Clinical Trial of Tolcapone for Cognition in Schizophrenia

• Sponsor: National Institute of Mental Health (NIMH) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00044083
• Collaborator: (none)
• Enrollment: 210
• Location: 1
• Arms: 2
• Duration (Months): 160
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

This study will evaluate whether Tolcapone improves cognition in healthy volunteers as well as patients with schizophrenia. Talcapone is a drug that has been FDA approved for Attention Deficit Disorder and allegedly increase the amount of the neurotransmitter dopamine in the frontal cortex of the brain.

...

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Other: Placebo; Drug: Tolcapone	Phase 2

Detailed Description

Psychopharmacological modulation of the catecholaminergic system can enhance some aspects of cognitive function. For example, COMT inhibitors can slightly improve working memory/executive function. Differences in the response between individuals might be related to a number of factors, including variations in the genes. The recent finding that a polymorphism in the catechol-o-methyl-transferase (COMT) gene, which produces a 4 fold change in enzyme activity, accounts for 4 percent of the variance in performance of working memory tasks in humans suggest that COMT genotype may predict response to COMT inhibitors. In the present investigation our goal is to examine, in normal controls and patients with schizophrenia, the effect of a centrally acting (tolcapone) and of a peripherally acting (entacapone) COMT inhibitor on cognitive function. We predict that both normal controls and patients with schizophrenia with the val/val genotype will have a significant, though transient, improvement in working memory in subjects treated with tolcapone but not in those treated with entacapone. Furthermore, in conjunction with other NIMH imaging protocols, we would like to examine the neurophysiological correlates related to working memory. We predict, in tolcapone treated subjects, improved measures in prefrontal 'efficiency' in subjects and patients specifically with the val/val genotype. The present protocol will provide new insights on the importance of this genetic polymorphism in the regulation of aminergic-controlled cognitive function in normal individuals. Furthermore, this protocol will test whether COMT inhibitors offer a new treatment-based on genotype - for cognitive impairment in schizophrenia. No IND is required for the present study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 210 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Randomized, Double-Blinded, Placebo Controlled Study of the Effects of Tolcapone and Entacapone on Cognitive Function in Patients With Schizophrenia and Normal Controls Based on COMT Genotype
• Study Start Date: Aug 1, 2002
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Arm Placebo one week	Other: Placebo; Placebo: One capsule 3 times a day from Day 1 to Day 7
Active Comparator: Tolcapone Arm Tolcapone one week	Drug: Tolcapone; Tolcapone: One capsule 3 times a day from Day 1 to Day 7; Other Names: Tasmar

Outcome Measures

Primary Outcome Measures

1. N-Back Task Performance [At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)]

   Working Memory was measured in HVs and patients with schizophrenia after a 7-day treatment with Tolcapone or placebo in a double-blind, cross-over fashion. The working memory was quantified by taking the number of trials entered correctly divided by the total number of trials multiplied by 100. Values range from 0 to 100. Zero indicates the poorest performance while 100 indicates perfect performance.

2. N-Back Task Activation Diagnosis Effect [At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)]

   Activation beta values (N-Back vs. 0-Back) were extracted within the Main Effect of Diagnosis cluster around the peak (p < 0.05 uncorrected) from the contrast maps in the Placebo condition. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.

3. N-Back Task Activation Drug Effect [At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)]

   Activation beta values (N-Back vs. 0-Back) extracted within the Main Effect of Drug cluster around the peak (p < 0.05 uncorrected) from the contrast maps across both groups. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.

4. N-Back Task Activation in DLPFC in Patients With Schizophrenia [At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)]

   Activation Beta values (N-Back vs. 0-Back) extracted within the Effect of Drug cluster around the peak (p < 0.05 uncorrected) from the contrast maps in patients with schizophrenia. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.

5. N-Back Task Activation in Healthy Volunteers [At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)]

   Activation Beta values (N-Back vs. 0-Back) extracted within the Effect of Drug cluster around the peak (p < 0.05 uncorrected) from the contrast maps in Healthy Volunteers. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.

