Memantine Add-On Therapy to Clozapine

The current (DSM) psychiatric diagnosis driven strategy for developing new
indications for psychotropic drugs is too expensive, too time consuming and
often invalid. We suggest an alternative, more efficient strategy that is
grounded in the principles of functional psychopharmacology. This strategy
entails: a) the selection of drugs that specifically target key psychological
functions due to their pharmacological characteristics, b) conduction of
proof-of-concept-studies for their introduction. Memantine is a NMDA receptor
antagonist, which, in combination with clozapine, is expected to improve
cognitive and social dysfunctions as well as negative and positive symptoms in
patients with treatment resistant schizophrenia. To demonstrate the utility of
the proposed strategy, the clinical value, tolerability, and safety of the NMDA
antagonist memantine will be evaluated versus placebo in combination with
ongoing clozapine treatment in patients with severe mental illness (SMI).

Lucena et al. (2009) treated 21 outpatients with refractory schizophrenia with
prevailing negative symptoms with either 20 mg memantine daily or placebo in
addition to clozapine for 12 weeks. A remarkable improvement was found on the
total BPRS score (effect size = - 2,75), its subscales of positive symptoms
(effect size = - 1.38), negative symptoms (effect size = - 3.33), the CGI score
(effect size = -1.56) and the MMSE (Mini-Mental State Exam) score (effect size
= 1.32). No significant changes in weight nor extrapyramidal symptoms were
observed using the Simpson-Angus Scale (SAS). In a six-week open-label study by
Krivoy et al. (2008) seven inpatients with refractory schizophrenia received
memantine with weekly increasing dosage (5, 10, 15, 20 mg) in addition to
ongoing antipsychotic treatment. All patients received first generation
antipsychotics in a long acting formulation and one patient received a
combination of zuclopentixol and clozapine. A significant improvement was found
of the PANSS score with the most prominent beneficial effect on negative signs,
leading to a total decrease of 21% between endpoint and entry scores. Also
improvements of the positive subscale of the PANSS score (15.6%) and the BPRS
(Brief Psychiatric Rating Scale) (18%) were reflected in clinical global
impression of change (CGI) (19%). Cognitive status showed no improvement, but
the lack of effect on cognitive functioning could be related to the relatively
short duration of memantine intervention (three weeks at maximal dosage). A
placebo-controlled study for 8 weeks by Lieberman et al. of 136 patients with
persistent residual psychopathology of schizophrenia showed no efficacy of
memantine as an adjunctive treatment to other atypical antipsychotics than
clozapine. Possibly when clozapine and memantine are combined, a special
glutamatergic environment is created in which clinical improvement is
sustained.

This proposal entails a proof-of-concept study into the neuropsychological
effects of memantine augmentation in a random cross-over comparison to placebo,
as add-on treatment to ongoing clozapine in severely mentally ill (SMI)
patients with refractory schizophrenia. A secondary aim is to demonstrate
clinical and biological effects and to assess its tolerability. The
neuropsychological variables are selected to be predictive of the beneficial
effects concerning the severity of the clinical, cognitive, and social
handicaps of SMI patients. Negative symptoms of schizophrenia are known to
predict worse social outcome. In addition to negative symptoms, residual
positive symptoms, debilitating cognitive disturbances, impaired social
cognition, and depressive symptoms contribute to functional impairment and
reduced quality of life. These are considered to reflect the need for care in
daily living and the quality of life of these more severily ill patients.
Treatment of poor-outcome patients with clozapine-resistant schizophrenia is
costly and challenging. If this proof-of-concept study on addition of the NMDA
antagonist memantine shows relevant clinical improvement in patients with
clozapine-refractory schizophrenia, clinical investigation should be the
follow-up for this augmentation strategy. The full project therefore consists
of a proof-of-concept study, followed by a monitored release project as a
prerequisite for financial reembursement. This proposal is limited to the first
part of this project.

The project has two aims: a) in general, following functional
psychopharmacological principles, to develop a procedure for identifying drugs
with psychopharmacological properties that specifically target specific
psychopathological dysfunctions, and b) to demonstrate the utility of this
research approach in the treatment of refractory severely mentally ill
patients.

Primary research questions:
1. Is memantine efficacious as an adjunctive treatment to clozapine in patients
with refractory schizophrenia to improve cognitive impairment?
2. Does memantine in combination with clozapine diminish the severity of
psychopathology, positive and negative symptoms?

