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Evaluation and management of breakthrough depressive episodes

Evaluation and Management of
Breakthrough Depressive Episodes
Paul E. Keck, Jr., M.D.
Clinicians are faced with a diagnostic challenge when a bipolar patient reports breakthrough de- pressive symptomatology. Breakthrough depressive symptoms during treatment for a bipolar depres-sive episode may be a manifestation of recurrent bipolar depression or the emergence of a mixed epi-sode. Treatment of recurrent bipolar depression and mixed episodes differs considerably, andantidepressant therapy during a mixed episode can worsen the episode and initiate or exacerbate rapidcycling. Therefore, accurate diagnosis and appropriate treatment are imperative to achieving a posi-tive outcome. Research indicates that optimizing the current mood stabilizer therapy or adding an-other mood stabilizer may be the best treatment options for patients with a history of rapid cycling—in patients without a history of rapid cycling, adding an antidepressant to a mood stabilizer may beless risky and therefore a reasonable choice. Combination therapy with a mood stabilizer and an atypi-cal antipsychotic may also be effective in managing bipolar depressive episodes.
(J Clin Psychiatry 2004;65[suppl 10]:11–15) linicians face a diagnostic challenge when a patient mixed episode can worsen the episode and initiate or exac- reports depressive symptomatology. Distinguishing erbate rapid cycling. To date, there is a paucity of research depressive symptoms as a manifestation of either major regarding how to identify and manage breakthrough de- depressive disorder or a bipolar depressive episode can pressive episodes in bipolar disorder; however, recogniz- be difficult. Studies1 indicate that a considerable number of ing prodromal symptoms may help in thwarting an emerg- patients with bipolar disorder (particularly bipolar II) are ing depressive episode, and optimizing treatment can aid initially misdiagnosed as having major depressive disor- in preventing additional breakthrough episodes. Bipolar der.2 For example, Ghaemi et al.2 found that 37% of pa- spectrum disorders are a common global health problem4,5 tients who sought treatment with a mental health clinician that is highly correlated with difficulties in workplace per- following their first manic or hypomanic episode were formance and social and family life, as well as criminal misdiagnosed with unipolar depression. Additionally, more behavior and jail time.6 Therefore, accurate diagnosis and than 50% of patients with bipolar disorder experience a de- appropriate treatment are imperative to achieving positive pressive episode as their first mood episode.3 outcomes that affect patients, their families, employers, Accurately distinguishing between unipolar depression or bipolar depression is not the only challenge associatedwith the presentation of depressive symptomatology. The appearance of depressive symptoms in patients who have been diagnosed with bipolar disorder may signal recurrentbipolar depression or the emergence of a mixed episode.
Mood state prior to onset of depression has been identi- This diagnostic distinction is crucial because treatment of fied as an indicator for treatment choice and a predictor of recurrent bipolar depression and mixed episodes differs treatment outcome in patients with bipolar disorder who considerably—antidepressant pharmacotherapy during a experience breakthrough depressive episodes. MacQueenet al.7 examined the role of prior mood state and the likeli-hood of treatment response in a cohort of patients with bi-polar depression who were treated with antidepressants From the Department of Psychiatry, University of and mood stabilizers in a naturalistic treatment setting.
