Posted by MB on July 28, 2003, at 11:39:24
Another article
MB
/////////////////////////////////Advances in the Treatment of Bipolar Depression
Disclosures
Irving Kuo, MD
Introduction
Recent research and clinical experience have indicated that it is the depressive part of the bipolar disease that is the most significantly disabling and the most difficult to treat. The presenters attempted to examine the phenomenology of bipolar depression, the course of the illness, and recent advances in the pharmacologic and psychological treatments of bipolar depression.
Jules Angst, MD,[1] Emeritus Professor of Psychiatry at Zurich University and a longtime contributor to bipolar disorder research, began by commenting on the enormity of the problem from an epidemiologic viewpoint. There appears to be a 20% to 25% lifetime prevalence of mood disorders in the general population, with the sense that this is the tip of the iceberg, especially in terms of bipolar disorder. He argues that there may be another 25% of the population with subthreshold mood disorders -- not meeting strict diagnostic criteria for an official diagnosis but often presenting with mood symptoms and functional impairments. He felt that this was especially true of bipolar II disorder, and that the prevalence rates of bipolar disorder in the population may be substantially underestimated.
Phenomenology of Bipolar DepressionPhillip Mitchell, MD,[2] Professor and Head of the School of Psychiatry at the University of South Wales in Sydney, Australia, then spoke on "Bipolar Depression -- Phenomenological Overview and Clinical Characteristics." He emphasized the importance of looking at the depressive part of bipolar disorder, stating that depressive symptoms predominate over manic/hypomanic and mixed symptoms. He also indicated that most depressions seen in bipolar patients are of the minor, dysthymic, or subsyndromal type.
Dr. Mitchell then described the prevalence of depression in bipolar I disorder. In the National Institutes of Mental Health Collaborative Depression Study,[3] 146 bipolar patients were followed for a mean of 12.8 years with their status assessed on a weekly basis. This study found that depressive symptoms were present for 32% of the weeks, a much higher percentage than for either manic/hypomanic (9%) or cycling/mixed states (6%). In terms of the nature of the depression, 14% had minor depression/dysthymia, 9% had subsyndromal depression, and 9% had a major depression. In addition, the study indicated that depression as the index episode predicted a greater chronicity in terms of the illness course.
A follow-up to this study[4] also looked at 86 patients with bipolar II disorder and followed them for a mean of 13.4 years, with weekly assessment of their status also done. For this group, depressive symptoms were present for 50% of the weeks vs 1% for manic/hypomanic and 12% for cycling/mixed states. Minor depression was seen in 24% of the patients, 14% had subsyndromal depression, and 13% had a major depression. Thus, Dr. Mitchell concluded that patients with bipolar II disorders were more likely to have major and minor depressive episodes and that they also had a more chronic course when compared with patients with bipolar I disorder. He also spoke about studies[5-7] that indicated that the average duration of bipolar depressive episodes was 3 to 6 months. The recovery rates also were seen as lower than for other bipolar states. After 8 weeks, there was a 44% recovery rate for depression, compared with mania (61%) and mixed/cycling (33%). After 1 year, the recovery rates were as follows: 78% for depression, 93% for mania, and 68% for mixed/cycling episodes.
Dysthymia in Bipolar DisorderDr. Mitchell continued with a discussion of the prevalence of dysthymia in bipolar disorder. In a recent, unpublished study, looking at 10,641 respondents chosen from the Australian National Epidemiological Study,[8] dysthymia was more prevalent (odds ratio of 8.4) than the rest of the sample. The question was asked whether there are distinctive clinical features distinguishing bipolar depression from unipolar depression that would aid in diagnosing the patient with a first-onset depression, who had an ambiguous past history of mania/hypomania, or who was a "unipolar" patient with a family history of bipolar illness. Recent studies[9,10] done in Sydney, Australia, tried to examine this question.
