CNS Drugs 2010;

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CNS Drugs 2010; 24 (1): 9-20 1172-7047/10/0001-0009/$49.95/0

LEADING ARTICLE

ª 2010 Adis Data Information BV. All rights reserved.

Progress in Defining Optimal Treatment Outcome in Schizophrenia Gary Remington,1,2,3 George Foussias1,2,3 and Ofer Agid1,3

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. 1 Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada 2 Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada 3 Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

Abstract

Historically, schizophrenia has been associated with early-onset, persistent symptoms, and progressive decline accompanied by poor functional recovery. The advent of effective drugs in the 1950s improved symptom control, at least from the standpoint of positive features (e.g. hallucinations, delusions). However, even here the response was limited and efficacy in other symptom domains (cognitive, deficit/negative) was minimal. With clozapine as the prototype, the second-generation antipsychotics arrived in the 1990s with claims of improved tolerability, as well as greater and broader clinical efficacy, all of which was to translate to gains in functional outcome and quality of life. The capacity of these drugs to effect such changes has since been tempered, but it remains that the research and hope generated served as an impetus to redefine outcomes. A medical-based model, centred on pharmacotherapy and symptom resolution, has given way to a re-conceptualization of schizophrenia and treatment goals. There is a clearer distinction between clinical and functional outcomes, and, with this, greater attention has been given to these other symptom domains that curtail improvement in the latter. At the same time, a concerted shift to shared decision making has underscored quality-of-life issues that benefit from, but cannot be guaranteed by, either clinical or functional improvement. To this end, the field has now embraced a recovery model that is seen as a process, multidimensional and individualized, rather than dichotomous and symptom driven.

1. Schizophrenia and Outcome: An Historical Perspective Kraepelin’s[1] dementia praecox, or ‘early dementia’, was a telling descriptor of how this illness was perceived at the turn of the 20th century. Bleuler[2] subsequently coined the term ‘schizophrenia’, recognizing the illness as more heterogeneous and suggesting that outcome was not so uniformly poor.

The 1950s heralded the first effective treatment for schizophrenia in the form of chlorpromazine.[3] Antipsychotic treatment, in conjunction with a growing civil liberties movement, contributed to a massive de-institutionalization that is still being felt today.[4] In fact, antipsychotics quickly established themselves as the cornerstone of treatment programmes; implicit in the early enthusiasm for these medications was the notion that symptomatic

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control was guaranteed and, in turn, would translate to functional recovery. These drugs were by no means a panacea though, burdened with adverse effects and limited efficacy. By the 1980s, a clearer distinction was being drawn between positive (e.g. hallucinations, delusions) and negative (e.g. amotivation, anhedonia) symptoms.[5,6] Antipsychotics demonstrated moderate efficacy with the former while their impact on the latter was minimal; indeed, the drugs themselves could be a source of ‘secondary’ negative symptoms.[7] Clozapine, synthesized and developed in the 1960s, had established itself as clinically unique with its decreased risk of extrapyramidal symptoms.[8] However, widespread use was stalled in the 1970s when, soon after release, it was linked to a cluster of deaths subsequently tied to a risk of agranulocytosis. However, by the late 1980s interest was peaked again when the efficacy of clozapine in refractory schizophrenia was demonstrated.[9] This set the stage for a new generation of ‘atypical’ or second-generation antipsychotics that were hoped to mirror the diminished risk of extrapyramidal symptoms and broader clinical profile of clozapine.[10,11] While the favourable extrapyramidal symptom profile could be explained by its low affinity for dopamine D2 receptors, the precise mechanism(s) by which clozapine demonstrated improved clinical response were speculative at best, with various models posited.[12,13] Until the seminal work examining clozapine in the late 1980s,[9] it was widely held that primary negative or deficit symptoms were not amenable to pharmacotherapy, instead being more representative of structural versus biochemical abnormalities.[6] Initial efficacy data with second-generation antipsychotics appeared promising and quickly translated to claims of clinical benefits across a number of outcome measures.[13] This enthusiasm was tempered by later data though, including largescale effectiveness trials.[14-16] Although the data are not entirely consistent,[17] it is held that clozapine remains superior amongst second-generation antipsychotics in refractory schizophrenia;[18,19] beyond this, the clinical benefits of the secondgeneration antipsychotics have proven to be, at best, modest.[20-22] As a class, they are associated

