uestion: Has the patient had an adequate trial of one or more
SSRIs, or bupropion SR?uestion: Has the patient had an adequate trial of one or more
SSRIs, or bupropion SR?
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Help: An SSRI or bupropion SR are the generally preferred first-line pharmacotherapy treatments for mild to moderate outpatient depression and dysthymia. The six currently available SSRI's (in the US, listed alphabetically) are:
An antidepressant trial, to be considered adequate, should be a total of at least 8 weeks in duration and should explore different doses if response is unsatisfactory, including a period on the maximum recommended dose if tolerated. Details on parameters for adequate trials of antidepressants may be found in Places to Go, under Adequate Trials of Antidepressants; or click here to go there now. If you select "No" [there has not been an adequate trial] you will arrive at a recommendation to try one of these, and alternatives will be discussed along with their relative merits and disadvantages.
Note that a study compared sertraline, imipramine, and placebo in dysthymia and found the SSRI to be as effective as the TCA with only 6% dropouts due to adverse effects vs. 18% for the imipramine.¹ Another study, in moderately depressed outpatients with major depression and ischemic heart disease, found 5% dropouts due to adverse effects with the SSRI paroxetine and 25% with nortriptyline (titrated to adequate blood levels). These sample studies and a recent review of 8 studies(1a) suggest that, generally, the SSRIs are equally effective and more often well tolerated than the tricyclics.²
In assessing this trial for adequacy, the issue of placebo response should be kept in mind. Placebo responders tend to be less ill and more likely in their first depressive episode. The rate can be as high as 70%, compared to the more globally impaired melancholic patients with recurrent illness.³ Indeed, for many of these patients, it may be hard to firmly advocate pharmacotherapy over psychotherapy or even over non-specific care and attention that would be the equivalent of placebo in these studies.(4)
¹Kocsis JH et al. Double-blind comparison of sertraline, imipramine, and placebo in the treatment of dysthymia: psychosocial outcomes. Am J Psychiatry 1997;143:390-395.
(1a)Hirschfeld RMA. Efficacy of SSRIs and newer antidepressants in severe depression: comparison with TCAs. J Clin Psychiatry 1999;60:see p. 332.
²Nelson JC et al. Treatment of major depression with nortriptyline and paroxetine in patients with ischemic heart disease. Am J Psychiatry 1999;156(7):1024-1028.
³Quitkin FM et al. Identification of a true drug response - use of pattern analysis. Arch Gen Psychiatry 1984; 41:782-786.
(4)Potter WZ, Schmidt ME. Treatment of major depression: selection of initial drug. In: Rush AJ, ed. Mood Disorders: Systematic Medication Management. (Part of series Modern Problems in Pharmacopsychiatry) Basil, Karger: 1997, pp. 1-16.
Try an SSRI or bupropion SR. These appear to be the best medications (with the least side effect burden) for pure dysthymia (and presumably its variants), major depression without melancholia, and major depression with melancholia that is not severe.¹ Click here for the recommended dosing strategies for these antidepressants, as well as for alternative antidepressants mentioned below. Note that the most cost-effective choice among the SSRIs is fluoxetine since it is available in a generic form. See drug costs table for comparative prices. Bupropion was recently added to our list of most favored first line antidepressants because of new data indicating that bupropion is equally effective as SSRIs on anxiety symptoms accompanying depression,² and because of data finding that it is effective in pure dysthymia (improvement rate 71%, comparable to the other antidepressants).³ The objection that bupropion has a higher rate of seizures has been addressed with the SR (sustained release) formulation, with which the seizure rate at doses of 300 mg per day or less is equal to or better than SSRIs (0.1%). The contraindication in eating disorders persists with bupropion SR, however, and if a history of eating disorders is present, one of the other first line choices would be preferred. The 2000 Revision of the APA Practice Guideline for the Treatment of Major Depressive Disorder also endorses bupropion as one of the choices "likely to be optimal" (i.e. - first line) for treatment of major depression.¹
We have removed nefazodone from the list of first-line choices because of the black box warning about the risk of hepatotoxicity that was required by the FDA in December, 2001. As of late 2001, nefazodone had been associated with 109 cases of serious liver toxicity since its introduction in 1994, out of 8.3 million patients treated: 23 cases progressed to liver failure, and 16 of these resulted in transplantation and/or death. Symptoms begin from a few weeks to 2 years after treatment initiation, most often within the first four months.(3A) Risk managers and experts seem to agree now that nefazodone should be used only after other medications have been tolerated poorly or been ineffective. Nefazodone never established a track record for being effective in pharmacotherapy resistant cases, so its main use would appear now to be limited to patients who fail to tolerate other classes of antidepressant medication. This is unfortunate considering the advantages of a low incidence of sexual side effects, and of sedation which is useful in the initial days and weeks of treatment of some patients with an anxiety/insomnia component of their depression. In selected cases where the patient fully understands the risks and benefits, early use could still be justified, with appropriate documentation of the discussion with the physician and explanation of the rationale for the patient's preference for nefazodone. The frequency of the problem is, in fact, very low, i.e. about 1 in 250,000 to 300,000 patients.
