Key Slides. Progress in Schizophrenia and Bipolar Disorder: Update Numbers of Patients at each Level 3,671 1,

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1 Of Ultimate Responders, 2/3 Responded by Week 6 What Have We Learned From STARD? Percent % N = 2876 Response = 5% QIDS-SR >13 Weeks Trivedi et al., Am J Psychiatry, 163(1):28-4, 26 Of Ultimate Remitters, 1/2 Remitted by Wk 6, but 1/2 Remitted in the 2 nd 6 wks Percent Trivedi et al., Am J Psychiatry, 163(1):28-4, % N = 2876 Remission = QIDS-SR 16 < >13 Weeks Remission Rate Remission Rates in STARD (QIDS-SRSR 16 5) 36.8 Numbers of Patients at each Level 3,671 1, Level 1 Level 2 Level 3 Level 4 Rush et al. Am J Psychiatry 26;163: Progress in Schizophrenia and Bipolar Disorder: Update 2 1

2 Relapse Rates in STARD (QIDS-SR SR 11) Star-D: Switch Options Relapse Rate Numbers of Patients entering follow-up 1, Level 1 Level 2 Level 3 Level 4 In remission Not remitted Failed step I and randomized to switch N=727 Level 2 SWITCH Bupropion-SR N=239 Sertraline N=238 Venlafaxine-XR N=25 Rush et al. Am J Psychiatry 26;163: Rush AJ et al. N Engl J Med 26;354: Remission Rates after Switch to Sertraline, Bupropion, or Venlafaxine Remission Rate Remission rates using QIDS-SR Bupropion SR N=239 Sertraline N=238 Venlafaxine XR N=25 Other Findings of STARD: No significant differences between any randomized treatments Rush AJ et al. N Engl J Med 26;354: Progress in Schizophrenia and Bipolar Disorder: Update 2 2

3 Is an Out-of-Class Switch more Effective than a Within Class Switch after SSRI failure? Other Updates A review and meta-analysis of 4 RCTs with 5 contrasts Switch to venlafaxine (3), mirtazapine (1), bupropion (1) The risk ratio was 1.29 (95% CI , p=.7) for remission. NNT = 22. The risk ratio for response was not significant Papakostas G et al. Biol Psychiatry 27, epub ahead of print Are Dual Action Agents (NE/5-HT) More Effective than SSRIs? Review and meta-analysis of 93 RCTs comparing a SSRI with a dual-action NE/5HT uptake inhibitor (N=17,36) Venlafaxine (39), duloxetine (8), milnacipran (6), mianserin (15), mirtazapine (13), moclobemide (12) The overall risk ratio was 1.6 (95% CI , p=.3). The NNT = 24. Although the mechanisms of the above drugs differ, there was little difference between the efficacy of various dual action agents Augmentation Strategies Lithium Thyroid Stimulants Modafinil Buspirone Pindolol Testosterone Estrogen Folate Papakostas G, Thase M, Fava M, Nelson JC, Shelton. Biol Psychiatry 27; 62(11): Progress in Schizophrenia and Bipolar Disorder: Update 2 3

4 Stimulant Augmentation Stimulant Augmentation -controlled controlled study of extended release methylphenidate 6 open series, N = 73 Can be rapidly effective Used in anergic or retarded pts Methylphenidate 5-1 mg t.i.d. or dextroamphetamine 5 mg t.i.d. Few studies with SSRIs Can aggravate anxiety, paranoia, irritability 6 MDD patients Resistant to > one adequate trial, with various ADs Randomly assigned to extended release methylphenidate (18-54 mg/d) vs placebo 4 week trial Similar adverse event rates HAMD Change MPD 1 p=.22 HAMD Response p=.12 Patkar AA et al. J Clin Psychopharmacol 26;26: Modafinil Augmentation A few open trials suggested the efficacy of Modafinil (in doses up to 4 mg/day) Menza MA et al, J Clin Psychiatry. 2 May;61(5):378-81; DeBattista C et al; APA Annual Meeting, New Orleans, LA, 21; Kogeorgos J et al. Eur Neuropsychopharmacology 12 (3):S , 22; Schwartz TL et al. Psychosomatics 43(3): , 22 A double-blind study was positive Aged 18-65, patients with MDD Partial response to SSRI monotherapy for 8 weeks Baseline 31-item HAMD of Epworth Sleepiness Scale >= 1 and Fatigue Scale >=4 Randomly assigned to modafinil or placebo for 8 weeks Modafinil Augmentation in SSRI Partial Responders With Persistent Fatigue and Sleepiness Patients (%) on the CGI-I Very much improved Much improved Minimally improved No change Minimally worse Much worse P =.2 (n = 152) Modafinil (n = 156) P =.2 for difference in overall distribution of scores between modafinil and placebo groups Fava M et al, J Clin Psychiatry 26;66: Fava M et al, J Clin Psychiatry 26;66: Progress in Schizophrenia and Bipolar Disorder: Update 2 4