with a lower risk of extrapyramidal symptoms than the first-generation antipsychotics, although this varies as a function of different factors: the specific second-generation antipsychotic; the comparator first-generation antipsychotic; and dose.[23-26] Liability for tardive dyskinesia also appears to be diminished.[27,28] In general, they appear better tolerated but adherence remains an issue, a reminder that non-adherence is complex and multi-factorial.[29] To say that gains have not been made though is misguided. The rejuvenated enthusiasm that these drugs brought to the field, and the accompanying research generated, has inextricably altered our approach to schizophrenia. Nowhere is this more evident than in discussions of outcome. This article follows this evolution from our initial clinical focus to the more recent interest in functional outcome, remission and recovery. It is not meant as an exhaustive review of any one of these topics, but instead is intended to put into perspective changes in how outcome is evaluated vis-a`-vis developments in the field. That the focus is tied so closely to antipsychotic development reflects the central role medications have played in schizophrenia treatment over the last 50 years. However, there has been a gradual shift in focus more recently to embrace a number of nonpharmacological interventions as it has become increasingly apparent that the newer antipsychotics have fallen short, including in the claims of their benefit with negative and cognitive symptoms. At the same time, interest in functional versus clinical recovery has grown and it is these symptom domains that seem critical here, more so than the positive features of the illness. The search for more effective drugs in this regard continues,[30] for at present negative and cognitive symptoms, both evident in the prodrome that predates firstepisode psychosis per se,[31-35] have not proven particularly amenable to pharmacotherapy.[20,22,36]



2. Clinical Outcome The symptom-based focus of pharmacotherapy is very much aligned with a clinical, rather than functional, evaluation. In this context, we have witnessed an expansion beyond positive CNS Drugs 2010; 24 (1)

Outcome in Schizophrenia

features as our conceptualization of schizophrenia has broadened to include multiple symptom domains. 2.1 Global Psychopathology

The 1950s witnessed the birth of modern psychopharmacology, and with it a need for objective response measures. The Clinical Global Impression (CGI) scale[37] and the Brief Psychiatric Rating Scale (BPRS)[38] were well suited to psychopharmacology research, both brief and providing global scores that could be compared across treatments, the latter including items specific to psychosis. Other scales, such as the Schedule for Affective Disorders and Schizophrenia-Change version (SADS-C),[39] are more diagnosis specific, although recent pharmacological trials have favoured measures such as the BPRS and the CGI.[40] Efforts have since been made to develop scales addressing the various symptom clusters of schizophrenia.

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(NIMH) MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Negative Symptom initiative.[51] Examination of underlying factor structures of the PANSS has called into question the items that constitute the negative symptom domain,[52] and it is of note that the MATRICS initiative focusing on negative symptoms more closely approximates the multidimensional approach of the SANS. Second-generation antipsychotics were initially purported to be superior to their conventional counterparts in managing both positive and negative symptoms, although current thinking indicates that the gains, if any, are modest.[20,21]

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. 2.2 Positive and Negative Symptoms

Kraepelin[1] was keenly aware of the importance of deficit-like symptoms in schizophrenia. Conventional antipsychotics were not particularly effective in this regard, supporting the hypothesis that negative symptoms are morphologically mediated and therefore not amenable to pharmacological manipulation.[6] The finding that these symptoms were responsive to clozapine[9] was rolled into expectations of similar actions in other second-generation antipsychotics, and with this came the need for scales specific to this domain. Both the Positive and Negative Syndrome Scale (PANSS)[41] and the Scale for the Assessment of Positive Symptoms (SAPS)/Scale for the Assessment of Negative Symptoms (SANS)[42,43] were seen as filling this gap. The Schedule for the Deficit Syndrome (SDS) speaks to the notion that negative symptoms may be distinguishable from core and enduring deficit features.[44] Other scales related to negative symptoms have been reviewed elsewhere.[45] Interest in negative symptoms has grown with evidence that they substantially impact functional outcome,[46-50] and is reflected in the recent National Institute of Mental Health ª 2010 Adis Data Information BV. All rights reserved.

