Original Contribution

An Innovative Design to Establish Proof of Concept of the

Antidepressant Effects of the NR2B Subunit Selective
N-Methyl-D-Aspartate Antagonist, CP-101,606, in Patients
With Treatment-Refractory Major Depressive Disorder
Sheldon H. Preskorn, MD,* Bryan Baker, RN, MSM, CCRC,* Sheela Kolluri, MS, PhD,y
Frank S. Menniti, PhD,z Michael Krams, MD,x and Jaren W. Landen, PhDk
Abstract: This randomized, placebo-controlled, double-blind study
was the first to evaluate the antidepressant efficacy, safety, and
tolerability of an NR2B subunitselective N-methyl-D-aspartate
receptor antagonist, CP-101,606. Subjects had major depression,
according to Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition criteria and a history of treatment refractoriness to
least 1 adequate trial of a selective serotonin reuptake inhibitor. The
study had 2 treatment periods. In period 1, subjects first received a
6-week open-label trial of paroxetine and a single-blind, intravenous
placebo infusion. Period 1 nonresponders (n = 30) then received a
randomized double-blind single infusion of CP-101,606 or placebo
plus continued treatment with paroxetine for up to an additional 4
weeks (period 2). Depression severity was assessed using the
sberg Depression Rating Scale and 17-item Hamilton
Montgomery-A
Depression Rating Scale. On the prespecified main outcome measure
sberg Depression Rating
(change from baseline in the Montgomery-A
Scale total score at day 5 of period 2), CP-101,606 produced a greater
decrease than did placebo (mean difference, 8.6; 80% confidence
interval, j12.3 to j4.5) (P < 0.10). Hamilton Depression Rating
Scale response rate was 60% for CP-101,606 versus 20% for
placebo. Seventy-eight percent of CP-101,606treated responders
maintained response status for at least 1 week after the infusion. CP101,606 was safe, generally well tolerated, and capable of producing
an antidepressant response without also producing a dissociative
reaction. Antagonism of the NR2B subtype of the N-methyl-Daspartate receptor may be a fruitful target for the development of a
new antidepressant with more robust effects and a faster onset
compared with those currently available and capable of working
when existing antidepressants do not.
(J Clin Psychopharmacol 2008;28:631637)

*Clinical Research Institute; yPfizer, New York, NY; zPfizer, Groton CT;
xWyeth, Collegeville, PA; and kPfizer, New London, CT.
Received January 2, 2008; accepted after revision July 28, 2008.
Pfizer Inc supported the conduct of this study.
Dr Preskorn and Mr Baker are employees of the Clinical Research Institute
which has received grant support from Pfizer. Drs Landren, Kolluri, and
Menniti are employees of Pfizer. Dr Krams is currently an employee of
Wyeth but was an employee of Pfizer during the course of this study.
Address correspondence and reprint requests to Sheldon H. Preskorn, MD,
Clinical Research Institute, 201 S. Hillside, Wichita, KS 67204. E-mail:
spreskorn@cri-research.net.
Copyright * 2008 by Lippincott Williams & Wilkins
ISSN: 0271-0749/08/2806-0631
DOI: 10.1097/JCP.0b013e31818a6cea