Secondary research questions:
1. Does memantine have a beneficial effect on depressive symptoms?
2. Does memantine add-on therapy to clozapine have a beneficial effect on
social cognition?
3. Does memantine improve obsessive-compulsive symptoms?
4. Are there differences in efficacy and tolerability of clozapine treatment
combined with memantine compared to clozapine treatment in combination with
placebo in other areas of clinical outcome: psychosocial functioning, quality
of life and dropout rate?

Study design:
A proof-of-concept cross-over, placebo-controlled cross-over study examining
the pharmacological efficacy of memantine versus placebo as add-on therapy to
ongoing clozapine treatment in patients with refractory schizophrenia.

Study setting:
Outpatients, age 18 to 60, both male and female, meeting DSM-IV criteria for
schizophrenia, based on the definitions in the Mini International
Neuropsychiatric Interview Plus (MINI-Plus) with persistent residual
psychopathology, failing to achieve the remission criteria, after adequate
treatment with clozapine for at least 6 months. Before the start of the study
clozapine plasma concentration has been at least 350 ng/ml for 12 weeks or has
not reached 350 ng/ml due to intolerability. Remission is defined as
simultaneous ratings of mild or less (<= 3 points) on 8 of the PANSS items
evaluating the core symptoms of schizophrenia (simultaneous ratings of mild or
less (<= 3 points) on 8 of the PANSS items evaluating the core symptoms of
schizophrenia) and a nonsatisfactory response to clozapine (duration of
clozapine treatment at least six months). Patients are recruited from in mental
health facilities of North Holland North.

Study duration:
This study will consist of two double-blind, randomized cross-over phases of 11
weeks testing the effects of the maximal daily dosage of 20 mg memantine (after
a titration phase of 1 week). The length of the washout period will be 2 weeks.
The total study duration is 26 weeks.

Sample size proof-of-concept study:
Based on the study of Lucena et al. (Effect size = 0.55, α = 0.05, Power =
0.80) the sample size for a non-cross-over randomized controlled trial would
amount to 84 patients.

t tests - Means: Difference between two independent means (two groups)
Analysis: A priori: Compute required sample size
Input: Tail(s) = One
Effect size d = 0.8
α err prob = 0.05
Power (1-β err prob) = 0.80
Allocation ratio N2/N1 = 1
Output: Noncentrality parameter δ = 2.5204166
Critical t = 1.6636492
Df = 82
Sample size group 1 = 42
Sample size group 2 = 42
Total sample size = 84
Actual power = 0.8036357

In order to perform a more accurate assessment of efficacy and safety of
memantine addition to clozapine, this proof-of-concept study is a placebo
controlled cross-over trial, in which each patient serves as his or her own
control. Due to the cross-over study design a relatively small number of
participants (half of patients calculated above) is required for this study to
have enough power. Therefore at least 42 patients are needed to complete the
study. Cross-over effects are negligible with a wash-out phase of 2 weeks.

Because of drop-out (estimated at 20%), 52 patients will be included.
Cross-over effects are negligible with a wash-out phase of 2 weeks.

Research/ treatment procedures:
1. Session in which the researcher provides information;
2. Session in which informed consent is obtained;
3. Baseline assessments for all patients;
4. Randomization and dose titration for 1 week according to protocol: random
allocation to either verum or placebo treatment for 11 weeks. The dosage
memantine starts with 10 mg daily and is increased with 10 mg daily after 1
week. In the second week patients receive either 20 mg (2 Ebixa®, 10 mg
tablets), or 2 matching placebo tablets;
5. Phase 1 treatment: 11 weeks of treatment with combination of clozapine and
memantine, or clozapine and placebo;
6. Single blind placebo wash-out period for 2 weeks: 1 placebo tablet daily;
7. Phase 2: patients treated with memantine switch to placebo and vice versa
for 12 weeks (dose titration for again 1 week, followed by treatment in the
maximal dosage of 20 mg memantine for 11 weeks);
8. Assessment at baseline, 12 weeks (phase 1), 14 weeks (after wash-out), 26
weeks (phase 2) or at withdrawal of study.

Time schedule of outcome assessment:
Assessment will take place at baseline, 12 weeks (phase 1), 14 weeks (after
wash-out), 26 weeks (phase 2) or at withdrawal of study. All assessments will
take place on one day, starting with a venipuncture (measurements a metabolic
screening, plasma clozapine level), measurements of blood pressure and waist
circumference, followed by the the PANSS, CANTAB, the tests for social
cognition and other questionnaires.

