psychiatry psychiatrie psychiatry psychiatrie ...

Vol 60, No 3, Supplement 2

March 2015 mars

T H E C A NA D I A N J O U R NA L O F

PSYCHIATRY

LA REVUE CANADIENNE DE

PSYCHIATRIE

Schizophrenia Ten Years of the Eli Lilly Chair Schizophrenia of Schizophrenia and 60 Years of Antipsychotic Use in Canada

The Canadian Journal of Psychiatry La Revue canadienne de psychiatrie The Official Journal of the Canadian Psychiatric Association La Revue officielle de l’Association des psychiatres du Canada

Contents

Editor-in-Chief Scott B Patten

Vol 60, No 3, Supplement 2, March 2015 mars

Deputy Editor Roger Bland

Associate Editors Paul Grof (Book Review Section) Glenda MacQueen David L Streiner (Statistical Consultant) Raymond Tempier (French Submissions)

Editorial Board James M Bolton Michael Bond Brian J Cox Nicholas Delva Carolyn S Dewa Anne Duffy Murray W Enns Abel Ickowicz Laurence Katz Stephen Kisely Diana Koszycki Paul Kurdyak Paul S Links Xiangfei Meng

Ashok K Malla Benoit H Mulsant Kathleen Pajer Bruce G Pollock Tamara Pringsheim Arun V Ravindran Neil A Rector Ronald A Remick Jitender Sareen Alexander Simpson Derryck H Smith Brett D Thombs Phil Tibbo

Former Editors-in-Chief Joel Paris, 2004–2014 Quentin Rae-Grant, 1995–2004 Edward Kingstone, 1977–1995 Frederick H Lowy, 1972–1977 F Rhodes Chalke, 1955–1971

Director, Scientific Publications Virginia St-Denis

Senior Copy Editor Sylvia L Pollard

Copy Editor Candace Taylor

Translator Claire Laberge

Advertising and Production Manager Smita Hamzeh

Desktop Publisher Elizabeth Payne

Chief Executive Officer, CPA Glenn G Brimacombe

Submit your manuscript at http://mc.manuscriptcentral.com/cjp

GUEST EDITORIAL S1 The 10th Anniversary of the Eli Lilly Chair of Schizophrenia From the University of Montreal Emmanuel Stip, Stéphane Potvin CHAPTER 1 S5 Who Pioneered the Use of Antipsychotics in North America? Emmanuel Stip CHAPTER 2 S14 What Does Schizophrenia Teach Us About Antipsychotics? Gary Remington, Ofer Agid, George Foussias, Gagan Fervaha, Hiroyoshi Takeuchi, Jimmy Lee, Margaret Hahn CHAPTER 3 S19 Response Trajectories to Clozapine in a Secondary Analysis of Pivotal Trials Support Using Treatment Response to Subtype Schizophrenia William G Honer, Andrea A Jones, Allen E Thornton, Alasdair M Barr, Ric M Procyshyn, Fidel Vila-Rodriguez CHAPTER 4 S26 Antipsychotic-Induced Changes in Blood Levels of Leptin in Schizophrenia: A Meta-Analysis Stéphane Potvin, Simon Zhornitsky, Emmanuel Stip CHAPTER 5 S35 Salience Network and Olanzapine in Schizophrenia: Implications for Treatment in Anorexia Nervosa Emmanuel Stip, Ovidiu V Lungu CHAPTER 6 S40 Impact of Switching to Long-Acting Injectable Antipsychotics on Health Services Use in the Treatment of Schizophrenia Jean Lachaine, Marie-Eve Lapierre, Nadine Abdalla, Alice Rouleau, Emmanuel Stip CHAPTER 7 S48 Psychotic Disorders Comorbid With Attention-Deficit Hyperactivity Disorder: An Important Knowledge Gap Emmanuelle Levy, Alexandru Traicu, Srividya Iyer, Ashok Malla, Ridha Joober

CanJPsychiatry 2015;60(3 Suppl 2):S1–S4

The Canadian Journal of Psychiatry Volume 60, Number 3

March 2015, Supplement 2

Guest Editorial

The 10th Anniversary of the Eli Lilly Chair of Schizophrenia From the University of Montreal Emmanuel Stip, MD, MSc1; Stéphane Potvin, PhD2 1

Psychiatrist and Professor, Department of Psychiatry, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Quebec; Chair, Department of Psychiatry, Faculty of Medicine, University of Montreal, Montreal, Quebec; Eli Lilly Chair of Schizophrenia, University of Montreal, Montreal, Quebec. Correspondence: Department of Psychiatry, University of Montreal, Pavillon Roger Gaudry, 2900 boulevard Edouard Montpetit, Bureau S-750, CP 6128 Succersale Centreville, Montreal, QC H3C 3J7; [email protected].

2

Associate Research Professor, Department of Psychiatry, Faculty of Medicine, University of Montreal, Montreal, Quebec; Researcher, Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal, Montreal, Quebec.

Key Words: schizophrenia, antipsychotics, chair Received, revised, and accepted June 2014.

open access

U

nder the initiative to create more research chairs in Canada, the Chair of Schizophrenia was founded in May 2003. With the initiative of the Hôpital Sacré-Cœur de Montréal and the Institut Universitaire en Santé Mentale de Montréal Foundations, a charter was established to form an alliance with a Canadian industrial partner. The medical company Eli Lilly Canada materialized this effort by allocating and dedicating a schizophrenia research budget. Further, the Centre Hospitalier de l’Université de Montréal has helped by increasing the allocated schizophrenia research budget.

The University of Montreal made a significant contribution to the management of the Chair position. It created an academic position, which validated the Chair holder mandate, guaranteeing the Chair intellectual and scientific independence. The Chair has organized annual scientific symposiums, distributed awards, received grants, and organized retreats, such as Windigo 2007.1 The symposium’s primary aim is to educate mental health professionals and the public on the cognitive functioning of patients with psychosis and the effects of neuroleptic medication. The Chair has studied the neural mechanisms involved in appetite dysregulation,2 memory deficits,3 and emotion–reward dysfunctions seen in patients with schizophrenia,4 while considering sex differences.5 Collaborations have been successful with Canadian researchers interested in cognition,6,7 psychopharmacology,8–10 metabolic problems,11 sleep,12 inflammation,13 environmental cognitive remediation,14,15 cognitive-behavioural therapy,16 and rehabilitation.17 The Chair, during the last 10 years, has managed to publish over 179 articles available on MEDLINE, which is an accomplishment on its own. The Subjective Scale to Investigate Cognition in Schizophrenia, a scale assessing subjective aspects of cognition in psychosis patients, was created and has been translated globally into 6 languages.18 The collaboration of colleagues, from each psychiatry faculty department in Quebec, has helped create an algorithm for long-acting medications,19 thoroughly discussed at the Association des Médecins Psychiatres du Québec Congress. To acknowledge and celebrate the tremendous accomplishment and scientific contribution of the Chair’s 10th year, and the commemoration of 60 years of APs in Canada, we have organized and dedicated this supplement with the collaboration of The Canadian Journal of Psychiatry.

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The Canadian Journal of Psychiatry, Vol 60, Supplement 2, March 2015 W S1

Guest Editorial

APs have been the mainstay of the pharmacological treatment of schizophrenia since being introduced by Jean Delay and Pierre Deniker in 1952. As largely assumed, APs were introduced in North America by Dr Heinz Lehmann. Dr Emmanuel Stip, in this supplement,20 challenges this potentially mistaken historical assumption by discussing a paper from Dr Roland Saucier, published in the French Canadian journal Le Saguenay.21 This paper was also published in 1954, 1 month apart from Dr Lehmann’s paper in the Archives of Neurology and Psychiatry,22 raising the possibility that Dr Saucier may actually have been the first physician to use chlorpromazine in patients with psychosis in North America. Since being discovered, APs have greatly improved the treatment of schizophrenia. However, important challenges remain unmet, as explained by Dr Gary Remington et al23 in this supplement. One of these challenges is that APs are mostly efficacious for the treatment of positive symptoms (for example, delusions and hallucinations). By contrast, their beneficial effects for the treatment of other symptoms of schizophrenia are milder, although decades of research have clearly shown that cognitive deficits and negative symptoms are more closely related to the social and occupational functioning than positive symptoms. Remington et al argue that the magic bullet era comes to a close, and that we should embrace polypharmacy, as it opens whole new avenues for future drug development in the field of schizophrenia research. Noticing that about 70% of patients with schizophrenia have a good response to APs, that about 30% to 60% of treatment-resistant patients have a favourable response to clozapine, and that therapeutic options are limited for those who respond poorly to both first-line APs and clozapine, Remington et al propose that schizophrenia should be subtyped based on these 3 profiles of AP response. In an empirical paper addressing some of the issues raised by Remington et al’s23 article, Honer et al,24 in this supplement, reanalyzed data from the 2 pivotal randomized, double-blind, multicentre trials performed in the 1980s to determine the proportion of patients with schizophrenia who are clozapine responders. Based on a sample of 470 patients diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Second or Third Edition, criteria schizophrenia, they found that regardless of treatment (clozapine or chlorpromazine), the proportion of good responders was, expectedly, higher in nonrefractory (73%) than in refractory (57.2%) patients. In nonrefractory patients, the proportion of good responders was similar in both treatment groups. However, in refractory patients, the proportion of patients having a good trajectory was higher in those receiving clozapine (59.2%), compared with those