5 Modafinil Augmentation A 12-week extension 1 suggested Response was sustained Initial nonresponders improved Advantages: more user-friendly than psychostimulants useful for residual fatigue and hypersomnia Thase ME et al. CNS Spectr 26;11: Controlled Lithium Augmentation Studies Meta-Analysis of Lithium augm entation Studies Study Treatment Control OR (fixed) or sub-category n/n n/n 95% CI Baum an 1996 Review: Lithium augmentation 6/1 2/14 Comparison: 1 Lithium augmentation studies Browne 199 3/7 2/1 Outcome: 1 Response rates Heninger /8 /7 Study Treatment Control OR (fixed) Weight OR (fixed) Joffe 1993 or sub-category n/n 9/17 n/n 3/16 95% CI % 95% CI Kantor /4 /3 Bauman /1 2/ [1.27, 63.89] Katona 1995 Browne 199 3/7 15/29 2/1 8/ [.35, 25.87] Heninger /8 / [1., 556.8] Nierenberg 23 Joffe /172/18 3/16 3/ [1.1, 23.57] Kantor /4 / [.9, 12.5] Schoepf 1989 Katona /297/14 8/32 / [1.9, 9.48] Nierenberg 23 2/18 3/ [.8, 4.1] Stein /16 4/18 Schoepf /14 / [1.35, ] Zusky 1988 Stein /163/8 4/18 2/ [.8, 3.19] Zusky /8 2/ [.21, 15.41] Total (95% CI) [1.8, 5.37] Total (95% CI) Total events: 53 (Treatment), 24 (Control) Total events: 53 Test (Treatment), for heterogeneity: Chi² 24 = 11.9, (Control) df = 9 (P =.22), I² = 24.4% Test for overall effect: Z 4.6 (P <.1) Test for heterogeneity: Chi² = 11.9, df = 9 (P =.22), I² = 24.4% Test for overall effect: Z = 4.6 (P <.1) Favors control Favors treatment Favors control Favors treatm ent Meta-analysis of 1 augmentation studies. Overall pooled rates of response: lithium 53/131 or 4.5% vs 24/138 or 17.4%. Crossley and Bauer, in press, J Clin Psychiatry Lithium Augmentation of SSRIs In controlled studies, the pooled response rates were 53/131 (4%) for lithium and 24/138 (17%) for placebo Effective levels >.4 meq/l Usual dose 6-9 mg/day Lithium Augmentation - Disadvantages In STARD, lithium not well tolerated, difficult to dose No large controlled studies (largest N=61, all others 35 or less) Often duration of prior failed treatment was short Few studies adding lithium to SSRIs Limited evidence in documented treatment resistant patients Progress in Schizophrenia and Bipolar Disorder: Update 2 5

