Evidence-Based Reviews

Soft bipolarity: How to recognize and treat bipolar II disorder

Current Psychiatry. 2009 July;8(7):41-48

References

1. Pies R. The “softer” end of the bipolar spectrum. J Psychiatr Pract. 2002;8(4):189-195.

2. Angst J. The bipolar spectrum. Br J Psychiatry. 2007;190(3):189-191.

3. Smith DJ, Ghaemi SN, Craddock N. The broad clinical spectrum of bipolar disorder: implications for research and practice. J Psychopharmacol. 2008;22(4):397-400.

4. Angst J, Gamma A, Bennazzi F, et al. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J Affect Disord. 2003;73:133-146.

5. Judd LJ, Akiskal HS. The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases. J Affect Disord. 2003;73:123-131.

6. Goldberg JF, Harrow M, Whiteside JE. Risk for bipolar illness in patients initially hospitalized for unipolar depression. Am J Psychiatry. 2001;58:1265-1270.

7. Smith DJ, Harrison N, Muir W, et al. The high prevalence of bipolar spectrum disorders in young adults with recurrent depression: toward an innovative diagnostic framework. J Affect Disord. 2005;84(2-3):167-178.

8. Sharma V, Khan M, Smith A. A closer look at treatment resistant depression: is it due to a bipolar diathesis? J Affect Disord. 2005;84(2-3):251-257.

9. Akiskal HS, Benazzi F, Perugi G. Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy. J Affect Disord. 2005;85(3):245-258.

10. Ghaemi SN, Wingo AP, Filkowski MA, et al. Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks. Acta Psychiatr Scand. 2008;118(5):347-356.

11. National Institute of Health and Clinical Excellence. Bipolar disorder: the management of bipolar disorder in adults, children and adolescents, in primary and secondary care. Issued July 2006. Available at: http://www.nice.org.uk/CG038. Accessed June 3, 2009.

12. American Psychiatric Association practice guidelines. Treatment of patients with bipolar disorder, 2nd ed. Issued April 2002. Available at: http://www.psychiatryonline.com/pracGuide/pracGuideTopic_8.aspx. Accessed June 3, 2009.

13. Judd LL, Akiskal HS, Schletter PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60:261-269.

14. Forty L, Smith D, Jones L, et al. Clinical differences between bipolar and unipolar depression. Br J Psychiatry. 2008;192(5):388-389.

15. Mitchell PB, Wilhelm K, Parker G, et al. The clinical features of bipolar depression: a comparison with matched major depressive disorder patients. J Clin Psychiatry. 2001;62:212-216.

16. Akiskal HS, Benazzi F. Family history validation of the bipolar nature of depressive mixed states. J Affect Disord. 2003;73(1-2):113-122.

17. Hirschfeld RMA, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: The Mood Disorder Questionnaire. Am J Psychiatry. 2000;157:1873-1875.

18. Angst J, Adolfsson R, Benazzi F, et al. The HCL-32: towards a self-assessment tool for hypomanic symptoms in outpatients. J Affect Disord. 2005;88(2):217-233.

19. Ghaemi SN, Millar C, Berv DA, et al. Sensitivity and specificity of a new bipolar spectrum diagnostic scale. J Affect Disord. 2005;84:273-277.

20. Allen R, Smith DJ. Screening for bipolar disorder: strengths and limitations of currently available instruments. Primary Care and Community Psychiatry. 2008;13(2):47-51.

21. Goodwin FK, Jamison KR. Manic-depressive illness: bipolar disorders and recurrent depression. 2nd ed. New York, NY: Oxford University Press; 2007.

22. Young AH, Hammond JM. Lithium in mood disorders: increasing evidence base, declining use? Br J Psychiatry. 2007;191(6):474-476.

23. Smith LA, Cornelius V, Warnock A, et al. Effectiveness of mood stabilizers and antipsychotics in the maintenance phase of bipolar disorder: a systematic review of randomized controlled trials. Bipolar Disord. 2007;9(4):394-412.

24. Licht RW, Gijsman H, Nolen WA, et al. Are antidepressants safe in the treatment of bipolar depression? A critical evaluation of their potential risk to induce switch into mania or cycle acceleration. Acta Psychiatr Scand. 2008;118(5):337-346.

25. Smith DJ, Forty L, Russell E, et al. Sub-threshold manic symptoms in recurrent major depressive disorder are a marker for poor outcome. Acta Psychiatr Scand. 2009;119(4):325-329.Epub 2008 Dec 16.

26. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-1722.

27. Thase ME, Madfadden 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 Psychopharmacology. 2006;26(6):600-609.

28. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194:4-9.

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31. Miklowitz DJ. Adjunctive psychotherapy for bipolar disorder: state of the evidence. Am J Psychiatry. 2008;165(11):1408-1419.Epub 2008 Sep 15.