One study examined 3 data sets composed of 83 bipolar and 904 unipolar patients and asked the question: "Is melancholia (as defined by DSM III or IIIR) overrepresented in patients with bipolar depression?" The study revealed that bipolar patients were significantly more likely to have the melancholic type of depression than unipolar patients (69% vs 37%). He then described data that he had collected on 270 inpatients and outpatients with a DSM-IV diagnosis of major depression and compared their depressive phenomenology with 39 currently depressed bipolar patients. The bipolar patients were significantly more likely to have been psychotic with their depression in their previous depressive episode, and were significantly more likely to have the symptoms of worthlessness, anticipatory anhedonia, subjective restlessness, leaden paralysis, and hypersomnia. They were less likely to be tearful vs their unipolar counterparts. The bipolar depressed patients also scored higher on measures of depressive psychomotor activity but lower on measures of anxiety and blaming others. Dr. Mitchell thus concluded that there was a "bipolar depression signature" that consisted of melancholic symptoms (worthlessness, unvarying mood, anticipatory anhedonia), atypical symptoms (hypersomnia, leaden paralysis), past history of psychotic depression, and less tearfulness, anxiety, initial insomnia, or tendency to blame others. He also briefly mentioned data that indicated that patients with bipolar II disorder had more atypical depressive features but no difference in the rates of psychomotor retardation.
Suicide RiskSuicide risk was then examined by Dr. Mitchell. He related that 10% to 19% of bipolar patients complete suicide,[11] that the suicide risk is estimated to be approximately 15 times that for the general population,[12] and that the large majority (79%) of these suicides occurs during the depressive phase.[13] Studies[14,15] have also indicated that attempted suicide rates are higher for bipolar disorder than for major depression and that 48% of bipolar patient attempt suicide.
Dr. Mitchell then went on to emphasize the functional impairment inherent in bipolar disorder and that functional levels appear to have an inverse correlation with the severity of the depression. He also related a study[16] that found that persistence of depressive symptoms in the first 2 years of follow-up predicted depressive symptoms 15 years later. He also indicated that bipolar depression appears to be more treatment resistant.
Course of Bipolar DepressionMauricio Tohen, MD, DrPH,[17] Lilly Clinical Research Fellow at Eli Lilly Research Laboratories, lectured on "Bipolar Depression: Course of Illness." He began by examining the lifetime prevalence of bipolar disorder in the general population.[11,15] For bipolar I disorder, the prevalence was 1.0% to 1.5% with equivalent prevalence in males and females. For bipolar II disorder, the prevalence was 0.5%, with greater prevalence in females vs males. Then there were the bipolar "spectrum" disorders, which had a rate in the population of 3.0% to 6.5%. He considered this latter group as the real challenge in diagnosis of the disorder. He related that a third of this group are misdiagnosed as having a unipolar depression.[18]
Dr. Tohen emphasized that depression is the predominant mood state in bipolar disorder. He then reviewed which factors of depression predicted bipolarity. These included psychosis, a family history of bipolar disease, a younger age of onset, pharmacologically induced hypomania/mania, atypical depressive features, psychomotor retardation, agitated depression, recurrent or chronic depression, and episodic anxiety disorder symptoms. As Dr. Mitchell did, he stressed that patients with bipolar illness spend the majority of time in a depressive phase. He also reiterated the high suicide risk of bipolar illness.
Dr. Tohen then spoke about treatment issues surrounding bipolar depression. Goals in the treatment of bipolar illness included treatment efficacy in acute depression and of depressive symptoms in mixed states, prevention of depression during treatment maintenance, low induction rates of switching to mania/hypomania or rapid cycling, few side effects, and good compliance. He discussed rates of induction of mania with the use of antidepressant medications. He stated that there were almost no studies of this with the selective serotonin reuptake inhibitor (SSRI) antidepressants. Studies do indicate a high induction rate for the tricyclic antidepressants as well as for the monoamine oxidase inhibitor antidepressants. He indicated that for placebo, the induction rate appeared to be approximately 5%. Venlafaxine had a rate of 13%, lamotrigine of 5.3%, olanzapine/fluoxetine of 6.4% and, in 1 study of SSRIs, of 3.7%.