6 Thyroid Augmentation Two types of studies T3 given at beginning of treatment to accelerate response T3 added to treatment in nonresponding patients T3 Augmentation to Accelerate Response 6 studies of T 3 plus tricyclic 1 5 of 6 studies showed significant effect Effects were greater if more women in sample Three recent studies T 3 plus sertraline, N=124, T3 > placebo 2 T 3 plus paroxetine, N=16, no difference between treatments 3 T3 plus various ADs, N=5, T3 > placebo 4 1. Altshuler LL et al. (review and meta-analysis). analysis). Am J Psychiatry 21;158: Cooper-Kazaz R et al. Arch Gen Psychiatry 27;64: Applehof BC et al. J Clin Endocrinol Metab 24;89: Posternak M et al. Int J Neuropsychopharmacol 27;13: Meta-Analysis of T3 Augmentation Trials for Treatment Resistant Depression Response Rate (%) All 8 Trials, N=298 OR=2.9 (95% CI ), P=.2 T Response Rate (%) Controlled Trials, N=75 OR= 1.53 (95% CI ), P=.29 T T 3 Augmentation in Resistant Depression Thyroid preparation almost all studies used T 3 Dosing usual dose 25-5 mcg/d Controlled studies with tricyclics, little data with SSRIs Two open studies in resistant patients, N=12 and N=2, suggest T3 augments SSRIs 1,2 Few side effects Aronson R, et al. Arch Gen Psychiatry 1996;53: Abraham et al. J Affect Disord 26;91: Iosifescu DV, et al. J Clin Psychiatry 25;66: Progress in Schizophrenia and Bipolar Disorder: Update 2 6

7 STARD Clinical Features (L-3 Augment) T3 and Lithium Augmentation Outcomes in STARD: Remission and Discontinuations Characteristic LITHIUM (N = 69) THYROID (N = 73) QIDS-SR 16 at entry a 13.± ±4.1 QIDS-SR 16 at exit 11.4 ± ±5. Mean Change in QIDS Percent Remission HRSD Remission Rates 13.2 QIDS-SR Percent Discontinuation Discontinuation Rates 23.2 X 2 =4.83, p= a p =.68 Lithium Thyroid N=69 N=73 Lithium Thyroid N=69 N=73 Nierenberg et al., Am J Psychiatry, 26;163: Nierenberg et al., Am J Psychiatry, 26;163: Open Studies Buspirone Augmentation N Response Remission Partial Jacobsen Bakish Joffe/Schuller Dimitriou/Dimitrou Bouwer and Stein Fischer et al Controlled Studies Landen et al Buspirone in SSRI Resistant Depression Double-blind, blind, placebo controlled trial of buspirone in 119 patients with Major Depression who failed at least 4 weeks of an SSRI. Percent Response Landen M et al. J Clin Psychiatry 1998 Buspirone N=57 N=6 Progress in Schizophrenia and Bipolar Disorder: Update 2 7

8 Pindolol Augmentation Double-blind blind studies of initial treatment Berman et al 1996 N= 4 Negative Perez et al 1996 N=111 Positive Tome et al 1997 N= 8 Positive Zanardi et al 1997 N= 63 Positive Bordet et al 1998 N=1 Positive Maes et al 1999 N=31 Positive Double-blind blind studies in resistant patients Moreno et al 1997 N=1 Drug= Perez et al 1999 N=8 Drug= -controlled controlled study in 78 treatment resistant depressed patients HAMD Pindolol Augmentation Pindolol N=39 N= Days Perez V...Artigas F. Arch Gen Psychiatry 1999 Double-blind phase Other Strategies DHEA 3 placebo controlled monotherapy trials indicate efficacy but no augmentation trials Testosterone 6 placebo controlled trials but only two augmentation trials. Both failed. Estrogen (+/- progesterone) several trials of various combinations and comparisons. One small, positive RCT Pope HG Jr et al: Am J Psychiatry. 23;16(1):15-111; gel (1% gel, 1 g/day) Five negative RCTs Other Strategies: Testosterone RCT N=3 Seidman and Roose J Sex Marital Ther 26 May June 32: RCT N=26 Seidman et Roose. J Clin Psychopharmacol 25. RCT N=74 Rabkin JG et al. Arch Gen Psychiatry 21; 58:43-4. RCT N=18 Orengo et al. J Ger Psychiatry Neurol 25 Mar 18:2-4. RCT N=123 Rabkin J et al. J Clin Psychopharmacol 24, Aug 24: Progress in Schizophrenia and Bipolar Disorder: Update 2 8

