atypical antipsychotics in bipolar disorders

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Evidence base for the use of atypical antipsychotics in bipolar disorders, psychopharmacological principles thereof


  • 1. Atypical Antipsychotics In Bipolar Disorder SeminarDr Ramkumar G S 10/3/2010Chair person Dr Jagadisha

2. 3. 4. 2 Asenapine 2 Ziprasidone 2 6 Aripirazole 2 5 11 40 Total 2 2 3 8 Quetiapine 1 2 9 Risperidone 6 13 Olanzapine Rapid cycling maintenance depression Mania 5. Overview of seminar

  • Summary of RCTs.
  • Systematic reviews.
  • Psycho pharmacological principles.
  • 2studies looked in detail.
  • Summary of presentation

6. 2 Asenapine 2 Ziprasidone 2 6 Aripirazole 2 5 11 40 Total 2 2 3 8 Quetiapine 1 2 9 Risperidone 6 13 Olanzapine Rapid cycling maintenance depression Mania 7. 8. Olanzapine- Mania QOL, working status haloperidol olan 234 +mixed, 6wks CBZ Olan+ CBZ 58 +mixed, 6wks olnz> plac in HDRS score Dival+Placebo Olan + dival 100 No difference in effect. RSPN Olanz165 3wks, paediatric placebo Olanz 107 4wks lithium olan features control study n Maintenance, time to ist mood episode placebo Olanz225 placebo olanz 55 RCT+open label ext.Qol placebo Olanplacebo olan 70 Val & olan >placebo at 3ks: olan> val ar 12wks Olanvsdivalvsplacebo ~200 Response, remission val Olan125 +mixed,response Placbo+ ms Olan+ MS 3wks val olan 63 47wks,Relapse rate was same dival olan Maintrnance,Clinical improv, QOL,Olanz alone Olanz+ MS 224 decreased disphoria,suicidality Val or Li olanz 85 12 months maintenance Lithium olanz CGI LithiumOlanz69 9. Olanzapine- depression features control study n FLU VS PLACEBO VSFlu+ olenz ~370 LOW SWITCH FOR OLANZ FLUVS OLANZVS (FLU+OLAN) 32 8WKS SAME effect, SIDE EFFECT NOT MORE FOR OLAN + FLUX OLAN VS placebovs OLAN+ FLUOX ~370 OPEN LABRAND SHIFTING TO OLANZ ALONE CAUSED WORSENING OLANZ Fluo+ OLAN cgi lamotrigine Olan+ lamotrig 205 CGI, 6 month lamotrigine Olan +fluoxetine 10. Systematic review and meta analysis 11. Olanzapine alone or in combination for acute mania Rendell JM, Gijsman HJ, Keck PK, Goodwin G, Geddes J 2003

  • Six trials (1422 participants).
  • There was a high rate of failure to complete treatment on all treatments which may have biased the estimates of relative efficacy.
  • OlanzapineVS placeboYMRS - WMD: -5.94, 95% CI -9.09 to -2.80
  • Olanz + lithium/valvs placebo+ lithium/val
  • YMRS-WMD -4.01, 95% CI -6.06 to -1.96).
  • Olanzapine was superior to divalproex at reducing manic symptoms
  • (SMD): -0.29, 95% CI -0.50 to -0.08).
  • Fewer patients discontinued treatment on olanzapine than placebo
  • (RR: 0.62, 95% CI 0.48 to 0.80).
  • Olanzapine caused more prolactin elevation than placebo . Olanzapine caused greater weight gain somnolenceand movement disorders than divalproex but less nausea

12. Olanzapine in long-term treatment for bipolar disorder Cipriani A, Rendell JM, Geddes J; 2003

  • Five trials (1165 participants)
  • Oanzapine ~ placebo (either alone or in combination with lithium or valproate) in terms of number of participants who experienced relapse into mood episode (random effects RR 0.68, 95% CI 0.43 to 1.07, p = 0.09; 2 studies, n=460),
  • however restricting the analysis to the trial that compared olanzapine monotherapy versus placebo, there was a statistically significant difference in favour of olanzapine
  • Olanzapine ~ other mood stabilisers (lithium or valproate) in preventing symptomatic relapse for any mood episode, however, olanzapine was more effective than lithium in preventing symptomatic manic relapse (RR 0.59, 95% CI 0.39 to 0.89, p = 0.01; 1 study, n=361).

13. Rendell JM, Gijsman HJ, Bauer MS, Goodwin G, Geddes J. Risperidone alone or in combination for acutemania.2006

  • Six trials (1343 participants)
  • Risperidone monotherapyVS placebo in reducing manic symptoms, using the YMRS WMD -5.75, 95% CI -7.46 to -4.04, P monotherapy with a mood stabilizer.
  • the pooled difference in mean scores was 4.41 (95% CI: 2.74, 6.07).
  • Significantly more participants on co-therapy met the response criterion (at least 50% reduction in YMRS score), RR 1.53 (1.31, 1.80).
  • With some drugs, co-therapy decreased tolerability compared with monotherapy, and resulted in greater weight gain.
  • CONCLUSION: The addition of antipsychotic treatment to established mood-stabilizer treatment is more effective than mood-stabilizer treatment alone.

