MEMANTINE AS AN ADJUNCT IN

REFRACTORY SCHIZOPHRENIA

OVERVIEW• Background:

– Link between glutamatergic neurotransmission and schizophrenia

• Overview of RCTs:– Lieberman et al.– Lucena et al.

• Implication to practice

Background

• Schizophrenia: Glutamate deregulation may be involved, mainly through N-methyl-D-aspartate receptor (NMDAR) dysfunction

• Memantine: Weak nonselective NMDAR antagonist

Acts as a brake on mesolimbic dopamine pathway

NMDA receptors that regulate mesocortical dopamine pathways may also be hypoactive

Normally acts as accelerators for dopamine neurons

A Randomized , Placebo-Controlled Study of Memantine

as Adjunctive Treatment in Patients with Schizophrenia

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

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

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

PATIENT ALLOCATION

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

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

Baseline Characteristics

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)

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

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

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

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)

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

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

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

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

Patient Allocation

Baseline Characteristics

Outcome Measures• Primary Outcomes:

– Total score on BPRS– BPRS subscales of positive and negative symptoms

• Secondary Outcomes:1. Severity of disease: CGI2. Cognition: MMSE3. EPS: Simpson-Angus Scale (SAS)4. Weight

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)

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

Results: BPRS Total

Results: BPRS Positive & Negative Symptoms

Results: CGI and MMSE Score

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

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

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

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

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