he chance discovery of the antidepressant efficacy of the

monoamine oxidase inhibitors and the tricyclic antidepressants ushered in the modern era of antidepressant pharmacotherapy and revolutionized the treatment of patients with
major depression. The initial mechanism of action of these
compounds seems to be the augmentation of monoaminergic,
and particularly serotonergic, signaling in the brain. This realization fostered the discovery of safer and better tolerated
treatments, specifically the selective serotonin reuptake inhibitor (SSRI) and the selective norepinephrine reuptake inhibitor.
Despite these important advances, the current monoaminergicbased antidepressants suffer 2 major limitations: (a) modest
gains with sequential trials of these agents and (b) a delayed
onset of meaningful antidepressant action of 2 weeks or more.
The first limitation was highlighted in the recently concluded
Sequenced Treatment Alternative to Relieve Depression trial
funded by the National Institute of Mental Health.17 This
study showed that there was a modest and diminishing return
from sequential trials of existing antidepressants in patients
who had not benefited from the SSRI, citalopram. The second
limitation was highlighted in the recent decision by the Food
and Drug Administration to put a black-box warning on all
antidepressants concerning the persistent risk of suicide early
in an SSRI trial before there has been an onset of antidepressant action. For both of these reasons, there is a need for
the development of mechanistically novel antidepressants that
differ from existing antidepressants in time to onset and magnitude of antidepressant effect.
Growing preclinical and clinical evidence suggests that
antagonism of N-methyl-d-aspartate (NMDA) receptors may
be an effective antidepressant mechanism of action. First,
NMDA antagonists have been shown to be active in animal
models predictive of antidepressant activity in humans.814
Second, there have been 2 positive crossover trials of the
nonselective NMDA antagonist, ketamine. In the first,
Berman et al15 have reported that a single dose of ketamine
produced a rapid and short-lived antidepressant effect.
Zarate et al16 replicated that finding in a second crossover
study of 17 subjects. However, the clinical applicability of
ketamine is limited by its propensity to cause psychomimetic
effects, observed in both the Berman et al15 and Zarate et al16
studies. Thus, further study is needed to determine whether

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631

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Preskorn et al

the therapeutic effects of NMDA receptor inhibition can be

realized under dosing regimens that do not cause psychomimetic effects.
In the present study, we investigated the antidepressant
efficacy of an NMDA receptor antagonist that is mechanistically distinct from ketamine, namely, the NR2B subunit
selective antagonist CP-101,606 (Menniti et al17, structure
provided in this reference). N-methyl-D-aspartate receptors
are tetrameric proteins composed of 2 NR1 subunits and 2
NR2 subunits.18 There are 4 different NR2 subunits
(NR2A-D) that are differentially localized throughout the
CNS. N-methyl-D-aspartate receptors containing the NR2B
subunit are localized primarily in the forebrain including
hippocampus, a regimen implicated in the pathophysiology of
major depression.19 Furthermore, CP-101,606 inhibits NMDA
receptors by an allosteric mechanism20 that is distinct from
that of ketamine, which blocks the receptor-gated ion channel.
This subunit selectivity and novel mechanism of CP-101,606
may account for its lack of adverse behavioral effects in
rodents and nonhuman primates and its good tolerability in
clinical studies.21,22
A significant impediment to the development of novel
antidepressants is the large clinical trials that have been needed
to establish antidepressant efficacy. These trials are expensive
in terms of direct cost, number of trials needed, and time
necessary to do the trials. Hence, the current study also tested
whether a study with a novel design conducted at a single site
with a small number of subjects could produce positive proof
of concept results.

METHODS
Patient Selection
Subjects were recruited from referrals from physicians
and through an extensive media campaign and the Internet. Men
and women, aged 18 to 55 years, who were outpatients and had
a major depressive disorder recurrent without psychotic features
according to Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition criteria, were eligible to participate.
Patients with Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition diagnosis of bipolar disorder or who
had a history of antidepressant- or substance-induced hypo-

mania or mania were excluded. All subjects were studied at the

Clinical Research Institute and Via Christi Regional Medical
Center in Wichita, Kan, between May 2004 and December
2005. Subjects were required to have a score of 18 or higher
on the 17-item Hamilton Depression Rating Scale (HDRS)
at screening and to have historically not benefited from at
least 1 adequate trial of a SSRI but could not have had been
unresponsive to adequate trials of 3 or more different classes
of antidepressants (adequacy of antidepressant trials was determined with the Antidepressant Treatment History Form).23
All subjects were in good physical health as determined
by medical history, physical examination, blood laboratory
results, electrocardiogram (ECG), chest radiography, and urinalysis and toxicology findings. Subjects had to be free of
comorbid substance abuse or dependence for at least 3 months,
have a negative urine toxicology screen, and judged clinically
not to have a serious suicide risk. Comorbid Axis I anxiety
disorder diagnoses were permitted if they did not require current
treatment. Final selection was made by consensus of the
investigator team.
The study was approved by the Via Christi Regional
Medical Center institutional review board. All subjects provided written informed consent before entry into the study.
Informed consents and ongoing study participation were monitored by the institutional review board.

