Overview Management of Bipolar Disorder When Interventions Fail Practical Tips Terence A. Ketter, MD Professor of Psychiatry and Behavioral Sciences Stanford University School of Medicine Stanford, California Candidates for beyond first-line interventions Inadequate efficacy, safety/tolerability, feasibility Urgent efficacy need Clinical circumstances important Accurate diagnoses (primary secondary) Illness phase (acute mania/depression, maintenance) Illness characteristics (rapid cycling, comorbidities, med Hx) Efficacy need (urgent non-urgent care) Primary priority (efficacy tolerability) Beyond first-line intervention options include Switching (no efficacy and/or inadequate tolerability) Augmenting (partial efficacy and adequate tolerability) Adjunctive psychosocial treatments Publishing, Inc.; 21. Established Clinical Correlates of Bipolar Depression Commonly antidepressant-resistant/exacerbated Antidepressant-resistance commonly already demonstrated Mixed Episodes (DSM-IV-TR) Commonly lithium-resistant Commonly antidepressant-resistant/exacerbated Rapid Cycling Commonly mood stabilizer-resistant Commonly antidepressant-resistant/exacerbated Comorbid Disorders Alcohol/substance use and anxiety disorders most common Not otherwise specified Subtype Misdiagnosis (eg, personality disorder, BD-I, BD-II) Missed diagnosis (eg, personality disorder, BD-I, BD-II) Adjunctive psychotherapy commonly underutilized, can be crucial BD-I = bipolar I disorder; BD-II = bipolar II disorder. Goldberg JF. J Clin Psychiatry. 28;9(3):9-9. Bipolar Disorders Symptoms are Chronic and Predominantly Depressive 1 BD-I Patients followed 12.8 years 8.9% 31.9%.9% 2.7% Percent of Weeks Asymptomatic Depressed Elevated 8 BD-II Patients followed 13. years.3% 1.3% 2.3%.1% Cycling / mixed Dep:Elevated/Cycling/mixed = 2.2:1 Dep:Elevated/Cycling/mixed = 1:1 Judd LL, et al. Arch Gen Psychiatry. 22;9():3-37. Judd LL, et al. Arch Gen Psychiatry. 23;(3):21-29. Additional Clinical Correlates of Early (Childhood > Adolescent) Onset Confounds/confounded by multiple unfavorable illness characteristics Episode Accumulation (eg, 1 episodes) Kindling Hypothesis (episodes beget illness/episode-related worsening) Episodes: spontaneous/frequent/severe, reactive/rx responsive Confounded by early onset, long illness duration, and aging Additional Comorbid Disorders Personality and eating disorders Less common than alcohol/substance use and anxiety disorders Major Depressive Episode with mixed features (DSM-) AKA Mixed Depression Limited data suggest antidepressants problematic Long Illness Duration (eg, 1 years) Confounded by early onset, episode accumulation, and aging Unfavorable Bipolar II Subtype Chronic, treatment-resistant, depressive illness (ie, BD clinic selection bias) Rather than episodic, treatment-responsive, psychotic illness (ie, not BD-I) Publishing, Inc.; 21. Unfavorable Illness Correlates of Early-Onset Bipolar Disorder Unfavorable Illness Characteristic Prevalence: Childhood- > Adolescent- > Adult-Onset Bipolar Disorder P <., P <.1, P <.1, P <.1 adult-onset. Holtzman JN, et al. J Affect Disord. 21;179:11-12.
Median Illness Course in 82 Patients with Severe Acute Mania FDA-Approved Agents for Bipolar Disorder Acute Depression Longer Term Moderate Mild Age 2 3 3 Mild Moderate Severe First Symptoms First Treatment First Hospitalization. hypo/manias (8 weeks duration); 8. depressions (11 weeks duration); hospitalizations; 1. episodes/year; 3 episodes year before NIMH NIMH = National Institute of Mental Health (Intramural Program). Post RM, et al. Am J Psychiatry. 1988;1(7):8-88. NIMH Admission 197 Lithium 1973 Chlorpromazine 199 Divalproex, ER (2) 2 Olanzapine 23 Risperidone 2, XR (28) 2 Ziprasidone 2 Aripiprazole 2 Carbamazepine ERC 29 Asenapine 21 Cariprazine 23 Olanzapine+fluoxetine combination 2, XR (28) 213 Lurasidone Unmet Need 197 Lithium 23 Lamotrigine 2 Olanzapine 2 Aripiprazole 28, XR (adjunct) 29 Risperidone LAI 29 Ziprasidone (adjunct) Unmet Need Adjunctive and monotherapy. ER, XR, ERC = extended release oral; LAI = long-acting injectable. Publishing, Inc.; 21. Tolerability- First Approach Psychotropic Medication Adverse Effect Schematic Adverse effect risk over placebo (NNH) Medication Class Acute Mania FDA-Approved Agents for Bipolar Disorder Acute Depression Longer Term More Adverse Effects (Go here if necessary) Medium ( 1%) (NNH = 1 2) Low (< %) (NNH > 2) Fewer Adverse Effects (Start here if appropriate) Ketter TA, et al. J Affect Disord. 