downloaded from wikipedia.org
 Therapy Management Summary
 Polypharmacy is not justified by
› Mechanistic benefits
› Evidence based medicine
› Cost
 Treatment resistant patient should work through the formulary, giving
serious consideration to pharmacist-assisted use of clozapine
 Gradual cross titration of antipsychotics is appropriate, but pharmacist
should monitor carefully to prevent inadvertent polypharmacy
 SGA not demonstrated superior to haloperidol + BNZ for agitation
 Newest agents are, in essence, “me-too” agents and are not easily
justified clinically or economically
 Conclusions
 Antipsychotic therapy is a moving target, with a
shifting debate on optimal therapy
 Therapy management consists of carefully, continuous,
and deliberately balancing efficacy and side effects
 To date, poly-pharmacy (2+antipsychotics) is not
rational, safe, cost-effective
 The formulary actually does a good job of balancing
efficacy and ADRs
 The opportunities for pharmacist to optimize therapy
are HUGE