Verabreichung von Medikamenten außerhalb der zugelassenen Indikationsgebiete („off-label-use”)

Zusammenfassung

Anliegen: In der Behandlung von psychiatrischen Patienten werden neben offiziell zugelassenen Medikamenten auch andere noch nicht zugelassene eingesetzt. Dieser so genannte „off-label-use” wird in den letzten Jahren unter verschiedenen Aspekten zunehmend diskutiert. Ein Urteil des Bundessozialgerichts hat den Rahmen, in dem ein „off-label-use” zulässig ist, stark eingegrenzt und eine Reihe von Bedingungen gestellt, die erfüllt sein müssen. Bei der Prüfung der Zulässigkeit des „off-label-use” sind nach diesem Urteil bevorzugt kontrollierte Studien heranzuziehen. Da im Einzelfall eine Suche von geeigneten Studien aufwändig ist, wurden in dieser Übersicht kontrollierte Studien aus den wesentlichen Problembereichen der Psychopharmakotherapie zusammengestellt: symptomatische Behandlung, Therapieresistenz, Vorliegen von Kontraindikationen bzw. schweren Nebenwirkungen, bisher keine hinreichend abgesicherte medikamentöse Behandlungsmöglichkeit und Zusatzmedikation. Die Probleme und rechtlichen Fragen, die sich bei der Behandlung mit (noch) nicht zugelassenen Medikamenten im Bereich der Psychiatrie ergeben können, werden erörtert.

Abstract

In the medical treatment of psychiatric patients drugs not registered for this specific indication are often prescribed. This so-called “off-label-use” is an increasing matter of discussion in the last years. In the article several aspects concerning “off-label-use” of psychotropic drugs debated in Germany are reviewed. According to a sentence of the German Supreme Court for Social Law an “off-label-use” is only allowed under strong conditions. Furthermore, controlled randomized studies are judged to be the basis of an evaluation of the permission to prescribe an “off-label” medication. Since in clinical practice a comprehensive research of suitable controlled studies is time consuming, in this article controlled randomized studies concerning the main problematic fields of psychopharmacotherapy: treatment of single psychopathological symptoms, therapy resistence, contraindications or severe side-effects, absence of well-established medical treatment strategies and “add-on”-therapy are reviewed. The problems and legal aspects of an “off-label-use” in psychiatry are discussed.

Literatur

• 1 Fritze J, Schmauß M. Off-label-use in der Psychopharmakotherapie.  Nervenarzt. 2002;  73 796-799
• 2 Hopf G. „Off-label-use”. Urteil schafft Klarheit.  Dtsch Ärztebl. 2002;  99 B891-B892
• 3 Bazire S. Psychotropic drug directory 2002. Wilts: M. Allen Publishing Ltd., Dinton, Nr Salisbury 2002
• 4 Fritze J, Schmauß M. Off-label-use in der Psychopharmakotherapie.  Psycho. 2002;  28 431-439
• 5 Citrome L, Levine J, Allingham B. Utilization of valproate: extent of inpatient use in the New York State Office of Mental Health.  Psychiatr Q. 1998;  69 283-300
• 6 Weiss E, Hummer M, Koller D, Ulmer H, Fleischhacker W W. Off-label-use of antipsychotic drugs.  J Clin Psychopharmacol. 2000;  20 695-698
• 7 Kassenärztliche Bundesvereinigung . Richtlinien über die Bewertung ärztlicher Untersuchungs- und Behandlungsmethoden gemäß § 135 Abs. 1 SGB V (BUB-Richtlinien).  Dtsch Ärztebl. 2000;  97 A865
• 8 Wigge P. Evidenz-basierte Richtlinien und Leitlinien.  MedR. 2000;  12 574-585