What about St. John's wort? Although previous studies have been regarded as poorly designed and inconclusive, Two larger, well-designed studies with placebo control have now been published and the results are not favorable for the herb. One(4) involved 340 outpatients with major depression and a Hamilton score of at least 20, which means moderate to severe depression. Patients were randomly assigned to sertraline 50-100 mg, SJW extract 900-1500 mg, or placebo for 8 weeks. Neither active treatment was better than placebo on the primary measures, but on some secondary measures such as the Clinical Global Impression, sertraline was better than placebo but SJW was not. In the second study of 200 patients, SJW at 900 mg per day was not much better than placebo, in patients with Hamiltons over 19, mean age 42, 67% female.(5) Remission rates were only 14% on SJW, vs 5% on placebo. More studies are underway comparing SJW with SSRIs and placebo. It is also a problem, meanwhile, that preparations of SJW vary widely in their purity and content, so that results with one formulation may not necessarily apply to another. Also, there are worries about drug interactions with the P450 3A4 enzyme and also occasional severe side effects.(6) So, we do not recommend SJW at this time, until there is more clear evidence of efficacy.
What about SAMe? S-adenosylmethionine is a naturally occurring compound that "donates" methyl groups and facilitates metabolic processes in the brain and elsewhere.(5A) It is available in health food stores and pharmacies. There is a very small clinical research literature supporting it as an antidepressant, plus some very ardent advocates based on personal experiences. One placebo controlled study in only 15 patients nevertheless demonstrated efficacy and it was very well tolerated at 800 mg twice a day.(5B) One patient became manic, so SAMe should certainly be avoided as monotherapy in bipolar patients. It is surprising that there has not been more study, but until there is, we cannot recommend it as a first-line option given that evidence-based medicine is the basis of this algorithm. Exaggerated claims by its proponents, especially those who profit in some manner from public interest in the compound, must be treated with skepticism at this point. If patients do decide to take it, it appears necessary to take supplemental folate, 800 mcg and Vitamin B12, 1000 mg daily. The enteric-coated versions are best (to avoid stomach upset) and they are most stable when sold in blister packs, because otherwise exposure to air inactivates the compound. Some patients do better if started at 400 mg once or twice a day.
Venlafaxine, especially venlafaxine XR the sustained-release version, could be considered as a first line treatment for these depressive disorders, especially if the dose is kept below 200 mg where the risk of blood pressure elevation is only 0.3%, although the inconvenience (for busy outpatient practitioners) of monitoring blood pressure would still be a small factor in the decision of whether to choose it as a first line agent. Check the link for more information. Mirtazapine, too could be first line. Going against that are its tendency to cause weight gain and the fact you have to warn the patient (according to the package insert) about the small risk of agranulocytosis.
The APA also endorses certain tricyclic antidepressants for first line use in major depression.³ Indeed, in much of the world, tricyclics are still commonly considered to be first-line antidepressants for general use. Cost is certainly a factor. It should be noted that there is some evidence that tricyclics are more effective than SSRIs in men as compared with women.(7) The difference is about a 10-15% response rate, but some dispute whether this is a statistical artifact.(8) (Conversely, SSRIs may be more effective in women, particularly pre-menopausal women, than in men. There are no claims of a gender difference with bupropion or nefazodone.) Despite these arguments in favor of tricyclics, we propose tricyclics as a first-line option only in the more severe forms of major depression delineated in this algorithm. Safety issues are the reason. The risk of severe, life-threatening side effects, although small, is greater with the TCAs: only the TCAs give you cardiac conduction problems, and the risk of death in the event of an overdose is greater.(9-11) (Interestingly, the APA guideline specifically mentions desipramine as a first-line option, seemingly unaware of the evidence, cited above, that desipramine seems to have a higher rate of death in overdose than other TCAs.) It is worth noting that the USA Food and Drug Administration has become very focused on the risks brought about by drugs with conduction, particularly QTc problems. They are not approving, or requiring bolded warnings on new drugs that have even mild problems in this area. They are starting to require revisions of the package inserts of older drugs, too, having recently added strong warnings about thioridazine, mesoridazine, and droperidol. Tricyclics have similar concerns.
