uestion: Have possible predisposing
factors for rapid cycling been sought and treated where possible?uestion: Have possible predisposing
factors for rapid cycling been sought and treated where possible?
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Help: Hypothyroidism may be a predisposing factor, including subclinical forms.¹ However, recent studies failed to confirm this. It may be that the earlier studies were confounded by suppression of thyroid by lithium, and possibly by other mood stabilizers.(1a) Undiagnosed complex partial seizures,² multiple sclerosis,³ and other neurological conditions(4) have been associated with rapid cycling. Covert substance abuse could be a factor, and concomitant antidepressants and other medications (e.g., stimulants) should be assessed for their possible role in the cycling:(5) tricylics are clearly the greatest offenders, but SSRI's and others could also be contributing. Non-compliance should also be considered as a factor: patients who abruptly discontinue lithium therapy often bring on rapid relapses,(6) and rapid cycling may develop if they do this repeatedly.(7)
¹Chang KD, Keck PE, Jr., Stanton SP, McElroy SL, Strakowski SM, Geracioti TD, Jr. Differences in thyroid function between bipolar manic and mixed states. Biol Psychiatry. 1998;43:730-3.
(1a)Sullivan G, Gorman JM. The use of thyroid hormones in mood disorders. Psychiatric Annals 2000;30(2):129-136.
²Brewerton TD. The phenomenology of psychosis associated with complex partial seizure disorder. Ann Clin Psychiatry. 1997;9:31-51.
³Casanova MF, Kruesi M, Mannheim G. Multiple sclerosis and bipolar disorder: a case report with autopsy findings. J Neuropsychiatry and Clin Neurosci. 1996;8:206-208.
(4)Jan JE, Abroms IF, Freeman RD, Brown GM, Espezel H, Connolly MB. Rapid cycling in severely multidisabled children: a form of bipolar affective disorder? Pediatric Neurology. 1994;10.
(5)Simpson HB, Hurowitz GI, Liebowitz MR. General principles in the pharmacotherapy of antidepressant-induced rapid cycling: a case series. J Clin Psychopharmacol. 1997;17:460-6.
(6)Baldessarini RJ, Tondo L, Floris G, Rudas N. Reduced morbidity after gradual discontinuation of lithium treatment for bipolar I and II disorders: a replication study. Am J Psychiatry. 1997;154:551-3.
(7)Goodwin GM. Recurrence of mania after lithium withdrawal: implications for the use of lithium in the treatment of bipolar affective disorder. Br J Psychiatry. 1994;164:149-152.
Address and remedy predisposing factors:
Antidepressants should be removed if possible. If the mood stabilizer dosage seems related to increase in cycling or severity of a mixed state, consider removing the offending agent.
If TSH is 5 or greater, there is a possibility of subclinical thyroid dysfunction (as might be further demonstrated by a TRH stimulation test): consider supplementing with oral thyroxine. T4 (levothyroxine) is recommended because it may produce more steady thyroid levels than use of T3. It is usually started at 100 ug/day and increased by 50 ug every week or two until a clinical response occurs, provided no signs of hyperthyroidism develop (nervousness, tachycardia, sweating, flushing, headache, or if severe, arrhythmias, angina, and heart failure).¹ TSH should be monitored to achieve levels below the normal range. When discontinuing thyroxine, lower by 50 ug every 3-7 days. Use half these doses for elderly patients and those with cardiac dysfunction.¹
If the patient is currently on lithium, it may be better to use T3 (tri-iodothyronine, Cytomel), the physiologically active form of thyroid hormone. There is evidence lithium inhibits the conversion of T4 to T3,¹ and it has been speculated that T4 may be more effective for restoring normal thyroid function in this situation. T3 is usually started at 25 ug once a day, although its short half life suggests that twice a day might be a better schedule. T3 at 25 ug is equivalent to 100 ug of T4. It may be increased to 37.5 or 50 ug after one week, but is not usually raised higher for this usage.
For a full discussion of the management of lithium-induced (and other causes of) subclinical hypothyroidism, see the paper by Kleiner et al.²
¹Sullivan G, Gorman JM. The use of thyroid hormones in mood disorders. Psychiatric Annals 2000;30(2):129-136.
²Kleiner J, Altshuler L, Hendrick V, Hershman JM. Lithium induced subclinical hypothyroidism: review of the literature and guidelines for treatment. J Clin Psychiatry 1999;90(4):249-255.
If the patient is psychotic, inclusion of an antipsychotic is recommended. Review the recommendation about using an antipsychotic.
Recommendation #41 (not psychotic) or #41P (psychotic)
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uestion: What is this patient's
current medication?
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Help: The treatment of this bipolar rapid cycling, currently depressed, patient will depend to some extent on what his/her current medications are. Is this a breakthrough depression in a patient on one or more mood stabilizers (and possibly other drugs)? In this case we will recommend that the mood stabilizer(s) in use be optimized to adequate blood level(s). The other possibility is that the depression developed in the context of the patient not being on any mood stabilizer. In this case, we will recommend starting valproate as the first-line mood stabilizer.
uestion: We assume you have optimized the dose of this
patient's mood stabilizer, and yet the patient remains depressed. Have you
tried adding a second mood stabilizer and optimizing it's dosage as well?