• 9 Rote Liste® Service GmbH (Hrsg) .Rote Liste® 2003. Aulendorf: Editio Cantor Verlag 2003
• 10 Bilder R M, Goldman R S, Volavka J, Czobor P, Hoptman M, Sheitman B, Lindenmayer J P, Citrome L, McEvoy J, Kunz M, Chakos M, Cooper T B, Horowitz T L, Lieberman J A. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder.  Am J Psychiatry. 2002;  159 1018-1028
• 11 Brieden T, Ujeyl M, Naber D. Psychopharmacological treatment of aggression in schizophrenic patients.  Pharmacopsychiatry. 2002;  35 83-89
• 12 Citrome L, Volavka J, Czobor P, Sheitman B, Lindenmayer J P, McEvoy J, Cooper T B, Chakos M, Lieberman J A. Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia.  Psychiatr Serv. 2002;  52 1510-1514
• 13 Schmahl C, Bohus M. Symptomorientierte Pharmakotherapie bei Borderline- Persönlichkeitsstörung.  Fortschr Neurol Psychiatr. 2001;  69 310-321
• 14 Soloff P H, George A, Nathan R S, Schulz P M, Ulrich R F, Perel J M. Progress in pharmacotherapy of borderline disorders. A double-blind study of amitriptyline, haloperidol, and placebo.  Arch Gen Psychiatry. 1986;  43 691-697
• 15 Soloff P H, Cornelius J, George A, Nathan S, Perel J M, Ulrich R F. Efficacy of phenelzine and haloperidol in borderline personality disorder.  Arch Gen Psychiatry. 1993;  50 377-385
• 16 Wetterling T. Organische psychische Störungen - Hirnorganische Psychosyndrome. Darmstadt: Steinkopff 2002
• 17 Battaglia J, Moss S, Rush J, Kang J, Mendoza R, Leedom L, Dubin W, McGlynn C, Goodman L. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study.  Am J Emerg Med. 1997;  15 335-340
• 18 Bieniek S A, Ownby R L, Penalver A, Dominguez R A. A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation.  Pharmacotherapy. 1998;  18 57-62
• 19 Salzman C, Solomon D, Miyawaki E, Glassman R, Rood L, Flowers E, Thayer S. Parenteral lorazepam versus parenteral haloperidol for the control of psychotic disruptive behavior.  J Clin Psychiatry. 1991;  52 177-180
• 20 Fleminger S, Greenwood R J, Oliver D L. Pharmacological management for agitation and aggression in people with acquired brain injury.  Cochrane Database Syst Rev. 2003;  CD003299
• 21 Tariot P N, Erb R, Podgorski C A, Cox C, Patel S, Jakimovich L, Irvine C. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia.  Am J Psychiatry. 1998;  155 54-61
• 22 Bryden K E, Carrey N J, Kutcher S P. Update and recommendations for the use of antipsychotics in early-onset psychoses.  J Child Adolesc Psychopharmacol. 2001;  11 113-130
• 23 Dorrego M F, Canevaro L, Kuzis G, Sabe L, Starkstein S E. A randomized, double-blind, crossover study of methylphenidate and lithium in adults with attention-deficit/hyperactivity disorder: preliminary findings.  J Neuropsychiatry Clin Neurosci. 2002;  14 289-295
• 24 Malone R P, Delaney M A, Luebbert J F, Cater J, Campbell M. A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder.  Arch Gen Psychiatry. 2000;  57 649-654
• 25 Street J S, Clark W S, Gannon K S, Cummings J L, Bymaster F P, Tamura R N, Mitan S J, Kadam D L, Sanger T M, Feldman P D, Tollefson G D, Breier A. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group.  Arch Gen Psychiatry. 2000;  57 968-976
• 26 Coccaro E F, Kavoussi R J. Fluoxetine and impulsive aggressive behavior in personality-disordered subjects.  Arch Gen Psychiatry. 1997;  54 1081-1088
