Atypical Antipsychotics In Bipolar Disorder

Seminar Dr Ramkumar G S

10/3/2010 Chair person Dr Jagadisha

Mania depression maintenance Rapid cycling

Olanzapine 13 6

Risperidone 9 2 1

Quetiapine 8 3 2 2

Aripirazole 6 2

Ziprasidone 2

Asenapine 2

Total 40 11 5 2

Overview of seminar

• Summary of RCTs.

• Systematic reviews.

• Psycho pharmacological principles.

• 2 studies looked in detail.

• Summary of presentation

Mania depression maintenance Rapid cycling

Olanzapine 13 6

Risperidone 9 2 1

Quetiapine 8 3 2 2

Aripirazole 6 2

Ziprasidone 2

Asenapine 2

Total 40 11 5 2

Olanzapine- Manian study control features

225 Olanz placebo Maintenance, time to ist mood episode

55 olanz placebo

Olan placebo RCT+open label ext.Qol

70 olan placebo

107 Olanz placebo 3wks, paediatric

165 Olanz RSPN No difference in effect.

234 olan haloperidol QOL, working status

100 Olan + dival Dival+Placebo +mixed, 6wks olnz> plac in HDRS score

58 Olan+ CBZ CBZ +mixed, 6wks

olan lithium 4wks

69 Olanz Lithium CGI

olanz Lithium 12 months maintenance

85 olanz Val or Li decreased disphoria,suicidality

224 Olanz+ MS Olanz alone Maintrnance,Clinical improv, QOL,

olan dival 47wks,Relapse rate was same

125 Olan val Response, remission

63 olan val 3wks

~200 Olan vs dival vs placebo Val & olan >placebo at 3ks: olan> val ar 12wks

Olan+ MS Placbo+ ms +mixed,response

Olanzapine- depressionn study control features

Olan +fluoxetine lamotrigine CGI, 6 month

205 Olan+ lamotrig lamotrigine cgi

Fluo+ OLAN OLANZ OPEN LAB RAND SHIFTING TO OLANZ ALONE CAUSED WORSENING

~370 OLAN VS placebo vs OLAN+ FLUOX 8WKS SAME effect, SIDE EFFECT NOT MORE FOR OLAN + FLUX

32 FLU VS OLANZ VS (FLU+OLAN) LOW SWITCH FOR OLANZ

~370 FLU VS PLACEBO VS Flu+ olenz

Systematic review and meta analysis

Olanzapine alone or in combination for acute maniaRendell 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.

• Olanzapine VS placebo YMRS - WMD: -5.94, 95% CI -9.09 to -2.80• • Olanz + lithium/val vs 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 somnolence and movement disorders than divalproex but less nausea

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).

Rendell JM, Gijsman HJ, Bauer MS, Goodwin G, Geddes J.

Risperidone alone or in combination for acute mania.  2006 • Six trials (1343 participants) • Risperidone monotherapy VS placebo in reducing manic

symptoms, using the YMRS WMD -5.75, 95% CI -7.46 to -4.04, P<0.00001; 2 trials) and in leading to response, remission and sustained remission.

• Effect sizes for monotherapy and adjunctive treatment comparisons were similar. Low levels of baseline depression precluded reliable assessment of efficacy for treatment of depressive symptoms.

• Overall risperidone caused more weight gain, extrapyramidal disorder, sedation and increase in prolactin level than placebo.

Rendell JM, Geddes J. Risperidone in long-term treatment

for bipolar disorder. 2006 • No randomised trials comparing Risperidone with other

treatments for the prevention of manic and depressive relapses were identified

• There is a need for randomised controlled trials comparing risperidone and other treatments for the prevention of relapse in bipolar disorder. The trials should involve randomisation of treatment for relapse prevention and involve long-term follow

up .

Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. Perlis et al 2006

• 12 studies with monotherapy, 6 adjuvant therapy• 4304 subjects• Aripiprazole, olanzapine, quetiapine, risperidone, and

ziprasidone all demonstrated significant efficacy in monotherapy (i.e., all confidence intervals exclude zero).

• no significant differences in efficacy among antipsychotics. Magnitude of improvement was similar whether the antipsychotic was utilized as monotherapy or adjunctive therapy.

• CONCLUSIONS: The 5 newer atypical antipsychotics were all superior to placebo in the treatment of bipolar mania. For monotherapy and add-on therapy, cross-trial comparisons suggest that differences in acute efficacy between the drugs, if any, are likely to be small

Acute bipolar mania: a systematic review and meta-analysis of co-therapy vs. monotherapy.Smith et al 2007

• Eight eligible studies were included (1124 participants).

• Haloperidol, olanzapine, risperidone and quetiapine as co-therapy > 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.

Second-generation antipsychotic agents in the treatment of acute mania: a systematic review and meta-analysis of randomized controlled trials. Sherk et 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)

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

• 5 trials (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 presentation atypical 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.

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.

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.

FDA approval

• All atypical antipsychotics except clozapine have received US FDA approval for treatment of mania associated with bipolar disorder in adults.

• Olanzapine, aripiprazole and quetiapine has approval for maintenance.

• Quetiapine (monotherapy) approved for depression

Spectrum of Efficacy in Mania , Depression , anxiety

Psychopharmachological principlesStahl’s 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 effectiveness also may not be justified.

• Lithium today is no longer used as high dose monotherapy.

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…

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

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 simultaneously.