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Help: Lithium should be increased to a level between 0.8 to 1.2 meq/L. Valproate should be at 50-125 ng/ml. Carbamazepine should be 4-12 ng/ml. Lamotrigine should be increased to 200 mg per day. All should stay at the higher level/dose for a few weeks if possible.
Most experts consider valproate to be the first-line recommendation for rapid cycling patients, even though evidence of efficacy of valproate for acute bipolar depression in general is weak.¹ There is evidence, at least from the pre-valproate literature, that lithium may be effective.²,³ Carbamazepine does not seem particularly effective in rapid-cycling bipolar depression. Side effect considerations and patient preference may determine which drug is selected.
Lamotrigine is an anticonvulsant that may have particular efficacy in bipolar depression, including rapid cycling patients.(4) A recent double-blind, placebo-controlled, prospective study of lamotrigine in the treatment of major depressive episodes associated with bipolar I disorder, which included 195 patients, found that 51% of the patients treated with 200 mg/day of lamotrigine showed significant clinical improvement, 41% improved on 50 mg, and 26% improved on placebo.(5) Lamotrigine could become a first-line option in the treatment of bipolar depression, if further studies continue to demonstrate its utility and safety. However, reports of switches to mania indicate it may sometimes behave more like an antidepressant.(5,6) Its efficacy in acute mania and for prevention of recurrences of bipolar mood episodes requires more study. A disadvantage of lamotrigine is the occurrence of potentially serious dermatologic reactions, and there have been rash-associated deaths. According to the package insert, rashes occur in 10% of patients, and the appearance of rash necessitates discontinuation of the medication. The dosage must be increased slowly to minimize the occurrence of these dangerous allergic reactions. Another disadvantage is that improvement in depression may occur rather slowly: 4 to 6 weeks was required in the study cited above. However, lithium may require a similar period to achieve its acute antidepressant efficacy.(7)
At this time, we do not yet consider lamotrigine a first-line recommendation, but this may change with further research and clinical experience. It will be among the recommendations for treatment-resistant cases.
Other anticonvulsants may have some utility in treating bipolar depression. Gabapentin appears to have some weak antidepressant efficacy in bipolar depression.(8,9) The roles of other newer mood-stabilizing agents such as topiramate(10) and tiagabine(11) remain to be defined.
If the patient is psychotic, inclusion of an antipsychotic is recommended. Review the recommendation about using an antipsychotic.
Recommendation #42 (not psychotic) or #42P (psychotic)
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¹Frances AJ, Kahn DA, Carpenter D, Docherty JP, Donovan SL. The Expert Consensus Guidelines for treating depression in bipolar disorder. J Clin Psychiatry. 1998;59 Suppl 4:73-9.
²Kukopulos A, Reginaldi D, Laddomada P et al. Course of the manic-depressive cyclic and changes caused by treatment. Pharmacopsychiatry 1980;13:156-167
³Wehr TA, Sack DA, Rosenthal NE, Cowdry RW. Rapid-cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry. 1988;145:179-184.
(4)Fatemi SH, Rapport DJ, Calabrese JR, Thuras P. Lamotrigine in rapid cycling bipolar disorder. J Clin Psychiatry 1997;58(12)522-527.
(5) Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 1999;60:79-88.
(6) Sporn J, Sachs G. The anticonvulsant lamotrigine in treatment-resistant manic-depressive illness. J Clin Psychopharmacol. 1997;17:185-9.
(7)A.P.A. Practice guideline for the treatment of patients with bipolar disorder. American Psychiatric Association. Am J Psychiatry. 1994;151:1-36.
(8)Ferrier IN. Lamotrigine and gabapentin. Neuropsychobiology. 1998;38:192-7.
(9)Ghaemi SN, Katzow JJ, Desai SP, Goodwin FK. Gabapentin treatment of mood disorders: a preliminary study. J Clin Psychiatry. 1998;59:426-9.
(10)Marcotte D. Use of topiramate, a new anti-epileptic as a mood stabilizer. J Affect Disord. 1998;50:245-51.
(11)Kaufman KR. Adjunctive tiagabine treatment of psychiatric disorders: three cases [In Process Citation]. Ann Clin Psychiatry. 1998;10:181-4.
uestion: What is this rapid-cycling
patient's bipolar subtype?
Help: If the patient remains depressed after two mood stabilizers in combination, the treatments to consider next depend on whether this rapid-cycling patient is Bipolar I or Bipolar II. Addition of a third mood stabilizer is an option common to both subtypes,¹ but patients with Bipolar I disorder, especially those with a clear history of antidepressant-induced cycling, could be candidates for ECT or the addition of one of the newer antipsychotic agents as the next move.² If none of these considerations is preferred, a cautious trial of an antidepressant is the next recommendation. The first-line preference is for an SSRI or bupropion. Due to its long half-life, fluoxetine might be best avoided in rapid cyclers.
¹Calabrese JR, Woyshville MJ. A medication algorithm for treatment of bipolar rapid cycling? J Clin Psychiatry. 1995;56:11-8.
