Clinical trial NCT01636037: Antipsychotic Augmentation With L-Dopa
Official title: Augmentation of Antipsychotics With L-Dopa (Sinemet)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Schizophrenia
Keywords: schizophrenia
negative symptoms
deficit syndrome
SANS
Sinemet
L-dopa
levodopa
carbidopa
augmentation
antipsychotics
Lead sponsor: Centre for Addiction and Mental Health
Sponsor class: OTHER
First posted: 2012-07-10
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

1. L-dopa will prove effective in improving deficit (also called 'primary negative' e.g. amotivation) and cognitive symptoms in schizophrenia.
2. It will be well tolerated and not increase risk of psychotic symptoms when administered in conjunction with their regular antipsychotic medications.

Detailed description: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: SANS - Schedule for the Assessment of Negative Symptoms
timeFrame: 8 weeks
Secondary outcomes:
measure: MATRICS-Consensus Cognitive Battery
timeFrame: 8 weeks
measure: BPRS - Brief Psychotic Rating Scale
timeFrame: 8 weeks
measure: SAPS - Schedule for the Assessment of Positive Symptoms
timeFrame: 8 weeks
measure: NIMH-MATRICS Brief Negative Symptoms Scale
timeFrame: 8 weeks
measure: CGI-S - Clinical Global Impression - Severity Scale
timeFrame: 8 weeks
measure: QLS - Quality of Life Scale
timeFrame: 8 weeks
measure: CDS - Calgary Depression Scale
timeFrame: 8 weeks
measure: SAS - Simpson Angus Scale for Extrapyramidal Symptoms
timeFrame: 8 weeks
measure: BARS - Barnes Akathisia Rating Scales
timeFrame: 8 weeks
measure: AIMS - Abnormal Involuntary Movement Scale
timeFrame: 8 weeks
measure: UKU - Udvalg for Kliniske Undersogelses
timeFrame: 8 weeks
measure: LUNSERS - Liverpool University Neuroleptic Side-Effect Rating Scale
timeFrame: 8 weeks
measure: BIS-11 - Barrett Impulsivity Scale
timeFrame: 8 weeks
measure: Y-BOCS - Yale-Brown Obsessive Compulsive Scale
timeFrame: 8 weeks
measure: DAI - Drug Attitude Inventory
timeFrame: 8 weeks
measure: fMRI - Functional Magnetic Resonance Imaging
timeFrame: 8 weeks
measure: SWN - Subjective Well-Being on Neuroleptics Scale
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Centre for Addiction and Mental Health
state: Ontario
Study officials:
affiliation: Centre for Addiction and Mental Health
name: Gary Remington, MD PhD FRCPC
role: PRINCIPAL_INVESTIGATOR
References: