University of Groningen. Lamotrigine in bipolar depression Loos, Marcus Lambertus Maria van der

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1 University of Groningen Lamotrigine in bipolar depression Loos, Marcus Lambertus Maria van der IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2011 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Loos, M. L. M. V. D. (2011). Lamotrigine in bipolar depression: a randomised placebo-controlled trial on the acute and long-term outcome of lamotrigine as add-on to lithium with the possibility of the addition of paroxetine Groningen: s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 13 Introduction 1

3 14 Chapter 1 Foreword Bipolar disorder (manic-depressive illness) is one of the great and maybe the most intriguing of psychiatric diseases, not only because of its high prevalence but also because of its spreading through time and cultures. The change of mood over a short time has already been described by ancient Greeks as a disturbance of the equilibrium between yellow and black bile. Where an excess of yellow bile was responsible for (hypo)manic episodes, an excess of black bile was a cause of melancholia. The term manic-depressive illness (manisch-depressieve Irresein) was introduced by Kraepelin(1) in The modern term bipolar disorder (which gives also the less severe (hypo) manic episodes a place and differentiates between unipolar and bipolar disorders) was introduced in 1957 by Leonard(2). The core characteristic of bipolar disorder is the alternation in mood between high, low and normal. Moreover, there are changes in energy, self esteem, sexual desire, need of sleep, keeping relations with other people. In the most serious forms psychosis, rage, and suicide can destroy or even end lives. In this thesis we will use the classification of bipolar disorders according to the DSM-IV(3) (table 1, page 18, 19, 20 and 21). The instability of the core characteristics of the self of patients may be one of the heaviest burdens of this disease. Who am I? An energetic, attractive, confident outgoing big spender who rules the world or the slow, gloomy, tired, suicidal bunch of misery or may be something in between? How can I rely on myself, make appointments, live together, raise children, follow a study, find and keep a job, etcetera when there is no stable Me? Questions enough for patients but also for relatives and treating physicians. There can be a great discrepancy between the goals of the physician and the patient. The main problem is the definition of stability. Whereas patients may perceive stability as plain and boring, family members and doctors may

4 Introduction 15 regard such a situation as desirable. The frequently used questionnaires to assess severity of illness such as the Montgomery-Åsberg Depression Rating Scale (MADRS)(4), the Hamilton Depression Rating Scale (HAM-D)(5), and the Young Mania Rating Scale (YMRS)(6) are all designed to measure the presence and severity (or absence) of symptoms. They don t say much about functioning of the patient or his satisfaction with life. For many patients hypomania or even mania is the most sought after situation. As one patient once stated: I prefer being secluded once in a few years as long as I don t have to take lithium and feel nothing at all. 1 In our society there is a great pressure on being enthusiastic, active, outgoing, sexual active, etcetera. In fact these characteristics can also be regarded as symptoms of hypomania. For that reason it is not so strange that drugs like cocaine and amphetamines which can bring users in a euphoric (or hypomanic ) state, are so popular. And even the depression and insomnia which come after the euphoria, are comparable with the depressive episodes which comes so often after a (hypo)manic episode. In the beginning these drugs were mostly used in the glamorous world of art, film and fashion. But also in bipolar disorder there is always a hint of romanticism and artistry. In 1993 Kay Redfield Jameson wrote Touched with fire, a book about the association of the artistic temperament with bipolar disorder. The first sentence of this book is a quote from Lord Byron: We writers are all insane. This romantic view of disease is in the medical world exclusive for psychiatric diseases; Patients suffering from addiction are viewed as bohemien, schizophrenic patients are hidden geniuses (see: A beautiful Mind (Sylvia Nasar 1998)) and last but not least bipolar patients are artists. Especially hypomanic episodes were hardly seen as part of a disease but more as the holy grail of psychiatry. A state of mind which gives way to all kinds of artistic eruptions. The other side of this high mood; the depression is a far less sexy kind of mood disorder, a prize to be paid preferentially in silence. This silence is best demonstrated with 932 hits in Pubmed for the combination of the search terms bipolar depression and randomised controlled trial versus hits for the combination depression