Abbreviations ADHD attention-deficit hyperactivity disorder AP

antipsychotic

LAI

long-acting injectable

S2 W La Revue canadienne de psychiatrie, vol 60, supplément 2, mars 2015

receiving chlorpromazine (31.8%). These results not only corroborate the superior efficacy for treatment-resistant schizophrenia but also show, more crucially, that a fair proportion of treatment-resistant patients do not respond satisfactorily to clozapine. Some APs, such as olanzapine, clozapine, and (less so) quetiapine, produce significant metabolic side effects, which are associated with poor drug compliance and high rates of type II diabetes mellitus and cardiovascular disease in schizophrenia.25,26 Unfortunately, the mechanisms underlying the cardio-metabolic side effects of APs remain incompletely understood. Along with central mechanisms involving appetite dysregulation27 and peripheral mechanisms involving metabolic disturbances, some authors have proposed that alterations in leptin levels may contribute to AP-induced weight gain and cardio-metabolic side effects. Leptin is an adipocyte-derived hormone exerting anorexigenic effects. Although multiple clinical trials have examined the effects of APs on peripheral leptin levels in schizophrenia, no systematic assessment of these effects has been performed. To fill this void, Potvin et al,28 in this supplement, performed a meta-analysis of 28 studies, including 39 treatment arms, which measured peripheral leptin levels before and after AP treatment in schizophrenia spectrum disorders. The meta-analysis showed that APs produce moderate increases in peripheral leptin levels. The most important elevations were observed with olanzapine, quetiapine, and olanzapine, whereas haloperidol and risperidone produced small changes. Regardless of the AP, increases in body mass index were positively associated with increases in leptin levels. Significant associations were also observed between changes in leptin levels and changes in various metabolic markers, namely, cholesterol, triglycerides, glucose, and low-density lipoprotein levels. Altogether, these results suggest that leptin acts as a negative feedback signal in the event of AP-induced fat increase in patients with schizophrenia. Such results may have implications for the adjuvant treatment of the cardiometabolic side effects of APs. The weight-inducing effects of (some) APs represent a major problem in the treatment of schizophrenia, but they may also open new avenues for the pharmacological treatment of eating disorders, including anorexia and bulimia nervosa. Based on previous findings showing that 16-week olanzapine treatment increases activations of key regions of the salient brain network, including the amygdala and the insula, Stip and Lungu,29 in this supplement, argue that olanzapine may serve as a prototype for the development of the first pharmacological treatment of anorexia. Their argument is strengthened by recent brain imaging findings showing that decreased activations in the anterior cingulate gyrus and the insula have been observed in patients with anorexia in response to appetitive cues,30,31 suggesting that some APs, such as olanzapine, may normalize these altered brain responses. Noting that this literature has produced heterogeneous results thus far, Stip and Lungu29 emphasize the need for paying attention, in the future, to the www.LaRCP.ca

The 10th Anniversary of the Eli Lilly Chair of Schizophrenia From the University of Montreal

methodological factors that may explain this heterogeneity, such as the difference between taste perception and cueinduced appetitive responses, as well as the different condition stimuli (for example, images and videos) that can be used to elicit these responses. Patients with schizophrenia are poorly compliant to drug treatment, and this poor compliance significantly worsens prognosis in schizophrenia. LAI formulations of APs are therapeutic alternatives that may help overcome this clinical problem. Randomized controlled trials have studied the efficacy, effectiveness, and overall tolerability of LAIs. For methodological reasons, such trials have been performed in patients who are drug compliant, and naturalistic data on LAIs are lacking. To determine the real-life tolerability of LAIs and the costs associated with their use, Lachaine et al,32 in this supplement, performed an analysis of the public database from the Régime de l’Assurance-Maladide du Québec. In a sample of 1992 patients with schizophrenia or schizoaffective disorder, the authors found that, compared with treatment with oral formulations of APs, treatment with LAIs improved drug compliance, reduced resource use (as determined by the number of days of hospitalizations), and significantly decreased treatment costs. Such results suggest that LAIs are a clinically and economically viable option for the treatment of patients with schizophrenia who are poorly drug compliant.

been described between ADHD and substance use disorders in this population. For instance, there is growing evidence showing that people with ADHD possess personality traits (for example, impulsivity and novelty seeking) that are associated with the onset of substance use in adolescence, which is, in turn, a risk factor for psychosis.37,38

Acknowledgements

Dr Stip is the holder of the Eli Lilly Chair of Schizophrenia from the University of Montreal. His research has received funding from Lundbeck Canada Inc. and Otsuka Canada Pharmaceutical Inc. He has served on the advisory boards and been a lecturer for Lundbeck Canada Inc, Otsuka Canada Pharmaceutical Inc, and Janssen. No funding was received for this editorial.

References

In clinical practice, APs are rarely prescribed as monotherapy and are frequently prescribed with other adjuvant drugs, including antidepressants, mood stabilizers, anticonvulsants, and anticholinergics. Compared with these other adjuvants, the use of psychostimulants has remained controversial. As explained by Levy et al33 in this supplement, concerns regarding the use of psychostimulants in schizophrenia may be origininated from neurobiological misconceptions. For instance, it is well known that schizophrenia is associated with increased striatal dopamine activity, and that APs produce their therapeutic effects by blocking striatal dopamine D2 receptors.34 Given that amphetamines increase striatal dopamine release, clinicians may fear using drugs that could potentially exacerbate the positive symptoms of schizophrenia. However, this whole argument fails to consider the opposing effects of tonic and phasic dopamine release. In theory, it has been proposed that the increased phasic dopamine release in the striatum in schizophrenia is secondary to decreased tonic dopamine release in the mesocortical system. Interestingly, amphetamines, at high doses, increase phasic dopamine release, whereas low doses of amphetamines decrease tonic dopamine release.35 In view of these preclinical findings, the authors argue that amphetamines at low doses could potentiate the therapeutic effects of APs. In support of this hypothesis, a recent systematic review36 has shown that amphetamines improve negative symptoms in schizophrenia without exacerbating positive symptoms. In contrast, evidence is lacking regarding the potential efficacy of amphetamines for the treatment of comorbid ADHD in schizophrenia. The authors highlight the need for further studies on the topic. ADHD is not highly prevalent in first-episode psychosis, but close relations have

1. Stip E. Les premières rencontres Windigo. Mosaïques de recherche/ Windigo II. Santé Mental au Québec. 2007;32(2):127. 2. Stip E, Lungu OV, Anselmo K, et al. Neural changes associated with appetite information processing in schizophrenic patients after 16 weeks of olanzapine treatment. Transl Psychiatry. 2012;2:e128. 3. Mendrek A, Laurens KR, Kiehl KA, et al. Changes in distributed neural circuitry function in patients with first-episode schizophrenia. Br J Psychiatry. 2004;185:205–214. 4. Mancini-Marïe A, Potvin S, Fahim C, et al. Neural correlates of the affect regulation model in schizophrenia patients with substance use history: a functional magnetic resonance imaging study. J Clin Psychiatry. 2006;67(3):342–350. 5. Mendrek A, Mancini-Marië A, Fahim C, et al. Sex differences in the cerebral function associated with processing of aversive stimuli by schizophrenia patients. Aust N Z J Psychiatry. 2007;41(2):136–141. 6. Purdon SE, Woodward N, Lindborg SR, et al. Procedural learning in schizophrenia after 6 months of double-blind treatment with olanzapine, risperidone, and haloperidol. Psychopharmacology (Berl). 2003;169(3–4):390–397. 7. Stip E, Caron J, Renaud S, et al. Exploring cognitive complaints in schizophrenia: the subjective scale to investigate cognition in schizophrenia. Compr Psychiatry. 2003;44(4):331–340. 8. Honer WG, Thornton AE, Chen EY, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med. 2006;354(5):472–482. 9. Remington G, Chue P, Stip E, et al. The crossover approach to switching antipsychotics: what is the evidence? Schizophr Res. 2005;76(2–3):267–272. 10. Chue P, Malla A, Bouchard RH, et al. The long-term clinical benefit and effectiveness of switching to once-daily quetiapine extended release in patients with schizophrenia. Curr Med Res Opin. 2013;29(3):227–239. 11. Sengupta SM, Klink R, Stip E, et al. Weight gain and lipid metabolic abnormalities in first-episode, drug-naïve patients with psychotic disorders. Schizophr Res. 2005;80(1):131–133. 12. Chouinard S, Poulin J, Stip E, et al. Sleep in untreated patients with schizophrenia: a meta-analysis. Schizophr Bull. 2004;30(4):957–967. 13. Potvin S, Stip E, Sepehry AA, et al. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63(8):801–808. 14. Lecardeur L, Stip E, Giguere M, et al. Effects of cognitive remediation therapies on psychotic symptoms and cognitive complaints in patients with schizophrenia and related disorders: a randomized study. Schizophr Res. 2009;111(1–3):153–158. 15. Sablier J, Stip E, Jacquet P, et al. Ecological assessments of activities of daily living and personal experiences with Mobus, an assistive technology for cognition: a pilot study in schizophrenia. Assist Technol. 2012;24(2):67–77. 16. O’Connor K, Stip E, Pélissier MC, et al. Treating delusional disorder: a comparison of cognitive-behavioural therapy and attention placebo control. Can J Psychiatry. 2007;52(3):182–190.

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Guest Editorial 17. Petersen KL, Nicholls TL, Groden D, et al. Redevelopment of tertiary psychiatric services in British Columbia: a prospective study of clinical, social, and residential outcomes of former long-stay inpatients. Schizophr Res. 2013;149(1–3):96–103. 18. Stip E, Caron J, Renaud S, et al. Exploring cognitive complaints in schizophrenia: the subjective scale to investigate cognition in schizophrenia. Compr Psychiatry. 2003;44(4):331–340. 19. Stip E, Abdel-Baki A, Bloom D, et al. Long-acting injectable antipsychotics: an expert opinion from the Association des médecins psychiatres du Québec. Can J Psychiatry. 2011;56(6):367–376. 20. Stip E. Who pioneered the use of antipsychotics in North America? Can J Psychiatry. 2015;60(3 Suppl 2):S5–S13. 21. Saucier R, Fischmeister LV. L’emploi du Largactil en psychiatrie. Saguenay Médical. 1954;3(2):226–231. 22. Lehmann HE, Hanrahan GE. Chlorpromazine: new inhibiting agent for psychomotor excitement and manic states. Arch Neurol Psychiatry. 1954;71(2):227–237. 23. Remington G, Agid O, Foussias G, et al. What does schizophrenia teach us about antipsychotics? Can J Psychiatry. 2015;60(3 Suppl 2):S14–S18. 24. Honer WG, Jones AA, Thornton AE, et al. Response trajectories to clozapine in a secondary analysis of pivotal trials support using treatment response to subtype schizophrenia. Can J Psychiatry. 2015;60(3 Suppl 2):S19–S25. 25. Moteshafi H, Zhornitsky S, Brunelle S, et al. Comparing tolerability of olanzapine in schizophrenia and affective disorders: a meta-analysis. Drug Saf. 2012;35(10):819–836. 26. Moteshafi H, Stip E. Comparing tolerability profile of quetiapine, risperidone, aripiprazole and ziprasidone in schizophrenia and affective disorders: a meta-analysis. Expert Opin Drug Saf. 2012;11(5):713–732. 27. Stip E, Lungu OV, Anselmo K, et al. Neural changes associated with appetite information processing in schizophrenic patients after 16 weeks of olanzapine treatment. Transl Psychiatry. 2010;2:e128.

