• Neurocognitive battery [ Time Frame: Measured at baseline and at 2 and 6 months after the acute ECT course ] [ Designated as safety issue: Yes ]
• Clinical evaluations, side effect evaluations, and blood level determinations [ Time Frame: Measured weekly for the first month, every 2 weeks until Week 12, and every 4 weeks for the remaining 12 weeks ] [ Designated as safety issue: Yes ]

This study will evaluate the effectiveness of electroconvulsive therapy (ECT) administered with medication for the treatment of a major depressive episode (unipolar or bipolar) and will compare two types of ECT.

This study addresses 2 issues in the optimization of ECT in patients with major depression: whether patients treated with ECT should receive concurrent treatment with antidepressant medications, and the relative efficacy and side effects of high dosage right unilateral (RUL) ECT compared to low dosage bilateral (BL) ECT.

This study has 2 phases. In Phase I, patients are randomized to receive nortriptyline, venlafaxine (Effexor), or placebo while they simultaneously receive either high dosage RUL ECT or low dosage BL ECT. Patients have an electrocardiogram (EKG), a chest x-ray, medical and neurological examinations, and blood tests. Memory function is assessed before and after ECT. Whenever feasible, patients are withdrawn from all prior psychotropic medication before the start of ECT. ECT is administered 3 times per week to inpatients and twice a week to outpatients. Patients continue ECT until they are asymptomatic or until there is a plateau in improvement over 2 treatments.

Patients who respond to ECT enter Phase II and add lithium to either nortriptyline or venlafaxine within 1-3 days of the last ECT. Clinical and side effect evaluations and blood level determinations are conducted weekly for the first month, every 2 weeks until Week 12, and every 4 weeks for the remaining 12 weeks. Following any indication of relapse, patients are monitored more intensively and are re-evaluated within 1 week. The neurocognitive battery is readministered to all patients at 2 and 6 months after the acute ECT course, regardless of ECT clinical outcome.

• Depression
• Depressive Disorder
• Bipolar Disorder

• Procedure: High dosage electroconvulsive therapy
• Drug: Nortriptyline
• Drug: Venlafaxine
• Drug: Lithium
• Procedure: Low dosage electroconvulsive therapy

• Experimental: Participants will receive nortriptyline and high dosage ECT. If the ECT is effective participants will receive lithium after ECT treatment.
• Experimental: Participants will receive venlafaxine and high dosage ECT. If the ECT is effective participants will receive lithium after ECT treatment.
• Placebo Comparator: Participants will receive placebo and high dosage ECT. If the ECT is effective participants will receive lithium after ECT treatment weeks.
• Experimental: Participants will receive venlafaxine and low dosage ECT. If the ECT is effective participants will receive lithium after ECT treatment.
• Experimental: Participants will receive placebo and low dosage ECT. If the ECT is effective participants will receive lithium after ECT treatment weeks.

• Sackeim HA, Haskett RF, Mulsant BH, Thase ME, Mann JJ, Pettinati HM, Greenberg RM, Crowe RR, Cooper TB, Prudic J. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA. 2001 Mar 14;285(10):1299-307.
• Sackeim HA, Prudic J, Devanand DP, Nobler MS, Lisanby SH, Peyser S, Fitzsimons L, Moody BJ, Clark J. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Psychiatry. 2000 May;57(5):425-34.
• McCall WV, Reboussin DM, Weiner RD, Sackeim HA. Titrated moderately suprathreshold vs fixed high-dose right unilateral electroconvulsive therapy: acute antidepressant and cognitive effects. Arch Gen Psychiatry. 2000 May;57(5):438-44.

Inclusion Criteria:

• Major depressive episode (unipolar or bipolar)
• Pre-ECT score of 20 or higher on Hamilton Rating Scale for Depression
• Able to withdraw psychotropic drugs (up to 3 mg/day lorazepam allowed)
• ECT indicated

Exclusion Criteria:

• Schizophrenia, schizoaffective disorder, or other psychosis
• Amnestic disorder, dementia, or delirium
• Pregnancy
• Epilepsy
• Current alcohol or substance abuse or dependence
• CNS disease or brain injury not associated with psychotropic drug exposure
• ECT in the past 6 months
• Medical contraindication for treatment with either nortriptyline or venlafaxine, including allergy to amitriptyline, nortriptyline, or venlafaxine; narrow angle glaucoma; sinus node disease; bundle branch disease; myocardial infarction; coronary artery bypass or angioplasty; or angina
• Type I antiarrhythmic medication
• Supine blood pressure >= 170 mmHg systolic or >= 105 mmHg diastolic at 3 readings over 2 days