Imaging Dopamine Release in Depression

Major Depressive Disorder Clinical Trial

Official title:

Ventrostriatal Dopamine Release and Reward Motivation in MDD

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02033369
• Other study ID #: #6853
• Secondary ID: 1R01MH099322-01A
• Status: Completed
• Phase: Phase 4
• Start date: February 2014
• Est. completion date: July 2017

Study information

• Verified date: October 2019
• Source: New York State Psychiatric Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 52
• Est. completion date: July 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
United States	New York State Psychiatric Institute	New York	New York

Sponsors (6)

Lead Sponsor	Collaborator
New York State Psychiatric Institute	Columbia University, Icahn School of Medicine at Mount Sinai, Mclean Hospital, National Institute of Mental Health (NIMH), Research Foundation for Mental Hygiene, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (6)

Forbes EE, Hariri AR, Martin SL, Silk JS, Moyles DL, Fisher PM, Brown SM, Ryan ND, Birmaher B, Axelson DA, Dahl RE. Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder. Am J Psychiatry. 2009 Jan;166(1):64-73. doi: 10.1176/appi.ajp.2008.07081336. Epub 2008 Dec 1. — View Citation

Kumar P, Waiter G, Ahearn T, Milders M, Reid I, Steele JD. Abnormal temporal difference reward-learning signals in major depression. Brain. 2008 Aug;131(Pt 8):2084-93. doi: 10.1093/brain/awn136. Epub 2008 Jun 25. — View Citation

Pizzagalli DA, Iosifescu D, Hallett LA, Ratner KG, Fava M. Reduced hedonic capacity in major depressive disorder: evidence from a probabilistic reward task. J Psychiatr Res. 2008 Nov;43(1):76-87. doi: 10.1016/j.jpsychires.2008.03.001. Epub 2008 Apr 22. — View Citation

Sanislow CA, Pine DS, Quinn KJ, Kozak MJ, Garvey MA, Heinssen RK, Wang PS, Cuthbert BN. Developing constructs for psychopathology research: research domain criteria. J Abnorm Psychol. 2010 Nov;119(4):631-9. doi: 10.1037/a0020909. — View Citation

Treadway MT, Zald DH. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev. 2011 Jan;35(3):537-55. doi: 10.1016/j.neubiorev.2010.06.006. Epub 2010 Jul 11. Review. — View Citation

Vrieze E, Pizzagalli DA, Demyttenaere K, Hompes T, Sienaert P, de Boer P, Schmidt M, Claes S. Reduced reward learning predicts outcome in major depressive disorder. Biol Psychiatry. 2013 Apr 1;73(7):639-45. doi: 10.1016/j.biopsych.2012.10.014. Epub 2012 Dec 8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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)	Baseline and 6 weeks
Secondary	Change in Snaith Hamilton Pleasure Scale	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.	Baseline and 6 weeks
Secondary	Change in Temporal Experience of Pleasure Scale - Anticipatory Subscale	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.	Baseline and 6 weeks
Secondary	Change in Mood and Anxiety Symptom Questionnaire, Short Form	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.	Baseline and 6 weeks
Secondary	Change in the Apathy Evaluation Rating Scale	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.	Baseline and 6 weeks
Secondary	Change in Clinical Global Improvement - Severity Scale	Seven-point Likert scale rating clinical severity of mental illness from 1 (least severe) to 7 ( most severe). Physician-rated scale. One item.	6 weeks
Secondary	Change in Temporal Experiences of Pleasure Scale -- Consummatory Subscale	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.	Baseline and 6 weeks