Some people in the population (several percent of Caucasians) may silently develop very high plasma levels of TCAs because they are genetically slow metabolizers of cytochrome P450 enzymes such as 2D6. They too are at higher risk of the cardiac side effects. Concern about this should appropriately motivate the physician to get at least one blood level of anyone on a tricyclic, and a pre-treatment EKG.(Preskorn SH. J Clin Psychopharmacol 1994;14:277-8) These at the least add inconvenience factors compared to using the other agents that we list as first line.
The physician should discuss the above options, as indicated, with the patient and choose after weighing side effects (particularly those that would be particularly problematic for the specific patient at hand) and considering patient preferences. We remind you that the algorithm provides only a STARTING POINT for that thinking, ensuring that the physician and patient have a reasonably solid idea of what evidence-supported medicine would call for as first line for the typical patient at that point in the algorithm.
For patients with severe melancholic depression, if you follow the algorithm there, we DO have tricylics and newer medications that are probably comparable such as venlafaxine, as first line. There's enough evidence that these have superior efficacy in this diagnostic situation, to overcome the side effect issues, at least for those who do not present particular risks (e.g. pre-existing conduction problems for the tricyclics). We also have them first line as the antidepressant of choice to combine with an antipsychotic for psychotic depression. We have the tricyclics as last choice, for the most part, for bipolar depression because of the evidence that they promote rapid cycling more than the others.
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¹American Psychiatric Association. Practice Guideline for the treatment of patients with major depressive disorder (Revision). Am J Psychiatry 2000 Supplement;157:4. Osser DN, Patterson RD. Algorithms for the pharmacotherapy of depression, Part One. Directions in Psychiatry 1998;18(3):303-317.
²Weihs KL, Settle ECJr., Batey SR, et al. Bupropion SR vs paroxetine for the treatment of depression in the elderly. J Clin Psychiatry 2000;61:196-202. Rush AJ, Trivedi MH, Batey, SR, et al. Anxiety and response to bupropion SR or sertraline. American Psychiatric Association Annual Meeting New Research Poster NR 508. Chicago, Illinois. May 17, 2000.
³Hellerstein DJ, Batchelder S, Kreditor D, Fedak M. Bupropion SR in the treatment of dysthymic disorder: an open-label study. J Clin Psychopharmacol 2001;21:325-329.
(3A)Gelenberg AJ. Nefazodone hepatotoxicity: black box warning. Biological Therapies in Psychiatry 2002;25(1):2.
(4)Hypericum Depression Trial Study Group. Effect of hhypericum perforatum (St. John's Wort) in major depressive disorder. JAMA 2002;287(14, April 10):1807-14.
(5)Shelton RC et al. Effectiveness of St. John's wort in major depression: a randomized controlled trial. JAMA 2001 April 18;285(18):1978-86
(5A)Spillmann M, Fava M. S-adenosylmethionine (Ademetionine) in psychiatric disorders. CNS Drugs 1996;9(6):416-425.
(5B)Kagan BL et al. Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 1990;147:591-595.
(6)Ruschitzka F et al. Acute heart transplant rejection due to St. John's wort. Lancet 2000;355:548-9.
(7)Kornstein SG et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry 2000;157(9):1445-1452.
(8)Quitkin FM, Stewart JW, McGrath PJ. Gender factors in response to antidepressants - letter to the editor, and reply of authors. Am J Psychiatry 2001;158(9):1531-3.
(9)Kapur S et al. Antidepressant medications and the relative risk of suicide attempt and suicide. JAMA 1992;268(24):3441-5
(10)Rose JC, Unis AS. A mortality index for postmarketing surveillance of new medications. Am J Emerg Med 2000;18(2):176-9
(11)Buckley NA, McManus PR. Can the fatal toxicity of antidepressant drugs be predicted with pharmacological and toxicological data? Drug Saf 1998;18(5):369-381
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