uestion: Is this bipolar II patient a potential
candidate for monotherapy with an antidepressant?uestion: Is this bipolar II patient a potential
candidate for monotherapy with an antidepressant?
Note: The patient would not be a good candidate if there is a history of significant impairment during prior hypomanic episodes, or if there is a history of antidepressant-induced hypomania or mania, or if the patient is currently on a mood stabilizer. Also, there may be other reasons, according to the physician's evaluation.
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¹Kupfer DJ, Carpenter LL, Frank E. Possible role of antidepressants in precipitating mania and hypomania in recurrent depression. Am J Psychiatry. 1988;145:804-8.
²Vieta E, Gasto C, Otero A, Nieto E, Vallejo J. Differential features between bipolar I and bipolar II disorder. Compr Psychiatry. 1997;38:98-101.
³Coryell W, Andreasen NC, Endicott J, Keller M. The significance of past mania or hypomania in the course and outcome of major depression. Am J Psychiatry. 1987;144:309-15.
(4)Frances A, Docherty JP, Kahn DA. The expert consensus guidelines for the treatment of bipolar disorder. J Clin Psychiatry. 1996;57[suppl 12A]:20.
(5)Amsterdam JD, Garcia-Espana F, Fawcett J, et al. Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. J Clin Psychopharmacol. 1998;18:435-440.
(6)Simpson SG, DePaulo JR. Fluoxetine treatment of bipolar II depression. J Clin Psychopharmacol. 1991;11:52-4.
(7)Amsterdam J. Efficacy and safety of venlafaxine in the treatment of bipolar II major depressive episode. J Clin Psychopharmacol. 1998;18:414-7.
(8)Himmelhoch JM, Thase ME, Mallinger AG, Houck P. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry. 1991;148:910-6.
(9)Akiskal HS, Mallya G. Criteria for the "soft" bipolar spectrum: treatment implications. Psychopharmacology Bulletin. 1987;23:68-73.
(10)Osser DN. A systematic approach to the classification and pharmacotherapy of nonpsychotic major depression and dysthymia. J Clin Psychopharmacol. 1993;13:133-44.
(11)Fawcett J. Bipolar II disorder. Psychiatric Annals. 1996;26:S440-S443.
(12)Ghaemi SN, Katzow JJ, Desai SP, Goodwin FK. Gabapentin treatment of mood disorders: a preliminary study. J Clin Psychiatry. 1998;59:426-9.
uestion: Has the patient had an adequate trial of an
SSRI or bupropion?
Help: The question asks if either of these antidepressants has already been tried. If not, it will be recommended but with a further statement of precautions in this situation.
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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 is unsuccessful, then the second antidepressant trial would be with whichever class of drug was not used first.
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The potential risks of antidepressant-associated hypomania/mania or rapid mood cycling should be explained to the patient.¹,² The risk of hypomanic/manic switches may be 2-4% over the first year period of treatment.(3-5) The potential benefits of mood stabilizers in decreasing this risk should also be explained, as well as their disadvantages including the possible loss of periods of mild hypomania associated with high productivity, creativity, and quality of life, and their other potential side effects (e.g., weight gain).
In considering which antidepressant to use, all SSRIs seem to be effective for bipolar depression, although the only placebo-controlled study was with fluoxetine.(6) However, fluoxetine's long half-life (7-10 days for its metabolite norfluoxetine) may be a relative disadvantage. Both SSRIs and bupropion seem to have a relatively low tendency to induce cycling into mania.(7)
Bupropion has a higher risk of seizures, namely about 0.44% at doses up to 450 mgs per day,(8) vs 0.1-0.2% for the SSRIs according to the package inserts. The seizure risk of the sustained release form of bupropion is lower (0.1 % at doses of 300 mg/day or below, rising to 0.4% at a dose of 400 mg/day according to the package insert), making it the preferred form for general use.(9) Patients with bipolar disorder taking anticonvulsants are possibly at lower risk, but the use of bupropion is relatively contraindicated in patients with comorbid eating disorders such as bulimia or anorexia nervosa, or with a history of seizures.
