Klinischer Stellenwert der Valproat-Therapie bei bipolaren Störungen

Zusammenfassung

In den letzten Jahren hat sich Valproat weltweit als ein Eckpfeiler der medikamentösen Therapie bipolarer Störungen etabliert. Die arzneimittelrechtliche Zulassung sowohl für die Maniebehandlung als auch die Langzeitprophylaxe erfolgte in Deutschland im Sommer 2005. Vor diesem Hintergrund stellt die vorliegende Übersichtsarbeit kompakt wissenschaftliche Evidenzlage und klinische Erfahrung namhafter Experten mit der Valproat-Therapie zusammen. Als Fazit ergab sich dabei, dass Valproat trotz der Zunahme der Therapiealternativen in jüngster Zeit weiterhin einen hohen klinischen Stellenwert genießen wird, sowohl in der Monotherapie als auch der Kombinationstherapie der akuten Manie, der Mischzustände sowie der Langzeitprophylaxe.

Abstract

During recent years valproate has been established as a cornerstone for the drug-treatment of bipolar disorder. In Germany, valproate was licensed both for the treatment of acute mania and for maintenance treatment in summer 2005. At this occasion, this review summarises the scientific evidence and clinical experience of well-known experts with valproate-treatment. It was concluded that valproate will continue to be of high clinical significance despite the recent increase of treatment alternatives, both in monotherapy and combination treatment of acute mania, mixed states and maintenance treatment.

Bipolare Störung - Manie-Depression - Valproat

bipolar disorder - mania-depression - valproate

Literatur

• 1 Emrich H M, Zerssen D von, Kissling W, Möller H-J, Windorfer A. Effect of sodium valproate on mania. The GABA-hypothesis of affective disorders.  Arch Psychiatr Nervenkr. 1980;  229 1-16
• 2 Grunze H, Walden J. Valproat bei manisch-depressiven (bipolaren) Erkrankungen. 2 ed. Stuttgart: Thieme Verlag 2004
• 3 Grunze H, Forsthoff A, Born C. Polypharmazie in der Behandlung bipolarer Störungen. In: Messer T, Schmauss M (Hrsg). Polypharmazie in der Behandlung psychischer Erkrankungen. Wien-New York: Springer 2005: 81-102
• 4 Perlis R H, Perlis C S, Wu Y, Hwang C, Joseph M, Nierenberg A A. Industry sponsorship and financial conflict of interest in the reporting of clinical trials in psychiatry.  Am J Psychiatry. 2005;  162 1957-1960
• 5 Heres S, Davis J, Maino K, Jetzinger E, Kissling W, Leucht S. Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics.  Am J Psychiatry. 2006;  163 185-194
• 6 Procyshyn R M, Chau A, Fortin P, Jenkins W. Prevalence and outcomes of pharmaceutical industry-sponsored clinical trials involving clozapine, risperidone, or olanzapine.  Can J Psychiatry. 2004;  49 601-606
• 7 Montgomery J H, Byerly M, Carmody T, Li B, Miller D R, Varghese F. et al . An analysis of the effect of funding source in randomized clinical trials of second generation antipsychotics for the treatment of schizophrenia.  Control Clin Trials. 2004;  25 598-612
• 8 Tohen M, Baker R W, Altshuler L L, Zarate C A, Suppes T, Ketter T A. et al . Olanzapine versus divalproex in the treatment of acute mania.  Am J Psychiatry. 2002;  159 1011-1017
• 9 Zajecka J M, Weisler R, Sachs G, Swann A C, Wozniak P, Sommerville K W. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder.  J Clin Psychiatry. 2002;  63 1148-1155
• 10 Lexchin J, Light D W. Commercial influence and the content of medical journals.  BMJ. 2006;  332 1444-1447
