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DOI: 10.1055/s-0028-1109324
© Georg Thieme Verlag KG Stuttgart · New York
Pharmakologische Kombinationsbehandlung bipolarer Störungen
Psychopharmacological Combination Therapy in Bipolar DisorderPublication History
Publication Date:
05 May 2009 (online)

Zusammenfassung
Die Behandlung der bipolaren Störung hat in den letzten Jahren einen Wandel erfahren: Bei leichten Verläufen von manischen und depressiven Episoden sind immer noch monotherapeutische Ansätze zielführend, wobei zunehmend häufiger neben den „klassischen” Medikamenten wie Lithium, Valproinsäure und Carbamazepin auch atypische Antipsychotika (AAP) eingesetzt werden. Für die Therapie der manischen Episode sind derzeit die meisten verfügbaren AAP zugelassen, und auch für die Rückfallprophylaxe und die Behandlung der depressiven Episode existieren bereits Zulassungen. Bei mittelschweren und schweren depressiven oder manischen Episoden werden zunehmend Kombinationen eingesetzt, da sie in der Regel schneller wirken und teilweise auch besser verträglich sind. In einer Vielzahl von Studien konnte die Überlegenheit der Kombinationsbehandlung im Gegensatz zu verschiedenen, etablierten Monotherapien gezeigt werden. Dieser Übersichtsartikel fasst die vorhandenen Studien und Ergebnisse mit Fokus auf die Kombinationsbehandlung zusammen, um aktuelle medikamentöse Therapieempfehlungen für eine effektive Behandlung der bipolaren Störung zu geben.
Abstract
In the course of time, the treatment regime of bipolar disorder has changed: in mild cases of manic and depressive episodes, monotherapeutic approaches are still commonly used. Besides the use of the common agents like lithium, valproatic acid and carbamazepine, other agents such as atypical antipsychotics (AAP) are used more frequently. For the therapy of manic episodes, most of the usual AAP are approved; some of them are or will be approved in the near future even for the continuation therapy and for depressive episodes. For moderate and severe courses of depressive or manic episodes, combination therapy strategies are used more often. Combination strategies seem to be more effective than monotherapeutic treatments, because of faster effects and better tolerance. In a lot of studies, these positive effects and advantages in contrast to monotherapeutic treatments could be proven. In this review article, studies and results with the focus on combination therapy will be summarised to recommend the ”state-of-the-art”-treatment for bipolar disorder.
Schlüsselwörter
bipolare Störung - Kombinationsbehandlung - Pharmakotherapie - Antipsychotika - Stimmungsstabilisierer
Key words
bipolar disorder - combination therapy - pharmacotherapy - antipsychotics - mood stabilizer
Literatur
- 1
Severus W E, Watzke S, Brieger P.
Bipolar affective disorders. Part II: Genetics, cognitions and therapy.
Fortschr Neurol Psychiatr.
2008;
76
294-304
Reference Ris Wihthout Link
- 2
Brieger P.
Bipolar affective disorders. Part I: diagnosis, epidemiology and course.
Fortschr Neurol Psychiatr.
2007;
75
673-682
Reference Ris Wihthout Link
- 3
Fountoulakis K N, Vieta E, Siamouli M. et al .
Treatment of bipolar disorder: a complex treatment for a multi-faceted disorder.
Ann Gen Psychiatry.
2007;
6
27
Reference Ris Wihthout Link
- 4
Yatham L N, Kennedy S H, O’Donovan C. et al .
Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management
of patients with bipolar disorder: consensus and controversies.
Bipolar Disord.
2005;
7 (Suppl 3)
5-69
Reference Ris Wihthout Link
- 5
O’Dowd A.
NICE issues new guidance to improve the treatment of bipolar disorder.
BMJ.
2006;
333
220
Reference Ris Wihthout Link
- 6
American Psychiatric Association.
Practice guideline for the treatment of patients with bipolar disorder (revision).
Am J Psychiatry.
2002;
159
1-50
Reference Ris Wihthout Link
- 7
Muller-Oerlinghausen B, Ahrens B, Grof E. et al .
The effect of long-term lithium treatment on the mortality of patients with manic-depressive
and schizoaffective illness.
Acta Psychiatr Scand.
1992;
86
218-222
Reference Ris Wihthout Link
- 8
Schou M.
Relapse prevention in manic depressive illness: important and unimportant factors.
Can J Psychiatry.
