Column

Print Friendly 

Gary J. Kennedy, MD


Primary Psychiatry.
2008;15(3):30-34

 

Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York.

Disclosure: Dr. Kennedy has received research support or honoraria from AstraZeneca, Eli Lilly, Forest, Janssen, Myriad, and Pfizer.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: gjkennedy@msn.com.

 


 

Treatment of bipolar depression is both a challenge and a paradox. It is a challenge because persistent disability and recurrence are common, and a paradox because antidepressants appear to be counterproductive. Although bipolar depression in late life is not common, the increasing number of older people in the population insures that primary care providers will confront the paradox. Data from the older adult segment of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study have yet to emerge, but a review of published studies offers considerable guidance. A combination of one or more mood stabilizers plus aggressive psychosocial intervention offers hope of more effective treatment.

 

Bipolar Depression Defined

Occurring in approximately 0.5% of the United States population, bipolar disorder type II is characterized by recurrent major depressive episodes (MDEs) interspersed with periods of hypomania.1 Hypomania is defined as a disturbance in which mood is persistently and abnormally elevated, irritable, or expansive for at least 4 days duration. Associated symptoms include grandiosity or inflated self-regard, decreased need for sleep, loquaciousness or pressured speech, flight of ideas, racing thoughts, distractibility, agitation, increased goal-directed activity, and increased pursuit of pleasures with high self-destructive potential. The symptoms represent an unequivocal, uncharacteristic, and socially disruptive change in behavior. The absence of psychosis and severe social impairment and the duration of symptoms less than one week distinguish hypomania from the mania of bipolar disorder type I.

Because the social disruption may be minimal, and some of the symptoms may even seem beneficial, past episodes of hypomania may be ignored or dismissed by the patient and family. MDEs also occur in bipolar disorder type I in which the occurrence of one or more manic episodes is the distinguishing diagnostic feature. And there are mixed states in which criteria for both mania and major depression are present. As a result, the term “bipolar depression” spans the spectrum of bipolar disorders. This broad rather heterogenous definition may explain why the array of proven treatments, especially for older patients, remains limited.

 

Aftermath of Bipolar Depression

Among older adults with bipolar disorder, mania is a more frequent cause of hospitalization than depression,2 but depression may account for more disability.3 Worse, the results of present treatment for older adults with bipolar disorders are not remarkably better than those recorded prospectively from 1959–1985.4 Indeed, few older people with the disorder experience a full functional recovery despite symptom remission. Perlis and colleagues5 prospectively assessed potential predictors of recurrent mood disturbance among 858 symptomatic patients who subsequently recovered from an episode of bipolar disorder. Of people followed for up to 2 years, nearly half experienced a recurrence. Further, depressive episodes were twice as frequent as manic. The proportion of days depressed or anxious in the preceding year as well as residual symptoms of depression or mania at recovery predicted a subsequent depressive episode. Proportion of days with elevated mood in the preceding year as well as residual symptoms of mania were associated with a shorter time to the recurrence of a manic, mixed, or depressive episode. Impairments in cognitive speed and executive dysfunction6,7 and changes in subcortical brain structures are common,8 further reducing the chances of return to full function.

 

Biomedical Interventions

Strakowski9 characterized the lack of data on bipolar depression by noting that nine agents are approved by the US Food and Drug Administration for the treatment of mania, but only two (quetiapine and the olanzepine/fluozetine combination) are approved specifically for bipolar depression. Table 1 displays the agents suitable for older adults with doses, precautions, and therapeutic levels. Ziprasidone and chlorpromazine were omitted due to cardiovascular hazards despite FDA approval for bipolar disorder. As seen in Table 1, several medications are approved for episodes of “mixed” mania and depression. Historically, off-label use of antidepressants for bipolar disorder has been common. However, numerous studies suggest that antidepressants may be counterproductive.

 

 
Sachs and colleagues3 sought to determine whether adding an antidepressant to a mood stabilizer (lithium or an antiepileptic) reduced symptoms of bipolar depression without increasing the risk of mania. They were also interested in the durability of recovery defined as a minimum of 8 weeks virtually free of depressive symptoms. Patients were randomized to receive a mood stabilizer plus either an antidepressant or placebo. Rates of treatment-emergent mania or hypomania were less among the mood stabilizer-only group. Similarly, slightly more than one quarter of those in the mood stabilizer-only group experienced a durable recovery compared to slightly less than one quarter among those who received an antidepressant as well. In neither case were the differences statistically significant. Thus, prescription on adjunctive treatment with an antidepressant conveyed no advantage above that observed for a mood stabilizer alone.

These data are similar to that of Nemeroff and colleagues10 who found that once lithium levels were 0.8 meq/liter, neither imipramine nor paroxetine conveyed any additional benefits for people with bipolar depression. Nierenberg and colleagues11 examined 66 bipolar patients in a current MDE who had not responded to adequate doses of mood stabilizers and at least one antidepressant. In an open-label study, the patients were randomly assigned to inositol, lamotrigine, or risperidone. Here again the primary outcome was an 8-week period virtually free of depressive symptoms. Although pair-wise comparisons did not reach statistical significance, the recovery rate, level of depressive symptoms, Clinical Global Impression, and Global Assessment of Functioning all favored lamotrigine. Even so, slightly less than one quarter of the lamotrigine group experienced a durable recovery.