• 11 Bowden C L, Calabrese J R, McElroy S L, Gyulai L, Wassef A, Petty F. 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
• 12 Grunze H. Valproat-Fokus auf die Behandlung bipolarer affektiver Störungen. Eine aktuelle Studienübersicht. Psychopharmakotherapie In press
• 13 Bowden C, Gogus A, Grunze H, Haggstrom L, Rybakowski J, Vieta E. A twelve-week open, randomized trial comparing sodium valproate to lithium in subjects with Bipolar I disorder suffering from a manic episode. Br J Psychiatry In press
• 14 McElroy S L, Keck P E, Stanton S P, Tugrul K C, Bennett J A, Strakowski S M. A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania.  J Clin Psychiatry. 1996;  57 142-146
• 15 Freeman T W, Clothier J L, Pazzaglia P, Lesem M D, Swann A C. A double-blind comparison of valproate and lithium in the treatment of acute mania.  Am J Psychiatry. 1992;  149 108-111
• 16 Bowden C L, Brugger A M, Swann A C, Calabrese J R, Janicak P G, Petty F. et al . Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group.  JAMA. 1994;  271 918-924
• 17 Revicki D A, Hirschfeld R M, Ahearn E P, Weisler R H, Palmer C, Keck Jr P E. Effectiveness and medical costs of divalproex versus lithium in the treatment of bipolar disorder: results of a naturalistic clinical trial.  J Affect Disord. 2005;  86 183-193
• 18 Vasudev K, Goswami U, Kohli K. Carbamazepine and valproate monotherapy: feasibility, relative safety and efficacy, and therapeutic drug monitoring in manic disorder.  Psychopharmacology Berl. 2000;  150 15-23
• 19 Kowatch R A, Suppes T, Carmody T J, Bucci J P, Hume J H, Kromelis M. et al . Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder.  J Am Acad Child Adolesc Psychiatry. 2000;  39 713-720
• 20 Frye M A, Altshuler L L, Szuba M P, Finch N N, Mintz J. The relationship between antimanic agent for treatment of classic or dysphoric mania and length of hospital stay.  J Clin Psychiatry. 1996;  57 17-21
• 21 Keck P E, McElroy S L, Tugrul K C, Bennett J A. Valproate oral loading in the treatment of acute mania.  J Clin Psychiatry. 1993;  54 305-308
• 22 Hirschfeld R M, Baker J D, Wozniak P, Tracy K, Sommerville K W. The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder.  J Clin Psychiatry. 2003;  64 841-846
• 23 Oluboka O J, Bird D C, Kutcher S, Kusumakar V. A pilot study of loading versus titration of valproate in the treatment of acute mania.  Bipolar Disord. 2002;  4 341-345
• 24 Allen M H, Hirschfeld R M, Wozniak P J, Baker J D, Bowden C L. Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania.  Am J Psychiatry. 2006;  163 272-275
• 25 Grunze H, Amann B, Schäfer M, Sterr A, Schaerer L, Wild E. et al . Wirksamkeit, Verträglichkeit und Praktikabilität von Valproat- Miniretardtabletten bei bipolaren affektiven Störungen.  Fortschr Neurol Psychiatr. 2000;  68 496-502
• 26 Wangemann M, Retzow A, Mazur D, Vens-Cappell B. Study on the dose proportionality of the pharmacokinetics of sustained release sodium valproate.  Int J Clin Pharmacol Ther. 2000;  38 395-401
• 27 Miller B P, Perry W, Moutier C Y, Robinson S K, Feifel D. Rapid oral loading of extended release divalproex in patients with acute mania.  Gen Hosp Psychiatry. 2005;  27 218-221
• 28 Grunze H, Erfurth A, Amann B, Giupponi G, Kammerer C, Walden J. Intravenous valproate loading in acutely manic and depressed bipolar I patients.  J Clin Psychopharmacol. 1999;  19 303-309
• 29 Norton J W, Quarles E. Intravenous valproate in neuropsychiatry.  Pharmacotherapy. 2000;  20 88-92
