uestion: Has the patient had a second
trial from among the choices of an SSRI or bupropion?uestion: Has the patient had a second
trial from among the choices of an SSRI or bupropion?
Help: If the initial trial of the SSRI or bupropion added to the mood stabilizer is unsuccessful, then the second antidepressant trial would be with whichever class of drug was not used first.
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uestion: Has the patient had a trial with venlafaxine added
to the mood stabilizer?
Help: The third antidepressant recommended in the algorithm sequence is venlafaxine.
At this point there are many other options for the clinician. The clinician could try augmentation of the bupropion or SSRI rather than changing to a different antidepressant. Augmentation could be with a stimulant, although that could induce mania, or thyroid hormone, although the effectiveness of thyroid augmentation is doubted by many clinicians, and the data is particulary sparce when it comes to bipolar depression (although if there is lithium-induced hypothyroidism, thyroid replacement would clearly be indicated.)
However, the patient is already on at least two medications, so an augmentation means adding one more. There has been new enthusiasm for using several drugs at once, the argument being that with modern knowledge of pharmacodynamics and pharmacokinetics, it is theoretically possible to accomplish improved efficacy and reduced side effects with the proper combinations.¹ In practice, however, these goals are often not met. Our preference is to go with single drug trials (added to the mood stabilizer) for three or four trials before going to other options.
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¹Stahl SM. Essential Psychopharmacology. New York, NY. Cambridge University Press, 1996. Second edition: in press.
Try the SSRI or bupropion, while continuing the mood stabilizer.
Some might consider venlafaxine here, and that will be our next recommendation. It comes next only because of the slightly inconvenient requirement of checking baseline and subsequent blood pressures.
Some clinicians might prefer an MAOI such as tranylcypromine at this point,¹ especially if the depression is an "anergic" depression with hypersomnia and low energy.² However, the small evidence of superiority does not seem to outweigh the considerable increase in complications involved in using an irreversible MAOI and the need for a low tyramine diet. In addition, one will have to wait at least 2 weeks after the SSRI washout (at least 5 weeks if fluoxetine was the last SSRI) before the MAOI can be started.
If the patient is psychotic, inclusion of an antipsychotic is recommended. Review the recommendation about using an antipsychotic.
Recommendation #22 (not psychotic) or #22P (psychotic)
¹Srisuarapanont M, Yatham LN, Zis AP. Treatment of acute bipolar depression: a review of the literature. Can J Psychiatry 1995;40:"533-544.
²Thase ME, Mallinger AG, McKnight D, Himmelhoch JM. Treatment of imipramine-resistant recurrent depression, IV: a double-blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry 1992;149:195-198.
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Substitute venlafaxine for the SSRI or bupropion. Recent uncontrolled evidence¹ and expert opinion² are converging to suggest that venlafaxine may be particularly efficacious in bipolar depression, with a low incidence of inducing mania.
Nefazodone and mirtazapine have not been used enough in bipolar depression to offer a strong impression of whether they have a role in a treatment-resistant patient such as the one who has reached this point in the algorithm. The clinician may elect to consider them because of their side effect profile (e.g. - the lack of sexual side effects). MAOIs and a number of other options will be considered next if this recommendation fails to be helpful.
If the patient is psychotic, inclusion of an antipsychotic is recommended. Review the recommendation about using an antipsychotic.
Recommendation #23 (not psychotic) or #23P (psychotic)
¹Amsterdam J. Efficacy and safety of venlafaxine in the treatment of bipolar II major depressive episode. J Clin Psychopharmacol. 1998;18:414-7.
²Potter WZ. Bipolar depression: specific treatments. J Clin Psychiatry. 1998;59 Suppl 18:30-6.