Study Design
This study used a design involving 2 periods (Fig. 1).
Period 1 consisted of 6 weeks of open-label treatment with
paroxetine, with a single-blind intravenous (IV) placebo infusion after the third week of paroxetine treatment. Paroxetine
nonresponders in period 1 were randomized in period 2 to
receive a single, double-blind, random-assignment IV infusion of either CP-101,606 or placebo and continued paroxetine treatment for an additional 4 weeks. All infusions
(periods 1 and 2) were identical in terms of volume infused
and duration. The schedule for infusions and outpatient visits
sberg Depression Ratincluding HDRS and Montgomery-A
ing Scale (MADRS) ratings and safety assessments are
shown in Table 1.
During period 1, subjects were started on 20 mg of
paroxetine in the morning (every morning) and then escalated
to 40 mg every morning within 1 week. At the end of week 3

FIGURE 1. Study schema.

632

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Journal of Clinical Psychopharmacology
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Antidepressant Effects of CP-101,606 in MDD

TABLE 1. Schedule of Study Assessments

Period 1
Wk 3
Assessments

Screen

HDRS
MADRS
12-Lead ECG

Infusion 1

Period 2

Days After Infusion 1

D2

D5

D8

D12

Wk 6
D15

D2

D5

D8

D12

D15

D30

X
X

X
X

X
X

X
X

X
X

X
X

X
X

X
X

PK samples

Safety labs

Infusion 2

Days After Infusion 2

X
X

X
X

Blood samples for drug analyses were obtained before drug infusion and then at 0, 0.5, 1.5, 4, 8, 10, 12, 24, and 96 hours after initiation of drug infusion.
PK indicates pharmacokinetic.

of period 1 (after 21 days of paroxetine treatment), all subjects

were admitted to the Clinical Research Unit (CRU) and had
their depression severity assessed using the HDRS and
MADRS just before receiving a continuous IV single-blind
placebo infusion and 24 hours after the infusion. Subjects
could be discharged from the CRU on day 2 approximately 24
hours after the start of the infusion or could be retained on the
CRU for an additional 24 to 48 hours (maximum of 72 hours
after the start of the infusion), depending on what was
determined to be medically appropriate by the investigator.
Subjects returned to the outpatient research clinic to have their
depression severity assessed using the HDRS and MADRS at
24 and 96 hours and at day 8 (end of week j2), day 12, and
day 15 (week j1) after the period 1 infusion.
Period 1 nonresponders (defined as e20% improvement
in the 17-item HDRS score at the end of period 1 compared
with the screening visit ) progressed to period 2 during which
they continued on 40 mg/d of paroxetine until the conclusion
of the study. These patients in a 1:1 ratio were randomly
assigned in a double-blind fashion to receive an IV infusion of
either CP-101,606 or placebo. As in period 1, subjects were
confined in the CRU for this infusion and could be discharged
on day 2 (after approximately 24 hours after the start of
infusion) or could be retained in the CRU for an additional 24
to 48 hours (maximum of 72 hours after the start of infusion),
depending on what was determined to be medically appropriate by the investigator. The assessment schedule in period 2
was also identical to that in period 1 with the addition of a day
30 assessment.