• 27 Robert P H, Allain H. Clinical management of agitation in the elderly with tiapride.  Eur Psychiatry. 2001;  16 Suppl 1 42s-47s
• 28 Lindenmayer J P, Kotsaftis A. Use of sodium valproate in violent and aggressive behaviors: a critical review.  J Clin Psychiatry. 2000;  61 123-128
• 29 Sival R C, Haffmans P M, Jansen P A, Duursma S A, Eikelenboom P. Sodium valproate in the treatment of aggressive behavior in patients with dementia - a randomized placebo controlled clinical trial.  Int J Geriatr Psychiatry. 2002;  17 579-585
• 30 Peuskens J, Möller H J, Puech A. Amisulpride improves depressive symptoms in acute exacerbations of schizophrenia: comparison with haloperidol and risperidone.  Eur Neuropsychopharmacol. 2002;  12 305-310
• 31 Adler L A, Peselow E, Rosenthal M, Angrist B. A controlled comparison of the effects of propranolol, benztropine, and placebo on akathisia: an interim analysis.  Psychopharmacol Bull. 1993;  29 283-286
• 32 Dumon J P, Catteau J, Lanvin F, Dupuis B A. Randomized, double-blind, crossover, placebo-controlled comparison of propranolol and betaxolol in the treatment of neuroleptic-induced akathisia.  Am J Psychiatry. 1992;  149 647-650
• 33 Fischel T, Hermesh H, Aizenberg D, Zemishlany Z, Munitz H, Benjamini Y, Weizman A. Cyproheptadine versus propranolol for the treatment of acute neuroleptic-induced akathisia: a comparative double-blind study.  J Clin Psychopharmacol. 2001;  21 612-615
• 34 Irwin M, Sullivan G, Van Putten T. Propranolol as a primary treatment of neuroleptic-induced akathisia.  Hillside J Clin Psychiatry. 1998;  10 244-251
• 35 Müller-Siecheneder F, Müller M J, Hillert A, Szegedi A, Wetzel H, Benkert O. Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome.  J Clin Psychopharmacol. 1998;  18 111-120
• 36 Chong S A, Remington G. Clozapine augmentation: safety and efficacy.  Schizophr Bull. 2000;  26 421-440
• 37 Freudenreich O, Goff D C. Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations.  Acta Psychiatr Scand. 2002;  106 323-330
• 38 Lam R W, Wan D D, Cohen N L, Kennedy S H. Combining antidepressants for treatment-resistant depression: a review.  J Clin Psychiatry. 2002;  63 685-693
• 39 Miller A L, Craig C S. Combination antipsychotics: pros, cons, and questions.  Schizophr Bull. 2002;  28 105-109
• 40 Potkin S G, Thyrum P T, Alva G, Bera R, Yeh C, Arvanitis L A. The safety and pharmacokinetics of quetiapine when coadministered with haloperidol, risperidone, or thioridazine.  J Clin Psychopharmacol. 2002;  22 121-130
• 41 Mayo-Smith M F. Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline.  JAMA. 1997;  278 144-151
• 42 Garcia-Borreguero D, Bronisch T, Apelt S, Yassouridis A, Emrich H M. Treatment of benzodiazepine withdrawal symptoms with carbamazepine.  Eur Arch Psychiatry Clin Neurosci. 1991;  241 145-150
• 43 Kaendler S H, Volk S, Pflug B. Benzodiazepinentzug mit Carbamazepin.  Nervenarzt. 1996;  67 381-386
• 44 Ries R K, Roy-Byrne P P, Ward N G, Neppe V, Cullison S. Carbamazepine treatment for benzodiazepine withdrawal.  Am J Psychiatry. 1989;  146 536-537
• 45 Bowden C L, Calabrese J R, McElroy S L, Gyulai L, Wassef A, Petty F, Pope H G Jr, Chou J C, Keck P E Jr, Rhodes L J, Swann A C, Hirschfeld R M, Wozniak P J. A randomised, 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
• 46 Calabrese J R, Bowden C L, Sachs G S, Ascher J A, Monaghan E, Rudd G D. 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
