Official Title: “Combining a Dopamine Agonist and Selective Serotonin Reuptake Inhibitor for Treatment of Depression: A Double-Blind, Randomized Study”

This study compares the effectiveness of the combination of antidepressants: Lexapro and Pramipexole, with the effectiveness of each antidepressant alone.

Purpose: Patients between 18 and 65 years of age with Major Depressive Disorder without psychotic features may be eligible for this 9-week study.

Candidates must currently be in a major depressive episode of at least 4 weeks' duration, have failed to respond to treatment with an SSRI (Prozac, Zoloft, Paxil, Luvox, Celexa), and not have failed to respond to more than four antidepressants for the current episode.

Candidates are screened with a physical examination, psychiatric evaluation, blood tests, review of vital signs, height and weight measurements, electrocardiogram (ECG), urine test for illegal drugs, and pregnancy test for women.

Participants are tapered off antidepressants or other medications prohibited during the study and remain drug-free for 1 week before starting treatment.

They are then randomly assigned to take pramipexole and escitalopram, pramipexole alone, or escitalopram alone for 6 weeks. During the study, participants come to the clinic eight times for health assessments and symptoms assessments, which include a check of vital signs and rating scales for depression and anxiety, adverse events, and sexual functioning. Blood and urine samples are collected periodically to monitor health, detect pregnancy in women, and detect illicit drug use.

At the end of the 6-week treatment period, participants have a physical examination, ECG, blood test, and check of vital signs. Short-term anti-depressant treatment is offered, and plans are made for long-term treatment.

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Study Type: Interventional

Study Design: Treatment, Randomized, Double-Blind, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: April 2006

Despite the availability of a wide range of antidepressant drugs, 30% to 40% of patients with major depression fail to respond to first-line antidepressant (e.g., selective serotonin reuptake inhibitors [SSRIs]) treatment, despite adequate dosage, duration, and compliance.

Furthermore, these medications may take weeks to months to achieve their full effects, and in the meantime, patients continue to suffer from their symptoms and continue to be at risk of self-harm as well as harm to their personal and professional lives. Thus, there is a clear need to develop novel and improved therapeutics for treatment-resistant major depression that are more effective and have a rapid onset of action. Preclinical and clinical studies suggest that antidepressants with a combined mechanism of action (e.g., combination of a selective serotonin-reuptake inhibitor (SSRI) and a norepinephrine reuptake inhibitor) may be more effective than either agent alone in achieving remission (Nelson et al 2004). Thus, it stands to reason that other combinations of antidepressants with other mechanisms of action when combined may have a synergistic effect that is superior to an antidepressant with a single mechanism of action. Preclinical and clinical studies suggest that the dopaminergic system may play a major role in the pathophysiology of depression. Preclinical studies suggest synergistic antidepressant effects with the combination of a SSRI and a selective D3 receptor agonist in animal models of depression.

Similarly, preliminary clinical studies suggest synergism with combination treatment that affects the serotonin and dopamine systems. Together, these data suggests that treatments which affect the serotonin and dopamine systems will be more effective than agents which use a single mechanism. We propose to compare the combination of a selective dopaminergic agonist and a SSRI in patients with treatment-resistant major depression. To our knowledge, this will be the only controlled double-blind study to date that will examine the efficacy of a serotonin and dopamine combination given from the start of treatment.

Patients, ages 18 years or older, with a diagnosis of major depression (without psychotic features), will be randomized to the combination of a selective dopaminergic receptor agonist and a SSRI or either drug alone for a period of 6 weeks. Acute efficacy will be determined by demonstrating a greater remission rate using specified criteria. Approximately 85 patients with acute major depression will be enrolled in the study.

Intervention(s) in this Clinical Trial

• Drug: Pramipexole
  • N/A
• Drug: Escitalopram
  • N/A

Primary Measures

• Assess the efficacy of acute therapy with the comb of a selective dopamine agonist & a serotonin reuptake inibitor compared with either agent alone in pts with major depression w/o psychotic features.
  • Time Frame: 6 weeks
    Safety Issue?: Yes

INCLUSION CRITERIA:

• 1. Male or female subjects, 18 to 65 years of age.
• 2. Female subjects of childbearing potential must be using a medically accepted means of contraception.
• 3. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
• 4. Subjects must fulfill DSM-IV criteria for Major Depression (296.33) without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview, SCID-P.
• 5. Subjects must have an initial score of greater than or equal to 20 on the MADRS at Visit 1 and Visit 2.
• 6. Subjects must not have a greater than a 25% decrease in the MADRS total scores during washout (between Visits 1 and 2).
• 7. Current or past history of lack of response to at least one adequate antidepressant trial (SSRI) operationally defined using the Antidepressant
• Treatment History Form (ATHF) (Sackeim 2001b). If this criteria has not been met, a four-week prospective trial of a standard antidepressant (at the patients' and clinicians' discretion) may be given. Subjects are excluded if greater than four failed antidepressant trials for the current major depressive (adequate dose and duration as defined by the ATHF).
• 8. Current major depressive episode of at least 4 weeks duration.

EXCLUSION CRITERIA:

• 9. Presence of psychotic features or a diagnosis of Schizophrenia or any other psychotic disorder or bipolar disorder as defined in the DSM-IV.
• 10. Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for nicotine or caffeine) within the preceding 3 months.
• 11. Previously failed to respond to an adequate trial (dose and duration) of escitalopram.
• 12. Female subjects who are either pregnant or nursing.
• 13. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
• 14. Subjects with uncorrected hypothyroidism or hyperthyroidism.
• 15. Subjects with one or more seizures without a clear and resolved etiology.
• 16. Previous treatment with pramipexole.
• 17. Treatment with a reversible MAOI within 2 weeks prior to Visit 2.
• 18. Treatment with fluoxetine within 5 weeks prior to Visit 2.
• 19. Treatment with any other concomitant medication not allowed (Appendix A) 7 days prior to study Visit 2.
• 20. Treatment with clozapine or ECT within 3 months prior to study Visit 2.
• 21. Judged clinically to be an acute suicidal risk.
• 22. Psychotherapy will not be permitted during the study.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Mental Health (NIMH)

Overall Clinical Trial Officials and Contacts

Overall Contact: Libby Jolkovsky (877) 646-3644 libby_jolkovsky@nih.gov

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00086307

Study ID Number: 040227

ClinicalTrials.gov Identifier: NCT00086307

Health Authority: United States: Federal Government

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