Understanding and Treating Bipolar Depression

Table 1

Table 2

Figure 1

Figure 2

Bipolar disorder is a longitudinal disorder defined by multiple episodes that may occur years apart. As a result, the proper diagnosis requires careful evaluation of both the current symptoms and the patient’s history. The majority of patients with bipolar disorder initially present during an episode of depression, which can be difficult to distinguish from major depressive disorder if there has not been a known manic or mixed episode in the past.¹ Not surprisingly, many bipolar patients report a history of diagnostic confusion and delayed treatment.²

CASE VIGNETTE

Mr Smith, a 32-year-old, is referred by a local family practitioner. He complains of a debilitating depression that has lingered for many months. He has not been able to enjoy his usual hobbies and has been feeling increasingly distant from his wife. He observes that his energy has been so low that his work has suffered; he fears that his job may be in jeopardy.

He has been staying home and sleeping more, and he cannot concentrate. Once an avid reader, he now can barely collect himself to watch television or hold a lengthy conversation. With some prodding, Mr Smith admits to a loss of sexual interest in his wife, which has led to marital problems. While he denies being overtly suicidal, Mr Smith concedes that he has been thinking about his death; he fantasizes about being accidentally killed.

His primary care physician diagnosed major depressive disorder last December and began the first of a series of antidepressant medications that eventually included fluoxetine, mirtazapine, and bupropion. Mr Smith tolerated the medications well but reports that none of them improved his mood. By the middle of March, his physician had grown concerned at his lack of progress and suggested that Mr Smith see a psychiatrist as soon as possible for further evaluation; it is now mid-April, and there has been no remission of symptoms.

When asked about his history, Mr Smith reveals that he has had a series of similar episodes, starting in early childhood. While none of the episodes were as debilitating as his current state, many persisted for more than 2 weeks and interfered with his ability to work as well as with family life.

He recounts that for a few weeks in 1998, his mood became quite elevated; the euphoria was accompanied by increased energy and a loss of any need to sleep. He reports that he felt like he was getting a lot of things accomplished but could not focus sufficiently to finish any of the projects he started. Nonetheless, he recalls the immense self-confidence that he had at the time. Ultimately, he was involved in an altercation with the local police and was hospitalized. Mr Smith does not recall what medications he received at the time. Shortly after being discharged, he discontinued the medications. He is embarrassed about the incident and does not like to discuss it. He denies any history of psychiatric symptoms in his first-degree relatives but notes that his grandmother often had “spells” and was hospitalized for a nervous breakdown.

A careful patient history is critical; on closer questioning, Mr Smith revealed what appears to have been a previous manic episode, as well as several potential signs of bipolar depression. He reports numerous episodes of depression that began when he was young and a possible family history of bipolar disorder. Bipolar symptoms in even a second-degree relative increase a person’s risk for the disorder. The atypical symptoms, such as increased sleep, may also suggest bipolar disorder. Other symptoms of bipolar disorder are listed in Table 1.^3-6

It is far from uncommon for patients such as Mr Smith to receive multiple courses of standard antidepressant medications.² Unfortunately, there are real risks associated with using these medications for bipolar depression. Standard antidepressants may precipitate manic episodes in a minority of bipolar patients and may be ineffective.⁷ A delayed diagnosis may prolong depression and further affect the patient’s ability to function effectively at home and at work. Prolonged depression may also increase the risk of self-harm.

Some studies suggest that there may be other, less concrete effects of prolonged depression in bipolar patients as well. Correlations have been observed between the number of past affective episodes and subtle cognitive losses in patients with bipolar disorder.^8-11 More recently, some preliminary neuroimaging studies have suggested a link between mood episodes and evidence of neuropathic changes in several regions of the brain.^12-15

Pharmacotherapeutic treatment options

An accurate diagnosis is, of course, the first step in making treatment decisions. Treatment choices in psychiatry are rarely straightforward, and bipolar depression is no exception to this general rule. Further complicating the process is the limited number of FDA-approved options. The number of FDA-approved medications for bipolar mania has literally tripled over the past decade while the pharmacopeia available for bipolar depression remains quite limited (Table 2).