21;19 Suppl 1:S2-S33. High (> 1%) (NNH < 1) CLZ OLZ RSP, QTP ZIP, ARI, ASN, ILO LUR, BREX, CARI Li, VPA, CBZ LTG FLX, SERT, PAR, BUP, MIRT, (ES)CIT, DLX, (DES)VEN, VTX, VIL, L-MILNA Older Newer SGAs Older Mood Stabilizers Newer Antidepressants 197 Lithium 1973 Chlorpromazine 199 Divalproex, ER (2) 2 Olanzapine 23 Risperidone 2, XR (28) 2 Ziprasidone 2 Aripiprazole 2 Carbamazepine ERC 29 Asenapine 21 Cariprazine 23 Olanzapine+fluoxetine combination 2, XR (28) 213 Lurasidone Unmet Need 197 Lithium 23 Lamotrigine 2 Olanzapine 2 Aripiprazole 28, XR (adjunct) 29 Risperidone LAI 29 Ziprasidone (adjunct) Unmet Need Publishing, Inc.; 21. Multiphase Treatment Strategy Acute Continuation Maintenance Duration 3 8 weeks 2 months Indefinite Symptoms Syndromal Subsyndromal / Absent Absent / Subsyndromal Episode Goals Overt Response Remission (Ideally) ± Overt / Covert (Partially / Fully Suppressed) Recovery Relapse Prevention Improved Function Absent / ± Overt Recurrence Relapse Prevention Full Function Priority Efficacy Efficacy Tolerability Balance Tolerability Medications Psychosocial Increase, Add Support / Structure Education Involve Family Continue, ± Decrease, ± Increase Adherence Cognitive, Behavioral, Family Institute Monitoring Optimize Address Prodromes Adherence Optimize Adaptation Anticipate Prodromes Publishing, Inc.; 21. Adapted from Sachs GS. J Clin Psychopharmacol. 199;1(2 Suppl 1):32S-7S. Sachs GS. J Clin Psychiatry. 23; Suppl 8:3-. Keller MB. J Clin Psychiatry. 2; Suppl 1:1-1. Swann AC. J Clin Psychiatry. 2; Suppl 1:7-12. Overview of Bipolar Disorder Registration Studies Numbers Needed to Treat for Response and Relapse Prevention, Rates Patients (%) NNT 3 2 1 Acute Mania Response Monotherapy Combination Monotherapy 2% 21% 31% (non-urgent) 28 2227 Li/VPA/ PBO CBZ/SGA 9% 18% 1% (urgent) 82 SGA + Li/VPA Li/VPA Acute Depression Response Maintenance Relapse Publishing, Inc.; 21. FDA-approved bipolar disorder treatments increase good outcomes by 18% 2%. Monotherapy/Combination /Monotherapy % 2% 3% (urgent) 1232 18 OFC/QTP/ PBO/ LUR Li/VPA Monotherapy 23% 3% Li/LTG/ SGA 7% (tolerability) 197 9 PBO Combination Monotherapy 2% % 19% (efficacy) 91 9 = N QTP/ZIP/ARI Li/VPA + Li/VPA
Treatments Bipolar Treatments Common usage definitions Preferred, standard, or first choice (Merriam-Webster Dictionary) First chosen for particular illness (Cambridge Dictionary) First given for disease (National Cancer Institute Dictionary of Cancer Terms) Top priority for most patients in such clinical circumstances Operational definition Optimal efficacy/tolerability/feasibility for patients in such clinical circumstances Feasibility factors Accessibility (including cost); Acceptability (including adherence) Ease of use (including drug interactions and dietary restrictions) Efficacy/tolerability evidence levels for individuals Observational (Historical patient ± first-degree relative(s)) In that particular patient in similar clinical circumstances ± In that patient s first-degree-relative(s) in similar clinical circumstances (?) Evidence-based (RCTs) In similar patient population in similar clinical circumstances RCT = randomized controlled trial. Publishing, Inc.; 21. Acute hypo/mania Lithium/divalproex monotherapy Efficacy > tolerability priority (urgent care, inpatient) Approved lithium/divalproex + newer SGA combinations Acute bipolar depression Lamotrigine, ADs (RCTs suggest particularly limited AD efficacy) Efficacy > tolerability priority (urgent care, inpatient) Lurasidone (monotherapy or added to lithium/divalproex) Bipolar maintenance Prior