The Need for Better Management of Treatment-Resistant Depression, Part 3:
Better Ways to Manage Treatment-Resistant Depression
David L. Dunner, M.D.

Rating Scales for Depression
Hamilton M. A rating scale for depression. J Neurol Neurosurg Rush AJ, Gullion CM, Basco MR, et al. The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561–571 Guidelines for Treating Subtypes
American Psychiatric Association. Practice Guideline for the Treatment of Patients With Major Depressive Disorder [Revision]. Am J Diagnostic Criteria
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: Duration
Kupfer DJ. Long-term treatment of depression. J Clin Psychiatry Fava M, Schmidt ME, Zhang S, et al. Treatment approaches to major depressive disorder relapse, part 2: reinitiation of antidepressant treatment. Psychother Psychosom 2002;71:195–199 Kupfer DJ, Frank E, Perel JM, et al. Five-year outcome for maintenance therapies in recurrent depression. Arch Gen Psychiatry Different Treatment
Augmenting Agents
Januel D, Poirier MF, D'alche-Biree F, et al. Multicenter double-blind randomized parallel-group clinical trial of efficacy of the combination clomipramine (150 mg/day) plus lithium carbonate (750 mg/day) versus clomipramine (150 mg/day) plus placebo in the treatment of unipolar major depression. J Affect Disord Nierenberg AA, Papakostas GI, Petersen T, et al. Lithium augmentation of nortriptyline for subjects resistant to multiple antidepressants. J Clin Psychopharmacol 2003;23:92–95 Hoencamp E, Haffmans J, Dijken WA, et al. Lithium augmentation of venlafaxine: an open-label trial. J Clin Psychopharmacol Baumann P, Nil R, Souche A, et al. A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic investigation. J Clin Psychopharmacol Dinan TG. Lithium augmentation in sertraline-resistant depression: a preliminary dose-response study. Acta Psychiatr Scand Goodwin FK, Jamison KR. Manic-Depressive Illness. New York, NY: Thyroid Hormones
Joffe RT. Triiodothyronine potentiation of fluoxetine in depressed patients. Can J Psychiatry 1992;37:48–50 Bauer MS, Whybrow PC. Rapid cycling bipolar affective disorder, 2: treatment of rapid cycling with high-dose levothyroxine: a preliminary study. Arch Gen Psychiatry 1990;47:435–440 Targum SD, Greenberg RD, Harmon RL, et al. Thyroid hormone and the TSH stimulation test in refractory depression. J Clin Psychiatry Goodwin FK, Prange AJ Jr, Post RM, et al. Potentiation of antidepressant effects by L-triiodothyronine in tricyclic nonresponders. Am J Psychiatry 1982;139:34–38 Atypical Neuroleptics
Dunner DL, Amsterdam JD, Shelton RC. Adjunctive ziprasidone in treatment-resistant depression: a pilot study [poster]. Presented at the 43rd annual meeting of the New Clinical Drug Evaluation Unit; Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry Benzodiazepines
Morishita S, Aoki S. Clonazepam augmentation of antidepressants: does it distinguish unipolar from bipolar depression? J Affect Disord2002;71:217–220 Smith WT, Londborg PD, Glaudin V, et al. Is extended clonazepam cotherapy of fluoxetine effective for outpatients with major depression? J Affect Disord 2002;70:251–259 Wells BG, Evans RL, Ereshefsky L, et al. Clinical outcome and adverse effect profile associated with concurrent administration of alprazolam and imipramine. J Clin Psychiatry 1988;49:394–399 Stimulants
Bader GM, Hawley JM, Short DD. Venlafaxine augmentation with methylphenidate for treatment-refractory depression: a case report.
Masand PS, Anand VS, Tanquary JF. Psychostimulant augmentation of second generation antidepressants: a case series. Depress Anxiety Fawcett J, Kravitz HM, Zajecka JM, et al. CNS stimulant potentiation of monoamine oxidase inhibitors in treatment-refractory depression.
Barbosa L, Berk M, Vorster M. A double-blind, randomized, placebo- controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry 2003;64:403–407 Rocha FL, Hara C. Lamotrigine augmentation in unipolar depression.
Barbee JG, Jamhour NJ. Lamotrigine as an augmentation agent in treatment-resistant depression. J Clin Psychiatry 2002;63:737–741 Normann C, Hummel B, Schärer LO, et al. Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled, double-blind study. J Clin Psychiatry 2002;63:337–344 Buspirone
Appelberg BG, Syvälahti EK, Koskinen TE, et al. Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study. J Clin Psychiatry Landén M, Björling G, Agren H, et al. A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. J Clin Psychiatry Dimitriou EC, Dimitriou CE. Buspirone augmentation of antidepressant therapy. J Clin Psychopharmacol 1998;18:465–469 Tryptophan
Tryptophan is no longer marketed in the United States.