2.3 Cognitive Symptoms

Widespread neurocognitive deficits have been identified in schizophrenia, including deficits in verbal memory, executive functions, verbal fluency and motor speed;[53] it has been argued that virtually all individuals with schizophrenia manifest some degree of deficit.[54,55] These are identifiable in the premorbid stages of schizophrenia, which fits with the notion that this illness represents a neurodevelopmental, rather than neuroprogressive, disorder.[56] The deficits seem relatively stable across time,[33] and evidence indicates that the gains claimed with second-generation antipsychotics are not sufficient to translate to notable changes functionally.[22] There is a growing body of evidence documenting deficits in social cognition (i.e. perception, interpretation and processing of social information).[57] These deficits are also evident in the earliest stages of schizophrenia,[58] and impact functional outcome.[59] Indeed, social cognition has been more closely linked to community functioning than general cognition or clinical symptoms.[60] That said, it is thought to mediate at least some aspects in the relationship between neurocognition and social skills,[61] linked as well to specific clinical symptoms (e.g. negative, paranoia).[62] Current evidence challenges the potential for improvement with existing antipsychotics.[63] Numerous cognitive measures have been employed, making comparison of findings difficult. This has been addressed with the NIMH-sponsored CNS Drugs 2010; 24 (1)

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MATRICS initiative, which has recommended a battery, estimated to take approximately 1 hour to administer and addressing speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition.[64,65] 2.4 Affective Symptoms

ratios reduces the variability that can be evident with the use of response rate differences; further, it is recommended that responder rates be examined in 25% steps up to 100% reduction from baseline.[74] A further criticism relates to our preoccupation with clinical symptoms. There has been a shift away from the traditional medical model, replaced by greater emphasis on shared care.[75] Studies have uncovered considerable discrepancy between the priorities of caregivers and consumers (including families), the latter often being focused more on functionally related goals.[76] In terms of symptoms, there has also been a marked shift in our understanding of the relationship between clinical and functional outcome. As attention turned to negative and cognitive symptoms, it has become increasingly apparent that these domains are more closely related to functioning,[47,59,77,78] and this is impacting treatment goals.

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. Depression is a significant clinical feature in schizophrenia, and it is estimated that co-morbid depression occurs in 50% of patients.[66] Affect is routinely addressed in clinical scales (e.g. PANSS and BPRS), and the Calgary Depression Scale (CDS) was specifically developed to evaluate depression in the context of schizophrenia.[67,68] 2.5 Other Domains

The PANSS provides three subscale measures: Positive; Negative; and General Psychopathology.[41] The General Psychopathology subscale has not found a niche in studies of clinical outcome and, in fact, reports have suggested more complex three-, four- and five-factor models.[69-71] While there is interest in these other models, efforts to replicate have provided conflicting results and they have not been widely embraced in characterizing specific symptom domains.[69-71] 2.6 Defining Clinical Response

For psychopharmacology trials, clinical change remains the cornerstone of outcome. Global improvement is often the primary measure (e.g. percentage total PANSS improvement from baseline to endpoint), while changes in specific symptoms (e.g. positive, negative) are frequently assessed as secondary outcome measures. This pattern is shifting with the evaluation of agents that may be focused on selective symptom domains (e.g. cognitive enhancers). One of the most common criticisms in defining clinical outcome is the use of response as dichotomous and arbitrary (e.g. a 20% reduction). Reductions of this magnitude, while meeting the criteria for ‘response’, may at a clinical level leave an individual quite symptomatic.[72,73] More recently, it has been suggested that the use of response rate ª 2010 Adis Data Information BV. All rights reserved.

3. Functional Outcome

A review of schizophrenia outcomes research in the mid-1990s highlighted our preoccupation with clinical measures and astutely predicted a focus on functional outcome as shrinking healthcare resources placed greater demand on costeffective interventions.[79] The work in the late 1980s with clozapine,[9] and the introduction of a new generation of antipsychotics thought to model its broader clinical benefits, primed the field for such a change.[80,81] Ironically, it was the same claims generating optimism that ultimately redefined the ratelimiting steps in functional outcome. Specifically, the newer antipsychotics were claimed to have benefits over their conventional counterparts in treating negative[82-85] and cognitive[80,86-88] symptoms, turning our attention to measures that would better capture the functional benefits of these gains. These pharmacological benefits were less robust than thought,[14,20,22,24,89] but in this process it was clarified that negative and cognitive symptoms played a greater role than positive symptoms in functional recovery.[47,90,91] By this point though, functional outcome was inalterably CNS Drugs 2010; 24 (1)


part of discussions examining outcomes. Furthermore, limitations of the second-generation antipsychotics in this regard encouraged renewed efforts to pursue novel pharmacological, as well as non-pharmacological, strategies to fill this gap.[22,36,92-95] The latter highlights the role of nonbiological or even clinical factors (e.g. socioeconomic, ethnocultural) in real world functioning. This was underscored more recently by evidence from CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) indicating that competitive employment was influenced more by receipt of disability payments and being Black than by clinical symptoms.[50]