effective acute treatment (with dose adjustment(s) for tolerability) Lamotrigine (esp. depression prevention)/lithium (esp. elevation prevention) AD = antidepressant; SGA = second-generation antipsychotic. Publishing, Inc.; 21. NOT Bipolar Treatments Acute hypo/mania Carbamazepine monotherapy (selected second-line) Olanzapine, risperidone, quetiapine monotherapy (third-line) Lithium/divalproex + SGA combinations (third-line) Efficacy > tolerability priority (urgent care, inpatient) Clozapine (fourth-line) Acute bipolar depression Nutriceuticals (fourth-line; limited efficacy data) Efficacy > tolerability priority (urgent care, inpatient) Olanzapine + fluoxetine combination (third-line) Bipolar maintenance SGAs (second- and third-line) Acute Hypo/mania Treatment Publishing, Inc.; 21. Non-urgent Care (Outpatient) Acute Hypo/mania Treatments Monotherapies (and selected combination therapies) First-line Lithium/divalproex (not carbamazepine/lamotrigine) monotherapy ie, Li/DVPX monotherapy Second-line Carbamazepine monotherapy (not lamotrigine) Newer approved SGA monotherapy ie, ARI/ZIP/ASN/CARI monotherapy Third-line Older approved SGA monotherapy ie, OLZ/QTP/RSP monotherapy Urgent care (inpatient) acute mania combination treatments (next slide) Fourth-line FGA monotherapy eg, haloperidol Lithium + antimanic anticonvulsant ie, Li + DVPX; or Li + CBZ; (but not Li + LTG) FGA = first-generation antipsychotic. Publishing, Inc.; 21. Urgent Care (Inpatient) Acute Mania Treatments Combination therapies First-line Lithium/divalproex + newer approved SGA eg, Li/DVPX + ARI/ASN Second-line Lithium/divalproex + older SGA ± newer SGA eg, Li/DVPX + OLZ/QTP/RSP ± ARI/ASN Third-line Li/DVPX + FGA ± older SGA ± newer SGA eg, Li/DVPX + haloperidol ± OLZ/QTP/RSP ± ARI/ASN Fourth-line Lithium/divalproex + clozapine ± FGA ± older SGA ± newer SGA eg, Li/DVPX + clozapine ± haloperidol ± OLZ/QTP/RSP ± ARI/ASN Electroconvulsive therapy (commonly + SGA/FGA) Publishing, Inc.; 21.
Overview of 2 Acute Mania Registration Studies Numbers Needed to Treat for Response, Rates Responders (%) ( % Mania Rating Decrease) 2 Monotherapy Combination Studies Therapy Studies NNT Monotherapy 1.% 2.3% Combination Monotherapy 9.% 18.1% 1.3% 3 31.2% 2 1 (non-urgent) (urgent) 28 2227 82 = N P <.1. Li/DVPX/CBZ/SGA PBO SGA + Li/DVPX Li/DVPX Publishing, Inc.; 21. Adjunctive SGA Therapy Monotherapy Increases Response Rate 18%. Acute Bipolar Depression Treatment Non-urgent Care (Outpatient) Acute Bipolar Depression Treatments Monotherapies (and selected combination therapies) First-line Lamotrigine monotherapy AD ± lithium/divalproex (AD monotherapy in certain BD-II, but not BD-I) RCTs suggest particularly limited antidepressant efficacy Second-line Lithium ± lamotrigine Adjunctive psychotherapy (CBT, FFT, IPSRT) Urgent care (inpatient) acute bipolar depression monotherapies (next slide) eg, LUR/QTP monotherapy Third-line Divalproex/carbamazepine Urgent care (inpatient) acute bipolar depression combination therapies (next slide) eg, SGA + MS (including QTP + LTG), SGA + AD Lithium + antimanic anticonvulsant eg, Li + DVPX, Li + CBZ Fourth-line Novel agents/adjunctive therapies eg, thyroid, pramipexole, topiramate, nutriceuticals, sleep dep, light Rx, CBZ/DVPX ± Li MS = mood stabilizer; CBT = cognitive-behavioral therapy; FFT = functional family therapy; IPSRT = interpersonal and social rhythm therapy. Publishing, Inc.; 21. Urgent Care (Inpatient) Acute Bipolar Depression Treatments Monotherapies and selected combination therapies First-line Newer approved SGA ie, LUR (monotherapy or added to Li/DVPX) Second-line Older approved SGA monotherapy ie, QTP monotherapy Adjunctive psychotherapy (CBT, FFT, IPSRT) Third-line Older approved SGA + antidepressant combination ie, OLZ + FLX Novel adjunctive therapies ie, armodafinil, modafinil, (QTP + LTG) Fourth-line Adjunctive neuromodulation eg, ECT, TMS, VNS Other novel adjunctive therapies eg, thyroid, pramipexole, topiramate, nutriceuticals, sleep dep, light Rx, CBZ/DVPX ± Li ECT = electroconvulsive therapy; TMS = transcranial magnetic stimulation therapy; VNS = vagus nerve stimulation. Publishing, Inc.; 21. Initial Treatment for Bipolar Disorder Patients in the United States in 22 23 Initial Prescription Rate 3 2 1 % N = 77 2% (17% AC, 8% Li) Antidepressants Mood Stabilizers AC = anticonvulsants; Li = lithium. Baldessarini RJ, et al. Psychiatr Serv. 27;8(1):8-91. 