Cincinnati College of Medicine, Cincinnati, Ohio. This article is derived from the teleconference “Managing Detailed life-charting data from 42 patients with 67 de- Bipolar Depression,” which was held June 18, 2003, and pressive episodes among them were reviewed, and pa- supported by an unrestricted educational grant fromGlaxoSmithKline. tients were categorized on the basis of preceding mood Corresponding author and reprints: Paul E. Keck, Jr., M.D., state and type of drug received for depression (antide- Department of Psychiatry, University of Cincinnati College ofMedicine, 231 Albert Sabin Way, ML0559, Cincinnati, OH pressant or mood stabilizer). Response rates and rates of switch into mania were then compared. They found that COPYRIGHT 2004 PHYSICIANS POSTGRADUA
revealed that as many as 80% of patients with bipolar I Figure 1. Percentage of Patients Who Responded or
Switched Into Mania or Hypomania After Treatment With

disorder were able to identify prodromal symptoms a Either Antidepressant or Mood Stabilizer Medicationa
mean length of 19 days prior to the recurrence of bipolardepression. The most robust early symptom of mania was sleep disturbance (median prevalence of 77%), and the 3 most common prodromal symptoms of bipolar depres- sion were mood change (48%), psychomotor symptoms (41%), and increased anxiety (36%). Jackson and col- leagues concluded that early symptoms of relapse in bi- polar disorder could usually be identified and that identi- fication of early symptoms could lead to treatment to Keitner et al.10 conducted a similar study to identify prodromal and residual symptoms of mania and depres- sion reported by patients with bipolar I disorder and their Reprinted with permission from MacQueen et al.7 Abbreviations: AD = antidepressant, ED = patients who became family members. Researchers asked 74 patients and depressed following a euthymic period, MD = patients who became 45 adult family members to report any prodromal symp- depressed following a manic or hypomanic episode, MS = moodstabilizer.
toms of mania and depression prior to breakthrough,and clinicians classified reported symptoms into 6 broadcategories: behavioral, cognitive, mood, neurovegetative, patients who became depressed following a period of eu- social, and other, categorizing all the symptoms as typical thymia were much more likely to respond to either mood or idiosyncratic. Seventy-eight percent of the patients stabilizers or antidepressants than those whose mood state reported prodromal depressive symptoms, and 87% re- had been mania or hypomania immediately prior to de- ported prodromal manic symptoms. Patients and their pression (Figure 1). In addition, patients who were euthy- families reported similarities as well as differences in per- mic before the depressive episode were less likely to ception and recognition of symptoms. Cognitive symp- switch to a manic episode than patients who had recently toms were the most consistently reported first warning been manic or hypomanic, especially with antidepressant signs of recurrent depression by both patients and family treatment rather than mood stabilizers. Thus, in patients members. Patients described the emergence of poor con- with bipolar depression, the mood state they were experi- centration and indecisiveness, and family members re- encing prior to a depressive episode breaking through ap- ported distractibility and anxious ruminations as the most peared to be relevant to drug response and to rates of common early warning signs of depression.
Although no single symptom occurs in every patient, these studies indicate that fundamentally recognizable signs of emerging bipolar depression are usually present.
Understanding what general symptoms to look for could The number of bipolar depressive episodes a patient aid patients, their families, and their physicians to make experiences has been identified as a strong indicator of individualized lists of prodromal symptoms that warn of functioning and well-being in patients with bipolar dis- an upcoming depressive episode. In this way, preventive order.8 The number of past depressions appears to be a stronger determinant of outcome than past manias,8and rapid intervention is necessary to minimize the num- ber of depressive episodes if patient functioning is to be Jackson and colleagues9 recently published a literature review of affective disorders in which data about prodro- Research concerning pharmacologic treatment for mal symptoms as harbingers for full-blown depressive breakthrough bipolar depressive episodes is limited.
recurrence were included. Seventy-three publications of However, in randomized, controlled trials for bipolar de- prodromal symptoms in bipolar and unipolar disorders pressive disorder, mood stabilizers continue to be the gold were identified by computer searches of 7 databases (in- standard.11 Therefore, one reasonable clinical approach in cluding MEDLINE and PsychLIT) supplemented by hand treating breakthrough depression in acute bipolar depres- searches of journals, and of these, 17 studies (total sion is to optimize mood stabilizer therapy.
