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Address correspondence to: Christoph U. Correll, MD, Division of Psychiatry Research, The Zucker Hillside Hospital, 75-59 263rd Street, Glen Oaks, NY 11004
Zucker Hillside Hospital, Psychiatry Research, North Shore–Long Island Jewish Health System, Glen Oaks, New YorkAlbert Einstein College of Medicine, Bronx, New YorkFeinstein Institute for Medical Research, Manhasset, New YorkHofstra North Shore LIJ School of Medicine, Hempstead, New York
Zucker Hillside Hospital, Psychiatry Research, North Shore–Long Island Jewish Health System, Glen Oaks, New YorkAlbert Einstein College of Medicine, Bronx, New YorkFeinstein Institute for Medical Research, Manhasset, New YorkHofstra North Shore LIJ School of Medicine, Hempstead, New York
To optimize the management of patients with schizophrenia, quantification of treatment effects is crucial. While in research studies, the use of quantitative assessments is ubiquitous, this is not the case in routine clinical practice, creating an important translational practice gap.
Objective
The aim of this study was to examine the relevance, methodology, reporting, and application of measurement-based approaches in the management of schizophrenia.
Methods
We summarized methodological aspects in the assessment of therapeutic and adverse antipsychotic effects in schizophrenia, including definitions and methods of measurement-based assessments and factors that can interfere with the valid quantification of treatment effects. Finally, we proposed pragmatic and clinically meaningful ways to measure and report treatment outcomes.
Results
Although rating scales are ubiquitous in schizophrenia research and provide the evidence base for treatment guidelines, time constraints and lack of familiarity with and/or training in validated assessment tools limit their routine clinical use. Simple but valid assessment instruments need to be developed and implemented to bridge this research-practice gap. In addition, results from research trials need to be communicated in clinically meaningful ways, including the reporting of effect sizes, numbers-needed-to-treat and -harm, confidence intervals, and absolute risk differences. Some important outcomes, such as treatment response, should be reported in escalating intervals using incrementally more stringent psychopathology improvements. Even with quantification, it remains challenging to weigh individual efficacy and adverse effect outcomes against one another and decide on the targeted or desired improvement or outcomes while also incorporating these in patient-centered and shared decision methods.
Conclusions
Quantification of treatment effects in schizophrenia is relevant for patient management, research, and the evaluation of health care systems. Beyond consensus about meaningful outcomes definitions, reporting strategies, pragmatic tool development and implementation, the discovery of novel treatment mechanisms and related biomarkers is hoped to advance measurement-based approaches in schizophrenia and thereby improve patient outcomes.
Despite multiple advances in the management of schizophrenia, there is still an enormous need to improve our understanding and treatment of patients suffering from schizophrenia. With the development of additional pharmacologic treatment options and the availability of technological tools that are hoped to help personalize treatment,
a careful assessment of treatment effects is needed. First and foremost, this requires the detailed clinical and research assessment of beneficial and adverse effects of the treatment options. Without quantifying these effects, clinicians are hampered when trying to decide on a given treatment strategy. Although treatment guidelines are helpful
World Federation of Societies of Biological Psychiatry (WFSBP)—guidelines for biological treatment of schizophrenia, part 1: acute treatment of schizophrenia.
because they synthesize research results across a number of dimensions, these guidelines can only be as accurate, detailed, and generalizable as the data they are based on. In addition, incidence rates of certain treatment effects and group means of rating scale scores can provide only a yardstick for the decision-making process. Ultimately, the efficacy and tolerability of a given treatment in a given patient can only be assessed directly. To date, measurement-based approaches are not used in the routine treatment of schizophrenia. The field needs to develop pragmatic but meaningful tools that can be used by busy practitioners working under enormous time constraints. The era of electronic medical records makes this even more relevant, as such real-world effectiveness assessments can be used in large pragmatic trials. Database outcomes research can include more generalizable treatment groups than are ordinarily involved in randomized controlled trials and also provide more detailed data than ordinary claims-based research. To establish measurement-based approaches in the treatment of schizophrenia, research approaches need to be adapted to real-world settings; simple, but valid and clinically meaningful tools and criteria are needed; and measured outcomes need to be placed in the context of the individual patient. In addition, it is important to have the patient's perspective on what is important to him or her in weighing efficacy and tolerability, as well as the relative salience of specific symptoms. Finally, the successful implementation of measurement-based principles in psychiatric practice needs to find ways to overcome the not uncommon fragmentation of care of severely mentally ill patients. This includes the orchestration of psychopharmacologic, psychotherapeutic, vocational, and social rehabilitative and physical medical care that is usually delivered by different people. In this case, effective communication is key, but quantified assessments can greatly help the integration of goals and identification of areas in need of additional improvement and synergy.
