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| ID | Type | Description | Link |
|---|---|---|---|
| 02-M-0239 | Other Identifier | Clinicaltrials.gov | |
| NCT00044083 | Other Identifier | Clinicaltrials.gov |
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Scientific Director request to use resources for other studies
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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.
...
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo Arm | Placebo Comparator | Placebo one week |
|
| Tolcapone Arm | Active Comparator | Tolcapone one week |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo | Other | Placebo: One capsule 3 times a day from Day 1 to Day 7 |
| |
| Measure | Description | Time Frame |
|---|---|---|
| N-Back Task Performance | 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. | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
| N-Back Task Activation Diagnosis Effect | 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. | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
| N-Back Task Activation Drug Effect | 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. | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
| N-Back Task Activation in DLPFC in Patients With Schizophrenia | 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. | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
| N-Back Task Activation in Healthy Volunteers |
| Measure | Description | Time Frame |
|---|---|---|
| Positive and Negative Syndrome Scale | 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. | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
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INCLUSION CRITERIA:
EXCLUSION CRITERIA:
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| Name | Affiliation | Role |
|---|---|---|
| Jose A Apud, M.D. | National Institute of Mental Health (NIMH) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | 20892 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 8518836 | Background | 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. doi: 10.1097/00008571-199304000-00008. | |
| 8784225 | Background | 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. doi: 10.1097/00004647-199609000-00005. |
| Label | URL |
|---|---|
| NIH Clinical Center Detailed Web Page | View source |
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No plan to share data
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo First Then Tolcapone | Placebo one week first: Tolcapone 200 mg second: |
| FG001 | Tolcapone First, Then Placebo | Tolcapone one week: Placebo one week second: |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (One Week)- HV's |
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| Second Intervention (One Week) HV's |
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| First Intervention (One Week) Patients |
| ||||||||||||||||||||||
| Second Intervention (One Week) Patients |
|
These numbers represent the total number of subjects (HV's+patients) plus HV's and patients separately that completed the first and second arm of the protocol.
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| ID | Title | Description |
|---|---|---|
| BG000 | Healthy Volunteers | Tolcapone 200 mg 1 week:Wash Out 1 week:Placebo 1 week: (or vice versa) |
| BG001 | Patients | Tolcapone 200 mg 1 week:Wash Out 1 week:Placebo 1 week: (or vice versa) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | N-Back Task Performance | 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. | 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. | Posted | Mean | Standard Error | % of Correct Trials | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
|
Day 1 to Day 21
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Healthy Volunteers on Placebo | Placebo Days 1-7, Healthy Volunteers | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment | Nausea was present in two patients in both arms of the protocol. |
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
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jose A. Apud | Office of the Clinical Director-NIMH-NIH-HHS | 3015946561 | apudj@mail.nih.gov |
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| ID | Term |
|---|---|
| D012559 | Schizophrenia |
| ID | Term |
|---|---|
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D000077867 | Tolcapone |
| ID | Term |
|---|---|
| D001577 | Benzophenones |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
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| Tolcapone |
| Drug |
Tolcapone: One capsule 3 times a day from Day 1 to Day 7 |
|
|
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. |
| At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
| N-Back Task Activation Genotype Effect in Healthy Volunteers | 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. | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
| N-Back Task Activation by Genotype in Patients With Schizophrenia | 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. | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
| 9208378 | Background | Arnsten AF. Catecholamine regulation of the prefrontal cortex. J Psychopharmacol. 1997;11(2):151-62. doi: 10.1177/026988119701100208. |
