Psychiatry Clinical Reviews Treating Bipolar Depression

Transcription

1 Mayo School of Continuous Professional Development Psychiatry Clinical Reviews Treating Bipolar Depression Mark A. Frye, MD October 6-8, 2016 Intercontinental Chicago Magnificent Mile Chicago, IL 2015 MFMER slide-1

2 Disclosures - Mark A. Frye M.D Grant Support - AssureRx, Janssen Research & Development, Mayo Foundation, Myriad, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institute of Mental Health (NIMH), Pfizer Consultant (Mayo) - Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Myriad Genetics, Neuralstem Inc., Sunovion, Supernus Pharmaceuticals, Teva Pharmaceuticals CME/Travel Support - American Physician Institute, CME Outfitters Speakers Bureau - NONE Financial Interest / Stock ownership / Royalties - NONE Mayo Clinic has a financial interest in AssureRx and the technology referenced in this presentation 2015 MFMER slide-2

3 Presentation Objectives Review FDA approved treatments for bipolar depression Review new /novel treatments for bipolar depression Evaluate the role of antidepressants in bipolar disorder 2015 MFMER slide-3

4 Bipolar Depression: Best Practices FDA approved Olanzapine Fluoxetine (OFC) Quetiapine monotherapy Lurasidone mono & adjunct therapy Maximize the mood stabilizer Antidepressants FDA off-label Do they work? Are they safe? Psychotherapy Novel Treatment FDA off-label antidepressants are not indicated for treatment of bipolar depression The Old Guitarist Pablo Picasso 1903 The Blue Period 2015 MFMER slide-4

5 Epidemiology Lifetime prevalence rate 4.5 % 1% for BPI, 1.1% BPII, 2.4% subthreshold Suicide 25% attempt, 15% succeed (5% never hospitalized) Comorbid anxiety and substance use disorders Greater risk suicidality and treatment emergent mania Work days lost/ ill worker/ year BP > UP, driven by depression, not mania Subsyndromal depression Functional disability & subsequent relapse Merikangas et al, Arch Gen Psychiatry 2007., Levander et al, J Affective Disorder 2007 Frye et al., Am J Psychiatry 2003., Ostacher et al, Am J Psychiatry 2010., Gitlin et al, J Clin Psychiatry 2011, Kessler et al. Am J Psychiatry 2006., Altshuler et al, J Clin Psychiatry 2002., Frye et al, J Clin Psychiatry MFMER slide-5

6 Frye, NEJM 2011;364(1): MFMER slide-6

7 Response rates of atypical antipsychotics in BP depression Placebo Active Active * * Percent Response * 10 0 OLZ/OFC Quetiapine Aripiprazole Ziprasidone 10 mg / 7.5 mg40mg 300 and 600 mg ~17 mg ~90 mg OFC, olanzapine/fluoxetine combination. *P<0.05; P<0.001 vs placebo. Calabrese et al. Am J Psychiatry Thase et al. J Clin Psychopharmacol. Tohen et al. Arch Gen Psychiatry Thase et al. J Clin Psychopharmacol. 2008;28(1): Sachs et al., J Clin MFMER slide-7

8 Lurasidone in Bipolar I depression: PREVAIL 2 Patients % % or mg/d Lurasidone P < % 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. * Loebel et al., American Journal of Psychiatry 2014; 171: and MFMER slide-8.

9 Cariprazine vs. placebo in Bipolar I depression a Mixed-effects model for repeated measures, intent-to-treat population; p values were not adjusted for multiple comparisons. Cariprazine 0.75 mg/day compared with placebo: *p<0.05; **p<0.01; ***p< Cariprazine 1.5 mg/day compared with placebo: p<0.05; p<0.01; p< Cariprazine 3.0 mg/day compared with placebo: #p<0.05; ##p<0.01; ###p< Date of download: 09/12/2016 Durgam et al., MFMER slide-9

10 Pros and cons of atypical antipsychotics in bipolar depression Pros As a class, effective in acute mania Rapid control of acute mania/mixed, rapid cycling, psychosis/no psychosis Sustained improvement of symptoms Cons Tardive dyskinesia, neuroleptic malignant syndrome Weight gain TD = tardive dyskinesia; EPS = extrapyramidal symptoms 2015 MFMER slide-10

