1. Schizophrenia in Teenagers and Young Adults From the Johns Hopkins Clinical Schizophrenia Program: Russell L. Margolis, M.D. Krista Baker, LCPC Tom Sedlak, M.D., Ph.D. For information about clinical services, contact Krista Baker, 410-550-0137 NAMI Maryland Conference October 18, 2013F

2. Pharmacological strategies for early stages of schizophrenia Russell L. Margolis, M.D. Johns Hopkins Clinical Schizophrenia Program NAMI Maryland Conference October 18, 2013

3. Disclosures Also, for Dr. Margolis, and 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 Our talks, or may not, discuss off-label use of pharmaceutical agents. It is not possible to predict ahead of time. Drs. Margolis and Sedlak are salaried employee of Johns Hopkins University; Ms. Baker of Johns Hopkins Bayview Medical Center: We are beholden to many who influence us: Dr Ray DePaulo Our Boss; chair of Psychiatry at JHU Dr. Rothman The Dean Johns Hopkins (watching over us from above) Michael Bloomberg (watching over us from NY)

4. 1. Person recently diagnosed with schizophrenia 2. Returning to outpatient care after hospitalization 3. Doing much better on medicines; not necessarily fully recovered symptomatically or functionally The situation:

5. 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).

6. 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 (Saphris) lorasidone (Latuda) * Long acting injectable forms also available

7. 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

8. 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

9. 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

10. 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 confirm that past nonadherence predicts future nonadherence 1579 patients in 3 year prospective naturalistic study taking oral antipsychotics

11. 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 belief that can stop meds once doing better fear of stigma Environmental factors Cost Access From Beck et al 2011, others

12. 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

13. 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

14. Avoid excessively high doses Davis and Chen, 2004

15. 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

16. Use long-acting injectables: Haloperidol and fluphenazine decanoate Risperidone (Consta) Olanzapine pamoate (Relprevv) Paliperidone palmitate (Sustenna) Aripiprazole (Abilify Maintena) Increase adherence to 60-80%, 2-3x better than pills Dosing every 2-4 weeks depending on the medicine

17. 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

18. Krista Baker, LCPC Clinical Supervisor Early Psychosis Intervention Clinic Johns Hopkins Bayview Medical Center No relevant disclosures

19. Where do I start? The importance of finding the right OP TEAM-need this for referrals to higher levels of care/continuity and coordination of care. Where can I get information? Getting an accurate diagnosis is so important to guide medication decisions Determine the appropriate level of care How does insurance or lack of insurance affect my decisions?

20. ALPHABET SOUP

21. Typical First Sessions in OP Complete Diagnostic and Psychosocial Evaluation Meet psychiatrist and discuss medication and current side effects Elicit concerns from patients and families (ex: recent dangerous behavior, substance abuse, acute symptoms, self-care deficit) Assess current level of functioning and need for referrals for additional services

22. Psychosocial Interventions Support & Psycho-education Creating a Comfortable Environment Social Skills/Social Contact Relationship Building Short and Long Term Goal Setting Relaxation Techniques Nutritional Information/Referral Discussing Medication Adherence Psycho-Social Interventions

23. Social Skills Training Discuss skills and identify where to start (most impairing) Discuss steps in achieving goals Model and review Provide positive and corrective feedback when necessary Find ways to have patient practice skill (PRP, home, hospital setting, online game) Provide behavioral reinforcement for successes Establishing and maintaining social contact is a necessity

24. Cognitive Behavior Therapy Rationale Client centered goals are the key to this treatment Can not proceed until the client identifies goals CBT for SZ is not a tx to eliminate symptoms but rather to deal with psychosis as a block to their goals (ex: I want a job in Hawaii but can’t get out of bed)- match the goal with specific interventions-this will more likely improve adherence Goals need to be revisited at every session

25. Cognitive Behavioral Therapy Interventions Continued focus on recognizing and reducing negative symptoms Reality or hypothesis testing-what evidence do you have to substantiate that? Pie charts….etc… “Floating an idea” Cognitive Restructuring Help patient to develop coping strategies for difficult symptoms (look/ point/name, graded task assignment, bring on sx’s to reinforce you get through them Normalizing symptoms and behaviors (a lot of people going through what your going through would not be able to sleep or feel nervous)

26. Psychiatric Rehabilitation Programs (PRP) Provide daily structure through intensive onsite services Supported housing services Supported employment services vs. competitive employment Rehabilitation coordination (bring together all services and supports-family, medical, psychiatric, residential and vocational) Provides offsite services when necessary

