Treatment of acute mania:

An update
E. Timuçin Oral, MD
Bakırköy Prof Mazhar Osman Research and Training Hospital
for Psychiatric & Neurological Diseases
İstanbul / Turkey
 Avicenna (İbn-i Sina)
Samarkand

Aretaeus
(Capadoccia)

Hippocrate
s (Island
Cos)
Ancient Anatolia
(II. Century AD)

Aretaeus of Cappadocia:
first to link mania and
melancholia

“… , ,
”

“The development of
mania is really a
worsening of the disease
(melancholia) rather than
a change into another
 Bipolar Disorder: What Determines the
Course?

 Mania is the hallmark of the classical

disease. Degrees of excitement
characterizes the type of the illness in
Classification Systems (BP-I or II?)

 Recurrence and severity of the depressions

dominate the illness (Mixed episodes and
QoL)

Thomas, 2002
 Goals of Therapy in Bipolar Mania
 Control “dangerous” symptoms
 Suicide, agitation, psychosis

 Stabilize mood
 Control mania without provoking

depression
 Treat all facets of mania - including
depressive, anxious, psychotic elements
 Restore premorbid functioning
Goals of Therapy in Bipolar Mania

 Avoid harming patient

 Overdose, severe toxicity, teratogenity

 Simplify patient’s daily routines

 Enhance compliance through simple
dosing
 Avoid annoying side effects or cognitive
dulling
 Limit need for medical procedures
Traditional Treatment Options for
Mania
Lithium
 More effective in classic type than mixed episode or RC?
 Relatively slow onset of action

Anticonvulsants
 Less effective in severe mania
 Tolerability problems
 More drug interactions

Conventional antipsychotics
 Effective in mania, but not in depressive symptoms (even
worsening?)
 Tolerability problems: particularly EPS
Is Mania a Psychotic Disorder?

NO in broad Leave me
concept :
alone! I am
It is different than
a prince… Exactly,
your
Schizophrenia or Relatedhighness
Disorders
YES in a narrow concept:
1/4 to 2/3 of all manic
episodes are associated
with delusions & 13-40%
with hallucinations.
Goodwin-Jamison, 1990
 Role of lithium in acute
mania
 10 early uncontrolled trials N=413
 81% responded

 Only 4 placebo controlled trials

 23 studies altogether
 over 1000 pts
 67% improved
 at least 10 days required
 Neuroleptics may have faster onset.
 Role of Valproate in Acute Mania

 McElroy et al 1996 randomized DB; n=36

 DVPX 20 mg/kg/day or HAL 0.2 mg/kg/day
 6 days: YMRS and SAPS
 Equally effective in reducing manic and
psychotic sx

 Bowden et al 1994 randomized DB; n=179

 DVPX 150 micrograms/mL or Li 1.5 mEq/L
 Proportion of pts improving at least 50%:
 Li 49%; DVPX 48% placebo 25%
 Conventional Antipsychotics
 Comparable in efficacy and onset of action
in acute mania to mood stabilizers
 More effective than lithium during initial
week
of treatment in highly agitated patients
 Limitations
 Neurologic, neuroendocrine and other systemic
side effects
 Obfuscation of response to mood stabilizer
 Possible depressogenic effects
McElroy SL et al. J Clin Psychiatry. 1996(Apr);57(4):142-146
 Second
Generation in Mania
Antipsychotics

SGA have been applied in mania

 to treat psychotic symptoms

 to control agitation
*(olanzapine and ziprasidone have also im forms)
4. they may have a spesific antimanic effect

Breier et al,
2002
 Bipolar Mania
Rapid
Euphoric Dysphoric Psychotic
Cycling

Li/VPA VPA Li/VPA VPA

+ AAP

+ BZ or AAP; VPA + Li VPA + Li; + Li or CBZ;

+ BZ + AAP

New AC Atypical AP’s Typical AP’s ECT

Gabapentin Olanzapine VPA+Li+CBZ
Omega-3
Lamotrigine Risperidone T4, T3
Topiramate Clozapine Ca++ blockers
AAP = atypical antipsychotic; BZ = benzodiazepine;