He then asked the question: "When should antidepressant medications be discontinued in the treatment of bipolar patients?" Recent data[19] showed that recurrence rates decreased most in patients on antidepressants for a full year vs those receiving antidepressant treatment for less than 6 months or not at all. Thus, continuation of antidepressant medication did appear to be associated with a decreased depression relapse rate.
Pharmacologic Treatment AdvancesPaul E. Keck, Jr., MD,[20] Professor and Vice Chairman for Research in the Department of Psychiatry at The University of Cincinnati College of Medicine, followed with a talk entitled, "Advances in Pharmacological Treatment of Depression." He concentrated on discussing recent studies of the acute treatment of bipolar depression that were double-blind, randomized, controlled trials. He related that there were 6 of these recent studies, 3 with agents used as monotherapy and 3 as adjunctive agents.
He began by looking at monotherapy trials. First, there was a study[21] of divalproex in the treatment of bipolar depression. Here, 43 patients were randomized to receive either divalproex (n = 21) or placebo (n = 22). By the end of the study (week 8), there was not a significant difference in efficacy. Divalproex seemed to be more effective at weeks 2 and 5, but no there was no difference by the end. Then there was a study[22] looking at lamotrigine, comparing the efficacy of 50 mg/day and 200 mg/day vs placebo over a 7-week period. Here, there was a significant decrease in the Montgomery-Asberg Depression Rating Scale beginning at week 3 of lamotrigine compared with placebo, with 200 mg/day apparently more effective than 50 mg/day. Last in this group of studies was one with the combination of olanzapine and fluoxetine,[23] which showed significant efficacy in treating bipolar depression with no increase in induction to mania rates. Dr. Keck discussed the possibility of an inherent antidepressant property of atypical antidepressants that is mediated by their 5HT2 antagonism properties.
Dr. Keck then looked at the question of breakthrough depressive symptoms in patients treated for bipolar disorder. He discussed a study[24] that compared the use of 2 mood stabilizer (lithium + divalproex) vs a mood stabilizer and paroxetine. Preliminary data indicate that there is no difference in the efficacy for either treatment modality. He then examined a study[25] where imipramine, paroxetine, or placebo was added to lithium for the treatment of bipolar depression. There did not appear to be a difference between the 3 groups in terms of overall efficacy. However, significant improvement was seen in the group of patients who were taking paroxetine and lithium with a serum level of < 0.8. Switch rates to mania were greater for imipramine than for either paroxetine or placebo. The last study[26] discussed by Dr. Keck in this group was a trial of pramipexole, a dopamine agonist, as an adjunct to a mood stabilizer vs placebo add-on. The study, containing 24 subjects, resulted in a 58% response rate in the pramipexole group vs a 17% rate with placebo.
Dr. Keck then discussed recent studies addressing the prevention of recurrence of bipolar depression. He reported on a recent study[27] looking at lamotrigine vs lithium in the maintenance phase of treatment, with lamotrigine appearing to be superior to lithium in preventing depressive relapse while lithium was better in preventing manic episodes. In another recent study[28] comparing the effects of olanzapine with lithium in relapse prevention, olanzapine appeared to be superior to lithium in prevention of mania. In another study[29] with olanzapine as an adjunct to a mood stabilizer indicated superior protective abilities of the combination when compared with the use of monotherapy with a mood stabilizer. According to Dr. Keck, studies indicate that combination therapies may have a more favorable outcome in preventing episode relapse in patients with bipolar disorder.
Psychological ApproachesThe last speaker in this segment was Jan Scott, MD,[30] Professor of Psychological Treatments Research at the Institute of Psychiatry in London. She spoke about "Psychological Therapies in Bipolar Disorder." She began by discussing the magnitude of the problem, with bipolar disorder being the sixth leading cause of disability in the world. Dr. Scott summarized the targets for psychological therapies in bipolar disorder, including enhancing treatment adherence, helping patients adjust to problems of stigma, reducing substance misuse, helping with interepisodic functional impairments, dealing with loss and other life events, helping interpersonal and family problems, and treating comorbid personality and/or psychiatric disorders. She spoke about the recent increase in psychological treatment studies in bipolar disorder, with 17 randomized, controlled trials, 8 published trials with data available for pooled analysis, and 4 trials with a sample size of > 100.