Only 1 medication and 1 medication combination are approved by the FDA to treat depression in patients with bipolar disorder. Quetiapine (both immediate- and extended-release) was approved on the basis of 2 large initial trials and a follow-up trial of the extended-release formulation.^16,17 Olanzapine in combination with fluoxetine was also found to be effective for bipolar depression in 2 large trials and was approved only in this combined formulation.¹⁸

These medications have not been compared in a head-to-head fashion, but a review by Gao and colleagues¹⁹ found higher effect sizes for quetiapine than for the olanzapine/fluoxetine combination, which suggests that the former may be more effective (Figure 1). In addition, the large weight gain sometimes observed with olanzapine and other potential adverse effects, including sedation, hyperglycemia, and hypercholesterolemia, can limit the usefulness of the olanzapine/fluoxetine combinations. Despite the FDA approval, some consensus guidelines, such as those of the World Federation of Societies of Biological Psychiatry, do not list the olanzapine/fluoxetine combination as first-line treatment for bipolar depression.²⁰ Quetiapine may also be associated with significant adverse effects, including sedation, weight gain, and metabolic syndrome.²¹

In addition to the 2 FDA-approved pharmacotherapies for bipolar depression, at least 1 other medication-lithium-is usually considered to be a first-line treatment option.^22,23 There is a wealth of clinical experience with lithium, and many practitioners report good clinical outcomes in depressed bipolar patients. Nonetheless, the published data are somewhat mixed. Findings from several small studies of lithium have been positive, but a double-blind study of lithium in bipolar depression did not find it to be significantly more effective than placebo.^24,25 The low mean serum drug concentration of 0.61 mEq/L, however, may have compromised the findings. Some studies suggest that a minimum serum lithium level of 0.8 mEq/L may be necessary for efficacy in depressed bipolar patients.²⁶

Lithium carries some advantages over atypical antipsychotics, including its affordability and wide availability. Lithium is also associated with a different collection of potentially significant adverse effects, including GI distress and thyroid and renal pathology. The need to monitor blood lithium levels and to obtain regular laboratory screening tests has probably limited its use by nonpsychiatrist clinicians.²⁷

Lamotrigine is often considered to be a first-line intervention for bipolar depression, but it has not been approved for this indication.²² As with lithium, there is anecdotal evidence for its efficacy but limited published study data. While results of a single large, randomized, double-blind, placebo-controlled trial have been positive, 4 smaller clinical trials did not find lamotrigine to be an effective treatment for bipolar depression. Nonetheless, a meta-analysis that included all 5 trials found lamotrigine to be particularly effective in patients with more severe depression. Lamotrigine has also been found to be useful in combination with other medications, particularly lithium.²⁸

Lamotrigine is associated with a number of potentially serious adverse effects that include Stevens-Johnson syndrome, a potentially fatal dermatological reaction. As a result, lamotrigine dosing should closely adhere to FDA guidelines for its approved uses.

A comparison of effect sizes suggests that quetiapine may be more effective than the olanzapine/fluoxetine combination, but without more data this suggestion is far from conclusive. While a single study that directly compared lithium with quetiapine suggests the latter to be more effective, these findings may have been driven by the low blood levels of lithium in study patients.²⁴

It is not unusual for patients to fail to respond to the first medication prescribed. If symptoms do not improve with the initial agent, a switch to a different first-line therapeutic agent may be beneficial. Alternatively, a combination of first-line medications-typically a combination of quetiapine with lithium or lithium with lamotrigine may work.^28-30 Many patients with bipolar depression do not respond to any of the usual first-line medications, and you may need to consider a second-line agent for which there is less evidence of efficacy.

Divalproex is often prescribed for bipolar depression, and while there are no large studies of this agent, 4 studies found the anticonvulsant to be effective, as did a recent meta-analysis.³¹ While divalproex is often well tolerated, patients may report fairly significant weight gain and there is a risk of hepatotoxicity. Divalproex is also considered by some clinicians to be contraindicated in young women. The medication may increase the rate of polycystic ovary syndrome, and-given the impulsivity often associated with bipolar disorder-the relatively high teratogenicity of divalproex can pose a potential problem.^32,33

Divalproex is often combined with a first-line agent, but caution must be exercised because of possible drug interactions. While divalproex can be combined with lamotrigine, FDA guidelines should be followed closely to avoid inadvertently increasing lamotrigine levels and increasing the risk of lamotrigine-related adverse effects.

