International Conference Istanbul-mania

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 worsening?)  Tolerability problems: particularly EPS

(even

Is Mania a Psychotic Disorder? Leave me NO in broad concept : alone! I am It is different than Exactly, a prince… your Schizophrenia or Related highness 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



 

at least 10 days required Neuroleptics may have faster onset. 



over 1000 pts 67% improved

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 2002

Breier et al,

Bipolar Mania Euphoric

Dysphoric

Psychotic

Rapid Cycling

Li/VPA

VPA

Li/VPA + AAP

VPA

VPA + Li; + BZ

+ Li or CBZ; + AAP

+ BZ or AAP; VPA + Li New AC Gabapentin Omega-3 Lamotrigine Topiramate

Atypical AP’s Olanzapine

Typical AP’s VPA+Li+CBZ

Risperidone Clozapine

T4, T3 Ca++ blockers

ECT

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   



Second line 



Combination of 2 mood stabilisers (preferably AC + lithium)

Third line 



Lithium Valproate Carbamazepine (limited data)

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 “Dangerous”

=

APs (im) / EKT

APA 1994 1st choice

Treatment of Acute Mania WFSBP 2003 BAP 2003 APA 2002

Li

Li, VPA, SGA, CBZ

Severe:

AP, VPA Mild-Mod:

Li, CBZ

Severe:

Li / VPA + AP

Texas Alg 200

Li, VPA, OLZ

Mild-Mod:

Li, VPA, OLZ VPA, CBZ

2 step nd

APs only for the rapid control of agitation

MS + SGA

Li / VPA + AP

Various combinations of two 1st choice agents

Various combinations of two 1st choice agents

ECT

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

Neuroendocrinolo gy LettersSupplement Vol. 26 No. 1, 2005 Editors: Marek Jarema & Norman Sartorius

Degree of Evidence Efficacy Monotherapy

Add-On

Lithium Valproate Carbamazepine Conventional AP*

A A A B

A A B A

5 5 5 5

Lamotrigine Benzodiazepins ECT

A B D

? B B

2 2 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

Amisulpride

Monotherapy

?

Add-On

?

?

Aripiprazole Clozapine

A D

? ?

5 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 reports.



LMT



Levatiracetam No findings of large scale RCTs



Zonisamide

Failed in small sample Not effective in treating mania. No findings large scale RCTs 2006 Goodnick,of Expert Opin 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 needed antimanic Barbini et al. Dark therapy for mania: lower a pilot study. Bipolar Disord 2005: 7 doses and discharged earlier doses and discharged 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 11.5 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 well 80 (%)

Psychoeducation (n=60) 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