Methods
This article summarizes methodological aspects in the assessment of beneficial and adverse effects of antipsychotics in schizophrenia. We provide information about the importance of measurement-based approaches in general and review definitions and methods of such assessments. In addition, we address factors that can interfere with the valid quantification of treatment effects in schizophrenia patients and ways that measurement-based outcomes should be reported to be clinically meaningful. Although psychosocial interventions are of enormous importance, we focus predominantly on pharmacologic treatments because psychosocial interventions are generally given in conjunction with antipsychotics, which are the cornerstone of management to which other treatments are added.
Importance of Measurement
Measurement is one of the most critical elements in the diagnosis and clinical management of any illness. We measure the frequency and severity of symptoms as well as their functional consequences to make a presumptive diagnosis. We continue to measure disease-related phenomena in the confirmation of our presumptive diagnosis, and eventually some types of measurement become the critical element in evaluating the response to treatment and the overall course of illness. Despite the ubiquitous requirements for some degree of measurement, psychiatry as a field has been remarkable in the lack of consistent clinical training for and application of valid and reliable measurement techniques.
Validity refers to the ability of a diagnosis or clinical assessment to reflect the “reality” of the situation. Is the diagnosis correct according to some gold standard or validating criteria? Reliability refers to the characteristics of an instrument or diagnosis and those who use it to arrive at the same conclusion, score, and the like when evaluating the same patient independently. Clinicians can be “wrong” in their measurements or conclusions (poor validity) but still agree with one another (good reliability). Therefore, one has to be careful to distinguish validity and reliability from each other. They are established in very different ways. It is also important to realize that a disorder is not defined by symptoms alone, but that either subjective distress or functional impairment is required.
Given the fact that there are no objective laboratory or other tests to confirm or measure psychiatric illnesses and that we depend to a large extent on the patient's and/or informant's subjective evaluation of mental states and behavior, the situation lends itself to considerable room for error, disagreement, and lack of adequate documentation. The requirements of clinical research to ensure validity and reliability of diagnosis and clinical assessments of outcomes have resulted in the development of numerous diagnostic (structured interviews) and assessment (clinician, patient and informant derived) instruments, but these are very rarely utilized in clinical practice.
There are a variety of obstacles (perceived and real) to implementing quantitative measures in clinical practice, but there are also important benefits to the application of such approaches (Table I).
Table IThe value of and barriers to implementing measurement-based approaches in psychiatry.
Every treatment decision that we make involves concepts like response, remission, relapse, and the like, yet these are often used in a very inconsistent fashion without any agreement as to how they should be defined and measured. Clinicians tend to rely on global clinical judgment, which can be difficult to document or replicate. How often do we see a note in a chart that states “patient better” or “patient has had a relapse” without any further indication of on what these statements are based. Tremendous emphasis has been appropriately placed on the application of evidenced-based medicine throughout health care, but the application of evidence requires an understanding of how the evidence was gathered, how generalizable it is, and to what extent it applies to the patient before us.
All of these issues hinge on the measurements and definitions involved. Here we review some of these concepts and definitions and discuss their relevance to clinical practice.
outlines common treatment goals and challenges to achieving these goals. Although terms like response, resolution of symptoms, remission, recovery, relapse, and treatment resistance are commonly used, they are used inconsistently and definitions vary.
