Org 24448 to Treat Major Depression
Condition: Depression
MeSH terms: Depression; Depressive Disorder
Intervention: Org 24448; Placebo
Intervention description: 250 mg once per day for first week, 250 mg twice per day for second week, 500 mg twice per day for third and fourth weeks, if response minimal or worse at four weeks then 750 mg twice per day for additional weeks; Inactive equivalent of 250 mg once per day for first week, 250 mg twice per day for second week, 500 mg twice per day for third and fourth weeks, if response minimal or worse at four weeks then 750 mg twice per day for additional weeks
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 9.0
Sex: All
Minimum age: 21 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Depression; Glutamate; Ampakine; Treatment; Memory; Major Depressive Disorder; AMPA Receptor Activation; BDNF

Summary:

      This study will evaluate the effectiveness of the experimental drug, Org 24448, for
      short-term treatment of depression. It will examine the effects of the drug on symptoms, such
      as low mood and persistent sadness, poor sleep and appetite, poor motivation and lack of
      enjoyment of things people normally enjoy, negative thinking, and feeling slowed down or
      having trouble concentrating. It will also assess whether the drug improves cognitive
      function, especially memory.

      Patient with major depression who do not have a serious, unstable medical illness and who are
      21 to 55 years of age may be eligible for this study. Candidates are screened with a
      psychiatric and medical history, diagnostic interview, physical examination,
      electrocardiogram, blood tests and, for women, a pregnancy test.

      Participants are tapered off anti-depression drugs (and any other medications not allowed on
      the study) over a 3-week period and then begin a 2-week drug-free period. During these 2
      weeks they have an electroencephalogram (EEG) with light stimulation, and those whose EEG
      indicates a seizure disorder are excluded from the study. Also at the beginning of the
      drug-free period they begin taking a placebo ("sugar pill") twice a day. After 2 weeks on
      placebo, some patients begin treatment with Org 24448, while others remain on placebo. They
      continue the medication for 8 weeks, during which time they have a weekly check of vital
      signs, blood and urine tests, and rating scales for depression and anxiety. Level of
      functioning is evaluated twice during the study. After 8 weeks of treatment, patients have a
      physical exam, electrocardiogram (ECG), EEG, blood tests, and begin to come off the study
      drug, tapering the medication over a week.

      In addition to the above procedures, some patients undergo the following tests during the
      2-week drug-free period and again toward the end of the 8-week medication phase:

        -  Neuropsychological testing, including measurements of cognitive abilities such as
           memory, attention, problem-solving, and language skills.

        -  Positron emission tomography (PET): This nuclear medicine test provides information
           about different brain regions. The patient lies on a table in the PET scanner (similar
           to a computed tomography (CT) scanner), with a mask placed over his or her face that
           helps keep the head still. A sugar fluid with a radioactive material attached to it is
           injected into a catheter (plastic tube) that has been inserted into a vein in the
           patient's arm. The scanner detects ...
    

Eligibility criteria:

        INCLUSION CRITERIA:

          1. Male or female subjects, 21 to 70 years of age.

          2. Female subjects who are not of childbearing potential (i.e., surgically sterile,
             postmenopausal for at least one year) or must be using a medically accepted means of
             contraception. Women using oral contraceptive medication for birth control must also
             be using a barrier contraceptive. Women of childbearing potential must also have a
             negative serum Beta-HCG (human chorionic gonadotropin) at pre-study.

          3. Subjects must fulfill DSM-IV criteria for Major Depression (296.3) without psychotic
             features, based on clinical assessment and confirmed by a structured diagnostic
             interview, the Structured Clinical Interview for DSM-IV TR Axis I Disorders, SCID-P.

          4. Subjects have a history of at least one previous episode of depression prior to the
             current episode.

          5. Subjects must have an initial score of greater than or equal to 32 on the Inventory of
             Depressive Symptoms, Clinician version (IDS-C) at Visit 1 and Visit 2.

          6. Subjects must not have greater than a 25% decrease in the IDS-C total scores during
             washout (between Visits 1 and 2).

          7. Each subject must have a level of understanding sufficient to agree to all tests and
             examinations required by the protocol and must sign an informed consent document.