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to work-related activities/performance, but must include more fundamental measures such as selfcare, independent living skills and social functions.[101] A distinction must be drawn between functional capacity measures, such as the UPSA, which are performance based and reflect potential (e.g. planning/organization), and scales such as the QLS, which reflect ‘real world’ functioning. The fact that six of the eight instruments were developed since 2000 is testimony to the growing recognition that functional measures must be integrated into any comprehensive evaluation of outcome. That said, this line of investigation faces its own methodological issues (e.g. interpretation of counter-intuitive results, lack of established validity with real-world outcomes and distinguishing between capacity and motivation).[79,99,102,103]

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. 3.1 Functional Outcome Measures

Perhaps the best known measure of functional status is the Global Assessment of Functioning (GAF), embedded in the DSM system as part of a multi-axial assessment.[96] It has been recommended for widespread use in inpatients with serious and persistent mental illness, and is comparable to the BPRS in terms of normative data, cost, ease of administration and sensitivity to change.[97] The 21-item Heinrichs-Carpenter Quality of Life Scale (QLS)[98] was designed to specifically assess the deficit syndrome and has found a role in psychopharmacology trials, which are often focused on outpatient samples (e.g. CATIE).[16] More specific than the GAF, it provides scores on four scales, including Instrumental Role. The University of California, San Diego Performance-Based Skills Assessment (UPSA) has received the most attention in the research literature,[99] and includes five subtests focused on basic daily living skills (planning/organization, finances, communication, travel and household).[100] Instruments for the evaluation of functional recovery in psychosis have been the subject of a recent review.[99] Eight measures were evaluated and, while no ‘gold standard’ was identified, it was concluded that performance-based, rather than self-report or clinical, measures appear most effective in predicting independent living and work. This point is echoed elsewhere, as is the reminder that functional outcome is not confined ª 2010 Adis Data Information BV. All rights reserved.

4. Other Measures

A number of other developments have influenced how we view outcome. Psychiatry, like other areas of medicine, has seen a move to engage patients in their own care, placing greater emphasis on subjective needs and shared care.[75] The recovery movement has offered further impetus in this regard, reframing treatment from a professional to a personal perspective.[104] Accordingly, increasing attention has turned to quality of life. The scope of this is, of course, both broad and complex, ranging from attitude to treatment (e.g. Drug Attitude Inventory [DAI]),[105] to global evaluation tools.[98] It has been the subject of review,[98,102,103] and more recently was identified as the primary outcome measure in a large effectiveness trial.[14] Selfreport measures are used to assess satisfaction across different domains (e.g. self-esteem, perceived illness burden), while objective measures tap into participation in the individual’s surrounding environment (e.g. activities and interpersonal relationships). Clinical symptoms (e.g. positive, negative) adversely influence quality of life, just as their reduction translates to improvement in such measures.[106-108] Similarly, neurocognition has been significantly related to quality of life, independent of clinical symptoms.[107] Both clinical symptoms and neurocognition influence functional CNS Drugs 2010; 24 (1)

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outcome,[49] which itself is linked to quality-oflife scores.[107] Individuals with schizophrenia have a lifespan that is shortened by as much as 25%, independent of suicide risk.[109] However, it has taken concerns about the second-generation antipsychotics and their identified liability for weight gain/metabolic disturbance for the field to really take on the issue of physical well-being.[110] Numerous guidelines have been published for medical monitoring,[86-90] and it is now being factored into discussions of longer term outcome. For example, recent development of a new clinical measurement tool geared to effectiveness identified four outcome domains: symptoms; treatment burden; disease burden; and health and wellness.[111] The progressive move in care from institutions to the community has also shifted services to families and a number of different caregivers, individuals better positioned to assist with dayto-day functioning and its assessment. Optimal treatment now involves a multidisciplinary, multidimensional team approach and this has, in turn, emphasized the need for instruments that better reflect this perspective. Carer outcomes can be subdivided into three domains: carers’ wellbeing; experience of caregiving; and need for professional support. A recent review has identified a number of candidate instruments and reinforced the need for regular evaluation if mental health services are to function effectively.[112]

