Imaging Dopamine Release in Depression

Ventrostriatal Dopamine Release and Reward Motivation in MDD

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02033369

Enrollment

Registered

2014-01-10

Start date

2014-02-28

Completion date

2017-07-31

Last updated

2019-11-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Major Depressive Disorder

Keywords

Major depressive disorder, MDD, depression, pramipexole

Brief summary

This study aims to determine whether ventral striatal dopamine release is a mechanism of reward motivation in major depression, whether dopamine release is low in depression, and whether DA release and reward motivation predict response to dopamine-targeted treatment with pramipexole.

Detailed description

Better understanding of the basic neurobiology of mood dysfunction appears necessary to enable further progress in the treatment of depression. Reward motivation (and the closely related construct of reward learning) is a core neurobehavioral domain.(1,2) In major depressive disorder (MDD), low reward motivation is a key aspect of anhedonia, a cardinal symptom of MDD, and is related to resistance to treatment.(2,3) Although much has been learned about reward motivation's neurobiology and relevance to psychopathology, important gaps in our knowledge have impeded the application of basic science findings to improving treatment of MDD. Reward motivation in healthy subjects involves ventrostriatal (VST) dopamine (DA)(4,5), and reduced reward motivation is linked to MDD and anhedonia.(3,6) These data suggest that VST DA dysfunction might be present in MDD and manifested clinically by anhedonia. While DA neuroreceptor imaging studies have failed to verify this, they have been methodologically compromised. Limitations include imaging methods with poor resolution of functional striatal subregions, MDD samples heterogeneous for antidepressant use, and use of self-report measures of anhedonia, rather than objective behavioral testing of the specific domain of reward motivation. This will be the first study of both VST DA release (by PET imaging) and reward motivation, and will include patients with MDD and healthy volunteers. Reward motivation will be captured and operationalized as reward learning in a probabilistic reward task (prior to imaging). This will clarify if VST DA dysfunction is linked to impaired motivation in MDD. To test clinical implications in MDD patients, we will assess the relationship of VST DA release, reward motivation, and anhedonia to outcome of subsequent open label treatment with the DA D2 receptor agonist pramipexole.

Interventions

DRUGPramipexole

Dose will be started at 0.125 mg bid, and increased by 0.25 mg/day every 3-4 days to a target range of 1.0 - 2.5 mg/day.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 50 Years

Healthy volunteers

Yes

Inclusion criteria

* Weight between 44 kg and 115 kg * Meets DSM-IV criteria for principal diagnosis of MDD, current major depressive episode, without psychotic features * Score of \>16 and \<29 on 17-item Hamilton Rating Scale for Depression * Psychotropic-naïve, as defined by lifetime \<2 weeks treatment with antidepressants, anxiolytics or antipsychotics * Able to tolerate a treatment-free period during study participation * Able to provide informed consent

Exclusion criteria

* A principal diagnosis of any current Axis I psychiatric disorder other than the MDD * Lifetime diagnosis of any psychotic disorder, bipolar disorder, mental retardation, attention deficit/hyperactivity disorder, or substance use disorders (including nicotine use disorders) * Serious suicidal risk or history of violent behavior which would make participation in the protocol unsafe * Any tobacco use in the prior three months (if not already excluded for abuse/dependence by #1) * Illicit drug use in the prior three months, as evidenced by history or urine toxicology screen * Women who are pregnant, nursing, postmenopausal, or using hormonal methods of birth control * Women who are not using an effective birth control method or sexual abstinence during the ten days before the scan * Any medical or neurological problem that might affect interpretation of findings or safety of participation (e.g., blood dyscrasias, lymphomas, hypersplenism, endocrinopathies, renal failure or chronic obstructive lung disease, malignancy, neurological diseases of the brain, history of seizures or head trauma), low hemoglobin (Hb \< 12 gm/dL in males, Hb \< 10.5 gm/dL in females)) * Blood donation within 4 weeks of study * Metal implants or paramagnetic objects in the body that might affect safety of undergoing MRI (e.g., heart pacemaker, shrapnel, bullets, surgical prostheses or surgical clips), as determined in consultation with a neuroradiologist and according to the guidelines set forth in the reference: Guide to MR procedures and metallic objects Shellock; Lippincott Williams and Wilkins, NY, 2001 * More than one major risk factor for coronary artery disease (e.g. hyperlipidemia, sedentary lifestyle). Smokers are already excluded by #4 above, and diabetics by #8 above * Systolic blood pressure \> 140 or diastolic blood pressure \> 90 based on at least two readings at rest * History of untoward reaction to amphetamine or other stimulant medication, or pramipexole * Any psychotropic treatment in the past 3 weeks (or depot medication in the past 6 months), except for lorazepam,which may be administered as needed prior to imaging day * Current, past or anticipated exposure to radiation in the workplace, or participation in nuclear medicine procedures, including research protocols (In case of previous exposure to activity due to research studies, subjects will be eligible if all conditions listed below are fulfilled: 1) The injected dose and dosimetry of the radiotracer are known; 2) Except for research studies, the subject has not been exposed to radiation (workplace and medical); 3) Adding prior exposure to the exposure due to the study will result in a yearly cumulative exposure lower than the FDA limit for research studies * Family history of schizophrenia in parents, siblings, or children * Ongoing cognitive-behavioral or interpersonal psychotherapy for depression (Supportive therapy is not an exclusion) * Ongoing treatment with cimetidine

Design outcomes

Primary

Measure	Time frame	Description
Change in Hamilton Rating Scale for Depression	Baseline and 6 weeks	Hamilton Rating Scale for Depression (HRSD), 17-item version. This standard scale will be used to assess severity of depression, looking at change in total score from baseline to week 6, rating severity of depression on a scale from 0 (least depression) to 50 (greatest depression)