28. Potvin S, Zhornitsky S, Stip E. Antipsychotic-induced changes in blood levels of leptin in schizophrenia: a meta-analysis. Can J Psychiatry. 2015;60(3 Suppl 2):S26–S34. 29. Stip E, Lungu OV. Salience network and olanzapine in schizophrenia: implications for treatment in anorexia nervosa. Can J Psychiatry. 2015;60(3 Suppl 2):S35–S39. 30. McFadden KL, Tregellas JR, Shott ME, et al. Reduced salience and default mode network activity in women with anorexia nervosa. J Psychiatry Neurosci. 2013;38:178–188. 31. Oberndorfer TA, Frank GK, Simmons AN, et al. Altered insula response to sweet taste processing after recovery from anorexia and bulimia nervosa. Am J Psychiatry. 2013;170:1143–1151. 32. Lachaine J, Lapierre ME, Abdalla N, et al. Impact of switching to long-acting injectible antipsychotics on health services use in the treatment of schizophrenia. Can J Psychiatry. 2015;60(3 Suppl 2):S40–S47. 33. Levy E, Traicu A, Iyer S, et al. Psychotic disorders comorbid with attention-deficit hyperactivity disorder: an important knowledge gap. Can J Psychiatry. 2015;60(3 Suppl 2):S48–S52. 34. Davis KL, Kahn RS, Ko G, et al. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991;148(11):1474–1486. 35. Opler LA, Frank DM, Ramirez PM. Psychostimulants in the treatment of adults with psychosis and attention deficit disorder. Ann NY Acad Sci. 2001;931(1):297–301. 36. Lindenmayer J-P, Nasrallah H, Pucci M, et al. A systematic review of psychostimulant treatment of negative symptoms of schizophrenia: challenges and therapeutic opportunities. Schizophr Res. 2013;147(2):241–252. 37. Kristensen K, Cadenhead KS. Cannabis abuse and risk for psychosis in a prodromal sample. Psychiatry Res. 2007;151(1):151–154. 38. Wilens TE. The nature of the relationship between attentiondeficit/hyperactivity disorder and substance use. J Clin Psychiatry. 2006;68:4–8.

1956 to 2015

of Medical Publishing Excellence

For 60 years, Canadian psychiatrists have turned to The Canadian Journal of Psychiatry for reliable research they can use in their clinical practices to improve patient care.

d’excellence en publication médicale

Depuis 60 ans, les psychiatres canadiens consultent La Revue canadienne de psychiatrie pour des études fiables qu’ils peuvent utiliser dans leurs pratiques cliniques afin d’améliorer les soins des patients.


Dr. F. Rhodes Chalke Editor, 1955 to 1971

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Chapter 1

Who Pioneered the Use of Antipsychotics in North America? Emmanuel Stip, MD, MSc, FRCP, DFAPA1 1

Psychiatrist and Professor, Department of Psychiatry, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, Quebec; Chair, Department of Psychiatry, Faculty of Medicine, University of Montreal, Montreal, Quebec; Eli Lilly Chair of Schizophrenia, University of Montreal, Montreal, Quebec. Correspondence: Department of Psychiatry, University of Montreal, Pavillon Roger Gaudry, 2900 boulevard Edouard Montpetit, Bureau S-750, CP 6128 Succersale Centreville, Montreal, QC H3C 3J7; [email protected].

Key Words: antipsychotics discovery, neuroleptics, history of psychiatry, Heinz Lehmann, chlorpromazine, Deniker, Delay Received July 2014, revised, and accepted August 2014.

open access

Objective: Neuroleptics were introduced into North America 60 years ago. The credit for this advance is generally accorded to Heinz Lehmann. I sought to explore whether Lehmann really was the first North American psychiatrist to study the effects of chlorpromazine (CPZ) and to provide a more balanced view of its application in a clinical context. Method: I searched for historical documents and published articles in several libraries and interviewed psychiatrists active from 1952–1970. Results: The first article in English was published in the July volume of the Archives of Neurology and Psychiatry in 1954 (n = 71). Another article, written in French by Roland Saucier and published in a journal called Le Saguenay Médical, also described the effects of CPZ on a Canadian psychiatric population in August 1954 (n > 200). However, the first prescription for CPZ was written by Roland Saucier, who brought the product back from Paris after a fellowship there. Ruth Kajander, in Ontario, was also one of the first prescribers of this drug, following her study of its use in anesthesia and a publication in the proceedings of a symposium. Conclusion: The contents of the 2 naturalistic studies were compared. Lehmann’s study started 1 month before that of Saucier. Lehmann was the first North American psychiatrist to publish an article on CPZ, but Roland Saucier nevertheless made an important contribution, being the first to prescribe this drug in North America and reporting results for a study with a sample size 3 times that of Lehmann’s study. WWW

Qui a instauré l’utilisation des antipsychotiques en Amérique du Nord? Objectif : Les neuroleptiques ont été introduits en Amérique du Nord il y a 60 ans. Le mérite de cette percée est généralement attribué à Heinz Lehmann. J’ai cherché à explorer si Lehmann était réellement le premier psychiatre nord-américain à étudier les effets de la chlorpromazine (CPZ) et à offrir une perspective mieux équilibrée de son application en contexte clinique. Méthode : J’ai cherché les documents historiques et les articles publiés dans plusieurs bibliothèques, et avons interviewé des psychiatres actifs de 1952 à 1970. Résultats : Le premier article en anglais a été publié dans le volume de juillet de Archives of Neurology and Psychiatry de 1954 (n = 71). Un autre article, écrit en français par Roland Saucier et publié dans une revue intitulée Le Saguenay Médical, décrivait aussi les effets de la CPZ sur une population psychiatrique canadienne en août 1954 (n > 200). Toutefois, la première prescription de CPZ a été écrite par Roland Saucier, qui a rapporté le produit de Paris après un stage là-bas. Ruth Kajander, en Ontario, a également été l’une des premières à prescrire ce médicament, après en avoir étudié l’utilisation en anesthésie et avoir publié à ce sujet dans le compte rendu d’un symposium. Conclusion : Les contenus de 2 études naturalistes ont été comparés. L’étude de Lehmann a commencé 1 mois avant celle de Saucier. Lehmann a été le premier psychiatre nord-américain à publier un article sur la CPZ, mais Roland Saucier a néanmoins fait une contribution importante, étant le premier à prescrire ce médicament en Amérique du Nord et à rendre compte des résultats d’une étude dont l’échantillon avait 3 fois la taille de celle de Lehmann.

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Chapter 1

N

euroleptics were introduced into North America 60 years ago. The credit for this introduction is generally accorded to Heinz Lehmann, a psychiatrist at the Verdun Hospital, which later became the Douglas Mental Health University Institute, affiliated to McGill University. The first neuroleptic prescribed was CPZ, which Jean Delay and Pierre Deniker had already been using for 2 years in France. In a previous article,1 published for the 50th anniversary of neuroleptics, I described the history of this AP and its introduction in Europe by Delay and Deniker. I suggest here that it might be erroneous to consider Lehmann as the pioneer of CPZ in North America. This article focuses not only on the first use of CPZ in North America but also provides a more rounded version of CPZ use in the clinical context. I also explore other instances of CPZ use at the time of Lehmann’s work and publications. Lehmann published his first article on this topic, in English, in 1954. This article, published in the Archives of Neurology and Psychiatry,2 is considered to report the first use of APs to treat a North American population. However, I have discovered another article, written in French and published in Le Saguenay Médical,3 that also describes the effects of CPZ (Largactil) on a Canadian psychiatric population. My examination of these 2 articles suggested that it was highly possible that the first North American study of an AP might actually have been carried out by Roland Saucier, a psychiatrist practicing in the Saguenay Lac-Saint-Jean region of Quebec. Therefore, I decided to compare these 2 articles. Saucier was born in Chicoutimi, in the Saguenay–Lac-SaintJean region, in 1906. He completed his classical studies at the Chicoutimi seminary, where he obtained his baccalaureate in rhetoric in 1919 and his Bachelor of Arts degree in 1926. Despite poor health, and with much effort, he earned a Doctor of Medicine degree in 1948, after which, he specialized in psychiatry. He interned at the Roy-Rousseau Clinic and the Enfant-Jésus Hospital in Quebec City. He continued his studies in France, taking courses in pathological psychology at the Sorbonne and Sainte-Anne Hospital in Paris. He received psychiatric training at the Mental and Brain Illness Clinic of the University of Paris, Faculty of Medicine, and trained in neurology at the Salpêtrière and Paul-Brousse hospitals, and was awarded a Foreign Assistant diploma by the University of Paris, Faculty of Medicine. In September 1950, Saucier returned to Chicoutimi, joining the medical staff of Hôtel-Dieu Saint-Vallier Hospital. In January 1952, Hôtel-Dieu Saint-Vallier opened a neuropsychiatry clinic and Saucier, a pioneer of psychiatry in the region, was appointed its director. He founded the hospital’s psychiatry

Abbreviations AP

antipsychotic

CPZ

chlorpromazine

DA

dopamine

RP Rhône-Poulenc S6 W La Revue canadienne de psychiatrie, vol 60, supplément 2, mars 2015

Clinical Implications •

There were diverse indications for neuroleptics when these drugs were first introduced into North America.

•

Observational studies were useful when APs were first introduced.

•

The criteria for drug approval has changed considerably during the last 60 years.

Limitations •

I was unable to meet Lehmann and Saucier. I was able to speak only with Dr Kajander for the writing of this article.

•

The historical method of data collection does not lend itself readily to objective and statistical validation.

•

There is some confusion about the article by Lehmann, which was published in volume 71 of the American Medical Association’s Archives of Neurology and Psychiatry, but indexed in volume 72, published in July 1954.

department, which he directed until August 1971. In 1969, under his direction, the department became affiliated with the department of psychiatry at Laval University. At the time, its staff was composed of 5 psychiatrists, 2 social workers, 1 psychologist, 1 occupational therapist, and several specialist nurses. One of these psychiatrists, Camille Plourde, was able to supply us with detailed information. Under Saucier’s leadership, Hôtel-Dieu Saint-Vallier opened a child psychiatry section, carrying out only outpatient treatment. At his retirement, Saucier left behind a first-rate department, with a team well equipped to continue his work. In 1973, the Quebec government honoured him by creating an institute bearing his name. Heinz Edgar Lehmann was born in Berlin, Germany, in July 1917. He was educated at the universities of Freiburg, Marburg, Vienna, and Berlin. He emigrated to Canada in 1937. In 1947, he was appointed Clinical Director of Montreal’s Douglas Hospital (Verdun Protestant Hospital). From 1971 to 1975, he was Chair of the McGill University Department of Psychiatry. He published over 300 articles, mostly on psychopharmacology. As suggested by Joel Paris4 and many others, Lehmann must therefore be seen as a pioneer in psychiatry. In the spring of 1953, Lehmann was seeking a new treatment for his more severely disturbed patients. A Rhône-Poulenc representative gave him a copy of Delay and Deniker’s article.5 Encouraged by the results, he and a resident, Gorman Hanrahan, used CPZ on a series of patients, obtaining encouraging results, as described below. They presented their findings at a psychiatry meeting organized by Ewen Cameron, Head of Psychiatry at McGill, at the Allen Memorial Institute of Montreal in March 1954.

