Refractory Mania

David Taylor

Maudsley Hospital

King’s College, London

Refractory mania

Rare as a condition (i.e. longstanding,

unremitting symptoms of mania are rare)

More often manifest as increased cycling

Evidence-based prescribing in short and long

term can reduce likelihood of treatment failure

and cycle acceleration

Where to start?

Meta-analysis of Randomized, Placebo-controlled

Trials in Acute Bipolar Mania: Response*

*Response = at least 50% improvement in Young Mania Rating Scale score

Smith et al. Bipolar Disorders 2007;9:551–560.

0.1 1 10 100

Brecher & Huizar 2003

Smulevich et al. 2005

Pooled effect

Tohen et al. 1999

Tohen et al. 2000

Pooled effect

Brecher & Huizar 2003

Paulsson & Huizar 2003

Pooled effect

Vieta et al. 2002

Smulevich et al. 2005

Hirschfeld et al. 2004

Pooled effect

Keck et al. 2003

Sachs et al. 2006

Pooled effect

Bowden et al. 1994

Paulsson & Huizar 2003

Pooled effect

Pope et al. 1991

Bowden et al. 1994

Pooled effect

Weisler et al. 2004

Weisler et al. 2005

Pooled effect

Haloperidol

Olanzapine

Quetiapine

Risperidone

Aripiprazole

Lithium

Valproate semisodium

Carbamazepine

Favours placebo Relative risk Favours drug

Prophylaxis

Relapse is common –

mania occurs in the context of failed treatment

Olanzapine vs placebo Tohen et al, Am J Psych, 163, 247-256, 2006

Subjects had reached remission on combination treatment and

were randomized to have olanzapine withdrawn or continued

Tohen et al, Br J Psychiatry 2004;184:337-45

MS +/- Olanzapine in Maintenance?

Time to Recurrence of Mania or Depression (Days)

Placebo + Lithium or Valproate (n=38)

Li=.75, VPA=67.6

Olanzapine + Lithium or Valproate (n=30)

Li=.78, VPA = 69.2

Pro

ba

bil

ity o

f R

em

ain

ing

in R

em

issio

n (

%)

0 100 200 300 400 500

* P=0.023

0

20

40

60

80

100

*

Use the right prophylaxis

Lancet 2010; 375: 385-95

3 6 9 12 15 18 21 24 27 30 33 Months

Time to event outcome measures- first admission or adjuvant treatment for

emerging mood episode

Lancet 2010; 375: 385-95

The problem of drug withdrawal

….choose patients carefully

Outcome after rapid vs gradual discontinuation of lithium

treatment in bipolar disorders G. L. Faedda, et al, ARCH GEN PSYCH, 1993, 50, 448-455

2.8

5.4 5.4

0

1

2

3

4

5

6

HR

Mania Depression Any (12

month)

Polarity

5 Year Hazard Ratio - Recurrence (n=64)

Recurrence HR,Fast vs Slow

Baldessarini, R.J. et al. 1997. Reduced morbidity after gradual discontinuation of lithium treatment

for bipolar I and II disorders: a replication study. Am J Psychiatry; 154: 551-553

Combination Therapy in Acute mania

Commonplace – often 3 drugs at once

Combination Therapy Versus Monotherapy in

Patients with Inadequate Mood Stabiliser Response

Response = at least 50% improvement in YMRS score, in randomized controlled trials comparing adjunct therapy with monotherapy.

Smith et al. Acta Psychiatr Scand 2007:115:12–20.

