Clinical trial NCT02033369: Imaging Dopamine Release in Depression
Official title: Ventrostriatal Dopamine Release and Reward Motivation in MDD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Major Depressive Disorder
Keywords: Major depressive disorder
MDD
depression
pramipexole
Lead sponsor: New York State Psychiatric Institute
Sponsor class: OTHER
Collaborators: name: Columbia University
name: Research Foundation for Mental Hygiene, Inc.
name: Mclean Hospital
name: Icahn School of Medicine at Mount Sinai
name: National Institute of Mental Health (NIMH)
First posted: 2014-01-10
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Hamilton Rating Scale for Depression
timeFrame: Baseline and 6 weeks
Secondary outcomes:
measure: Change in Snaith Hamilton Pleasure Scale
timeFrame: Baseline and 6 weeks
measure: Change in Temporal Experience of Pleasure Scale - Anticipatory Subscale
timeFrame: Baseline and 6 weeks
measure: Change in Mood and Anxiety Symptom Questionnaire, Short Form
timeFrame: Baseline and 6 weeks
measure: Change in the Apathy Evaluation Rating Scale
timeFrame: Baseline and 6 weeks
measure: Change in Clinical Global Improvement - Severity Scale
timeFrame: 6 weeks
measure: Change in Temporal Experiences of Pleasure Scale -- Consummatory Subscale
timeFrame: Baseline and 6 weeks
Other outcomes:
Locations:
city: New York
country: United States
facility: New York State Psychiatric Institute
state: New York
Study officials:
affiliation: NYSPI
name: Franklin Schneier, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
citation: 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.
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.
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.
citation: Whitton AE, Reinen JM, Slifstein M, Ang YS, McGrath PJ, Iosifescu DV, Abi-Dargham A, Pizzagalli DA, Schneier FR. Baseline reward processing and ventrostriatal dopamine function are associated with pramipexole response in depression. Brain. 2020 Feb 1;143(2):701-710. doi: 10.1093/brain/awaa002.
citation: Schneier FR, Slifstein M, Whitton AE, Pizzagalli DA, Reinen J, McGrath PJ, Iosifescu DV, Abi-Dargham A. Dopamine Release in Antidepressant-Naive Major Depressive Disorder: A Multimodal [11C]-(+)-PHNO Positron Emission Tomography and Functional Magnetic Resonance Imaging Study. Biol Psychiatry. 2018 Oct 15;84(8):563-573. doi: 10.1016/j.biopsych.2018.05.014. Epub 2018 May 25.