Bipolare Depression: Neue Therapieoptionen

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1 Bipolare Depression: Neue Therapieoptionen Michael Bauer Klinik für Psychiatrie und Psychotherapie Universitätsklinikum Carl Gustav Carus Technische Universität Dresden

2 Phasen Bipolarer Störungen Mania Mixed state Hypomania Normal mood Maintenance Depression Stahl SM. Essential Psychopharmacology 2000;

3 Longitudinal study: depression is more common than mania in bipolar disorders mixed 13% Weeks without symptoms 52.7% Weeks with symptoms 47.3% Depressiv 67% Mania / Hypomania 20% Patients with bipolar disorder experienced mood symptoms nearly half of the time during a 12.8-year follow-up period Depressive symptoms were predominant Depression was 3.5-fold more frequent than mania 90% of patients had at least 1 week of depressive symptoms Judd et al 2002

4 Depressive episodes and symptoms predominate in bipolar disorder Judd et al 2002 (n=146) M-type D-type Total Post et al 2003 (n=146) Joffe et al 2004 (n=138) Paykel et al 2004 (n=204) Baldessarini et al 2010 (n=303) Morbidity from D-type symptoms is approximately 3 times greater than from M-type symptoms Overall, 5 studies (n=1049) Time ill (%) M-type (mania, hypomania, psychosis); D-type (depression, dysthymia, dysphoric mixed states) Baldessarini RJ, et al. Bipolar Disord. 2010;12:

5 Box 1. Behandlung einer akuten bipolaren Depression Schlüsselprinzipien der pharmakologischen Therapie Ziele Hauptziel: vollständige Remission ohne subsyndromale Symptome bei völliger Wiederherstellung des Funktionsniveaus. Zwei häufige klinische Konstellationen: o Szenario A: neue (1. oder wiederholte) depressive Episode (de novo bipolar depression), ohne prophylaktischen Stimmungsstabilisierer o Szenario B: Durchbruchdepression ( breakthrough depression ), tritt im Kontext einer stimmungsstabilisierenden Rezidivprophylaxe Bauer et al. (2011) Bipol Disorders, Pfennig et al. (2012) Nervenarzt

6 Box 1. Behandlung einer akuten bipolaren Depression Schlüsselprinzipien der pharmakologischen Therapie De novo bipolar depression: Mangel an Evidenz in Bezug darauf, welche Wirkstoffe in der Behandlung akuter Depressionen wirksam sind; als Konsequenz daraus gibt es keine einheitliche Meinung bezüglich der am besten wirksamen und verträglichen Therapien Die Monotherapie mit Quetiapin ist durch starke Evidenz (5 Plazebo-RCT) gestützt; eine placebo-kontrollierte RCT unterstützt Olanzapin Lamotrigin und Carbamazepin scheinen bei bipolarer Depression nützlich zu sein, jedoch ist die langsame Auftitrierung von Lamotrigin ein Nachteil für die praktische Anwendung Antidepressiva können kurzfristig einen gewissen Nutzen bieten. Patienten mit Bipolar-Typ II-Erkrankung könnten besser auf Antidepressiva ansprechen als Patienten mit Bipolar-I-Erkrankung Bauer et al. (2011) Bipol Disorders, Pfennig et al. (2012) Nervenarzt

7 Box 1. Behandlung einer akuten bipolaren Depression Schlüsselprinzipien der pharmakologischen Therapie Breakthrough depression: Lamotrigin sollte als Option für Patienten mit einer Breakthrough-Episode unter Lithiumbehandlung erwogen werden. Es gibt keine Evidenz für den Einsatz von Antidepressiva im Allgemeinen oder eines bestimmten Wirkstoffs im Besonderen bei Patienten, die bereits einen Stimmungsstabilisierer erhalten. Es gibt allerdings Hinweise aus der klinischen Erfahrung, dass dies eine Second-Line-Option sein könnte, wenn Lithium und Lamotrigin nicht verabreicht werden. Bauer et al. (2011) Bipol Disorders, Pfennig et al. (2012) Nervenarzt

8 Box 1. Behandlung einer akuten bipolaren Depression Schlüsselprinzipien der pharmakologischen Therapie Monotherapie Kombinations -therapie De Novo Depression Quetiapin OR Olanzapin Lamotrigine Lithium + Lamotrigin Stimmungsstabilisierer + Antidepressivum Breakthrough Depression N/A Lithium + Lamotrigin Stimmungsstabilisierer + Antidepressivum Bauer et al. (2012) Bipolar Disorders