• 47 Frye M A, Ketter T A, Kimbrell T A, Dunn R T, Speer A M, Osuch E A, Luckenbaugh D A, Cora-Ocatelli G, Leverich G S, Post R M. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders.  J Clin Psychopharmacol. 2000;  20 607-614
• 48 Fassino S, Leombruni P, Daga G, Brustolin A, Migliaretti G, Cavallo F, Rovera G. Efficacy of citalopram in anorexia nervosa: a pilot study.  Eur Neuropsychopharmacol. 2002;  12 453
• 49 Attia E, Haiman C, Walsh B T, Flater S R. Does fluoxetine augment the inpatient treatment of anorexia nervosa?.  Am J Psychiatry. 1998;  155 548-551
• 50 Bacaltchuk J, Hay P. Antidepressants versus placebo for people with bulimia nervosa.  Cochrane Database Syst Rev. 2001;  4 CD003391
• 51 Keck Jr P E, Mendlwicz J, Calabrese J R, Fawcett J, Suppes T, Vestergaard P A, Carbonell C. A review of randomized, controlled clinical trials in acute mania.  J Affect Disord. 2000;  59 Suppl 1 S31-S37
• 52 Berk M. Lamotrigine and the treatment of mania in bipolar disorder.  Eur Neuropsychopharmacol. 1999;  9 Suppl 4 119-123
• 53 Ichim L, Berk M, Brook S. Lamotrigine compared with lithium in mania: a double-blind randomized controlled trial.  Ann Clin Psychiatry. 2000;  12 5-10
• 54 Segal J, Berk M, Brook S. Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial.  Clin Neuropharmacol. 1998;  21 176-180
• 55 Chengappa K N, Gershon S, Levine J. The evolving role of topiramate among other mood stabilizers in the management of bipolar disorder.  Bipolar Disord. 2001;  3 215-232
• 56 Grunze H, Walden J, Dittmann S, Berger M, Bergmann A, Bräunig P, Dose M, Emrich H M, Gastpar M, Greil W, Krüger S, Möller H J, Uebelhack R. Psychopharmakotherapie bipolarer affektiver Erkrankungen.  Nervenarzt. 2002;  73 4-17
• 57 Macritchie K, Geddes J R, Scott J, Haslam D, de Lima M, Goodwin G. Valproate for acute mood episodes in bipolar disorder.  Cochrane Database Syst Rev. 2003;  CD004052
• 58 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
• 59 Calabrese J R, Delucchi G A. Spectrum of efficacy of valproate in 55 patients with rapid-cycling bipolar disorder.  Am J Psychiatry. 1990;  147 431-434
• 60 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
• 61 Janicak P G, Sharma R P, Pandey G, Davis J M. Verapamil for the treatment of acute mania: a double-blind, placebo-controlled trial.  Am J Psychiatry. 1998;  155 972-973
• 62 Pande A C, Pollack M H, Crockatt J, Greiner M, Chouinard G, Lydiard R B, Taylor C B, Dager S R, Shiovitz T. Placebo-controlled study of gabapentin treatment of panic disorder.  J Clin Psychopharmacol. 2000;  20 467-471
• 63 Cowdry R W, Gardner D L. Pharmacotherapy of borderline personality disorder. Alprazolam, carbamazepine, trifluoperazine, and tranylcypromine.  Arch Gen Psychiatry. 1998;  45 111-119
• 64 Gardner D L, Cowdry R W. Positive effects of carbamazepine on behavioral dyscontrol in borderline personality disorder.  Am J Psychiatry. 1986;  143 519-522
• 65 Fuente J M de la, Lotstra F. A trial of carbamazepine in borderline personality disorder.  Eur Neuropsychopharmacol. 1994;  4 479-486
• 66 Zanarini M C, Frankenburg F R. Olanzapine treatment of female borderline personality disorder patients: a double-blind, placebo-controlled pilot study.  J Clin Psychiatry. 2001;  62 849-854
• 67 Rocca P, Marchiaro L, Cocuzza E, Bogetto F. Treatment of borderline personality disorder with risperidone.  J Clin Psychiatry. 2002;  63 241-244