6. N-Back Task Activation Genotype Effect in Healthy Volunteers [At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)]

   Activation beta values (N-Back vs. 0-Back) extracted within the Effect of Genotype cluster around the peak (p < 0.05 uncorrected) in right and left DLPFC from the contrast maps in Healthy Volunteers. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.

7. N-Back Task Activation by Genotype in Patients With Schizophrenia [At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)]

   Activation beta values (N-Back vs. 0-Back) extracted from DLPFC from the contrast maps in Patients with schizophrenia. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.

Secondary Outcome Measures

1. Positive and Negative Syndrome Scale [At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)]

   Rating Scales PANSS. The Positive Scale ranges for 7 to 49 with a higher score indicating greater severity of symptoms. The Negative Scale ranges for 7 to 49 with a higher score indicating greater severity of symptoms. The General Scale ranges from 16 to 112, the higher score indicating greater severity of symptoms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

• INCLUSION CRITERIA:

1. Prior participation under NIH protocol number 95-M-0150, or new normal volunteers or schizophrenic patients that meet criteria for NIH protocol number 95-M-0150 (NCT00001486).

2. No Axis I or Axis II diagnosis in normal volunteers.

3. Age range: 18-50 years.

EXCLUSION CRITERIA:

1. Normal volunteers with an Axis I or Axis II disorder obtained either from prior SCID interview in Protocol 95-M-0150 or through a screening interview will be excluded.

2. Subjects with a history of cardiovascular disease, liver disease and other medical illnesses, and untreated or uncontrolled hypertension will be excluded. An electrocardiogram, blood pressure, pulse rate and metabolic panel including LFTs will be checked on all subjects prior to participation in the study. Individuals with persistent tardive dyskinesia or abnormal LFTs, or individuals with significant history of alcoholism or liver enzyme elevation will be excluded from the study.

3. Schizophrenic patients taking clozapine, a COMT inhibitor, any illicit drugs of abuse, or MAO inhibitors will be excluded.

4. Normal control subjects taking any medications other than occasional NSAI will be excluded.

5. Pregnant women. Women of childbearing potential will undergo a urine pregnancy test the day the study initiates and screened by history for the possibility of pregnancy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Jose A Apud, M.D., National Institute of Mental Health (NIMH)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Aksoy S, Klener J, Weinshilboum RM. Catechol O-methyltransferase pharmacogenetics: photoaffinity labelling and western blot analysis of human liver samples. Pharmacogenetics. 1993 Apr;3(2):116-22.
• Andreasen NC, Arndt S, Cizadlo T, O'Leary DS, Watkins GL, Ponto LL, Hichwa RD. Sample size and statistical power in [15O]H2O studies of human cognition. J Cereb Blood Flow Metab. 1996 Sep;16(5):804-16.
• Arnsten AF. Catecholamine regulation of the prefrontal cortex. J Psychopharmacol. 1997;11(2):151-62. Review.

• Responsible Party: National Institute of Mental Health (NIMH)
• ClinicalTrials.gov Identifier: NCT00044083
• Other Study ID Numbers: 020239; 02-M-0239
• First Posted: Aug 19, 2002
• Last Update Posted: Sep 27, 2018
• Last Verified: Mar 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by National Institute of Mental Health (NIMH): Catecholamines; Dopamine; Clinical Trial; fMRI; PFC; Vitamin B2; Riboflavin; Tolcapone; Placebo; Normal Volunteers; Schizophrenia; Healthy Volunteers; HV
• Additional relevant MeSH terms: Schizophrenia; Tolcapone

Study Results

Participant Flow

Recruitment Details	Patients with schizophrenia were recruited through families, physicians and community organizations. Healthy volunteers were recruited through the NIH Normal Volunteers Office. Subjects first participated in Protocol # 95-M-0150 to obtain genotype data. If eligible after the study, they were invited to participate in the Tolcapone protocol.