• Quantitative difference in neurotransmitters dysfuctional circuits that are “ too low” in depression as against “too high” in mania dysfunctional circuits as being “out of tune” or chaotic.

Possible mechanisms

• D2 antagonism or partial agonist properties reduce psychotic symptoms.

• 5HT2A antagonist properties reduce nonpsychotic mania and depressive symptoms.(could be by reduction of glutamate hyperactivity from overly active pyramidal neurons)

Other mechanisms in bipolar depression

• By increasing availability of trimonoamine neurotransmitters serotin, dopamine and norepinephrine as they are known to be critical in the action of antidepressants in unipolar depression.

• Such actions are predicted to have favourable effect not only in mood but also in cognition.

• Some independent action on sleep and neurogenesis.

A RCT of maintenance treatment with adjunctive Risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Macfadden et al Bipolar Disord 2009: 11: 827–839

This study included patients with bipolar disorder type I with four mood episodes in the 12 months prior to study entry.

Following a 16-week, open-label stabilization phase with RLAT plus TAU, remitted patients entered a 52-week, double-blind, placebo-controlled, relapse prevention phase.

Randomized patients continued treatment with adjunctive RLAT (25–50 mg every two weeks) plus TAU (n = 65) or switched to adjunctive placebo injection plus TAU (n = 59). The primary outcome measure was time to relapse to any mood episode.

Macfadden et al Bipolar Disord 2009: 11: 827–839

• Of 240 enrolled patients, 124 entered double-blind treatment.• Time to relapse was longer in patients receiving adjunctive RLAT (p =

0.010). • Relapse rates were 23.1% (n = 15) with adjunctive RLAT versus 45.8% (n

= 27) with adjunctive placebo; • relative relapse risk was 2.3-fold higher with adjunctive placebo (p =

0.011). Completion rates were: adjunctive RLAT, 60.0% (n = 39) and adjunctive placebo 42.4% (n = 25; p = 0.050).

• Adverse event (AE)-related discontinuations were 4.6% (n = 3) and 1.7% (n = 1), respectively.

• Common AEs (adjunctive RLAT versus adjunctive placebo) were: tremor (24.6% versus 10.2%), insomnia (20.0% versus 18.6%), muscle rigidity (12.3% versus 5.1%), weight increased (6.2% versus 1.7%), and hypokinesia (7.7% versus 0.0%)

.• Conclusions: Adjunctive RLAT significantly delayed time to relapse in

patients with bipolar disorder type I who relapse frequently. Safety and tolerability of RLAT were generally consistent with that previously reported.

Medicating mood with maintenance inmind: bipolar depression pharmacotherapy.Malhi et al Bipolar Disord 2009: 11 (Suppl. 2): 55–76

• A detailed literature review was undertaken with a particular emphasis on pharmacological treatment strategies for bipolar depression across the acute and maintenance phases of the illness

• lithium and lamotrigine as first-line treatment in preference to valproate, and indicates that, for acute episodes, quetiapine and olanzapine have perhaps achieved equivalence at least in terms of efficacy.

• However, the effectiveness of the atypical antipsychotics in maintenance therapy is constrained by the potential for significant side effects of individual agents and the lack of both long-term research data and clinical experience in treating bipolar disorder as compared to other agents.

• Conversely, lithium and the anticonvulsants are generally slower to effect symptomatic change, and this limits their usefulness and useful acute treatments are typically continued in maintenance. Therefore, when medicating mood in acute bipolar depression it is imperative to keep maintenance in mind as it is this aspect of treatment that determines long-term success.

• Atypical agent as a class provide some of the broadest efficacy in bipolar disorder available – indeed broader than that for most anticonvulsants and comparable or better than that for lithium. Increasingly therefore bipolar is not only treated with 2 or more agents but with one of those as an atypical antipsychotic.

Summary

• Atypical antipsychotics has proven efficacy in all phases of bipolar disorder and therefore increasingly being used as a mood stabilizer.

• Monitoring for side effects needed while using it for maintenance treatment.

• Combination treatment is replacing monotherary.• Psychopharmachological understanding is giving

greater insights into possible mechanisms of action in Bipolar disorder.

• Current evidence base insufficient for guiding the clinician in the long term management of this essentially chronic disorder.

References• 1.      Benjamin J. Sadock , Virginia A. Sadock , Pedro Ruiz. Kaplan and sadock’s Comprehensive textbook of psychiatry.

9th edition.Wolters kluwer.• 2.      Cipriani A, Rendell JM, Geddes J. Olanzapine in long-term treatment for bipolar disorder. Cochrane Database of Systematic

Reviews 2009.• 3.      Gao K, Ganocy SJ, Gajwani P, Muzina DJ, Kemp DE, Calabrese JR. A review of sensitivity and tolerability of antipsychotics in

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placebocontrolled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Bipolar Disord 2009: 11: 827–839.

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• 10.  Rendell JM, Geddes J. Risperidone in long-term treatment for bipolar disorder. Cochrane Database of Systematic Reviews 2006.• 11.  Scherk H, Pajonk FG, Leucht S. Second- generation antipsychotic agents in the treatment of acute mania: a systematic review and

meta-analysis of randomized controlled trials: Arch Gen Psychiatry. 2007 Apr;64(4):442-55. • 12.  Smith LA, Cornelius V, Warnock A, Tacchi MJ, Taylor D. Acute bipolar mania: a systematic review and meta-analysis of co-therapy

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