• 30 Jagadheesan K, Duggal H S, Gupta S C, Basu S, Ranjan S, Sandil R. et al . Acute antimanic efficacy and safety of intravenous valproate loading therapy: an open-label study.  Neuropsychobiology. 2003;  47 90-93
• 31 Severus E, Grunze H. Bipolare Mischzustände-diagnostische und therapeutische Herausforderung.  PPT. 2003;  10 87-93
• 32 World Health Organization .The ICD-10 Classification of Mental and behavioural Disorders. Clinical Descriptions and Diagnostic Guidelines. Geneva: WHO 1992
• 33 American Psychiatric Association .Diagnostisches und statistisches Manual psychischer Störungen DSM-IV. Göttingen, Bern, Toronto, Seattle: Hogrefe 1996
• 34 Calabrese J R, Woyshville M J, Kimmel S E, Rapport D J. Predictors of valproate response in bipolar rapid cycling.  J Clin Psychiatry. 1993;  13 280-283
• 35 Chen S T, Altshuler L L, Melnyk K A, Erhart S M, Miller E, Mintz J. Efficacy of lithium vs. valproate in the treatment of mania in the elderly: a retrospective study.  J Clin Psychiatry. 1999;  60 181-186
• 36 Swann A C, Bowden C L, Morris D, Calabrese J R, Petty F, Small J. et al . Depression during mania. Treatment response to lithium or divalproex.  Arch Gen Psychiatry. 1997;  54 37-42
• 37 Vieta E. The treatment of mixed states and the risk of switching to depression.  Eur Psychiatry. 2005;  20 96-100
• 38 Swann A C, Bowden C L, Calabrese J R, Dilsaver S C, Morris D D. Mania: differential effects of previous depressive and manic episodes on response to treatment.  Acta Psychiatr Scand. 2000;  101 444-451
• 39 Sachs G, Collins M A, Altshuler L, Ketter T, Suppes T, Rasgon N. et al .Divalproex sodium versus placebo for the treatment of bipolar depression. APA 2002 Syllabus & Proceedings Summary 2002
• 40 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
• 41 Lambert P A. Acute and prophylactic therapies of patients with affective disorders using valpromide (dipropylacetamide). In: Emrich HM, Okuma T, Müller AA (Hrsg). Anticonvulsants in affective disorders. Amsterdam, Oxford, Princeton: Elsevier Science Publishers 1984: 33-44
• 42 Tohen M, Bowden C, Calabrese J, Lin D, Forrester T D, Sachs G S. et al .Factors Associated With Increased Time With Subsyndromal Symptoms in Bipolar Patients After Remission From a Manic or Mixed Episode. Br J Psychiatry In press
• 43 Tohen M, Zarate C A, Hennen J, Khalsa H M, Strakowski S M, Gebre-Medhin P. et al . The McLean-Harvard First-Episode Mania Study: prediction of recovery and first recurrence.  Am J Psychiatry. 2003;  160 2099-2107
• 44 Bromet E J, Finch S J, Carlson G A, Fochtmann L, Mojtabai R, Craig T J. et al . Time to remission and relapse after the first hospital admission in severe bipolar disorder.  Soc Psychiatry Psychiatr Epidemiol. 2005;  40 106-113
• 45 Bowden C L, Swann A C, Calabrese J R, McElroy S L, Morris D, Petty F. et al . Maintenance clinical trials in bipolar disorder: design implications of the divalproex-lithium-placebo study.  Psychopharmacol Bull. 1997;  33 693-699
• 46 Sachs G S, Printz D J, Kahn D A, Carpenter D, Docherty J P. The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000.  Postgrad Med Spec Report. 2000;  1-104
• 47 Post R M, Leverich G S, Altshuler L L, Frye M A, Suppes T M, Keck P E. et al . An overview of recent findings of the Stanley Foundation Bipolar Network (Part I).  Bipolar Disord. 2003;  5 310-319
• 48 Coryell W, Endicott J, Keller M. Rapidly cycling affective disorder. Demographics, diagnosis, family history, and course.  Arch Gen Psychiatry. 1992;  49 126-131