Arm/Group Title	Placebo First Then Tolcapone	Tolcapone First, Then Placebo
Arm/Group Description	Placebo one week first: Tolcapone 200 mg second:	Tolcapone one week: Placebo one week second:
Period Title: First Intervention (One Week)- HV's
STARTED	74	73
COMPLETED	64	66
NOT COMPLETED	10	7
Period Title: First Intervention (One Week)- HV's
STARTED	64	66
COMPLETED	64	66
NOT COMPLETED	0	0
Period Title: First Intervention (One Week)- HV's
STARTED	31	32
COMPLETED	30	30
NOT COMPLETED	1	2
Period Title: First Intervention (One Week)- HV's
STARTED	30	30
COMPLETED	30	29
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Healthy Volunteers	Patients	Total
Arm/Group Description	Tolcapone 200 mg 1 week:Wash Out 1 week:Placebo 1 week: (or vice versa)	Tolcapone 200 mg 1 week:Wash Out 1 week:Placebo 1 week: (or vice versa)	Total of all reporting groups
Overall Participants	130	59	189
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	130 100%	59 100%	189 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.5 (9.1)	26.9 (6.8)	32.1 (9.1)
Sex: Female, Male (Count of Participants)
Female	59 45.4%	18 30.5%	77 40.7%
Male	71 54.6%	41 69.5%	112 59.3%
Region of Enrollment (participants) [Number]
United States	130 100%	59 100%	189 100%

Outcome Measures

1. Primary Outcome

Title	N-Back Task Performance
Description	Working Memory was measured in HVs and patients with schizophrenia after a 7-day treatment with Tolcapone or placebo in a double-blind, cross-over fashion. The working memory was quantified by taking the number of trials entered correctly divided by the total number of trials multiplied by 100. Values range from 0 to 100. Zero indicates the poorest performance while 100 indicates perfect performance.
Time Frame	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)

Outcome Measure Data

Analysis Population Description

147 HV's recruited, 8 left after signing consents, 8 excluded for other reasons, 57 excluded for excessive motion, inferior quality or not completion. 63 patients recruited, 4 removed for different reasons, 26 excluded from image analyses for not completing the second phase of the study, excessive motion or bad image quality.

Arm/Group Title	Healthy Volunteer on Placebo	Healthy Volunteer Tolcapone	Patient on Placebo	Patients on Tolcapone
Arm/Group Description	Placebo Days 1-7, Healthy voluntee	Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid	Placebo Days 1-7, Patient	Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
Measure Participants	74	74	33	33
Mean (Standard Error) [% of Correct Trials]	86.10 (1.13)	85.50 (1.10)	76.21 (2.31)	80.94 (1.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer on Placebo, Patient on Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Diagnosis effect on placebo
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Patient on Placebo, Patients on Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0034
	Comments	Drug Effect on Patients
	Method	ANOVA
	Comments

2. Primary Outcome

Title	N-Back Task Activation Diagnosis Effect
Description	Activation beta values (N-Back vs. 0-Back) were extracted within the Main Effect of Diagnosis cluster around the peak (p < 0.05 uncorrected) from the contrast maps in the Placebo condition. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
Time Frame	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)

Outcome Measure Data

Analysis Population Description

74 Healthy Volunteers and 33 Patients with Schizophrenia

Arm/Group Title	Healthy Volunteer on Placebo	Patient on Placebo
Arm/Group Description	Placebo Days 1-7, Healthy Voluntreers	Placebo Days 1-7, Patients
Measure Participants	74	33
Right DLPFC	0.15 (0.02)	0.20 (0.03)
Left DLPFC	0.18 (0.02)	0.23 (0.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer on Placebo, Healthy Volunteer Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Diagnosis Effect on Placebo in right DLPFC
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer on Placebo, Healthy Volunteer Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments	Diagnosis Effect of Placebo in left DLPFC
	Method	ANOVA
	Comments