Clinical Description of the Effect of Chlorpromazine

I describe and summarize the results of the 2 articles2,3 in tables 1 to 4. www.LaRCP.ca

Who Pioneered the Use of Antipsychotics in North America?

Table 1 The publications of Lehmann and Saucier Characteristics of the study

Lehmann2

Saucier3

Medication

Chlorpromazine, Largactil, 4560 RP, Compound 2601-A

Chlorpromazine, Largactil, 4560 RP, Compound 2601-A

Indication

Psychiatric disorders

Psychiatric disorders Preparation for anesthesia Potentialized anesthesia Artificial hibernation Controlled hypotension First aid for major burns Anti-emetic for morning sickness

Sample size, n

71

>200

Characteristics of the population

Psychiatric patients, aged 18 to 82 years, recruited at Verdun Protestant Hospital

Patients with neurosis, psychosis, or hysteriform symptoms: 17 hypochondriacs, 46 hysterics. See Table 3 for the various disorders treated.

Duration of study

4 months

1 year

Duration of treatment

A few weeks; at least 2 to 3 weeks to avoid relapses

See Table 3

Pharmacodynamics

Mode of action unknown

Acts on autonomic nervous system: parasympathicolytic and sympathicolytic effects Acts on central nervous system: sedative effect Antispasmodic effect and effect on nerve endings

Both papers2,3 documented a beneficial effect of the medication. Lehmann’s study population consisted mostly of patients with schizophrenia and mania. Four subjects had undergone a lobotomy, which was a common treatment at the time.6–9 Saucier included subjects with a broader range of conditions in his study: paranoid psychosis, depressive state, anxiety neurosis, and mystic delusional disorder. Similar dose ranges were used in the 2 studies. No response to treatment was reported for 8% of the patients studied by Saucier and for 15% of those studied by Lehmann.

Chronology

In 1954, Lehmann published an article in Archives of Neurology and Psychiatry, a monthly journal produced by the American Medical Association. The editor was T J Putnam, with Wilder Penfield of Montreal acting as a kind of associate editor. In the bound volume, the article appears on page 227 of the July 1954 (volume 72, number 1) issue. This volume covers the communication period from January to June 1954. Therefore, it is extremely difficult to determine the exact date of publication. On page 135 of the same volume, there is an article entitled “Cortical Ablation in Dogs,” which was published in February 1954 (volume 71, number 2) and Lehmann’s article is followed, on page 271, by an article entitled “Spinal Cord Compression Studies,” published in March 1954 (volume 71, number 3). Therefore, it appears highly plausible that the article was actually published before March 1954. The sample size for Lehmann’s first article2 was only 71 subjects; in his second article, which appeared in the Canadian Medical Association Journal in 1955,10 the authors described the completed study with 289 patients. The study appears to www.TheCJP.ca

have begun in 1953: “We started using chlorpromazine at the Verdun Protestant Hospital in May 1953.”10, p 91 The medication was provided by Rhône-Poulenc: “we are indebted to Poulenc Limited for providing us with supplies to carry out our initial investigations.”10, p 91 Based on this information, I believe that the study began in May 1953 and was published no later than July 1954. Saucier’s article was published, in French, in the Saguenay Médical August 1954 volume.3 This medical journal was published quarterly by the Hôtel-Dieu Saint-Vallier hospital, in Chicoutimi, Quebec. The editors were Wilfred Lachance and Edmond Potvin. Saucier described the study as commencing in June 1953 and continuing until 1954: “Depuis le 1er juin 1953 jusqu’au 30 juin 1954 nous avons administré le largactil à plus de 200 malades”3 p 54 [“From June 1, 1953, to June 30, 1954, we administered Largactil to more than 200 patients”]. Therefore, the results were published after the completion of the study, which included at least 200 patients. If this journal had been published monthly, would the results have appeared before July 1954? The 2 protagonists were probably unaware, at the time, of their race to publish first. Lehmann’s study seems to have started 1 month before that of Saucier, and his article was published in English 1 month before the article in French. However, Saucier’s study included a sample 3 times the size of that studied by Lehmann. This examination of these 2 seminal articles suggests that it is not incorrect to consider Lehmann to be the first North American psychiatrist to publish an article on CPZ. However, in recognizing this fact, psychiatrists should not forget the contribution of another team—a small The Canadian Journal of Psychiatry, Vol 60, Supplement 2, March 2015 W S7

Chapter 1

Table 2 Therapeutic results with chlorpromazine (Lehmann2) Clinical outcome Disorder

n

Preventiona

Recoveryb

Great improvementc

Schizophrenia

22

2

0

3

Improvementd

Unchanged

Still being treated

9

7

1

Schizoaffective disorder

3

0

0

1

2

0

0

Mania, acute

22

2

8

2

7

0

3

Mania, chronic

12

0

4

1

3

1

3

Psychoneurosis

4

0

1

0

1

2

0

Post-lobotomy

4

0

0

0

2

1

1

Mental deficiency

1

0

0

0

0

1

0

Senile psychosis

3

0

0

0

3

0

0

a

Prevention was an aversion of imminent psychotic attacks during the prodromal period.

b

Recovery was a sustained cessation of symptoms within 40 days.

c

Great improvement was a reduction of symptoms to the point that the patient can leave the hospital within 40 days.

d

Improvement was a constant decrease in symptoms over 40 days, but the patient still unable to leave the hospital.

French-speaking team, working in a dynamic environment far from the big city, which generated and published interesting and naturalistic results at about the same time. I was able to question key players and to obtain valuable information about when 4560 RP, as the drug was then known, was first prescribed in Quebec. I interviewed Anne-Marie Bouchard and Chantale Bouchard, psychiatrists and daughters of Grégoire Bouchard, a psychiatrist working with Roland Saucier on his return from France with CPZ in his suitcase, who died in 2011. I was also able to interview Camille Plourde, a retired psychiatrist who worked with Saucier at Hôtel-Dieu Saint-Vallier in 1952–1953 and who remembers the first prescription being issued in late 1952 or early 1953. I was also able to interview Pierre Vincent, a psychiatrist who won the Heinz Lehmann award from the Association des médecins psychiatres du Québec in 2013. He confirmed that Roland Saucier passed this drug on to Maurice Coulombe, a psychiatrist at the Roy-Rousseau Clinic in Quebec City. Coulombe then administered the drug to a patient at Roy-Rousseau Clinic, a few days after Saucier. This historical account of the introduction of CPZ would not be complete without mention of Ruth Kajander’s early research on CPZ, which she reported to a professional psychiatry forum on November 27, 1953, several months before the publication of the work of Lehmann and Saucier.11–14 Kajander (née Koeppe) was also originally from Germany, and she moved to Ontario in 1952, after training at the University of Gottingen, Berlin, and in Helsinki. In 1953, she worked with Elizabeth Martin, an anesthetist, during a rotating internship at the Oshawa General Hospital, and she used 4560 RP, obtained from Rhône-Poulenc. Kajander was interested in the calming effect of the drug, without total sedation, during anesthesia. In the fall of 1953, she took up a position as resident in psychiatry at Ontario Hospital, London. She convinced the Medical Director, Douglas Wickware, to let her use S8 W La Revue canadienne de psychiatrie, vol 60, supplément 2, mars 2015

CPZ on a small number of patients in November 1953. She described her findings to a meeting of the Ontario Neuropsychiatric Association in Whitby in February 1954. Kajander acted entirely on her own initiative. She knew from the Rhône-Poulenc representative that Lehmann had also used the drug successfully, but her first contact with him was as a discussant for his article at the March meeting in Montreal. The archives of the Canadian Psychiatric Association hold a copy of her paper, but Kajander’s findings were never published in a scientific journal, appearing instead only in the proceedings of the meeting in Ontario. This deprived her of the credit she deserved until the publication of an interview with her carried out by Sam Sussman.15 She reported 3 cases. The first 2 cases involved women suffering from agitated depression and the third involved an immigrant woman who became psychotic shortly after giving birth to an illegitimate child. She had delusions of having given birth to a dog. She was diagnosed with paranoid schizophrenia, and the clinical effects of the drug were remarkable.

The Nature of Scientific Articles

The clinical research protocols for assessing drug efficacy in 1954 were clearly very different from those prevailing in 2015. The requirements and criteria have evolved, and it is now necessary to demonstrate the superiority of the test molecule to a placebo or a widely used treatment. Adherence to the following conditions is strictly required: statement of hypotheses (and null hypothesis) to be tested, control of the conditions through inclusion and exclusion criteria, double-blind or single-blind design, duration, randomization, statement of statistical power, and required sample size. Four phases of clinical trials are required (phases 1, 2, 3, and 4), and clinical data and results must be presented to regulatory agencies, such as the US Food and Drug Administration, the Institut national d’excellence en santé et en services sociaux in Quebec, and the Therapeutic www.LaRCP.ca


Table 3 Therapeutic results with chlorpromazine (Saucier3) Progression of condition n

Treatment duration

Mania

2

8 to 10 weeks

2

0

0

Paranoid psychosis

10

4 weeks

5

2

3

Schizophrenia

4

0

0

3

1a

Anorexia nervosa

1

154 days

0

1

0

Mystic delusions

7

3 to 8 weeks

4

1

2

Condition

Good

Improved

Not improved

Postpartum psychosis

3

3 to 7 weeks

3

0

0

Depressive states

63

2 to 3 weeks

48

6

9

Severe depressive states

4

0

1

3

0

Anxiety neurosis

14

3 to 7 weeks

11

1

2

Obsessions

4

4 weeks

1

3

0

Insomnia

4

3 weeks

4

0

0

Psychogenic headaches

4

1 to 2 weeks

4

0

0

a

Complete relapse 2 or 3 weeks later.

