Antipsychotics: New agents and new perspectives on older agents Ted D. Williams PharmD, PGY1 Resident Syracuse VAMC June 9, 2010
Transcript
Slide 1
Slide 2
Slide 3
Psychotic Disorders Pathophysiology & Pharmacology Typical
vs. Atypical Antipsychotics Side Effect Management Therapy
Management A closer look at select agents
Slide 4
Psychosis Inappropriate processing of sensory information
Disturbed views of reality and self Not recognized by sufferer
Neurosis Abnormal reactions Recognized by sufferer by abnormal
Slide 5
Big Three Schizophrenia Bipolar Disorder Delirium in Dementia
Other Causes Depression Major Depressive Disorder Secondary
Depression Post Traumatic Stress Disorder Drug Induced
Slide 6
Positive Symptoms Disordered thoughts Delusions Paranoia
Hallucinations Loose ideation Negative Symptoms Flat Affect
Anhedonia loss of emotional response
Slide 7
Current models suggest psychotic symptoms to be a disregulation
in dopaminergic pathways These models primary built on efficacy of
dopamine antagonist in schizophrenia
Slide 8
D2 receptor occupancy of 65%70% correlates with maximal
antipsychotic efficacy 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 Extrapyramidal Symptoms (EPS) appear beyond 78% D2
occupancy without any increase in benefits at higher rates of
occupancy Ineffective EPS Optimal Response Nasrallah, HA, Dandon,
R.Textbook of Psychopharmacology:Chapter 27. Classic Antipsychotic
Medications
Slide 9
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
Slide 10
Meso- cortical MesolImbic Mesolimbic Overactivity of mesolimbic
pathway produce positive symptoms Mesocortical Underactivity of
mesocortical pathways produces negative symptoms Tuberoinfundibular
and Nigrostriatal pathways unaffected by Schizophrenia Tuberoin-
fundibular Nigrostriatal
Slide 11
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
Slide 12
FGA provide a strong dopama-lyticresponse 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
Slide 13
Meso- cortical MesolImbic Dopamine blockade correct mesolimbic
positive symptoms Serotonin corrects mesocortical negative symptoms
Too much dopamine blockade causes EPS via nigrostriatal Lactation
via Tuberoinfundibular The models dont 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
Tuberoin- fundibular Nigrostriatal MesolImbic
FGA have high D2 affinity and low 5HT affinity Newer SGA have
balanced D2 and 5HT affinities
Slide 16
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
Slide 17
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.
Slide 18
First vs. Second Generation Antipsychotics Metabolic Side
Effects
Slide 19
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
Slide 20
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
Slide 21
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
Slide 22
CATIE Trial Greater than 7% increase in body weight (p <
0.001) Olanzapine 30% Quetiapine 16% Risperidone 14% Perphenazine
12% Ziprasidone 7%
Slide 23
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 AntipsychoticInduced 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-nave first-episode schizophrenia aptients: A
double-blind, placebo-controlled study. American Journal of
Psychiatry 2008; 165:352358
Slide 24
Morrato, EH et al. Metabolic screening after the American
Diabetes Associations consensus statement on antipsychotic drugs
and diabetes. Diabetes Care 2009;32:1037-1042
Slide 25
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.pdfhttp://www.cqaimh.org/pdf/tool_aims.pdf
Treatment/Prevention Anticholinergics Diphenhydramine
Benztropine
Slide 26
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
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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
Slide 29
Comparison of three switching strategies RR of early
discontinuation was 0.77 (CI 0.610.99) 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
Slide 30
Each agent should undergo a 6 week trial for efficacy AIMS
testing and lipid screening is required with ALL SGA at initiation
and every 6 months. Risperidone Quetiapine Risperidone Quetiapine
Aripiprazole Ziprasidone Aripiprazole Ziprasidone Candidate for
Clozapine Candidate for Clozapine No Clozapine Olanzapine
Paliperidone Yes
Slide 31
MedicationChlorpromazine 100mg/day equivalents (mg) Typical
dosage range (mg) VA cost based on maximum daily dose
Clozapine50250-500$3 Quetiapine75300-800$6 Olanzapine515-30$22
Ziprasidone6080-160$8 Risperidone22-6$1 Aripiprazole7.510-30$6
Haloperidol3*~15$0.37 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
*Haloperidol equivalent dose is 3 mg at 20 mg/d
Slide 32
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;33:12211224 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; 163:600610 Alvir, JMJ, et al. Clozapine-Induced
Agranulocytosis -- Incidence and Risk Factors in the United States.
NEJM 1993;329:162-167
Slide 33
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
Slide 34
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
Slide 35
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
Slide 36
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
Slide 37
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