Table 2

Possible indicators of bipolarity in apparently unipolar depression

Atypical features
First-degree relative with bipolar disorder
Antidepressant-induced mania or hypomania
Multiple family members with major depression
Early onset of depression (age
Lack of response to ≥3 antidepressant trials
Psychotic features (before age 35)
Mixed depressive episodes
Brief but frequent episodes of depression
Complex comorbidity (anxiety disorders, drug and alcohol misuse, previous diagnosis of borderline personality disorder)
Source: References 2,13,14

Treatment strategies for BP II

As with all psychiatric disorders, treatment needs to multimodal and tailored to the individual. For a detailed assessment of pharmacologic and psychological options, see Goodwin and Jamison’s authoritative text, chapters 17 to 20.²¹

Pharmacologic options. Because few clinical trials have focused exclusively on BP II patients, much psychiatric practice has been extrapolated from trials involving BP I patients. Obviously, trials with BP II samples are needed, but these may be limited by the restrictive DSM-IV-TR definition of hypomania.

Lithium has the most supporting evidence, showing efficacy for all 3 phases of BP II—treatment of hypomania, treatment of bipolar depression, and prophylaxis against hypomanic and depressive relapses.²² Different medications used in bipolar disorder appear to have different efficacy profiles, however. For example, a systematic review of 14 randomized controlled trials with 2,526 patients found that although lithium, lamotrigine, olanzapine, and valproate were more effective than placebo at preventing relapse due to any mood episode:

only lithium and olanzapine significantly reduced manic relapses
only lamotrigine and valproate significantly reduced depressive relapses.²³

Most guidelines warn against antidepressant monotherapy for bipolar depression, but uncertainty and debate surround antidepressants’ effectiveness and risks (in terms of switching to mania or hypomania) when prescribed alongside mood stabilizers for bipolar depressive episodes.^10,24 In a study of nearly 600 patients with recurrent MDD, we found that those with a history of subthreshold manic symptoms were significantly more likely than those without manic features to respond poorly to antidepressants (P 25

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial did not find any therapeutic benefit or increased risk of switching to mania for anti depressants plus mood stabilizer vs mood stabilizer alone.²⁶ Many trials of bipolar depression have recruited such heterogeneous groups of patients (including BP I, BP II, and BP NOS; schizoaffective disorder, bipolar type; and even recurrent MDD) that it is difficult to make firm recommendations about pharmacologic options for the depressive phase of BP II disorder.

In my experience, approximately one-third of BP II patients have a history of poor response to antidepressants or adverse effects from antidepressants (extreme irritability, activation, and antidepressant-induced hypomania). In the long term, these patients often do much better on mood stabilizer monotherapy or a combination of mood stabilizers such as lithium plus lamotrigine. The key is to be flexible with treatment options within recommended guidelines and to tailor treatment choices to the individual’s pattern of illness and treatment preferences.

Clinical Point

Psychoeducation given in families and groups can be an effective long-term option as an adjunct to medications for BP II disorder

Placebo-controlled evidence supports the short-term (8 weeks) treatment of BP II depression with quetiapine monotherapy.²⁷ A recent systematic review and meta-analysis of individual patient data from randomized, controlled trials comparing lamotrigine with placebo found that lamotrigine has a modest beneficial effect on depressive symptoms in the depressed phase of bipolar disorder.²⁸

Psychological interventions. Some evidence supports cognitive-behavioral therapy (CBT) and interpersonal and social rhythm therapy (IPSRT) in long-term treatment of bipolar disorders, although—as with medication trials—we need to be careful about extrapolating these findings to BP II disorder.²⁹ For example, a recent large-scale randomized controlled trial of CBT for bipolar disorder was largely negative.³⁰ Psychoeducation given in families and groups can be effective long-term options when used as adjuncts to medications.³¹

Clinical Point

Lithium remains a gold-standard treatment for BP II disorder; quetiapine or lamotrigine may be helpful for acute BP II depression

Managing comorbidities. BP II tends to be a complex, highly comorbid disorder that requires a coordinated, multifaceted approach. Unfortunately, we know little about which combinations of pharmacologic and nonpharmacologic interventions are most beneficial for BP II patients with comorbidities such as alcohol abuse. For this reason, optimal long-term management of the BP II patient requires a high degree of skill, flexibility, and coordination within the treating clinical team (Table 3).

Table 3

Recommendations for treating patients with BP II disorder

Most BP II patients require a multimodal team approach
Look for and treat psychiatric comorbidities, such as alcohol abuse
Lithium remains a gold standard treatment for BP II disorder
Quetiapine or lamotrigine may be helpful for acute bipolar II depression
Avoid antidepressant monotherapy for bipolar depression; some patients should avoid antidepressants altogether
CBT and IPSRT are useful psychological interventions
Family-focused and group psychoeducation are helpful in the long term
Always tailor treatments to the individual
BP II: bipolar II disorder; CBT: cognitive-behavioral therapy; IPSRT: interpersonal and social rhythm therapy