A shorter half life SSRI is preferred, such as citalopram, sertraline or paroxetine. Click here for dosing information. If the patient is currently taking carbamazepine, be aware that dosing requirements may be higher due to induction of 3A3,4 metabolism of the SSRI. The SSRI may in turn affect the carbamazepine's 3A3,4 metabolism: for example, sertraline will inhibit it and paroxetine will have only a minor effect. Our drug interaction computer program is available for more detailed cytochrome interaction information.
If the patient is psychotic, inclusion of an antipsychotic is recommended. Review the recommendation about using an antipsychotic.
Recommendation #37 (not psychotic) or #37P (psychotic)
¹Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry. 1995;152:1130-8.
²Howland RH. Induction of mania with serotonin reuptake inhibitors. J Clin Psychopharmacol. 1996;16:425-7.
³Amsterdam J. Efficacy and safety of venlafaxine in the treatment of bipolar II major depressive episode. J Clin Psychopharmacol. 1998;18:414-7.
(4)Amsterdam JD, Garcia-Espana F, Fawcett J, et al. Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. J Clin Psychopharmacol. 1998;18:435-440.
(5)Simpson SG, DePaulo JR. Fluoxetine treatment of bipolar II depression. J Clin Psychopharmacol. 1991;11:52-4.
(6)Cohn JB, Collins G, Ashbrook E, Wernicke JF. A comparison of fluoxetine, imipramine, and placebo in patients with bipolar depressive disorder. Int Clin Psychopharmacol. 1989;4:313-322.
(7)Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry 1994;164:549-550. Sachs GS, Lafer B, Stoll AL, et al. A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psychiatry 1994;55:391-393.
(8)Rosenstein DL, Nelson JC, Jacobs SC. Seizures associated with antidepressants: a review. J Clin Psychiatry 1993;54:289-299
(9) Dunner DL, Zisook S, Billow AA, Batey SR, Johnston JA, Ascher JA. A prospective safety surveillance study for bupropion sustained-resease in the treatment of depression. J Clin Psychiatry. 1998;59:366-373.
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According to Akiskal¹, hyperthymic individuals are people with hypomanic features that are integrel to their usual selves. They are more cheerful, optimistic, extroverted, exuberant, overtalkative, confident, and self-assured than most people. They need less sleep and have a high energy level. They tend to be demanding and controlling in relationships but usually do not become overinvolved or intrusive like manics, and their judgment is usually adequate to avoid overinvolvement in activities that will bring them to a bad end. Rather, they tend to be charismatic and successful, leaders in their fields, who help create opportunities for others and are well-liked. Occasionally they do take excessive risks, and promiscuity may get them into trouble. They may have irritable or dysphoric periods, and frank depressive episodes.
¹Akiskal HS. Grayscaling the affective disorders. Part I: Soft bipolar disorders and temperament. (Currents Interview) Currents in Affective Disorders 1994;13(3):5-13.
Try the SSRI or bupropion, again.
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 #38 (not psychotic) or #38P (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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uestion:
Has the patient had a trial with venlafaxine?
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. However, the response to lithium augmentation in bipolar depression does not seem particularly robust.¹ 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.)
Our slight preference is to go with single drug trials for three or four trials before going to other options.
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¹Price LH, Charney DS, Henninger GR. Variability of response to lithium augmentation in refractory depression. Am J Psychiatry. 1986;143:1387-1392.
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 is also some evidence that they are associated with more mild manias than those associated with use of tricyclics (or SSRI's, when they induce mania).(ref. 1A) More experience is needed to confirm this impression, which was based on a retrospective chart review study and a small number of patients (eight) on MAOI's in the study.
There are some practical difficulties which may go against the use of an MAOI, 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.
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) Other monotherapy antidepressant options include nefazodone and mirtazapine. 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) 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 #40 (not psychotic) or #40P (psychotic)
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.
(1A)Stoll AL, Mayer PV, Kolbrener M, et al. Antidepressant-associated mania: a controlled comparison with spontaneous mania. Am J Psychiatry 1994;151:1642-1645.
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.
(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.
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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 #39 (not psychotic) or #39P (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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