This study seeks to understand if the medication pramipexole improves social connectedness and functioning in adults (ages 18-50) who experience anxiety or depression. The study plans to enroll 108 participants total across two sites (University of California San Diego and New York State Psychiatric Institute). Pramipexole will be given in a 6-week randomized, double-blind, placebo-controlled trial. Social reward processing will be assessed using measures of brain function (fMRI), behavior, and self-report at baseline and week 6. Knowledge gained from this study will help determine the therapeutic potential of targeting the dopamine system to remediate social disconnection as an anxiety and depression intervention.

This study seeks to understand how modulating functioning of the neurotransmitter dopamine affects brain circuits, behaviors, and subjective experiences that are believed to underlie an individual's motivation to establish and maintain positive social connections. This knowledge will help advance understanding of brain mechanisms that can be used to better treat social functioning impairments in people experiencing anxiety or depression. The R61 phase project will evaluate the effects of pramipexole (a medication that increases dopamine signaling in the brain) on responses to different types of positive social cues or contexts. The study drug will be given in a 6-week randomized, double-blind, placebo-controlled trial for individuals with clinical levels of anxiety or depression.

Aim 1 will test the hypothesis that pramipexole increases the anticipation of social rewards compared to placebo. Aim 2 will determine which dose of pramipexole (1.0 or 2.5 mg/d) produces a greater effect on social reward anticipation. To achieve these aims, approximately 108 participants (ages 18-50) with clinically elevated anxiety or depression will be randomized across two sites and randomized in equal proportions to one of two doses of pramipexole (1.0 mg/d or 2.5 mg/d) or placebo. They will complete standardized paradigms assessing social reward processing using measures of brain function (fMRI), behavior, and self-report at baseline and week 6. Knowledge gained from this study will help determine the therapeutic potential of targeting the dopamine system to remediate social disconnection.

Inclusion Criteria:

1. Clinically elevated levels of anxiety (OASIS ≥ 8) or depression or (PHQ-9 ≥ 10).
2. Moderate or greater social disability assessed with clinician-rating (SDS - Social ≥ 5).
3. Below the normative mean for temperamental reward sensitivity (ATQ - Approach < 35).
4. Age 18-50.
5. Ability to provide written informed consent.
6. English proficiency.

Exclusion Criteria:

Exclusion criteria are included to ensure that participation does not place subjects at undue risk, and to minimize confounding interpretation of our findings:

1. Current, imminent risk of suicide assessed with Clinical Interview and Columbia Suicide Severity Rating Scale (C-SSRS) "yes" response to items 4, 5 (past month), 6 (past 3 months), or suicide attempt in the past year.
2. History of bipolar or psychotic disorders.
3. History of major neurological disorder or moderate to severe traumatic brain injury.
4. History of severe or unstable medical conditions that might be compromised by participation in the study (e.g., cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease; history of seizure disorder).
5. Past 6-month substance use disorder (any severity) with the exception of mild alcohol, cannabis, or tobacco use disorder, which will be permitted in the study.
6. History of impulse control problems (e.g., pathological gambling).
7. First-degree relative with a diagnosis of schizophrenia-spectrum or other psychotic disorder or bipolar disorder.
8. History of cocaine or stimulant use (e.g., amphetamine, cocaine, methamphetamine; except for physician prescribed stimulants) in the past 6 months.
9. History of dopaminergic agonists drug use (e.g., pramipexole, ropinirole, apomorphine, rotigotine) in the past 6 months.
10. Positive urinalysis screen for psychoactive drug use (that is not physician prescribed or THC).
11. Abnormal and clinically relevant blood count, liver, renal or EKG findings as determined by physician.
12. Women who are pregnant, breastfeeding, or planning to become pregnant within the next 6 months. Individuals of childbearing potential must agree to use an acceptable method of contraception from at least 21 days prior to the first dose of study drug and for 3 months after the last dose of study drug for study entry.
13. Concurrent empirically supported psychosocial treatments for anxiety or mood disorders (e.g., cognitive behavioral therapy).
14. Use of any psychotropic medication (e.g. SSRIs, benzodiazepines) within 14 days before study entry [except for fluoxetine within 30 days]. Concurrent use is prohibited during the study
15. Anticipated inability to attend regular study appointments.
16. Anticipated inability to complete the study procedures as determined by study personnel.
17. Clinical conditions assessed by the interviewer that necessitate more imminent clinical care. These criteria are in place so participants with these other, more severe symptoms can be referred for appropriate services (e.g. self-injurious behavior or exposure to a severe traumatic event in the past week).
18. Non-correctable vision or hearing problems, as some tests require intact sensory functioning.
19. No telephone or easy access to telephone.
20. MRI contraindications
21. CGI-S score of 6 or 7.

Data from this study will be submitted to the National Institute of Health Data Archive (NDA).

Every 6 months following the NDA submission schedule.

Eligible researches can submit a Data Access Request to the NDA to obtain access to de-identified study data for research purposes.

The pharmacy will blind drug and placebo through identical encapsulation. Placebo will match the study drug in mode of administration, color, size, and taste.