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For a fourth trial, an MAOI should be considered, since MAOI's have demonstrated efficacy in bipolar depression, especially tranylcypromine for anergic bipolar depression.¹ There are some practical difficulties which argue against this, however. If the patient was on bupropion, paroxetine, sertraline, fluvoxamine, citalopram, or venlafaxine, a wash-out period of two weeks should occur before an MAOI can be started, and if the SSRI used was fluoxetine, the wash-out period will need to be at least 5 weeks. The other difficulty is that a depressed bipolar patient might not maintain the level of dietary compliance required for the safe administration of an irreversible, nonselective MAOI. For this reason, some experts still favor the use of tricyclic antidepressants² in combination with a mood stabilizer at this point, due to their proven efficacy in the treatment of acute bipolar depression. However, the use of TCA's is associated with a high rate of manic switch, even when mood stabilizers are given,³ so TCA's are avoided in this algorithm and other options are favored. These will be described below under the heading of Refractory Bipolar Depression.
ECT can be reconsidered as an alternative to any of the four antidepressant pharmacotherapy trials. This highly effective treatment for bipolar depression appears to be underutilized by clinicians.(4) It may be followed by maintenance ECT, which has also been shown to be a safe and cost-effective treatment alternative for some highly refractory cases of bipolar depression.(5)
Review possible comorbid conditions whose successful treatment could bring about a positive overall outcome.
REFRACTORY BIPOLAR DEPRESSION:
Possible covert compliance problems and substance abuse need to be explored and addressed if present. The diagnosis should be reviewed and possible comorbid medical conditions should again be excluded, such as thyroid dysfunction, underlying neurologic problems, and drug interactions. Comorbid Axis I and Axis II disorders which may be contributing to the refractoriness of the depression should be diagnosed and appropriate treatment initiated and optimized.
If the patient's depression remains refractory, there are other potential treatment options to be considered. The examples given below are not listed in any order of preference. The supporting evidence is limited for many of these treatment modalities when applied to patients with bipolar depression. Individual patient considerations will determine their appropriateness.
Other monotherapy antidepressant options include nefazodone and mirtazapine. Antidepressant augmentation strategies include addition of thyroid hormone, using either levothyroxine (T4) or liothyronine (T3),(6,7) and addition of stimulants.(4,8) Supraphysiologic thyroid treatment (i.e., to produce T4 levels 150% of the upper limit of normal) has been successful in treating some cases of highly refractory bipolar depression.(9-11) This may be the time to consider the newer mood stabilizers, including lamotrigine, gabapentin, topiramate, or tiagabine. Different combinations of mood stabilizers(12,13)could also be considered. The calcium channel blockers have occasionally been effective for the depressed phase of bipolar patients, in particular nimodipine.(14,15) Some patients, especially those with a seasonal component to their depression, have benefited from bright light therapy, and others have reportedly responded to repeated cycles of total sleep deprivation.(16) One case report in a 21 year old chronically and severely (unipolar) depressed patient testified for a robust acute effect from an omega-3 fatty acid preparation (ethyl ester of eicosapentaenoic acid: ethyl-EPA, 4 g per day).(16a) A small placebo-controlled trial also found some efficacy with another O-3-FA, for depression relapse prevention in bipolar disorder.(16b) Antipsychotic agents may be useful treatments for some refractory patients, even if they are not psychotic.(17-19) Patients with psychotic bipolar depression may benefit from a switch to a different antipsychotic agent. As noted earlier, the new generation antipsychotics are probably better for treating bipolar depression compared with the older neuroleptics. The atypical antipsychotic clozapine was reportedly effective in about 50% of psychotic bipolar depressed patients with unsatisfactory response to other antipsychotics.(20)
If the patient is psychotic, inclusion of an antipsychotic is recommended. Review the recommendation about using an antipsychotic.