1991;
36
502-506
Reference Ris Wihthout Link
- 9
Roy-Byrne P P, Post R M, Hambrick D D. et al .
Suicide and course of illness in major affective disorder.
J Affect Disord.
1988;
15
1-8
Reference Ris Wihthout Link
- 10
Sussman N, Mullen J, Paulsson B. et al .
Rates of remission/euthymia with quetiapine in combination with lithium/divalproex
for the treatment of acute mania.
J Affect Disord.
2007;
100 (Suppl 1)
S55-S63
Reference Ris Wihthout Link
- 11
Zarate C A, Quiroz J A.
Combination treatment in bipolar disorder: a review of controlled trials.
Bipolar Disord.
2003;
5
217-225
Reference Ris Wihthout Link
- 12
Miller D S, Yatham L N, Lam R W.
Comparative efficacy of typical and atypical antipsychotics as add-on therapy to mood
stabilizers in the treatment of acute mania.
J Clin Psychiatry.
2001;
62
975-980
Reference Ris Wihthout Link
- 13
Perlis R H.
Treatment of bipolar disorder: the evolving role of atypical antipsychotics.
Am J Manag Care.
2007;
13
S178-S188
Reference Ris Wihthout Link
- 14
Perlis R H, Welge J A, Vornik L A. et al .
Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized,
placebo-controlled trials.
J Clin Psychiatry.
2006;
67
509-516
Reference Ris Wihthout Link
- 15
Leverich G S, Altshuler L L, Frye M A. et al .
Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression
during acute and continuation trials of venlafaxine, sertraline, and bupropion as
adjuncts to mood stabilizers.
Am J Psychiatry.
2006;
163
232-239
Reference Ris Wihthout Link
- 16
Young L T, Joffe R T, Robb J C. et al .
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
Reference Ris Wihthout Link
- 17
Prien R F, Kupfer D J, Mansky P A. et al .
Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders.
Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine,
and a lithium carbonate-imipramine combination.
Arch Gen Psychiatry.
1984;
41
1096-1104
Reference Ris Wihthout Link
- 18
Prien R F.
NIMH report. Five-center study clarifies use of lithium, imipramine for recurrent
affective disorders.
Hosp Community Psychiatry.
1984;
35
1097-1098
Reference Ris Wihthout Link
- 19
Sachs G S, Nierenberg A A, Calabrese J R. et al .
Effectiveness of adjunctive antidepressant treatment for bipolar depression.
N Engl J Med.
2007;
356
1711-1722
Reference Ris Wihthout Link
- 20
Merkl Jr A, Regen F, Schindler F. et al .
Mixed episodes in bipolar disorder: a review.
Fortschr Neurol Psychiatr.
2007;
75
323-330
Reference Ris Wihthout Link
- 21
Grunze H, Kasper S, Goodwin G. et al .
World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological
treatment of bipolar disorders. Part I: Treatment of bipolar depression.
World J Biol Psychiatry.
2002;
3
115-124
Reference Ris Wihthout Link
- 22
Post R M, Leverich G S, Altshuler L. et al .
Lithium-discontinuation-induced refractoriness: preliminary observations.
Am J Psychiatry.
1992;
149
1727-1729
Reference Ris Wihthout Link
- 23
Smith L A, Cornelius V, Warnock A. et al .
Effectiveness of mood stabilizers and antipsychotics in the maintenance phase of bipolar
disorder: a systematic review of randomized controlled trials.
Bipolar Disord.
2007;
9
394-412
Reference Ris Wihthout Link
- 24
Calabrese J R, Rapport D J.
Mood stabilizers and the evolution of maintenance study designs in bipolar I disorder.
J Clin Psychiatry.
1999;
60 (Suppl 5)
5-13
Reference Ris Wihthout Link
- 25
Bowden C L, Calabrese J R, McElroy S L. et al .
A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment
of outpatients with bipolar I disorder. Divalproex Maintenance Study Group.
Arch Gen Psychiatry.
2000;
57
481-489
Reference Ris Wihthout Link
- 26
Freeman T W, Clothier J L, Pazzaglia P. et al .
A double-blind comparison of valproate and lithium in the treatment of acute mania.
Am J Psychiatry.
1992;
149
108-111
Reference Ris Wihthout Link
- 27
Calabrese J R, Rapport D J, Kimmel S E. et al .
Rapid cycling bipolar disorder and its treatment with valproate.
Can J Psychiatry.
