1. MEMANTINE AS AN ADJUNCT IN REFRACTORY SCHIZOPHRENIA

2. OVERVIEW Background: –Link between glutamatergic neurotransmission and schizophrenia Overview of RCTs: –Lieberman et al. –Lucena et al. Implication to practice

3. Background Schizophrenia: Glutamate deregulation may be involved, mainly through N- methyl-D-aspartate receptor (NMDAR) dysfunction Memantine: Weak nonselective NMDAR antagonist

4. Acts as a brake on mesolimbic dopamine pathway

5. NMDA receptors that regulate mesocortical dopamine pathways may also be hypoactive Normally acts as accelerators for dopamine neurons

6. A Randomized, Placebo- Controlled Study of Memantine as Adjunctive Treatment in Patients with Schizophrenia

7. Purpose To examine the efficacy and safety of memantine + atypical antipsychotics Patients: Schizophrenic patients with partial response to antipsychotic treatment but with persistent residual psychopathology

8. Inclusion Criteria Schizophrenia or schizoaffective disorder for at least 2 years Residual positive symptoms at screening and baseline: > 26 on BPRS (Brief Psychiatry Rating Scale) Residual positive symptoms for at least 3 months immediately preceding the trial –No exacerbation in the last 4 weeks Olanzapine, risperidone, quetiapine, aripiprazole, or ziprasidone for at least 3 months before randomization –stable dose for at least 4 weeks before randomization and during study Permitted meds: Lithium, divalproex, SSRIs, venlafaxine, mirtazapine

9. Exclusion Criteria A 20% change in total BPRS score from screening to baseline Bipolar I disorder, either manic or mixed episode Active suicide or homicide intent, or in the preceding 6 months Organic brain disease, dementia, or a traumatic brain injury Evidence or history of malignancy Significant hematological, endocrine, cardiovascular, respiratory, renal, hepatic, or gastrointestinal disease

10. PATIENT ALLOCATION

11. Study Design 8-week, double-blind, placebo-controlled, randomized Dosing titration: –Week 1: 5 mg/day –Week 2: 10 mg/day –Weeks 3-8: 20 mg/day Required sample size determination: –A clinically meaningful difference: 8.5 points in total PANSS score Intent-to-treat population Primary efficacy parameter: change from baseline to week 8 in PANSS total score Last Observation Carried Forward (LOCF) used for missing values

12. Safety Assessments Adverse events and concomitant medications Physical examination Monitoring of EPS (Barnes Akathisia Scale, Abnormal Involuntary Movement Scale, Simpson-Angus Scale) Vital sign measurements ECG, laboratory tests, urine drug screen

13. Baseline Characteristics

14. Outcome Measures Primary outcome measure: –Total score on the positive and negative symptoms scale at baseline (week 0) and weeks 1,2,3,4,6 and 8 Secondary outcome measures: –Positive and negative PANSS scores (all visits) –PANSS responders ( >10% reduction in total PANSS score) –Calgary Depression Scale for Schizophrenia (CDSS; week 0 and 8) –Clinical Global Impressions of Severity (CGI-I; week 4,6 and 8) –Composite z-scores and total construct scores of Brief Assessment of Cognition in Schizophrenia (BACS; weeks 0,4 and 8)

15. Results: Efficacy Baseline: groups well matched except gender and use of non-SSRIs Efficacy: –Mean change in total PANSS score: -4.5+ 10.9 (Memantine) vs. -3.7 +10.2 –Secondary outcomes: Insignificant difference

17. Results: Safety Memantine: –Higher discontinuation rate –Most frequent SAE: exacerbation of schizophrenia (2.9% vs. 6.0% in placebo) –Dizziness & auditory hallucinations incidence 2x that of placebo groups –Increases in auditory hallucinations not thought to be related to study medication by clinicians Author still highlights this

19. Investigators’ Conclusions No evidence of therapeutic benefits Possibility of worsening of psychotic symptoms by memantine Increased incidence of miscellaneous side effects Participants may not have been optimal population –May be helpful in more pronounced cognitive impairment or with severe residual psychopathology Safety profile less favourable than established profile

20. Factors affecting trial’s outcome The variety of atypical antipsychotics used Not sufficiently powered to detect individual interactions with memantine Relatively short duration of the trial Relatively long titration period (3 weeks) exposure to a max daily dose for only 62.5% time of the trial (5 weeks)