Infusions
The infusions in periods 1 and 2 were identical in
volume and duration. The first 7 subjects in the trial received
an 8-hour infusion. The CP-101,606 infusion during period 2
for these patients consisted of 0.75 mg/kg per hour for 1.5
hours followed by 0.15 mg/kg per hour for 6.5 hours. Four of
these first 7 subjects experienced a moderate to severe dissociative response after the double-blind infusion. The blind
was not broken at the site but was broken by sponsor to
ensure that the target concentration had not been exceeded.
All patients experiencing the dissociative response had
received active CP-101,606 treatment. Although target
plasma concentrations had not been exceeded, the dosage of

CP-101,606 was reduced for all subsequent patients by decreasing the infusion duration to 1.5 hours and the dose to 0.5
mg/kg per hour with the intent of accomplishing 3 goals: (a)
ensure patient safety, (b) maintain the study blind, and (c)
determine if antidepressant effect could be achieved at doses
that did not cause a dissociative response. The duration of the
placebo infusions was also correspondingly decreased to 1.5
hours in both periods 1 and 2.

Outcome Measures
The primary efficacy end point was change from
baseline in the MADRS total score 4 days after the period 2
infusion (approximately 96 hours after this infusion; period 2,
day 5). The baseline measurement for the MADRS total score
was defined as the mean of the measurements at the end of
week j1 (ie, after 6 weeks of paroxetine treatment) and at hour
0 (pre-dose) on day 1 of period 2. Secondary efficacy end point
was change from baseline in the HDRS total score. Safety
evaluations included the incidence and magnitude of ECG
changes, adverse events (AEs), and the rate of laboratory and
vital sign abnormalities in subjects treated with CP-101,606
versus those administered placebo. The schedule of depression
and safety assessments are given in Table 1.

Staff
The infusions and the efficacy ratings were done by
different research staff. Neither the infusion staff nor the patients
discussed with the efficacy rating staff how the patients did
during the infusions. The efficacy rating staff were on the unit
only for the ratings, leaving before the infusion started and
returning 24 hours later for the day 2 ratings.

Statistical Analysis
Sample Size
A sample size of 15 subjects per group (a total of 30
subjects) was selected to provide at least 80% power to detect a
true difference of 8 points in mean for change from baseline in
the total score of MADRS on day 5, based on a 1-sided, 2sample t test at ! = 10%. This calculation assumed a common
SD of 10 points for change from baseline in the total score
of MADRS.

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Preskorn et al

Primary Analysis
The primary end point was analyzed as a continuous
measurement using a linear model including the following
terms:
& Treatment (CP-101,606 placebo)
& Baseline total scores of MADRS
Based on the above linear model, a 1-sided test was used
to compare the CP-101,606 group with the placebo group at a
10% level of significance. An 80% 2-sided confidence interval
(CI) was provided for the true mean difference between the 2
treatment groups. All analyses were performed using available
data only. No multiplicity adjustments were made to the P
values or the CIs.
The analysis methodology described above for the
primary end point was also used for the key secondary end
points which were as follows: (1) change from baseline in the
total score of MADRS at each planned time point in period 2
other than the primary time point (ie, day 5) and (2) change
from baseline in the total HDRS score at each planned time
point in period 2.
A post hoc statistical analysis following the same parameters as the prespecified statistical plan was performed
on the 23 participants who received the reduced IV infusion
of CP-101,606 or placebo. A similar analysis was not done for
the high-dose infusion patients because this group contained
only 7 subjects (4 receiving CP-101,606 and 3 receiving
placebo). This number is so small that it was not feasible to
apply the statistical model to obtain reliable estimates of the
treatment effects.
Descriptive statistics (n, arithmetic mean, SD) for all
efficacy end points were presented for the treatment group.