• 49 Alarcon R D. Rapid cycling affective disorders: a clinical review.  Compr Psychiatry. 1985;  26 522-540
• 50 Kupka R W, Nolen W A, Altshuler L L, Denicoff K D, Frye M A, Leverich G S. et al . The Stanley Foundation Bipolar Network: 2. Preliminary summary of demographics, course of illness and response to novel treatments.  Br J Psychiatry. 2001;  178 S177-S183
• 51 Coryell W, Solomon D, Turvey C, Keller M, Leon A C, Endicott J. et al . The long-term course of rapid-cycling bipolar disorder.  Arch Gen Psychiatry. 2003;  60 914-920
• 52 Calabrese J R, Rapport D J, Youngstrom E A, Jackson K, Bilali S, Findling R L. New data on the use of lithium, divalproate, and lamotrigine in rapid cycling bipolar disorder.  Eur Psychiatry. 2005;  20 92-95
• 53 Akiskal H, Bourgeois M L, Angst J, Post R, Möller H-J, Hirschfeld R M. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders.  J Affect Disord. 2000;  59 Suppl 1 5-30
• 54 Judd L L, Akiskal H S, Schettler P J, Coryell W, Endicott J, Maser J D. et al . A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder.  Arch Gen Psychiatry. 2003;  60 261-269
• 55 Rihmer Z, Pestality P. Bipolar II disorder and suicidal behavior.  Psychiatr Clin North Am. 1999;  22 667-673
• 56 Hadjipavlou G, Mok H, Yatham L N. Pharmacotherapy of bipolar II disorder: a critical review of current evidence.  Bipolar Disord. 2004;  6 14-25
• 57 Winsberg M E, DeGolia S G, Strong C M, Ketter T A. Divalproex therapy in medication-naive and mood-stabilizer-naive bipolar II depression.  J Affect Disord. 2001;  67 207-212
• 58 Scheffer R E, Kowatch R A, Carmody T, Rush A J. Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium.  Am J Psychiatry. 2005;  162 58-64
• 59 Findling R L, McNamara N K, Gracious B L, Youngstrom E A, Stansbrey R J, Reed M D. et al . Combination lithium and divalproex sodium in pediatric bipolarity.  J Am Acad Child Adolesc Psychiatry. 2003;  42 895-901
• 60 Kowatch R A, Sethuraman G, Hume J H, Kromelis M, Weinberg W A. Combination pharmacotherapy in children and adolescents with bipolar disorder.  Biol Psychiatry. 2003;  53 978-984
• 61 McElroy S L, Altshuler L L, Suppes T, Keck P E, Frye M A, Denicoff K D. et al . Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder.  Am J Psychiatry. 2001;  158 420-426
• 62 Dittmann S, Biedermann N C, Grunze H, Hummel B, Schärer L, Kleindienst N. et al . The Stanley Foundation Bipolar Network: Results of the naturalistic follow-up study (NFS) after 2 œ years of follow-up in the German centres.  Neuropsychobiology. 2002;  46 Suppl 1 2-9
• 63 Vieta E, Colom F, Martinez-Aran A, Benabarre A, Reinares M, Gasto C. Bipolar II disorder and comorbidity.  Compr Psychiatry. 2000;  41 339-343
• 64 Brady K T, Sonne S C. The relationship between substance abuse and bipolar disorder.  J Clin Psychiatry. 1995;  56 Suppl 3 19-24
• 65 Keller M B. Prevalence and impact of comorbid anxiety and bipolar disorder.  J Clin Psychiatry. 2006;  67 Suppl 1 5-7
• 66 Strakowski S M, Tohen M, Stoll A L, Faedda G L, Goodwin D C. Comorbidity in mania at first hospitalization.  Am J Psychiatry. 1992;  149 554-556
• 67 Frye M A, Altshuler L L, McElroy S L, Suppes T, Keck P E, Denicoff K. et al . Gender differences in prevalence, risk, and clinical correlates of alcoholism comorbidity in bipolar disorder.  Am J Psychiatry. 2003;  160 883-889