11 Metaanalysis Lamotrigine in Acute BP Depression Study SCAB2001 SCAA2010 SCA40910 SCA30924 SCA10022 LAMLIT Overall (95% CI) Risk Ratio Favors Placebo Favors Drug Risk Ratio (95% CI) 1.71 (1.08,2.69) 1.11 (0.83,1.48) 1.09 (0.81,1.48) 1.24 (0.91,1.70) 1.26 (0.95,1.67) 1.63 (1.05,2.53) 1.26 (1.10,1.44) Weight (%) Geddes JR. British Journal Psychiatry 2009 Van der Loos ML, et al. J Clin Psychiatry MFMER slide-11

12 Metaanalysis Divalproex in Acute BP Depression 100 * P < 0.05 DVPX Serum Level µg/ml 54 µg/ml 0 DVPX (n = 17) Relative risk of remission in patients treated with divalproex versus placebo Muzine et al., J Clin Psychiatry 2011, Davis J Affect Disord 2005, Ghaemi J Clin Psychiatry MFMER slide-12

13 Pros and cons of antiepileptics (divalproex, carbamazepine) in bipolar depression Pros Effective in manic and mixed episodes Effective in alcohol withdrawal & relapse prevention Several effective in migraine prevention Cons Ineffective in acute mania (LTG, TPX, GBP) P450 3A/4 heteroinduction Weight gain & endocrine disturbances (VAL) Teratogenicity (VAL, CBZ) Rash risk CBZ = carbamazepine; VAL = valproate; LTG = lamotrigine; GBP = gabapentin; OLZ = olanzapine. DVPX = divalproex; TPX = topiramate Novick et al: 2009; Goodwin et al: 2010; Frye et al: 2006; Harden et al: 2009; Goodwin et al: 2009, Jiang et al: MFMER slide-13

14 Maximize the mood stabilizer: lithium and BP depression Mean Change in HAM-D Score n=19 n=19 n=14 Li + PAR n = 33 Li + < 0.8 meq/l Li=lithium, IMI=impramine, PAR=paroxetine n=17 Li + IMI n = 36 Li meq/l p < 0.05 * n=22 n=21 Li Only n = 43 Nemeroff et al., 2004 AM J Psychiatry 2015 MFMER slide-14

15 TSH associated with depressive relapse in lithium-maintained bipolar patients Mean TSH (µiu/ml) * 4.4 ± ± 0.4 (N = 40) (N = 13) No Drop out Drop Out For Depression Lithium Maintenance Frye et al., Acta Psychiatrica 2009; 120: MFMER slide MFMER slide-15

16 Antidepressants not effective for bipolar depression Meta-analysis 16 studies acute AD Rx vs. placebo or active comparator in BPI / II depressed patients (n=3113) The pooled treatment estimates Clinical response (RR=1.17, 95% CI, ; p=0.28) Clinical remission (RR=1.14, 95% CI, ; p=0.28) Pooled treatment estimates for 1000 patients No increase risk of switch In smaller analysis 43% TCA, 15% venlafaxine, 7% SSRI, 5% bupropion Sidor and MacQueen Journal Clnical Psychiatry 2011 and MFMER slide-16

17 Depressive episode relapse with antidepressant discontinuation 1.0 % Subjects without Relapse >12 months AD 6-12 months AD <6 months AD Number of Weeks Until Relapse Cox regression analyses log rank = 10.09, P = Altshuler L et al. Am J Psychiatry. 2003;160(7): MFMER slide-17

18 Risk Factors for Switch Mixed Depression Tricyclic antidepressants (TCA) vs Venlafaxine History of antidepressant-induced mania (AIM) Absence of Antimanic Mood Stabilizer First 3 months associated with greatest liability Low thyroid stimulating hormone (with TCAs) Polymorphism (s/s or s/l) at 5-HTTLPR Hyperthymic temperament Comorbid alcoholism Female gender and comorbid anxiety disorder Age (peripubertal > adolescents) BP I > BP II Viktorin et al., 2014 Am J Psychiatry Frye et al., 2009 Am J Psychiatry 2015 MFMER slide-18