Refractory schizophrenia represents a select population with defined criteria, distinguishable from a partially responsive sample. It has important implications from the standpoint of outcome, as clozapine is superior to other antipsychotics, including second-generation antipsychotics, in these individuals.[11,14,19,116] There are also criteria for an ‘ultraresistant population’ (i.e. clozapine partial or non-responders),[117] although strategies proving effective in this subsample remain elusive.[17,118] Remission dovetails nicely with a growing interest in antipsychotic effectiveness.[14,16] While past definitions have focused on symptom reduction,[74] the most recent criteria are somewhat more stringent,[119,120] addressing different dimensions of psychopathology (positive, negative, disorganization), as well as severity, and requiring in addition a minimum interval of 6 months improvement.[121] The implications of remission are only now being examined more closely. Reports indicate 30–70% of treated individuals achieve this stricter definition of remission;[122-127] other criteria provide similar figures.[125] It appears to occur early in response to treatment for many, but it is not static.[124,128] In a 3-year follow-up study, for example, 35% of individuals meeting criteria for remission failed to sustain this.[129] Remission is necessary, but may not be sufficient, for functional gains or even improved subjective well-being;[121] it appears more closely related to the latter rather than functional remission.[124] That remission is not as closely related to functional improvement may, in part, reflect the fact that criteria for cognition are not presently incorporated,[121,130] and cognition is a domain strongly tied to functional outcome.[47,91,121,130] However, it remains that individuals in remission are as a group functioning more effectively than non-remitters.[124,127,128,131,132] Finally, even in remission very few people are without clinical symptoms.[120,124] In the face of these data, recovery may seem an unnecessary discussion; it is certainly a topic of debate,[104,133-136] even from the standpoint of those with the illness.[137] There are a number of reasons, though, why this dialogue will continue,

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. 5. Response, Relapse, Refractory, Remission and Recovery

Evaluation of antipsychotics has relied on response and relapse to examine efficacy, with a distinction between natural and interventional relapse to accommodate the episodic course of schizophrenia in the absence of treatment.[113] At its simplest, relapse is defined as ‘the return of a disease after partial recovery’;[114] in practice, it hinges on symptom severity. Although hospitalization as a threshold criterion is less tenable in the current community-based treatment environment, 6 of 11 studies in a recent meta-analysis comparing relapse rates between antipsychotics used hospitalization in their definition.[115] ª 2010 Adis Data Information BV. All rights reserved.

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not the least of which is the President’s New Freedom Commission report that ensures ‘recovery’ is integral in guiding mental health policy and practice.[138] Moreover, the shift in treatment focus to consumers and families has demanded a change in priorities and goals.[104,138,139] There is, as well, a small but notable body of evidence supporting such optimism. As we have tracked this illness, its prognosis appears to have improved,[140] and there is clear evidence that at least a subgroup of those with schizophrenia ‘recover’, with or without treatment.[126,135] Recovery, as presently defined, is (i) a process rather than dichotomous; and (ii) not equated with the absence of symptoms. It is better conceptualized as ‘recovery in’ serious mental illness rather than ‘recovery from’.[104] The recovery process is different from ‘recovered’,[141] just as symptomatic and functional recovery must be distinguished. The relationship between remission and recovery is less than clear,[142,143] although measurement tools that may clarify these issues are being developed.[144] As this unfolds, measures such as symptom control and remission represent reasonable goals in evaluating outcome.[145]

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Quality of life

Optimal outcome

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. 6. Conclusion

Schizophrenia is a heterogeneous disorder, following different trajectories that range from rapid and progressive deterioration to resolution and return to premorbid levels of functioning.[146,147] It remains unclear as to whether we can alter the fundamental course of this illness for a particular individual or whether, in fact, schizophrenia ‘has a life of its own’. Defining and optimizing outcome in this lifelong illness has evolved beyond symptom control (figure 1). These different dimensions are interactive, but also somewhat independent. Clinically, our present medications provide their greatest benefits in the control of positive symptoms, with evidence of possible modest benefits in cognitive and negative features. With the present limitations in pharmacological treatment, it has been suggested that emphasis be on ‘management’ rather than ‘treatment’, the latter conjurª 2010 Adis Data Information BV. All rights reserved.