FigureTreatment coals and challenges. SXS = symptoms.
After diagnosis and the establishment of a treatment plan, evaluating response to treatment is critical. Response can be considered to be a clinically significant improvement of the psychopathology of a patient, regardless of whether or not the person continues to have symptoms. In clinical trials, thresholds in the sense of a minimum percentage reduction from the initial score on a scale such as Brief Psychiatric Rating Scale (BRPS)
are used for this purpose. The problem is that there is no agreement as to which cutoff should be used. In the literature, at least 20%, 30%, 40%, 50%, and 60% reductions from the initial score have all been applied, but the clinical meaning of the cutoffs is unclear. Several publications using data from several thousand participants who were rated simultaneously with the BPRS/PANSS and the Clinical Global Impressions Scale
Clinical Global Impression in ECDEU Assessment Manual for Psychopharmacology, Revised (DHEW Publ No ADM 76-338). National Institute of Mental Health,
Rockville, MD1976
Equipercentile linking of percentage improvement of the BPRS/PANSS with Clinical Global Impressions (CGI) improvement score showed that a 25% reduction of the BPRS/PANSS baseline score corresponded roughly to a minimal improvement according to the CGI, whereas a 50% reduction corresponded to “much improved.” As many acutely ill patients with schizophrenia often respond well to therapy, we concluded that for such patients the 50% cutoff would be a more clinically meaningful criterion than lower cutoffs. However, in chronic or treatment-resistant patients, even a slight improvement might represent a clinically significant effect, justifying the use of the 25% cutoff in treatment-refractory patients. Interestingly, the 20% cutoff was used initially in a study of refractory patients
Such a table covers the extreme ranges of patients whose symptoms did not change or worsened during a trial (≤0% BPRS/PANSS reduction), patients who responded at least minimally (25% BPRS/PANSS reduction), patients who were at least much improved (50% BPRS/PANSS reduction), and patients who had exceptionally good responses compared with other participants in such studies (>75% BPRS/PANSS reduction). This methodology of reporting different levels of response has already been adopted.
Effectiveness of antipsychotics in first-episode schizophrenia and schizophreniform disorder on response and remission: an open randomized clinical trial (EUFEST).
In this context, it is also reasonable to use cross-sectional “remission” criteria as a measure of response because this would identify patients who have only mild or absent symptoms on key symptom measures.
Clinical Global Impression in ECDEU Assessment Manual for Psychopharmacology, Revised (DHEW Publ No ADM 76-338). National Institute of Mental Health,
Rockville, MD1976
Many assume that ≥75% BPRS/PANSS reduction is rare in schizophrenia. Nevertheless, in an analysis of 1870 patients in randomized amisulpride trials, approximately 25% of the participants reached at least 75% BPRS reduction.
The advantage of such a presentation is that the reader gets an impression of the distribution of the response. Presenting results based on 1 cutoff only cannot provide such information, and the choice of the cutoff remains somewhat arbitrary. It should be noted that when 1 to 7 scaling of the BPRS/PANSS was used, the 18/30 minimum score needs to be subtracted when calculating percentage reduction from baseline.
For the statistical analysis of a clinical trial, it is important to choose a primary cutoff a priori to avoid problems of multiple testing. Even if only the CGI scale
Clinical Global Impression in ECDEU Assessment Manual for Psychopharmacology, Revised (DHEW Publ No ADM 76-338). National Institute of Mental Health,
Rockville, MD1976
was used as a response criterion, the results could be shown in a similar fashion presenting the number of participants who were unchanged, minimally improved, and much improved or not ill, mildly ill, severely ill, and the like. A new version of the CGI that is specific for schizophrenia has been developed recently. The schizophrenia version uses the same items and scores but provides clear anchors as to what “mildly ill” or “moderately ill” means. Furthermore, there are subscales for positive, negative, depressive, and cognitive symptoms using the same scoring system. In contrast to the original CGI, the psychometric properties of the new version have been examined and found to be sufficient.