• 68 Salloum I M, Cornelius J R, Daley D C, Kirisci L, Himmelhoch J M, Thase M E. Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study.  Arch Gen Psychiatry. 2005;  62 37-45
• 69 Brady K T, Sonne S C, Anton R, Ballenger J C. Valproate in the treatment of acute bipolar affective episodes complicated by substance abuse: a pilot study.  J Clin Psychiatry. 1995;  56 118-121
• 70 Goldberg J F, Garno J L, Leon A C, Kocsis J H, Portera L. A history of substance abuse complicates remission from acute mania in bipolar disorder.  J Clin Psychiatry. 1999;  60 733-740
• 71 Suppes T, Dennehy E B, Swann A C, Bowden C L, Calabrese J R, Hirschfeld R M. et al . Report of the Texas Consensus Conference Panel on medication treatment of bipolar disorder 2000.  J Clin Psychiatry. 2002;  63 288-299
• 72 Yatham L N, Kennedy S H, O’Donovan C, Parikh S, Macqueen G, McIntyre R. 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
• 73 Grunze H, Walden J, Dittmann S, Berger M, Bergmann A, Bräunig P. et al . Psychopharmakotherapie Bipolarer Affektiver Erkrankungen.  Nervenarzt. 2002;  73 4-17
• 74 Goodwin G M. Evidence-based guidelines for treating bipolar disorder: recommendations from the British Association for Psychopharmacology.  J Psychopharmacol. 2003;  17 149-173
• 75 McElroy S L. Diagnosing and treating comorbid (complicated) bipolar disorder.  J Clin Psychiatry. 2004;  65 Suppl 15 35-44
• 76 Lum M, Fontaine R, Elie R. Divalproex sodium's antipanic effect in panic disorder. A placebo-controlled study.  Biol Psychiatry. 1990;  27 279
• 77 Baetz M, Bowen R C. Efficacy of divalproex sodium in patients with panic disorder and mood instability who have not responded to conventional therapy.  Can J Psychiatry. 1998;  43 73-77
• 78 Giedd J N. Bipolar disorder and attention-deficit/hyperactivity disorder in children and adolescents.  J Clin Psychiatry. 2000;  61 Suppl 9 31-34
• 79 West S A, Strakowski S M, Sax K W, McElroy S L, Keck P E, McConville B J. Phenomenology and comorbidity of adolescents hospitalized for the treatment of acute mania.  Biol Psychiatry. 1996;  39 458-460
• 80 Turner W J. The usefulness of diphenylhydantoin in treatment of non-epileptic emotional disorders.  Int J Neuropsychiatry. 1967;  3 Suppl 20
• 81 Donovan S J, Stewart J W, Nunes E V, Quitkin F M, Parides M, Daniel W. et al . Divalproex treatment for youth with explosive temper and mood lability: a double-blind, placebo-controlled crossover design.  Am J Psychiatry. 2000;  157 818-820
• 82 Amann B, Schlösser S, Sterr A, Hummel B, Schäfer M, Padovan C S. et al . Anticonvulsants in the treatment of aggression in the demented elderly.  Psychiatric Networks. 2000;  3 87-95
• 83 Fava M. Psychopharmacologic treatment of pathologic aggression.  Psychiatr Clin North Am. 1997;  20 427-451
• 84 Kavoussi R J, Coccaro E F. Divalproex sodium for impulsive aggressive behavior in patients with personality disorder.  J Clin Psychiatry. 1998;  59 676-680
• 85 Zanarini M C. Update on pharmacotherapy of borderline personality disorder.  Curr Psychiatry Rep. 2004;  6 66-70
• 86 Hollander E, Allen A, Lopez R P, Bienstock C A, Grossman R, Siever L J. et al . A preliminary double-blind, placebo-controlled trial of divalproex sodium in borderline personality disorder.  J Clin Psychiatry. 2001;  62 199-203
• 87 Frankenburg F R, Zanarini M C. Divalproex sodium treatment of women with borderline personality disorder and bipolar II disorder: a double-blind placebo-controlled pilot study.  J Clin Psychiatry. 2002;  63 442-446
