uestion: Has the patient had an adequate
trial of a tricyclic antidepressant, venlafaxine, or mirtazapine as
monotherapy, or a combination of an SSRI and a tricyclic? uestion: Has the patient had an adequate
trial of a tricyclic antidepressant, venlafaxine, or mirtazapine as
monotherapy, or a combination of an SSRI and a tricyclic?
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Help: If a depressed patient has not responded to an adequate trial of an SSRI, there is about a 50% chance that the patient will do well with an adequate trial of a tricyclic alone.¹ In a retrospective record review study, patients who had two failed antidepressant trials (or augmentations) still had about a 50% chance of responding to another trial, either a switch or an augmentation.²
If you choose "No," you will receive a recommendation for a tricyclic, and options such as venlafaxine and mirtazapine, or possibly an SSRI/tricylic combination
Click here for information about adequate trials of antidepressants. In the inpatient setting, there will be intense pressure to make changes sooner than 4 weeks, and it may not be possible to resist these pressures. However, these short trials can not be considered adequate.³
¹Keller M et al. The treatment of chronic depression, part II: a double-blind, randomized [crossover] trial of sertraline and imipramine. J Clin Psychiatry 1998;59:598-607.
²Posternak MA, Zimmerman. Switching versus augmentation: a prospective, naturalistic comparison in depressed, treatment-resistant patients. J Clin Psychiatry 2001;62:135-142.
³Osser DN. A systematic approach to the classification and pharmacotherapy of nonpsychotic major depression and dysthymia. J Clin Psychopharmacol 1993; 13:133-144.
[Click here for dosing suggestions for an adequate trial of any antidepressant, or utilize the link from the "Places to Go" menu on your desktop, at any time.]
If the patient has had one adequate trial of an SSRI or bupropion SR, and his or her clinical condition is at the highest level of urgency for relief, or if the patient has had two adequate trials from among the SSRI's and bupropion SR, (regardless of the urgency factor), the first-line recommendations are either a tricyclic antidepressant, venlafaxine, or mirtazapine, or a combination of an SSRI plus a tricyclic.² Neither data nor expert opinion appear able to distinguish if any of these options has greater merit at this point.
For tricyclics and venlafaxine, evidence suggests a 50% chance of therapeutic response, despite failure on an adequate trial of one or more SSRI (e.g. - 200 mg of sertraline).(1,9a)
It may be reasonable to add (as opposed to substitute) a tricyclic to an SSRI at this point: this may produce a faster response than if the drugs are used alone(3) although more data and experience are needed to confirm this possibility. It may be that the better results reported on the combination, in people who failed on both drugs alone, is due to higher blood levels of tricyclic in combination than when previously used as monotherapy.(3a) Also, the dose of fluoxetine in that study was 20 mg in the "adequate trial" preceding the combination, and in this algorithm an adequate trial of an SSRI will require an effort at doses up to 60 mg or the equivalent with other SSRIs.(3a) If the clinician intends to substitute, rather than add, the tricyclic, there will usually still be a crossover period in which the drugs will be combined. If the patient starts to improve during this period, the clinician may prefer to continue the combination. Later on, patients on combination therapy who have had improvement should receive a trial off the SSRI to be sure the latter was required for the positive outcome. Dosage of the tricyclic will have to be adjusted carefully taking into consideration cytochrome enzyme interactions of the SSRI and tricyclic.
A tricyclic is absolutely or relatively contraindicated in at least the following situations: pre-existing cardiac conduction problems including bundle branch block in its various forms,(4) cardiac ischemia,(5) obstructive uropathy, dementia, untreated narrow-angle glaucoma, and patients at particular risk for morbidity from complications of orthostasis or severe constipation. However, the newer generation antidepressants venlafaxine and mirtazapine seem to duplicate the efficacy and perhaps the spectrum of pharmacodynamic activity of tricyclics.