RESULTS
Patients
The recruitment campaign started with the 260,000
persons who were within the ages of 18 to 55 years living
within convenient driving distance to the research facility. An
estimated 4333 individuals in this population had SSRI nonresponsive major depression; 1272 went through a thorough
screening via telephone, and 192 went through a face-to-face
interview to yield a total of 47 patients who were entered to
period 1. A total of 30 subjects (15 subjects per group) were
randomized to period 2.
Subjects ranged in age from 21 to 54 years. The majority
of the subjects were white (90%) and female (73%). All
subjects had a primary diagnosis of major depressive disorder.
There was no difference between those treated with CP101,606 versus placebo in period 2 in terms of age, sex,
ethnicity, body mass index, severity of depressive symptoms as
measured by the 17-item HDRS scale, or number of previous
failed SSRI trials. There were no other presenting conditions or
medical histories that the investigator considered sufficient to
affect the conduct of the study or to represent potential risk to
the subject during study participation.

Efficacy
Table 2 presents change from baseline in MADRS and
17-item HDRS scores by time point for CP-101,606 versus

634

placebo-treated patients. Based on the primary statistical

analysis, CP-101,606 was superior to placebo on the primary
end point (ie, difference in the change from baseline in
MADRS total score on day 5 of period 2 between CP101,606 and placebo-treated patients). The estimated treatment difference (CP-101,606 j placebo) was j8.4 (80% CI,
j12.3 to j4.5), and the 1-sided test for superiority of CP101,606 over placebo was statistically significant (at the 10%
level of significance) per the prespecified statistical plan.
Hamilton Depression Rating Scale total scores showed
changes similar to those seen in the MADRS total scores (ie,
improvement in the CP-101,606 group relative to placebo),
with the greatest improvement seen on day 5.
A post hoc analysis of data from the 23 patients who
received the reduced infusions of either CP-101,606 or placebo
revealed approximately the same magnitude of reduction in
MADRS scores as observed in the total population. Specifically,
the difference in the MADRS scores between CP-101,606 and
placebo was j8.9 (80% CI, j13.0 to j4.8) on day 5. This
difference was statistically significant in a 1-sided test for
superiority (at the 10% level of significance).
The response and remission rates for patients treated
with CP-101,606 and placebo were calculated following
common convention: response was defined as a 50% or
greater reduction in the HDRS score from baseline to day 5
of period 2, and remission was defined as an HDRS score of
7 or less on day 5. Of the CP-101,606treated subjects, 60%
met criteria for response, and 33% met criteria for remission
on day 5. Of those patients who met responder criteria on day
5, 78%, 58%, 42%, and 32% continued to meet responder
criteria on days 8, 12, 15, and 30, respectively.
Of the 6 CP-101,606treated patients who had a dissociative response, 4 met HDRS criteria for antidepressant
response, and 2 did not. Conversely, 5 of the 9 CP-101,606
treated patients who met HDRS criteria for antidepressant response did not have a dissociative response from the infusion.

Adverse Events
There were no deaths or discontinuations due to AEs
or abnormal laboratory findings. Fifteen subjects from the
CP-101,606-plus-paroxetine group had 55 AEs versus 61
AEs for the 15 subjects from the placebo-plus-paroxetine
group. Six CP-101,606treated patients experienced a dissociative reaction (2 mild, 2 moderate, and 2 severe). Two
placebo-treated patients experienced a mild dissociative
reaction. Most AEs were mild and did not differ between
CP-101,606 and placebo-treated patients. These AEs included feeling abnormal, dizziness, paresthesia, somnolence,
dry mouth, and abnormal urine odor.
A dissociative reaction was defined as the symptoms
caused in healthy humans by other NMDA antagonists such as
ketamine or phencyclidine.24,25 These include difficulty initiating and sustaining attention; memory impairment; disturbance in time, body, and/or environmental perception; stilted
speech; emotional withdrawal; impaired coordination; psychomotor retardation; dizziness; a sense of intoxication; emotional
blunting; intense emotional reactions; anxiety; feelings of
unreality and loss of control over thought processes; concrete
thinking; bizarre reasoning; illusory experiences in all sensory
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Journal of Clinical Psychopharmacology
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Antidepressant Effects of CP-101,606 in MDD

