Pharmacological strategies for early stages of schizophrenia

Russell L. Margolis, M.D.Johns Hopkins Clinical Schizophrenia Program

NAMI Maryland Conference October 11, 2013

Disclosures

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.

I am a salaried employee of Johns Hopkins University:Beholden to many

Dr DePaulo My boss

Dr. RothmanThe Dean

Johns Hopkins (watching over me from heaven)

Michael Bloomberg(watching over us from NY)

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

The situation:

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: 80-94% 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

• 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)

Atypical (second generation) antipsychotics (

• 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 effectsMovement disorders: older agents, but also newer agentsMetabolic syndrome: marked variation among meds

Newcomer, 2005

3. Cost: 1 month haloperidol $4, lurasidone $165-379 on-line

Clozapine as third line agentClozapine most effective agent for patients who fail other antipsychotics

Current conventional wisdom: Use after two good trials of another agent

Example: Agid et al, 2011244 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% responded3rd 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

rate commentCramer & Rosenheck, 1998 60% Review, old studiesNose et al, 2003 30% Review Lacro et al, 2002 41-50% ReviewAscher-Svanum et at, 2006 19% Large single studyTiihonen et al, 2011 54% Finnish, rate one month

after discharge from first hospitalization

Best predictor of nonadherence: Nonadherence!Ascher-Svanum et al, 2006

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

1579 patients in 3 year prospective naturalistic study taking oral antipsychotics

Conceptualization of non-adherence Patient-centered factors

Passive: forgetfulness/confusion apathyActive: avoidance of side effects belief that medicines are not helpful general mistrust of treatment

Environmental factorsCostAccess

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 strategies1. Medicine supervision

Caregiver supervisionMobile treatmentAssisted living environmentCapitation programs

2. Medicine strategiesSpecific adherence rating scalesPill countsElectronic monitoringAutomated reminder systemsChoose 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 medicinesolanzapine may be best of newer agentsclozapine 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