Abstract
Background
In a previous pilot study, MK-0777, a GABAA α2/α3 partial agonist, was reported to improve delayed memory and cognitive measures of prefrontal cortical function in people with schizophrenia. The current study was designed to further examine the efficacy and safety of MK-0777 for the treatment of cognitive impairments in schizophrenia.
Methods
Sixty people with DSM-IV schizophrenia entered a 4-week, multi-center, double-blind, placebo-controlled, randomized clinical trial. Participants were randomized to either: MK-0777 3mg BID (n=18); MK-0777 8mg BID (n=21); or placebo (n=21). Participants were clinically stable. The MATRICS Consensus Cognitive Battery (MCCB), AX-CPT and N-Back were used to assess cognition. The UCSD Performance Based Skills Assessment-2 (UPSA-2) and the Schizophrenia Cognition Rating Scale (SCoRS) assessed functional capacity and served as functional outcome co-primary measures.
Results
There were no significant group differences on the primary outcome measure, the MCCB composite score. Secondary analyses suggested that participants randomized to placebo performed significantly better on visual memory and reasoning/problem-solving tests than participants assigned to either MK-0777 dose. There were no significant group differences on the AX-CPT or N-Back d prime scores or UPSA-2 and SCoRS total scores. In general, MK-0777 was well tolerated with minimal side effects.
Conclusions
The study results suggest that MK-0777 has little benefit for cognitive impairments in people with schizophrenia. The GABAA receptor remains a promising target, but a more potent partial agonist with greater intrinsic activity at the GABAA α2 site may be needed for cognitive enhancement in schizophrenia.
Keywords: schizophrenia, gamma-amino-butyric acid (GABA), clinical trial, cognition, functional capacity, symptoms
INTRODUCTION
People with schizophrenia have a broad range of neurocognitive impairments, including abnormalities in attention, executive function, visual and verbal learning and memory, working memory, processing speed, and social cognition (1). These impairments are major determinants of functional outcome in schizophrenia (2,3). First and second generation antipsychotics have limited benefits for these impairments (4). The use of add-on pharmacological agents may offer a viable approach for the treatment of these impairments, since they can be used to modulate specific neurotransmitter systems hypothesized to be involved in the pharmacology of cognitive functions.
Gamma-amino-butyric acid (GABA) is the major CNS inhibitory neurotransmitter. GABAergic mechanisms are important for regulation of prefrontal cortical function, through their modulation of glutamatergic pyramidal cells (5). In particular, the GABAergic chandelier cell type interneuron inhibits pyramidal neuron output through activation of GABA receptors containing the α2 subunit located on the axon initial segment, a mechanism thought to support the development and maintenance of recurrent activity necessary for intact prefrontal function (5).
Post-mortem studies have found decreased levels of glutamic acid decarboxylase (GAD)67 mRNA expression in the prefrontal cortex (6–9). GAD67 reduction appears to be restricted to those cells that contain the calcium-binding protein parvalbumin, which includes chandelier cell interneurons (7,10). In people with schizophrenia with decreased GAD67, there is also a decrease in GABA reuptake transporter mRNA levels (11); the density of chandelier cell connections with the pyramidal cell axon initial segment (12,13); and immunoreactivity of the GABA plasma membrane transporter-1 in chandelier cell axon terminals (12). Finally, there appears to be a marked increase in GABAA α2 subunit density on the axon initial segment (14).
These post-mortem results are consistent with a marked decrease in GABAergic inhibition of DLPFC pyramidal cell glutamatergic transmission, which could have important implications for our understanding of cognitive impairments in schizophrenia (5). Specifically, intact GABAergic function has been shown to be required for normal working memory (15–18). People with schizophrenia have been shown to have verbal and visual working memory impairments (1,19–24). Working memory may also be critical for a number of other cognitive processes, so that improvement of working memory function could lead to improvement in other cognitive domains. Agents that increase GABA inhibition of cortical pyramidal cells would be hypothesized to improve working memory and possibly other cognitive impairments.
MK-0777 is a GABAA α2/α3 partial agonist, with approximately 10–20% of the potency of a full GABAA α2 agonist. MK-0777 is functionally selective for the α2 and α3 subunits, with virtually no activity for the α1 and α5 subunits (25,26). Therefore, it is hypothesized to cause less sedation than benzodiazepines (27). In animal studies, MK-0777 was observed to cause less sedation, interact less with alcohol, and exhibit less abuse potential and physical dependence than benzodiazepines (25,26). In a previous pilot study, MK-0777 improved delayed memory performance and decreased reaction time on selected measures of prefrontal cortical function (28). The purpose of the current study was to conduct a larger scale trial to examine the efficacy and safety of two doses of MK-0777, 3mg BID and 8mg BID, in the treatment of cognitive impairments in people with schizophrenia.
