The purpose of this study is to determine whether cysteamine bitartrate, an FDA-approved
drug for a non-psychiatric condition, is safe and effective for the treatment of major
Major depressive disorder (MDD) is a chronic, disabling illness affecting about 17% of the
general population. Despite advances in treatment, about two-thirds of patients fail to
respond to an initial trial of pharmacotherapy. Brain-derived neurotrophic factor (BDNF) is
a neural growth-promoting polypeptide found in the central nervous system, and has been
implicated in the pathophysiology and potential treatment of MDD. A multitude of studies
have shown low levels of BDNF in subjects with MDD, which have normalized after treatment
with an antidepressant. Traditional antidepressants such as serotonin reuptake inhibitors
may increase BDNF via an indirect intracellular pathway. The current study drug, cysteamine
bitartrate (Cystagon), is FDA approved for the treatment nephropathic cystinosis and has
been shown to increase BNDF in neuronal tissue, and to stimulate cell growth. Cysteamine has
already been investigated in humans as a potential treatment for Huntington's Disease. Given
the evidence of decreased levels in major depression, and subsequent increase post-treatment
with antidepressants, BDNF may play a key role in developing novel treatments for patients
who have failed conventional agents. Therefore, drugs that can demonstrably increase central
BDNF, such as cysteamine, may have significant potential as novel antidepressant
1. Male or female patients, 21-65 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 B-HCG at pre-study.
3. Subjects must fulfill DSM-IV criteria for Major Depression without psychotic
features, based on clinical assessment by a study psychiatrist 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 (recurrent major depressive disorder) or have chronic major
depressive disorder (at least two years' duration).
5. Subjects have not responded to an adequate trial of one antidepressant in the current
episode as determined by Antidepressant Treatment History Form (ATHF) criteria (score
> 3) (Sackeim 2001)
6. Subjects must have an initial score of ³ 32 on the IDS-C at both Visit 1 and Visit 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 is of at least 4 weeks duration
1. Presence of psychotic features, diagnosis of schizophrenia or any other psychotic
disorder, or bipolar disorder/cyclothymia as defined in the DSM-IV.
2. Lifetime histories of autism, mental retardation, pervasive developmental disorders,
OCD, or Tourette's
3. Current Eating Disorder
4. Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for
nicotine or caffeine) within the preceding 3 months.
5. Female subjects who are either pregnant or nursing.
6. Serious, unstable illnesses including hepatic, renal, respiratory, cardiovascular
(including ischemic heart disease), endocrinologic, neurologic (including history of
severe head injury), immunologic, or hematologic disease.
7. Hypersensitivity to cysteamine or penicillamine
8. Past history of severe gastrointestinal disease (including peptic ulcers or
inflammatory bowel disease), or current gastroesophageal reflux disease
9. Subjects with a history of neutropenia or medication-induced blood dyscrasia.
10. Clinically significant abnormal findings of laboratory parameters, physical
examination, or ECG.
11. Subjects with uncorrected hypothyroidism or hyperthyroidism.
12. Subjects with one or more seizures without a clear and resolved etiology.
13. Treatment with a reversible MAOI within 2 weeks prior to Visit 2.
14. Treatment with fluoxetine within 4 weeks prior to Visit 2.
15. Treatment with any other concomitant medication not allowed 14 days prior to study
16. Treatment with clozapine or ECT within 3 months prior to study Visit 2.
17. Judged clinically to be at serious suicidal or homicidal risk.
18. Participation in a clinical trial of another investigational drug within 1 month
prior to study entry.
19. Patients starting hormonal treatment (e.g., estrogen) in the last 3 months prior to
20. Psychotherapy or nonpharmacological antidepressant treatments (e.g. light therapy