5 16 Chapter 1 and randomised controlled trial. In this thesis we try to add some knowledge to the treatment of the bipolar depression; an understudied but very significant medical problem. Stabilizing mood and treatment of depression Although suffering and also mortality due to suicide is high in bipolar depression, the focus of research into the treatment of bipolar disorder has until recently been mostly on the acute treatment of manic episodes (e.g. with antipsychotics) and on maintenance treatment (e.g. with lithium). The treatment of bipolar depression was hardly studied as apparently the same treatments were used as for unipolar (i.e. non-bipolar) depression: initially since the 1940ies electroconvulsive therapy (ECT) and since the 1950ies and 1960ies the antidepressants, originally the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) and later the selective serotonin reuptake inhibitors (SSRIs) and other related compounds. Only after the 1980ies there became some interest for alternatives for these treatments, especially when it became evident that the regular antidepressants might also induce a switch to (hypo)mania and an increase of episode frequency; cycle acceleration(7;8). With the introduction of lithium in the 1970ies(9) there became also interest in treatments that were effective against both poles (mania and depression) of the illness, not only to reduce the symptoms of the mood episodes (as acute treatment) but also to prevent further episodes, as long-term or maintenance treatment. For the latter purpose the quest was for a mood stabilizer. The main problem with this concept is that the term mood stabilizer has many definitions. The most stringent definition is that a true mood stabilizer demonstrates efficacy in the acute treatment of both manic and depressive episodes and prevents against further manic and depressive episodes (fig 1).

6 Introduction 17 Figure 1. What is a mood stabilizer? 1. Effective in treating acute mania Both acutely and in continuation Without causing depression 1 2. Effective in treating acute bipolar depression Both acutely and in continuation Without causing mania 3. Effective in preventing recurrence of both mania and depression (prophylaxis) (And also in rapid cycling) Figure 2. Treatments from above and from below Treat from above Mania Symptoms Normalcy Stabilize from above Stabilize from both sides Symptoms Depression Stabilize from below Treat from below

7 18 Chapter 1 The loosest definition requires efficacy in only one pole without worsening of the other pole. Although it is in our opinion justified to use a strict definition, it makes sense to differentiate between mood stabilizing from below (i.e. to diminish depression) and mood stabilizing from above (i.e. to diminish mania)(10). Until recently lithium came closest to meeting the strictest definition as a mood stabilizer. Also valproic acid/valproate and carbamazepine claimed this term but unfortunately all three compounds were considered (and partly also found) more effective in treating and preventing manic episodes than depressive episodes. As a result, bipolar depressed patients were mostly treated with antidepressants which had largely been tested only in unipolar depression. As evidence grew that the efficacy of antidepressants is limited(11;12) and that there may be the risk of induction of (hypo) mania or cycle acceleration(7;8), the treatment of bipolar depression became an unmet need: for a mood stabilizer from below without inducing a (hypo)manic episode (fig 2). Lamotrigine After some case reports in the 1990ies(13;14) it became clear that lamotrigine might be such a drug. In 1999, the first randomized, placebocontrolled trial showed efficacy of lamotrigine in the acute treatment of bipolar depression, although not on the a priori chosen primary outcome measure (the HAM-D) but only on secondary outcome measures (e.g. the MADRS) (15). However, four subsequent studies could not replicate this finding(16). At the same time two other randomized placebo-controlled trials studying the long-term effect of lamotrigine showed a preventive effect against further depressive episodes but not against manic episodes, while in the same studies lithium was found effective in the prevention of manic episodes but not of depressive episodes(17;18). This brought us to the idea to start a double-blind randomized placebocontrolled trial into the effect of lamotrigine as add-on to ongoing treatment

8 Introduction 19 with lithium in patients with a bipolar depression. During Phase I of that study lamotrigine or placebo was added to ongoing treatment with lithium for 8 weeks. After 8 weeks responders continued their combination of medication whereas paroxetine was added open label in non-responders in both groups (lithium plus lamotrigine and lithium plus placebo) (Phase II). At 16 weeks responders continued their medication regime and were followed until a new depressive or (hypo)manic relapse or until the maximum duration of the study (68 weeks) (Follow-up). 1 Outline of this thesis In chapter II we will review the pharmacological profile and the place of lamotrigine in bipolar disorder. In chapter III the results obtained during the first 8 weeks of the study (phase I) will be discussed. In chapter IV the results obtained during week 9-16 (phase II) will be discussed. In chapter V the results obtained during follow-up (until 68 weeks) of responders at week 16 will be discussed. In chapter VI the overall results of our study and more specifically the place of lamotrigine among the other options in the treatment of bipolar depression and the advantages and disadvantages of the design of our study in comparison with other long-term studies that have been performed in bipolar disorder will be discussed. Finally, some suggestions for future research will be presented.

