Treatment of Bipolar disorder

Transcription

1 8/6/215 Treatment of Bipolar disorder Pichai Ittasakul, M.D. Department of Psychiatry, Ramathibodi Hospital, Mahidol University Bipolar disorder Manic-depressive Illness. is characterized by the occurrence of at least one manic or mixed-manic episode. Most patients also have one or more depressive episodes at other times. Bipolar disorder is multisystemic Mood & affect instability Medical burden Circadian rhythm instability Cognition & executive functioning 1

2 Hazard Ratio for mortality 8/6/215 Comorbidity and Mortality in bipolar disorder 12 Women Men Suicide Influenza DM COPD Stroke CVD IHD Cancer Crump C et al. JAMA psychiatry. 213 Sep 1;7(9): Classification of bipolar disorder Unipolar depression Bipolar I Bipolar II Cyclothymia Bipolar NOS Depressive episodes Manic and depressive episodes Hypomanic, depressive episodes Hypomania, subthreshold depression Subthreshold hypomania, subthreshold depression From DSM IV-TR to DSM V Criterion A for manic and hypomanic episode : includes an emphasis on changes in activity and energy as well as mood Bipolar I disorder, mixed episode has been removed. A new specifier, with mixed features, has been added. Anxious distress specifier is delineated. 2

3 8/6/215 The presence of manic/hypomanic symptoms in patients with recurrent unipolar depression Cassano et al. Am J psychiatry 24 Mixed mania vs mania More prior mixed episodes 3,8 Less congruent psychotic features 1-8 More suicidal risk 8 Less inter-episodic remission 3 (residual symptomatology) 1. Dell Osso et al. 1993; 2. Perugi et al. 1997; 3. Akiskal et al. 1998; 4. Himmelhoch et al. 1976; 5. Dilsaver et al. 1993; 6. Strakowski et al. 1996; 7. Goldberg et al. 1998; 8. Perugi et al

4 Prevalence of suicidality 8/6/215 Mixed mania is associated with a higher risk of suicide % 57.9% 1.3% 63/184 (1/77) 62/17 All pure mania mixed mania Goldberg et al. Am J psychiatry 1998 Treatment of Bipolar disorder Treatment Pharmacotherapy Psychosocial intervention Mood stabilizer Anticonvulsants Antipsychotic Psychoeducation Interpersonal and social rhythm therapy CBT Family intervention 4

5 8/6/215 Treatment aims Achieve functional recovery, not just treat or control mood episodes Improve physical health Reduce stigma and social exclusion Address subthreshold symptoms and their drivers Augment personal autonomy, and well-being to improve quality of life Strategy and time course Acute Continuation Maintenance -8 wks Syndromal Recovery Maximize mood stabilizers; adjunctive treatment Support/structure; Education; involve family 1-6 months Functional Recovery Optimize tolerability; Taper adjunctive Medications when Possible Cognitive behavioral systems; Indefinite Maximize function; Stability Optimize efficacy And tolerability; Anticipate prodromes Strategies to Optimize adaptation And remission Pharmacotherapy Bipolar disorder pharmacotherapy depends on Illness Subtypes Phase Clinical features 5

6 8/6/215 Pharmacological treatment targets Neurotransmitter/ Neurohormonal dysreguration Intracellular signaling Neural mechanism Dopamine, Serotonin, Glutamate Inosital monophosphatese, GSK3, PKC, Calcium channels Corticolimbic emotion control circircuit Sleep and circardian regulation Circadian clock associated with impaired sleep and weight changes US FDA-approved treatments for Bipolar disorder Acute Mania Acute Depression Long-term treatment Year Drug Year Drug Year Drug 197 Lithium 1973 Chlorpromazine 1994 Divalproex 2 Olanzapine* 23 Risperidone* 24 Quetiapine* 24 Ziprosidone 24 Aripiprazole* 24 Carbamazepine 29 Asenapine* OLZ + fluoxetine Quetipine, XR (28) Lurasidone Unmet need Lithium Lamotrigine Olanzapine Aripiprazole Quetiapine, XR(adjunct) Risperidone LAI* Ziprasidone Unmet need * Adjunctive and monotherapy Treatment of mania Lithium, Chloropromanize Antiepileptics Second-generation antipsychotics Differences in both efficacy and tolerability between agents Antipsychotic drugs seem to be better than lithium and anticonvulsants Olanzapine, risperidone and haloperidol seem to have the best profile of available agent Cipriani A. et al., Lancet. 211;378:

7 Percent Responders ( 5% mania rating decrease) Percent responders ( 5% mania rating decrease) 8/6/215 Overview of 22 Acute Mania Registration Studies Monotherapy Studies 49.9% 2.% 5 Combination Therapy Studies NNT 5 6 Monotherapy vs Combination vs Monotherapy 59.4% 18.1% 41.3% % 1 p <.1. N = 2258 Li/DVPX/CBZ/SGA N = 1798 N = 862 SGA + Li/DVPX N = 646 Li/DVPX Ketter Montherapy TA (ed). vs. Handbook, of Combination Diagnosis and therapy Treatment vs. of Monotherapy Bipolar Disorder, increase Am Psych Response Pub, Inc., Rate Washington, approximately DC, 21. 2%. Acute Mania Monotherapy Registration Studies NNT Somnolence / Sedation NNH Weight Gain NNH ? N=134 N=261 N=223 N=124 N=434 N=357 N=268 N=26 N=357 Lithium Divalproex Carbamazepine Olanzapine Risperidone Quetiapine Ziprasidone Aripiprazole Asenapine Adapted from: Ketter TA (ed). Handbook Weight of Diagnosis gain > Somnolence and Treatment of / Bipolar Sedation Disorder, > Antimanic Am Psych Pub, variability. Inc., Washington, DC, 21. N=1938 (pooled) Treatment of bipolar depression Is a major challenge, with few treatment options. 7

8 Percentage of patients 8/6/215 Time Spent Depressed (12.8 yr follow up) Mixed/rapid cycling 5.9% Mixed/rapid cycling 2.3% Asymptomatic 52.9% Depressed 31.9% Manic 8.9% Asymptomatic 46.1% Depressed 5.3% Hypomanic 1.3% Bipolar I Bipolar II (n = 146) (n = 86) Judd LL et al. Arch Gen Psychiatry 22;59(6): Judd LL et al. Arch Gen Psychiatry. 23;6(3) Misdiagnosis of Bipolar Disorder 25 MDD patients MINI 6 patients were diagnosed BP 19 (7.6%) BP I 41 (16.4%) BP II Waleeprakhon et al. 214 Meta-analysis of antidepressant in acute bipolar depression Response/Remission rates 41.% Antidepressant 38.2% N=41 N=68 7.7% 7.2% Antidepressant Switching rate NNT 36 NNH 2 Sador MM, Macqueen GM, J Clin Psychiatry 211 Feb;72(2):

9 Percent Responders ( 5% depression rating decrease) 8/6/215 Correlates of antidepressant: related switching into hypomania/mania Younger age Bipolar I > Bipolar II subtype Rapid cycling (> 4 episodes) in the past year Mixed depression TCAs > second-generation antidepression Norepinephrine active > serotonin or dopamine Substance abuse history If not antidepressant Single or combinations of conventional mood stabilizers* Lamotrigine*, Lithium* Second generation antipsychotic : olanzapine+fluoxetine : quetiapine : lurasidone Other pharmacotherapies* Psychotherapy * not approved by US FDA for acute bipolar depression Overview of Acute Bipolar Depression Studies NNT Approved Treatments Unapproved Treatments % 3% 59% 4% ** 47% * 39% 38% 3% OFC PBO QTP PBO OLZ PBO LTG PBO Tohen 3 Calabrese 5, Thase 6 Tohen 3 Geddes 9 = N * p <.5, ** p <.1, p <.1 vs. PBO. 9

10 Percentage with relapse 8/6/215 US FDA-approved treatments for Bipolar disorder Acute Mania Acute Depression Long-term treatment Year Drug Year Drug Year Drug 197 Lithium 1973 Chlorpromazine 1994 Divalproex 2 Olanzapine* 23 Risperidone* 24 Quetiapine* 24 Ziprosidone 24 Aripiprazole* 24 Carbamazepine 29 Asenapine* OLZ + fluoxetine Quetipine, XR (28) Lurasidone Unmet need Lithium Lamotrigine Olanzapine Aripiprazole Quetiapine, XR(adjunct) Risperidone LAI* Ziprasidone Unmet need * Adjunctive and monotherapy Long-term maintenance treatment Lithium is an efficacious treatment, however, the benefits of lithium are restricted by adverse effects and low therapeutic effects. Divalproex, although not approved for bipolar maintenance monotherapy, is commonly used as monotherapy or adjunctive therapy. NNT % 6.6% Lithium (n = 369) (n = 41) 32.3% 25.% 13.8% 23.6% Overall relapse Depressive relapse Hypo/manic relapse Summary form 5 double-blind lithium monotherapy VS placebo maintenance trails from 1973 and 23. ** p <.1 (Geddes et al. 24) 1