9 Algorithmus der Empfehlungen zur Behandlung der Depression S3-Leitlinie zur Diagnostik und Therapie bipolarer Störungen Entwicklungsproz und wesentliche Empfehlungen (Pfennig A et al 2012b Nervenarzt 83: ) 1 Beachte hohes Interaktionsrisiko, 2 Beachte Erfordernis langsame Aufdosierung, 3 Evidenz für Überlegenheit der Kombination mit Fluoxetin ist spärlich, 4 nicht zur alleinigen Phasenprophylaxe geeignet, 5 Grad B in lebensbedrohlichen Situationen, *Fluoxetin, Paroxetin, Sertralin. Empfehlungsgrade: B, 0, KKP (klinischer Konsenspunkt). BUP Bupropion, CBZ Carbamazepin, EKT Elektrokonvulsionstherapie, FFT familienfokussierte Therapie, IPSRT interpersonelle und soziale Rhythmustherapie, KVT kognitive Verhaltenstherapie, LAM Lamotrigin, LT Lichttherapie, OLZ Olanzapin, QUE Quetiapin, SSRI selektiver Serotoninwiederaufnahmehemmer, WT Wachtherapie

10 Bipolar depression: MADRS total score over 8 weeks for quetiapine vs placebo BOLDER and EMBOLDEN Mean change in MADRS total score *** *** Weeks *** *** *** *** Quetiapine 300 mg/day (n=811) Quetiapine 600 mg/day (n=816) Placebo (n=580) *** *** *** *** ***p<0.001 vs placebo (ITT; LOCF) NNT: response = 6, remission = 5 Young et al 2009

11 MADRS response a rates across six lamotrigine multicentre acute bipolar depression studies Patients (%) p=0.005 p=0.89 p=0.36 p=0.42 p=0.21 p= Bipolar I Bipolar I & II Bipolar I Bipolar I Bipolar II Bipolar I & II a Response: 50% improvement over baseline Pooled relative risk of response: 1.22; CI ; p=0.005 Van der Loos et al 2009 Geddes et al 2009; Calabrese et al 2008

12 Lamotrigine for treatment of bipolar depression compared with placebo: meta-analysis of 5 randomised trials Geddes J R et al. BJP 2009;194:4-9

13 Valproat in der Behandlung Bipolarer Depression: Systematisches Review und Meta-Analyse Smith et al. J Affect Disord 2010;122(1-2):1-9

14 Lithium s Critical Role in Mood Disorders Relapse prevention Antisuicidal activity Augmentation of antidepressants

15 Lithium for prevention of relapse in bipolar disorder Placebo-controlled RCTs Manic/hypomanic and depressive relapses

16 Lithium Treatment Moderate-Dose Use Study (LiTMUS) for Bipolar Disorder: A Randomized Comparative Effectiveness Trial of Optimized Personalized Treatment With and Without Lithium (Am J Psychiatry. 2013;170(1): ) Figure Legend: Overall Illness Severity Over Time (Observed Cases) in a Study of Optimized Personalized Treatment With and Without Lithium aa CGI- BP-S=Clinical Global Impression Scale for Bipolar Disorder Severity; OPT=optimized personalized treatment (guideline-informed, evidence-based, and personalized based on current symptoms, prior treatment history, and course of disorder). No significant differences were observed between groups.

17 Sparcle-Studie: Behandlungserfolg hängt signifikant vom Lithium- Serumspiegel ab (Nolen et al. Bipolar Disord 2012;15: )

18 Long term outcome of bipolar depressed patients receiving lamotrigine as add on to lithium with the possibility of the addition of paroxetine in nonresponders: a randomized, placebo controlled trial with a novel design (Loos et al. Bipolar Disorders 2011;13:11-117)

19 Evidenz-basierte Behandlungsoptionen bei Bipolarer Depression Quetiapine ++ Antidepressants + Lamotrigine + Lithium + Olanzapine + Valproate + Aripiprazole - Chlorpromazine - Risperidone - Ziprasidone - Amisulpride? Asenapine? Carbamazepine? Clozapine? Gabapentin? Haloperidol? Oxcarbazepine? Paliperidone? Tamoxifen? Topiramate? ++ = At least 1 fully powered, randomised, placebo-controlled, double-blind, parallel-group, positive monotherapy trial with moderate to large effect-size + = At least 1 positive randomised, controlled trial or small placebo-controlled, double-blind, parallel-group trial or small effect size - = Controlled evidence of lack of efficacy? = No data Vieta 2009