In applying the response measure in clinical practice and clinical trials, it is also important to understand the context. For example, we and others have recently investigated the early response paradigm, in which improvement (or rather lack of improvement) after only 1 or 2 weeks is used as a “biomarker” to predict subsequent response.
but this is early response and should not be confused with ultimate response, when such “minimal” improvement would be unacceptable.
Remission
Remission can be defined as a state of absence of significant symptoms. This is an important treatment goal. However, similarly to the different available response criteria, clinical and epidemiological studies on the frequency of remission in schizophrenia have been hampered by the lack of a uniformly accepted definition. For example, a series of long-term studies suggested that many patients might be in remission or even recover in the long run (for a review, see Leucht and Lasser
), but any comparison is difficult because of the variety of definitions used. In 2005, American and European expert groups suggested a remission definition for schizophrenia,
are rated as “mildly present” or better (Table III). In addition to the severity criterion, there is also a time component that requires that this low level of symptoms persist for at least 6 months, although short-term trials may only apply the severity criterion on a cross-sectional basis as previously mentioned.
Table IIIProposed items for remission criteria as defined by the Remission in Schizophrenia Working Group.
For symptomatic remission, maintenance during a 6-month period of simultaneous ratings of mild or less on all items is required. Rating scale items are listed by item number.
Use of BPRS criteria may be complemented by use of the SANS criteria for evaluating overall remission.
Item Number
Psychoticism (reality, distortion)
Delusions
Delusions (SAPS)
20
Delusions
P1
Grandiosity
8
Suspiciousness
11
Unusual thought content
G9
Unusual thought content
15
Hallucinations
Hallucinations (SAPS)
7
Hallucinatory behavior
P3
Hallucinatory behavior
12
Disorganization
Disorganized speech
Positive formal thought disorder (SAPS)
34
Conceptual disorganization
P2
Conceptual disorganization
4
Grossly disorganized or catatonic behavior
Bizarre behavior (SAPS)
25
Mannerisms/posturing
G5
Mannerisms/posturing
7
Negative symptoms (psychomotor poverty)
Negative symptoms
Affective flattening (SANS)
7
Blunted effect
N1
Blunted affect
16
Avolition-apathy (SANS)
17
Social withdrawal
N4
No clearly related symptom
Anhedonia-asociality (SANS)
22
Alogia (SANS)
13
Lack of spontaneity
N6
No clearly related symptom
BPRS = Brief Psychiatric Rating Scale; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition); PANSS = Positive and Negative Syndrome Scale; SANS = Scale for Assessment of Negative Symptoms; SAPS = Scale for Assessment of Positive Symptoms.
For symptomatic remission, maintenance during a 6-month period of simultaneous ratings of mild or less on all items is required. Rating scale items are listed by item number.
† The PANSS scale is the simplest instrument on which a definition of symptom remission can be practically based.
‡ Use of BPRS criteria may be complemented by use of the SANS criteria for evaluating overall remission.
The rationale for the selection of the 8 PANSS items was that they reflect core symptoms that are required according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) for the diagnosis of schizophrenia. The rationale for the severity threshold “mildly present at worst” was that such mild symptoms would not interfere with a patient's psychosocial functioning. This definition is also a compromise accounting for the reality of clinical trials. Two analyses of large databases of double-blind trials showed that very few patients reach the clinical state of being fully free of symptoms,
so that a more stringent threshold (“not more than questionable symptoms” or “no symptoms at all”) would not have been clinically realistic. In addition, it was also taken into consideration that there is a dimensional distribution of mild and quasi-psychotic symptoms in a subgroup of the general population, and that, for similar reasons, the remission criteria of other chronic illnesses, such as polyarthritis, also do not require the complete absence of symptoms.
Advantages and Disadvantages of Response and Remission Criteria
The difference between response and remission is that response based on a percentage BPRS or PANSS reduction from baseline does not provide information on how symptomatic the patient is at the endpoint. A reduction on the PANSS from 120 to 60 points is a 50% reduction, as is a change from 80 to 40 points. (In addition, the PANSS is an interval scale, which means that a score of 6 is not necessarily twice as severe as a score of 3.