Recommendation #24 (not psychotic) or #24P (psychotic)
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¹Thase ME, Mallinger AG, McKnight D, Himmelhoch JM. Treatment of imipramine-resistant recurrent depression, IV: A double- blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry. 1992;149:195-8. ²Yatham LN, Kusumakar V, Parikh SV, et al. Bipolar depression: treatment options. Can J Psychiatry. 1997;42 Suppl 2:87S-91S. ³Bottlender R, Rudolf D, Strauss A, Moller HJ. Antidepressant-associated maniform states in acute treatment of patients with bipolar-I depression. Eur Arch Psychiatry Clin Neurosci. 1998;248:296-300. (4)Zarate CA, Jr., Tohen M, Baraibar G, Kando JC, Mirin J. Prescribing trends of antidepressants in bipolar depression. J Clin Psychiatry. 1995;56:260-4. (5)Bonds C, Frye MA, Coudreaut MF, et al. Cost reduction with maintenance ECT in refractory bipolar disorder. Journal of ECT. 1998;14:36-41. (6) Prange AJ, Jr. Novel uses of thyroid hormones in patients with affective disorders. Thyroid. 1996;6: 537-543. (7)Joffe RT. The use of thyroid supplements to augment antidepressant medication. J Clin Psychiatry. 1998;59:26-9; discussion 30-1. (8)Fawcett J, Kravitz HM, Zajecka JM, Schaff MR. CNS stimulant potentiation of monoamine oxidase inhibitors in treatment- refractory depression. J Clin Psychopharmacol. 1991;11:127-132. (9)Baumgartner A, Bauer M, Hellweg R. Treatment of intractable non-rapid cycling bipolar affective disorder with high-dose thyroxine: an open clinical trial. Neuropsychopharmacology. 1994;10:183-189. (10)Bauer M, Hellweg R, Graf KJ, Baumgartner A. Treatment of refractory depression with high-dose thyroxine. Neuropsychopharmacology. 1998;18:444-55. (11)Bauer MS, Whybrow PC. Rapid cycling bipolar affective disorder. II. Treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary study. Arch Gen Psychiatry. 1990;47:435-40. (12)Post RM, Leverich GS, Denicoff KD, Frye MA, Kimbrell TA, Dunn R. Alternative approaches to refractory depression in bipolar illness. Depress Anxiety. 1997;5:175-89. (13)Freeman MP, Stoll AL. Mood stabilizer combinations: a review of safety and efficacy. Am J Psychiatry. 1998;155:12-21. (14)Pazzaglia PJ, Post RM, Ketter TA, George MS, Marangell LB. Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation. Psychiatry Res. 1993;49:257-72. (15)Pazzaglia PJ, Post RM, Ketter TA, et al. Nimodipine monotherapy and carbamazepine augmentation in patients with refractory recurrent affective illness. J Clin Psychopharmacol. 1998;18:404-13. (16)Barbini B, Colombo C, Benedetti F, Campori E, Bellodi L, Smeraldi E. The unipolar-bipolar dichotomy and the response to sleep deprivation. Psychiatry Res. 1998;79:43-50. (16a)Puri BK et al. Eicosapentaenoic acid in treatment-resistant depression. Arch Gen Psychiatry 2002;59(1):91-92. (16b)Stoll ALet al.Omega 3 fatty acids in bipolar disorfder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999;56:407-412. (17)Shelton R, Tollefson G, Tohen M, et al. The study of olanzapine plus fluoxetine in treatment-resistant major depressive disorder without psychotic features, Poster 90. New Clinical Drug Evaluation Unit Conference. Boca Raton, Florida: National Institute of Mental Health; 1998. (18)Hendrick V, Altshuler LL, Szuba MP. Is there a role for neuroleptics in bipolar depression? J Clin Psychiatry. 1994;55:533-5. (19)Vieta E, Gasto C, Colom F, Martinez A, Otero A, Vallejo J. Treatment of refractory rapid cycling bipolar disorder with risperidone [letter]. J Clin Psychopharmacol. 1998;18:172-4. (20)Zarate CA, Jr., Tohen M, Baldessarini RJ. Clozapine in severe mood disorders. J Clin Psychiatry. 1995;56:411-7.
Try venlafaxine
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Reconsider ECT.