METHODS AND MATERIALS
The NIMH Treatment Units for Research on Neurocognition in Schizophrenia Network implemented the 4-week, placebo-controlled, parallel group, double-blind study. Inpatients or outpatients aged 18 to 60, who met DSM-IV-TR criteria for schizophrenia, were selected for study entry. Participants were diagnosed based on information from the Structured Clinical Interview for DSM-IV (29), direct assessment, family informants, and past medical records. Participants were required to be clinically stable, in the non-acute phase of their illness, and to meet the following inclusion criteria (30): a) treatment with one second generation antipsychotic medication, other than clozapine, for the previous two months, with no dose change in the month prior to study entry; b) Brief Psychiatric Rating Scale (BPRS; 31) hallucinatory behavior and unusual thought content item scores ≤4; c) BPRS conceptual disorganization item ≤4; d) Simpson-Angus Scale (SAS; 32) total score ≤ 6; and e) Calgary Depression Scale (CDS; 33) total score ≤10 (30,34). In order to facilitate recruitment, the above criteria were amended halfway through the study to allow treatment with no more than two second generation antipsychotic medications, other than clozapine, and the cut-off score for BPRS hallucinatory behavior and unusual thought content items was changed to ≤ 5.
Participants were required to validly complete the MATRICS Consensus Cognitive Battery (MCCB; 35,36), i.e., the neuropsychological tester and the site neuropsychologist judged their performance to reliably reflect their ability on those aspects of cognition that the test was intended to measure. To minimize potential ceiling effects, participants were required to score at least one standard deviation below maximum on one or more of the following tests: Letter-Number Span; Hopkins Verbal Learning Test, and Identical Pairs Continuous Performance Test (CPT). Finally, participants were required to have a Wechsler Test of Adult Reading (37) raw score ≥ 6.
Participants were excluded if they had a DSM-IV diagnosis of alcohol or substance abuse (other than nicotine) within the last month, alcohol or substance dependence (other than nicotine) within the last 6 months, or mental retardation; had a history of significant head injury/trauma or clinically significant medical or neurological disease; were treated with drugs known to act at the GABAA receptor or to inhibit CYP3A4; had a history of severe benzodiazepine withdrawal; or participated in a clinical trial of investigational medication within 60 days. Women of childbearing age were included if using adequate birth control.
The institution IRBs approved the study protocol and informed consent procedures. Written informed consent was obtained from all participants after study procedures had been fully explained and prior to study participation. Participant ability to provide valid informed consent was documented using study specific procedures.
Assessments
The MCCB was used to assess neuropsychological test performance. The MCCB is comprised of 10 tests, which assess seven cognitive domains (35). The MCCB composite score is a standardized mean of the seven domain scores. T-scores are standardized to normative data, and have an estimated mean of 50 and SD of 10 in the general healthy population (36).
In addition, because of their previous use to evaluate cognitive effects with this compound (28), the AX-CPT (38) and the N-Back (39) were used to assess prefrontal cortical cognitive function. The AX-CPT is a modification of the traditional CPT, in which AX trial frequency is increased to 70%. The increased AX trial frequency requires greater use of context to overcome the induced propensity to respond to the “X” probe on trials that do not contain the “A” cue (40). The N-Back is a sequential letter working memory task, which varies working memory load by requiring the participant to identify whether the test stimulus is identical to the immediately preceding letter (0-back), the letter presented 1 trial back (1-back) or two trials back (2-back) (39).
A modified version of the UCSD Performance-Based Skills Assessment (UPSA; 40), the UPSA-2, was used to assess functional capacity. The UPSA-2 contains a sixth component: Medication Management, and the content complexity and number of items required to be remembered were increased for the Comprehension/Planning, Financial Skills, and Transportation components to reduce potential for ceiling effects. The Schizophrenia Cognition Rating Scale (SCoRS; 41) is an interview-based measure used to assess cognition. The MCCB, UPSA-2, SCoRS, AX-CPT and N-back were obtained at Evaluation Week 1 and Treatment Phase Week 4. The BPRS positive symptom item total score was used to assess positive symptom change.
The BPRS positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness. The modified Scale for the Assessment of Negative Symptoms (SANS; 42) total score was used to assess negative symptom change. The CDS was used to assess depressive symptom change. The CGI severity of illness item (CGI-S) was used to assess global changes. The BPRS, SANS, CDS and CGI-S were obtained at Screening, Evaluation Phase Week 2 and biweekly during the Treatment Phase.
MCCB and UPSA raters were trained on the administration and scoring of these instruments using video and group training sessions and were individually certified by an expert on these assessments. The SCoRS raters were trained in a group education format, in which they viewed and scored a series of videotapes. Symptom raters were required to be reliable on the BPRS and SANS (ICC ≥ 0.80). Quarterly reliability meetings were conducted throughout the study to ensure that the raters maintained the inter-site ICC criterion of ≥0.80. All raters were blind to treatment assignment.
Safety Assessments
The Simpson Angus Scale (SAS; 32) and Abnormal Involuntary Movement Scale (AIMS; 43) were used to assess abnormal motor movements. The SAS and AIMS were administered at Screening, Evaluation Phase Week 2 and biweekly during the Treatment Phase.
A standard chemistry panel, complete blood count, urinalysis and urine toxicology screen, and EKG were obtained at Screening and at the end of the Treatment Phase. The Side Effect Checklist (SEC) was used to assess side effects and monitor vital signs. The SEC is comprised of 22 common side effects, which are rated from 1 (none) to 4 (severe). The SEC and vital sign ratings were conducted at Evaluation Phase Weeks 1 and 2 and weekly during the Treatment Phase.