Products Directorate in Canada, for agency audits and clinical trial registries. Publication criteria include peer review and the use of evidence-based medicine. Further, ethics committees must approve trials and conflicts of interest must be declared. Government agencies may reject drugs owing to a lack of convincing evidence of their efficacy, safety, and economic impact. Moreover, studies of the biological effects of CPZ have generated almost 20 000 published studies listed by PubMed, second only to Aspirin (over 50 000), largely owing to its abundant side effects. Neither of the studies considered here had an experimental design based on the rejection of a null hypothesis. Nevertheless, observational or naturalistic studies with APs are not uncommon. However, such studies generally follow controlled studies and are conducted after approval of the drug for clinical use. Current guidelines and treatment algorithms for schizophrenia are based on outcome data from randomized controlled trials on selected patients with limited follow-up. Most of these trials have small sample sizes, and most patients displaying physical illness; poor compliance; or suicidal, substance abuse, or antisocial behaviour are excluded. Therefore, it is difficult to generalize data from such trials to broader community settings. Largerscale observational studies could provide insight into these important aspects. In addition, AP discontinuation rates are a powerful indicator of a drug’s effectiveness in schizophrenia. These aspects have been highlighted by a series of studies, including the Schizophrenia Outpatient Health Outcomes study, a 3-year prospective, observational study in outpatients, which investigated the discontinuation of AP treatment.16

clinical impressions during his work with antihistamines and his empirical observation of useful sedation in some subjects, not recruited as psychotic patients per se.21 The first DA hypothesis of schizophrenia, according to which hyperactive DA transmission was responsible for the disorder, did not emerge until 10 years after the first publication on Largactil. This hypothesis was based on early observations that DA receptors are activated by psychostimulants, that nonreserpine neuroleptics are DA antagonists, and that DA plays a clear role in the extrapyramidal system. The classical DA hypothesis received further support from the correlation between clinical doses of APs and their potency to block DA D2 receptors,22 and the psychosis-inducing effects of DAenhancing drugs. Much of the evidence underlying these concepts came from the seminal work of Arvid Carlsson, who characterized DA in the brain and the effects of neuroleptics on monoaminergic indices, less than 10 years after the first publication on Largactil (see Carlsson and Lindqvist23 and Carlsson24,25).

Moreover, there was no psychopharmacological model in 1954, when neuroleptics were first used. There was only one model, for methylene blue, as an oxidative agent.17–19 In fact, the phenothiazines are a family of heterocyclic compounds, the structure of which is best exemplified by methylene blue.20 The only justification for their use was Henri Laborit’s

Pharmacological interventions to treat psychosis have generally focused on the modification of dysfunctional neurotransmitter systems (for example, DA) to improve symptoms. Interestingly, Jean Delay’s book, Méthodes biologiques en clinique psychiatrie,26, p 375–382 published in 1950, 2 years before the articles on 4560 RP, indicates that antibiotics, such as penicillin, were among the recommended treatments for psychosis. There is now a growing body of evidence to suggest that inflammation, infection, oxidative stress, changes in the glutamatergic system, and neurotrophins are involved in schizophrenia. These new insights into pathophysiology are leading to the exploration of new treatment strategies. For instance, minocycline, an antibiotic used to treat infections, can modulate glutamate-induced excitotoxicity, with antiinflammatory, antioxidant, and neuroprotective effects. Clinical trials have indicated that minocycline may be useful for treating schizophrenia. CPZ has antimicrobial activity

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Chapter 1

Table 4 Summary of psychological and (or) psychiatric effects documented in the 2 studies2,3 Lehmann An intramuscular dose of 50 to 100 mg generally controls most states of agitation. Administration of chlorpromazine for 3 to 4 days during prodromal symptoms seems to prevent psychosis. Emotional tension well controlled with small doses (50 to 200 mg/day). Controlled agitated delirium in a patient whose condition was refractory to any other treatment. No effect on hallucinations and delusions. Marked effect on manic-depressives patients in a chronic manic state for at least 1 year who did not respond to other treatments. Triggered depression in 4 manic-depressives patients over the age of 45 years in a manic state. If no normal physiological response after treatment = less likely to respond to medication (except elderly people). No emotional disinhibition. If daily doses of 100 to 200 mg given orally do not produce satisfactory results, larger doses will not help. Lethargy, quiescence. Patients have a lack of spontaneous interest in the environment, are lucid, and answer questions slowly and monotonously. Silent and immobile if left alone. Often aware of their improvement, not euphoric. Fatigue and weakness in some patients. Higher psychic functions preserved: attention, reflection, and concentration. Best results in manic-depressives patients in manic and hypomanic states: ↓ psychomotor agitation in the 24 hours following treatment, patient cooperation. Saucier No effect on people with hypochondria. In hysteria, only temporary cessation, transient sedation. Series of clinical cases: Elimination of delirium and hallucinations in 2 days, 37 days, and 3 weeks (3 clinical cases). Persecution delusions vanished after 2 weeks (1 case). Relief of headaches (patient’s complaint) in 9 days (1 case). Eliminated the feeling of chronic sadness, resolved sleep, and appetite problems in 14 days (2 cases) and 19 days (1 case) (3 cases in all). Disappearance of neurotic symptoms in 14 days, 19 days, and 3 weeks (3 cases). Gradual elimination of suicidal ideations and of sadness and self-accusation (the patients left after 13 or 17 days, despite the physician’s recommendations) (2 cases). Elimination of obsessive ideas in 28 days in a patient with an intellectual disability. Did not enhance intellectual capacities, even after 28 days of treatment.

against Staphylococcus aureus in vitro, at concentrations greatly exceeding those achieved clinically.27 The activity of CPZ against various microorganisms, including intracellular pathogens (Leishmania, trypanosomes, amoebae),28,29 has been studied in vitro and in vivo.

Antecedents to Chlorpromazine Use in North America

The first North American prescribers of 4560 RP were probably aware of the limitations of antibiotics in psychiatry and happy to administer the first neuroleptic to help their patients, who, as the articles show, presented a broad range of diagnoses. This was probably the first seroquelization initiative in psychiatry.34,35

The history of medicine is littered with examples of how problematic it can be determining who was first in medical research. Before its arrival in Canada, there had already been debates about who was first to use 4560 RP in France. Largactil, the first neuroleptic, was the product of research into antihistamines, which were discovered in 1937 by the Swiss-born Italian pharmacologist Daniel Bovet, who won the Nobel Prize for Medicine in 1957.36–38 In 1944, he isolated phenothiazine and diethazine (Diparcol), which Jean Sigwald used to treat Parkinson disease (1946).39 Bernard Halpern introduced the use of antihistamine phenothiazines, such as promethazine (Phenergan), into medicine. French psychiatrists were the first to carry out clinical trials of antihistamines for psychiatric indications. Georges Daumezon used a derivative of benzylaniline


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However, these activities of CPZ reside in the side chains of the molecule and have led to the development of this phenothiazine as an anti-malarial agent.20,28–30 This creates a kind of loop, bringing us back to the malaria parasite, which was used to treat mental illness from the early 1920s to the late 1950s.31–33


to treat manic depressive attacks (1943), whereas Paul Guiraud proposed the use of promethazine to treat agitated states (1950). In the United States, OR Bryant also tested antihistamines for use in manic states (1950).40–44 CPZ was synthesized in 1950, by Paul Charpentier at the Rhône-Poulenc laboratories.43,45 Roland Saucier was in Paris, on a fellowship, at the time. In 1952, Henri Laborit, Pierre Huguenard, and Raymond Alluaume published the first clinical study of a new autonomic stabilizer: 4560 RP.21 In his work on potentialized anesthesia and artificial hibernation, Laborit reported that some somnolence was observed with 50 to 100 mg of intravenous CPZ, together with, above all, a “lack of interest by the patient in his surroundings.”21 p 207 He predicted the extension of the use of this drug to obstetric analgesia and psychiatry. In December 1951, a clinical trial of 4560 RP was conducted by 2 psychiatrists, Jean Sigwald (born in 1903, medical degree awarded in 1932) and Daniel Bouttier (qualified in 1948) at the Paul Brousse Psychiatric Hospital. Their article, published in 1953, in Annales de médecine,39 reported CPZ to be effective in a case series of patients showing some change in the mechanism of auditory hallucinations and their interpretation, and as an antidepressant. Léon Chertok, one of the most remarkable characters in the history of psychiatry and hypnosis, carried out what was probably the first clinical experiment in a psychiatric setting with 4560 RP alone. After interning in psychiatry at Mount Sinai Hospital in New York and undergoing analysis with Jacques Lacan, Chertok served as assistant to the psychiatrist Marcel Montassut at the Villejuif Psychiatric Hospital. In 1950, he and Victor Gachkel founded the Center for Psychosomatic Medicine there. At the time, he was working mainly with anesthetists and urological surgeons. In 1951, the anesthetist Jean Lassner told him about Laborit and his mysterious molecule. In fact, the molecule in question, 4560 RP, was not at all mysterious, as its anti-allergenic properties were already well known, but Laborit had noticed, essentially by chance, that it seemed to have a euphoric effect on patients and he wanted to experiment with it in psychiatry. Chertok was enthusiastic and he convinced his superior, Marcel Montassut. This led to an experiment being carried out in Villejuif on a fellow psychiatrist, Cornelia Quarti, whose comments during the experience were recorded. At the time, Laborit’s molecule was not yet available in tablet form. Therefore, it had to be administered intravenously to Quarti, but Chertok had no idea what dose to use. At the end of the injection, Quarti lost consciousness. However, a quarter of an hour later, she felt optimistic, relaxed, and full of affection for everyone. Chertok was then ready to continue and to begin experimenting on patients, but Montassut was unwilling to do so.

