
    severe side effects & lack of target engagement
  
['depression']
['diazoxide', 'placebo']

        -  INCLUSION CRITERIA:

               -  18 to 65 years of age.

               -  Women of child bearing potential must have a negative serum pregnancy test and
                  confirmed (by the investigator) use of two effective methods of contraception
                  (see below).

               -  Each subject must be capable of understanding all required tests and examinations
                  and must sign an informed consent document.

               -  Subjects must fulfill DSM-IV criteria for MDD, single episode or recurrent
                  without psychotic features, based on clinical assessment and confirmed by a
                  structured diagnostic interview (SCID-P). Subjects must be experiencing a current
                  major depressive episode of at least four weeks duration.

               -  Subjects must have an initial score of at least 20 on the MADRS at screening and
                  at baseline of study Phase I.

               -  Subjects must have a current or past history of lack of response to two adequate
                  antidepressant trials (may be from the same chemical class) operationally defined
                  using the modified-Antidepressant Treatment History Form (ATHF).

        EXCLUSION CRITERIA:

          -  Current psychotic features or a current or past diagnosis of schizophrenia or any
             other psychotic disorder as defined in the DSM-IV.

          -  Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for
             caffeine or nicotine dependence) within the preceding three months.

          -  Head injury that results in loss of consciousness exceeding five minutes (for the
             imaging component of the study).

          -  Subjects with a DSM IV Axis II diagnosis of borderline or antisocial personality
             disorder.

          -  Pregnant or nursing women or women of child bearing potential not using two medically
             accepted means of contraception (including oral, injectable, or implant birth control,
             condoms, a diaphragm with spermicide; intrauterine devices (IUD); tubal ligation;
             abstinence; or partner with vasectomy).

          -  Serious, unstable medical illnesses including hepatic, renal, gastroenterologic,
             respiratory, cardiovascular (including ischemic heart disease), endocrinologic,
             neurologic, immunologic, or hematologic disease.

          -  Subjects with hyperthyroidism or clinical hypothyroidism.

          -  Subjects with one or more seizures without a clear and resolved etiology.

          -  Clinically significant abnormal laboratory tests (including blood glucose).

          -  Diabetes

          -  Fasting plasma glucose concentration >120 mg/dl

          -  Upright diastolic blood pressure <60mmHg on three occasions 30 minutes apart (based on
             scheduled research measurements).

          -  Treatment with a reversible MAOI within four weeks of study Phase II.

          -  Treatment with fluoxetine within five weeks of study Phase II.

          -  Treatment with any other disallowed concomitant medication 14 days before
             randomization.

          -  Treatment with clozapine or ECT within one month of randomization.

          -  Lifetime history of deep brain stimulation.

          -  Subjects who, in the investigator's judgment, pose a current serious suicidal or
             homicidal risk.

          -  Positive HIV test

          -  Contraindications to MRI (metal in body, claustrophobia, etc)

        No structured psychotherapy will be permitted during the study.

        Definition of treatment-resistance

        All subjects are required to have previously failed to respond to two adequate
        antidepressant trials (may be from the same chemical class). Adequacy of antidepressant
        trials will be determined via the clinician administered modified ATHF.
      