Study Design
Participants who met inclusion criteria entered a 2-week Evaluation Phase during which they underwent baseline cognitive, symptom and safety assessments. Participants who continued to meet inclusion criteria entered the 4-week, double-blind Treatment Phase and were randomized to MK-0777 3mg BID; MK-0777 8mg BID; or placebo BID. Participants randomized to MK-0777 8mg BID were started on 3mg BID and their dose was titrated over the first week to the target dose. Participants randomized to MK-0777 3mg BID were started on this dose. The MK-0777 t1/2 is approximately 7 hours and the Tmax is 6–7 hours, therefore we used a twice daily dosing schedule.
If side effects interfered with the tolerability of the study medication, the participant was instructed to skip a dose and then resume treatment with the prescribed dose. If still unable to tolerate the study medication, then the dose could be lowered to alleviate side effects. The side effects most likely to affect MK-0777 tolerability were dizziness, incoordination, and sedation. At the end of the Treatment Phase, all participants were tapered off of their study medication to minimize potential withdrawal effects.
The study biostatistician established computer-generated randomization sequences for each site. Randomization was performed using the permuted block method, randomly drawing from 3 or 6 size blocks, in order to limit imbalance in numbers between groups. Until the trial was concluded, the randomization sequence was only available to the biostatistician and to an unblinded pharmacist at each site, whose only role was to dispense medication. In response to a randomization request, the biostatistician sent a code number to the unblinded pharmacist, which identified the next treatment selection to be dispensed from the treatment sequence. Randomization was stratified by site.
Medication compliance was assessed by weekly pill count. All participants who received 75% or more of their assigned study medication were considered compliant.
Statistical Analyses
The sample size was determined using the analysis of covariance power formula, n=2[za+zβ]2s2 (1−R2)/d2, with za=2.24, zβ=0.842 (corresponding to power=0.80), R=the correlation between baseline and end of study measures of the primary outcome (estimated to equal 0.6 for the MCCB composite score), d the difference between groups, and s the standard deviation of the primary outcome. We planned to enroll 30 participants per group, which would have enabled us to detect an effect size=0.73 with power=0.80. The actual recruitment was only about 20 participants per group, but the observed R≅0.9, suggesting power to detect an effect size of 0.49.
An analysis of covariance (ANCOVA), adjusting for baseline scores, was used to compare treatment groups on cognitive and functional measures. The predefined primary cognition outcome measure was the MCCB composite T-score, tested at overall two-sided alpha=0.05. The predefined primary functional outcome measure was the UPSA summary score. Exploratory analysis of variation in treatment effects among the different MCCB measures was performed using the mixed model for repeated measures ANCOVA: week 4 T-score=baseline T-score + measure + treatment + treatment × measure, where measure was a categorical variable indicating the different MCCB tests, and the treatment × measure effect tested whether the treatment effect differed significantly among the various tests.
AX-CPT and N-back accuracy results were summarized using the d-prime statistic (44). For the AX-CPT, only BX trials were used to calculate the false alarm rate. For the N-back, trials with novel and repeated distractors were pooled in calculating the false alarm rate. N-back response times (RTs) were analyzed using the ANCOVA model log(RT)=baseline log(RT) + response type + treatment + treatment × response type, where response type distinguishes target, repeat non-target and novel non-target trials.
Symptom data were analyzed using a mixed model for unbalanced repeated measures ANCOVA, using data from all participants who completed at least one symptom assessment to fit the model: follow-up score=baseline score + treatment + week + treatment × week, where the treatment effect tests the average difference across weeks between treatment groups, and the treatment × week interaction assesses whether this difference varies between weeks 2 and 4. Mixed models were fitted with SAS PROC MIXED®, using the Kenward-Rogers method to estimate degrees of freedom. The treatment × week interaction was non-significant for all variables assessed, and only average difference tests and estimates are reported.
Group differences on SAS and AIMS total scores were examined by calculating the tau-b rank correlation between score and week for each participant, and comparing the distribution of these trend scores using the Conover-Salsburg rank test (45,46). Fisher’s exact test was used to compare treatments on the number of participants who, at any point during follow-up, had new or worsened (compared to baseline) side effect severity. The effects of treatment on laboratory assays were tested using ANCOVA, while the effects of treatment on vital signs were tested using mixed model ANCOVA.
RESULTS
The study was conducted between July 2007 and June 2009. Sixty-four participants were randomized: 19 were randomized to MK-0777 3mg BID; 22 were randomized to MK-0777 8mg BID; and 23 were randomized to placebo (see Figure 1 for participant flow details). Fifty-three participants completed the study: MK-0777 3mg BID: 18; MK-0777 8mg BID: 18; placebo: 17. Three participants dropped out prior to receiving study drug (one randomized to each group) and 1 participant dropped out prior to any post-randomization ratings (randomized to placebo). These participants were not included in either efficacy or safety analyses. The demographic and baseline clinical characteristics of participants included in either analysis are presented in Table 1.