20 Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo controlled clinical trial with inhaled loxapine (Kwentus et al. Bipolar Disord 2012;14:31-40)

21 Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo controlled clinical trial with inhaled loxapine (Kwentus et al. Bipolar Disord 2012;14:31-40)

22 Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo controlled clinical trial with inhaled loxapine (Kwentus et al. Bipolar Disord 2012;14:31-40)

23 A randomized, double blind, placebo controlled clinical trial of acamprosate in alcohol dependent individuals with bipolar disorder: a preliminary report (Tolliver et al. Bipolar Disord 2012;14:54-63)

24 Atypikum Lurasidon: PREVAIL 2 Trial 6 week randomized double blind trial of lurasidone monotherapy for acute bipolar I depression N = 505 Bipolar I depression MADRS 20 R Lurasidone mg/day n = 166 Lurasidone mg/day n =169 Placebo n = 170 Atypisches Antipsychotikum: D2- und 5HT2A Rezeptorbloackade Loebel A et al. 165th Annual Meeting of the American Psychiatric Association (APA 2012). Poster Presentation

25 PREVAIL 2: Results Patients, % P < % or mg/d Lurasidone 30.0% Placebo Compared with placebo, lurasidone associated with statistically significant reductions in MADRS scores from baseline to week 6 (primary endpoint) 13.9% Lurasidone 7.7% Placebo 9.4% Lurasidone 2.4% Placebo Response Rates* NNT = 5 Nausea NNH = 17 Akathisia NNH = 15 *Response: 50% MADRS decrease. 1. Loebel A et al. APA Poster Presentation NR4-58.

26 6-Week, Randomized Placebo-Controlled Evaluation of Adjunctive Modafinil for Bipolar Depression N = 85 Bipolar I/II depression Inadequate response to mood stabilizers ± AD Rx Randomized to modafinil (mean dose, 177 mg/d) or placebo Mean Baseline to Endpoint Change in IDS C Score Modafinil well tolerated; headache most common AE No difference (modafinil vs placebo) in weight gain or treatmentemergent mania a hypersomnia, energy level, cognitive slowing, and leaden paralysis. AD: antidepressant; IDS-C: Inventory for Depressive Symptomatology Clinician. 1. Frye M et al. Am J Psychiatry. 2007;164:

27 8-Week Randomized Double-Blind Adjunctive Armodafinil in Acute Bipolar I Depression: Results P =.015 Percentage of Patients % Armodafinil 34.2% Placebo 5.6% Armodafinil 3.5% Placebo 1.6% 4.4% Armodafinil Placebo Response Rates a NNT = 9 AE Discontinuation NNH = 50 7% Weight Gain NNH = 37 a Response: 50% IDS-C30 decrease. 1. Ketter TA et al. 25th U.S. Psychiatric & Mental Health Congress, San Diego, CA, November 8-11, 2012.

28 Ketamine for Treatment Resistant Bipolar Depression- Replication Ketamine noncompetitive NMDA antagonist FDA approved as a general anesthetic 0.5 mg/kg over 40 minutes vs one infusion of saline placebo. Almost immediate reductions in depression rating scores. Zarate et al, 2012

29 Lithium Mood Disorders Thyroid System

30 L-thyroxine does not separate from placebo in men, but in women Stamm et al. (2013) J Clinical Psychiatry, in press

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32 Agomelatine adjunctive therapy for acute bipolar depression: preliminary open data Calabrese et al. Bipolar Disorders 2007; 9:

33 Efficacy of electroconvulsive therapy (ECT) in bipolar versus unipolar major depression: a meta analysis (Dierckx et al Bipolar Disorders 14: )

34 Intensive Psychotherapies Improve Bipolar Depression Cumulative Proportion Not Recovered CC CBT IPSRT FFT Time to Recovery (Days) N = 293 bipolar depressed outpatients Protocol meds + 9 mos: FFT (family-focused therapy) IPSRT (interpersonal and social rhythm therapy) CBT (cognitive behavior therapy) CC (collaborative care) Intensive psychotherapies Higher recovery rate Shorter time to recovery 1.6x more likely to be clinically well during any study month Miklowitz DJ et al. Arch Gen Psychiatry. 2007;64:

35 Zusammenfassung Schwierige Behandlung, wenig Evidenz Optionen Quetiapine, Olanzapine (AAP) Lamotrigine, Valproat Lithium, Schilddrüse In der Entwicklung Lurasidon, Loxapin (AAP) Modafinil/armodafinil Ketamin Antidepressiva EBM: keine Monotherapie Agomelatine

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