L-DOPA vs. Placebo for Depression and Psychomotor Slowing in Older Adults

Sponsor

New York State Psychiatric Institute (Other)

Overall Status

Suspended

CT.gov ID

NCT03761030

Collaborator

National Institute of Mental Health (NIMH) (NIH)

Enrollment

Location

Arms

47.7

Anticipated Duration (Months)

1.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Individuals with Late Life Depression (LLD) often have cognitive problems, particularly problems with memory, attention, and problem solving, all of which contribute to antidepressant non-response. Our group and others have shown that decreased thinking speed is the central cause of functional problems in patients with LLD. Similarly, decreased walking speed is associated with depression and carries additional risk for falls, hospitalization, and death. Available evidence suggests that declining functionality in the brain's dopamine system contributes to age-related cognitive and motor slowing. The central hypothesis of this study is that by enhancing dopamine functioning in the brain and improving cognitive and motor slowing, administration of carbidopa/levodopa (L-DOPA) will improve depressive symptoms in older adults.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder Dysthymia Depression	Drug: L-DOPA Drug: Placebo Oral Tablet	Phase 4

Detailed Description

N=90 adults of which 30 participants will undergo scanning procedures, aged 60 and older with (1) a DSM 5 depressive disorder, (2) significant depressive symptoms, and (3) decreased thinking or walking speed will receive 8 weeks of treatment with L-DOPA up to 450mg. We will test whether L-DOPA increases brain dopamine release using neuroimaging and whether it speeds up thinking and walking speed. Data collected in the proposed studies may help identify a new treatment for LLD, which could have large public health ramifications given the prevalence, frequent treatment resistance, and chronicity characteristic of LLD. This project also will elucidate the neurobiology of slowing at molecular, structural, and functional levels of analysis, increasing our understanding of the interplay between these aging-associated processes and the pathophysiologic changes underlying late life neuropsychiatric disorders. Exploring patient characteristics that predict response to L-DOPA may provide useful information to guide differential therapeutics and develop personalized medicine for LLD.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

90 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Double Blind

Primary Purpose:

Treatment

Official Title:

Targeting Dopaminergic Mechanisms of Slowing to Improve Late Life Depression

Actual Study Start Date :

Jan 9, 2019

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: L-DOPA Arm Those assigned to L-DOPA will begin taking 37.5mg carbidopa/150 mg levodopa once daily (with placebo twice daily) for one week, then increase to 75mg carbidopa/300mg levodopa (37.5 mg carbidopa/150mg levodopa twice daily and placebo once daily) for one week, and finally increase to 112.5mg carbidopa/450mg levodopa (37.5 mg carbidopa/150mg levodopa three times daily and no placebo) for the final six weeks. Each subject assigned to the L-DOPA arm will be titrated to 450mg L-DOPA unless they cannot tolerate higher doses, in which case subjects will have their dosage reduced to the maximum tolerable dose	Drug: L-DOPA We will be using generic sinemet 25/100 tablets in this study. Other Names: carbidopa/levodopa (Sinemet)
Placebo Comparator: Placebo Arm Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study.	Drug: Placebo Oral Tablet 25/100 placebo tablets Other Names: Placebo

Arm

Intervention/Treatment

Experimental: L-DOPA Arm

Those assigned to L-DOPA will begin taking 37.5mg carbidopa/150 mg levodopa once daily (with placebo twice daily) for one week, then increase to 75mg carbidopa/300mg levodopa (37.5 mg carbidopa/150mg levodopa twice daily and placebo once daily) for one week, and finally increase to 112.5mg carbidopa/450mg levodopa (37.5 mg carbidopa/150mg levodopa three times daily and no placebo) for the final six weeks. Each subject assigned to the L-DOPA arm will be titrated to 450mg L-DOPA unless they cannot tolerate higher doses, in which case subjects will have their dosage reduced to the maximum tolerable dose

Drug: L-DOPA

We will be using generic sinemet 25/100 tablets in this study.

Other Names:

carbidopa/levodopa (Sinemet)

Placebo Comparator: Placebo Arm

Subjects assigned to the placebo arm will take placebo oral tablet three times daily throughout the study.

Drug: Placebo Oral Tablet

25/100 placebo tablets

Other Names:

Placebo

Outcome Measures

Primary Outcome Measures

Hamilton Rating Scale for Depression (HRSD) [8 Weeks]
Our target is depressive symptomatology as measured by the Hamilton Rating Scale for Depression (HRSD). The HRSD is a 24-item questionnaire used as an indication of depression and a guide to evaluate recovery. Total scores range from 0-74, not including atypical symptoms sub-scale. A score of 16 or above is typically considered to indicate the presence of depressive symptoms. Higher scores indicate greater severity.

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Aged 60 years and older
DSM 5 non-psychotic Major Depressive Disorder, Dysthymia, or Depression Not Otherwise Specified
Hamilton Rating Scale for Depression (HRSD) > 15
Decreased processing speed (defined as performance > 0.5SD below age-adjusted norms on Digit Symbol Substitution Test or Trail Making Test Part A) OR decreased gait speed (defined as average walking speed over 15' course < 1m/s)
Willing to and capable of providing informed consent and complying with study procedures
Alternative standard treatments for MDD, Dysthymia, or Depression NOS (e.g., antidepressant medication or psychotherapy) have been discussed and the individual agrees to be involved in an experimental treatment.

Exclusion Criteria:

Diagnosis of substance abuse or dependence (excluding Tobacco Use Disorder) within the past 12 months.
History of or current psychosis, psychotic disorder, mania, or bipolar disorder
Diagnosis of probable Alzheimer's Disease, Vascular Dementia, or Parkinson's Disease (PD)
Mini Mental Status Exam (MMSE) < 25
HRSD ≥ 28; HRSD suicide item > 2 or the presence of significant suicide risk as judged by clinician or Clinical Global Impressions (CGI)-Severity score of 7 at baseline.
Current or recent (within the past 4 weeks) treatment with antidepressants, antipsychotics, dopaminergic agents, or mood stabilizers.
History of allergy, hypersensitivity reaction, or severe intolerance to L-DOPA
Acute, severe, or unstable medical or neurological illness
Mobility limiting osteoarthritis of any lower extremity joints, symptomatic lumbar spine disease, mobility limiting history of joint replacement surgery, or history of spine surgery

FOR SUBJECTS RECEIVING PET/MRI SCANS ONLY:

Having contraindication to MRI scanning (such as metal in body) or unable to tolerate the scanning procedures
History of significant radioactivity exposure (nuclear medicine studies or occupational exposure)