Sachs et al. Expert Guideline Series. 2000

 World Federation of Societies of
Biological Psychiatry 2003 Guidelines
 Acute bipolar mania, mild to moderate
 First line
 Lithium
 Valproate
 Atypical antipsychotic (best evidence: olanzapine or
risperidone)
 Carbamazepine (limited data)
 Second line
 Combine mood stabiliser with 2nd mood stabiliser or
atypical antipsychotic -or- change mood stabiliser
 Adjunctive treatment with benzodiazepines
Grunze H, Kasper S, Goodwin G et al. World J Biol Psychiatry 2003;4:5-13.
and/or low potency/atypical antipsychotics when
 World Federation of Societies of
Biological Psychiatry 2003 Guidelines
 Acute bipolar mania, severe
 First line
 Lithium
 Valproate
 Carbamazepine (limited data)
 Second line
 Combination of 2 mood stabilisers (preferably AC +
lithium)
 Third line
 ECT
 Adjunctive treatment with benzodiazepines and/or
atypical antipsychotic/high potency antipsychotic
(also injectable) when indicated
Grunze H, Kasper S, Goodwin G et al. World J Biol Psychiatry 2003;4:5-13.
 Ayşegül Özerdem, Manic-Hypomanic Episode Treatment.
Treatment Guidelines for Bipolar Disorders
Psychiatric Association of Turkey (S Vahip, O Yazici, S Kultur:
eds),
TPD Yayınları No:1 April 2003 İstanbul
 Treatment of BP Mania in
TURKEY 2004

Acute Period

Cooperative = Li (and/or VPA) + AP

Rezistant or = APs (im) / EKT

“Dangerous”
 Treatment of Acute
APA 1994
Mania
WFSBP 2003 BAP 2003 APA 2002 Texas Alg 200

1st Li Li, VPA, Severe: Severe: Li, VPA,

choice
SGA, CBZ AP, VPA Li / VPA OLZ
Mild-Mod: +
Li, CBZ AP
Mild-Mod:
Li, VPA,
OLZ

Various Various
VPA, MS + SGA Li / VPA combinations combinations
CBZ + of two 1st of two 1st
AP choice agents choice agents
APs only for
the rapid ECT
2 nd control of
step agitation

Fountoulakis et al. J Affect Dis, 2005;86:1-10

Neuroendocrinolo
gy Letters-
Supplement Vol.
26 No. 1, 2005

Editors:
Marek Jarema &
Norman Sartorius
 Degree of Evidence Efficacy

Monotherapy Add-On

Lithium A A 5
Valproate A A 5
Carbamazepine A B 5
Conventional AP* B A 5
Lamotrigine A ? 2
Benzodiazepins B B 2
ECT D B 5

*Haloperidol & Chlorpromazine

Oral ET. Neuroendocrinology Letters Supplement Vol. 26 No. 1, 2005

Degree of Evidence
• Multiple double-blind randomized clinical trials
(RCT) of the drug versus placebo and an active
comparator
• At least 1 double-blind RCT of the drug versus
placebo or an active comparator
• At least one single-blind, controlled trial or more
than one open-label non-placebo controlled trials
• Open-label studies and case-series studies

Efficacy
5. Quite effective (≥50% of patients responded)
4. Generally positive reports about the efficacy
3. Possible efficacy, but more data is necessary
2. Does not seem to be effective
1. Generally not favorable
 Degree of Evidence Efficacy

Monotherapy Add-On

Amisulpride ? ? ?
Aripiprazole A ? 5
Clozapine D ? 5
Olanzapine A A 5
Risperidone A A 5
Quetiapine A A 5
Ziprasidone A B 4
Zotepine D ? 5

Oral ET. Neuroendocrinology Letters Supplement Vol. 26 No. 1, 2005

 Sedation can be a desired effect in treatment
of mania as it aims to control agitation,
impulsivity and aggression in the shortest
time possible.

 SGAs appear to be similar in their antimanic

effects, as shown in 3 week double-blind
placebo controlled clinical trials. (reduce YMRS
50% in half the patients after 3 weeks)

 Case reports of switch into mania with SGAs

did not proved by large controlled trials, and
they were probably 'spontaneous' switches
Oral ET. Neuroendocrinology Letters Supplement Vol. 26 No. 1, 2005
Mean Doses of SGA in Mania
Trials
• 15.5 mg/day for olanzapine
• 600 mg/day for quetiapine
• 4.5 mg/day for risperidone
• 130 mg/day for ziprasidone
• 28 mg/day for aripiprazole
“Real Life Doses” for SGA in
Mania
 Results from CATIE
• NY and Australian
Examples

Citrome-Jaffe-Levine, WFBP Vienna 2005

Anticonvulsants in Acute Mania - US
 VPA & CBZ Approved by the US FDA
 OXCBZ Never been found significantly
effective in large-scale
studies.
 Gabapentin Failed in large-scale investigations
 Topiramate Failed in large-scale investigations
 Tiagabine Failed in small sample
reports.
 LMT Not effective in treating mania.
 Levatiracetam No findings of large scale RCTs
 Zonisamide No findings
Goodnick,of large
Expert scale
Opin RCTs 2006
Pharmacother
Anticonvulsants in Acute Mania - EU