Clinical

Functional

Fig. 1. Outcome in schizophrenia defined on three inter-related, but somewhat independent, dimensions. Clinical improvement is symptom focused and response driven; effective treatment can transition into remission over time. Symptomatic remission favours improved functional outcome and quality of life but guarantees neither. Cognitive and deficit symptoms seem most relevant to functional outcome, which may account for why it does not necessarily parallel clinical remission as presently defined. Quality of life can be enhanced by both clinical and functional improvement but is not simply the product of these; it is, at least in part, subjectively and systems driven. Recovery, as currently conceptualized, is a process rather than dichotomous, incorporating each of these dimensions on an individualized basis.

ing up greater expectations of full recovery.[148] All antipsychotics have adverse effects that must be minimized to enhance outcome, and extraneous issues compromising response (e.g. adherence, substance abuse) also have to be addressed.[148-151] Early intervention and effective pharmacological treatment are linked to improved outcome, with decreased relapse rates and symptomatic remission reasonable goals.[152] Refractory schizophrenia can often be identified early in the course of treatment; clozapine represents the treatment of choice and should be initiated sooner rather than later.[19,146] Symptomatic remission favours improved functional outcome and quality of life but guarantees neither.[121] Cognitive and negative symptoms, identifiable at the onset of the illness, appear to be the major stumbling blocks in functional remission, and the limitations of present antipsychotics, both conventional and atypical, demand the search for better pharmacological treatments CNS Drugs 2010; 24 (1)

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(which may take the form of add-on strategies).[20,22,93,94] Current limitations in this regard have also crystallized the need to explore and develop non-pharmacological approaches (e.g. cognitive remediation).[153] Quality of life extends beyond symptom control or even functional remission. Optimizing outcome here speaks to fundamental basics: access to appropriate care, including medical, adequate housing and financial support.[134,136,154,155] To speak about recovery in schizophrenia is misdirected if we define it as symptom resolution and return to a premorbid level of functioning. Notable exceptions remind us this can occur,[135,147] but current evidence simply does not support this as a realistic standard against which we measure outcome in schizophrenia.[156,157] Optimal symptom control, with parallel interventions to maximize functional outcome and quality of life in the face of limitations, represents a more reasonable and flexible approach. Recovery, individually defined in this context, becomes achievable and avoids the pessimism that can arise from unreasonable standards. Inherent in this approach, though, is a clear understanding by all parties, including family members and payers, what is and is not meant by recovery in order to avoid unrealistic expectations and demands.[139] It may well be that the greatest gains in outcome over the next years are not medication related, but the result of a more comprehensive model of care.

3. Lopez-Munoz F, Alamo C, Cuenca E, et al. History of the discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry 2005; 17: 113-35 4. Kirkby KC. Social context and health consequences of the antipsychotics introduction. Ann Clin Psychiatry 2005; 17: 141-6 5. Andreasen NC, Olsen S. Negative v positive schizophrenia: definition and validation. Arch Gen Psychiatry 1982; 39: 789-94 6. Crow TJ. Positive and negative schizophrenic symptoms and the role of dopamine. Br J Psychiatry 1980; 137: 383-6 7. Carpenter Jr WT, Heinrichs DW, Wagman AM. Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry 1988; 145: 578-83 8. Hippius H. A historical perspective of clozapine. J Clin Psychiatry 1999; 60 Suppl. 12: 22-3 9. Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988 Sep; 45 (9): 789-96 10. Fleischhacker W. ‘Atypical antipsychotics’ and the semantics of psychopharmacology. Curr Opin Psychiatry 2002; 15: 1-2 11. Remington G, Kapur S. Atypical antipsychotics: are some more atypical than others? Psychopharmacology (Berl) 2000; 148 (1): 3-15 12. Kapur S, Remington G. Dopamine D2 receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry 2001; 50 (11): 873-83 13. Remington G. Understanding antipsychotic ‘atypicality’: a clinical and pharmacological moving target. J Psychiatry Neurosci 2003; 28 (4): 275-84 14. Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63 (10): 1079-87 15. Kahn RS, Fleischhacker WW, Boter H, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 2008; 371 (9618): 1085-97 16. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353 (12): 1209-23 17. Elkis H. Treatment-resistant schizophrenia. Psychiatr Clin North Am 2007; 30 (3): 511-33 18. Lewis SW, Barnes TR, Davies L, et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006; 32 (4): 715-23 19. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006; 163 (4): 600-10 20. Buckley PF, Stahl SM. Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or cul-de-sac? Acta Psychiatr Scand 2007; 115 (2): 93-100

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. Acknowledgements

No sources of funding were used to assist in the preparation of this review. Dr Remington has received grant support from Novartis, and acted in a consultant role for Cannasat Therapeutics Inc., Impax Laboratories Inc. and Medicure Inc. In the past 5 years, Dr Agid has received speaker honoraria from Eli Lilly and Janssen-Ortho. Dr Foussias has no conflicts of interest that are directly relevant to the content of this review.

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Correspondence: Dr Gary Remington, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada. E-mail: [email protected]

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