N = 1191) met criteria for inclusion in a systematic re- Evidence suggests that in patients being treated with view. Included in the 17 studies were 8 that reported lithium for bipolar disorder, increasing lithium levels to prodromal symptoms of bipolar depression. The analyses a reasonably high therapeutic range may help ward off COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
a depressive episode as it emerges. In support of this levels may be a useful intervention, not just in patients re- suggestion, Nemeroff et al.12 compared lithium plus ad- ceiving lithium, but for all patients with bipolar depressive junctive paroxetine, imipramine, or placebo and found disorder experiencing breakthrough depressive episodes.
that depression improved in patients receiving low con-centrations of lithium (< 0.8 mmol/L) plus paroxetine compared with lithium plus placebo. However, patients re- Besides optimizing the current mood stabilizer, other ceiving higher concentrations of lithium achieved no sub- treatment options for patients with breakthrough depres- stantial benefit from the addition of either antidepressant sion in bipolar disorder include adding either a second to lithium compared with placebo. These findings may mood stabilizer or an atypical antipsychotic or supple- suggest that in mid-to-upper therapeutic serum concentra- menting the current mood stabilizer with an antidepressant tions, lithium monotherapy provides adequate antidepres- or lamotrigine. Young et al.15 compared the addition of sant benefit that is comparable to augmentation with an antidepressant versus a second mood stabilizer for 27 paroxetine in patients who can not tolerate such lithium inpatients being treated for bipolar depression. The pa- tients, who were receiving either lithium or divalproex and Prophylactic lithium use has been reported to alter thy- had experienced breakthrough depressive symptoms, were roid function, possibly leading to hypothyroidism and trig- randomly assigned to groups that received double-blind gering mood instability and a recurrence of depressive treatment with paroxetine or the alternative mood stabi- symptoms. Frye et al.13 conducted a post hoc analysis of lizer (lithium or divalproex) for 6 weeks. Both treatment a 3-year study comparing maintenance treatment with groups showed substantial improvement in depressive lithium or carbamazepine monotherapies or the combina- symptoms during the 6-week trial; however, fewer patients tion of both agents in patients with bipolar depressive dis- taking paroxetine withdrew from the study than those tak- order to examine the relationship between changes in thy- ing a second mood stabilizer, suggesting that the addition roid indices and mood stability. For the first 2 years of the of an antidepressant may have greater clinical utility in original study, 30 patients with bipolar depressive disorder the treatment of bipolar depression than the addition of a were randomly assigned to receive either 1 year of treat- second mood stabilizer. In fact, the only patient who ment with lithium and then 1 year of treatment with car- switched into mania during the course of the study was a bamazepine, or 1 year of treatment with carbamazepine patient receiving combination mood stabilizer therapy.
and then 1 year of treatment with lithium. In the third However, the findings were somewhat limited by the small year, both patient groups were treated with lithium plus carbamazepine. Researchers used a stepwise regression The first randomized, multicenter, double-blind study16 analysis to evaluate the degree and timing of lithium- and to compare divalproex, lithium, and placebo as prophylac- carbamazepine-induced thyroid changes and to determine tic therapy for depression comprised 2 trial periods (a their subsequent relationship to long-term mood stability.
90-day open-label phase and 52-week randomized mainte- Results indicated that a lower mean level of serum free nance phase). Patients with bipolar I disorder who may thyroxine (T ) was associated with more affective epi- have been treated with open-label lithium or divalproex sodes and a greater severity of depression during mono- and who met recovery criteria within 3 months of the onset therapy treatment with either lithium or carbamazepine.
of a manic episode (N = 372) were randomly assigned to Overall, the lower the free T level, the greater the instabil- receive maintenance treatment with divalproex, lithium, or ity of mood regardless of mood stabilizer treatment.
placebo in a 2:1:1 ratio. Over the first 2 weeks of mainte- Therefore, clinical monitoring of free T levels is war- nance treatment, open-label divalproex or lithium was ta- ranted to help prevent a breakthrough episode.