21. Improvement of Negative and Positive Symptoms in Treatment- Refractory Schizophrenia: A Double-Blind, Randomized Placebo-Controlled Trial With Memantine as Add-On Therapy to Clozapine

22. Study Design Double Blind (Subject, Caregiver, Investigator, Outcome Assessor), placebo-controlled, randomized trial Adult outpatients in Brazil with refractory schizophrenia On clozapine over the last 10 years with partial remission of negative symptoms Dosing titration: –Week 1: 5 mg/day –Week 2: 10 mg/day –Week 3: 15 mg/day –Week 4-12: 20 mg/day

23. Methods Assessments by trained psychiatrist blinded to treatment condition –Completed at weeks 4, 8 and 12 Required sample size determined using assumption that: –A clinically meaningful difference b/w 2 groups = 10 points in total BPRS score

24. Exclusion Criteria Any significant medical illness Use of any additional psychotropic agent except benzodiazepines or substance abuse Pregnant At reproductive age and not taking contraceptives

25. Patient Allocation

26. Baseline Characteristics

27. Outcome Measures Primary Outcomes: –Total score on BPRS –BPRS subscales of positive and negative symptoms Secondary Outcomes: 1. Severity of disease: CGI 2. Cognition: MMSE 3. EPS: Simpson-Angus Scale (SAS) 4. Weight

28. Results Baseline: No significant group differences in –Positive –Negative symptoms on the BPRS total –BPRS positive –BPRS negative symptom scores Week 12: Significantly greater decreases in memantine group in: –BPRS total score (week 12, 19.00 vs. 43.18, P=.001) –Positive score (week 12, 4.10 vs. 9.18, p=0.007) –Negative score (week 12, 6.10 vs 13.55, p=0.001)

29. Results Week 12 in Memantine group –CGI: Significantly greater improvement in overall functioning –Rated as significantly less ill –Significantly greater improvement in cognitive symptoms –SAS & weight: no significant difference –SEs: nausea & dizziness (1 Memantine, 3 placebo) Study supports initial hypothesis by Andreasen et al. –Improving glutamatergic tonus in prefrontal, thalamic and cerebro-cerebellar regions by NMDA partial activation could be responsible for the improvement of negative & positive symptoms

30. Results: BPRS Total

31. Results: BPRS Positive & Negative Symptoms

32. Results: CGI and MMSE Score

33. Clozapine & Memantine Clozapine increases expression of NMDARs and glutamate metabotropic receptors (mGluRs) Hyper expression of mGluR  increased brain-derived neurotrophic factor (BDNF) Chronic clozapine  elevated mGluR5  improved glutametergic tonus Special glutamatergic environment –Improvement with combination vs. failure with other associations –Appears to stabilize dopaminergic neurons dampening both hyperactivity and hypoactivity

34. Investigators’ Conclusion Memantine improved positive symptoms without worsening of psychosis: broader actions than previously realized Can prevent neuronal damage  prevents dopamine deficit Thus may act like antipsychotics by: –chronically reducing neuronal oxidative stress in treated patients –decrease neuroprogression & death Trial supports the use of memantine as an adjunctive to clozapine

35. Limitations Baseline: placebo group had slightly more severe symptoms on the BPRS and its subscales –Overestimation of memantine’s efficacy –Adjustment was done using ANCOVA –Less refractory more likely to respond Serum clozapine levels not measured –Adherence? Larger trials with longer follow-up period required MMSE not the most sensitive measure of cognition

36. Implications to Practice Could be tried in patients with partial response to clozapine May help with negative and cognitive symptoms RCTs with more subjects and longer trials required Positive results cannot be generalized to patients with less severe symptoms and without clozapine use

37. References Lieberman et al. A Randomized, Placebo-Controlled Study of Memantine as Adjunctive Treatment in Patients with Schizophrenia. Neuropsychopharmacology (2009) 34, 1322–1329 Lucena et al. Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a double-blind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine. J Clin Psychiatry. 2011 Aug;72(8):1157. Stahl Stephen M. Beyond the Dopamine Hypothesis to the NMDA Glutamate Receptor Hypofunction Hypothesis of Schizophrenia CNS Spectr. 2007;12(4):265-268. Available from: http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=1037