19 Baseline mixed depression associated with treatment emergent mania (TEM) Prior to Antidepressant Treatment 3 YMRS items significantly higher in TEM motor-energy speech thought content Factor analysis to identify clusters of YMRS items that covaried and analysis of variance only identified motor/verbal activation (F(2,169)=3.99, p=.02) YMRS = Young Mania Rating Scale TEM= Treatment Emergent Mania Frye et al, Am J Psychiatry MFMER slide-19

20 DSM5 mixed features specifier BP-IV Hyperthymia + Depression Depressive Mixed State Hyperthymic Temperament Recurrent Unipolar Akiskal HS et al. J Affect Disord. 2000;59(Suppl 1):S5-S MFMER slide-20

21 Mayo Clinic Individualized Medicine Biobank for Bipolar Disorder (BP) SLC6A4 polymorphism; antidepressant induced mania 2011 MFMER slide MFMER slide-21

22 SLC6A4 S allele and AIM: metaanalysis results Study Cases Controls (N) (N) Mundo Rousseva Serretti Masoliver Ferreira Mayo Summary OR = 1.35 (95% CI: ) P = OR Metaanalysis marginally significant evidence of association between S allele and AIM+ (p=0.059) Frye et al 2015 J Clin Psychiatry 2015 MFMER slide-22

23 Ketamine for treatment resistant BP 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, MFMER slide-23

24 8-Week randomized double-blind adjunctive armodafinil in acute bipolar I depression P =.015 Percentage of Patients % Armodafinil 34.2% Placebo Response Rates a NNT = 9 a Response: 50% IDS-C30 decrease. 5.6% Armodafinil 3.5% Placebo AE Discontinuation NNH = % 4.4% Armodafinil Placebo 7% Weight Gain NNH = -37 Calabrese et al., J Clin Psychiatry 2014 epub ahead of print MFMER slide-24

25 (Pooled) 6-week randomized double-blind adjunctive pramipexole in acute BP Depression Percentage of Patients Response Rates NNT 3 ** 63.6% 1.7 mg/d N = 22 Pramipexole vs Placebo 49.4% 14.3% N = 21 **p = vs. PBO NNH Switch Rates -231 Pramipexole vs Placebo 15 BPI, 28 BPII on Li (N=18, 0.7 meq/l) DVPX (N = 18, 77 ug/ml) LTG (N=6) GBP (N=3) CBZ (N=2) 0.4% 9.1% 9.5% Pramipexole Placebo Pramipexole Placebo Response: 50% HDRS/MADRS decrease Goldberg JF, et al. Am J Psychiatry 2004;161:564-6; Zarate CA, et al. Biol Psychiatry 2004;56: MFMER slide-25

26 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: MFMER slide-26

27 Maintenance of antidepressant response after group IPSRT for Bipolar Disorder * 18 * * * 15 Baseline Post (2 wk) 12-week YMRS IDS-C BDI-II * p<0.05, N=6, YMRS (Young Mania Rating Scale); IDS-C (Inventory of Depressive Symptomatology-Clinician Rated); BDI-II (Beck Depression Inventory-II) Hoberg et al., MFMER slide-27

28 Evidence base for treatment of BP Depression Quetiapine ++ Modafinil Armodafinil +/-/- Lurasidone ++ Fluoxetine + Lamotrigine + Lithium + Olanzapine + Pramipexole + Valproate + Aripiprazole Ziprasidone High dose Thyroxine + Sleep Dep / Pindolol + ECT + Clozapine? TMS / DBS? Ketamine +/+ ++ = At least 1 fully powered, randomized, placebo-controlled, double-blind, parallel-group, positive trial with moderate-to-large effect-size; + = At least 1 positive randomized, controlled trial or small placebo-controlled, double-blind, parallel-group trial or small effect size; = Controlled evidence of lack of efficacy;? = No data. Vieta E. 2009; Zarate CA. 2004; Diazgranados N. 2010; Goldberg JF. 2004; Frye MA. 2007; Calabrese JR MFMER slide-28

29 Conclusions Evidence-based options OFC, Quetiapine, Lamotrigine, Lurasidone Maximize the mood stabilizer Evidence base + Comorbidity Psychotic depression or psychotic illness AAP Weight neutrality ARI, LUR, ZIP, LTG Migraine valproate Smoking cessation bupropion (with MS) Antisuicidal or classic illness- lithium Antidepressants in BP depression Evidence base does not support monotherapy use Switch rate is not 0% 2015 MFMER slide-29