3. Primary Outcome

Title	N-Back Task Activation Drug Effect
Description	Activation beta values (N-Back vs. 0-Back) extracted within the Main Effect of Drug cluster around the peak (p < 0.05 uncorrected) from the contrast maps across both groups. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
Time Frame	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)

Outcome Measure Data

Analysis Population Description

74 Healthy Volunteers and 33 Patients with Schizophrenia

Arm/Group Title	Healthy Volunteers on Placebo	Healthy Volunteers on Tolcapone	Patients on Placebo	Patients on Tolcapone
Arm/Group Description	Placebo Days 1-7, Healthy Volunteers	Tolcapone 100 mg TID on Day 1, 200 mg TID Days 2-7.	Placebo Days 1-7, Patients	Tolcapone 100 mg TID on Day 1, 200 mg TID Days 2-7
Measure Participants	74	74	33	33
Right DLPFC	0.09 (0.03)	0.11 (0.02)	0.12 (0.04)	0.07 (0.03)
Left DLPFC	0.27 (0.04)	0.25 (0.04)	0.23 (0.05)	0.09 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer on Placebo, Healthy Volunteer Tolcapone, Patient on Placebo, Patients on Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments	Drug Effect across both groups in left DLPFC
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer on Placebo, Healthy Volunteer Tolcapone, Patient on Placebo, Patients on Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.32
	Comments	Drug Effect across both groups in right DLPFC
	Method	ANOVA
	Comments

4. Primary Outcome

Title	N-Back Task Activation in DLPFC in Patients With Schizophrenia
Description	Activation Beta values (N-Back vs. 0-Back) extracted within the Effect of Drug cluster around the peak (p < 0.05 uncorrected) from the contrast maps in patients with schizophrenia. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
Time Frame	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)

Outcome Measure Data

Analysis Population Description

33 Patients with Schizophrenia

Arm/Group Title	Patients on Placebo	Patients on Tolcapone
Arm/Group Description	Placebo Days 1-7, Patients	Day 1 Tolcapone 100 mg tid, days 2-7 Tolcapone 200 mg tid, Patients
Measure Participants	33	33
Right DLPFC	0.26 (0.02)	0.24 (0.018)
Left DLPFC	0.25 (0.02)	0.23 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer on Placebo, Healthy Volunteer Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments	The Effect of Drug on Patients with Schizophrenia in right DLPFC
	Method	t-test, 1 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer on Placebo, Healthy Volunteer Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.078
	Comments	Effect of Drug on Patients with Schizophrenia in left DLPFC
	Method	t-test, 1 sided
	Comments

5. Primary Outcome

Title	N-Back Task Activation in Healthy Volunteers
Description	Activation Beta values (N-Back vs. 0-Back) extracted within the Effect of Drug cluster around the peak (p < 0.05 uncorrected) from the contrast maps in Healthy Volunteers. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
Time Frame	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)

Outcome Measure Data

Analysis Population Description

74 Healthy Volunteers

Arm/Group Title	Healthy Volunteer on Placebo	Healthy Volunteer on Tolcapone
Arm/Group Description	Placebo Days 1-7, Healthy Volunteer	Day 1 Tolcapone 100 mg tid, days 2-7 Tolcapone 200 mg tid
Measure Participants	74	74
Right DLPFC	0.09 (0.03)	0.11 (0.02)
Left DLPFC	0.38 (0.03)	0.36 (0.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer on Placebo, Healthy Volunteer Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments	Drug Effect on Healthy Volunteers in left DLPFC
	Method	t-test, 1 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer on Placebo, Healthy Volunteer Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.73
	Comments	Drug Effect on Healthy Volunteers in right DLPFC
	Method	t-test, 1 sided
	Comments