TABLE 2. Summary of Statistical Analysis

CP-101,606

Placebo

LS Means*
Difference From Placebo (80% CI)

t Statistic (df )

P (1-Sided)

Change from baseline in MADRS total score by time point, CP-101,606 vs placebo
Period 2, wk 0 (day 2)
n
Arithmetic mean (SD)
LS means

15

15

j8.0 (9.5)
j7.7

j7.6 (8.2)
j7.8

0.1 (j4.1 to 4.3)

0.02 (27)

0.491

Period 2, wk 0 (day 5)
n
Arithmetic mean (SD)

15

15

j14.1 (8.1)

j5.5 (7.9)

j14.0

LS means

j5.6

j8.4 (j12.3 to j4.5)

j2.81 (27)

0.005y

j6.2 (j10.5 to j1.8)

j1.85 (23)

0.0383

Period 2, wk 1 (day 8)
n
Arithmetic mean (SD)
LS means

14

12

j14.2 (10.1)
j13.7

j7.1 (6.1)
j7.6

Period 2, wk 1 (day 12)

n
Arithmetic mean (SD)

12

10

j8.1 (10.6)

j7.6 (3.8)

j7.7

LS means

j8.0

0.3 (j4.6 to 5.2)

0.08 (19)

0.468

0.7 (j6.0 to 7.4)

0.14 (17)

0.447

j0.4 (j3.0 to 2.3)

j0.17 (27)

0.432

j5.9 (j8.7 to j3.1)

j2.79 (27)

0.005

j3.5 (j6.6 to j0.4)

j1.47 (23)

0.077

j0.1 (j3.2 to 3.0)

j0.03 (19)

0.487

1.7 (j2.1 to 5.5)

0.58 (17)

0.284

Period 2, wk 2 (day 15)

n
Arithmetic mean (SD)
LS means

12

j10.5 (10.3)
j9.0

j7.6 (10.2)
j9.7

Change from baseline in 17-item HDRS total score by time point, CP-101,606 vs placebo
Period 2, wk 0 (day 2)
n
Arithmetic mean (SD)

15

15

j4.2 (5.4)

j3.7 (5.6)

j4.1

LS means

j3.7

Period 2, wk 0 (day 5)
n
Arithmetic mean (SD)

15
j9.6 (4.8)
j9.5

LS means

15
j3.5 (6.4)
j3.6

Period 2, wk 1 (day 8)
n
Arithmetic mean (SD)

14

12

j8.5 (4.8)

j4.5 (6.7)

j8.3

LS means

j4.8

Period 2, wk 1 (day 12)

n
Arithmetic mean (SD)

12
j5.1 (6.0)
j4.7

LS means

10
j4.3 (4.5)
j4.7

Period 2, wk 2 (day 15)

n

12

Arithmetic mean (SD)

LS means

j7.3 (5.7)
j6.6

8
j7.3 (6.6)
j8.2

*Least-squares mean.
y
This represents the P value for the primary analysis. Note that all other P values are presented only for descriptive purposes.

domains; out-of-body experience; tunnel vision; derealization;

depersonalization; suspiciousness; ideas of reference; paranoid
thoughts; loosening of association; thought derailment; conceptual disorganization; and confusional states.