Table 1.
Demographics and Baseline Clinical Characteristics
| Placebo (N=21) | MK-0777, 3mg BID (N=18) | MK-0777, 8mg BID (N=21) | |
|---|---|---|---|
| Mean (± S.D.) | Mean (± S.D.) | Mean (± S.D.) | |
| Age, yrs. | 40.0 (10.9) | 43.3 (9.3) | 44.9 (8.7) |
| Education, yrs. | 12.2 (2.5) | 13.3 (3.0) | 14.2 (2.4) |
| Gender (male) | 77.3% | 61.1% | 61.9% |
| Race (white) | 45.4% | 50.0% | 42.9% |
| WTAR reading score | 29.2 (10.3) | 27.1 (12.0) | 29.7 (14.0) |
| MCCB Composite Score | 30.1 (13.1) | 31.0 (12.6) | 27.8 (12.2) |
| BPRS Total Score | 26.8 (6.4) | 28.9 (5.2) | 29.8 (6.2) |
| BPRS Positive Symptom Item Score | 7.0 (3.5) | 7.6 (2.8) | 6.8 (2.1) |
| SANS Total Score | 18.6 (11.5) | 17.8 (10.5) | 20.6 (14.7) |
| CDS Total Score | 1.6 (1.5) | 2.1 (2.4) | 2.0 (2.1) |
| SAS Total Score | 1.1 (1.5) | 0.8 (1.2) | 1.4 (1.6) |
MCCB (see Table 2)
Table 2.
MATRICS Consensus Cognitive Battery (MCCB) Composite and Individual Test T-scores, mean (±SD)*
| Measure | Week | Placebo | MK-0777, 3 mg BID | MK-0777, 8 mg BID | ANCOVA | ||
|---|---|---|---|---|---|---|---|
| (N=17) | (N=15) | (N=18) | F | df | p | ||
| MCCB Composite | 0 | 30.1 (13.1) | 31.0 (12.6) | 27.8 (12.2) | 1.61 | 2,49.0 | 0.210 |
| 4 | 32.5 (14.0) | 31.3 (13.9) | 27.9 (12.7) | ||||
| CPT-IP | 0 | 38.8 (9.2) | 41.3 (13.7) | 36.9 (9.8) | 0.72 | 2,46.8 | 0.492 |
| 4 | 38.1 (12.0) | 42.9 (13.7) | 36.8 (10.6) | ||||
| BACS symbol coding | 0 | 33.9 (10.8) | 36.4 (10.1) | 32.9 (11.8) | 0.06 | 2,46.8 | 0.492 |
| 4 | 33.5 (12.5) | 35.3 (11.2) | 32.0 (11.7) | ||||
| Category Fluency | 0 | 40.2 (8.5) | 42.7 (8.0) | 39.9 (10.4) | 0.39 | 2,47.0 | 0.679 |
| 4 | 41.7 (9.6) | 42.7 (8.2) | 39.3 (12.2) | ||||
| Trails A | 0 | 38.8 (15.3) | 40.5 (12.2) | 35.2 (11.5) | 0.09 | 2,46.8 | 0.917 |
| 4 | 40.2 (15.2) | 41.5 (11.4) | 38.3 (14.4) | ||||
| BVMT-R | 0 | 36.4 (12.2) | 36.5 (11.1) | 34.5 (14.6) | 3.18 | 2,46.9 | 0.051 |
| 4 | 39.7 (11.9) | 35.9 (10.5) | 33.1 (11.9) | ||||
| HVLT-R | 0 | 39.7 (9.8) | 38.0 (9.6) | 37.8 (7.7) | 1.44 | 2,47.0 | 0.248 |
| 4 | 43.2 (8.8) | 39.3 (12.2) | 37.7 (8.7) | ||||
| MSCIET | 0 | 40.2 (10.8) | 36.9 (18.9) | 35.3 (11.1) | 0.40 | 2,47.1 | 0.671 |
| 4 | 39.0 (11.2) | 37.8 (16.4) | 37.7 (14.1) | ||||
| NAB Mazes | 0 | 40.2 (9.4) | 40.1 (6.3) | 37.7 (8.5) | 3.77 | 2,46.7 | 0.030 |
| 4 | 44.1 (10.6) | 41.3 (6.6) | 37.9 (7.6) | ||||
| WMS-III Spatial Span | 0 | 38.7 (10.1) | 42.7 (7.2) | 39.8 (13.2) | 0.20 | 2,46.4 | 0.816 |
| 4 | 40.8 (13.2) | 42.9 (8.6) | 40.2 (13.6) | ||||
| LNS | 0 | 37.1 (12.1) | 35.9 (12.7) | 38.7 (12.6) | 1.88 | 2,45.8 | 0.163 |
| 4 | 36.7 (11.9) | 40.0 (14.2) | 38.6 (13.4) | ||||
There was no significant variation in the magnitude of treatment differences among the cognitive measures (F=0.73, df=18, 61, p=0.76).