There are several third-line interventions that can also be considered. These include carbamazepine and olanzapine. Although a few small studies suggest that carbamazepine may be effective for bipolar depression, the findings from a randomized, double-blind, placebo-controlled study were mixed.²⁰ Olanzapine monotherapy was associated with statistically significant improvement in patients with bipolar depression, but the effect size was quite low (Figure 1) and probably not clinically significant.¹⁹ Other atypical antipsychotic medications have not been found to be effective for bipolar depression.

Several other medications have shown some limited efficacy for bipolar depression in combination with more typical treatments. Two studies have found that as adjunctive medication, both an isomer of modafinil and modafinil itself (an FDA-approved medication for wakefulness) may improve response.^34,35 Two small studies also found adjunctive levothyroxine to be helpful in treating bipolar patients with treatment-resistant depression.^36,37 Zonisamide-another anticonvulsant-used as adjunctive treatment, improved symptoms of bipolar depression, but the medication was very poorly tolerated, with high dropout rates in all 4 trials.^38-41 Inositol is another possible treatment for bipolar depression, although evidence for its efficacy is limited.^42,43

The anticonvulsant gabapentin showed weak antidepressant effects as a monotherapeutic agent, with limited evidence of efficacy when given as an adjunct.^44-46 Although ω-3 fatty acids are often recommended for both bipolar mania and bipolar depression, only 1 small study of ethyl-eicosapentaenoic acid found evidence of efficacy, while a second study failed to observe clinical effects.^47,48

Findings from several small case series and chart reviews, and 2 small studies of patients with bipolar disorder type I and II also suggest that pramipexole-a medication approved for Parkinson disease and restless legs syndrome-may be effective for at least some patients with bipolar depression.^49-55

The adjunctive use of standard antidepressants in patients with bipolar depression remains fairly controversial. While there is a strong consensus against treating bipolar patients with standard antidepressants as monotherapy, limited data suggest that standard antidepressants may play an adjunctive role in treating otherwise treatment-resistant symptoms of bipolar depression.^20,23 Antidepressant medications differ a great deal in their propensity to induce mania, and adjunctive mood-stabilizing medications appear to protect against treatment-emergent affective switch. Nonetheless, the large STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder) analysis did not observe improvement in patients who received standard antidepressants.^7,56 Other meta-analyses that have purported to observe an effect may be methodologically flawed.⁵⁷

Nonpharmacological treatment modalities

In addition to pharmacological treatments for bipolar depression, nonpharmacological modalities have shown promise in improving symptoms in patients with bipolar depression. Probably the most effective nonpharmacological option is electroconvulsive therapy (ECT), which may improve symptoms in some treatment-resistant patients.⁵⁸ However, many patients are reluctant to consider ECT because of widespread negative associations with “shock treatment” and fears of memory loss.

Two behaviorally focused forms of psychotherapy-cognitive-behavioral therapy and family-focused therapy-have been found to improve outcomes in patients with bipolar depres-sion. In addition, interpersonal social rhythm therapy may be effective as an adjunct of medication-based interventions.⁵⁹ Sleep deprivation has long been known to improve symptoms of depression. A few open-label trials suggest that this approach may also be effective in bipolar depression. However, the intervention is not without risk; some patients developed treatment-related manic symptoms, similar to those sometimes observed in bipolar patients treated with standard antidepressants.^60-62 Phototherapy has demonstrated some efficacy but may also induce mania in susceptible individuals.^60,62-64 In addition, decreased stress and exercise may alleviate some symptoms.⁶⁵

A look at the treatment horizon

Although, the number of new treatments for bipolar depression has lagged well behind that for bipolar mania, there are some innovative interventions on the horizon. A recent double-blind study looked at the adjunctive use of the N-methyl-d-aspartate antagonist ketamine for bipolar depression. Ketamine infusions were associated with an exceptionally rapid response in a high proportion of the patients.^66,67 Repetitive transcranial magnetic stimulation, currently approved for treatment-resistant unipolar depression, has showed some promise for treatment of bipolar depression. Vagus nerve stimulation is also approved for treatment-resistant unipolar depression and may be effective in bipolar depression as well.⁵⁸