• 88 Hollander E, Swann A C, Coccaro E F, Jiang P, Smith T B. Impact of trait impulsivity and state aggression on divalproex versus placebo response in borderline personality disorder.  Am J Psychiatry. 2005;  162 621-624
• 89 Kilbourne A M, Cornelius J R, Han X, Pincus H A, Shad M, Salloum I. et al . Burden of general medical conditions among individuals with bipolar disorder.  Bipolar Disord. 2004;  6 368-373
• 90 Angst F, Stassen H H, Clayton P J, Angst J. Mortality of patients with mood disorders: follow-up over 34 - 38 years.  J Affect Disord. 2002;  68 167-181
• 91 Kim E, Humaran T J. Divalproex in the management of neuropsychiatric complications of remote acquired brain injury.  J Neuropsychiatry Clin Neurosci. 2002;  14 202-205
• 92 Monji A, Yoshida I, Koga H, Tashiro K, Tashiro N. Brain injury-induced rapid-cycling affective disorder successfully treated with valproate.  Psychosomatics. 1999;  40 448-449
• 93 Pope Jr H G, McElroy S L, Satlin A, Hudson J I, Keck Jr P E, Kalish R. Head injury, bipolar disorder, and response to valproate.  Compr Psychiatry. 1988;  29 34-38
• 94 Evans D L, Byerly M J, Greer R A. Secondary mania: diagnosis and treatment.  J Clin Psychiatry. 1995;  56 Suppl 3 31-7
• 95 Bowden C L, Singh V. Valproate in bipolar disorder: 2000 onwards.  Acta Psychiatr Scand. 2005;  Suppl. 426 13-20
• 96 Tohen M, Ketter T A, Zarate C A, Suppes T, Frye M, Altshuler L. et al . Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study.  Am J Psychiatry. 2003;  160 1263-1271
• 97 Cipriani A, Pretty H, Hawton K, Geddes J R. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials.  Am J Psychiatry. 2005;  162 1805-1819
• 98 Baldessarini R J, Tondo L. Suicide risk and treatments for patients with bipolar disorder.  JAMA. 2003;  290 1517-1519
• 99 Strakowski S M, McElroy S L, Keck P E, West S A. Suicidality among patients with mixed and manic bipolar disorder.  Am J Psychiatry. 1996;  153 674-676
• 100 Ahrens B, Müller-Oerlinghausen B. Die antisuizidale und mortalitätssenkende Wirkung von Lithium. In: Müller-Oerlinghausen B, Greil W, Berghöfer A (Hrsg). Die Lithiumtherapie: Nutzen, Risiken, Alternativen. Berlin, Heidelberg: Springer 1997: 262-277
• 101 Müller-Oerlinghausen B, Berghofer A, Ahrens B. The antisuicidal and mortality-reducing effect of lithium prophylaxis: consequences for guidelines in clinical psychiatry.  Can J Psychiatry. 2003;  48 433-439
• 102 Meltzer H Y, Alphs L, Green A I, Altamura A C, Anand R, Bertoldi A. et al . Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT).  Arch Gen Psychiatry. 2003;  60 82-91
• 103 Goodwin F K, Fireman B, Simon G E, Hunkeler E M, Lee J, Revicki D. Suicide risk in bipolar disorder during treatment with lithium and divalproex.  JAMA. 2003;  290 1467-1473
• 104 Yerevanian B I, Koek R J, Mintz J. Lithium, anticonvulsants and suicidal behavior in bipolar disorder.  J Affect Disord. 2003;  73 223-228
• 105 Rush A J, Giles D E, Schlesser M A, Fulton C L, Weissenburger J, Burns C. The Inventory for Depressive Symptomatology (IDS): preliminary findings.  Psychiatry Res. 1986;  18 65-87
• 106 Vieta E, Goikolea J M. Atypical antipsychotics: newer options for mania and maintenance therapy.  Bipolar Disord. 2005;  7 Suppl 4 21-33
• 107 Müller-Oerlinghausen B, Retzow A, Henn F, Giedke H, Walden J. Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania. A prospective, randomized, double- blind, placebo-controlled multicenter study.  J Clin Psychopharmacol. 2000;  20 195-203