1% Sedatives 11% Antipsychotics Tolerability-Prioritized Unapproved Bipolar Depression Rx Benefits and Harms NNT and NNH, Response and Adverse Effect Rates Lamotrigine Benefit (NNT) Harm (NNH) MADRS Response Somnolence NNT / NNH 12 38 Lamotrigine Lamotrigine.% 8.% 38.1% Benefit / Harm (%) 3 Antidepressants Benefit (NNT) Harm (NNH) Response/Remission Mood Switch 29 29 Antidepressant 1.7% 38.2% 2 1 2.7%.% 9.%.8% 7.7% 7.2% 1 3 = N 1 8 = N LTG PBO LTG PBO AD PBO AD PBO Geddes JR, et al. Br J Calabrese JR et al. Bipolar Disord. Sidor MM, et al. J Clin Psychiatry. Psychiatry. 29;19(1):-9. 28;1(2):323-333. Geddes JR et al. 211;72(2):1-17. P <.1 PBO. Br J Psychiatry. 29;19(1):-9. MADRS = Montgomery-Åsberg Depression Rating Scale. Lamotrigine and antidepressants more than twice as likely to yield benefit as harm compared to PBO. 3.% Antidepressant
Antidepressant-Induced Mania More Common in Bipolar II Compared to Unipolar Depression Switching to Mania (%) 1 12 1 8 Meta-Analysis from Clinical Trials Unipolar Depression Bipolar II Depression 11.2% 3.7%.2% 2.%.7%.2% 3788 1,2 = N 271 12 22 8 = N Statistical Significance: TCA = SSRI > PBO TCA > SSRI = PBO SSRI = selective serotonin reuptake inhibitor (fluoxetine, fluvoxamine, paroxetine, or sertraline); TCA = tricyclic antidepressant. Switch Risk: Bipolar II > Unipolar; TCA SSRI PBO. Peet M. Br J Psychiatry. 199;1():9-. Increased Switching with Adjunctive Venlafaxine Compared to Bupropion and Sertraline in Bipolar Depression Patients (%) 3 2 1 % 1 BUP YMRS > 13 NNH 1 13 VEN BUP P =. 1% VEN Harm (NNH) Mood Switch VEN SERT 7% 8 SERT CGI-M Increase 2 1% 1 BUP VEN BUP P <.1 29% VEN SERT 73% BD-I, 2% BD-II, 1% bipolar NOS; 8% double-blind, 1% open. YMRS = Young Mania Rating Scale; CGI-M = Clinical Global Impression Mania. Post RM, et al. Br J Psychiatry. 2;189:12-131. Adjunctive venlafaxine (compared to sertraline, bupropion) yielded more switching. VEN SERT 9% 8 YMRS > 13 or CGI-M 3 1% BUP VEN BUP P =.3 31% 1% 1 8 = N VEN 7 VEN SERT SERT Newer Efficacy-Prioritized Approved Bipolar Depression Rx Benefits and Harms NNT and NNH, Response and Adverse Effect Rates Lurasidone Monotherapy 1 Adjunctive Lurasidone 2 Benefit (NNT) Harm (NNH) Benefit (NNT) Harm (NNH) MADRS Response Akathisia MADRS Response Nausea NNT / NNH Lurasidone 1 Lurasidone 7 Lurasidone 1 Lurasidone Response / Harm (%) 3 2.% 21.8% 3.2% 7.% 1.% 2.% 2 3 17.%.% 1 9.% 7.% 11.% 323 12 = N 183 11 = N LUR PBO LUR 2.% PBO LUR PBO LUR PBO P <.1, P <.1 PBO. 1 Loebel A, et al. Am J Psychiatry. 21;171(2):1-18. 2 Loebel A, et al. Am J Psychiatry. 21;171(2):19-177. Older Efficacy-Prioritized Approved Bipolar Depression Rx Benefits and Harms NNT and NNH, Response and Adverse Effect Rates Olanzapine + Fluoxetine (OFC) Benefit (NNT) 1 Harm (NNH) 1 Benefit (NNT) 2,3 Harm (NNH) 2,3 MADRS Response 7% Weight Gain MADRS Response Sedation/Somnolence NNT / NNH Olanzapine + Fluoxetine Olanzapine + Fluoxetine 8.%.1% 18.2% 2.7%.3% 3 3.% 3.% 2 19.% 2.9% 1 19.2%.3%.% 82 3 = N 8 33 = N OFC PBO OFC PBO QTP PBO QTP PBO Response / Harm (%) P <.1 PBO. 1 Tohen M, et al. Arch Gen Psychiatry. 23;(11):179-188. 2 Calabrese JR, et al. Am J Psychiatry. 2;12(7):131-13. 3 Thase ME, et al. J Clin Psychopharmacol. 2;2():-9. NNT / NNH Benefit or Harm (%) 8 7 3 2 1 8-Week Olanzapine + Fluoxetine in Pediatric Acute Bipolar I Depression NNT and NNH, Response and 7% Weight Gain Rates Benefit (NNT) CDRS-R Response Olanzapine + Fluoxetine 78.2% Mean 7.7 + 37. OFC 19.% 9.2% 17 8 = N PBO Harm (NNH) 7% Weight Gain 3 Olanzapine + Fluoxetine P <.1, P <.1 PBO. 2% OFC 8% % PBO CDRS-R = Children s Depression Rating Scale Revised. Detke HC, et al. J Am Acad Child Adolesc Psychiatry. 21;(3):217-22. Comparative Evaluation of QUEtiapine plus Lamotrigine in Bipolar Depression (CEQUEL) NNTs and Remission Rates Week 12 Week 2 Benefit (NNT) Benefit (NNT) QIDS Remission ( ) QIDS Remission ( ) NNT 7 Lamotrigine + Lamotrigine + + + 3 3% 3 31% 2 1% 23% 2 1 1% 1 13% 8 81 = N = N LTG + QTP PBO + QTP LTG + QTP PBO + QTP P <. PBO. QIDS = Quick Inventory of Depressive Symptomatology. Geddes JR, et al. Lancet Psychiatry. 21;3(1):31-39. 7% BD-I, 2% BD-II. QIDS Remission (%)