• 68 Salzman C, Wolfson A N, Schatzberg A, Looper J, Henke R, Albanese M, Schwartz J, Miyawaki E. Effect of fluoxetine on anger in symptomatic volunteers with borderline personality disorder.  J Clin Psychopharmacol. 1995;  15 23-29
• 69 Hollander E, Allen A, Lopez R P, Bienstock C A, Grossman R, Siever L J, Merkatz L, Stein D J. A preliminary double-blind, placebo-controlled trial of divalproex sodium in borderline personality disorder.  J Clin Psychiatry. 2001;  62 199-203
• 70 Pearlstein T. Selective serotonin reuptake inhibitors for premenstrual dysphoric disorder: the emerging gold standard?.  Drugs. 2002;  62 1869-1885
• 71 Greil W, Ludwig-Mayerhofer W, Erazo N, Engel R R, Czernik A, Giedtke H, Müller-Oerlinghausen B, Osterheider M, Rudolf G AE, Sauer H, Tegeler J, Wetterling T. Lithium vs carbamazepine in the maintanence treatment of schizoaffective disorder: a randomised study.  Eur Arch Psychiatry Clin Neurosci. 1997;  247 42-50
• 72 Volavka J, Czobor P, Sheitman B, Lindenmayer J P, Citrome L, McEvoy J P, Cooper T B, Chakos M, Lieberman J A. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder.  Am J Psychiatry. 2002;  159 255-262
• 73 Conley R R, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder.  Am J Psychiatry. 2001;  158 765-774
• 74 Tohen M, Zhang F, Keck P E, Feldman P D, Risser R C, Tran P V, Breier A. Olanzapine versus haloperidol in schizoaffective disorder, bipolar type.  J Affect Disord. 2001;  67 133-140
• 75 Tran P V, Tollefson G D, Sanger T M, Lu Y, Berg P H, Beasley Jr C M. Olanzapine versus haloperidol in the treatment of schizoaffective disorder. Acute and long-term therapy.  Br J Psychiatry. 1999;  174 15-22
• 76 Janicak P G, Keck Jr P E, Davis J M, Kasckow J W, Tugrul K, Dowd S M, Strong J, Sharma R P, Strakowski S M. A double-blind, randomized, prospective evaluation of the efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder.  J Clin Psychopharmacol. 2001;  21 360-368
• 77 Keck Jr P E, Reeves K R, Harrigan E P. Ziprasidone Study Group. Ziprasidone in the short-term treatment of patients with schizoaffective disorder: results from two double- blind, placebo-controlled, multicenter studies.  J Clin Psychopharmacol. 2001;  21 27-35
• 78 Pande A C, Davidson J R, Jefferson J W, Janney C A, Katzelnick D J, Weisler R H, Greist J H, Sutherland S M. Treatment of social phobia with gabapentin: a placebo-controlled study.  J Clin Psychopharmacol. 1999;  19 341-348
• 79 Williams P S, Rands G, Orrel M, Spector A. Aspirin for vascular dementia.  Cochrane Database Syst Rev. 2000;  (4) CD001296
• 80 Erkinjuntti T. Broad therapeutic benefits in patients with probable vascular dementia or Alzheimer's disease with cerebrovascular disease after treatment with galantamine.  Eur J Neurol. 2002;  9 541-545
• 81 Kertesz A. Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomized trial.  Curr Neurol Neurosci Rep. 2002;  2 503-504
• 82 Marder K. Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomized trial.  Curr Neurol Neurosci Rep. 2002;  2 389-390
• 83 Orgogozo J M, Rigaud A S, Stöffler A, Möbius H J, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300).  Stroke. 2002;  33 834-1839
• 84 Wilcock G, Möbius H J, Stöffler A.. On behalf of the MMM 500 group . A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500).  Int Clin Psychopharmacol. 2002;  17 297-305