) However, the patient with a score of 60 is far more symptomatic than the patient with a score of 40, although the absolute score change was 60 rather than 40 points. The remission criteria provide information as to where patients end up, that is, are they still symptomatic? At the same time, the remission criteria do not reflect the amount of change. For example, if at baseline the participants were on the average only mildly ill, many will be in remission at the end of the trial, although there was not a major reduction in symptoms.
Based on this, we suggest that the best way of reporting symptomatic outcomes in schizophrenia trials is to display both measures.
Treatment Resistance
Compared with simple “nonresponse,” treatment resistance or refractoriness implies a more persistent lack of improvement despite adequate treatment. It is important to emphasize that adequate treatment implies adequate adherence. It is likely that many patients are inappropriately considered to be treatment resistant when they are actually nonadherent.
World Federation of Societies of Biological Psychiatry (WFSBP)—guidelines for biological treatment of schizophrenia, part 1: acute treatment of schizophrenia.
Most often, such criteria focus on positive symptoms, but negative symptoms, affective symptoms, disturbed behavior, and cognitive dysfunction can also play a role, because they are associated with psychosocial and educational or vocational dysfunction. From a conceptual point of view, such definitions can span a wide range. Such definitions are often used in research. A good example are the criteria applied in a landmark study demonstrating clozapine's superiority over chlorpromazine in treatment refractory patients.
Based on history, patients had received in the preceding 5 years, 2 antipsychotics from 2 different classes at a dosage of at least 1000 mg/d chlorpromazine equivalents for at least 6 weeks without significant clinical improvement, and without good functioning in the last 5 years (Table IV). Cross-sectionally, the patients had a BPRS total score ≥45, were at least moderately ill according to the CGI and exhibited at least moderately pronounced symptoms on at least 2 BPRS-positive symptoms. Prospectively, the patients had not responded to a 6-week trial with haloperidol of up to 60 mg/d (nonresponse was defined as <20% BPRS reduction and BPRS total score >35 and a CGI severity score >3). It is also important to acknowledge the attempt of an international study group, which described treatment resistance by combining symptoms and social functioning on a scale from 1 (complete remission) to 7 (severe therapy resistance).
Historical: no period of good functioning or significant symptomatic relief within preceding 5 years despite at least 2 courses of antipsychotics (dosage: ≥1000 mg/d chlorpromazine) for 6 weeks
Cross-sectional: BPRS score ≥45, score of ≥4 on at least 2 of the following factors: conceptual disorganization, suspiciousness, hallucinatory behavior, unusual thought contents, CGI score of ≥−4
Prospective: 6-week trial of haloperidol (60 mg/d) fails to reduce BPRS by 20% or to <35, or fails to reduce CGI to <3
Treatment resistance is suggested by a lack of satisfactory clinical improvement despite the sequential use of the recommended doses for 6–8 weeks of at least 2 antipsychotic drugs, at least 1 of which should be an atypical
American Psychiatric Association, Lehman et al, 2004
Treatment resistance is defined as little or no symptomatic response to multiple (at least 2) antipsychotic trials of an adequate duration (at least 6 weeks) and dose (therapeutic range)
World Federation of Societies of Biological Psychiatry, Falkai et al, 2005
World Federation of Societies of Biological Psychiatry (WFSBP)—guidelines for biological treatment of schizophrenia, part 1: acute treatment of schizophrenia.
Treatment resistance is assumed if there is either no improvement at all or only insufficient improvement in the target symptoms, despite treatment at the recommended dosage for a duration of at least 6–8 weeks with at least 2 antipsychotics, 1 of which should be an atypical antipsychotic
Australian National Schizophrenia Guideline, McGorry, 2005
Two adequate trials (at least 6 weeks of 300–1000 mg in CPZ equivalents) of antipsychotic medication, of which at least 1 agent should be atypical, should have been conducted
International Pharmacological Algorithm Project, 2006
(1) No period of good functioning in previous 5 years; (2) prior nonresponse to at least 2 antipsychotic drugs of 2 different chemical classes for at least 4–6 weeks each at dosages ≥400 mg equivalents of chlorpromazine or 5 mg/d risperidone; (3) moderate to severe psychopathology, especially positive symptoms: conceptual disorganization, suspiciousness, delusions, or hallucinatory behavior. IPAP also recommend considering patients as treatment-resistant if they exhibit persistent psychotic symptoms, recurrent mood symptoms, repeated suicide attempts or suicidal ideation, uncontrolled aggressive behavior, moderate-severe negative symptoms or moderate-severe cognitive impairment after the adequate treatment mentioned above.