• 108 Riva R, Albani F, Contin M, Baruzzi A. Pharmacokinetic interactions between antiepileptic drugs. Clinical considerations.  Clin Pharmacokinet. 1996;  31 470-493
• 109 Schweitzer I, Tuckwell V. Risk of adverse events with the use of augmentation therapy for the treatment of resistant depression.  Drug Saf. 1998;  19 455-464
• 110 Wong S L, Cavanaugh J, Shi H, Awni W M, Granneman G R. Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics.  Clin Pharmacol Ther. 1996;  60 48-53
• 111 Solomon D A, Ryan C E, Keitner G I, Miller I W, Shea M T, Kazim A. 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
• 112 Denicoff K D, Smith-Jackson E E, Disney E R, Ali S O, Leverich G S, Post R M. Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder.  J Clin Psychiatry. 1997;  58 470-478
• 113 Denicoff K D, Smith-Jackson E E, Bryan A L, Ali S O, Post R M. Valproate prophylaxis in a prospective clinical trial of refractory bipolar disorder.  Am J Psychiatry. 1997;  154 1456-1458
• 114 Rinnerthaler M, Luef G, Mueller J, Seppi K, Wissel J, Trinka E. et al . Computerized tremor analysis of valproate-induced tremor: a comparative study of controlled-release versus conventional valproate.  Epilepsia. 2005;  46 320-323
• 115 Rottach K G, Weiss-Brummer J, Wieland U, Schmauss M. Valproinsäure als Phasenprophylaktikum- Ein Fall von Valproat-Enzephalopathie.  Nervenarzt. 2000;  71 401-403
• 116 Dreyfuss F E. Valproic acid. Toxicity. Antiepileptic drugs. New York: Raven Press 1995: 641-648
• 117 Ader M, Kim S P, Catalano K J, Ionut V, Hucking K, Richey J M. et al . Metabolic dysregulation with atypical antipsychotics occurs in the absence of underlying disease: a placebo-controlled study of olanzapine and risperidone in dogs.  Diabetes. 2005;  54 862-871
• 118 Robert E, Guibaud P. Maternal valproic acid and congenital neural tube defects.  Lancet. 1982;  2 937
• 119 Morrow J, Russell A, Guthrie E, Parsons L, Robertson I, Waddell R. et al . Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register.  J Neurol Neurosurg Psychiatry. 2006;  77 193-198
• 120 Adab N, Kini U, Vinten J, Ayres J, Baker G, Clayton-Smith J. et al . The longer term outcome of children born to mothers with epilepsy.  J Neurol Neurosurg Psychiatry. 2004;  75 1575-1583
• 121 Gaily E, Kantola-Sorsa E, Hiilesmaa V, Isoaho M, Matila R, Kotila M. et al . Normal intelligence in children with prenatal exposure to carbamazepine.  Neurology. 2004;  62 28-32
• 122 Rasalam A D, Hailey H, Williams J H, Moore S J, Turnpenny P D, Lloyd D J. et al . Characteristics of fetal anticonvulsant syndrome associated autistic disorder.  Dev Med Child Neurol. 2005;  47 551-555
• 123 Eriksson K, Viinikainen K, Monkkonen A, Aikia M, Nieminen P, Heinonen S. et al . Children exposed to valproate in utero-population based evaluation of risks and confounding factors for long-term neurocognitive development.  Epilepsy Res. 2005;  65 189-200
• 124 Rasgon N L, Altshuler L L, Fairbanks L, Elman S, Bitran J, Labarca R. et al . Reproductive function and risk for PCOS in women treated for bipolar disorder.  Bipolar Disord. 2005;  7 246-259
• 125 Tank J E, Palmer B F. Simultaneous “in series” hemodialysis and hemoperfusion in the management of valproic acid overdose.  Am J Kidney Dis. 1993;  22 341-344