There were no overall significant group differences on MCCB composite score change (F=1.61; df=2,49; p=0.21). In exploratory post hoc pairwise analyses of individual test scores, there were nominally significant differences (unadjusted p<0.05) between the MK-0777 8mg BID and placebo groups on the Brief Visual Memory Test-Revised (t=2.45; df=46.9; p=0.02) and the NAB mazes test (t=2.71; df=46.8; p=0.009), with participants randomized to placebo exhibiting greater improvement on both of the measures.
The test-retest reliability for the MCCB composite score was 0.95 (Pearson correlation between baseline and end of study assessments), with the correlation for each of the individual domains ranging from 0.72–0.90 (see Table S1 in Supplement 1). In the placebo group, there were small but significant time effects for the MCCB composite score (t=5.25; df=16; p<0.001); and the verbal learning (t=2.12; df=16; p=0.05) and reasoning/problem-solving (t=4.28; df=16; p<0.001) domains (see Table S1 in Supplement 1).
Ancillary Cognitive Measures (see Table 3)
Table 3.
N-Back and AX-CPT d-prime Scores, mean (±SD)
| Placebo | MK-0777, 3mg BID | MK-0777, 8mg BID | ANCOVA | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Measure | Week 0 (N=17) | Week 4 (N=17) | Week 0 (N=16) | Week 4 (N=16) | Week 0 (N=18) | Week 4 (N=17) | F | df | p |
| N-Back | |||||||||
| 0-Back | 3.7 (0.5) | 3.7 (0.6) | 3.7 (0.6) | 3.7 (0.6) | 3.4 (0.5) | 3.6 (0.6) | 0.01 | 2,46 | 0.98 |
| 1-Back | 2.7 (0.8) | 2.8 (0.8) | 3.0 (0.6) | 3.0 (0.7) | 2.7 (0.8) | 2.6 (0.6) | 0.35 | 2,46 | 0.71 |
| 2-Back | 1.4 (0.8) | 1.6 (0.6) | 1.4 (0.6) | 1.4 (0.6) | 1.5 (0.8) | 1.4 (0.6) | 0.97 | 2,46 | 0.39 |
| AX-CPT | (N=16) | (N=16) | (N=16) | (N=16) | (N=15) | (N=15) | |||
| d-prime | 2.4 (1.1) | 2.2(1.4) | 2.5(1.1) | 2.5 (1.2) | 2.0 (1.2) | 2.0 (1.1) | 0.25 | 2,43 | 0.78 |
There were no overall significant group differences for change in AX-CPT performance (F=0.25; df=2,43; p=0.78). The overall ANCOVA tests for group differences on the 0-back (F=0.01; df=2,46; p=0.99), 1-back (F=0.35; df=2,46; p=0.71), and 2-back (F=0.97; df=2,46; p=0.39) d-prime scores were all statistically non-significant. The post hoc pair-wise group comparisons for the AX-CPT and N-back d prime measures were all non-significant. The 2-back RTs for the different response types: target hit; novel correct rejection; and repeated correct rejection are presented in Table 4. The overall ANCOVA for treatment differences in RTs for the three different response types was not significant (F=1.23; df=2,47; p=0.30), nor was the response type by treatment group interaction (F=0.95; df=4,54.2; p=0.44).
Table 4.
2-Back Response Times by Treatment and Response Type, mean (±SD)
| Response Type | Week | Mean (SD) | ||
|---|---|---|---|---|
| Placebo | MK-0777, 3mg BID | MK-0777, 8mg BID | ||
| Target Hit | 0 | 825.8 (228.8) | 732.9 (181.9) | 822.9 (267.1) |
| 4 | 869.6 (286.1) | 772.8 (211.0) | 768.4 (289.4) | |
| Novel Correct Rejection | 0 | 862.2 (337.7) | 790.4 (241.0) | 773.7 (185.6) |
| 4 | 724.9 (279.3) | 798.8 (156.7) | 766.1 (319.0) | |
| Repeated Correct Rejection | 0 | 813.1 (292.8) | 767.1 (343.9) | 779.6 (265.5) |
| 4 | 801.7 (242.7) | 861.9 (225.9) | 788.3 (318.7) | |
ANCOVA tests for treatment effects: F=0.10, df=2, 46.7, p=0.91 for overall treatment differences across response type; F=0.29, df=4,52.2, p=0.88 for treatment × response type interaction.
The test-retest reliability for AX-CPT d-prime was 0.67 and for the N-back measures ranged from 0.68 (0-back) to 0.84 (1-back) (see Table S2 in Supplement 1). In the placebo group, there was a significant time effect for the 2-back d-prime measure (t=2.18; df=16; p=0.04) (see Table S2 in Supplement 1).
Functional Assessments
The overall ANCOVA for treatment effects on the UPSA-2 summary score was non-significant (placebo: Week 0: 95.0±16.26 and Week 4: 96.5±15.5; MK-077 3mg BID: Week 0: 85.0±18.8 and Week 4: 86.3±18.7; MK-077 8mg BID: Week 0: 91.7±13.4 and Week 4: 90.4±12.8; F=0.77; df=2,50; p=0.47). There was a significant group difference on the UPSA Comprehension/Planning component (see Table S3 in Supplement 1). In the post hoc, pair-wise analyses, participants randomized to placebo improved significantly more than those randomized to MK-0777 8mg BID (t=2.68; df=50; p=0.01), with a trend for the placebo group to also perform better than the MK-077 3mg BID group (t=1.96; df=50; p=0.06) on this measure. There were no other significant treatment group differences on the UPSA component measures.