Conclusions

There are no clear-cut correct choices. Treating psychiatric illness typically requires an individualized care plan, and bipolar depression is no exception. The construction of a care plan is further complicated by the lack of FDA-approved medications. Most treatment algorithms agree that first-line treatment consists of monotherapy with a proven agent such as quetiapine; an olanzapine/fluoxetine combination; lithium, dosed to a minimum serum level of 0.8 mEq/L; or possibly lamotrigine.

There are few reliable indicators of clinical efficacy to guide the treatment decisions; thus, each option should be discussed with the patient. The final choice is often driven by which medication is likely to be best tolerated. Only if the patient fails to respond to a first-line medication or a combination of first-line agents (eg, lithium and quetiapine, lithium and lamotrigine, olanzapine/fluoxetine combination) should second- and third-line agents be added (Figure 2).

A review of current treatment algorithms highlights how subjective treatment approaches to bipolar depression remain. Many guidelines differ significantly, even with regard to what agents are considered primary interventions. These discrepancies emphasize the need for both more effective treatments for depressed patients with bipolar disorder and more research on existing pharmacotherapies. A review of older treatment algorithms, even those written just a few years ago, is also educational. Treatment approaches have evolved substantially over just a few years; the bulk of these changes have resulted from new research studies of existing medications. It is clear that we need to increase the pace of research on treatments for bipolar depression; it is equally clear that we are moving in the right direction.

NOTE TO READERS: This article was originally presented as an independent educational activity under the direction of CME LLC and published in the July 2011 issue of Psychiatric Times (2011;28[7]66-71). The ability to receive CME credits has expired. The article is presented here for your reference.

References:

