CanJPsychiatry 2015;60(3 Suppl 2):S14–S18
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
www.LaRCP.ca
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
www.TheCJP.ca
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 (
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
www.LaRCP.ca
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
www.TheCJP.ca
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 (
