Beyond clozapine: a review of the literature on clozapine resistance

Transcription

1 Beyond clozapine: a review of the literature on clozapine resistance Jan Bogers j.bogers@ggzleiden.nl Dutch Clozapine Collaboration Group Mental Health Services Rivierduinen Congress of the World Psychiatric Association, Madrid, sep

2 Statement of Potential Conflicts of Interest BEYOND CLOZAPINE: A REVIEW OF THE LITERATURE FOR CLOZPAINE- RESISTANCE. Relating to this presentation, there are no relationships that could be perceived as potential conflict of interests: 2

3 Beyond clozapine Clozapine, what else?! Clozapine, or... something completely different Recommendations 3

4 Clozapine, what else? 4

5 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 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

6 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 Clozapine, or something else! Amfetamines Duloxetine Galantamine L-Dopa Sildenafyl Acetylcysteïn Anti-inflammatory medication (Celecoxib en acetylsalicylic acid) Ondansetron Allopurinol Opiats 6

7 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

8 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

9 An illustration from Taylor & Smith 2009

10 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

11 Conclusion from this MA: Individual 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 11

12 All antipsychotics added to clozapine: Only for negative symptoms And a trend for affective Veerman, Schulte, Beggeman, de Haan, Pharmacopsychiatry 2014;47 12

13 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

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

15 Mood stabilisers added to clozapine Veerman, Schulte, Beggeman, de Haan, Pharmacopsychiatry 2014;47 15

16 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

17 Memantine augmentation for clozapine For positieve, negative, cognitive function Lucena, Fernandes, Berk et al. Bipolar Disorders

18 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

19 For women: Estrogen augmentation of AP 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

20 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

21 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

22 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

23 Recommendable Combine AP (most research combined with clozapine) Add Lithium for schizoaffective disorders Consider Lamotrigine with clozapine Consider Memantine with clozapine Anti-inflammatory drugs with antipsychotics Antidepressants for negative symptoms In the future: E-EPA? Estrogens? 29

24 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

25 Thanks for your attention 31