Venlafaxine has robust efficacy versus placebo for melancholia at higher doses (over 200 mg per day)(6) and may work faster than tricyclics(7,8) and better than SSRI's(9,9a) in this population. It occasionally elevates blood pressure and some patients have difficulty tolerating the nausea and other gastrointestinal side effects. Some studies have shown that the SR form of venlafaxine has slightly fewer GI side effects,(9b) but this does not seem confirmed by other studies.(9c) The nausea does seem to markedly decrease if the patient can tolerate the drug into the second week.(9b)
GI side effects may occur when the drug is given soon after an SSRI was used, perhaps due to early elevation of its blood level from the inhibitory effect on its cytochrome P450 2D6 metabolism by the remaining SSRI. Perhaps this is especially true with fluoxetine because the long half-life of its main active metabolite may result in inhibitory activity persisting long after it has been tapered or stopped.
The role of mirtazapine here is somewhat unclear: more experience is needed. Like venlafaxine, it may be better than an SSRI in severely depressed patients,(10) and it also has an impact on both norepinephrine and serotonin (although by a different mechanism). In other studies in which it was found to be comparable in efficacy to amitriptyline, the doses of the latter were less than 150 mg, so this evidence of comparability is questionable.(11) Patients must be warned of the risk of agranulocytosis, which occurred in 2 of 2,790 patients in the premarketing trials, and this may influence some patients to prefer one of the other options. However, it is encouraging, and may be noted in the informed consent discussion, that in post-marketing surveys in the Netherlands and in the US, there has only been one report of agranulocytosis in over 100,000 patients treated.(12)
There is no significant evidence that nefazodone is useful in patients who have failed to respond to two adequate trials of antidepressants such as the first-line choices in this algorithm. In addition there is a black box warning since December 2001 in the package insert because of the greater risk of hepatotoxicity with this antidepressant. Therefore we are not enthusiastic about considering it at this point in the algorithm. Click here for more information about nefazodone.
There are many other options among the other augmentation strategies that could be considered at this point. For any particular patient, one or another of these might seem the best choice depending on the patient's predicted susceptibility to side effects, past medication treatment history, comorbitity, or preferences following informed consent discussion of these alternatives. For example, lithium addition is commonly considered.(13,14) However, in one study of lithium augmentation of fluoxetine, many patients who had an initially good result lost efficacy on followup. A comparison group of lithium-augmented tricyclic-treated patients retained their benefits over a one year period.(15) In a meta-analysis of 9 randomized trials of lithium augmentation, only one of the trials involved lithium augmentation of an SSRI (citalopram).(15a) So, the evidence-basis for lithium augmentation of SSRIs is actually quite weak. Also, lithium as an augmentor presents a rather unfavorable side effect profile, although at the doses generally used (blood level 0.4 to 1.0 meq/L, 600-900 mg per day (15a)) the side effects may be milder than in treating manic patients. However, a recent study in geriatric patients found that lithium-augmented patients suffer significant tremor, urinary urgency, and renal/thyroid laboratory abnormalities.(16)
Thyroid hormone (T3 appears best, 25-50 ug/day)(14) augmentation is another option that, like lithium augmentation, has mostly been used to augment tricyclics, and here the results are modest at best.(17) There was one study involving thyroid augmentation of SSRIs in 15 elderly patients, which found the thyroid hormone to be effective, but the dose of fluoxetine did not exceed 20 mg before the thyroid was added.(18) The results are therefore of questionable significance since the fluoxetine dosage had not been optimized.