agitation was obtained but the effect was insufficiently strong, and electroconvulsive therapy was eventually required.46 The first publication on the continuous, long-term treatment of psychiatric disorders with CPZ, by Delay, Deniker, and Harl, appeared on May 26, 1952, on the occasion of the centenary of the Société medico-psychologique.47 Five other publications followed, covering about 40 diseases and describing the properties of CPZ (delay, without prior assumptions concerning the possible therapeutic spectrum of this drug).5,48–51 The first trials of CPZ took place under constant supervision by physicians and nurses; psychological changes were monitored and vital signs were tested several times daily.43,52 In France, CPZ was available under the proprietary name Largactil, for large action.32,40 Advertisements from the period boasted of the 4 areas of use for the drug: surgery, for preparation for anesthesia, and the prevention and treatment of traumatic postoperative shock; obstetrics, for obstetric analgesia, eclampsia, and vomiting during pregnancy; internal medicine, for neurotoxicosis, dermatosis, and vomiting; and psychiatry, for manic excitement, psychosis, and psychomotor agitation. The dose for adults was 75 to 150 mg per day. Following the first publication on May 26, 1952, at the centennial meeting of the Société médico-psychologique,47 the St Anne team published 6 articles during a 6-month period,5,47–51 paving the way for the introduction of CPZ in psychiatry.52,53 Other publications in 1952 included a report by Follin,54 on the successful treatment of an aggressive paranoid patient at Montauban mental hospital in France,42 and an article by Rigotti,55 on 20 psychiatric patients in Padua, Italy. The first tests outside France, such as those of Arnold in Vienna and Labhardt in Basel, Switzerland, generated similar results.17,45,56–58 Doses were then increased to 150 to 300 mg intramuscularly and 300 to 500 mg by mouth, sometimes more.40 The first British report, from Anton-Stephens,59 identified indifference as the greatest effect on patients, this response being considered similar to that for psychosurgery, a frontal lobe syndrome.40 The term chemical lobotomy was used by some early authors, including Lehmann.10 By the end of 1955, there were also reports on the effects of CPZ on psychiatric patients from Switzerland,60,61 Germany,62 Hungary,63 Latin America,64 Australia,65 the Union of Soviet Socialist Republics,66 and the United States.67 CPZ was marketed in the United States as Thorazine by SmithKline and French, and in England as Largactil by May and Baker.45,68,69

Conclusion

In March 1952, 3 psychiatrists at Val-de-Grâce Hospital in Paris, Hamon, Paraire, and Velluz, published a case study of a patient with manic attacks treated with CPZ, in association with either pentobarbital or pethidine: temporary sedation of the

The problem of the greater visibility of high-impact journals, such as the Archives of Neurology and Psychiatry, than of the lower impact local journals, particularly those publishing in other languages, such as the French-language journal in which Saucier’s article appeared, is not specific to psychiatry. The history of the name change of Les annales de l’Institut Pasteur and the disappearance of the Union medicale du Canada highlight the difficult sociological question of the value of language choice in a scientific

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Chapter 1

domain.70 It is no great surprise that the North American psychiatric community first looked (as it still does) at the higher-impact journals and received its information from there. The current status of French-language journals in the world of psychiatry and the rate of publications on CPZ at the time in the European French-language journals highlight the importance of this contextual question. For example, The Canadian Journal of Psychiatry accepts papers for publication in French, but the number of articles published in French decreases the impact factor of the journal, which is also called Revue canadienne de psychiatrie. In conclusion, the introduction of APs (neuroleptics) in North America was a turning point in psychiatry.17,68,71–73 I recognize that this “article is neither a comprehensive history of comparative treatment effect size nor a history of mentalities, but falls somewhere in between the two.”17, p. 394 The first 2 articles2,3 published on the subject both appeared in 1954 and were both by Canadians based in Quebec. Heinz Lehmann, Roland Saucier, and Ruth Kajander obtained CPZ from RhônePoulenc, which had developed this drug and tested it with clinical researchers and psychiatrists in France during the preceding 2 years. Closer inspection shows that Lehmann published at least a month before Saucier, that Saucier’s study included 3 times more patients than that by Lehmann, that both studies were naturalistic, and that patients with a very wide range of diagnoses were included, not just those with schizophrenia-type psychoses. These 2 articles provide information about this period in the history of psychiatry and the first use of chemical treatments for mental illnesses. They also highlight how far physicians have come since those days, in terms of rigour, epistemology, and the drug approval process. The beneficial effect of CPZ was instrumental in the reintegration of psychiatry with other medical disciplines74 and in the development of neuropsychopharmacology. These 2 or 3 studies describe the introduction of neuroleptics into North America, during a period that led to a decrease in the number of beds in psychiatric hospitals and the first steps toward deinstitutionalization.32 Sixty years ago, CPZ researchers and prescribers “were not doing science in accordance with conventional theories of how science is suppose to operate.”17, p 402 In 2014, neuroleptics still work, but psychiatrists now need to find alternatives, with or without a model.

References

I thank Dr Maurice Dongier at McGill; Dr Ruth Kajander in Thunder Bay; Dr Jean Pierre Olié and Dr Henry Loo at St Anne’s Hospital Paris; Dr Pierre Vincent and Dr Roch Hugo Bouchard at Institut Universitaire en Santé Mentale de Québec; Dr Anne Marie Bouchard at Institut Pinel; Dr Denis Rochette, Dr Camille Plourde, and Dr Claude Voisine in Saguenay; Dr John Court, Corporate Archivist, Centre for Addiction and Mental Health, and Assistant Professor, Department of Psychiatry, University of Toronto; Dr David Wright, Professor of History and Canada Research Chair in the History of Health Policy; and the personnel of the libraries of Institut universitaire en santé mentale de Montréal, Douglas Institute.

1. Stip E. Happy birthday neuroleptics! 50 years later: la folie du doute. Eur Psychiatry. 2002;17(3):115–119. 2. Lehmann HE, Hanrahan GE. Chlorpromazine: new inhibiting agent for psychomotor excitement and manic states. AMA Arch Neurol Psychiatry. 1954;71(2):227–237. 3. Saucier R, Fischmeister LV. L’emploi du Largactil en psychiatrie. Saguenay Médical. 1954;3(2):226–231. 4. Paris J. In memoriam: Heinz Lehmann. McGill Reporter. 1999. Available from: http://reporter-archive.mcgill.ca/Rep/r3115/ memoriam.html. 5. Delay J, Deniker P. Le traitments de psychoses par une method neurolytique dérivée de l’hibernothérapie; le 4560 RP utilise seul en cure prolongée et continue. CR Congr Méd Alién Neurol (France). 1952;50:497–502. 6. Stip E, Bigras MJ, Mancini-Marïe A, et al. Long-term effect of prefrontal lobotomy on verbal fluency in patients with schizophrenia. Brain Cogn. 2004;55(3):466–469. 7. Black DN, Stip E, Bédard M, et al. Leukotomy revisited: late cognitive and behavioral effects in chronic institutionalized schizophrenics. Schizophr Res. 2000;43(1):57–64. 8. Hurley RA, Black DN, Stip E, et al. Surgical treatment of mental illness: impact of imaging. J Neuropsychiatry Clin Neurosci. 2000;12(4):421–424. 9. Pressman J. Psychosurgery and the limits of medicine. New York (NY): Cambridge University Press; 1998. 10. Lehmann HE. Therapeutic results with chlorpromazine (Largactil) in psychiatric conditions. CMAJ. 1955;72(2):91–99. 11. Koeppe R. Largactil—some preliminary clinical observations. Papers given at meetings of the Ontario Neuropsychiatrc Association [later OPA], at Ontario Hospital; 27 November 1953; Whitby (ON). 12. Koeppe R. Summary on the use of Largactil in psychiatry. Synopsis of 1953a. Papers given at the meeting of the Ontario Neuropsychiatric association, Ontario Hospital St Thomas, 1954. Toronto (ON): CAMH Archives; 1954. 13. Griffin JD. An historical oversight. (Letter to the Editor, Dialogue). Mississauga (ON): Ontario Psychiatric Association; 1993. p 9–10. 14. Centre for Addiction and Mental Health (CAMH) Archives. Bio file—Ruth E (Koeppe) Kajander. Toronto (ON): CAMH; 2004. 15. Sussman S. Dr. Ruth Kajander: a pioneer in Canadian psychiatry. London (ON): Sussco Publishing Limited; 1999. 16. Hong J, Novick D, Brugnoli R, et al. Clinical consequences of switching from olanzapine to risperidone and vice versa in outpatients with schizophrenia: 36-month results from the Worldwide Schizophrenia Outpatients Health Outcomes (W-SOHO) study. BMC Psychiatry. 2012;12:218. 17. Healy D. Some discontinuities and discontinuities in the pharmacotherapy of nervous conditions before and after chlorpromazine and imipramine. Hist Psychiatry. 2000;11;393–412. 18. Bodoni, M. La bleu de methylene comme calmant chez les alienes. Sem Med. 1899;7:56. 19. Swazey J. Chlorpromazine. Cambridge (MA): MIT Press; 1974. 20. Wainwright M, Amaral L, Kristiansen JE. The evolution of antimycobacterial agents from non-antibiotics. Open Pharmacol J. 2012;2:1. 21. Laborit H, Huguenard P, Alluaume R. Un noveau stabilisateur végétatif (le 4560 RP). La Presse Médicale. 1952;60:206–208. 22. Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science. 1975;188(4194):1217–1219. 23. Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol. 1963;20(2):140–144. 24. Carlsson A. Neuropsychopharmacology. In: Ban TA, Healy D, Shorter E, editors. The rise of psychopharmacology and the story of CINP. Budapest (HU): Animula; 1998. p 124–128. 25. Carlsson A. The discovery of chlorpromazine—impact on basic research. Int J Neuropsychopharmacol. 2004;7(Suppl 1):22. 26. Delay J. Nouvelles chimiothérapies en psychiatrie. In: Méthodes biologiques en clinique psychiatrique. Paris (FR): Masson; 1950. p 375–382. 27. Ordway D, Viveiros M, Leandro C, et al. Chlorpromazine has intracellular killing activity against phagocytosed Staphylococcus