²Vieta 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.
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Add a second mood stabilizer. The choice will usually be valproate or lithium, depending on what was chosen for first-line treatment. Some clinicians are considering gabapentin at this point, because of its more benign side effect profile, even though it is much less established as an effective treatment. When it does work, the benefits appear to be modest.¹ However, in mild to moderately ill patients, this alternative may have a risk/benefit ratio favorable to its consideration, and it is being increasingly used by clinicians. If it is ineffective, the standard second-step recommendation should be employed. As noted elsewhere in the algorithm, lamotrigine has been reported to be useful in rapid cycling patients with depression,² but given its greater side effect risks (rashes) and the still limited experience with it, consideration of it would usually be postponed to a later point.
If the patient is psychotic, inclusion of an antipsychotic is recommended. Review the recommendation about using an antipsychotic.
Recommendation #43 (not psychotic) or #43P (psychotic)
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¹Ghaemi SN, Katzow JJ, Desai SP, Goodwin FK. Gabapentin treatment of mood disorders: a preliminary study. J Clin Psychiatry. 1998;59:426-9.
²Fatemi SH, Rapport DJ, Calabrese JR, Thuras P. Lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry. 1997;58:522-7.
This bipolar I rapid cycling patient has failed to respond to two mood stabilizers in combination. We are still reluctant to introduce an antidepressant. It will probably temporarily relieve the patient's depressed state, but with a high risk of stimulating further cycling and worsening the long term course of the disorder. A third mood stabilizer, perhaps one with particular evidence of antidepressant efficacy such as lamotrigine (as summarized at earlier points in the algorithm), might be considered. Gabapentin is often chosen, although its efficacy in depression seems modest at best. This is a good point to reconsider ECT.
The new generation of antipsychotics are being examined intensively to delineate their role in the treatment of bipolar disorder. They appear to be first line when psychotic symptoms are present. Some evidence has been presented that they may have antidepressant effects and stabilize rapid cycling patients.¹ This would be a reasonable time to consider them, instead of turning to an antidepressant.
If the considerations above are not deemed appropriate for this particular patient by the clinician, we recommend adding an SSRI or bupropion to the patient's mood stabilizer regimen. All SSRIs seem to be effective for bipolar depression, although the only placebo-controlled study was with fluoxetine.² However, for patients with prior histories of antidepressant-induced mania or in whom a later trial of an MAOI can be anticipated, fluoxetine's long half-life (7-10 days for its metabolite norfluoxetine) is a relative disadvantage. Both SSRIs and bupropion seem to have a relatively low tendency to induce cycling into mania.³
Bupropion has a higher risk of seizures, namely about 0.44% at doses up to 450 mgs per day,(4) 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.(5) 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 #44 (not psychotic) or #44P (psychotic)
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If the SSRI or bupropion did not produce a satisfactory response, the sequence of antidepressants and other treatments to consider from this point on is the same as for patients with Bipolar I and II, non-rapid-cycling. Click here to join the non-rapid-cycling algorithm and continue with questions and recommendations for further treatment.
¹Vieta 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.
²Cohn 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.
³Peet 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.
(4)Rosenstein DL, Nelson JC, Jacobs SC. Seizures associated with antidepressants: a review. J Clin Psychiatry 1993;54:289-299
(5) 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.
This bipolar II rapid cycling patient has failed to respond to two mood stabilizers in combination. We are still reluctant to introduce an antidepressant. It will probably temporarily relieve the patient's depressed state, but with a high risk of stimulating further cycling and worsening the long term course of the disorder. A third mood stabilizer, perhaps one with particular evidence of antidepressant efficacy such as lamotrigine¹ (as summarized at earlier points in the algorithm), might be considered. Gabapentin is often chosen, although its efficacy in depression seems modest at best.
If the considerations above are not deemed appropriate for this particular patient by the clinician, we recommend adding an SSRI or bupropion to the patient's mood stabilizer regimen. All SSRIs seem to be effective for bipolar depression, although the only placebo-controlled study was with fluoxetine.² However, for patients with prior histories of antidepressant-induced mania or in whom a later trial of an MAOI can be anticipated, fluoxetine's long half-life (7-10 days for its metabolite norfluoxetine) is a relative disadvantage. Both SSRIs and bupropion seem to have a relatively low tendency to induce cycling into mania.³
Bupropion has a higher risk of seizures, namely about 0.44% at doses up to 450 mgs per day,(4) 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.(5) 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 #45 (not psychotic) or #45P (psychotic)
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If the SSRI or bupropion did not produce a satisfactory response, the sequence of antidepressants and other treatments to consider from this point on is the same as for patients with Bipolar I and II, non-rapid-cycling. Click here to join the non-rapid-cycling algorithm and continue with questions and recommendations for further treatment.
¹Fatemi SH, Rapport DJ, Calabrese JR, Thuras P. Lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry. 1997;58:522-7. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 1999;60:79-88.
²Cohn 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.
³Peet 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.
(4)Rosenstein DL, Nelson JC, Jacobs SC. Seizures associated with antidepressants: a review. J Clin Psychiatry 1993;54:289-299
(5) 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.