Is everything that makes sense true?

Transcription

1 Do Long Acting Injectables (LAIs) Antipsychotics Enhance Adherence In Schizophrenia? Is everything that makes sense true? Are LAI-SGA different from LAI-FGA? Michael Davidson MD

2 Conflicts Over the last 15 years, I have benefited from almost every endeavor which had, has, or intends to market a treatment for schizophrenia. Hence, everything I do, say, or even think, represents a conflict of interests. I own stocks in CTR and received grant support and/or travel support and/or speaker fees and/or consultancy fees from: JNJ, Pfizer, Lundbeck, Teva, BioLineRx, Lilly, Sanofi-Aventis, Roche, GSK, Servier, Envivo, Novartis, Abbott, Otzuka, Takeda and Minerva.

3 The bleak outcome of schizophrenia 1. Approximately 90% of patients will remain too ill to lead a normal life 2. Only between 5 10% of patients are gainfully employed in regular jobs 3. Life expectancy is years shorter than in the general population 4 A pessimist is an optimist with access to data 1. Jääskeläinen E et al. Schizophr Bull 2013;39: ; 2. Davidson M et al. Schiz Bull 2015;

4 Treatments for schizophrenia The Wish List Rapidly suppress psychosis in all individuals Prevent exacerbation Change disease course Suppress aberrant behaviour and negative symptoms Improve cognition and vocation Be well tolerated and cost-effective Have easy-to-understand, biologically plausible mechanism The Reality In a few, severely ill patients, ameliorate delusions, hallucinations, and poor thought process for intermittent periods Suppress agitation and induce sedation (tranquilise) in a dosedependent manner In mild-to-moderately ill patients, and in asymptomatic patients, decrease risk of worsening or exacerbation of psychosis

5 Major tranquilizers for symptoms or disease-centered drugs? The initial description based on observations was consistent with a non-specific tranquilizing effect Subsequently, this view was replaced by the Koch-like approach (pathogen-disease-treatment) Contributed to the disease-centered drug approach: mirage of DA hypothesis advent of the DSM the physician s and the public quest for certainty regulatory mandates commercial considerations.

6 How do major tranquilizers become anti-psychotics?

7 What do physicians do when needs are not met*? Increase doses of antipsychotics Change antipsychotics Combine antipsychotics Add another psychotropic: Anticonvulsants Benzodiazepines Antidepressants Lithium ECT, TMS, abracadabra Is it useful? Is it right? What should they do? *most not evidence based

8 Are second-generation antipsychotics more effective than fist generation? Is it a matter of dosing? EUFEST Olanzapine and amisulpride better than ziprasidone and quetiapine. All four better than haloperidol in a statistically significant manner on the main outcome 23. Kahn R et al. Lancet 2008;371:

9 Are the differences a matter of dosing? CATIE EUFEST Multiple MET-ANAYSES Small but statistically significant advantages for SGA. What is clinically significant vs. statistically significant?

10 Poor adherence with Rx Are LAI the solution?

11 Poor adherence and poor insight are not schizophrenia related phenomena % Adherence among Patients Receiving Treatment for Chronic Conditions 100% Percent Adherence 50% Chronic Hemodialysis COPD Different Transplantation Populations Type II Diabetes Hypertension Patients with chronic diseases (average) Restrepo, et al. Int J Chron Obstruct Pulmon Dis Dew et al. Transplantation 2007 Osterberg L. NEJM 2005 Rudd P. Am Heart J 1995 Schmid, et al. Eur J Med Res Adherence to long-term therapies. World Health Organization 2003

12 What is it all about? Adherence to medication Sloppy life style Denial Poor risk assessment Correct risk assessment (intuitively) Poor communication

13 Consequences of Poor Adherence If the drug helps not taking it is bad for your health Unidentified non-adherence may lead to unnecessary: Medication changes Dosage increases Concomitant medications Labeling of patients as treatment resistant Byerly M, et al. Psychiatry Res. 2005;133: Velligan DI, et al. Schizophr Bull. 2006;32: Velligan DI, et al. Psychiatric Services. 207;58:

14 Relapse is not good for your health Successive Relapses Prolonged the Time to Remission. Why what does it mean? 3-Episode Group (n=10) First episode Second episode Third episode *P= * Median Time to Remission (Weeks) Lieberman JA, et al. Neuropsychopharmacology. 1996;14(3 suppl):13s-21s.

