This study is testing a process (rEEG)for selecting the most appropriate medication(s) to treat a patient's depression versus a control group being treated according to a standardized method, the modified Star*D Algorithm. Qualified subjects will be randomized to the experimental (rEEG guided) group, or the control group and treated for 12 weeks. Medications utilized in this study are currently marketed. All visits, physical exam, rEEG, labs, rating scales and medications are provided at no cost to the patient.

This study is testing a process (rEEG)for selecting the most appropriate medication(s) to treat a patient's depression versus a control group being treated according to a standardized method, the modified Star*D Algorithm. Qualified subjects will be randomized to the experimental (rEEG guided) group, or the control group and treated for 10 weeks. Medications utilized in this study are currently marketed. All visits, physical exam, rEEG, labs, rating scales and medications are provided at no cost to the patient.

To qualify for entry into the study, patients must be:

1. 18 years of age or older.
2. Diagnosis of Major Depressive Disorder. Subjects may meet criteria for both melancholic and atypical depression.
3. Have failed 1 or more SSRIs, or have failed 2 or more antidepressants in at least 2 drug classes.

And patients must not have:

1. History of: closed head injury with unconsciousness, craniotomy, cerebral metastases, cerebrovascular accident; no current diagnosis of seizure disorder, bipolar disorder, schizophrenia, dementia, mental retardation, substance abuse, or major depression with psychotic features; or use of depot neuroleptics in last 12 months.
2. Known pregnancy and/or lactation, or intent to become pregnant during this study.

Medications that can be used in this study are:

Anti-depressants: fluoxetine, sertraline, paroxetine, desipramine, imipramine, nortriptyline,amitriptyline, clomipramine, bupropion, venlafaxine

Stimulants & MAO Inhibitors: moclobemide, tranylcypromine, selegiline, methylphenidate, dextroamphetamine, dexlevoamphetamine, pemoline, lamotrigine, topiramate

Benzodiazepines: lorazepam, clonazepam, alprazolam

Anti-convulsants: carbamazepine, lithium, divalproex, gabapentin

Beta Blockers: metoprolol, propranolol, atenolol

Inclusion Criteria:

1. 18 years of age or older.
2. Diagnosis of Major Depressive Disorder validated by SCID. Subjects may meet criteria for both melancholic and atypical depression per this protocol.
3. Have failed three or more antidepressant regimens during the current depressive episode with minimum daily dose(s) as defined in the Medication History for Depression Case Report Form and for a minimum duration of treatment of at least 4 weeks. For purposes of the Study, augmentation will be considered a separate regimen.
4. Able to stop all medications for 5 half-lives of the medication(s), with the exception of hormones, thyroid, hydrochlorthiazide and Ambien. See Appendix II for a list of the half-lives of medications.

Exclusion Criteria:

1. History of: closed head injury with unconsciousness, craniotomy, cerebral metastases, cerebrovascular accident; no current diagnosis of seizure disorder, bipolar disorder, schizophrenia, dementia, mental retardation, substance abuse, or major depression with psychotic features; or use of depot neuroleptics in last 12 months.

2. Participation in any other therapeutic drug study evaluating a treatment for depression within 60 days preceding inclusion, unless drug(s) half-life is known.

3. Known pregnancy and/or lactation, or intent to become pregnant during this study.

4. Doesn't qualify via rEEG analysis due to:

   • Potential physiologic abnormality
   • Low abnormality in comparison to current rEEG database
   • No strong prediction by rEEG analysis for any particular medication class