Meta-analysis of response rates*

Risk ratio

Favours monotherapy Favours adjunct therapy

Atypical antipsychotic

Tohen, 2002b (149/220 51/114)

Sachs, 2004 (44/81 29/89)

DelBello, 2002 (13/15 8/15)

Yatham, 2003 (40/68 30/73)

Subtotal

Risk ratio

(95% CI)

Study

1.51 (1.21, 1.89)

1.67 (1.16, 2.39)

1.63 (0.97, 2.72)

1.43 (1.02, 2.01)

1.53 (1.31, 1.80)

%

Weight

51.0

21.0

6.1

22.0

100.0

0.5 1 2 5

Antipsychotic

Brecher, 2003 (55/99 35/101)

Subtotal

Atypical antipsychotic

Tohen, 2000 (35/54 24/56)

Tohen, 1999 (34/70 16/66)

Hirschfeld, 2004 (55/127 29/119)

Brecher, 2003 (43/102 35/101)

Paulsson, 2003 (57/107 27/97)

Subtotal

Mood stabiliser

Bowden, 1994 (32/67 18/72)

Bowden, 1994 (17/35 18/72)

Pope, 1991 (9/20 2/23)

Paulsson, 2003 (51/98 27/97)

Subtotal

Risk ratio

(95% CI)

Study

1.60 (1.16, 2.21)

1.60 (1.16, 2.21)

1.51 (1.05, 2.17)

2.00 (1.23, 3.27)

1.78 (1.22, 2.58)

1.22 (0.86, 1.73)

1.91 (1.33, 2.76)

1.64 (1.38, 1.95)

1.91 (1.03, 3.55)

1.94 (1.00, 3.76)

5.18 (1.26, 21.20)

1.87 (1.29, 2.71)

2.02 (1.52, 2.67)

%

Weight

100.0

100.0

17.7

12.3

22.4

26.4

21.2

100.0

23.6

17.9

3.8

54.7

100.0

Risk ratio

Favours active drug Favours placebo

0.5 1 10 25

Antipsychotic or mood stabiliser in mania

– response rates

2 5

Combination Therapy Versus Monotherapy in

Patients with Inadequate Mood Stabiliser Response

b. Haloperidol + mood stabiliser

Sachs, 2002 (1/53 2/51)

Subtotal

c. Olanzapine + ms

Tohen, 2002b (25/229 2/115)

Subtotal

e. Risperidone + ms

Sachs, 2004 (5/91 6/100)

Sachs, 2002 (2/52 2/51)

Yatham, 2003 (1/75 3/75)

Subtotal

Risk ratio

(95% CI)

0.48 (0.05, 5.14)

0.48 (0.05, 5.14)

6.28 (1.51, 26.04)

6.28 (1.51, 26.04)

0.92 (0.29, 2.90)

0.98 (0.14, 6.70)

0.33 (0.04, 3.13)

0.79 (0.32, 1.95)

%

Weight

100.0

100.0

100.0

100.0

61.6

22.1

16.3

100.0

Risk ratio 0.02 0.2 5 50 1

Favours adjunct therapy Favours monotherapy

Meta-analysis of withdrawal caused by adverse event

Study

Smith et al. Acta Psychiatr Scand 2007:115:12–20.

Use the right drug

www.thelancet.com Published online August 17, 2011 DOI:10.1016/S0140-6736(11)60873-8

www.thelancet.com Published online August 17, 2011 DOI:10.1016/S0140-6736(11)60873-8

Adverse effects and tolerability

Refractory mania

Clozapine

Tamoxifen

Verapamil

? others

Clozapine

All subjects failed

CPZ 500mg + Li

Calabrese JR et al Am J Psychiatry. 1996 Jun;153(6):759-64.

Clozapine for treatment-refractory mania.

Double-blind, randomized, placebo-controlled 6-week study on the efficacy and

safety of the tamoxifen adjunctive to lithium in acute bipolar mania

Journal of Affective Disorders, Volume 129,

Issues 1–3, March 2011, 327-331

Rapid cycling

Thyroxine

Thyroxine

up to

400mcg/day

Quetiapine

Summary

Treat………

Acute mania with MS+AS?

Prophylaxis with MS+AS

Refractory mania with clozapine (? verapamil, etc)

Rapid cycling with quetiapine

Consider tamoxifen, nimodipine, thyroxine, etc.