15 Factors Affecting Adherence with Treatment Specific To Schizophrenia Lack of insight Lack of information Experience of unpleasant side effects Discrimination associated with the illness and medication Ease of access to treatment Cultural beliefs, illness concepts, attitude towards medications Degree of family or social support Cognitive impairment Substance abuse/misuse Efficacy of treatment APA Practice Guidelines for treatment of patients with schizophrenia; 2004, 2nd ed

16 Is non-adherence always a patient's irrational decision? Psychotic exacerbation and/or hospitalization might not such terrible options; Dealing with prescriptions, doctors, injections and the mental health system might be too painful; Partial adherence might be the patients method to achieve the lowest effective dose; What about the ¼ of the patients for whom medication is ineffective? Everything considered, might life be better without medication?

17 What Do We Really Know about Our Patients Adherence (and response)? The difficulties in measuring adherence in patients with schizophrenia

18 How easily are we fooled! Adherence to Treatment Among Outpatients With Schizophrenia 100 Adherence Rate (%) Self-Report Clinician rating Pill Count MEMS* Adherence Measure *Medication Event Monitoring System (MEMS ) Remington G et al. Scz Res 2007

19 Is Targeted-Intermittent Treatment The Solution? 5 trials, in the 1990s, show that intermitend treatment is less effective than continuous treatment Is this the end of story? Does this mean that missing several oral doses or being late for the depot medication affects effectiveness? Is there a way around it? 1. Carpenter WT, et al. Am J Psychiatry, Gaebel, W, et al. Br J Psychiatry, Herz, MI, et al. Arch Gen Psychiatry Jolley AG. Br Med Journal, Schooler NR, In: Oldham & Riba (Eds.) Continuing medical education syllabus and scientific proccedings. 146 th meeting of the APA

20 Why so few first episode (recent onset) patients are on LAI? Paradoxically they are: Best responders to treatments Worst in terms of adherence More likely to reintegrate back into society Hence, they have the have the best benefit/risk ration LAI are only for chronic, non-responders, proven to be non-adherent?

21 Do LAI increase adherence? Are LAI more effective then oral drugs?

22

23 -Most recent meta-analysis of RCTs failed to find relapse prevention tolerability, adherence, hospitalization advantages for LAIs over oral antipsychotics. -Only older studies (using older drugs, primarily LAI fluphenazine) found LAI advantages Kishimoto et al. Schizophrenia Bulletin 2014

24 Relapse Rates on Oral Fluphenazine vs. LAI Fluphenazine Why does it take so long to demonstrate the difference? Hogarty et al. Arch Gen Psychiatry 1979 The non-responders who are a significant proportion of the patients in trials do not respond to anything regardless of adherence

25 LAIs vs. Oral Treatment - Methodological Issues Technique Advantages Disadvantages Results of comparison studies Randomized blinded Controlled Trials (RCT) Injectable placebo vs. active oral treatment Randomization Blinded Controlled Selective recruitment Represent only adherent patients No differences, some differences in secondary or global outcomes Observational Prospective studies Patients on oral treatment vs. patients on LAI treatment Real life naturalistic studies Non-randomized. Compare different types/generations of antipsychotics Conflicting and inconclusive: FGA-LAIs better than oral-fga (remission/rehospitalization) Oral-SGA better than FGA-LAIs (remission/rehospitalization) Mirror image studies LAI treatment vs. oral treatment immediately preceding LAI initiation Same patients are treated with oral and than LAI Initial treatment with oral medication ends with treatment failure LAIs are better (length and number of admissions) Haddad PM et al. Br J Psy 2009

26 Independently funded head to head comparison JAMA individuals diagnosed with schizophrenia at risk of relapse due to history of noncompliance or substance abuse Randomized to paliperidone palmitate IM monthly or haloperidol decanoate IM monthly Follow-up up to 2 years

27

28

29 Similar rates of adverse events + side effects for paliperidone palmitate and haloperidol decanaoate

30 Significantly more weight gain with LAI paliperidone. No significant differences on other metabolic measures

31 Significantly more akathisia with LAI haloperidol Significantly higher prolactin levels with LAI paliperidone Trends favoring PP on other neurologic side effects, and favoring HD on prolactin-related effects

32 Are potential differences between LAI the result of doses, dosing and pharmacokinetics?

33

34

35 What is new in the foreseeable future? Paliperidone palmitate injectred once every 3 months Inhalator antipsychotics Oral long acting

36 What is new in the non- foreseeable future? 1. If I knew I would be there now 2. Try non-hypothesis driven anything that has CNS activity (Employ careful, observational, experimental pharmacology) 3. Decompose schizophrenia and target specific symptoms (Rdoc) 4. Walk the road from genetic mutation(s) to protein to brain circuit to pharmacological target and back to genetic mutation(s) 5. Retire and let the smarter more dedicated people figure it out A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die and a new generation grows up that is familiar to it. Max Planck

37 I hope I have not affected your views on LAI or the Rx of schizophrenia in general Any questions?