11 8/6/215 LiTMUS study Lamotrigine maintenance study Lamotrigine and lithium were superior to placebo in time to intervention for any mood episode Larmotrigine was superior to placebo for time to intervention for depression Mean LTG dose was 245 ay, mean serum LI level was.7 meq/l Goodwin et al

12 Percent Relapse/Recurrence 8/6/215 Overview of Bipolar Monotherapy Maintenance Studies NNT Lamotrigine vs * 61% 11% 5% Lithium vs 16% 45% Olanzapine vs *** 33% 47% 8% Aripiprazole vs * 19% 25% 43% Risperidone vs 56% 26% 3% Quetiapine Lithium vs vs Quetiapine unapproved for maintenance monotherapy 52% 29% 26% 26% 23% LTG PBO Li OLZ PBO ARI PBO RSP PBO QTP PBO Li Goodwin 4 Tohen 6 Keck 6 Quiroz 1 Weisler 9 * p <.5, *** p <.1, p <.1 vs. PBO. Ketter TA (ed). Handbook Approved of Diagnosis maintenance and Treatment treatments of Bipolar Disorder, have Am single-digit Psych Pub, Inc., NNTs. Washington, DC, 21. = N Atypical Antipsychotics: Summary of Long-Term Data Adjunct or Monotherapy Index Episode Any mood event = at least 1 randomized controlled trial (RCT) showing significant effects = at least 1 RCT showing some effect = adequately powered, RCT evidence of a lack of significant effects? = inadequately powered, uncertain, or no controlled data available Delay of Episode Recurrence Mania/Mixed Depression Olanzapine M Mania/Mixed Risperidone Quetiapine A and M A and M Mania/Mixed/ Remission Mania/Mixed/ Depression Ziprasidone A Mania/Mixed? Aripiprazole M Mania/Mixed? Asenapine M Mania/Mixed? Paliperidone - -??? Tohen et al, 23b; Tohen et al, 26; Keck et al, 27; Vieta et al, 28b; Vieta et al, 28c; Young et al, 28a; McElroy et al, 28; Weisler et al, 28; Suppes et al, 29; Vieta et al, 29.?? Recommendations on antidepressants use in bipolar disorder 1th International Conference on Bipolar Disorders (ICBD), Miami, USA. the result of a review of 173 studies to assess the quality of the evidence for antidepressant use in bipolar depression. 12

13 8/6/215 Should be avoided Antidepressant Monotherapy - Adjunctive treatment with SNRI and TCA be considered only after other antidepressants have been tried. Acute depressive episode Mood Stabilizer 1th International Conference on Bipolar Disorders (ICBD). Maintenance treatment Mood Stabilizer Antidepressant Antidepressant may be considered if a patient relapses into a depressive episode after stopping antidepressant therapy. 1th International Conference on Bipolar Disorders (ICBD). 13

14 Percentage Recovered 8/6/215 Antidepressant use in mixed states Should be avoided during manic and depressive episodes with mixed features. bipolar patients with predominantly mixed states. Previously prescribed antidepressants should be discontinued in patients experiencing current mixed states. Psychosocial treatment targets Responses to stressful event High expressed emotion and negative family interactions Sleep and circadian regulation Drug Adherence STEP-BD Randomized Bipolar Depression Studies NNT *p <.5 6 Bupropion - 3 (N = 86) * 64.4% 4 Paroxetine - 3 (N = 93) 51.5% % 27.3% Mood Stabilizer Mood Stabilizer + Antidepressant = N Intensive Brief Psychotherapy Psychoeducation Sachs GS, et al. N Engl J Med 27;356: Miklowitz DJ, et al. Arch Gen Psychiatry 27;64:

15 8/6/215 Adjunctive Psychosocial therapy: NNT for Relapse/Recurrence prevention Psychoeducation Nonstructured therapy N Relapse/ Recurrence Rate% NNT VS comparator Sample, Source After 6+ months of remission Colom 23 Family focused therapy After acute episode. Crisis management Miklowitz 23 Cognitive therapy When euthymic/ No psychotherapy subsyndromal 23 Conclusion Treatment of bipolar disorder focuses on acute stabilization and on maintenance. Balancing between efficacy and tolerability needs to be considered for treatment options. Important unmet needs - well-tolerated treatments for acute depression and maintenance Efficacy of treatment can be enhanced by the combination of psychosocial treatment with drugs. 15