STEP-BD Bipolar Depression Studies Numbers Needed to Treat for Recovery, Rates Recovered (%) NNT -2 8 Mood Stabilizer + Antidepressant Mood Stabilizer + Bupropion - 3 (median, n = 8) Paroxetine - 3 (median, n = 93) 2 3.8% 23.% P =. 27.3% 8 Intensive Psychotherapy Brief Psychoeducation.% 12.9% 1.% Bipolar Maintenance Treatment 179 187 P <. Mood Stabilizer Mood Stabilizer Intensive Brief control + Antidepressant + Psychotherapy Psychoeducation Sachs GS, et al. N Engl J Med. Miklowitz DJ, et al. Arch Gen Psychiatry. 27;3(17):1711-1722. 27;():19-27. Publishing, Inc.; 21. Adjunctive psychotherapy (but not adjunctive antidepressants) increased recovery rate. 13 13 = N Efficacy-Tolerability Balanced Bipolar Maintenance Treatments Monotherapies and selected combination therapies First-line Prior effective acute treatment(s) (with dose adjustment(s) for tolerability) Lamotrigine (esp. depression prev.)/lithium (esp. elevation prev.) monotherapy Second-line Adjunctive psychotherapy (PE, CBT, FFT, IPSRT) Divalproex monotherapy Newer approved SGA monotherapy ie, ARI monotherapy Third-line Older approved SGA monotherapy ie, OLZ/RSP LAI monotherapy Approved lithium/divalproex + SGA combo therapy ie, Li/DVPX + ARI/QTP/RSP LAI/ZIP monotherapy Fourth-line Carbamazepine monotherapy; Clozapine monotherapy/adjunctive therapy FGA monotherapy eg, haloperidol Lithium + mood-stabilizing anticonvulsant ie, Li + DVPX, Li + CBZ, Li + LTG PE = prolonged exposure. Publishing, Inc.; 21. Overview of Bipolar Monotherapy Maintenance Studies Numbers Needed to Treat for Relapse/Recurrence Prevention, Rates NNT Relapse/Recurrence (%) 8 7 3 2 1 9 Lamotrigine 11% % 1% 7 Lithium 1% % 223 188 1 LTG PBO Li Goodwin Contemporary Registration Studies 3 Olanzapine 33% 7% 8% 22 13 OLZ PBO Tohen P <., P <.1, P <.1 PBO. Publishing, Inc.; 21. Aripiprazole 19% 2% 3% 77 83 ARI PBO Keck Risperidone 2% 3% % 1 13 RSP PBO Quiroz 1 unapproved for maintenance monotherapy 29% 23% 2% Lithium 2% 2% 3 QTP PBO Li Weisler 11 = N Overview of Bipolar Monotherapy Maintenance Studies Numbers Needed to Treat and Harm, 7% Weight Gain Rates NNT NNH 7% Weight Gain (%) 1 1 9 7% wt gain Lamotrigine Lithium 2 7% wt gain In stabilization not reported 1.9% 3.3% 7.%.1% 7 Contemporary Registration Studies 31 2 8 8 11.8% 3 Olanzapine BUT 3% 7% wt gain In stabilization 1.1% 13.8% 2.8%.% 2.% 2.3% 17 131 13 22 13 1 13 3 = N LTG PBO Li OLZ PBO ARI PBO RSP PBO QTP PBO Li Sachs Tohen Keck Quiroz 1 Weisler 11 P <., P <.1, P <.1 PBO. Publishing, Inc.; 21. Mood stabilizers antipsychotics slightly less efficacy, but better tolerability. Aripiprazole 7% wt gain In stabilization not reported 12.% 12.% Risperidone BUT 17% 7% wt gain In stabilization 11.% 12 8.8% 13 1.% BUT 17% 7% wt gain In stabilization unapproved for maintenance monotherapy 8.% 3 Lithium 2.8%.% Overview of Adjunctive Psychosocial Maintenance Studies Numbers Needed to Treat for Relapse/Recurrence Prevention, Rates Relapse/Recurrence (%) Contemporary Manualized Intensive Psychotherapy Studies After Sustained Recovery After Acute Episode When Euthymic / Subsyndromal NNT 1 8 2 Psychoeducation Group Non-structured Group 2.%.7% 91.7% Family Focused Therapy Crisis Management 18.8% 3.%.3% Cognitive Therapy No Psychotherapy 31.3% 3.8% 7.% 31 7 8 8 = N Psychoeducation Non-structured Family Focused Crisis Cognitive No Group Group Therapy Management Therapy Psychotherapy Colom 3 Miklowitz 3 Lam 3 P <.1, P <.1 control. Publishing, Inc.; 21. Psychotherapies had single-digit NNTs, comparable to approved pharmacotherapies.