27. Other treatments to consider… Cognitive Remediation Multi-Family Groups Participation in NAMI peer to peer or family to family Referral to a wellness program for exercise Occupational Therapy Referral for a nutritionist Residential Treatment Facilities

28. Summary There is no right or wrong combination-IT’S INDIVIDUAL SPECIFIC! Communication between providers on a regular basis is mandatory for effective treatment If unsure, get a second opinion Family members should get support It’s the big picture that counts-don’t let set backs discourage you

29. Krista Baker, LCPC Clinical Supervisor Early Psychosis Intervention Clinic (EPIC) Johns Hopkins Bayview Medical Center kbaker1@jhmi.edu

30. Marijuana — Its Impact on the Patient with Psychotic Symptoms Thomas Sedlak, MD, PhD Schizophrenia Center Schizophrenia Consultation Clinic Johns Hopkins School of Medicine Disclosures: No relevant financial relationships with commercial interests

31. Drug Use In The Patient With Psychotic Symptoms Why is this important? Greater severity of symptoms Treatment becomes less effective Reduced chance of full recovery Increased medical complications Increased risk of violence Increased risk of suicide

32. Violence and Schizophrenia Substance abuse accounts for the bulk of the risk

33. Illicit Drug Use Is Highest In Youths Past Month Illicit Drug Use among Persons Aged 12 or Older, by Age: 2011 and 2012 (source SAMHSA)

34. Marijuana Use in Teens (2012) 14% Past month 1.2% 0.7%

35. Marijuana attitudes have changed over time Prohibition Hayes code censorship of Hollywood Reefer Madness (1936) 1920s-40s Tied to counter culture movements 1960s Organized movement for legalization “Medicalization” 1980s-today

36. Marijuana Effects Iversen Euphoria, perceptual alterations Increased appetite Paranoia Decreased motivation Impaired memory, attention, cognition Greater marijuana use = greater impairment

37. Can There Be Marijuana Withdrawal? Source: Kouri 2000 Anger, aggression, irritability Anxiety, depression Loss of appetite Restlessness, insomnia, tremor Chills, sweats, stomach pain Duration up to 7-28 days Yes

38. Association of Marijuana Use and Schizophrenia Marijuana use has long been known to exacerbate psychotic symptoms Marijuana leads to worse outcomes in Schizophrenia even after controlling for: use of other drugs medication compliance [Jablensky 1992, Hides 2006]

39. Cannabis and Risk of Schizophrenia Purpose: Was Marijuana (cannabis) use associated with any risk of later being diagnosed with schizophrenia? Longitudinal (retrospective) study of 45,570 Swedish men in required military service Included over 97% of the male population age 18-20 Does Cannabis Use Cause Psychotic disorders?

40. Cannabis and Risk of Schizophrenia 3-6 fold increased risk of later developing schizophrenia if individuals smoked marijuana 50 times or more Replicated multiple times in other studies

41. Synthetic Cannabinoids of Abuse Often sold as herbal “incense” packets in convenience stores Smoked or eaten Brand names such as “Spice” and “K2” received the most attention in the media, but there are many varieties 11,406 Emergency Room visits in 2010 attributed to these Vomiting, altered blood pressure, seizures, hallucinations 11% of US high school seniors tried it in the past year Different brands are mixtures of different synthetics Packets often do not even contain the herbs they say they do (chemical analysis not consistent with labeling)

42. Institute of Environmental Science and Research (7/2011) study found 11 synthetic cannabinoid ingredients in 41 synthetic cannabis brands sold in New Zealand

43. Can you buy drugs on the internet?

44. Other drugs Use of multiple additional drugs impairs functioning in psychotic symptoms Cocaine Amphetamines Abuse of prescription drugs (ex. snort Adderall) Opioids and Heroin Alcohol Hallucinogens (LSD, PCP, ketamine) Inhalants, sniffing glue

45. Treating the Patient Using Illicit Drugs “Confrontation with a smile” Hard to fully treat until they stop using drugs Marijuana often dismissed as no risk Need for periodic drug testing Many facilities have specialized “dual diagnosis” clinics and providers Hospitalization may be required

46. Many Unknowns Exist: Your help is needed Predicting who is at risk Predicting the course of illness Predicting the best treatments Reducing side effects Better treatments for cognition Obtaining the highest degree of functioning Consider participating in research