Other augmentation options for SSRI's that have been proposed are pindolol (Viskin), a beta blocker, and bupropion. There have been a dozen or so studies with pindolol 2.5 mg three times a day, most finding acceleration of the response to the SSRI (e.g. time to sustained response to fluoxetine of 10 days with pindolol vs.18 days with placebo(19)), and/or variable amounts of augmentation of the end-point response.(20) Pindolol also speeded response to nefazodone in one report.(21) Not all reports are positive: one double-blind, placebo-controlled study found no efficacy.(22) One possible explanation of the inconsistent response is that the dose used in trials is too low: a PET study found a modest but significant occupancy of 5-HT1A autoreceptors by pindolol 5 mg tid, whereas there was no occupancy at 2.5 mg tid.(22a) Pindolol augmentation may be a plausible approach if the patient can accept the side effects of taking a beta blocker, and does not have a relative contraindication such as asthma. It used to be said that diabetes was a contraindication to beta blockers, but several recent studies have failed to demonstrate any suppression of the symptoms of hypoglycemia by beta blockers, and this may be one of the most persisting myths of practice that persist despite solid contrary evidence.(22b)
Anecdotal enthusiasm for bupropion seems high, but research studies are relatively lacking, with only one significant case series published involving 14 patients and no controlled studies.(23) Another report with 23 patients described only a 35% response rate and 39% had serious side effects necessitating discontinuation.(24) The maintenance efficacy and long term side effect potential of these augmentation strategies are unclear and will need to be monitored by clinicians. Regular formulation bupropion carries an above average risk of seizures, but the sustained-release form (bupropion SR, Zyban) the seizure rate is low (0.1%) as long as the dose does not exceed 300 mg per day (there are no studies using doses higher than 300).(25) Bupropion plasma levels (and seizurogenic potential) may be elevated by inhibition of its cytochrome P450 metabolism by SSRI's, so if bupropion is used as an augmentation of an SSRI the seizure risk will be hard to assess.(26) Bupropion is itself a moderately potent inhibitor of Cytochrome P450 2D6 [Data on file with the manufacturer], so most SSRI blood levels will be elevated by this combination, and that may be the mechanism for enhanced efficacy as well as toxicity symptoms in patient treated with the combination. Remember that bupropion is contraindicated in patients with eating disorders due to the elevated risk of seizures in those patients.
Buspirone also has uncontrolled reports of effectiveness as an augmentor of SSRIs. But now, there are two double-blind, placebo-controlled study where there was no benefit compared to placebo.(27,28) There was a high placebo response rate of 47% (51% on the buspirone) which may have confounded the result in the study, though. In the second, while there was no overall benefit, the severely depressed patients showed a very small benefit at weeks 4 and 6. But, these studies do provide much basis for enthusiasm for this augmentation.
Recommendation #03
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(1)Thase ME, Keller MB, Gelenberg AJ, Hirschfeld RMA, Schatzberg AF. Double-blind crossover antidepressant study: sertraline versus imipramine. . American Psychiatric Association Annual Meeting New Research. Miami, Florida; 1995:101-102.
(2) Zajecka JM, Jeffriess H, Fawcett J. The efficacy of fluoxetine combined with a heterocyclic antidepressant in treatment-resistant depression: a retrospective analysis. Journal of Clinical Psychiatry. 1995;56:338-343.
(3) Nelson JC, Mazure CM, Bowers MB, Jatlow PI. A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Archives of General Psychiatry. 1991;48:303-307.
(3a) Levitt AJ, Joffe RT, Kamil R, McIntyre R. Do depressed subjects who have failed both fluoxetine and TCAs respond to the combination? J Clin Psychiatry 1999;60:613-616.
(4) Roose SP, Glassman AH, Giardina EGV, Walsh BT, Woodring S, Bigger JT. Tricyclic antidepressants in depressed patients with cardiac conduction disease. Archives of General Psychiatry. 1987;44:273-275.
(5) Glassman AH, Roose SP, Bigger JTJ. The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. Journal of the American Medical Association. 1993;269:2673-2675.
(6) Guelfi JD, White C, Hackett D, Guichoux JY, Magni G. Effectiveness of venlafaxine in patients hospitalized for major depression and melancholia. Journal of Clinical Psychiatry. 1995;56:450-458.
(7) Derivan A, Entsuah AR, Kikta D. Venlafaxine: measuring the onset of antidepressant action. Psychopharmacology Bulletin. 1995;31:439-447.
(8) Benkert O, Grunder G, Wetzel H, Hackett D. A randomized, double-blind comparison of a rapidly escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia. Journal of Psychiatric Research. 1996;30:441-451.
(9) Clerc GE, Ruimy P, Verdeau-Pailles J, Group VFIS. A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. International Clinical Psychopharmacology. 1994;9:139-143.
(9a) Poirier MF, Boyer P. Venlafaxine and paroxetine in treatment-resistant depression. Double-blind, randomised comparison. Br J Psychiatry 1999;175(July):12-16.
(9b) Cunningham LA and the Venlafaxine XR 208 Study Group. Once-daily venlafaxine XR and venlafaxine IR in outpatients with major depression. Ann Clin Psychiatry 1997;9(3):157-164.
(9c) Rudolph RL, Feiger AD. A double-blind, randomized, placebo-controlled trial of once-daily venlafaxine XR and fluoxetine for the treatment of depression. J Affect Disord 1999;56:171-181.