IPAP = International Pharmacological Algorithm Project; CPZ = chlorpromazine.
were necessary in the context of the reintroduction of a potentially life-threatening antipsychotic drug (ie, clozapine and its risk for agranulocytosis). Nevertheless, at least in schizophrenia practice guidelines, a certain consensus regarding criteria for treatment resistance seems to emerge (Table IV).
World Federation of Societies of Biological Psychiatry (WFSBP)—guidelines for biological treatment of schizophrenia, part 1: acute treatment of schizophrenia.
The American Psychiatric Association guideline defines treatment resistance as “little or no symptomatic response to multiple (at least two) antipsychotic trials of an adequate duration (at least 6 weeks) and dose (therapeutic range).”
World Federation of Societies of Biological Psychiatry (WFSBP)—guidelines for biological treatment of schizophrenia, part 1: acute treatment of schizophrenia.
or those of other national psychiatric associations, present similar definitions (Table IV).
Relapse
Relapse is another important outcome measure, as it often triggers a change in treatment or locus of care. Relapse can be caused by many different factors, ranging from comorbid substance abuse to nonadherence, but it might also mean that a patient has “broken through” medication. (On some level, a patient who relapses despite taking an adequate dose of antipsychotic medication could be considered to be treatment resistant, but that is not how the latter term is usually used.) Because relapse implies an exacerbation or recurrence of symptoms, the critical question is what degree of worsening or what threshold of signs and symptoms is necessary before triggering such a classification? Should the degree of worsening imply a change in functional status or is a purely symptomatic definition sufficient? Relapse is a commonly used outcomes measure in clinical trials intended to investigate the efficacy and effectiveness of treatments in the intermediate- and long-term management of schizophrenia. Again, the context of use of the term relapse is important, as a trial that includes a placebo arm might have different relapse criteria than an active-active comparator trial in that, from an ethical standpoint, one would want to minimize the risks associated with placebo, while still maintaining the overall goals of the trial. In addition, it is clear that symptoms can wax and wane in schizophrenia without having a sufficient impact to consider that a relapse has taken place.
The degree of variability in relapse rates seen across studies with similar entry criteria (Table V) also suggests that patient populations as well as clinician and rater behavior can be different even within the same general protocol design. Although relapse does not necessarily require a change in functional status, many criteria include a change in treatment requirements, intensity of services, or locus of care. These in turn are influenced by functional considerations, as are, to some extent, the severity ratings of specific domains of psychopathology (ie, a symptom that influences behavior or functioning is a more severe symptom than one that does not). Table V
ZEUS Study Group A 1-year, double-blind, placebo-controlled trial of ziprasidone 40, 80 and 160 mg/day in chronic schizophrenia: the Ziprasidone Extended Use in Schizophrenia (ZEUS) study.
Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol.
The treatment of negative symptoms and deficit states of chronic schizophrenia: olanzapine compared to amisulpride and placebo in a 6-month double-blind controlled clinical trial.
Prevention of schizophrenia relapse with extended release quetiapine fumarate dosed once daily: a randomized, placebo-controlled trial in clinically stable patients.
Paliperidone extended-release tablets for prevention of symptom recurrence in patients with schizophrenia: a randomized, double-blind, placebo-controlled study.
Maintenance treatment with risperidone or low-dose haloperidol in first-episode schizophrenia: 1-year results of a randomized controlled trial within the German Research Network on Schizophrenia.