Use of co-intervention:
To enhance generalizability to the reference population and the feasibility of
the study, concomitant medications are allowed, but doses per day need to be
documented throughout the study and all medication should remain as stable as
possible. In case of concomitant medication changes (except for
benzodiazepines; maximal dosage lorazepam 2,5 mg three times daily or its
equivalent is allowed), we will end the double blind study for this patient,
but will continue to follow the patient for further analysis. To monitor for
potential confounders, co-medication and psychotherapeutic intervention will be
assessed at baseline and at outcome assessments. Changes in lifestyle should be
avoided. Use of substances such as nicotine, which interacts with clozapine,
but also drugs and alcohol should not change during the course of the study.

Description and justification of route of administration and dosage:
In order to allow for good generalizability, the dose range is chosen according
to clinical practice in patients with Alzheimer*s disease and the result of a
recent trial (Lucena et al, 2009). Clozapine dosage is at the discretion of the
treating physician, but will remain as constant as possible. Distribution will
take place by tablets of 10 mg, containing either placebo or memantine. To
maintain blind treatment assignment, bottles will also have identical
appearance.

Clozapine combined with ebixa (memantine) starting with 10 mg during the first
week, built up after one week to 20 mg daily.

Burden:
Patients will be randomly allocated to addition of memantine or placebo to
their ongoing treatment with clozapine (duration of clozapine treatment at
least six months). One session is needed to inform the patient on the study
design and procedure. After the information session the patient has to give
informed consent. After 2 weeks, 13 weeks and 26 weeks two sessions are needed
to assess outcome data, possibly two extra sessions at drop-out. Before
treatment initiation plasma clozapine level (12 +/- 0,5 hours after ingestion)
will be measured. This measurement will be repeated after 13 weeks and 26
weeks. No additional venipuncture will be necessary since the investigational
venipunctures will be combined with the regular venipunctures for regular
controls of white blood cell count (WBC). At these three points of measurements
a metabolic screening will be assessed (glucose sober in plasm, triglycerides,
LDL, HDL and total cholesterol, including blood pressure and waist
circumference).

Risk:
There is a risk on adverse effects related to the treatment with clozapine.
This is no special risk related to the trial since the patient was treated with
clozapine for at least 6 months prior to the start of the trial. Special risks
of the trial are related to memantine, which is licensed for treatment of
moderate and severe Alzheimer*s disease with a favorable safety and
tolerability profile. The DCH GCP guidelines report no cause for concern, which
can be considered as giving some reassurance, since memantine is on the market
for nearly twenty years in Europe. No major differences have been reported in
the frequency of SAEs between memantine and placebo. The majority of SAEs were
assessed as unrelated to study medication. The safety and tolerability of
memantine in combination with clozapine in patients with schizophrenia is
widely unknown, although the trial of Lucena et al. did not show any
differences in adverse events or changes in extrapyramidal symptoms between
addition of placebo or memantine to clozapine (Lucena et al., 2009). In the
study of Lieberman et al. addition of memantine was associated with a higher
incidence of serious adverse events compared to placebo (8.7 versus 6.0%).
Discontinuations of treatment because of adverse events were higher in the
memantine group than in the placebo group (11.6 versus 3.0%). The most frequent
adverse events in the memantine group were headache, insomnia, constipation,
fatigue and dizziness (Lieberman et al, 2009). Careful clinical procedures will
be performed to detect adverse events with weekly Likert scales and respond to
them as needed. White blood cell counts will be monitored in all patients
according to official regulations to detect clozapine-induced agranulocytosis.
The dosage memantine will be increased during three weeks to the maximal, usual
dosage of 20 mg daily. This dosage is also administered in Alzheimer's disease
and other studies into the efficacy and tolerability of memantine for other
indications than Alzheimer's disease. Clozapine dosage is at the discretion of
the treating physician, but will remain as much unaltered as possible.
Concomitant medications are allowed, but doses per day need to be documented
throughout the study and all medication will remain as stable as possible.
Although no pharmacokinetic interaction is known between clozapine and
memantine, plasma clozapine level (12 +/- 0,5 hours after ingestion) will be
measured at three points of measurements.

Benefits: The combination of memantine and clozapine may be associated with
favourable effects on cognitive and social functioning, positive and negative
symptoms, reflected in improvement of daily functioning and quality of life in
patients with refractory schizophrenia. Possibly memantine has a beneficial
effect on depressive and obsessive-compulsive symptoms.

Group relatedness: The study specifically targets patients with refractory
schizophrenia, treated with clozapine, because the combination of clozapine and
memantine is considered to create a specific glutamatergic environment, in
which neurotransmission is improved and clinical improvement is sustained.