Leverich and colleagues12 randomized bipolar depressed patients to a mood stabilizer plus either bupropion, sertaline, or venlafaxine. Depending on the agent and whether or not there was a past history of mania, 20% to 35% of patients experienced either treatment-emergent mania or hypomania. In less than 25% of patients was there a sustained response to the antidepressant without a switch into mania or hypomania. The lowest risk of a switch was found with bupropion, and the highest with venlafaxine. Goldberg and colleagues13 also tested the adjunctive antidepressant hypothesis among bipolar patients with mixed mania and depression. They found significantly higher mania symptom severity after 3 months of follow-up associated with antidepressant therapy compared to mood stabilizers alone. The addition of an antidepressant did not speed recovery.

Thus, the emerging consensus based on expert opinion9,14 published guidelines,15-17 and the STEP-BD reports12,13 is that mood stabilizers are preferable both for acute treatment and the prevention of recurrence in late-life bipolar depression. An algorithm based on the expert opinions of Hilty and colleagues17 and Dolder and colleagues18 appears in the Figure. The prescribing pathway is characterized more by off-label than FDA-approved indications. Beyond the initial step of prescribing either lithium or lamotrigine, next steps are dictated by the patient’s symptom profile. For episodes of depression in both bipolar types I and II where the patient’s history exhibits relatively less mania, the antidepressant bupropion is a reasonable addition. However, for instances characterized by mixed symptoms or more frequent episodes of mania, an atypical antipsychotic or a second mood stabilizer is advisable. Purely on the basis of side-effect profile and likelihood of drug interactions, lamotrigine would appear to be preferable to lithium, divalproex, and carbamazepine.

 

 

 

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) has a long history in the treatment of mania,19 but the data for bipolar depression are minimal to nonexistent for seniors.20 Although cardiovascular complications and transient amnesia are the most frequent adverse reactions to ECT, ECT-induced mania has also been reported.21 Nonetheless, when bipolar depression is associated with life-threatening weight loss, suicidal intent, or refusal of life-saving medications (antiarrhythmics, insulin), or when pharmacotherapy proves ineffective or intolerable, ECT should be recommended.

 

Psychosocial Interventions

Evidenced-based psychosocial interventions for bipolar depression have grown in number and sophistication but mainly focused on younger rather than older adults. Intensive psychosocial interventions prevent hospitalization associated with recurrence22,23 and improve functional recovery.24 As implemented in the STEP-BD study, patients were randomized to collaborative care or one of thee intensive psychosocial interventions applied in three 30-minute sessions. People in the collaborative care condition received a self-care workbook, viewed an educational videotape, and were counseled on sleep monitoring and relapse prevention. The intensive psychosocial interventions included cognitive-behavioral therapy (CBT), interpersonal and social rhythms therapy (ISRT), and family-focused treatment (FFT).

In individual CBT, patients and therapists discussed behavioral activation exercises, problem solving, and cognitive restructuring, all meant to reverse negative self attributions and increase rewarding habits. In ISRT, interpersonal problems and difficulties maintaining a physiologically stable schedule of sleep, waking, and activity were examined with a goal of preventing destabilizing social and interpersonal situations. For people with at least one family member willing to participate, FFT focused on shared planning for relapse prevention, improved listening and communication, and problem solving skills. Compared to three sessions of collaborative/educational care, the improvements in relationship functioning and life satisfaction associated with the psychosocial interventions went beyond those expected from improvements in mood. Thus, the benefits were independent of improvements in mood. However, enthusiasm for these psychosocial interventions must be tempered by the frequency with which cognitive impairment accompanies bipolar disorder even when patients are euthymic.6,7 Cognitive remediation may be necessary in order to improve function in social roles and recreational activities.24

 

Conclusion

With the increase in the older adult population, primary care physicians and general psychiatrists will inevitably encounter the paradox and challenge of late-life bipolar depression. Data from the older adult segment of the STEP-BD study will add considerably to the empirical basis for treatment. Results from the Geriatric Bipolar Disorder study of late-life mania25,26 should provide guidance on the benefit versus burden comparison of lithium to divalproex for bipolar depression as well. In the meanwhile, inferences based on guidelines,15-17 the STEP-BP publications,12,13,22 and others27-29 provide considerable guidance for both biomedical and psychosocial interventions. Initial treatment should begin with a mood stabilizer. For people who remain symptomatic despite reaching adequate dose or therapeutic level, ongoing adjunctive therapy with a second mood stabilizer or an atypical antipsychotic may be superior to the addition of an antidepressant. Nonetheless, people with little or no history of mania may still benefit from an antidepressant.