In terms of symptom reduction, Dr. Scott indicated that studies have shown that depressive symptoms will be significantly reduced when psychotherapy is introduced as compared with continuing the usual treatment. Studies have also indicated that psychotherapy as part of the treatment program will enhance and restore patient functioning. In terms of relapse prevention, a number of studies have indicated positive, significant findings in this area. Different types of therapies appear to be efficacious, with the effective therapies having these shared characteristics: a coherent theoretical model, a structured approach with logical (to the patient) interventions, an emphasis on skills development with a goal towards increased patient independency, and patient change attributed to the patients themselves.
Dr. Scott then spoke about the issue of when to introduce psychotherapy into the treatment mix. She related that the data show that patient outcomes are improved when patients are either euthymic or a month past the last episode. She summarized her talk by stating that psychotherapy as an adjunct to medications can reduce symptoms, improve functioning, prevent relapse, and help patients with overall treatment compliance.
References1. Angst J. Advances in the treatment of bipolar depression. Program and abstracts of the 5th International Conference on Bipolar Disorder; June 12-14, 2003; Pittsburgh, Pennsylvania. Symposium II.
2. Mitchell P. Bipolar depression -- phenomenological overview and clinical characteristics. Program and abstracts of the 5th International Conference on Bipolar Disorder; June 12-14, 2003; Pittsburgh, Pennsylvania. Symposium II.
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15. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III--R psychiatric disorders in the United States: results from the National Comorbidity Study. Arch Gen Psychiatry. 1994;51:8-19. Abstract
16. Coryell W, Turvey C, Endicott J, et al Bipolar I affective disorder: predictors of outcome after 15 years. J Affect Disord. 1998;50:109-116. Abstract
17. Tohen M. Bipolar depression: course of illness. Program and abstracts of the 5th International Conference on Bipolar Disorder; June 12-14, 2003; Pittsburgh, Pennsylvania. Symposium II
18. Hirschfeld RM, Holzer C, Calabrese JR, et al. Validity of the Mood Disorder Questionnaire: a general population study. Am J Psychiatry. 2003;160:178-180. Abstract
19. Altshuler L, Suppes T, Black D, et al. Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up. Am J Psychiatry. 2003;160:1252-1262. Abstract
20. Keck PE. Advances in the pharmacological treatment of bipolar depression. Program and abstracts of the 5th International Conference on Bipolar Disorder; June 12-14, 2003; Pittsburgh, Pennsylvania. Symposium II.
21. Gyulai L, Bowden CL, McElroy SL, et al. Maintenance efficacy of divalproex in the prevention of bipolar depression. Neuropsychopharmacology. 2003;28:1374-1382. Abstract
22. 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. Abstract
23. Tohen M, Risser R, Baker RW, et al. Olanzapine in the treatment of bipolar depression. Program and abstracts of the American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. Abstract NR489.
24. Young LT, Joffe RT, Robb JC, MacQueen GM, Marriott M, Patelis-Siotis I. Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression. Am J Psychiatry. 2000;157:124-126. Abstract
25. 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. Abstract
26. 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. Abstract
27. Bowden CL, Calabrese JR, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60:392-400. Abstract
28. Tohen M. Olanzapine superior lithium for preventing mania relapse in bipolar disorder. Program and abstracts of the Third European Stanley Foundation Conference on Bipolar Disorder; September 12-13, 2002; Freiburg, Germany.
29. Tohen M, Risser R, Baker RW, et al. Olanzapine in the treatment of bipolar depression. Program and abstracts of the American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. Abstract NR489.
30. Scott J. What is the role for psychotherapy in bipolar disorders? Program and abstracts of the 5th International Conference on Bipolar Disorder; June 12-14, 2003; Pittsburgh, Pennsylvania. Symposium II.
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