 Oxcarbazepine: Efficacy in mania is similar

to that of the CBZ
 Lamotrigine: Best alternative to lithium in
depressive episodes
 Topiramate: Not effective in acute mania
 Levatiracetam: Some benefits, but no
RCT
 Gabapentin: Efficacy are controversial
 Tiagabine: Negative open trials

Perez-Ceballos et al. Actas Esp Psiquiatr. 2006

 Mixed Episodes

 Mixed episodes comprise up to 40 %

of acute admissions.
 There were very few RCT studies
specifically designed.
 Acute mixed states do not respond
favourably to lithium. VPA & CBZ are
drugs of first choice.
Kruger et al. Psychiatr Prax. 2006
Specific Cases
 Rapid cycling
 VPA & LMT first-line monotherapy in US
 Not approved in many European countries
 Drug combination as a more frequent strategy in
Europe
> Li + SGA
> Li + SSRI
> Li + CBZ + SGA / SSRI

 Mixed states
 Monotherapy (VPA / SGA / Li) recommended in
the US for severely ill patients
 AD dosage reduction and MS augmentation more
frequent in Europe
Inadequately controlled
symptoms
If symptoms are inadequately controlled
with optimized doses of the first-line
medicine and/or mania is very severe
 Consider dosing or add another
medicine

 Consider clozapine in more refractory

illness
 ECT may be considered for manic
patients who are severely ill and/or
whose mania is treatment resistant, who
 Treatment of Acute Mania:
Other considerations – Enough
Evidence?

 ECT
 TMS

 Newer options??
 ECT
 Well established efficacy and safety in both
mania and depression

 Two controlled early studies: ECT >

Comperator

 Useful in continuation and maintenance: No

RCTs

 Recently published case series: 6 treatment

resistant patients (3 in mania, 2 depressed
Fink. 1994; Potter &Rudorfer 1993; Gitlin 2001; Vaidia et al. 2003
and 1 mixed)
* Macedo-Soares et al J ECT 2005; 21:31-34
TMS in Mania

16 patients, 14-day double-blind, controlled

trial of right versus left prefrontal TMS at 20
Hz (2-second duration per train, 20
trains/day for 10 treatment days).
right > left prefrontal TMS
The therapeutic effect of TMS in mania may
show laterality

Griseous et al. Am J Psychiatry. 2000 May;157(5):835-6

TMS in Mania

19 out of 25 patients completed right TMS

vs sham TMS
Right TMS was no more effective than sham
TMS. It is possible that the previous results
were due to an effect of left TMS to worsen
mania

Kaptsan et al. Bipolar Disord. 2003 Feb;5(1):36-9

 Extended
bedrest &
darkness

http://www.psycheducation.org/depression/darkrx.htm
 Dark Therapy
 16 inpatients in manic episode were applied
14 h of enforced darkness (6 pm-8 am) for 3
days
 Inpatients compared with a control group of
16 treated with therapy as usual (TAU) by
YMRS
 DT + TAU resulted in a significantly faster
decrease of YMRS scores
 ⇑duration of illness ⇓effect with DT
 GoodB responders
Barbini needed
et al. Dark therapy for mania: lower antimanic
a pilot study. Bipolar Disord
2005: 7
doses and discharged
doses and discharged earlier earlier
High above the roof tops,
Higher than the milky way,
Slipping through the hour glass,
Shooting up the desert plain,
You are one life older than before,
But you can't stop the chill,
Now you're falling in slow motion,
Though the air is still.

If you close your eyes than I can take you all

the way,
Let me close your eyes and I will take it all the
way.
……………………………………………………..
 I kissed you and you
became a prince why are
you unhappy?
Psychosocial Interventions

Goals:
- Educating
- Adherence
- Dealing with triggers (psychosocial
stress)
- Communication: problem-solving
 FFT: Reduce the severity of depressive and
manic symptoms over two years period and
levels of drug adherence were also higher
(Miklowitz 2003)

 CBT: Less symptomatic with less relaps in 1-

1.5 year (Scott 2001,
Lam 2003)

 Group Psychoeducation: Less

recurrence&longer duration till recurrence
(Colom 2003)
Group psychoeducation reduces recurrence
in medicated patients with bipolar disorder
Patients 100
remaining Psychoeducation
(n=60)
well 80
(%) Usual care (n=60)

60

40

20

0
0 6 12 24 30 36
Months

Receiving standard pharmacotherapies p<0.001 vs usual care

Colom et al 2003
 “Illusion of Rising”
The Essence of Bipolarity