• 85 Emeriau J P, Lehert P, Mosnier M. Efficacy of naftidrofuryl in patients with vascular or mixed dementia: results of a multicenter, double-blind trial.  Clin Ther. 2000;  22 334-344
• 86 Moretti R, Torre P, Antonello R M, Cazzato G. Rivastigmine in subcortical vascular dementia: a comparison trial on efficacy and tolerability for 12 months follow-up.  Eur J Neurol. 2001;  8 361-362
• 87 Freeman M P, Stoll A L. Mood stabilizer combinations: a review of safety and efficacy.  Am J Psychiatry. 1998;  155 12-21
• 88 Macritchie K A, Geddes J R, Scott J, Haslam D R, Goodwin G M. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder.  Cochrane Database Syst Rev. 2001;  (3) CD003196-CD003196;
• 89 Hilger E, Barnas C. Atypische Antipsychotika in der Behandlung der bipolaren affektiven Störung.  Fortschr Neurol Psychiatr. 2002;  70 234-242
• 90 Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde .Praxisleitlinien in Psychiatrie und Psychotherapie. Band 5: Behandlungsleitlinie Affektive Erkrankungen. Darmstadt: Steinkopff 2000: 42
• 91 Aronson R, Offman H J, Joffe R T, Naylor C D. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis.  Arch Gen Psychiatry. 1997;  53 842-848
• 92 Joffe R T. The use of thyroid supplements to augment antidepressant medication.  J Clin Psychiatry. 1998;  59 Suppl 5 26-29
• 93 Franz M, Dlabal H, Kunz S, Ulferts J, Gruppe H, Gallhofer B. Treatment of alcohol withdrawal: tiapride and carbamazepine versus clomethiazole. A pilot study.  Eur Arch Psychiatry Clin Neurosci. 2001;  251 185-192
• 94 Normann C, Hummel B, Scharer L O, Horn M, Grunze H, Walden J. Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled, double-blind study.  J Clin Psychiatry. 2002;  63 337-344
• 95 König F, Hippel C von, Petersdorff T, Neuhoffer-Weiss M, Wolfersdorf M, Kaschka W P. First experiences in combination therapy using olanzapine with SSRIs (citalopram, paroxetine) in delusional depression.  Neuropsychobiology. 2001;  43 170-174
• 96 Narendran R, Young C M, Valenti A M, Pristach C A, Pato M T, Grace J J. Olanzapine therapy in treatment-resistant psychotic mood disorders: a long-term follow-up study.  J Clin Psychiatry. 2001;  62 509-516
• 97 Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush A J. Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania.  Am J Psychiatry. 1999;  156 1164-1169
• 98 Tohen M, Chengappa K N, Suppes T, Zarate Jr C A, Calabrese J R, Bowden C L, Sachs G S, Kupfer D J, Baker R W, Risser R C, Keeter E L, Feldman P D, Tollefson G D, Breier A. 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
• 99 Vieta E, Reinares M, Corbella B, Benabarre A, Gilaberte I, Colom F, Martinez-Aran A, Gasto C, Tohen M. Olanzapine as long-term adjunctive therapy in treatment-resistant bipolar disorder.  J Clin Psychopharmacol. 2001;  21 469-473
• 100 McIntyre R S, Mancini D A, McCann S, Srinivasan J, Sagman D, Kennedy S H. Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study.  Bipolar Disord. 2002;  4 207-213
• 101 Bauer M, Zaninelli R, Müller-Oerlinghausen B, Meister W. Paroxetine and amitriptyline augmentation of lithium in the treatment of major depression: a double-blind study.  J Clin Psychopharmacol. 1999;  19 164-171
• 102 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
• 103 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