(10) Wheatley D, Kremer C. A randomized, double-blind comparison of mirtazapine and fluoxetine in patients with major depression. . American Psychiatric Association Annual Meeting New Research. San Diego, California; 1997:124.
(11) Hopkins HS. Mirtazapine. Biological Therapies in Psychiatry Newsletter. 1997;20:2-4.
(12) Stahl S, Sussman N. Mirtazapine: a clinical profile. Primary Psychiatry. 1997;4:83.
(13) Nierenberg AA, White K. What next? A review of pharmacologic strategies for treatment resistant depression. Psychopharmacology Bulletin. 1990;26:429-460.
(14) Nelson JC. Treatment of antidepressant nonresponders: augmentation or switch? J Clin Psychiatry 1998;59[suppl 15]:35-41. Bauer M, Linden M, Schaaf B, Weber HJ. Adverse effects and tolerability of the combination of fluoxetine/lithium compared with fluoxetine. Journal of Clinical Psychopharmacology. 1996;16:130-134.
(15) Ontiveros A, Fontaine R, Elie R. Refractory depression: the addition of lithium to fluoxetine or desipramine. Acta Psychiatrica Scandinavica. 1991;83:188-192.
(15a) Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. J Clin Psychopharmacol 1999;19:427-434.
(16) Hardy BG, Shulman KI, Zucchero BA. Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression. Journal of Clinical Psychopharmacology. 1997;17:22-26.
(17) Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression: a meta-analysis. Archives of General Psychiatry. 1996;53:842-848.
(18) Barak Y, Stein D, Levine J, et al. Thyroxine augmentation of fluoxetine treatment for resistant depression in the elderly: an open trial. Human Psychopharmacology 1996;11:463-467.
(19) Perez V et al.. Augmentation of fluoxetine's antidepressant action by pindolol: analysis of clinical, pharmacokinetic, and methodologic factors. J Clin Psychopharmacol 2001;21:36-45.
(20) Maes M et al. Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patients, including those with treatment resistance. J Clin Psychopharmacol 1999;19:177-182; McAskill R, Mir S, Taylor D. Pindolol augmentation of antidepressant therapy. Br J Psychiatry 1998;173:203-208.
(21) Bakish D, Hooper CL, Thornton MD, Wiens A, Miller CA, Thibaudeau CA. Fast onset: an open study of the treatment of major depressive disorder with nefazodone and pindolol combination therapy. New Clinical Drug Evaluation Unit Program. Boca Raton, Florida; 1997.
(22) Perez V, Soler J, Puigdemont D, et al. A double-blind, placebo-controlled trial of pindolol augmentation in depressive patients resistant to SSRIs. Arch Gen Psychiatry 1999;56:375-379.
(22a) Rabiner EA et al. Pindolol augmentation of SSRIs: PET evidence that the dose used in clinical trials is too low. Am J Psychiatry 2001;158:2080-2082.
(22b)Paauw DS. Did we learn evidence-based medicine in medical school? Some common medical mythology. In: Geyman JP, Deyo RA, Ramsey SD, eds. Evidence-based clinical practice: concepts and approaches. Butterworth Heinemann. Boston, 2000:13-19.
(23) Bodkin JA, Lasser RA, Wines JDJ, Gardner DM, Baldessarini RJ. Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. Journal of Clinical Psychiatry. 1997;58:137-145.
(24) Boyer WF, Feighner JP. The combined use of fluoxetine and bupropion. American Psychiatric Association Annual Meeting, New Research. San Francisco, CA. 1993:NP746.
(25)Bupropion (Zyban) for smoking cessation. The Medical Letter on Drugs and Therapeutics. 1997;39:77-78.
(26) Preskorn SH, Burke M. Somatic therapy for major depressive disorder: selection of an antidepressant. Journal of Clinical Psychiatry. 1992;53[suppl 9]:5-18.
(27) Landen M, Bjorling 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 1998;59:664-668.
(28)Appelberg BG et al. Patients with severe depression may benefit from buspirone augmentation of SSRIs: results from a placebo-controlled, randomized, bouble-blind placebo wash-in study. J Clin Psychiatry 2001;62(6):448-452