          8. Current major depressive episode of at least 4 weeks duration.

          9. Subjects who have not responded to adequate previous trials of at least one
             antidepressant as determined by the Antidepressant Treatment History Form (ATHF)
             criteria (score greater than or equal to 3). Additionally, patients who have not
             completed antidepressants trials of adequate dose and duration due to intolerance to
             therapy may be induced if they have demonstrated intolerance to greater than or equal
             to 3 antidepressant medications in the current or a previous episode, and did not meet
             ATHF criteria for a single adequate treatment trial in the current episode. 3
             intolerant trials would count as an adequate failed trial. If this criteria has not
             been met, the Principal Investigator may allow for a four-week prospective trial of a
             standard antidepressant (at the patients' and clinicians' discretion) for potential
             participants who have not responded to at least one adequate trial for the current
             episode per inclusion criteria.

             EXCLUSION CRITERIA:

         10. Presence of psychotic features or a diagnosis of Schizophrenia or any other psychotic
             disorder or bipolar disorder as defined in the Diagnostic and Statistical Manual,
             Version IV (DSM-IV).

         11. Subjects with a diagnosis of Obsessive Compulsive Disorder as defined in the DSM-IV.

         12. Subjects reporting Borderline or Antisocial Personality disorders. Other Axis II
             disorders do not qualify one for exclusion from the study.

         13. Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for
             nicotine or caffeine) within the preceding 3 months.

         14. Female subjects who are either pregnant or nursing.

         15. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory,
             cardiovascular (including ischemic heart disease), endocrinologic, neurologic,
             immunologic, or hematologic disease.

         16. Subjects with a history of neutropenia or medication-induced blood dyscrasia.

         17. Clinically significant abnormal findings of laboratory parameters, physical
             examination, EEG, or ECG.

         18. Subjects with a lifetime history of autism, mental retardation, pervasive
             developmental disorders, or Tourette's syndrome.

         19. Subjects with uncorrected hypothyroidism or hyperthyroidism.

         20. Subjects with one or more seizures without a clear and resolved etiology.

         21. Treatment with a reversible monoamine oxidase inhibitor (MAOI) within 2 weeks prior to
             Visit 2.

         22. Treatment with fluoxetine within 4 weeks prior to Visit 2.

         23. Treatment with clozapine or electroconvulsive therapy (ECT) within 3 months prior to
             study Visit 2.

         24. Judged clinically to be at serious suicidal or homicidal risk.

         25. Participation in a clinical trial of another investigational drug within 1 month prior
             to study entry (visit 1).

         26. Patients starting hormonal treatment (e.g., estrogen) in the last 3 months prior to
             visit 1.

         27. Patients undergoing current nonpharmacologic antidepressant treatments, such as light
             therapy and psychotherapy.

         28. Patients will be excluded who have previously failed greater than or equal to 3
             lifetime adequate antidepressant trials by ATHF criteria (Sackeim 2001).

         29. Patients with any evidence of a seizure disorder as assessed by an EEG with photic
             stimulation.

        ADDITIONAL INCLUSION AND EXCLUSION CRITERIA FOR PET SCANS ONLY: THIRTY SUBJECTS WITH MAJOR
        DEPRESSIVE DISORDER WILL PARTICIPATE IN THE IMAGING COMPONENT OF THIS STUDY.

        INCLUSION:

          1. Subjects who are ages 21-70.

          2. Subjects with an early age of onset (before age 40).

          3. Subjects who either meet melancholic subtype criteria and/or have a first degree
             relative with bipolar disorder.

          4. Negative pregnancy test within 24 hours of positron emission tomography (PET) in women
             of childbearing potential.

        EXCLUSION:

          1. Subjects will have been off psychotropic drugs (including zolpidem) for at least 3
             weeks (8 weeks for fluoxetine) prior to PET.

          2. Subjects with a history of lifetime DSM-IV substance dependence (except for nicotine
             or caffeine).

          3. Subjects with substance abuse within 12 months (except for nicotine or caffeine).

          4. Subjects with a current or lifetime history of hypertension or diabetes.

          5. Subjects who have reached the annual research radiation exposure limit.