• 104 Müller-Oerlinghausen B, Retzow A, Henn F A, 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. European Valproate Mania Study Group.  J Clin Psychopharmacol. 2000;  20 195-203
• 105 Cheine M, Ahonen J, Wahlbeck K. Beta-blocker supplementation of standard drug treatment for schizophrenia.  Cochrane Database Syst Rev. 2001;  3 CD000234
• 106 Leucht S, McGrath J, White P, Kissling W. Carbamazepine augmentation for schizophrenia: how good is the evidence?.  J Clin Psychiatry. 2002;  63 218-224
• 107 Addington D, Addington J, Patten S, Remington G, Moamai J, Labelle A, Beauclair L. Double-blind, placebo-controlled comparison of the efficacy of sertraline as treatment for a major depressive episode in patients with remitted schizophrenia.  J Clin Psychopharmacol. 2002;  22 20-25
• 108 Wassef A A, Dott S G, Harris A, Brown A, O'Boyle M, Meyer W J 3rd, Rose R M. Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia.  J Clin Psychopharmacol. 2000;  20 357-361
• 109 Dose M, Hellweg R, Yassouridis A, Theison M, Emrich H M. Combined treatment of schizophrenic psychoses with haloperidol and valproate.  Pharmacopsychiatry. 1998;  31 122-125
• 110 OLG Köln . Urteil vom 30.5.1990. Az.  27 U 169/87 Pharma Recht. 1999;  1 18-23
• 111 Wetterling T. Psychiatrische Notfälle. In: Braun J, Preuss R (Hrsg). Klinikleitfaden Intensivmedizin. 5. Aufl. München: Urban & Fischer 2002: S379-396
• 112 Fegert J M, Häßler F, Rothärmel S. Atypische Neuroleptika in der Jugendpsychiatrie. Dürfen Schutzbestimmungen dazu führen, dass Jugendlichen psychopharmakologischer Fortschritt vorenthalten bleibt?.  Psychopharmakotherapie. 2000;  7 18-26
• 113 Walter-Sack H, Haefeli W E. Arzneimittelsicherheit auch für Kinder.  Dtsch Ärztebl. 2001;  98 A447-A449
• 114 Aman M G, De Smedt G, Derivan A, Lyons B, Findling R L. Risperidone Disruptive Behavior Study Group. Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence.  Am J Psychiatry. 2002;  159 1337-1346
• 115 Buitelaar J K, Gaag R J van der, Cohen-Kettenis P, Melman C T. A randomized controlled trial of risperidone in the treatment of aggression in hospitalized adolescents with subaverage cognitive abilities.  J Clin Psychiatry. 2001;  62 239-248
• 116 Research Units on Pediatric Psychopharmacology Autism Network . Risperidone in children with autism and serious behavioral problems.  N Engl J Med. 2002;  347 314-321
• 117 Turgay A, Binder C, Snyder R, Fisman S. Long-term safety and efficacy of risperidone for the treatment of disruptive behavior disorders in children with subaverage IQs.  Pediatrics. 2002;  110 e34-e34
• 118 Zarcone J R, Hellings J A, Crandall K, Reese R M, Marquis J, Fleming K, Shores R, Williams D, Schroeder S R. Effects of risperidone on aberrant behavior of persons with developmental disabilities: I. A double-blind crossover study using multiple measures.  Am J Ment Retard. 2001;  106 525-538
• 119 Braconnier A, Le Coent R, Cohen D. DEROXADO Study Group . Paroxetine versus clomipramine in adolescents with severe major depression: a double-blind, randomized, multicenter trial.  J Am Acad Child Adolesc Psychiatry. 2003;  42 22-29
• 120 Emslie G J, Heiligenstein J H, Wagner K D, Hoog S L, Ernest D E, Brown E, Nilsson M, Jacobson J G. Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial.  J Am Acad Child Adolesc Psychiatry. 2002;  41 1205-1215