1. Pharmacological strategies for early stages of schizophrenia Russell L. Margolis, M.D. Johns Hopkins Clinical Schizophrenia Program NAMI Maryland Conference October 11, 2013

2. 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. Rothman The Dean Johns Hopkins (watching over me from heaven) Michael Bloomberg (watching over us from NY)

3. 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:

4. 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).

5. 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)

6. 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

7. 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) 1 st trial : up to three months of increasing doses of risperidone or olanzapine 75% responded (olanzapine a little better) 2 nd trial: Nonresponders to first trial put on the other medicine 17% responded 3 rd trial: nonresponders to 2 nd 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

8. Non-adherence to antipsychotics treatment in schizophrenia : Common!!! sampling of the literature ratecomment Cramer & Rosenheck, 199860%Review, old studies Nose et al, 200330%Review Lacro et al, 200241-50%Review Ascher-Svanum et at, 200619%Large single study Tiihonen et al, 201154%Finnish, rate one month after discharge from first hospitalization

9. Best predictor of nonadherence: Nonadherence! Ascher-Svanum et al, 2006 Prior to enrollmentOdds ratio (Confidence Interval) Non- adherence in past 6 months4.1 (3.1-5.6) Illicit drug use1.8 (1.1-3.0) Alcohol use1.6 (1.1-2.2) Antidepressant use1.4 (1.1-1.9) Medicine-related cognitive concerns1.3 (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

10. 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

11. 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

12. 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

13. Avoid excessively high doses Davis and Chen, 2004

14. 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

15. 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

16. Summary Medicines needed for treating first episode psychosis Multiple choices of medicines olanzapine may be best of newer agents clozapine is valuable as 3 rd 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