Overview of Adjunctive Pharmacotherapy Bipolar Preventive Studies Numbers Needed to Treat for Relapse/Recurrence Prevention, Rates Relapse/Recurrence (%) NNT 3 2 1 Adjunctive Adjunctive 31.1% 19.3% 7.% 8 Contemporary Registration Studies Adjunctive Risperidone Adjunctive 22.7% 23.1% 2.1.8% 9 QTP+L/V PBO+L/V RSP+TAU PBO+TAU Suppes 13 Macfadden 9 Publishing, Inc.; 21. Approved adjunctive maintenance treatments generally have single-digit NNTs. 8 Adjunctive Ziprasidone Adjunctive 32.% 12.7% 19.7% 11 127 111 ZIP+L/V PBO+L/V Bowden 1 1 Adjunctive Aripiprazole Adjunctive p <., p <.1, p <.1. PBO. 1.% 2.% 1.9% 1.7 18 19 = N ARI+L/VPBO+L/V Marcus 11 Meta-Analysis of Antidepressants in Bipolar Maintenance Benefit (NNT) Harm (NNH) Depressive Relapse Manic Relapse NNT / NNH 1 8 Antidepressant Antidepressant 3 3.% 3 1.2% 29.8% 2 2.3% 13.% 2 1 1.3% 1 178 172 = N AD ± MS MS or PBO AD ± MS MS or PBO Patients with BD-I, BD-II, or bipolar NOS. P <., P <.1 PBO. Ghaemi SN, et al. Acta Psychiatr Scand. 28;118():37-3. Patients (%) Antidepressant Continuation Beneficial in Some (1%?) Bipolar Patients n = 1 (3% relapsed) P =. n = 3 (7% relapsed) Prospective 1-year follow-up Remission of MDE with AD added to mood stabilizer Enriched sample 1.3% (8/9) of patients responded and tolerated AD 2 months Continuation: AD > months Discontinuation: AD < months Seeking Functional Recovery (Thinking Beyond Medications and Not Settling for Sustained Clinical Remission) MDE = major depressive episode. Altshuler L, et al. Am J Psychiatry. 23;1(7):122-122. Bipolar Disorders Symptoms are Chronic and Predominantly Depressive 1 BD-I Patients followed 12.8 years 8.9% 31.9%.9% 2.7% Percent of Weeks Asymptomatic Depressed Elevated 8 BD-II Patients followed 13. years.3% 1.3% 2.3%.1% Cycling / mixed Dep:Elevated/Cycling/mixed = 2.2:1 Dep:Elevated/Cycling/mixed = 1:1 Judd LL, et al. Arch Gen Psychiatry. 22;9():3-37. Judd LL, et al. Arch Gen Psychiatry. 23;(3):21-29. Pharmacotherapy Studies Focus on Symptom Control. Illness Transition Points (The Rs, borrowed from MDD) Response Clinically significant (eg, %) improvement Partially suppressed index episode still present Remission Virtual absence of symptoms < 2 months Fully suppressed index episode still present Recovery Virtual absence of symptoms 2 months Index episode ended (ie, no episode present) Relapse Index episode returns after Response or Remission Recurrence New episode emerges after Recovery Mood Disorder Recovery Definitions Focus on Symptom Control. Publishing, Inc.; 21.; Adapted from Kupfer DJ. J Clin Psychiatry. 1991;2 Suppl 2:28-3. Frank E, et al. Arch Gen Psychiatry. 1991;8(9):81-8.