www.LaRCP.ca

Acknowledgements

Who Pioneered the Use of Antipsychotics in North America? aureus at clinical concentrations. J Infect Chemother. 2002;8(3):227–231. 28. Amaral L, Molnar J. Why and how the old neuroleptic thioridazine cures the XDR-TB patient. Pharmaceuticals (Basel). 2012;5(9):1021–1031. 29. Molnár J, Mándi Y, Király J. Antibacterial effect of some phenothiazine compounds and R-factor elimination by chlorpromazine. Acta Microbiol Acad Sci Hung. 1976;23(1):45–54. 30. Ehrlich P. In: Himmelweit F, Marquart M, Dale H, editors. The collected papers of Paul Erhlich. London (GB): Pergamon Press; 1956. p 500–508. 31. Bonfigli A, Fanfera E, Corbellini G. [Malariatherapy in Italy. A historical account of therapeutic inoculation of malaria parasites in Italian psychiatric clinics]. Med Secoli. 2004;16(1):1–19. [Italian]. 32. Postel J, Quetel C, editors. Nouvelle histoire de la psychiatrie. Toulouse (FR): Privat; 1983. 33. Tsay CJ. Julius Wagner-Jauregg and the legacy of malarial therapy for the treatment of general paresis of the insane. Yale J Biol Med. 2013;86(2):245–254. 34. Zhornitsky S, Potvin S, Moteshafi H, et al. Dose-response and comparative efficacy and tolerability of quetiapine across psychiatric disorders: a systematic review of the placebo-controlled monotherapy and add-on trials. Int Clin Psychopharmacol. 2011;26(4):183–192. 35. Stip E. Psychosis: a category or a dimension? Can J Psychiatry. 2009;54(3):137–139. 36. Ban TA. Pharmacotherapy of mental illness. A historical analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25:709–727. 37. Charpentier P, Gailliot P, Jacob R, et al. Recherches sur les diméthylaminopropyl-N phénothiazines substituées. C R Acad Sci. 1952;235:59–60. 38. Courvoisier S, Fournel J, Ducrot R, et al. Propriétés pharmacodynamiques du chlorhydrate de chloro-3-(diméthylamino3′-propyl)-10-phénothazine (4560 RP). Étude expérimentale d’un niveau corps utilisé dans l’anesthésie potentialisée et dans l’hibernation artificielle. Arch Int Pharmacodyn Ther. 1953;92:305–361. 39. Sigwald J, Bouttier D. “Le chlorhydrate de chloro-3 (diméthylamine-3’propyl)-10 phénothiazine en pratique neuro-psychiatrique courante.” Annales de médecine. 1953;54(2):150–182. 40. Lemperiere T, Ginestet D. Les medicaments antipsychotiques. Début et étapes de la découverte des neuroleptiques. In: Olié JP, Dalery J, Azorin JM, editors. Médicaments antipsychotiques. Paris (FR): Acanthe; 2001;3–22. 41. Ban TA. Neuropsychopharmacology and the history of pharmacotherapy in psychiatry. A review of developments in the 20th century. In: Ban TA, Healy D, Shorter E, editors. Reflections on twentieth-century psychopharmacology. Budapest (HU): Animula; 2004. p 697–720. 42. Caldwell AE. Origins of psychopharmacology from CPZ to LSD. Springfield (IL): Charles C Thomas; 1970. p 23–35. 43. Thuillier J. Ten years that changed the face of mental illness. London (GB): Martin Dunitz; 1999. p 111–123. 44. Bryant OR. Treatment of manic psychoses with antihistamine drugs. Am Pract Dig Treat. 1950;1(2):132. 45. Ban TA, Healy D, Shorter E. Preface. In: Ban TA, Healy D, Shorter E, editors. The rise of psychopharmacology and the story of CINP. Budapest (HU): Animula; 1998. p VII–VIII. 46. Hamon J, Paraire J, Velluz J. Remarques sur l’action du 4560 RP sur l’agitation maniaque. Ann Med Psychol (Paris). 1952;110(1 3):331–335. 47. Delay J, Deniker P, Harl JM. Utilisation en thérapeutique d’une phénothiazine d’action centrale selective. Annales MédicoPsychologiques. 1952;110:112–118. 48. Delay J, Deniker P. 38 cas de psychoses traitèes par la cure prolongèe et continuè de 4560 RP. CR Congr Méd Alién Neurol (France). 1952;50:503–513.

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49. Delay J, Deniker P. Réactions biologiques observées au cours du traitement par l’chlorhydrate de deméthylaminopropyl-Nchlorophénothiazine. CR Congr Méd Alién Neurol (France). 1952;50:514–518. 50. Delay J, Deniker P, Harl JM. Traitement des ètats d’excitation et d’agitation par une méthode médicamenteuse dérivè de l’hibernothèrapie. Ann Med Psychol. 1952;110:267–273. [French]. 51. Delay J, Deniker P, Harl JM, et al. Traitements d’ètats confusionnels par l’chlorhydrate de diméthylaminopropyl—N—chlorophénothiazine (4560 RP). Ann Med Psychol. 1952;110:112–117. French. 52. Olie JP. The discovery of chlorpromazine: a historical account. Int J Neuropsychopharmacol. 2004;7(Suppl 1):21. 53. Deniker P. Qui a inventé les neuroleptiques? Paris (FR): Confrontations Psychiatriques; 1975;13:7–15. 54. Follin S. Discussion. Ann Med Psychol. 1952;110:126–127. French. 55. Rigotti S. Del blocco del SN vegetativo all’ibernazione artificiale primi risultati di un nuevo indirizzo di terapia psichiatrica. Rass Neurol Veg. 1952;9:197–210. Italian. 56. Arnold OH, Hilt S, Solma W. Über die Anwendung eines vegatativen Hemmungs stoffes in der psychiatrischen Therapie. Wien Med Wochenschr . 1952;102:965–969. German. 57. López-Muñoz F, Alamo C, Cuenca E, et al. History of the discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry. 2005;17(3):113–135. 58. Elkes J, Elkes CH. Effects of chlorpromazine on the behavior of chronically overactive psychotic patients. BMJ. 1954;2:560–576. 59. Anton-Stephens D. Preliminary observations on the psychiatric uses of chlorpromazine (Largactil). J Ment Sci. 1954;100:543–557. 60. Staehelin JE, Kielholz P. Largactil, ein neues vegatativen Dämp-fungsmittel bei psychischen Störungen. Wien Med Wochenschr. 1953;83:581–586. German. 61. Staehelin JE. Einige allgemeine Bemerkungen uber die Largactiltherapie in der psychiatrischen Universitatsklinik Basel. Schweiz Arch Neurol Psychiatr. 1954;73:288–291. German. 62. Bente D, Itil TM. Zur Wirkung des Phenothiazin Körpers Megaphen auf das menschliche Hirnströmbild. Arzneimeittel Forschung. 1954;4:418–423. German. 63. Kardos G, Pertorini R. Largactil a psychiátriában. Ideggyogy Sz. 1955;8:65–61. Hungarian. 64. Sal y Rosas F, Jerí R, Sanchez J. Chlorpromzine in neuropsychiatry. JAMA. 1954;156:558. 65. Webb RR. Largactil in psychiatry. Med J Aust. 1955;1:759–761. 66. Tarasov GK. Aminazine, review of the literature on the psychiatric use of a phenothiazine derivative. Zhurnal Nevropatologii i Psikhiatria Korsakov. 1955;55:296–310. 67. Winkelman NW. Chlorpromazine in the treatment of neuropsychiatric disorders. J Am Med Assoc. 1954;155:18–21. 68. Pichot P. Psychopharmacotherapy and the history of psychiatry. In: Healy D. The psychoparmacologist. London (GB): Chapman Hall; 1996. p 1–20. 69. Hollister LE. Review of International Colloquium on Chlorpromazine. In: Ban TA, Hippius H, editors. Towards CINP. Brentwood (TN): JM Productions; 1994. p 18–23. 70. Gingras Y. La valeur d’une langue dans un champ scientifique. Recherches Socigraphiques. 1984:25(2):285–296. 71. Shorter E. A history of psychiatry: from the era of the asylum to the age of Prozac. New York (NY): John Wiley; 1997. 72. Ayd FJ. A clinical analysis of the differential effects of phenothiazine derivatives. In: Bradley PB, Deniker P, RadoucoThomas C, editors. Neuropsychopharmacology. Amsterdam (NL): Elsevier; 1959. p 487–488. 73. Cook L. Early pharmacology of chlorpromazine. The Int J Neuropsychopharmacol. 2004;7(Suppl 1):21. 74. Lambert P. Chlorpromazine: a true story of the progress affected by this drug. In: Ban TA, Healy D, Shorter E, editors. The rise of psychopharmacology and the story of CINP. Budapest (HU): Animula; 1998. p 237–243.



Chapter 2

What Does Schizophrenia Teach Us About Antipsychotics? Gary Remington, MD, PhD, FRCPC1; Ofer Agid, MD2; George Foussias, MD, PhD, FRCPC3; Gagan Fervaha, BSc (PhD Candidate)4; Hiroyoshi Takeuchi, MD, PhD5; Jimmy Lee, MBBS, MMed6; Margaret Hahn, MD, PhD, FRCPC3 1

Professor, Department of Psychiatry, University of Toronto, Toronto, Ontario; Lead, Subspecialty Clinics, Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario; Senior Scientist, Campbell Family Mental Health Research Institute, Toronto, Ontario; Faculty, Institute of Medical Science, Toronto, Ontario. Correspondence: Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8; [email protected].

2

Associate Professor, Department of Psychiatry, University of Toronto, Toronto, Ontario; Medical Leader, Home Intervention Program, Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario; Faculty, Institute of Medical Science, Toronto, Ontario.

3

Assistant Professor, Department of Psychiatry, University of Toronto, Toronto, Ontario; Staff Psychiatrist, Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario; Scientist, Campbell Family Mental Health Research Institute, Toronto, Ontario.

4

Student, Institute of Medical Science, Toronto, Ontario.

5

Post-doctoral Fellow, Department of Psychiatry, University of Toronto, Toronto, Ontario; Assistant Professor, Department of Neuropsychiatry, Keio University, Tokyo, Japan.

6

Post-doctoral Fellow, Department of Psychiatry, University of Toronto, Toronto, Ontario; Psychiatrist and Consultant, Department of General Psychiatry, Institute of Mental Health, Singapore, Singapore; Assistant Professor, Office of Clinical Sciences, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.