The overall ANCOVA for treatment effects on the SCoRS Interviewer Global rating was non-significant (placebo: Week 0: 3.8±2.3 and Week 4: 3.6±1.8; MK-077 3mg BID: Week 0: 4.8±2.3 and Week 4: 4.6±2.1; MK-077 8mg BID: Week 0: 4.1±2.3 and Week 4: 4.0±2.4; F=0.17; df=2,47; p=0.84). There were also no significant treatment differences on the participant, informant and interviewer change rating scores (all F values < 0.50 and all p values > 0.30; see Table S4 in Supplement 1).
Symptom Measures
The BPRS, SANS, CDS and CGI-S data are presented in Table 5. The overall ANCOVA revealed non-significant treatment effects for BPRS total score (F=0.17; df=2,54.2; p=0.84); BPRS positive symptoms items (F=1.01; df=2,54.4; p=0.37); SANS total score (F=0.81; df=2,56; p=0.45); and CDS total score (F=0.01; df=2,54.3; p=0.99). There was a significant treatment difference for the CGI-S (F=4.21; df=2,56.4; p=0.02). The follow-up pair-wise comparisons revealed that participants randomized to MK-0777 3mg BID exhibited small but statistically significant worsening on this measure compared to participants assigned to placebo (t=2.33; df=53.8; p=0.02) or to MK-0777 8mg BID (t=2.34; df=53.1; p=0.02).
Table 5.
Symptom Outcome Measures, mean (±SD)
| Measure | Week | Placebo | MK-0777, 3mg BID | MK-0777, 8mg BID |
|---|---|---|---|---|
| BPRS Total Score | 0 | 26.8 (6.4) | 28.9 (5.2) | 29.8 (6.2) |
| 4 | 26.5 (6.5) | 28.4 (5.6) | 29.7 (6.7) | |
| BPRS Positive Symptom Item Score | 0 | 7.0 (3.5) | 7.6 (2.8) | 6.8 (2.1) |
| 4 | 7.1 (3.6) | 6.7 (2.2) | 6.7 (2.1) | |
| CDRS Total Score | 0 | 1.6 (1.5) | 2.1 (2.4) | 2.0 (2.1) |
| 4 | 1.5 (2.6) | 1.7 (2.1) | 1.9 (2.3) | |
| SANS Total Score | 0 | 18.6 (11.5) | 17.8 (10.5) | 20.6 (14.7) |
| 4 | 20.2 (10.6) | 17.7 (10.7) | 21.6 (15.8) | |
| CGI Severity Score | 0 | 3.7 (0.6) | 3.4 (0.7) | 3.5 (0.9) |
| 4 | 3.6 (0.7) | 3.7 (0.8) | 3.5 (0.9) |
The overall ANCOVA test for treatment effects: BPRS total score: F=0.17; df=2,54.2; p=0.84; BPRS positive symptoms item score: F=1.01; df=2,54.4; p=0.37; SANS total score: F=0.81; df=2,56; p=0.45; CDS total score: F=0.01; df=2,54.3; p=0.99; CGI-S: F=4.21; df=2,56.4; p=0.02.
Safety Measures
The study drug was well tolerated. Only one participant required a reduction in their dose (randomized to MK-0777 8mg BID; dose was reduced to 5 mg in the morning and 8 mg in the evening). In pair-wise comparisons between placebo and the two experimental groups, there were no significant treatment differences on the AIMS total score or the SAS total score (see Table 6). On the SEC, there were no overall significant treatment differences in the frequency of participants reporting new or worsened side effects (all p values>0.10; see Table S5 in Supplement 1). There were minor treatment group differences in vital signs (see Table S6 in Supplement 1). There were no significant treatment group differences in fasting glucose or cholesterol levels; liver enzymes; or renal measures (all F values<1.30 and all p values>0.25; see Table S7 in Supplement 1).
Table 6.
Abnormal Involuntary Movement Scale (AIMS) and Simpson Angus Scale (SAS) Total Scores, mean (±SD)
| Measure | Week | Mean | ||
|---|---|---|---|---|
| Placebo | MK-0777, 3mg BID | MK-0777, 8mg BID | ||
| AIMS Total Score* | 0 | 0.6 (2.0) | 0.2 (0.3) | 0.9 (1.5) |
| 4 | 0.3 (0.6) | 0.2 (0.4) | 1.0 (2.0) | |
| SAS Total Score** | 0 | 1.1 (1.5) | 0.8 (1.2) | 1.4 (1.6) |
| 4 | 1.2 (1.3) | 0.7 (1.0) | 1.2 (1.5) | |
AIMS total score: placebo versus MK-0777 3mg BID: F=0.19; df=1,37; p=0.66; placebo versus MK-0777 8mg BID: F=0.52; df=1,37; p=0.22
SAS total score: placebo versus MK-0777 3mg BID:z F=0.65; df=1,34; p=0.43; placebo versus MK-0777 8mg BID: F=0.01; df=1,36; p=0.91
DISCUSSION
The study results suggest that MK-0777 does not significantly improve cognitive impairments in people with schizophrenia. There were no significant differences between the two MK-0777 treatment arms and placebo on the MCCB composite score. In secondary analyses, participants randomized to placebo compared to those randomized to MK-0777 8mg BID exhibited greater improvement on the Brief Visual Memory Test-Revised and the NAB mazes tests. However, neither of these two group differences would have been significant after correcting for multiple comparisons. There were no significant group differences on the two ancillary cognitive measures: the N-back and AX-CPT or on the two functional measures: the UPSA summary score or the SCoRS interviewer global rating score. The only observed group difference in the UPSA component measures favored the placebo group.
