Clozapine resistance: what is a rational pharmacotherapeutic next step? Jan Bogers Dutch Clozapine Collaboration Group Mental Health Services Rivierduinen European Conference on Schizophrenia Research – 24/25/26 September 2015 Berlin - Germany 1

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: 2

Beyond clozapine Clozapine, what else?! Clozapine, or.... “something completely different” Recommendations 3 Dutch Clozapine Plus Collaboration Group ECSR 2015

Clozapine, what else? 4 Dutch Clozapine Plus Collaboration Group ECSR 2015

Country% clozapine Taiwan26.9 China26.7 Australia19.0 Thailand17.9 Korea12.7 India12.7 Hong Kong11.0 Denmark10.2 Singapore 7.0 Malaysia 4.0 USA 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 Dutch Clozapine Plus Collaboration Group ECSR 2015

Clozapine, or something else! Antipsychotic combinations Mood stabilizers (Electro Convulsive Therapy) Antidepressant medication Glutaminergic medication 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 Amfetamines Duloxetine Galantamine L-Dopa Sildenafyl Acetylcysteïn 6

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

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 Dutch Clozapine Plus Collaboration Group ECSR 2015

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 Dutch Clozapine Plus Collaboration Group ECSR

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 Dutch Clozapine Plus Collaboration Group ECSR

All antipsychotics added to clozapine : –Only for negative symptoms –And a trend for affective Dutch Clozapine Plus Collaboration Group ECSR 2015 Veerman, Schulte, Beggeman, de Haan, Pharmacopsychiatry 2014;47 12 <negative <affective

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 Dutch Clozapine Plus Collaboration Group ECSR

Mood stabilisers added to clozapine Tiihonen et al 2009 Veerman et al

Mood stabilisers added to clozapine Veerman, Schulte, Beggeman, de Haan, Pharmacopsychiatry 2014;47 Dutch Clozapine Plus Collaboration Group ECSR

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 16

Memantine augmentation for clozapine For positieve, negative, cognitive function Only one small trial Lucena, Fernandes, Berk et al. Bipolar Disorders Dutch Clozapine Plus Collaboration Group ECSR 2015

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 Dutch Clozapine Plus Collaboration Group ECSR 2015

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 Dutch Clozapine Plus Collaboration Group ECSR 2015

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 Dutch Clozapine Plus Collaboration Group ECSR 2015

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 Dutch Clozapine Plus Collaboration Group ECSR 2015

Testosteron (DeHydroEpiAndrosteron) Resultaten ‘inconclusive’, tegengestelde bevindingen…geen evidence (mogelijk wel gunstig voor neg sympt) Elias, Kumar. Cochrane Database of Systematic Reviews 2007 Ko e.a. J Clin Psychiatry 2008 ß-Blokkers Geen antipsychotisch effect Cheine e.a. Cochrane Database of Systematic Reviews 2002 Chinese kruiden (ginkgo biloba) Mogelijk effectief, indien gecombineerd met ap Rathbone e.a. Cochrane Database of Systematic Reviews 2005 Sarsasapogenin is safe maar helpt niet Xiao e.a

Benzodiazepinen Veel voorgeschreven i.c.m. antipsychotica Antipsychotisch effect vaak initieel en niet duurzaam Hoge doses mogelijk antipsychotisch Vooralsnog: anxiolytische en sedatieve ondersteuning van antipsychotische behandeling Gaillard e.a. Encephale 2006 Wolkowitz & Pickar AJP 1991 Donezepil (choline-esterase remmer)  2 kleine dubbel-blinde studies Met wisselende resultaten: 1 niet effectief bij clozapine; Ander: effectief bij diverse AP op neg symp.  1 RCT bij risperidon voor cognitieve sympt: geen effect Stryjer e.a. Hum Psychopharmacol 2004 Risch e.a. Schizophr Res 2007 Friedman e.a. Biol Psychiatry

Galantamine (choline-esterase remmer) 1 RCT, 32 pts, 6 maanden; additie bij Risperidon depot Geen effect op cognitief functioneren Lindenmayer & Khan 2010 Deprenyl (Selegiline): MAO-B remmer (M.Parkinson) Verondersteld effectief tegen negatieve symptomen 3 placebo gecontroleerde trials met tegengestelde resultaten Jungerman e.a. J Clin Psychopharmacol 1999 Bodkin e.a. AJP 2005 Amira e.a. Hum Psychopharmacol 2008 Modafinil Bij additie verondersteld effectief tegen sedatie, negatieve symptomen, voor cognitief functioneren (is stimulator bij narcolepsie) Review 6 trials/5 RCT’s: tegenstrijdige uitkomsten of geen effect (neg en cogn sympt) Saavedra e.a. J Clin Psychaitry

Armodafinil (long-acting Modafinil) Additie bij diverse AP, nieuw en oud, 4-6weken, n=60 Tegenstrijdige resultaten, 1 studie gunstig voor neg symp, niet voor cogn functie Kane e.a Bobo e.a Anti-inflammatoir: Celecoxib (NSAID) en acetylsalicylzuur Celecoxib: 3 placebo gecontroleerde trials als additie bij NA met tegengesteld resultaat (2 pos en 1 neg ) Rapaport e.a. Biol Psych 2005 Muller e.a. AJP 2002 Akhondzadah e.a. Schizo Res 2007 Müller. Cur Op Invest Drugd 2010 ASZ: 1 RCT met 1000mg ASZ bij diverse AP: gunstig op positieve symptomen en PANSS totaal Laan. Proefschrift UMCU 2008 Laan e.a. JCP

Ondansetron (5HT3 antagonist) Als additie bij haloperidol; 1 RCT, 121 ptn, 12 weken Gunstig effect op m.n. PANSS negatieve, cognitieve, algemene symptomen Zhang e.a. Schizophr Res 2006 Allopurinol als additie bij diverse antipsychotica: gunstig voor positieve en soms negatieve symptomen (2 RCT’s, 2 case reports) Buie, Oertel, Cala. Ann Psychopharm 2006 Opiaten Diverse 80-er-jaren literatuur Als additie bij diverse antipsychotica; 1 RCT (n=7): klinisch matig gunstig effect Brizer, Hartman, Sweeney e.a. Am J Psych 1985 Cobo, Ramos,Pelaez e.a. Acta Neuropsychiatrica 2006 L-Dopa Review 30 studies, 716 ptn en Meta-analyse 5 st, 160 ptn Als additie bij diverse ap gunstig effect Jaskiw & Popli

Amfetaminen Additie bij SGA: verbetering cogn fie door train-effect (herhaald meten met zelfde lijsten) Pietrzak e.a Duloxetine Bij clozapine RCT, 33 pts, 16 weken Gunstig voor neg symptomen en general PANSS (niet op cogn functioneren) Mico e.a Sildenafil (Viagra®) Additie bij risperidon 6mg RCT, 40 pts, 8 weken Mogelijk gunstig voor neg symptomen (repliceren) Akhondzadeh e.a Trimethoprim Additie bij AP RCT, 91 pts, 8 weken Geen effect Shibre e.a

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? 28 Dutch Clozapine Plus Collaboration Group ECSR 2015

Recommendable 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? 29 Dutch Clozapine Plus Collaboration Group ECSR 2015

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 30 Dutch Clozapine Plus Collaboration Group ECSR 2015

Thanks for your attention 31 Dutch Clozapine Plus Collaboration Group ECSR 2015

Aripiprazol and clozapine Dutch Clozapine Plus Collaboration Group ECSR

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,