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 Nmethyl-D-aspartate receptor (NMDAR)
dysfunction
• Memantine: Weak nonselective NMDAR
antagonist
Acts as a brake on
mesolimbic
dopamine pathway
Normally acts as
accelerators for
dopamine neurons
NMDA receptors that
regulate mesocortical
dopamine pathways
may also be hypoactive
A Randomized , PlaceboControlled 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 TreatmentRefractory 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: CGI
2. Cognition: MMSE
3. 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