MK-0777 did not exhibit any significant benefits for BPRS total or positive symptom item scores, SANS total score, or CDS total score. In participants randomized to MK-0777 3mg BID there was a small, but significant worsening on the CGI-S score. Both doses of MK-0777 were well tolerated with minimal side effects.
The present results stand in contrast to those from the previous MK-0777 study. In particular, Lewis and colleagues found a significant group difference on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS; 47) delayed memory index (28); whereas, in the current study, there were no significant group differences that favored MK-0777 on any of the MCCB test measures. In addition, Lewis and colleagues reported a significant group difference in the combined N-back and Preparing to Overcome Prepotency Task (POP) reaction time measure; there were no other significant group differences on the AX-CPT, N-Back, and POP ancillary measures (28). In the current study, there were no significant performance or reaction time differences with either the AX-CPT or N-back ancillary measures. There are several possible explanations for these differences between the two studies. The most important of which is the small sample size of the Lewis and colleague study, which limits the reliability of their estimate of subject test performance and experimental drug effects. Second, although Lewis and colleagues found a significant benefit for MK-0777 for the RBANS delayed memory index, other RBANS measures, including the visuospatial constructional and attention indices, showed a numerically larger if not statistically significant advantage for placebo, which suggests that the limited benefits observed in the current study may accurately reflect MK-0777 efficacy for neuropsychological test measures. Finally, the group difference in the combined POP/N-back reaction time measure was largely driven by marked slowing of POP reaction times (RTs) in the placebo group. The MK-0777 group showed modest RT decreases on the two measures. In the current study, the placebo participants exhibited decreased RT in two of the three 2-back measures, whereas there tended to be a minimal to small RT increase on these measures in the MK-0777 3mg BID group and a minimal to small RT decrease on these measures in the MK-0777 8mg BID group.
The MCCB composite score and each of the domain scores exhibited good to excellent test-retest reliability. The placebo group exhibited small but significant practice/learning effects for the MCCB composite score and the verbal learning and reasoning/problem-solving domains.
There are several potential limitations of the current study. The most important is that the sample size is relatively small, so there is a possibility of a Type II error, i.e., MK-0777 is truly better than placebo, but there was not sufficient power to detect the difference. However, across all efficacy measures the observed changes were numerically better in the placebo group and the only significant differences favored the placebo group. Moreover, the current study utilized a rigorous study design intended to minimize potential confounding variables in the evaluation of potential cognitive-enhancing drugs (30,34)
If the current study results accurately reflect the cognitive benefits of MK-0777, then what are the implications for future studies of GABAA α2 agonists? First, the rationale for the GABAA α2 target is compelling, with significant preclinical and clinical evidence to support the hypothesis that a drug that activates this receptor could have cognitive-enhancing effects. However, MK-0777 is a relatively weak GABAA α2 partial agonist, with 10–20% of the potency of a full GABAA α2 agonist and may not represent the most rigorous assessment of the hypothesized mechanism. Moreover, although MK-0777 is relatively selective for the GABAA α2 and α3 receptor units, new or worsened sedation was observed numerically more frequently in the experimental treatment arms than in the placebo arm. In the Lewis and colleague study, somnolence was reported more frequently in the MK-0777 than placebo group. These sedative effects could have adversely affected cognitive performance; a hypothesis that receives partial support from the observation that participants randomized to MK-0777 were less likely than those randomized to placebo to exhibit practice/learning effects for the MCCB composite score. In combination, these considerations suggest that a more selective agent with greater intrinsic activity at the GABAA α2 site may still be worth pursuing for the treatment of cognitive impairments in schizophrenia.