9 20 Chapter 1 Table 1 Bipolar II Disorder-Diagnostic Features The essential feature of Bipolar II Disorder is a clinical course that is characterized by the occurrence of one or more Major Depressive Episodes accompanied by at least one Hypomanic Episode. Hypomanic Episodes should not be confused with the several days of euthymia that may follow remission of a Major Depressive Episode. Episodes of Substance- Induced Mood Disorder (due to the direct effects of a medication, or other somatic treatments for depression, a drug of abuse, or toxin exposure) or of Mood Disorder Due to a General Medical Condition do not count toward a diagnosis of Bipolar I Disorder. In addition, the episodes are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified. Criteria for Major Depressive Episode A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations. 1. depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g. appears tearful). Note: In children and adolescents, can be irritable mood. 2. markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others) 3. significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains. 4. insomnia or hypersomnia nearly every day 5. psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) 6. fatigue or loss of energy nearly every day

10 Introduction feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) 8. diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) 9. recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide 1 B. The symptoms do not meet criteria for a Mixed Episode. C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). E. The symptoms are not better accounted for by bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation. Criteria for Manic Episode A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary). B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: 1. inflated self-esteem or grandiosity 2. decreased need for sleep (e.g., feels rested after only 3 hours of sleep) 3. more talkative than usual or pressure to keep talking 4. flight of ideas or subjective experience that thoughts are racing 5. distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli)

11 22 Chapter 1 6. increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7. excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) C. The symptoms do not meet criteria for a Mixed Episode. D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. E. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatments) or a general medical condition (e.g., hyperthyroidism). Note: Manic-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of Bipolar I Disorder. Criteria for Mixed Episode A. The criteria are met both for a Manic Episode and for a Major Depressive Episode (except for duration) nearly every day during at least a 1-week period. B. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. C. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism). Criteria for Hypomanic Episode

12 Introduction 23 A. A distinct period of persistently elevated, expansive, or irritable mood, lasting throughout at least 4 days, that is clearly different from the usual nondepressed mood. B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: 1. inflated self-esteem or grandiosity 2. decreased need for sleep (e.g., feels rested after only 3 hours of sleep) 3. more talkative than usual or pressure to keep talking 4. flight of ideas or subjective experience that thoughts are racing 5. distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli) 6. increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7. excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) 1 C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic. D. The disturbance in mood and the change in functioning are observable by others. E. The episode is not severe enough to cause marked impairment in social or occupational functioning, or to necessitate hospitalization, and there are no psychotic features. F. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism). Note: Hypomanic-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of Bipolar II Disorder.

13 24 Chapter 1 References 1. E.Kraepelin. Psychiatrie. Ein Lehrbuch fur Studirendeund Aerzte. II Band Sechste Auflage. Leipzig, Verlag von Johann Ambrosius Barth K.Leonhard. Aufteilung der Endogenen Psychosen. Berlin, Academie Verlag American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Washington DC, American Psychiatric Press Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979 Apr;134: HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960 Feb;23: Young RC, Nysewander RW, Schreiber MT. Mania scale scores, signs, and symptoms in forty inpatients. J Clin Psychiatry 1983 Mar;44(3): Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 1995 Aug;152(8): Licht RW, Gijsman H, Nolen WA, Angst J. 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 Nov;118(5): SCHOU M, JUEL-NIELSEN N, STROMGREN E, VOLDBY H. The treatment of manic psychoses by the administration of lithium salts. J Neurol Neurosurg Psychiatry 1954 Nov;17(4): Ketter TA, Calabrese JR. Stabilization of mood from below versus above baseline in bipolar disorder: a new nomenclature. J Clin Psychiatry 2002 Feb;63(2): Ghaemi SN, Wingo AP, Filkowski MA, Baldessarini RJ. Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks. Acta Psychiatr Scand 2008 Aug 24.

14 Introduction Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 2007 Apr 26;356(17): Smith D, Baker G, Davies G, Dewey M, Chadwick DW. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia 1993 Mar;34(2): Calabrese JR, Fatemi SH, Woyshville MJ. Antidepressant effects of lamotrigine in rapid cycling bipolar disorder. Am J Psychiatry 1996 Sep;153(9): Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A doubleblind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry 1999 Feb;60(2): Calabrese JR, Huffman RF, White RL, Edwards S, Thompson TR, Ascher JA, et al. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord 2008 Mar;10(2): Calabrese JR, Bowden CL, Sachs G, Yatham LN, Behnke K, Mehtonen OP, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 2003Sep;64(9): Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, 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 Apr;60(4):

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