6. Primary Outcome

Title	N-Back Task Activation Genotype Effect in Healthy Volunteers
Description	Activation beta values (N-Back vs. 0-Back) extracted within the Effect of Genotype cluster around the peak (p < 0.05 uncorrected) in right and left DLPFC from the contrast maps in Healthy Volunteers. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
Time Frame	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Volunteer COMT Val/Val Genotype on Placebo	Healthy Volunteer COMT Val/Met Genotype on Placebo	Healthy Volunteers COMT Met/Met Genotype on Placebo	Healthy Volunteer COMT Val/Val Genotype on Tolcapone	Healthy Volunteer COMT Val/Met Genotype on Tolcapone	Healthy Volunteer COMT Met/Met Genotype on Tolcapone
Arm/Group Description	Placebo Days 1-7, Healthy Volunteer COMT Val/Val Genotype	Placebo Days 1-7, Healthy Volunteer COMT Val/Met Genotype	Placebo Days 1-7, Healthy Volunteers COMT Met/Met Genotype	Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Val/Val Genotype	Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Val/Met Genotype	Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Met/Met Genotype
Measure Participants	24	29	21	24	29	21
Right DLPFC	0.22 (0.03)	0.23 (0.03)	0.14 (0.04)	0.22 (0.03)	0.25 (0.03)	0.15 (0.04)
Left DLPFC	0.14 (0.03)	0.19 (0.03)	0.10 (0.03)	0.14 (0.03)	0.18 (0.03)	0.09 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer on Placebo, Healthy Volunteer Tolcapone, Patient on Placebo, Patients on Tolcapone, Healthy Volunteer COMT Val/Met Genotype on Tolcapone, Healthy Volunteer COMT Met/Met Genotype on Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	Main Effect of Genotype across both Placebo and Tolcapone in right DLPFC

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer on Placebo, Healthy Volunteer Tolcapone, Patient on Placebo, Patients on Tolcapone, Healthy Volunteer COMT Val/Met Genotype on Tolcapone, Healthy Volunteer COMT Met/Met Genotype on Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.167
	Comments
	Method	ANOVA
	Comments	Main Effect of Genotype across both Placebo and Tolcapone in left DLPFC

7. Primary Outcome

Title	N-Back Task Activation by Genotype in Patients With Schizophrenia
Description	Activation beta values (N-Back vs. 0-Back) extracted from DLPFC from the contrast maps in Patients with schizophrenia. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
Time Frame	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)

Outcome Measure Data

Analysis Population Description

33 patients with schizophrenia

Arm/Group Title	Patients COMT Val/Val Genotype on Placebo	Patients COMT Val/Met Genotype on Placebo	Patients COMT Met/Met Genotype on Placebo	Patients COMT Val/Val Genotype on Tolcapone	Patients COMT Val/Met Genotype on Tolcapone	Patients COMT Met/Met Genotype on Tolcapone
Arm/Group Description	Placebo Days 1-7, Patients COMT Val/Val Genotype	Placebo Days 1-7, Patients COMT Val/Met Genotype	Placebo Days 1-7, Patients COMT Met/Met Genotype	Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid	Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid	Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
Measure Participants	9	13	11	9	13	11
right DLPFC	0.33 (0.05)	0.23 (0.03)	0.24 (0.04)	0.25 (0.05)	0.20 (0.03)	0.22 (0.03)
left DLPFC	0.28 (0.04)	0.24 (0.03)	0.21 (0.04)	0.18 (0.05)	0.26 (0.04)	0.17 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer on Placebo, Healthy Volunteer Tolcapone, Patient on Placebo, Patients on Tolcapone, Healthy Volunteer COMT Val/Met Genotype on Tolcapone, Healthy Volunteer COMT Met/Met Genotype on Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.189
	Comments	Drug by Genotype Effect in left DLPFC
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer on Placebo, Patients on Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.041
	Comments	Drug Effect on Val/Val Genotype in left DLPFC
	Method	t-test, 1 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Healthy Volunteer Tolcapone, Healthy Volunteer COMT Val/Met Genotype on Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.718
	Comments	Drug Effect on Val/Met Genotype in left DLPFC
	Method	t-test, 1 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Patient on Placebo, Healthy Volunteer COMT Met/Met Genotype on Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.469
	Comments	Drug Effect of Met/Met Genotype in left DLPFC
	Method	t-test, 1 sided
	Comments