Recovery in Bipolar Disorder Schizophrenia: Definitions and Studies Narrower Definition Bipolar Disorder (Clinical; Shorter duration) 1 2 threshold-level depressive/mood elevation symptoms 8 weeks Schizophrenia (Clinical & Functional; Longer Duration) 2 mild symptoms mild relationship/employment deficits 2 years Fewer Psychosocial Treatment Studies Bipolar Disorder Limited studies 3 Functional Remediation Schizophrenia Multiple studies Cognitive Remediation, Social Cognition Training... 1 Perlis RH, et al. Psychiatr Serv. 27;8:8-91. 2 Faerden A, et al. Psychopathology. 28;1():271-278. 3 Torrent C, et al. Am J Psychiatry. 213;17(8):82-89. Kern RS, et al. Schizophr Bull. 29;3(2):37-31. Symptomatic Much More Than Functional Recovery in Bipolar Disorder Patients (%) 1 7 2 Months after Hospitalization 78% (33/2) Mild or No Affective Symptoms Dion GL, et al. Hosp Community Psychiatry. 1988;39():2-7. 21% (9/2) Employed Full Time at Expected Level 21 Weekly 9-Minute Adjunctive Functional Remediation (but not Psychoeducation) Sessions Diminished Dysfunction in Recovered Bipolar Disorder Patients 3 Functional Impairment (Functioning Assessment Short Test) 32 3 28 2 2 22 ±, Improvement from Baseline Effect Size.22.1.93 : Bipolar I Depression 2 ±P <. PE; P <.1 TAU. Error bars are SE of mean. Completion rates FR 71.%, PE 7.%, TAU 82.% (NS). Paper-and-pencil tasks/group exercises for memory, attention, Pre-Treatment problem solving, reasoning, multitasking, and organization. Torrent C, et al. Am J Psychiatry. 213;17(8):82-89. Post-Treatment Functional Remediation (n = 77) Psychoeducation (N = 82) (n = 82) Treatment-As-Usual (N = 8) (n = 8) : Background Demographics - 21-year-old Asian single female undergraduate senior Chief complaints - Persistent depression, anxiety/panic, and insomnia History of present illness - Recently self-discontinued lurasidone due to akathisia Past psychiatric history - Recurrent MDEs since age 12 - Paranoid ± referential delusions (when depressed) since age 1 - Recurrent delusional mixed episodes since age 17 - Hospitalized at age 21 for mixed episode with S/A by overdose - Prior pharmacotherapy SGAs (3 prior SGAs self-discontinued due to side effects) - Lurasidone, Aripiprazole -> akathisia; -> sedation - Never had Olanzapine, Ziprasidone, Risperidone, Clozapine Never had Mood stabilizers, Antidepressants, Benzodiazepines, ECT - No alcohol/substance use disorder - Current therapy No pharmacotherapy (self-discontinued lurasidone due to akathisia) No psychotherapy : Background (continued) Medical history Noncontributory (no obesity, diabetes, dyslipidemia) Weight 12 lbs; Height feet, inches; BMI 19. kg/m 2 Family history Sister (younger) with depression, ADHD, and panic disorder Maternal aunt hospitalized for bipolar disorder Paternal family history not available Social history College IT/philosophy senior (graduating in 9 months) Already had good job offer in NYC Lived in dorm on campus, with parents between terms
: Outpatient Visit Current depressive symptoms Sadness, anhedonia, insomnia ( hours) Feelings of guilt, psychomotor agitation, distractibility Passive suicidal ideation without intent, preparation, or plans Current psychotic symptoms Subthresold paranoid delusions ( severe anxiety) Current mood elevation symptoms Distractibility, psychomotor agitation Don t count towards DSM- mixed depression Current anxiety symptoms Panic attacks (2 in prior week, academic stress triggers) Generalized anxiety (daily) Current attitude towards medication Asking for treatment for depression, anxiety, and insomnia Question 1: Current Advisability of Antidepressants 1. Worth considering 2. Avoid Question 1: Current Advisability of Antidepressants Question 2: Current Advisability of Benzodiazepines Worth considering (probably not) Effective for unipolar MDD and anxiety Generally adequate somatic tolerability May exacerbate depression, destabilize mood Akathisia, suicidality, sexual dysfunction risks Avoid (probably) Inefficacy risk (likely also need antipsychotic) May exacerbate depression, destabilize mood Suicidality, sexual dysfunction, akathisia risks Effective for unipolar MDD and anxiety Generally adequate somatic tolerability 1. Worth considering 2. Avoid Question 2: Current Advisability of Benzodiazepines Worth considering (probably) Prominent panic/anxiety/insomnia/psychomotor agitation Generally adequate tolerability Limited sedation risk; can attenuate (rather than trigger) akathisia Limited utility of other agents Mood stabilizers have at best most modest anxiolytic effects Antidepressants might destabilize mood 3 SGAs already overly sedating/activating No personal/family history of alcohol/substance use disorder May ultimately prove necessary to attenuate akathisia Addiction potential (not extreme in this patient) Unlikely to relieve psychosis (unless actually severe anxiety) May exacerbate depression (?) Avoid (probably not) Addiction potential (not extreme in this patient) Might exacerbate depression (?) Follow-up Visits 2 and 3 Started weekly individual psychotherapy Lorazepam. mg twice daily Adequately tolerated Modestly attenuated anxiety/panic, insomnia, subthreshold psychosis No improvement in depression Lorazepam. mg each morning + 1 mg each bedtime Inadequately tolerated (sedation) No additional attenuation of anxiety/panic, insomnia, subthreshold psychosis Patient self-discontinued due to sedation and poorer academic productivity
