Pharmacological strategies for early
stages of schizophrenia
Russell L. Margolis, M.D.
Johns Hopkins Clinical Schizophrenia Program
NAMI Maryland Conference October 11, 2013
Disclosures
I am a salaried employee of Johns Hopkins University:
Beholden to many
Dr DePaulo
My boss
Dr. Rothman
The Dean
Johns Hopkins
(watching over me
from heaven)
Michael Bloomberg
(watching over us from NY)
Also, of no obvious direct relevance:
• cells licensed to Merck
• Huntington’s disease clinical trials funded by Pfizer/Forest/Medivation/Prana/Neurocrine
• Funding from the NIH, Cure Huntington’s Disease Initiative, Hereditary Disease Foundation
This talk may, or may not, discuss off-label use of pharmaceutical agents. It is
not possible to predict ahead of time.
The situation:
1. Person recently diagnosed with schizophrenia
2. Returning to outpatient care after hospitalization
3. Doing much better on medicines; not necessarily
fully recovered clinically or functionally
Need for continued medicine: little doubt
104 patients who responded to treatment after first episode of illness (Robinson et
al, 1999): Total relapse rate by the end of 5 years: 82%
Predictors of relapse
Social or academic difficulties prior to illness onset: 1.5 x higher
Not taking medicines: ~5x higher
Non-predictors: sex, scz vs scz-aff, obstetrical complications, duration of psychotic
symptoms, type of symptoms at baseline, psychotic response to methylphenidate, EPS,
growth hormone, homovanillic acid levels, brain volume measures, neuropsychological
measures, time until treatment response, extent of residual symptoms
Nearly identical findings in a recent study of 140 patients (Caseiro et al, 2012)
Studies in which patients deliberately taken off medicines after first episode: 8094% relapse rate within 2-3 years (e.g., Emsley et al, 2012; Zipursky et al, 2013).
Choice of medicines: Currently available
antipsychotics in U.S.
Typical (first generation)
antipsychotics
Atypical (second generation)
antipsychotics (
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haloperidol (Haldol)
fluphenazine (Prolixin)
chlorpromazine (Thorazine)
droperidol (Inapsine)
loxapine (Loxitane)
mesoridazine (Serentil)
molindone (Moban)
pimozide (Orap) (off-label)
perphenazine (Trilafon)
thioridazine (Mellaril)
thiothixene (Navane)
trifluoperazine (Stelazine)
aripiprazole (Abilify)
clozapine (Clozaril)
olanzapine (Zyprexa)
quetiapine (Seroquel)
risperidone (Resperidal)
ziprasidone (Geodon)
paliperidone (Invega)
iloperidone (Fanapt)
asenapine (Serapis)
lorasidone (Latuda)
Which to choose?
1. Efficacy: Conflicting evidence. Olanzapine a little better?
2. Minimize side effects
Movement disorders: older agents, but also newer agents
Metabolic syndrome: marked variation among meds
Newcomer, 2005
3. Cost: 1 month haloperidol $4, lurasidone $165-379 on-line
Clozapine as third line agent
Clozapine most effective agent for patients who fail other antipsychotics
Current conventional wisdom: Use after two good trials of another agent
Example: Agid et al, 2011
244 individuals with first episode psychosis (average age ~22)
1st trial : up to three months of increasing doses of risperidone or olanzapine
75% responded (olanzapine a little better)
2nd trial: Nonresponders to first trial put on the other medicine
17% responded
3rd trial: nonresponders to 2nd trial put on clozapine:
75% responded
Should clozapine be a first or second line treatment option?
Problem is logistics (weekly blood draw) and side effects: agranulocytosis,
myocarditis, sialorrhea, tachycardia, myoclonus, seizures, constipation, etc
Non-adherence to antipsychotics treatment in
schizophrenia : Common!!!
sampling of the literature
Cramer & Rosenheck, 1998
Nose et al, 2003
Lacro et al, 2002
rate
60%
30%
41-50%
comment
Review, old studies
Review
Review
Ascher-Svanum et at, 2006
Tiihonen et al, 2011
19%
54%
Large single study
Finnish, rate one month
after discharge from
first hospitalization
Best predictor of nonadherence: Nonadherence!
Ascher-Svanum et al, 2006
1579 patients in 3 year prospective naturalistic study taking oral antipsychotics
Prior to enrollment
Odds ratio (Confidence Interval)
Non- adherence in past 6 months
4.1 (3.1-5.6)
Illicit drug use
1.8 (1.1-3.0)
Alcohol use
1.6 (1.1-2.2)
Antidepressant use
1.4 (1.1-1.9)
Medicine-related cognitive concerns 1.3 (1.1-1.5)
Prior adherence had a 79% level of accuracy in predicting future adherence
Other factors: depressive symptoms, violence/arrests, victimization, subjective
medicine related adverse events , cognitive impairment
Multiple other studies have confirmed past nonadherence predicting future
Conceptualization of non-adherence
Patient-centered factors
Passive:
forgetfulness/confusion
apathy
Active:
avoidance of side effects
belief that medicines are not helpful
general mistrust of treatment
Environmental factors
Cost
Access
From Beck et al 2011, others
General Psychotherapeutic Strategies
1. Explore prior experiences with antipsychotics:
avoid agents with objective or perceived negatives
2. Persuasion about both perceived concerns and perceived benefits
3. A focus on illness insight may not be necessary or useful
4. Improving general attitude toward pharmacotherapy
Other conditions require chronic treatment: e.g, asthma, etc
Antipsychotics used for many purposes
5. Therapeutic relationship—requires stability of treatment team
Specific adherence strategies
1. Medicine supervision
Caregiver supervision
Mobile treatment
Assisted living environment
Capitation programs
2. Medicine strategies
Specific adherence rating scales
Pill counts
Electronic monitoring
Automated reminder systems
Choose medicine with once daily dosing
Avoid excessively high doses
Davis and Chen, 2004
Treat metabolic side effects
Wu et al, JAMA, 2008
128 first-episode patients with weight gain on an antipsychotic
Randomized to 750 mg/day metformin, life style intervention ( education, diet,
exercise), both, or neither and followed for 12 weeks;
Similar results for other metabolic measures
Use long-acting injectables:
Haloperidol and fluphenazine decanoate: oil suspension
Risperidone Consta: dissolvable microspheres
Olanzapine palmitate:
Risperidone Consta: dissolving microspheres
Paliperidone palmitate (Sustenna)
Abilify Maintena
Increase adherence to 60-80%, 2-3x better than pills
Summary
Medicines needed for treating first episode psychosis
Multiple choices of medicines
olanzapine may be best of newer agents
clozapine is valuable as 3rd line, earlier?
Side effects problematic: can be managed
Adherence can be increased: therapeutic alliance, new
home, once daily dosing, treat side effects, avoid
overly high doses