Secondary

Measure	Time frame	Description
Change in Temporal Experience of Pleasure Scale - Anticipatory Subscale	Baseline and 6 weeks	A validated self-rated scale shown to assess anticipatory pleasure. It will be used for exploratory analyses of anhedonia. 18 items were measured on a scale of 1 (very false for me) to 6 (very true for me). Higher scores indicate higher pleasure. Item scores were added for a lowest possible score of 18 and highest possible score of 108.
Change in Mood and Anxiety Symptom Questionnaire, Short Form	Baseline and 6 weeks	Change in Mood and Anxiety Symptom Questionnaire, Short Form. A 62-item scale assessing anxiety and depression. Items were measured on a scale of 1-5, higher number indicating higher levels of symptoms.The lowest possible score was 62, and the highest 310.
Change in Snaith Hamilton Pleasure Scale	Baseline and 6 weeks	Fourteen-item self-rated anhedonia scale. Items were comprised of statements that participants rated as strongly disagree (1), disagree (2), agree (3), or strongly agree (4). The lowest possible score was 14, the highest possible score was 56.
Change in Clinical Global Improvement - Severity Scale	6 weeks	Seven-point Likert scale rating clinical severity of mental illness from 1 (least severe) to 7 ( most severe). Physician-rated scale. One item.
Change in Temporal Experiences of Pleasure Scale -- Consummatory Subscale	Baseline and 6 weeks	A validated self-rated scale shown to assess consummatory pleasure. It will be used for exploratory analyses of anhedonia. 18 items were measured on a scale of 1 (very false for me) to 6 (very true for me). Higher scores indicate higher pleasure. Item scores were added for a lowest possible score of 18 and highest possible score of 108.
Change in the Apathy Evaluation Rating Scale	Baseline and 6 weeks	A validated self-rated 18 item scale assessing apathy. Items were rated from 1 (not at all true) to 4 (very true). Higher scores indicate lower apathy, lower scores indicate higher apathy. Lowest possible score is 18, highest possible score is 72.

Countries

United States

Participant flow

Participants by arm

Arm	Count
MDD Patients Six weeks of treatment with oral pramipexole, initiated at 0.25 mg/day and titrated to a maximum daily dose of 2.5 mg. Pramipexole: Dose will be started at 0.125 mg bid, and increased by 0.25 mg/day every 3-4 days to a target range of 1.0 - 2.5 mg/day	26
Healthy Control Patients Healthy control patients did not receive study medication and only have baseline measures.	25
Total	51

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	1	0
Overall Study	Not a good demographic match	0	2
Overall Study	Physician Decision	1	2
Overall Study	Protocol Violation	2	0
Overall Study	Withdrawal by Subject	1	1

Baseline characteristics

Characteristic	Total	MDD Patients	Healthy Control Patients
Age, Continuous	26.5 years STANDARD_DEVIATION 5.8	26.5 years STANDARD_DEVIATION 6.1	26.5 years STANDARD_DEVIATION 5.6
Apathy Evaluation Rating Scale	33.0 units on a scale STANDARD_DEVIATION 11.8	41.8 units on a scale STANDARD_DEVIATION 9.7	23.8 units on a scale STANDARD_DEVIATION 4.9
Clinical Global Impression Severity	1.9 units on a scale STANDARD_DEVIATION 0.4	3.9 units on a scale STANDARD_DEVIATION 0.7	1.0 units on a scale STANDARD_DEVIATION 0
Ethnicity (NIH/OMB) Hispanic or Latino	19 Participants	10 Participants	9 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	32 Participants	16 Participants	16 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Hamilton Rating Scale for Depression	10.4 units on a scale STANDARD_DEVIATION 10.3	20.3 units on a scale STANDARD_DEVIATION 2.7	0.2 units on a scale STANDARD_DEVIATION 0.4
Mood and Anxiety Symptom Questionnaire	130.1 units on a scale STANDARD_DEVIATION 50.8	174.5 units on a scale STANDARD_DEVIATION 28.6	83.9 units on a scale STANDARD_DEVIATION 13.3
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	6 Participants	3 Participants	3 Participants
Race (NIH/OMB) Black or African American	10 Participants	5 Participants	5 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	13 Participants	6 Participants	7 Participants
Race (NIH/OMB) White	22 Participants	12 Participants	10 Participants
Sex: Female, Male Female	25 Participants	13 Participants	12 Participants
Sex: Female, Male Male	26 Participants	13 Participants	13 Participants
Snaith Hamilton Pleasure Scale	25.7 units on a scale STANDARD_DEVIATION 8.7	31.9 units on a scale STANDARD_DEVIATION 6.5	18.9 units on a scale STANDARD_DEVIATION 4.8
Temporal Experience of Pleasure Scale - Anticipatory Subscale	42.4 units on a scale STANDARD_DEVIATION 9.3	36.1 units on a scale STANDARD_DEVIATION 8	49.0 units on a scale STANDARD_DEVIATION 5.2
Temporal Experience of Pleasure Scale - Consummatory Subscale	34.1 units on a scale STANDARD_DEVIATION 8.5	29.9 units on a scale STANDARD_DEVIATION 7.6	38.4 units on a scale STANDARD_DEVIATION 7.2

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 22
other Total, other adverse events	22 / 22
serious Total, serious adverse events	0 / 22

Outcome results

Primary

Change in Hamilton Rating Scale for Depression

Hamilton Rating Scale for Depression (HRSD), 17-item version. This standard scale will be used to assess severity of depression, looking at change in total score from baseline to week 6, rating severity of depression on a scale from 0 (least depression) to 50 (greatest depression)

Time frame: Baseline and 6 weeks