Question 3: Current Advisability of Mood Stabilizers SGAs 1. Certain mood stabilizers 2. Certain SGAs Question 3: Current Advisability of Mood Stabilizers SGAs Certain mood stabilizers (probably not) Lithium, divalproex, carbamazepine, lamotrigine At best, only modest antidepressant, anxiolytic, and antipsychotic effects Lithium acne, tremor, weight gain Divalproex PCOS exacerbation risk Carbamazepine drug interactions Generally less sedation, akathisia, weight gain than SGAs Certain SGAs (probably) History of prominent psychotic symptoms Olanzapine + fluoxetine, quetiapine, lurasidone approved for bipolar depression Generally more side effects than mood stabilizers Already failed quetiapine, lurasidone, and aripiprazole Question : Choice of SGA 1. Olanzapine (with fluoxetine) 1 2. Ziprasidone 2,3 3. Risperidone. Clozapine 1 Tohen M, et al. Arch Gen Psychiatry. 23;(11):179-188. 2 Lombardo I, et al. J Clin Psychopharmacol. 212;32():7-78. 3 Sachs GS, et al. J Clin Psychiatry. 211;72(1):113-122. Shelton RC, et al. J Clin Psychiatry. 2;(12):171-1719. Suppes T, et al. Am J Psychiatry. 1999;1(8):11-119. Question : Choice of SGA Olanzapine with fluoxetine (probably) Established efficacy for bipolar depression/anxiety 1 Limited akathisia risk 2,3 Weight gain/metabolic > sedation/somnolence risks Ziprasidone (probably not) Inefficacy risk, ; akathisia risk Weight neutral Risperidone (probably not) Inefficacy risk; akathisia, other EPS, hyperprolactinemia risks Potent antipsychotic effect; as adjunct may help rapid cycling Clozapine (probably not) 7 Side effects risks (agranulosytosis/sedation/weight gain/metabolic) Inefficacy risk (very limited antidepressant benefit) May attenuate insomnia/anxiety; minimal akathisia risk 1 Tohen M, et al. Arch Gen Psychiatry. 23;(11):179-188. 2 Lieberman JA, et al. N Engl J Med. 2;33(12):129-1223. 3 Gao K, et al. J Clin Psychopharmacol. 28;28(2):23-29. Lombardo I, et al. J Clin Psychopharmacol. 212;32():7-78. Sachs GS, et al. J Clin Psychiatry. 211;72(1):113-122. Shelton RC, et al. J Clin Psychiatry. 2;(12):171-1719. 7 Suppes T, et al. Am J Psychiatry. 1999;1(8):11-119. Unapproved SGAs in Bipolar Depression Efficacy intolerability concerns Olanzapine (monotherapy) 1,2 Inefficacy and intolerability concerns Risperidone 3, clozapine (no published placebocontrolled depression trials) Inefficacy concerns Aripiprazole, ziprasidone,7 Asenapine, iloperidone (no published controlled trials) ± Cariprazine (limited controlled data) 8 1 Tohen M, et al. Arch Gen Psychiatry. 23;(11):179-188. 2 Tohen M, et al. Br J Psychiatry. 212;21():37-382. 3 Shelton RC, et al. J Clin Psychiatry. 2;(12):171-1719. Suppes T, et al. Am J Psychiatry. 1999;1(8):11-119. Thase ME, et al. J Clin Psychopharmacol. 28;28(1):13-2. Lombardo I, et al. J Clin Psychopharmacol. 212;32():7-78. 7 Sachs GS, et al. J Clin Psychiatry. 211;72(1):113-122. 8 Durgam S, et al. Am J Psychiatry. 21;173(3):271-281. Follow-up Visits and Olanzapine plus fluoxetine Titrated to Olanzapine 7. mg at bedtime Fluoxetine 2 mg each morning Good efficacy, with substantially attenuated Anxiety/panic and insomnia Depression Good tolerability No akathisia, minimal sedation Weight gain lbs at 12 weeks (BMI 19. -> 2.2 kg/m 2 ) Good academic function All A s last term
Conclusions Practical Take-Aways Candidates for beyond first-line interventions Inadequate efficacy, safety/tolerability, feasibility Urgent efficacy need Clinical circumstances important Accurate diagnoses (primary secondary) Illness phase (acute mania/depression, maintenance) Illness characteristics (rapid cycling, comorbidities, med Hx) Efficacy need (urgent non-urgent care) Primary priority (efficacy tolerability) Beyond first-line intervention options include Switching (no efficacy and/or inadequate tolerability) Augmenting (partial efficacy and adequate tolerability) Adjunctive psychosocial treatments Publishing, Inc.; 21. Treatment resistance risks Bipolar depression, mixed episodes Comorbid disorders, rapid cycling Treatment options (commonly combination therapy) SGAs (± mood stabilizers, antidepressants, anxiolytics) Caution with antidepressants (± SGA/MS counter-balance) Novel adjuncts occasionally beneficial Thyroid, pramipexole, topiramate, nutriceuticals, sleep dep, light Rx Adjunctive psychosocial interventions Try to move from symptomatic to functional recovery Publishing, Inc.; 21.