DeBattista C, Doghramji K, Menza MA, et al, for the Modafinil in Depression Study Group. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry 2003;64:1057–1064 Pindolol
Pérez V, Puiigdemont D, Gilaberte I, et al, for the Grup de Recerca en Trastorns Afectius. Augmentation of fluoxetine’s antidepressant action by pindolol: analysis of clinical, pharmacokinetic, and methodologic factors. J Clin Psychopharmacol 2001;21:36–45 Perry EB, Berman RM, Sanacora G, et al. Pindolol augmentation in depressed patients resistant to selective serotonin reuptake inhibitors: a double-blind, randomized, controlled trial. J Clin Martinez D, Mawlawi O, Hwang DR, et al. Positron emission tomography study of pindolol occupancy of 5-HT(1A) receptors in humans: preliminary analyses. Nucl Med Biol 2000;27:523–527 Switching Agents
Thase ME, Blomgren SL, Birkett MA, et al. Fluoxetine treatment of patients with major depressive disorder who failed initial treatment with sertraline. J Clin Psychiatry 1997;58:16–21 Focus on Atypical Neuroleptic Augmentation of SSRIs
Risperidone Augmentation of Fluoxetine or
Ostroff RB, Nelsen JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry Olanzapine Augmentation of Fluoxetine
Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry Ziprasidone Augmentation of Sertraline
Dunner DL, Amsterdam JD, Shelton RC. Adjunctive ziprasidone in treatment-resistant depression: a pilot study [poster]. Presented at the 143rd annual meeting of the New Clinical Drug Evaluation Unit; Risperidone Augmentation of Citalopram
Rapaport MH, Canuso CM, Loescher A, et al. Preliminary results from the ARISe-D (risperidone augmentation in resistant depression)trial. In: New Research Abstracts of the 156th Annual Meeting ofthe American Psychiatric Association; May 19, 2003; San Francisco,Calif. Abstract NR179:66 How Atypical Neuroleptic Augmentation of SSRIs
May Improve Depression
Monoamine Receptor Hypothesis
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on Monoamines in the Rat Prefrontal Cortex
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Neuropsychopharmacology 2000;23:250–262 New Treatment Approaches
New Electrotherapies
High-Dose Right Unilateral (RUL) Electroconvulsive
Therapy (ECT)
Heikman P, Kalska H, Katila H, et al. Right unilateral and bifrontal electroconvulsive therapy in the treatment of depression: a McCall WV, Reboussin DM, Weiner RD, et al. Titrated moderately suprathreshold vs fixed high-dose right unilateral electroconvulsive therapy: acute antidepressant and cognitive effects. Arch Gen Sackeim HA, Prudic J, Devanand DP, et al. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Vagus Nerve Stimulation (VNS)
Marangell LB, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for major depressive episodes: 1 year outcomes. Biol Sackeim HA, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology Repetitive Transcranial Magnetic Stimulation (rTMS)
Grunhaus L, Schreiber S, Dolberg OT, et al. A randomized controlled comparison of electroconvulsive therapy and repetitive transcranial magnetic stimulation in severe and resistant nonpsychotic majordepression. Biol Psychiatry 2003;53:324–331 Martin JL, Barbanoj MJ, Schlaepfer TE, et al. Repetitive transcranial magnetic stimulation for the treatment of depression: systematicreview and meta-analysis. Br J Psychiatry 2003;182:480–491 Magnetic Seizure Therapy
Kosel M, Frick C, Lisanby SH, et al. Magnetic seizure therapy improves mood in refractory major depression. Neuropsychopharmacology Lisanby SH, Luber B, Schlaepfer TE, et al. Safety and feasibility of magnetic seizure therapy (MST) in major depression: randomized within-subject comparison with electroconvulsive therapy.
Neuropsychopharmacology 2003;28:1852–1865 Deep Brain Stimulation
Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005;45:651–660 New Medications
Feiger AD. A double-blind comparison of gepirone extended release, imipramine, and placebo in the treatment of outpatient major depression. Psychopharmacol Bull 1996;32:659–665 McGrath PJ, Stewart JW, Quitkin FM, et al. Gepirone treatment of atypical depression: preliminary evidence of serotonergic involvement. J Clin Psychopharmacol 1994;14:347–352 Amsterdam JD. Gepirone, a selective serotonin (5HT1A) partial agonist in the treatment of major depression. Prog Neuropsychopharmacol Biol Psychiatry 1992;16:271–280 Jenkins SW, Robinson DS, Fabre LF Jr, et al. Gepirone in the treatment of major depression. J Clin Psychopharmacol 1990;10(suppl Selegiline Patch
Benedictis E. 20mg transdermal selegiline daily may be effective and well tolerated in adults with major depression. Evid Based Ment Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Bodkin JA, Amsterdam JD. Transdermal selegiline in major depression: a double-blind, placebo-controlled, parallel-group study in outpatients. Am J Psychiatry 2002;159:1869–1875 Other New Medications
Kramer MS, Winokur A, Kelsey J, et al. Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist inmajor depression. Neuropsychopharmacology 2004;29:385–392 Ranga K, Krishnan R. Clinical experience with substance P receptor (NK1) antagonists in depression. J Clin Psychiatry 2002;63(suppl 11):25–29 Steinberg R, Alonso R, Griebel G, et al. Selective blockade of neurokinin-2 receptors produces antidepressant-like effects associated with reduced corticotropin-releasing factor function.
Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity by blockade of central substance P Corticotropin Releasing Factor (CRF) Antagonists Kunzel HE, Zobel AW, Nickel T, et al. Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects. J Psychiatr Res 2003;37:525–533 O'Brien D, Skelton KH, Owens MJ, et al. Are CRF receptor antagonists potential antidepressants? Hum Psychopharmacol 2001;16:81–87 Mansbach RS, Brooks EN, Chen YL. Antidepressant-like effects of CP-154,526, a selective CRF1 receptor antagonist. Eur J Pharmacol Sequenced Treatment Alternatives to Relieve
Depression (STAR*D)
Epidemiology Data Center, University of Pittsburgh. Sequenced Treatment Alternatives to Relieve Depression (STAR*D). Available at: Accessed June 29, 2004 Wisniewski SR, Stegman D, Trivedi M, et al. Methods of testing feasibility for sequenced treatment alternatives to relieve depression (STAR*D). J Psychiatr Res 2004;38:241–248 Rush AJ, Fava M, Wisniewski SR, et al. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design.
Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am 2003;26:457–494, x


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