pered off, and all other psychotropic medications were dis- In addition to the clinical management of free T levels, continued. The primary outcome measure was time to physicians can help stave off a breakthrough depressive recurrence of any mood episode, and secondary measures episode by monitoring serum thyrotropin levels. Cole et were time to a manic episode, time to a depressive episode, al.14 found that patients with bipolar disorder who had average change from baseline in Schedule for Affective lower-than-median values of free thyroxine index (FTI) Disorders and Schizophrenia-Change Version subscale and higher-than-median levels of thyrotropin experienced scores for depression and mania, and Global Assessment slower response to antidepressant therapy than other pa- of Functioning scores. The initial analysis showed that the tients. In fact, patients with levels of FTI below the me- active treatments were equally effective at preventing a dian and thyrotropin above the median experienced an av- mood episode and that divalproex was slightly more effec- erage time-to-remission of depressive symptoms that was tive than lithium on some secondary outcome measures.
4 months longer than patients with levels on the opposite Those who experienced breakthrough depression were al- sides of those median levels. It is important to note that all lowed adjunctive therapy with a selective serotonin reup- patients except 1 had FTI and thyrotropin values within take inhibitor (SSRI), sertraline or paroxetine. An analysis the normal range. Therefore, checking thyroid hormone of these patients indicated that the combination of dival- COPYRIGHT 2004 PHYSICIANS POSTGRADUA
studies have suggested that olanzapine may have ben- Figure 2. Early Discontinuation Due to Depression
in Patients Taking a Mood Stabilizer Plus a Selective

eficial effects in depressed bipolar patients.18 However, Serotonin Reuptake Inhibitor (SSRI)a
until there are systematic data from long-term, controlledfollow-up studies on the comparative efficacy of these agents with mood stabilizers, atypical antipsychotics should be used with caution, preferably only in combina- tion with a mood stabilizer during the maintenance phase Further randomized controlled trials of patients with bipolar disorder and breakthrough depressive symptoms need to be conducted. Available research indicates that, after optimizing current mood stabilizer therapy, the bestclinical option for treating breakthrough depressive epi- aReprinted with permission from Gyulai et al.17 sodes in patients with a history of rapid cycling maybe adding a second mood stabilizer. In patients without ahistory of rapid cycling, adding an antidepressant to the proex with an SSRI was a more effective treatment for mood stabilizer may be less risky and therefore the better breakthrough depression than the combination of lithium choice. Combination therapy with a mood stabilizer and and an SSRI, although this difference was not significant.
an atypical antipsychotic may also be effective; however, Treatment with divalproex plus an SSRI was significantly more long-term controlled follow-up studies are needed more effective than placebo plus an SSRI, whereas lithium on the comparative efficacy of these agents with mood Gyulai et al.17 recently published a report describing in further detail the above study16 of divalproex, lithium, and Drug names: carbamazepine (Epitol, Tegretol, and others), divalproex(Depakote), imipramine (Tofranil and others), lamotrigine (Lamictal), placebo as prophylactic therapy for depression in order to lithium (Lithobid, Eskalith, and others), olanzapine (Zyprexa), paroxe- elucidate the effect of divalproex on multiple dimensions tine (Paxil and others), risperidone (Risperdal), sertraline (Zoloft).
of depressive morbidity in bipolar disorder. They found Disclosure of off-label usage: The author has determined that, to the that patients who were previously hospitalized for affec- best of his knowledge, carbamazepine is not approved by the U.S.
tive episodes or who had taken divalproex in the open pe- Food and Drug Administration for the treatment of bipolar disorder; riod of the study had a longer time to relapse with dival- and sertraline, divalproex, imipramine, lamotrigine, paroxetine, andrisperidone are not approved for the treatment of bipolar depression.