Supplementary Material
Acknowledgments
This study was funded by NIMH contract HHSN278200441003C to the University of California, Los Angeles (Stephen R. Marder, Principal Investigator). Double-blind medications were provided by Merck & Co., Inc. We wish to thank the following for their assistance in the conduct of the study: New York State Psychiatric Institute and College of Physicians and Surgeons, Columbia University: Marlene Carlson; Duke University Medical Center: Trina Walker and Leslie Yusko; Massachusetts General Hospital, Harvard Medical School: Shannon Sorenson and Joanne Wojcik; Maryland Psychiatric Research Center: Sharon August and Ilene Verovsky; Washington University in St. Louis School of Medicine: Meghan Flatley and Emily Thomason; and UCLA Semel Institute for Neuroscience and Human Behavior: Ayala Ofek and Ewa Witt
Footnotes
Disclosure of Significant Financial Interests and Potential Conflicts of Interest: Ms. Ball reported consultant services with ePharmaLearning Inc. to provide training for a Pfizer trial. Dr. Barch disclosed the receipt of research funding from the National Institute of Mental Health, the McDonnell Center for Higher Brain Function, NARSAD, Allon, and Novartis. Dr. Buchanan has served as a DSMB member for Cephalon, Otsuka, and Pfizer; a consultant to Abbott, Glaxo-Smith-Kline, Sanofi-Aventis, Scherring-Plough; and as an Advisory Board member for Abbott, AstraZeneca, Cypress Bioscience, Merck, Pfizer, Roche, Solvay Pharmaceuticals, Inc., Wyeth. He has received grant support from Janssen Pharmaceutica. Dr. Csernansky reported receipt of honoraria for service on Data Monitoring Committees for clinical trials sponsored by Eli Lilly and Sanofi Aventis. Dr. Goff has served as consultant and/or advisor to: Xytis, Forest Labs, Pfizer, Indevus Pharmaceuticals, H. Lundbeck, Schering-Plough, Eli Lilly, Takeda, Biovail, Solvay, Hoffman-La Roche, and Dianippon Sumitomo; served on a DSMB for Otsuka and Wyeth; and received research funding from Pfizer, Janssen, Novartis, and Glaxo-Smith-Kline. Dr. Gold disclosed royalties from the BACS and has served as a consultant for Pfizer, Solvay, Glaxo-Smith-Kline, AstraZeneca, and Merck. Dr. Green has been a consultant to Abbot Laboratories, Astellas, Cypress Bioscience, Dainippon Sumitomo Pharma, Glaxo-Smith-Kline, Lundbeck, Otsuka, Sanofi Aventis, Takeda, and Wyeth, and a speaker for Janssen Cilag. Dr. Jarskog has received grant support from Novartis and Glaxo-Smith-Kline. Dr. Javitt serves as Chair, scientific advisory board and major shareholder of Glytech, Inc. and Amino Acids Solutions, Inc. Over the past two years, Dr. Javitt has served as a consultant for pharmaceutical companies including Sanofi Aventis, Solvay, Organon, Lundbeck, AstraZeneca, NPS Pharmaceuticals, Takeda, and Sepracor. He currently serves on a new treatment development advisory board for Pfizer, serves on the Scientific Advisory Board for Promentis Pharmaceuticals, and has received research support from the pharmaceutical industry including, in the past year, Pfizer, Roche, and Jazz pharmaceuticals. Dr. Keefe reports having received investigator-initiated research funding support from the National Institute of Mental Health, Department of Veterans Affairs, Allon, Glaxo-Smith-Kline, Novartis, and the Singapore National Medical Research Council, and an unrestricted educational grant from AstraZeneca. He disclosed receiving honoraria, served as a consultant, or advisory board member for Abbott, Acadia, AstraZeneca, BiolioneRx, BrainCells, Bristol Myers Squibb, CHDI, Cypress Bioscience, Dainippon Sumitomo Pharma, Eli Lilly, En Vivo, Johnson & Johnson, Lundbeck, Memory Pharmaceuticals, Merck, Neurosearch, NeuroCog Trials, Novartis, Orexigen, Orion, Otsuka, Pfizer, Prophase, Roche, SanofiAventis, Shire, Solvay, Takeda, Wyeth, and Xenoport. Dr. Keefe reports being a shareholder in NeuroCog Trials, Inc., as well as receiving royalties from the Brief Assessment of Cognition in Schizophrenia (BACS) testing battery and the MATRICS Consensus Cognitive Battery (BACS Symbol Coding). Dr. Kern receives financial support from MATRICS Assessment, Inc., a non-profit organization that facilitates the distribution of the MATRICS Consensus Cognitive Battery. He also has received consultation fees from Otsuka. Dr. Kimhy has received an instrument grant from VivoMetrics. Dr. Lieberman received grant/research funding from Allon, Glaxo-Smith-Kline, Merck, Novartis, Pfizer, Sepracor, and Targacept and also served on advisory boards for Bioline, Eli Lilly, Glaxo-Smith-Kline, Intracellular Therapies, Pierre Fabre and Psychogenics, and he holds a patent for Repligen. Dr. Marder reports having received consulting fees from the following companies: Wyeth, Otsuka, Pfizer, Schering Plough, Bristol Meyers Squibb, Roche, Lundbeck, Sanofi Aventis, and Acadia. He received research support from Novartis and Glaxo-Smith-Kline. Dr. McEvoy has received grants from Glaxo-Smith-Kline, Pfizer, and Novartis, as well as honoraria from Eli Lilly. Dr. Larry J. Seidman reports no financial disclosures or conflicts of interest for the past 2 years. He has been a speaker for Shire Pharmaceuticals and received an unrestricted education grant from Janssen Pharmaceuticals in the past 5 years. All other authors report no biomedical financial interests or potential conflicts of interest.
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