what is a rational pharmacotherapeutic next step?

Clozapine resistance: what is a rational
pharmacotherapeutic next step?
Jan Bogers
[email protected]
www.clozapinepluswerkgroep.nl
Dutch Clozapine Collaboration Group
Mental Health Services Rivierduinen
European Conference on Schizophrenia Research – 24/25/26 September 2015
Berlin - Germany
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Statement of Potential Conflicts of Interest
Clozapine resistance: what is a rational pharmacotherapeutic next step?
Relating to this presentation, there are no relationships that
could be perceived as potential conflict of interests:
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Beyond clozapine
• Clozapine, what else?!
• Clozapine, or.... “something completely different”
• Recommendations
Dutch Clozapine Plus Collaboration Group
ECSR 2015
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Clozapine, what else?
Dutch Clozapine Plus Collaboration Group
ECSR 2015
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Country
% clozapine
Taiwan
26.9
China
26.7
Australia
19.0
Thailand
17.9
Korea
12.7
India
12.7
Hong Kong
11.0
Denmark
10.2
Singapore
7.0
Malaysia
4.0
USA
Dutch Clozapine Plus Collaboration Group
ECSR 2015
1.8-2.5-4.4
Xiang et al, Aust NZ J Psychiatry 2011
Malalagama et al, Australasian Psychiatry 2011
Nielsen et al, Eur Neuropsychopharmacol 2012
Meltzer, Schizophr Relat Psychoses 2012
Gören et al, Psychiatr Serv 2013
Stroup et al, Psychiatr Serv 2014
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Clozapine, or something else!
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Antipsychotic combinations
• Amfetamines
Mood stabilizers
• Duloxetine
(Electro Convulsive Therapy)
• Galantamine
Antidepressant medication
• L-Dopa
• Sildenafyl
Glutaminergic medication
• Acetylcysteïn
Memantine
Fatty acids
Estrogen
Testosteron
ß-Blockers
Chinese herbs
Benzodiazepines: acute
Donezepil
Deprenil
Modafinil
Armodafinil
Anti-inflammatory medication (Celecoxib en acetylsalicylic acid)
Ondansetron
Allopurinol
Opiats
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Adding an antipsychotic to an antipsychotic
randomised, not necessarily blinded studies
• 2 meta-analyses on AP + clozapine
• 1 meta-analysis on AP + AP
• 1 meta-analysis on sulpiride + clozapine
Taylor & Smith. Acta Psychiatr Scand 2009
Barbui e.a. Schizoph Bull 2009
Correll e.a. Schizophr Bull 2009
Wang e.a. Schizophr Bull 2010
Dutch Clozapine Plus Collaboration Group
ECSR 2015
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Conclusion from “the 4”
 Small effect
 Longer trials (>10 weeks), better effect
 Best effects in open studies
Taylor & Smith. Acta Psychiatr Scand 2009
Barbui e.a. Schizoph Bull 2009
Correll e.a. Schizophr Bull 2009
Wang e.a. Schizophr Bull 2010
Dutch Clozapine Plus Collaboration Group
ECSR 2015
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An illustration…
from Taylor & Smith 2009
Adding an antipsychotic to clozapine
randomised blinded studies
• For individual antipsychotics and
• Antipsychotics as a group
Veerman, Schulte, Beggeman, de Haan, Pharmacopsychiatry 2014;47
Sommer et al. J. Clin Psychiatry 2012
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ECSR 2015
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Conclusion from this MA:
• Separate antipsychotics added to clozapine:
- Sulpiride (pos/neg/overall) and
- Amisulpride (aff)
- Trend for aripiprazol for negative symptoms:
Veerman, Schulte, Beggeman, de Haan, Pharmacopsychiatry 2014;47
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ECSR 2015
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• All antipsychotics added to clozapine:
– Only for negative symptoms
– And a trend for affective
<negative
<affective
Veerman, Schulte, Beggeman, de Haan, Pharmacopsychiatry 2014;47
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Mood stabilisers
Only effective for schizoaffective disorder
Leucht, Kissling, McGrath. Cochrane Databse of Systematic Reviews 2007
Kontaxakis e.a. European Psychiatry 2005
Small e.a. 2003
Dutch Clozapine Plus Collaboration Group
ECSR 2015
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Mood stabilisers
added to clozapine
Tiihonen et al 2009
Veerman et al 2014
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Mood stabilisers
added to clozapine
Veerman, Schulte, Beggeman, de Haan, Pharmacopsychiatry 2014;47
Dutch Clozapine Plus Collaboration Group
ECSR 2015
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Antidepressant medication
• Effective for negative symptoms (Cochrane review)
• Citalopram for negative (1RCT) and affective (1RCT) symptoms
• Mirtazepine
 with FGA for positive and negative symptoms (1 RCT);
 with risperidon for negative symptoms and total PANSS (1 RCT);
 with clozapine: for negative symptoms (2 conflicting RCT)