Four of the 6 patients who had a dissociative reaction

after CP-101,606 treatment had received the higher infusion
dose. Two of these 4 patients had a moderate dissociative reaction, and 2 had a severe dissociative reaction. The dissociative

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Preskorn et al

reaction was mild in 2 CP-101,606treated patients after the

dose reduction and was not qualitatively or quantitatively different from that which occurred in 2 patients in the placebotreated group.
All of the dissociative reactions resolved within 6 hours
of the discontinuation of the infusion. However, one of the
high-dose CP-101,606 patients experienced an acute exacerbation of depressive symptoms upon awakening from a nap
shortly after she had gone home from the unit, approximately
30 hours after the infusion. She was hospitalized for this acute
exacerbation which resolved after approximately 20 hours
without any change in her treatment beyond hospitalization. At
this time, she experienced a dramatic improvement in her
depressive symptoms and was discharged from the hospital
and subsequently completed the study.
There were no clinically significant changes in laboratory values, ECGs, or vital signs. Ten subjects had 1 or more
changes in systolic or diastolic blood pressure that met the
predefined reporting criteria (ie, changes Q20 mm Hg for
diastolic or 30 mm Hg for systolic from baseline). Four of these
subjects were in the CP-101,606-plus-paroxetine group, and 6
were in the placebo group. One subject in the CP-101,606-plusparoxetine group had 1 corrected QT interval (Bazett corrected)
that increased more than 60 milliseconds from baseline (from
409 to 471 milliseconds). However, this finding was judged by
the investigator to be not clinically significant.

DISCUSSION
In this study, the NR2B subunitselective NMDA
antagonist, CP-101,606, produced a significant antidepressant effect in patients with major depression refractory to
treatment with SSRI therapy. On day 5 of period 2, there
was an 8.4-point greater reduction in the MADRS score in
patients receiving CP-101,606 versus those receiving placebo. To provide context for these results, the magnitude of
this effect is 2 to 3 times greater than those seen in the positive registration trials of SSRIs.26 The response and remission rates were 2.5 times higher than those seen in the
Sequenced Treatment Alternative to Relieve Depression
study when nonresponders to citalopram were crossed over
to bupropion, sertraline, or venlafaxine19 and comparable to
those seen in the 2 ketamine studies.16,23
Methodologically, this study differed from the ketamine
studies in several ways: (1) the use of a parallel group versus
a crossover design, (2) the use of a prospective adequate trial
of an SSRI (paroxetine) to confirm treatment refractoriness,
and (3) the addition of the NMDA antagonist to SSRI
therapy. Whereas the ketamine studies looked at earlier time
points to assess antidepressant activity, the statistical plan
for this study prespecified assessing antidepressant response
on day 5 after the double-blind infusion because the HDRS
and MADRS, as originally designed, assess change over
days rather than over hours. That is particularly true for the
HDRS, which assesses items such as insomnia, appetite,
work and activities, and sex drive. Nevertheless, the improvement in the mental status examination including mood was
frequently apparent on day 2 after infusion of CP-101,606 in
those patients who met response and remission criteria on
day 5.

