Antipsychotic Augmentation With L-Dopa

Study Overview
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Brief Summary
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Dopamine, a chemical in the brain, has been linked to schizophrenia for a number of years. More recently, there is evidence that certain areas affected in schizophrenia (e.g. motivation, cognition) may reflect too little dopamine, whereas symptoms like hallucinations and delusions have been linked to too much dopamine. This study is designed to evaluate the safety, tolerability, and efficacy of giving L-dopa (Sinemet) to see if it will improve those symptoms related to too little dopamine. L-dopa has been approved for other medical conditions (e.g. Parkinson's disease) and works to increase levels of dopamine. The investigators are linking this study with neuroimaging (fMRI) which will allows us to link any changes the investigators might find in clinical symptoms with changes in the brain. This information can prove useful in better understanding the mechanisms that account for these symptoms, as well as possible new treatments. At present , treatments for these other symptoms that seem important in functional measures of outcome (i.e. deficit symptoms, including amotivation; cognitive symptoms) in schizophrenia have not proven particularly effective. It is hoped that L-dopa may provide a treatment that is more effective; going forward, this information would also be useful in drug development and future lines of investigation. L-dopa will prove effective in improving deficit (also called 'primary negative' e.g. amotivation) and cognitive symptoms in schizophrenia. It will be well tolerated and not increase risk of psychotic symptoms when administered in conjunction with their regular antipsychotic medications.

Detailed Description
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Pharmacological (and non-pharmacological) strategies that may significantly improve the negative and cognitive symptoms of schizophrenia represent a critical unmet therapeutic need. There is wide acceptance of the notion that both negative and cognitive symptoms are best understood as features of hypo- rather than hyperdopaminergic activity. The primary negative and cognitive symptoms appear central to schizophrenia and predate the neurodevelopmental changes that subsequently give rise to the hyperdopaminergic state underlying positive symptoms. In using L-Dopa specifically, we avoid the abuse potential of agents such as the psychostimulants, or perturbations in pharmacological action as a function of dose, as observed with dopamine agonists. Further, more recent neuroimaging studies have provided in vivo evidence in keeping with the underlying rationale. First, imaging studies have demonstrated that L-dopa induces shifts in activity in both cortical and subcortical structures linked to reward, affect and cognition. Along similar lines, L-dopa-induced changes have been associated with improvement in motivation, cognitive tasks, and affect.

Official Title
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Augmentation of Antipsychotics With L-Dopa (Sinemet)

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: levodopa/carbidopa (generic version of Sinemet)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: SCID-confirmed (Structured Clinical Interview for DSM-IV Axis I Disorders) diagnosis of schizophrenia ages 18-55 Exclusion Criteria: history of substance abuse or dependence within 3 months; (ii) positive urine drug screen history or evidence of any disorder that might adversely influence cognitive measures (e.g. mental retardation) presence of serious neurological or general medical condition (e.g., Parkinson's disease, cardiac arrhythmia, epilepsy) clinical or laboratory evidence of uncompensated cardiovascular, endocrine, hematologic, hepatic, pulmonary (including bronchial asthma), or renal disease, narrow-angle glaucoma, malignant melanoma pregnancy/nursing or women of child-bearing age not on regular contraceptive therapy (effects of L-dopa unknown)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L-Dopa (Sinemet)<br>Augmentation of current antipsychotic treatment with oral L-Dopa (levodopa/carbidopa) up to 900mg daily for 8 weeks | Drug: levodopa/carbidopa (generic version of Sinemet)<br>* Oral levodopa 900mg daily as tolerated.<br>* Other names: Sinemet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SANS - Schedule for the Assessment of Negative Symptoms |  | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MATRICS-Consensus Cognitive Battery |  | 8 weeks | 
| BPRS - Brief Psychotic Rating Scale |  | 8 weeks | 
| SAPS - Schedule for the Assessment of Positive Symptoms |  | 8 weeks | 
| NIMH-MATRICS Brief Negative Symptoms Scale |  | 8 weeks | 
| CGI-S - Clinical Global Impression - Severity Scale |  | 8 weeks | 
| QLS - Quality of Life Scale |  | 8 weeks | 
| CDS - Calgary Depression Scale |  | 8 weeks | 
| SAS - Simpson Angus Scale for Extrapyramidal Symptoms |  | 8 weeks | 
| BARS - Barnes Akathisia Rating Scales |  | 8 weeks | 
| AIMS - Abnormal Involuntary Movement Scale |  | 8 weeks | 
| UKU - Udvalg for Kliniske Undersogelses | Measures General Side Effects | 8 weeks | 
| LUNSERS - Liverpool University Neuroleptic Side-Effect Rating Scale |  | 8 weeks | 
| BIS-11 - Barrett Impulsivity Scale |  | 8 weeks | 
| Y-BOCS - Yale-Brown Obsessive Compulsive Scale |  | 8 weeks | 
| DAI - Drug Attitude Inventory |  | 8 weeks | 
| fMRI - Functional Magnetic Resonance Imaging | Changes in Regional Brain Activity | 8 weeks | 
| SWN - Subjective Well-Being on Neuroleptics Scale |  | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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schizophrenia, negative symptoms, deficit syndrome, SANS, Sinemet, L-dopa, levodopa, carbidopa, augmentation, antipsychotics