1993;
38
S57-S61
Reference Ris Wihthout Link
- 28
Davis L L, Bartolucci A, Petty F.
Divalproex in the treatment of bipolar depression: a placebo-controlled study.
J Affect Disord.
2005;
85
259-266
Reference Ris Wihthout Link
- 29
Gyulai L, Bowden C L, McElroy S L. et al .
Maintenance efficacy of divalproex in the prevention of bipolar depression.
Neuropsychopharmacology.
2003;
28
1374-1382
Reference Ris Wihthout Link
- 30
Owen R T.
Extended-release carbamazepine for acute bipolar mania: a review.
Drugs Today.
2006;
42
283-289
Reference Ris Wihthout Link
- 31
Hartong E G, Moleman P, Hoogduin C A. et al .
Prophylactic efficacy of lithium versus carbamazepine in treatment-naive bipolar patients.
J Clin Psychiatry.
2003;
64
144-151
Reference Ris Wihthout Link
- 32
Bowden C L, Calabrese J R, 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
Reference Ris Wihthout Link
- 33
Brown E B, McElroy S L, Keck P E. et al .
A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus
lamotrigine in the treatment of bipolar I depression.
J Clin Psychiatry.
2006;
67
1025-1033
Reference Ris Wihthout Link
- 34
Calabrese J R, Goldberg J F, Ketter T A. et al .
Recurrence in bipolar I disorder: a post hoc analysis excluding relapses in two double-blind
maintenance studies.
Biol Psychiatry.
2006;
59
1061-1064
Reference Ris Wihthout Link
- 35
Calabrese J R, Bowden C L, Sachs G S. 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
Reference Ris Wihthout Link
- 36
Kushner S F, Khan Jr A, Lane R. et al .
Topiramate monotherapy in the management of acute mania: results of four double-blind
placebo-controlled trials.
Bipolar Disord.
2006;
8
15-27
Reference Ris Wihthout Link
- 37
Vieta E, Manuel G J, Martinez-Aran A. et al .
A double-blind, randomized, placebo-controlled, prophylaxis study of adjunctive gabapentin
for bipolar disorder.
J Clin Psychiatry.
2006;
67
473-477
Reference Ris Wihthout Link
- 38
Smith L A, Cornelius V, Warnock A. et al .
Pharmacological interventions for acute bipolar mania: a systematic review of randomized
placebo-controlled trials.
Bipolar Disord.
2007;
9
551-560
Reference Ris Wihthout Link
- 39
Rendell J M, Gijsman H J, Bauer M S. et al .
Risperidone alone or in combination for acute mania.
Cochrane Database Syst Rev.
2006;
CD004043
Reference Ris Wihthout Link
- 40
Gopal S, Steffens D C, Kramer M L. et al .
Symptomatic remission in patients with bipolar mania: results from a double-blind,
placebo-controlled trial of risperidone monotherapy.
J Clin Psychiatry.
2005;
66
1016-1020
Reference Ris Wihthout Link
- 41
Tohen M, Jacobs T G, Grundy S L. et al .
Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled
study. The Olanzapine HGGW Study Group.
Arch Gen Psychiatry.
2000;
57
841-849
Reference Ris Wihthout Link
- 42
Tohen M, Greil W, Calabrese J R. et al .
Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month,
randomized, double-blind, controlled clinical trial.
Am J Psychiatry.
2005;
162
1281-1290
Reference Ris Wihthout Link
- 43
Bowden C L, Grunze H, Mullen J. et al .
A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine
or lithium as monotherapy for mania in bipolar disorder.
J Clin Psychiatry.
2005;
66
111-121
Reference Ris Wihthout Link
- 44
Cookson J, Keck P E, Ketter T A. et al .
Number needed to treat and time to response/remission for quetiapine monotherapy efficacy
in acute bipolar depression: evidence from a large, randomized, placebo-controlled
study.
Int Clin Psychopharmacol.
2007;
22
93-100
Reference Ris Wihthout Link
- 45
Weisler R H, Calabrese J R, Thase M E. et al .
Efficacy of Quetiapine Monotherapy for the Treatment of Depressive Episodes in Bipolar
I Disorder: A Post Hoc Analysis of Combined Results From 2 Double-Blind, Randomized,
Placebo-Controlled Studies.
J Clin Psychiatry.
2008;
69
769-782
Reference Ris Wihthout Link
- 46
Altamura A C, Salvadori Jr D, Madaro D. et al .