9 Other Strategies: Estrogen 3 Early studies augmenting TCAs in mixed age women failed Open retrospective studies in post-menopausal women found Two found HRT + SSRI > PLBO, 1,2 one did not 3 In perimenopausal women Partial responders N=17, AD + estrogen > AD + PLBO 4 Peri- and Post-menopausal women Escitalopram > Estrogen+progestogen N=4 5 Other Strategies: Estrogen (cont d) Postmenopausal women (findings mixed) SSRI + estrogen patch = SSRI + PLBO N=22 6 Venlafaxine + 3 hormone combos and placebo N=72 7 Ven + testosterone > Ven + PLBO Ven + estrogen and progesterone > (trend) Ven + PLBO Estradiol = PLBO for depression N=83 8 HRT + fluoxetine > HRT + PLBO, N= Schneider LS et al. Am J Geriatr Psychiatry 1997;5: Schneider LS et al. Am J Geriatr Psychiatry 21;9: Goldstein KM et al. Am J Geriatr Psychiatry 25; Jul 13: Morgan ML et al. J Clin Psychiatry 25 Jun 66: Soares CN et al Menopause 26 aug (epub ) 6. Rasgon NL et al. J Psychiatr Res 26, (epub) 7. Dias RS Menopause 26 Mar-Apr 13: Morrison MF et al. Biol Psychiatry 24 Feb 55: Liu P et al. Clin Med J. 24 Feb 117: Other Strategies: Folate Augmentation with Folate High homocysteine and low folate related to depression Chen et al Am J Geriatri Psychcaitry. 25;13: Sachdev PS et al Psychol Med 25; Apr 35: Tolmunen T et al Am J Clin Nutr 24;Dec 8: Low folate predicts reduced response, longer time to response, greater relapse Papakostas GI et al. J Clin Psychiatry 24;65:19-5. Papakostas GI et al Int J Neuropsychopharmacol 25;8: Papakostas GI et al. J Clini Psychiatry 24;65: Patients with MDD, HAMD > 19 Randomly assigned to fluoxetine 2 mg + folate 5 mcg or placebo 1 week trial Folate levels rose in women, less in men Response Rates in Women Response Rate (%) p=.5 Folate Coppen A and Bailey J Affect Disord 2;16: Progress in Schizophrenia and Bipolar Disorder: Update 2 9

10 Other Strategies RCT Inositol (up to 12 gr/day) - recent double-blind study failed Nemets B et al; J Neural Transm. 1999;16(7-8):795-8 Open Studies Oxymorphone Stoll AL, Rueter S; Am J Psychiatry. 1999;156:217 Buprenorphine Bodkin JA et al; J Clin Psychopharmacol. 1995;15:49-57 Eicosapentaenoic acid (EPA) Puri BK et al; Int J Clin Pract. 21;55:56-3 SAMe (8-16 mg/day) Alpert JE et al; APA Annual Meeting, 24 Is Augmentation With Atypical Antipsychotics Useful for Treating Antidepressant-Resistant MDD? Risperidone Augmentation of SSRIs after a mean of 7 weeks of SSRI treatment in 8 patients with non-psychotic Major Depression HAMD Score Before After 2 weeks of Risperidone Patients Patient did not return for rating, but complete remission reported. Ostroff R and Nelson JC, J Clin Psychiatry 1999:6: Atypical Antipsychotic Augmentation: A Meta-Analysis of Remission Shelton et al. Shelton et al. Corya et al. Keitner et al. Khullar et al. Mattingly et al. McIntyre et al. Thase et al. Thase et al. Gharabawi et al. Combined Papakostas GI et al. (27), J Clin Psychiatry 68(6): Favors Favors Atypical Antipsychotic Risk Ratio Progress in Schizophrenia and Bipolar Disorder: Update 2 1