1. Roy-Byrne P, Post RM, Uhde TW, et al. The longitudinal course of recurrent affective illness: life chart data from research patients at the NIMH. Acta Psychiatr Scand Suppl. 1985;317:1-34.
2. Ghaemi SN, Boiman EE, Goodwin FK. Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study. J Clin Psychiatry. 2000;61:804-808.
3. Akiskal HS, Walker P, Puzantian VR, et al. Bipolar outcome in the course of depressive illness. Phenomenologic, familial, and pharmacologic predictors. J Affect Disord. 1983;5:115-128.
4. Geller B, Luby J. Child and adolescent bipolar disorder: a review of the past 10 years [published correction appears in J Am Acad Child Adolesc Psychiatry. 1997;36:1642]. J Am Acad Child Adolesc Psychiatry. 1997;36:1168-1176.
5. Marchand WM. Recognizing and treating bipolar disorder. Hosp Physician. 2003;10(12):21-30.
6. Perlis RH, Brown E, Baker RW, Nierenberg AA. Clinical features of bipolar depression versus major depressive disorder in large multicenter trials. Am J Psychiatry. 2006;163:225-231.
7. Salvadore G, Quiroz JA, Machado-Vieira R, et al. The neurobiology of the switch process in bipolar disorder: a review. J Clin Psychiatry. 2010;71:1488-1501.
8. Denicoff KD, Ali SO, Mirsky AF, et al. Relationship between prior course of illness and neuropsychological functioning in patients with bipolar disorder. J Affect Disord. 1999;56:67-73.
9. Donaldson S, Goldstein LH, Landau S, et al. The Maudsley Bipolar Disorder Project: the effect of medication, family history, and duration of illness on IQ and memory in bipolar I disorder. J Clin Psychiatry. 2003;64:86-93.
10. Lebowitz BK, Shear PK, Steed MA, Strakowski SM. Verbal fluency in mania: relationship to number of manic episodes. Neuropsychiatry Neuropsychol Behav Neurol. 2001;14:177-182.
11. van Gorp WG, Altshuler L, Theberge DC, et al. Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence. A preliminary study. Arch Gen Psychiatry. 1998;55:41-46.
12. Adler CM, DelBello MP, Weber W, et al. Prefrontal N-acetylaspartate concentrations in manic bipolar patients associated with treatment response to quetiapine. Presented at: 49th Annual Meeting of the American College of Neuropsychopharmacology; December 5-9, 2010; Miami.
13. Brambilla P, Harenski K, Nicoletti M, et al. Differential effects of age on brain gray matter in bipolar patients and healthy individuals. Neuropsychobiology. 2001;43:242-247.
14. López-Larson MP, DelBello MP, Zimmerman ME, et al. Regional prefrontal gray and white matter abnormalities in bipolar disorder. Biol Psychiatry. 2002;52:93-100.
15. Lyoo IK, Kim MJ, Stoll AL, et al. Frontal lobe gray matter density decreases in bipolar I disorder. Biol Psychiatry. 2004;55:648-651.
16. Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162:1351-1360.
17. Thase ME, Macfadden W, Weisler RH, et al; BOLDER II Study Group. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study) [published correction appears in J Clin Psychopharmacol. 2007;27:51]. J Clin Psychopharmacol. 2006;26:600-609.
18. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression [published correction appears in Arch Gen Psychiatry. 2004;61:176]. Arch Gen Psychiatry. 2003;60:1079-1088.
19. Gao K, Gajwani P, Elhaj O, Calabrese JR. Typical and atypical antipsychotics in bipolar depression. J Clin Psychiatry. 2005;66:1376-1385.
20. Grunze H, Vieta E, Goodwin GM, et al; WFSBP Task Force on Treatment Guidelines for Bipolar Disorders. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: update 2010 on the treatment of acute bipolar depression. World J Biol Psychiatry. 2010;11:81-109.
21. Adler CM, Fleck DE, Brecher M, Strakowski SM. Safety and tolerability of quetiapine in the treatment of acute mania in bipolar disorder. J Affect Disord. 2007;100(suppl 1):S15-S22.
22. Suppes T, Kelly DI. Treatment and monitoring guidelines for the patient with bipolar disorder. US Psychiatry Rev. November 2008.
23. Yatham LN, Kennedy SH, Schaffer A, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disord. 2009;11:225-255.
24. Young AH, McElroy SL, Bauer M, et al; EMBOLDEN I (Trial 001) Investigators. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry. 2010;71:150-162.
25. Zornberg GL, Pope HG Jr. Treatment of depression in bipolar disorder: new directions for research. J Clin Psychopharmacol. 1993;13:397-408.
26. 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;158:906-912.
27. Gerrett D, Lamont T, Paton C, et al. Prescribing and monitoring lithium therapy: summary of a safety report from the National Patient Safety Agency. http://www.bmj.com/content/341/bmj.c6258.short?rss=1&utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%253A+bmj%252Frecent+%2528Latest+from+BMJ%2529. Accessed May 24, 2011.
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.
29. Calabrese JR, Huffman RF, White RL, et al. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord. 2008;10:323-333.
30. Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry. 1999;60:79-88.
31. Bond DJ, Lam RW, Yatham LN. Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis. J Affect Disord. 2010;124:228-234.