Key Words: schizophrenia, first-episode psychosis, prodrome, treatment resistance, pharmacotherapy, antipsychotics, polypharmacy, classification, outcome Received, revised, and accepted June 2014.

open access

Objective: To examine how advances in our understanding of schizophrenia have shaped thinking about antipsychotics (APs) and their role in treatment. Method: Three specific developments in the field of schizophrenia are highlighted: advances in knowledge related to the earliest stages of schizophrenia, specifically the prodrome; reconceptualization of schizophrenia as an illness of multiple symptom domains; and greater clarification regarding the efficacy of clozapine and a new generation of APs. Results: Evidence indicating that negative and cognitive symptoms are present during the prodrome suggests that intervention at the time of first-episode psychosis constitutes late intervention. The limited efficacy of APs beyond psychosis argues against a magic bullet approach to schizophrenia and for polypharmacy that is symptom domain–specific. Clozapine’s unique, but limited, efficacy in treatment resistance supports subtyping schizophrenia based on treatment response. Conclusions: Advances in our understanding of schizophrenia have important implications regarding the current use of APs, expectations regarding response, and future drug development. WWW

Que nous enseigne la schizophrénie sur les antipsychotiques? Objectif : Examiner comment les progrès de notre compréhension de la schizophrénie ont formé notre idée sur les antipsychotiques (AP) et leur rôle dans le traitement. Méthode : Trois développements spécifiques du domaine de la schizophrénie sont présentés : le progrès des connaissances relatives aux stades précoces de la schizophrénie, spécialement le prodrome; la reconceptualisation de la schizophrénie comme étant une maladie de multiples domaines de symptômes; et une clarification accrue concernant l’efficacité de la clozapine et d’une nouvelle génération d’AP. Résultats : Les données probantes indiquant que des symptômes négatifs et cognitifs sont présents durant le prodrome suggèrent que l’intervention au moment du premier épisode psychotique constitue une intervention tardive. L’efficacité limitée des AP au-delà de la psychose est un argument défavorable à une approche de solution magique pour la schizophrénie, et en faveur de la polypharmacie qui est propre au domaine de symptômes. L’efficacité unique mais limitée de la clozapine dans la résistance au traitement soutient le soustypage de la schizophrénie selon la réponse au traitement. Conclusions : Les progrès de notre compréhension de la schizophrénie ont d’importantes implications pour l’utilisation actuelle des AP, les attentes quant à la réponse, et le développement pharmaceutique futur. S14 W La Revue canadienne de psychiatrie, vol 60, supplément 2, mars 2015

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What Does Schizophrenia Teach Us About Antipsychotics?

D

rug development in the field of schizophrenia has flourished since the 1990s, beginning with clozapine’s reintroduction and paralleled by technological advances in areas (for example, neuroimaging and electrophysiology) that have markedly impacted thinking regarding the illness’ underlying neurobiology. Shifts in how we conceptualize the illness clinically, combined with a greater understanding regarding how medications work within these newer frameworks, offer yet another opportunity to advance pharmacotherapy and form the basis of the present discussion. Here we comment on 3 developments that have evolved out of these advances, developments we argue hold important ramifications regarding expectations about APs, and the search for new agents.

Antipsychotic Treatment, by Definition, Constitutes Late Intervention in First-Episode Schizophrenia

The 1990s also witnessed a growing interest in the early stages of schizophrenia, specifically FEP. Driving this line of thinking was evidence that considerable delays in implementing treatment often occur, and, further, delayed treatment (that is, DUP) compromises outcome. While a body of evidence has supported this hypothesis, findings have been inconsistent, and debate regarding the benefits of early intervention continues.1–5 Notably, there appears to be a disparity between clinical and functional outcome in as much as remission in psychosis does not guarantee functional recovery.6,7 As this work unfolded, schizophrenia was being reconceptualized, no longer positioned as an illness of only positive symptoms. Through the 1980s, negative or deficit symptoms garnered attention,8–11 and their importance was reflected in the development of clinical scales that clearly differentiated, while capturing, both positive and negative symptoms.12–14 Through the 1990s, increased focus was given to neurocognition, and by the turn of the century, the notion of schizophrenia as an illness of multiple symptom domains was firmly established.15–17 Shedding further light on these other symptoms was an evolving line of investigation also focused on the early stages of schizophrenia, but in this case the illness’ prodrome. This stage precedes the first psychotic break, can span a period of years, and is characterized by various nonpsychotic symptoms and behavioural changes often

Abbreviations AP

antipsychotic

DA

dopamine

DUP

duration of untreated psychosis

FEP

first-episode psychosis

TRS

treatment-resistant schizophrenia

URS

ultra-resistant schizophrenia

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Clinical Implications •

Positive symptoms represent the end stage in schizophrenia, with evidence that other key symptom domains are in place by the time of FEP.

•

The idea that a single agent will prove useful across these different symptom domains (the magic bullet approach) is naïve and has not been substantiated, endorsing a new form of polypharmacy that is presently being pursued.

•

From the standpoint of psychosis, evidence based on treatment response defines 3 subgroups that should be treated as such as we seek to understand the underlying neurobiology.

Limitations •

Efforts to intervene earlier than FEP remain hampered by the absence of clearly established clinical and (or) biomarkers that accurately delineate those who will convert.

•

Acknowledging schizophrenia’s heterogeneity represents an important advance that also highlights major gaps in treatment (for example, negative and cognitive symptoms; clozapine-resistant schizophrenia).

associated with functional deterioration. Evidence gathered suggests that cognitive deficits (both neurocognition and social cognition), as well as negative symptoms, are in place during the prodrome.18–21 Why are these details important? A closer examination of functional outcome and its determinants has established that domains other than psychotic or positive symptoms may be more relevant. While such a statement may be skewed, in that people are generally being treated for their positive symptoms, it remains that both cognitive and negative symptoms have been posited to play a more important role in functional recovery.22–24 The implications of these different lines of investigation are considerable. First, from a clinical standpoint, the onset of positive symptoms really represents a late stage of schizophrenia regarding its evolution; by the time a first psychotic break occurs, the other key symptom domains are already established. Second, it is these domains that seem to play a critical role in functional recovery. Finally, evidence indicates that APs are not particularly effective in treating these other symptoms.25–27 That early intervention with APs has not dramatically impacted measures of functional outcome is consistent with this, and highlights the current limitations facing FEP programs and the concept of early intervention, as well as the potential impact of APs, even used in the earliest stages of psychosis, on functional outcome.

Embracing Polypharmacy: the Myth of Magic Bullets

The magic bullet era surrounding APs may be drawing to a close. In retrospect, it was relatively short lived, and our embracing of this model seems a complex interplay of The Canadian Journal of Psychiatry, Vol 60, Supplement 2, March 2015 W S15

Chapter 2

science, hope, and marketing. The era was short lived in that APs were seen as just that (that is, anti-psychosis drugs) almost exclusively prior to clozapine’s reintroduction in the early 1990s. As noted, interest in the negative symptoms really only took a foothold in the 1980s (and largely argued against the potential use of APs, or pharmacotherapy generally, in effectively treating primary negative-deficit symptoms).9–11 Similarly, interest in neurocognition did not gain momentum until the 1990s.15–17 The finding that clozapine also appeared to impact negative symptoms in the work involving TRS28 seems an important catalyst in setting the stage for expectations that APs could be more than that. It is likely that time further contributed to this shift; almost immediately on the heels of clozapine came the advent of the newer atypical APs, drugs that were to mirror clozapine and, ideally, circumvent its burdensome side effect profile. The next decade saw claims regarding the benefits of these new medications expand considerably,29 perhaps fuelled by aggressive marketing. In fairness, it was likely driven as well by the hope that we could set behind us the therapeutic nihilism accompanying the evolution of the conventional APs and the growing recognition that even highly selective DA D2 antagonists (for example, haloperidol and pimozide), which theoretically should represent the ideal AP, fell woefully short.30–32 Be that as it may, claims of broader, as well as greater, efficacy grew, but the science to firmly establish these could simply not keep pace. As a result, we have, more recently, witnessed a series of investigations that temper, if not dismiss, these claims.33–35 As the dust settles, we face a very different landscape. For example, evidence that these drugs meaningfully impact cognitive deficits and negative symptoms has not been forthcoming.25–27 Remembering what resurrected clozapine (that is, efficacy in TRS), it is now also clear that these other new drugs are not comparable.36,37 That said, enthusiasm generated by the introduction of a new class of APs generated renewed interest in research that fundamentally changed how we conceptualize the illness. It is now patently evident that schizophrenia represents much more than psychosis.38 Further, the apparent disconnect between clinical and functional outcome might better be understood in the context of these other symptom domains.22–24 It is here we pick up the polypharmacy story, which had, to a considerable extent, been built around the practice of using multiple APs to manage TRS. Evidence has been equivocal, at best, particularly when other factors, such as cost and side effect burden, are taken into consideration.39–41 However, the field of schizophrenia is now courting polypharmacy through another door. It has become increasingly apparent that our expectations of a magic bullet approach to schizophrenia were overly optimistic at best, or simply misguided at worst. In abandoning such an approach, we are still left to deal with an illness that has multiple domains, and the more recent shift in focus from clinical to functional recovery only reinforces this. S16 W La Revue canadienne de psychiatrie, vol 60, supplément 2, mars 2015

Our new definition of polypharmacy is no longer about combining APs. It is now about the possibility of accessing other drugs that can be used in conjunction with antipsychosis agents to improve these other symptoms. Indeed, it may well provide indirect support for some of the other forms of polypharmacy identified as prevalent (that is, use of multiple psychotropics for treatment of anxiety or depression).40 Only now we will be looking to add antinegative symptom drugs, anti-cognitive deficit drugs, and perhaps others as our understanding of schizophrenia’s complexity evolves. Interestingly, this approach very much aligns with the growing interest in personalized or individualized medicine. Clinical practice tells us that people with schizophrenia differ markedly across these different symptom clusters, a point captured in the multi-domains now detailed for clinical assessment in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.42 By having different drugs for each, we can individualize treatment in a fashion that best suits a particular individual. What is less clear at present, though, is whether the foreseeable future will provide us agents that can effectively treat these other symptoms in a clinically meaningful way.

Subtyping Schizophrenia by Antipsychotic Response

With the exception of clozapine in TRS,36,37 APs are generally considered to be similar in terms of clinical response. Moreover, all APs share in common DA D2 antagonism, considered critical to their AP effects.43 Clinicians routinely initiate AP treatment with the goal of symptom remission, switching agents in the case of suboptimal response to achieve this. Evidence suggests that, as a group, people with first-episode schizophrenia demonstrate a high response rate to the first AP, in the range of 70%, regardless of drug choice. Thereafter, the response rate drops precipitously, findings indicating that subsequent trials are associated with a response in the range of 20% or less.44 Operational criteria have been established to define TRS, and for this group about 30% to 60% of people will demonstrate a favourable response.28,45,46 For those who prove ultra-resistant (that is, suboptimal response to clozapine), no treatment or combination of treatments has proven to demonstrably capture a substantial number of this population.47 This implies at least 3 types of schizophrenia based on treatment response.48 The first group, the largest, responds to one of the currently available APs (other than clozapine as it cannot be used at this point), and can be designated AP responsive. There is no compelling evidence that atypical agents are superior in this group, although findings do suggest there is a modest chance (