11 Atypical Antipsychotic Augmentation: A Meta- Analysis of Response and Remission Rates Rate (%) Response RCTs, N=1,5; Papakostas GI et al. (27), J Clin Psychiatry 68(6): Atypical Antipsychotic Remission Atypical Antipsychotic Neuropharmacology Receptor ARI CLZ HAL OLZ QUE RIS ZIP D D D D , HT 1A ,1 >1, 2, HT 2A HT 2c 15 8 >1, α H M 1 >1, 1.9 >1, >1, >1, ARI = aripiprazole (Abilify); OLZ = olanzapine (Zyprexa); RIS = risperidone (Risperdal); QUE = quetiapine fumarate (Seroquel); ZIP = ziprasidone (Geodon); CLZ = clozapine (Clozaril); HAL = haloperidol (Haldol); Data represented as K i (nm); Data with cloned human receptors; Bymaster FP et al. (1996), Neuropsychopharmacology 14(2):87-96; Daniel DG et al. (1999), Neuropsychopharmacology 2(5):491-55; Farah A (25), Prim Care Companion J Clin Psychiatry 7(6): ; Package insert Aripiprazole (26). Available at: Accessed Aug. 14, 27; Shayegan DK, Stahl SM (24), CNS Spectr 9(1 Suppl 11):6-14 Olanzapine + Fluoxetine (Prozac) for Nonpsychotic TRD 6-week, open-label, N=28: FLX 2-6 mg/day 8-week, double-blind Continued FLX + placebo Olanzapine 5-2 mg + placebo FLX + olanzapine FLX = fluoxetine; Shelton RC et al. (21), Am J Psychiatry 158(1): MADRS Mean Change Olanzapine + Fluoxetine for TRD Patients treated with fluoxetine (N=1) Patients treated with olanzapine (N=8) Patients treated with combination (N=1) Week p<.5 vs. fluoxetine; p<.5 vs. olanzapine; Shelton RC et al. (21), Am J Psychiatry 158(1) Progress in Schizophrenia and Bipolar Disorder: Update 2 11

12 Olanzapine/Fluoxetine Combination for Treatment-Resistant Nonpsychotic MDD 8-Week, Double-Blind, N=5 SSRI failure + 7-week nortriptyline (Pamelor) failure Randomized double-blind to: OFC 6/25 or 12/5 mg/day, N=146 OLZ 6-12 mg/day, N=144 FLX 25-5 mg/day, N=142 NRT mg/day, N=68 OFC = olanzapine/fluoxetine combination; NRT = nortriptyline; Shelton RC et al. (25), J Clin Psychiatry 66(1): Olanzapine/Fluoxetine Combination for Non-psychotic TRD (Cont.) 8-Week, Double-Blind, N=5 The olanzapine/fluoxetine combination did not differ significantly from the other therapies at endpoint although it demonstrated a more rapid response that was sustained until the end Shelton RC et al. (25), J Clin Psychiatry 66(1): Olanzapine/Fluoxetine Combination for Treatment-Resistant Nonpsychotic MDD Two, 8-Week, Double-Blind, N=65 SSRI failure + 8-week FLX 5 mg/day failure 8-week double-blind Continued FLX 5 mg/day + placebo Olanzapine 6 mg/day + placebo FLX 5 mg/day + olanzapine 6 mg/day Olanzapine/Fluoxetine Combination for Nonpsychotic TRD (Cont.) 2 Pooled, 8-Week, Double-Blind, N=65 Study 1: no significant differences Study 2: OFC > OLZ and FLX Pooled: OFC > OLZ and FLX Thase ME et al. (27), J Clin Psychiatry 68(2): Thase ME et al. (27), J Clin Psychiatry 68(2): Progress in Schizophrenia and Bipolar Disorder: Update 2 12