Efficacy and tolerability of quetiapine in the treatment of bipolar disorder: preliminary
evidence from a 12-month open-label study.
J Affect Disord.
2003;
76
267-271
Reference Ris Wihthout Link
- 47
Keck P E, Marcus Jr R, Tourkodimitris S. et al .
A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole
in patients with acute bipolar mania.
Am J Psychiatry.
2003;
160
1651-1658
Reference Ris Wihthout Link
- 48
Keck P E, Calabrese J R, McQuade R D. et al .
A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently
manic patients with bipolar I disorder.
J Clin Psychiatry.
2006;
67
626-637
Reference Ris Wihthout Link
- 49
Keck Jr P E, Calabrese J R, McIntyre R S. et al .
Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100-week,
double-blind study versus placebo.
J Clin Psychiatry.
2007;
68
1480-1491
Reference Ris Wihthout Link
- 50
Thase M E, Jonas Jr A, Khan A. et al .
Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized,
placebo-controlled studies.
J Clin Psychopharmacol.
2008;
28
13-20
Reference Ris Wihthout Link
- 51
Keck P E, Versiani Jr M, Potkin S. et al .
Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled,
double-blind, randomized trial.
Am J Psychiatry.
2003;
160
741-748
Reference Ris Wihthout Link
- 52
Potkin S G, Keck P E, Segal Jr S. et al .
Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled
replication trial.
J Clin Psychopharmacol.
2005;
25
301-310
Reference Ris Wihthout Link
- 53
Versiani M.
Ziprasidone in bipolar disorder.
Expert Opin Pharmacother.
2006;
7
1221-1228
Reference Ris Wihthout Link
- 54
Pande A C, Crockatt J G, Janney C A. et al .
Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy.
Gabapentin Bipolar Disorder Study Group.
Bipolar Disord.
2000;
2
249-255
Reference Ris Wihthout Link
- 55
Muller-Oerlinghausen B, Retzow A, Henn F A. et al .
Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes
of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter
study. European Valproate Mania Study Group.
J Clin Psychopharmacol.
2000;
20
195-203
Reference Ris Wihthout Link
- 56
Tohen M, Chengappa K N, Suppes T. et al .
Efficacy of olanzapine in combination with valproate or lithium in the treatment of
mania in patients partially nonresponsive to valproate or lithium monotherapy.
Arch Gen Psychiatry.
2002;
59
62-69
Reference Ris Wihthout Link
- 57
Sachs G S, Grossman F, Ghaemi S N. et al .
Combination of a mood stabilizer with risperidone or haloperidol for treatment of
acute mania: a double-blind, placebo-controlled comparison of efficacy and safety.
Am J Psychiatry.
2002;
159
1146-1154
Reference Ris Wihthout Link
- 58
Yatham L N, Grossman F, Augustyns I. et al .
Mood stabilisers plus risperidone or placebo in the treatment of acute mania. International,
double-blind, randomised controlled trial.
Br J Psychiatry.
2003;
182
141-147
Reference Ris Wihthout Link
- 59
Vieta E, Herraiz M, Parramon G. et al .
Risperidone in the treatment of mania: efficacy and safety results from a large, multicentre,
open study in Spain.
J Affect Disord.
2002;
72
15-19
Reference Ris Wihthout Link
- 60
Vieta E, T’joen C, McQuade R D. et al .
Efficacy of Adjunctive Aripiprazole to Either Valproate or Lithium in Bipolar Mania
Patients Partially Nonresponsive to Valproate/Lithium Monotherapy: A Placebo-Controlled
Study.
Am J Psychiatry.
2008;
165
1316-1325
Reference Ris Wihthout Link
- 61
Sajatovic M, Brescan D W, Perez D E. et al .
Quetiapine alone and added to a mood stabilizer for serious mood disorders.
J Clin Psychiatry.
2001;
62
728-732
Reference Ris Wihthout Link
- 62
Delbello M P, Kowatch R A, Adler C M. et al .
A double-blind randomized pilot study comparing quetiapine and divalproex for adolescent
mania.
J Am Acad Child Adolesc Psychiatry.
2006;
45
305-313
Reference Ris Wihthout Link
- 63
Sachs G, Chengappa K N, Suppes T. et al .
Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized,
double-blind, placebo-controlled study.
Bipolar Disord.
2004;
6
213-223
Reference Ris Wihthout Link
- 64
Yatham L N, Paulsson B, Mullen J. et al .