proex than those patients who received lithium during themaintenance period. Divalproex improved several dimen- sions of depressive morbidity and reduced the probabilityof depressive relapse in bipolar disorder, especially in pa- 1. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar tients who had responded to divalproex during a manic disorder: how far have we really come? results of the national depressiveand manic-depressive association 2000 survey of individuals with bipolar episode and among patients with a more severe course of disorder. J Clin Psychiatry 2003;64:161–174 illness. Those taking divalproex plus an SSRI discontin- 2. Ghaemi SN, Boiman EE, Goodwin FK. Diagnosing bipolar disorder and ued treatment due to depression at a lower rate than those the effect of antidepressants: a naturalistic study. J Clin Psychiatry 2000;61:804–808 taking lithium plus an SSRI and at a significantly lower 3. Angst J, Sellaro R. Historical perspectives and natural history of bipolar rate than the placebo plus SSRI group (Figure 2).
disorder. Biol Psychiatry 2000;48:445–457 Augmenting a mood stabilizer with an atypical antipsy- 4. Murray CJL, Lopez AD, eds. The Global Burden of Disease: a Comprehensive Assessment of Mortality and Disability From chotic, such as olanzapine, is another treatment option for Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020.
patients with bipolar disorder with breakthrough depres- Cambridge, Mass: Harvard University Press; 1996 sive episodes. Due to the lower potential for neurotoxicity 5. Hirschfeld RMA, Calabrese JR, Weisman MM, et al. Screening for bipolar disorder in the community. J Clin Psychiatry 2003;64:53–59 and preliminary evidence that suggests improved efficacy 6. Calabrese JR, Hirschfeld RMA, Reed M, et al. Impact of bipolar disorder in bipolar disorder over typical antipsychotics,18 atypical on a US community sample. J Clin Psychiatry 2003;64:425–432 antipsychotics are increasingly having a more prominent 7. MacQueen GM, Young LT, Marriott M, et al. Previous mood state predicts response and switch rates in patients with bipolar depression.
role in the pharmacologic management of bipolar disorder.
Double-blind controlled studies with atypical antipsy- 8. MacQueen GM, Young LT, Robb JC, et al. Effect of number of episodes chotics in managing breakthrough depressive episodes on wellbeing and functioning of patients with bipolar disorder. ActaPsychiatr Scand 2000;101:374–381 and in providing long-term treatment of bipolar disorder 9. Jackson A, Cavanagh J, Scott J. A systematic review of manic are still largely unavailable; however, recent uncontrolled and depressive prodromes. J Affect Disord 2003;74:209–217 COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
10. Keitner GI, Solomon DA, Ryan CE, et al. Prodromal and residual 15. Young LT, Joffe RT, Robb JC, et al. Double-blind comparison of addition symptoms in bipolar I disorder. Compr Psychiatry 1996;37:362–367 of a second mood stabilizer versus an antidepressant to an initial 11. Zornberg GL, Pope HG Jr. Treatment of depression in bipolar disorder: mood stabilizer for treatment of patients with bipolar depression.
new directions for research. J Clin Psychopharmacol 1993;13:397–408 12. Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo- 16. Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo- controlled comparison of imipramine and paroxetine in the treatment controlled 12-month trial of divalproex and lithium in treatment of of bipolar depression. Am J Psychiatry 2001;158:906–912 outpatients with bipolar I disorder. Arch Gen Psychiatry 2000;57:481–489 13. Frye MA, Denicoff KD, Bryan AL, et al. Association between lower 17. Gyulai L, Bowden CL, McElroy SL, et al. Maintenance efficacy of dival- serum free T4 and greater mood instability and depression in lithium- proex in the prevention of bipolar depression. Neuropsychopharmacology maintained bipolar patients. Am J Psychiatry 1999;156:1909–1914 14. Cole DP, Thase ME, Mallinger AG, et al. Slower treatment response in 18. Brambilla P, Barale F, Soares JC. Atypical antipsychotics and mood bipolar depression predicted by lower pretreatment thyroid function.
stabilization in bipolar disorder. Psychopharmacology (Berl) 2003; COPYRIGHT 2004 PHYSICIANS POSTGRADUA


Clinical thyroidology november 2008 volume 20 issue 3


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