8. Secondary Outcome

Title	Positive and Negative Syndrome Scale
Description	Rating Scales PANSS. The Positive Scale ranges for 7 to 49 with a higher score indicating greater severity of symptoms. The Negative Scale ranges for 7 to 49 with a higher score indicating greater severity of symptoms. The General Scale ranges from 16 to 112, the higher score indicating greater severity of symptoms.
Time Frame	At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)

Outcome Measure Data

Analysis Population Description

There were 74 Healthy Volunteers and 33 Patients with Schizophrenia

Arm/Group Title	Healthy Volunteer on Placebo	Healthy Volunteer Tolcapone	Patient on Placebo	Patients on Tolcapone
Arm/Group Description	Placebo Days 1-7, Healthy volunteer	Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid	Placebo Days 1-7, Patient	Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
Measure Participants	74	74	33	33
Positive Subscale	7.01 (0.01)	7.02 (0.03)	12.15 (0.51)	12 (0.54)
Negative Subscale	7.36 (0.14)	7.27 (0.13)	16.51 (1.00)	15.88 (1.02)
General Psychopathology	16.36 (0.10)	16.33 (0.09)	27.12 (0.78)	26.24 (0.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Patient on Placebo, Patients on Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7
	Comments	Drug Effect on Positive Syndrome for Patients
	Method	t-test, 1 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Patient on Placebo, Patients on Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4
	Comments	Drug Effect on Negative Syndrome for Patients
	Method	t-test, 1 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Patient on Placebo, Patients on Tolcapone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.12
	Comments	Drug Effect on General Pathology for Patients
	Method	t-test, 1 sided
	Comments

Adverse Events

Time Frame	Day 1 to Day 21
Arm/Group Title	Healthy Volunteers on Placebo		Healthy Volunteers on Tolcapone		Patients on Placebo		Patients on Tolcapone
Arm/Group Description	Placebo Days 1-7, Healthy Volunteers		Tolcapone 100 mg TID on Day 1, 200 mg TID Days 2-7.		Placebo Days 1-7, Patients		Tolcapone 100 mg TID on Day 1, 200 mg TID Days 2-7
All Cause Mortality
	Healthy Volunteers on Placebo		Healthy Volunteers on Tolcapone		Patients on Placebo		Patients on Tolcapone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/131 (0%)		0/131 (0%)		0/59 (0%)		0/60 (0%)
Serious Adverse Events
	Healthy Volunteers on Placebo		Healthy Volunteers on Tolcapone		Patients on Placebo		Patients on Tolcapone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/131 (0%)		0/131 (0%)		0/59 (0%)		0/60 (0%)
Other (Not Including Serious) Adverse Events
	Healthy Volunteers on Placebo		Healthy Volunteers on Tolcapone		Patients on Placebo		Patients on Tolcapone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/131 (19.1%)		29/131 (22.1%)		17/59 (28.8%)		22/60 (36.7%)
Gastrointestinal disorders
Nausea	8/131 (6.1%)		16/131 (12.2%)		8/59 (13.6%)		5/60 (8.3%)
Diarrhea	5/131 (3.8%)		9/131 (6.9%)		4/59 (6.8%)		7/60 (11.7%)
General disorders
Appetite Problems	6/131 (4.6%)		8/131 (6.1%)		6/59 (10.2%)		5/60 (8.3%)
Musculoskeletal and connective tissue disorders
Stiffness	2/131 (1.5%)		6/131 (4.6%)		6/59 (10.2%)		11/60 (18.3%)
Nervous system disorders
Sleep Problems	8/131 (6.1%)		10/131 (7.6%)		6/59 (10.2%)		17/60 (28.3%)
Psychiatric disorders
Halluciantions	0/131 (0%)		0/131 (0%)		10/59 (16.9%)		9/60 (15%)

Limitations/Caveats

There was an early termination due to a request from the NIMH leadership to assess if was justifiable to continue when considering costs of this research and needs to assess resources to develop new protocols for the Branch

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.