Quetiapine versus placebo in combination with lithium or divalproex for the treatment
of bipolar mania.
J Clin Psychopharmacol.
2004;
24
599-606
Reference Ris Wihthout Link
- 65
Yatham L N, Vieta E, Young A H. et al .
A double blind, randomized, placebo-controlled trial of quetiapine as an add-on therapy
to lithium or divalproex for the treatment of bipolar mania.
Int Clin Psychopharmacol.
2007;
22
212-220
Reference Ris Wihthout Link
- 66
Vieta E, Panicali F, Goetz I. et al .
Olanzapine monotherapy and olanzapine combination therapy in the treatment of mania:
12-week results from the European Mania in Bipolar Longitudinal Evaluation of Medication
(EMBLEM) observational study.
J Affect Disord.
2008;
106
63-72
Reference Ris Wihthout Link
- 67
Wehr T A, Goodwin F K.
Rapid cycling in manic-depressives induced by tricyclic antidepressants.
Arch Gen Psychiatry.
1979;
36
555-559
Reference Ris Wihthout Link
- 68
Quitkin F M, Kane J, Rifkin A. et al .
Prophylactic lithium carbonate with and without imipramine for bipolar 1 patients.
A double-blind study.
Arch Gen Psychiatry.
1981;
38
902-907
Reference Ris Wihthout Link
- 69
Denicoff K D, Smith-Jackson E E, Disney E R. et al .
Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in
bipolar disorder.
J Clin Psychiatry.
1997;
58
470-478
Reference Ris Wihthout Link
- 70
Solomon D A, Ryan C E, Keitner G I. et al .
A pilot study of lithium carbonate plus divalproex sodium for the continuation and
maintenance treatment of patients with bipolar I disorder.
J Clin Psychiatry.
1997;
58
95-99
Reference Ris Wihthout Link
- 71
Denicoff K D, Smith-Jackson E E, Bryan A L. et al .
Valproate prophylaxis in a prospective clinical trial of refractory bipolar disorder.
Am J Psychiatry.
1997;
154
1456-1458
Reference Ris Wihthout Link
- 72
Tohen M, Chengappa K N, Suppes T. et al .
Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood
stabiliser v. mood stabiliser alone.
Br J Psychiatry.
2004;
184
337-345
Reference Ris Wihthout Link
- 73
Vieta E, Goikolea J M, Corbella B. et al .
Risperidone safety and efficacy in the treatment of bipolar and schizoaffective disorders:
results from a 6-month, multicenter, open study.
J Clin Psychiatry.
2001;
62
818-825
Reference Ris Wihthout Link
- 74
Yatham L N, Binder C, Riccardelli R. et al .
Risperidone in acute and continuation treatment of mania.
Int Clin Psychopharmacol.
2003;
18
227-235
Reference Ris Wihthout Link
- 75
Vieta E, Suppes T, Eggens I. et al .
Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance
of patients with bipolar I disorder (international trial 126).
J Affect Disord.
2008;
109
251-263
Reference Ris Wihthout Link
- 76
Altamura A C, Mundo E, Dell’Osso B. et al .
Quetiapine and classical mood stabilizers in the long-term treatment of Bipolar Disorder:
A 4-year follow-up naturalistic study.
J Affect Disord.
2008;
110
135-141
Reference Ris Wihthout Link
- 77
Sachs G S, Lafer B, Stoll A L. et al .
A double-blind trial of bupropion versus desipramine for bipolar depression.
J Clin Psychiatry.
1994;
55
391-393
Reference Ris Wihthout Link
- 78
Nemeroff C B, Evans D L, 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
Reference Ris Wihthout Link
- 79
Young L T, Joffe R T, Robb J C. et al .
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
Reference Ris Wihthout Link
- 80
Vieta E, Martinez-Aran A, Goikolea J M. et al .
A randomized trial comparing paroxetine and venlafaxine in the treatment of bipolar
depressed patients taking mood stabilizers.
J Clin Psychiatry.
2002;
63
508-512
Reference Ris Wihthout Link
- 81
Tohen M, Vieta E, Calabrese J. et al .
Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar
I depression.
Arch Gen Psychiatry.
2003;
60
1079-1088
Reference Ris Wihthout Link
Dr. med. Arnim Quante
Klinik und Hochschulambulanz für Psychiatrie und Psychotherapie, Charité – Campus
Benjamin Franklin
Eschenallee 3
14050 Berlin
Email: arnim.quante@charite.de