17. Second-generation antipsychotic agents in the treatment of acute mania: a systematic review and meta-analysis of randomized controlled trials. Sherket al 2007.

  • 24 studies with 6187 patients
  • SGA > placebo SMD 0.45(-0.57-0.32)
  • SGA+MS> MS+placebo -0.35(-.047 0.24)
  • SGA=MS 0.75 (-0.33 0.00)
  • SGA not superior to haloperidol
  • 0.11(-0.10 +0.32)

18. Atypical antipsychotics in bipolar disorder: systematic review of randomised trials.Derry S, Moore R A .2007

  • 5trials (2,206 patients) - depressive episode,
  • 25 trials (6,174 patients) - manic or mixed.
  • In 8-week studies presenting with depression,quetiapine and olanzapine> placebo, with NNTs of 5-6, but more adverse event withdrawals (NNH 12).
  • With mania or mixed presentationatypical antipsychotics> placebo, with NNTs of about 5 up to six weeks, and 4 at 6-12 weeks, but more adverse event withdrawals (NNH of about 22) in studies of 6-12 weeks.
  • In comparisons with established treatments, atypical antipsychotics had similar efficacy, but significantly fewer adverse event withdrawals (NNT to prevent one withdrawal about 10).
  • In maintenance trials atypical antipsychotics had significantly fewer relapses to depression or mania than placebo or active comparator.

19. Antipsychotic-induced extrapyramidal side effects in bipolar disorder and schizophrenia: a systematic review.Gao K et al 2008 .

  • Eleven trials in mania, 4 in bipolar depression, and 8 in schizophrenia were included.
  • Haloperidol significantly increased the risk for akathisia, overall EPS, and anticholinergic use in both mania and schizophrenia, with a larger magnitude in mania, an NNTH for akathisia of 4 versus 7, EPS of 3 versus 5, and anticholinergic use of 2 versus 4, respectively
  • Among atypical antipsychotics, only ziprasidone significantly increased the risk for overall EPS and anticholinergic use in both mania and schizophrenia, again with larger differences in mania, an NNTH for overall EPS of 11 versus 19, and anticholinergic use of 5 versus 9.
  • In addition, risks were significantly increased for overall EPS (NNTH = 5) and anticholinergic use (NNTH = 5) in risperidone-treated mania, akathisia in aripiprazole-treated mania (NNTH = 9) and bipolar depression (NNTH = 5), and overall EPS (NNTH = 19) in quetiapine-treated bipolar depression.
  • CONCLUSIONS: Bipolar patients, especially in depression, were more vulnerable to having acute antipsychotic-induced movement disorders than those with schizophrenia.

20. A review of sensitivity and tolerability of antipsychotics in patients with bipolar disorder or schizophrenia: focus on somnolence. Gao et al 2008

  • Ten acute trials in mania, 3 in bipolar depression, and 8 in schizophrenia were identified, along with 2 maintenance studies in bipolar disorder and 2 in schizophrenia
  • CONCLUSION: Patients with bipolar disorder appear more sensitive to antipsychotics, and depressed patients are less tolerant to somnolence than those with either mania or schizophrenia.

21. FDA approval

  • Allatypical antipsychotics except clozapine have received US FDA approval for treatment of mania associated with bipolar disorder in adults.
  • Olanzapine, aripiprazole andquetiapinehas approval for maintenance.
  • Quetiapine(monotherapy) approved for depression

22. Spectrum of Efficacy in Mania , Depression,anxiety 23. 24. Psychopharmachological principles Stahls essential psychopharma 3rd edi.

  • For many reasons, the use of lithium has declined in recent years , particularly among younger psychopharmachologists.
  • Selectively not using it in rapid cycling or mixed episodes as against euphoric mania citing lack of effectivenessalso may not be justified.
  • Lithium today is no longer used as high dose monotherapy.

25. Mood stabilizing

  • Mood stabilizers have evolved significantly. Include agents that are mania-minded and treat mania as well as preventing manic relapse as well as depression minded and treat bipolar depression while preventing depressive relapse.
  • Because of limits of efficacy and tolerability combination therapy has become the rule.
  • Evidence base fast evolving as to how to combine these agents

26. Atypical antipsychotics: not just for psychotic mania

  • Its effect on core non psychotic symptoms of mania and for maintenance treatment to prevent recurrence of mania came as a surprise with some proving effective for bipolar depression and preventing its recurrence

27. Putative pharmacological mechanism of atypical antipsychotics in mania and bipolar depression

  • It is still a mystery how Bipolar disorder can create seemingly opposite symptoms during various phases of the illness as well as the combination of both manic and depressive symptoms si


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