32. Joffe H, Cohen LS, Suppes T, et al. Longitudinal follow-up of reproductive and metabolic features of valproate-associated polycystic ovarian syndrome features: a preliminary report. Biol Psychiatry. 2006;60:1378-1381.
33. Kaplan PW. Reproductive health effects and teratogenicity of antiepileptic drugs. Neurology. 2004;63(10 suppl 4):S13-S23.
34. Calabrese JR, Ketter TA, Youakim JM, et al. Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry. 2010;71:1363-1370.
35. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164:1242-1249.
36. Bauer M, Hellweg R, Gräf KJ, Baumgartner A. Treatment of refractory depression with high-dose thyroxine. Neuropsychopharmacology. 1998;18:444-455.
37. Bauer M, London ED, Rasgon N, et al. Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression. Mol Psychiatry. 2005;10:456-469.
38. Anand A, Bukhari L, Jennings SA, et al. A preliminary open-label study of zonisamide treatment for bipolar depression in 10 patients. J Clin Psychiatry. 2005;66:195-198.
39. Ghaemi SN, Zablotsky B, Filkowski MM, et al. An open prospective study of zonisamide in acute bipolar depression. J Clin Psychopharmacol. 2006;26:385-388.
40. McElroy SL, Suppes T, Keck PE Jr, et al. Open-label adjunctive zonisamide in the treatment of bipolar disorders: a prospective trial. J Clin Psychiatry. 2005;66:617-624.
41. Wilson MS, Findling RL. Zonisamide for bipolar depression. Expert Opin Pharmacother. 2007;8:111-113.
42. Eden Evins A, Demopulos C, Yovel I, et al. Inositol augmentation of lithium or valproate for bipolar depression. Bipolar Disord. 2006;8:168-174.
43. Nierenberg AA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry. 2006;163:210-216.
44. Altshuler LL, Keck PE Jr, McElroy SL, et al. Gabapentin in the acute treatment of refractory bipolar disorder. Bipolar Disord. 1999;1:61-65.
45. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20:607-614.
46. Wang PW, Santosa C, Schumacher M, et al. Gabapentin augmentation therapy in bipolar depression. Bipolar Disord. 2002;4:296-301.
47. Frangou S, Lewis M, McCrone P. Efficacy of ethyl-eicosapenta-enoic acid in bipolar depression: randomised double-blind placebo-controlled study. Br J Psychiatry. 2006;188:46-50.
48. Keck PE Jr, Mintz J, McElroy SL, et al. Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biol Psychiatry. 2006;60:1020-1022.
49. El-Mallakh RS, Penagaluri P, Kantamneni A, et al. Long-term use of pramipexole in bipolar depression: a naturalistic retrospective chart review. Psychiatr Q. 2010;81:207-213.
50. Goldberg JF, Frye MA, Dunn RT. Pramipexole in refractory bipolar depression. Am J Psychiatry. 1999;156:798.
51. Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry. 2004;161:564-566.
52. Gupta S, Vincent JL, Frank B. Pramipexole: augmentation in the treatment of depressive symptoms. CNS Spectr. 2006;11:172-175.
53. Perugi G, Toni C, Ruffolo G, et al. Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series. Pharmacopsychiatry. 2001;34:137-141.
54. Sporn J, Ghaemi SN, Sambur MR, et al. Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review. Ann Clin Psychiatry. 2000;12:137-140.
55. Zarate CA Jr, Payne JL, Singh J, et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry. 2004;56:54-60.
56. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356:1711-1722.
57. Ghaemi SN. Antidepressants in bipolar depression: a new meta-analysis for an old controversy. Psychiatr Times. 2010;27(12):1-10.
58. Loo C, Katalinic N, Mitchell PB, Greenberg B. Physical treatments for bipolar disorder: a review of electroconvulsive therapy, stereotactic surgery and other brain stimulation techniques. J Affect Disord. 2010 Sep 20; [Epub ahead of print].
59. Hollon SD, Ponniah K. A review of empirically supported psychological therapies for mood disorders in adults. Depress Anxiety. 2010;27:891-932.
60. Benedetti F, Dallaspezia S, Fulgosi MC, et al. Phase advance is an actimetric correlate of antidepressant response to sleep deprivation and light therapy in bipolar depression. Chronobiol Int. 2007;24:921-937.
61. Riemann D, Voderholzer U, Berger M. Sleep and sleep-wake manipulations in bipolar depression. Neuropsychobiology. 2002;45(suppl 1):7-12.
62. Wu JC, Kelsoe JR, Schachat C, et al. Rapid and sustained antidepressant response with sleep deprivation and chronotherapy in bipolar disorder. Biol Psychiatry. 2009;66:298-301.
63. Sit D, Wisner KL, Hanusa BH, et al. Light therapy for bipolar disorder: a case series in women. Bipolar Disord. 2007;9:918-927.
64. Wirz-Justice A, Benedetti F, Berger M, et al. Chronotherapeutics (light and wake therapy) in affective disorders. Psychol Med. 2005;35:939-944.
65. Ng F, Dodd S, Berk M. The effects of physical activity in the acute treatment of bipolar disorder: a pilot study. J Affect Disord. 2007;101:259-262.
66. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793-802.
67. Kaplan A. Ketamine: a possible role for patients who are running out of options? Psychiatr Times. 2011;28(4):1-13.