• 126 Wangemann M, Retzow A, Vens-Cappell B. Pharmacokinetic characteristics of a new multiple unit sustained release formulation of sodium valproate.  Int J Clin Pharmacol Ther. 1999;  37 100-108
• 127 Dulac O, Alvarez J C. Bioequivalence of a new sustained-release formulation of sodium valproate, valproate modified-release granules, compared with existing sustained-release formulations after once- or twice-daily administration.  Pharmacotherapy. 2005;  25 35-41
• 128 The World Health Organisation .The Use of Essential Drugs. Ninth Report of the WHO Expert Committee (Including the Revised Model List of Essential Drugs) Eleventh Model List of Essential Drugs. 2000
• 129 Zarin D, Pincus H A, McIntyre J S. APA Practice Guideline For The Treatment Of Patients With Bipolar Disorder. http://www.psych.org/clin_res/pg_bipolar.cfm 2002
• 130 Suppes T, Dennehy E B, Hirschfeld R M, Altshuler L L, Bowden C L, Calabrese J R. et al . The Texas Implementation of Medication Algorithms: Update to the Algorithms for Treatment of Bipolar I Disorder.  J Clin Psychiatry. 2005;  66 70-886
• 131 Grunze H, Kasper S, Goodwin G, Bowden C L, Baldwin D, Licht R W. et al . The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders. Part II: Treatment of Mania.  World J Biol Psychiatry. 2003;  4 5-13
• 132 Grunze H, Kasper S, Goodwin G, Bowden C L, Möller H-J, WFSBP T ask. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders. Part III: Maintenance treatment.  World J Biol Psychiatry. 2004;  5 120-135
• 133 Pope H G, McElroy S L, Keck P E, Hudson J I. Valproate in the treatment of acute mania. A placebo-controlled study.  Arch Gen Psychiatry. 1991;  48 62-68
• 134 Brennan M J, Sandyk R, Borsook D. Use of Sodium Valproate in the Management of Affective Disorders: Basic and Clinical Aspects. In: Emrich HM, Okuma T, Müller AA (eds). Anticonvulsants In Affective Disorders. [626.] Amsterdam-Oxford-Princeton: Elsevier Science Publishers B.V. Excerpta Medica, International Congress Series 1984: 56-65
• 135 Hirschfeld R M, Allen M H, McEvoy J P, Keck Jr P E, Russell J M. Safety and tolerability of oral loading divalproex sodium in acutely manic bipolar patients.  J Clin Psychiatry. 1999;  60 815-818
• 136 Sachs G, Chengappa K N, Suppes T, Mullen J A, Brecher M, Devine N A. 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
• 137 Yatham L N, Grossman F, Augustyns I, Vieta E, Ravindran A. 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
• 138 Tohen M, Chengappa K N, Suppes T, Zarate C A, Calabrese J R, Bowden C L. 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
• 139 Sachs G S, Grossman F, Ghaemi S N, Okamoto A, Bowden C L. 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
• 140 DelBello M P, Schwiers M L, Rosenberg H L, Strakowski S M. A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania.  J Am Acad Child Adolesc Psychiatry. 2002;  41 1216-1223
• 141 Pande A C, Crockatt J G, Janney C A, Werth J L, Tsaroucha G. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group.  Bipolar Disord. 2000;  2 249-255
• 142 Elger C E, Bauer J, Bergmann A, Despland P A, Mamoli B, Noachtar S. et al . Der Stellenwert von Valproat in der Therapie von Altersepilepsien. Ergebnisse eines Expertentreffens, Zürich, 12. und 13. Mai 2006.  Aktuelle Neurologie. 2006;  33 453-457

1 Das Expertentreffen wurde durch die Firmen Sanofi-Aventis Deutschland GmbH und Desitin Arzneimittel GmbH mit einem „unrestricted educational grant” unterstützt.

2 Ergenyl® chrono, Ergenyl® Chronosphere®, Orfiril® long