13 OFC for Treatment-Resistant MDD MADRS Change: 2 Pooled Studies Adjunctive Aripiprazole for Incomplete Responders In Nonpsychotic MDD Week OFC (N=198) FLX (N=23) OLZ (N=197) p<.5 OFC vs. FLX; p<.5 OFC vs. OLZ; Thase ME et al. (27), J Clin Psychiatry 68(2): week double-blind (N=362) after 8-week antidepressant unsuccessful ARI 2-2 mg/day or placebo Primary outcome: mean MADRS change Baseline 26 Endpoint ARI 8.8, PBO 5.8, (p<.1) Berman RM et al. (27), J Clin Psychiatry 68(6): Adjunctive Aripiprazole for Incomplete Responders In MDD: MADRS Mean Change Mean (±SE) Change in MADRS Total Score From End of Prospective Treatment Phase to End of Randomized Treatment Phase Week Baseline p<.1 vs. placebo; Berman RM et al. (27), J Clin Psychiatry 68(6): (N=172) Aripiprazole (N=181) Remission (%) Adjunctive Aripiprazole for Incomplete Responders In MDD: Remission Rates (N=172) Aripiprazole (N=181) Week p<.5 vs. placebo; p<.1 vs. placebo; In the placebo group, 4 participants discontinued prior to undergoing any efficacy assessment; In the aripiprazole group, 1 patient discontinued prior to undergoing any efficacy assessment; Berman RM et al. (27), J Clin Psychiatry 68(6): Progress in Schizophrenia and Bipolar Disorder: Update 2 13

14 Risperidone vs. Augmentation for Treatment-Resistant Depression 274 subjects with MDD Incomplete response to 8 weeks of antidepressant 6-week, double-blind, design RIS.25 mg to 2. mg Percent of Patients 1 Gharabawi et al. (26), Neuropsychopharmacology 31(suppl 1):S Response Risperidone RIS vs PLBO, p= Remission Risperidone vs. Augmentation for Treatment-Resistant Depression Incomplete response to 5 weeks of antidepressant Start.25 mg, maximum 3. mg/day risperidone Treat for 4 weeks 4-Week, Double-Blind, N= Keitner GI et al. (26), Presented at the 159th Annual Meeting of the American Psychiatric Association (APA), NR526. Toronto, Canada: May 2-25 Percent of Patients Response Risperidone P=.5 P=.1 Remission Quetiapine (N=21) vs. (N=11) Augmentation for Resistant Depression Incomplete response to 8 weeks of antidepressant Dose: Start 5 mg/day, mean final 268 mg/day 8-Week, Double-Blind Mattingly G et al. (26), Presented at the 46th Annual Meeting of the NCDEU, Poster I-58. Boca Raton, Fla.: June Percent of Patients Response Quetiapine p<.2 43 p<.5 15 Remission Ziprasidone Augmentation for SSRI-Resistant Resistant Nonpsychotic MDD 8-Week, Double-Blind, N=61 Open-label sertraline 1-2 mg/day, 6 weeks Double-blind sertraline plus placebo or ziprasidone 8 mg/day or ziprasidone 16 mg/day Trends favored ziprasidone (MADRS change and response rates), but not statistically significant Dunner DL et al. (27), J Clin Psychiatry 68: Progress in Schizophrenia and Bipolar Disorder: Update 2 14

15 Atypical Augmentation: Summary Several studies show efficacy Antipsychotic side effect burden Weight gain Metabolic syndrome EPS, akathisia Sedation Orthostatic hypotension Cost Emphasis of marketing Summary of Combination Studies Still no placebo-controlled bupropion-ssri combination study One placebo-controlled mirtazapine study, 1 N=26, MIR>placebo One placebo-controlled desipramine + fluoxetine study, combination > either single agent 2 Atomoxetine augmentation Carpenter LL, Yasmin S, Price LH. Biol Psychiatry 22;15;51(2): Nelson JC, Mazure CM, Jatlow PI, et al. Biol Psychiatry 24;55: SSRI Augmentation with Atomoxetine Summary 276 MDD Patients treated with sertraline 146 Had persistent depression after 8 weeks Randomized to atomoxetine or placebo and treated for another 8 weeks % Response Atomoxetine We have several options for switching, augmentation and combination strategies Little evidence that one is more effective than another Few predictors of which to select Generally we use augmentation after partial response On the positive side the cumulative response and remission rates after several trials is encouraging For the future look for combination strategies earlier in the course of treatment Michelson D, et al. J Clin Psychiatry 27 Progress in Schizophrenia and Bipolar Disorder: Update 2 15