| 23794107 | Derived | Magalona SC, Rasetti R, Chen J, Chen Q, Gold I, Decot H, Callicott JH, Berman KF, Apud JA, Weinberger DR, Mattay VS. Effect of tolcapone on brain activity during a variable attentional control task: a double-blind, placebo-controlled, counter-balanced trial in healthy volunteers. CNS Drugs. 2013 Aug;27(8):663-73. doi: 10.1007/s40263-013-0082-x. |
| Withdrawal by Subject |
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| Pregnancy |
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| Used illegal drugs |
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| Abnormal MRI |
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| Drank while on protocol |
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| NOT COMPLETED |
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| NOT COMPLETED |
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| NOT COMPLETED |
|
|
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Placebo Days 1-7, Healthy voluntee |
| OG001 | Healthy Volunteer Tolcapone | Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid |
| OG002 | Patient on Placebo | Placebo Days 1-7, Patient |
| OG003 | Patients on Tolcapone | Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid |
|
|
|
| Primary | N-Back Task Activation Diagnosis Effect | 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. | 74 Healthy Volunteers and 33 Patients with Schizophrenia | Posted | Mean | Standard Error | beta value | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
|
|
|
|
| Primary | N-Back Task Activation Drug Effect | 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. | 74 Healthy Volunteers and 33 Patients with Schizophrenia | Posted | Mean | Standard Error | beta value | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
|
|
|
|
| Primary | N-Back Task Activation in DLPFC in Patients With Schizophrenia | 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. | 33 Patients with Schizophrenia | Posted | Mean | Standard Error | beta value | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
|
|
|
|
| Primary | N-Back Task Activation in Healthy Volunteers | 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. | 74 Healthy Volunteers | Posted | Mean | Standard Error | beta value | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
|
|
|
|
| Primary | N-Back Task Activation Genotype Effect in Healthy Volunteers | 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. | Posted | Mean | Standard Error | beta value | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
|
|
|
|
| Primary | N-Back Task Activation by Genotype in Patients With Schizophrenia | 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. | 33 patients with schizophrenia | Posted | Mean | Standard Error | beta value | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
|
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|
|
| Secondary | Positive and Negative Syndrome Scale | 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. | There were 74 Healthy Volunteers and 33 Patients with Schizophrenia | Posted | Mean | Standard Deviation | units on a scale | At end of treatment period (at 7th day for first intervention and at 21st day for second intervention) |
|
|
|
|
| 131 |
| 0 |
| 131 |
| 25 |
| 131 |
| EG001 | Healthy Volunteers on Tolcapone | Tolcapone 100 mg TID on Day 1, 200 mg TID Days 2-7. | 0 | 131 | 0 | 131 | 29 | 131 |
| EG002 | Patients on Placebo | Placebo Days 1-7, Patients | 0 | 59 | 0 | 59 | 17 | 59 |
| EG003 | Patients on Tolcapone | Tolcapone 100 mg TID on Day 1, 200 mg TID Days 2-7 | 0 | 60 | 0 | 60 | 22 | 60 |
|
| Sleep Problems | Nervous system disorders | Non-systematic Assessment | Sleep problems was present in three patients in both arms of the protocol. |
|
| Appetite Problems | General disorders | Non-systematic Assessment | Appetite problem was present in two patients in both arms of the protocol. |
|
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment | Diarrhea was present in one patient in both arms of the protocol. |
|
| Stiffness | Musculoskeletal and connective tissue disorders | Non-systematic Assessment | Stiffness present in four patients in both arms of the protocol. |
|
| Halluciantions | Psychiatric disorders | Non-systematic Assessment | Hallucination was present in nine patients in both arms of the protocol. On patient reported hallucinations only on the placebo arm of the protocol. |
|
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| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D009596 | Nitrophenols |
| D010636 | Phenols |
| D007659 | Ketones |
| D009574 | Nitro Compounds |
Diagnosis Effect of Placebo in left DLPFC |
| Other |
| Left DLPFC |
|
| 0.32 |
Drug Effect across both groups in right DLPFC |
| Other |
Effect of Drug on Patients with Schizophrenia in left DLPFC |
| Other |
Drug Effect on Healthy Volunteers in right DLPFC |
| Other |
| Left DLPFC |
|
| ANOVA |
Main Effect of Genotype across both Placebo and Tolcapone in left DLPFC |
| 0.167 |
| Other |
| left DLPFC |
|
| 0.041 |
Drug Effect on Val/Val Genotype in left DLPFC |
| Other |
| t-test, 1 sided | 0.718 | Drug Effect on Val/Met Genotype in left DLPFC | Other |
| t-test, 1 sided | 0.469 | Drug Effect of Met/Met Genotype in left DLPFC | Other |
| Negative Subscale |
|
| General Psychopathology |
|
Drug Effect on Negative Syndrome for Patients |
| Other |
| t-test, 1 sided | 0.12 | Drug Effect on General Pathology for Patients | Other |