Antipsychotic Augmentation With L-Dopa

Augmentation of Antipsychotics With L-Dopa (Sinemet)

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: levodopa/carbidopa (generic version of Sinemet)

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.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 1R8
      • Centre for Addiction and Mental Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: L-Dopa (Sinemet); 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); Oral levodopa 900mg daily as tolerated.; Other Names: Sinemet; Levodopa/carbidopa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Centre for Addiction and Mental Health
• Investigators: Principal Investigator: Gary Remington, MD PhD FRCPC, Centre for Addiction and Mental Health

Publications and helpful links

Helpful Links

• Information about research at the Centre for Addiction and Mental Health, Canada's largest mental health and addiction teaching hospital. It is fully affiliated with the University of Toronto, and is a PAHO/WHO Collaborating Centre.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: July 5, 2012
• First Submitted That Met QC Criteria: July 9, 2012
• First Posted (Estimate): July 10, 2012

Study Record Updates

• Last Update Posted (Estimate): March 15, 2016
• Last Update Submitted That Met QC Criteria: March 11, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: schizophrenia; levodopa; antipsychotics; L-dopa; negative symptoms; augmentation; carbidopa; deficit syndrome; SANS; Sinemet
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunologic Factors; Dopamine Agonists; Dopamine Agents; Adjuvants, Immunologic; Antiparkinson Agents; Anti-Dyskinesia Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Levodopa; Carbidopa; Carbidopa, levodopa drug combination
• Other Study ID Numbers: 156/2011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No