Table 2 provides consumer and advocacy information. PP

 

 

 

References

1.  Mitchell PB, Wilhelm K, Parker G, Austin MP, Rutgers P, Malhi GS.. The clinical features of bipolar depression: a comparison with matched major depressive disorder patients. J Clin Psychiatry. 2001;62(3):212-216.
2.  Sajatovic M, Blow FC, Ignacio RV, Kales HC. New-onset bipolar disorder in later life. Am J Geriatr Psychiatry. 2005;13(4):282-289.
3.  Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Eng J Med. 2007;356(17):1711-1722.
4.  Angst J, Preisig M. Outcome of a clinical cohort of unipolar, bipolar, and schizoaffective patients. Results of a prospective study from 1959 to 1985. Schweiz Arch Neurol Psychiatr. 1995;146(1):17-23.
5.  Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the systematic Treatment Enhancement Program for Bipolar Disorders (STEP-BD). Am J Psychiatry. 2006;163(2):217-224.
6.  Gildengers AG, Butters MA, Chisholm D, et al. Cognitive functioning and instrumental activities of daily living in late-life bipolar disorder. Am J Geriatr Psychiatry. 2007;15(2);174-179.
7.  Murphy FC, Sahakian BJ, Rubinsztein JS, et al. Emotional bias and inhibitory control processes in mania and depression. Psychol Med. 1999;29(6):1307-1321.
8.  McDonald WM, Krishnan KR, Doraiswamy PM, Blazer DG. Occurrence of subcortical hyperintensities in patients with mania. Psychiatry Res. 1991;40(4):211-220.
9.  Strakowski SM. Approaching the challenge of bipolar depression: results from STEP-BD. Am J Psychiatry. 2007;164(9):1301-1303.
10.  Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry. 2001;158(6):906-912.
11. Nierenberg AA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotriginne, inositol, or risperidone. Am J Psychiatry. 2006;163(2):210-216.
12. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch on mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006;163(2):232-239.
13. Goldberg JF, Perlis RH, Ghaemi SN, et al. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms; findings from the STEP-BD. Am J Psychiatry. 2007;164(9):1348-1355.
14. Keck PE, McElroy SL, Nemeroff CB. Anticonvulsants in the treatment of bipolar disorder. J Neuropsychiatry Clin Neurosci. 1992;4(4):395-405.
15. Hirschfeld RMA: Guideline Watch: Practice Guideline for the Treatment of Patients With Bipolar Disorder. Arlington, VA: American Psychiatric Association. Available at: www.psych.org/psych_pract/treatg/pg/prac_guide.cfm. Accessed February 1, 2008
16. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
17. Hilty DM, Leamon MH, Lim RF, Kelly RH, Hales RE. Diagnosis and treatment of bipolar disorder in the primary care setting: a concise review. Primary Psychiatry. 2006;13(7);77-85.
18. Dolder CR, Depp CA, Jeste DV. Biological treatments of bipolar disorder in later life. In: Sajatovic M, Blow FC, eds. Bipolar Disorder in Later Life. Baltimore, MD: Johns Hopkins Press; 2007:71-93.
19. Lisanby SH. Electroconvulsive therapy of depression. N Engl J Med. 2007;357(19):1939-1945.
20. Sackeim HA, Prudic J. Length of ECT course in bipolar and unipolar depression. J ECT. 2005;21(3):195-197.
21. Serby M. Manic reactions to ECT. Am J Geriatr Psychiatry. 2001;9(2):180.
22. Miklowitz DJ, George EL, Richards JA, Simoneau TL, Suddath RL. A randomized study of family-focused psychoeducation and pharmacotherapy in the outpatient management of bipolar disorder. Arch Gen Psychiatry. 2003;60(9):904-912.
23. Miklowitz DJ, Otto MW, Frank E, et al. Psychosocial treatments for bipolar depression: a 1-year randomized trial from the systematic treatment enhancement program. Arch Gen Psychiatry. 2007;64(4):419-426.
24. Miklowitz GJ, Otto MW, Frank E, et al. Intensive psychosocial intervention enhances functioning in patients with bipolar depression: results from a 9-month randomized controlled trial. Am J Psychiatry. 2007;164(9):1340-1347.
25. Acute pharmacotherapy of late-life mania (GERI-BD). Available at: www.clinicaltrials.gov/ct2/show/record/NCT00254488. Accessed February 1, 2008.
26. Young RC, Beyer J, Gyulai L, et al. A randomized controlled trial of acute treatments in late-life mania. Abstract presented at: the 6th International Meeting of the International Society of Bipolar Disorder; Pittsburgh, PA; June 2005.
27. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of lamotrigine in outpatients with bipolar I depression. Lamical 602 Study Group. J Clin Psychiatry. 1999;60(2):79-88.
28. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol. 2006;26(6):600-609.
29. Perlis RH, Welge JA, Vornik LA, Hirshfeld RM, Keck PE Jr. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry. 2006;67(4):509-516.
30. National Alliance on Mental Illness. Avaiable at: www.nami.org. Accessed February 1, 2008.
31. Depression and Bipolar Support Alliance. Available at: www.dbsalliance.org. Accessed February 1, 2008.
32. The Geriatric Mental Health Foundation. Available at: www.gmhfonline.org. Accessed February 12, 2008.