636

Dissociative responses occurred in 6 participants on CP101,606 and 2 on placebo, raising the possibility that the
improvement after CP-101,606 could be related to the unblinding of the rater. There are 3 factors against this possibility. First,
the staff doing the efficacy ratings did not observe the patients
from the ratings done immediately before the infusion to those
done 24 hours after the infusion, at which time any cognitive
adverse effects had resolved. Second, the staff who did the
efficacy ratings was instructed to not ask the patients how they
responded to the infusion on day 1, and patients and infusion
staff were similarly instructed to not comment to the efficacy
rating staff how the patient had done on the infusion day. Third,
5 of the 9 CP-101,606treated patients who met criteria for
antidepressant response did not experience a dissociative
response as a result of the infusion. Fourth, the post hoc analysis
of the 23 patients after the reduction in the infusion found a
statistically significant better response in the CP-101,606
treated compared with placebo-treated patients, and the difference in MADRS scores between CP-101,606 and placebo in
these 23 patients was numerically the same as that seen in the
entire group of 30 patients (ie, both the high- and low-infusion
patients). With this lower infusion, there was no difference in the
rate of dissociative reactions reported by CP-101,606 and
placebo-treated patients (2 of 11 vs 2 of 12, respectively), and all
4 of these dissociative reactions were mild in severity.
In contrast to the ketamine studies, the lower infusion of
CP-101,606 produced a rapid and robust antidepressant response without producing a dissociative reaction. There are
several possible reasons for this difference. First, lower doses
of ketamine that do not cause dissociative states may nonetheless be antidepressive. Second, the administration of CP101,606 in combination with paroxetine may have reduced
the severity of the neuropsychiatric side effects. Third, the
NMDA receptor subunit selectivity and allosteric mechanism
of action may yield a bona fide greater therapeutic index for
CP-101,606 compared with ketamine.
This study demonstrated statistical superiority of the
active versus placebo treatment despite the small number of
patients studied (n = 30). To accomplish this goal, the study
had to have a low placebo response rate, which was made
more daunting because the study drug had to be given
intravenously and thus required admission to a clinical
research unit. For these reasons, the study design included
the following elements: (a) an inclusion criteria requiring a
history of nonresponse to an adequate trial of at least 1 SSRI,
(b) prospective evidence of nonresponse to an adequate trial
of paroxetine plus a single-blind placebo infusion which was
identical to the subsequent randomized infusion, (c) the use
of HDRS score to qualify the patient for entry into the openlabel trial (period 1) and to progress to the double-blind trial
(period 2) but the use of the MADRS as the primary outcome
measurement, and (d) the use of different and blinded staff to
do the efficacy ratings from those who cared for the patient
during their time on the clinical research unit. The exclusion
of patients who had not benefited from adequate trials of
more than 2 mechanistically different forms of antidepressant
treatment was done to avoid enrolling patients whose
depressive illness was so treatment resistant that they could
produce a false-negative result.
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Journal of Clinical Psychopharmacology
Volume 28, Number 6, December 2008

In summary, the results suggest that targeting the

NMDA receptor, and specifically the NR2B subtype
expressed in the forebrain, can produce rapid and robust
antidepressant efficacy with good tolerability. Additional
studies are thus warranted to (a) explore further doseresponse relationships, (b) establish the optimal frequency of
administration, and (c) determine efficacy alone (ie, with
concomitant paroxetine treatment), and in both less and more
refractory patients than those studied here. This line of research holds the potential to develop a new class of antidepressants for patients who have not benefited from adequate
trials of the current, most commonly used antidepressants,
SSRIs, and to expand our knowledge of the pathophysiology
of this illness.
ACKNOWLEDGMENT
The authors thank the following individuals for their
contributions: Robert Berman, MD; Mohamed Ramadan,
MD; Jeremy Tan, MD; Jane Krull, RN; Kelli Omo, RN;
Donna Collie, RN; Michele Erickson, RN, ARNP; and Alisa
Klick-Davis, RN, ARNP.
AUTHOR DISCLOSURE INFORMATION
Dr Preskorn has received grants, given to the Clinical
Research Institute, from Athenagen, Biovail, BoehringerIngleheim, Bristol-Myers Squibb, Cyberonics, GlaxoSmithKline, Merk, Memory, Organon, Otsuka, Pfizer, Sepracor,
Somerset, and Wyeth. He has received grants/contracts from
and served on a study section for the National Institute of
Mental Health. Dr Preskorn has served as a consultant for
Athenagen, Biovail, Bristol-Myers Squibb, Covedien, Cyberonics, Eli Lilly, Eisai, EnViVo, Evotec, Fabre-Kramer, GlaxoSmithKline, Jazz, Memory, Organon, Otsuka, Pfizer,
Somerset, Tikvah, Transcept, and Wyeth. He has served on
the Advisory Board for Athenagen, Biovail, Bristol-Myers
Squibb, Eli Lilly, Eisai, Fabre-Kramer, GlaxoSmithKline, Jazz,
Pfizer, Somerset, Transcept, and Wyeth. Dr Preskorn has been
a speaker for Bristol-Myers Squibb, Otsuka, Pfizer, and Wyeth.
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