• Antidepressants with clozapine (4RCT in meta-analysis): trend
for negative symptoms
Rummel, Kissling, Leucht. Cochrane Database of Systematic Reviews 2006
Zisook et al. Citalopram augmentation for subsyndromal depressive symptoms .J Clin Psychiatry 2009
Lan et al. Citalopram and clozapine.Chin. Ment. Health J.2006
Joffe et al. Add on mirtazapine enhances ap effect of first gen schizopgr: a RCT. Schizophr Res 2009
Zoccali et al. Mirtazapine bij clozapine. Int Clin Psychopharm 2004
Berk et al. Mirtazapine bij clozapine. Hum Psychopharm 2009
Abbasi et al. Mirtazapine bij risperidon 2010
Veerman, Schulte, Beggeman, de Haan, Pharmacopsychiatry 2014;47
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Memantine augmentation for clozapine
• For positieve, negative, cognitive function
Only one small trial
Lucena, Fernandes, Berk et al. Bipolar Disorders 2009
Dutch Clozapine Plus Collaboration Group
ECSR 2015
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E-EPA
• Might be effective for negative and positive symptoms, but
conflicting results (Cochrane review)
• 3 grams added to clozapine (1 RCT): not effective
• 2 grams added to clozapine (1 RCT): positive, negative,
overall and affective symptoms
• Lowers transition to psychosis in HR adolescents (1 RCT)
Joy, Mumby-Croft, Joy. The Cochrane Database of Systematic Reviews 2006
Emsley et al. Am J Psychiatry 2002
Peet & Horrobin. J Psychiatr Res 2002
Arvindakshan et al.Schizophrenia Research 2003
Amminger et al. 2010
Dutch Clozapine Plus Collaboration Group
ECSR 2015
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Estrogen augmentation of AP
For women:
• Effective on positive, sometimes negative and general
symptoms (2 small RCT, 1 big RCT)
100mcg transdermal or 0.05mg/day
For men:
• Only faster effect for general symptoms (1 very short RCT)
Chua et al. Cochrane Database of Systematic Reviews 2007
Riecher-Rössler. Curr Op Psych 2003
Kulkarni et al. Schizophr Res 2001
Kulkarni et al. Arch Gen Psych 2008
Akhondzadeh et al. Prog Neuro-Pschopharm Biol Psychiatry 2003
Kulkarni et al. Schizoph Res 2010
Dutch Clozapine Plus Collaboration Group
ECSR 2015
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Anti-inflammatory drugs augmentation of AP
celecoxib and acetylsalicylic acid
• Moderate effect on positive symptoms and total PANSS score
• Small effect on negative symptoms
Sommer et al. J. Clin Psychiatry 2012
Dutch Clozapine Plus Collaboration Group
ECSR 2015
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Ginkgo biloba augmentation of AP
• Possibly effective (Cochrane review)
• Effective on positive symptoms as add-on to clozapine (1RCT)
Rathbone et al. Cochrane Database of Systematic Reviews 2005
Doruk et al. Int Clin Psychopharmacol 2008
Dutch Clozapine Plus Collaboration Group
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Summary
• Clozapine is effective in therapy resistancy
• For next steps: evidence is limited
• Much research is of poor quality with poor outcomes
• BUT: daily practice asks for next steps
• What is recommendable?
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Recommendable
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Combine AP (most research combined with clozapine)
Add Lithium for schizoaffective disorders
Consider Lamotrigine with clozapine
Maybe Memantine with clozapine
Anti-inflammatory drugs with antipsychotics
Antidepressants for negative symptoms
In the future: E-EPA? Estrogens?
Dutch Clozapine Plus Collaboration Group
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and….
• No beneficial results in conventional trials justify
unconventional next steps
• In that process trial and error fits, but remember:
• Take informed consent from patient and relatives
• Evaluate
• Stop/change/switch your pharmacological treatment
when it fails
Dutch Clozapine Plus Collaboration Group
ECSR 2015
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Thanks
for your attention
[email protected]
www.clozapinepluswerkgroep.nl
Dutch Clozapine Plus Collaboration Group
ECSR 2015
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Aripiprazol and clozapine
Dutch Clozapine Plus Collaboration Group
ECSR 2015
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Non-pharmacologic: ECT
 As mono-therapy vs ap: ap more effective
 As add-on: more pronounced effect, in short and
long term
 Added to flupentixol: 54,5% response;
 Added to clozapine (Kho): 75% response;
 Often temporary effect: fall-back 45-75%;
 In that case: chronic ECT helps
 RCT: 50% effective
Tharyan & Adams. Cochrane Database of Systematic Reviews 2005
Kho e.a. Eur Arch Psychiatry Clin Neurosci 2004
Havaki-Kontaxaki e.a. Clin Neuropharmacol 2006
Enterman & Kho. Psyfar 2010
Chanpattana & Sackheim 2010
Petrides et al, AJP, 2014
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