Relapse prevention and remission attainment in first-episode non-affective psychosis A randomized, controlled 1-year follow-up comparison of haloperidol, risperidone and olanzapine.
Clinical Global Impression in ECDEU Assessment Manual for Psychopharmacology, Revised (DHEW Publ No ADM 76-338). National Institute of Mental Health,
Rockville, MD1976
ZEUS Study Group A 1-year, double-blind, placebo-controlled trial of ziprasidone 40, 80 and 160 mg/day in chronic schizophrenia: the Ziprasidone Extended Use in Schizophrenia (ZEUS) study.
Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol.
The treatment of negative symptoms and deficit states of chronic schizophrenia: olanzapine compared to amisulpride and placebo in a 6-month double-blind controlled clinical trial.
Prevention of schizophrenia relapse with extended release quetiapine fumarate dosed once daily: a randomized, placebo-controlled trial in clinically stable patients.
Paliperidone extended-release tablets for prevention of symptom recurrence in patients with schizophrenia: a randomized, double-blind, placebo-controlled study.
Maintenance treatment with risperidone or low-dose haloperidol in first-episode schizophrenia: 1-year results of a randomized controlled trial within the German Research Network on Schizophrenia.
Relapse prevention and remission attainment in first-episode non-affective psychosis A randomized, controlled 1-year follow-up comparison of haloperidol, risperidone and olanzapine.
It is also important to note that in some studies hospitalization is used as a proxy for relapse. Because hospitalization can be influenced by many environmental and health economic factors, those influences must be kept in mind as well when hospitalization is equated with relapse. In addition, not all patients who worsen and get close to a relapse need to be hospitalized, as appropriate treatment changes can be made to avoid this. For example, in a study of patients with recent-onset schizophrenia that examined the clinical course after antipsychotic discontinuation, 96% of the patients experienced an exacerbation or relapse within 2 years, whereas only 13% were hospitalized.
Recovery is an outcome domain that much more clearly requires functional measures. This is a term that has taken on particular salience with patients and families, as well it should. Health care providers are at times focused on symptoms and signs to the exclusion of functioning and quality of life. The recovery criteria in schizophrenia are to some extent the most meaningful possible outcome measure. At the same time, however, criteria for recovery are not only influenced by the availability of psychosocial treatments, family and community supports, but also by supportive employment and supportive education as well as available jobs and the like. Liberman and Kopelewicz
The Vermont longitudinal study of persons with severe mental illness: II Long-term outcome of subjects who retrospectively met DSM-III criteria for schizophrenia.
The Vermont longitudinal study of persons with severe mental illness: II Long-term outcome of subjects who retrospectively met DSM-III criteria for schizophrenia.
Increasing attention has been focused in recent years on the importance of patient-reported outcomes in informing research results and clinical practice.
US Food and Drug Administration Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.
US Food and Drug Administration,
Washington, DC2006
defines these measures as “any report coming directly from patients about a health condition and its treatment.” Given the subjective nature of many aspects of psychopathology, it is particularly important in psychiatry to have this perspective. Yet, at the same time, in schizophrenia there are concerns about insight, cognitive dysfunction, reality testing, and communicative ability, which must be recognized in the acquisition and interpretation of such data. It is also important to recognize the role that such data play in the process of shared decision making.
Traditionally, clinicians have been more focused on the alleviation and control of illness symptoms and disease treatment rather than on adverse effects, subjective well-being, and quality of life.
An emphasis on self-report also contributes to enhanced patient self-esteem and a sense of empowerment. In addition to symptoms, adverse effects and quality of life self-report measures can also provide insight into the patient's knowledge of his or her illness and the treatments being prescribed and into other areas, such as access, quality of care, and health system issues.
It is beyond the scope of this article to review the various constructs involved in the generation of these instruments or the various characteristics of specific instruments. In addition, further work needs to be done to better understand the relationship between clinician-rated and patient-rated outcomes to inform their most appropriate utilization and interpretation. It would also be important to determine the value of these measures as predictors of various aspects of outcomes, including treatment acceptance and adherence as well as overall response, relapse, long-term outcomes, tolerability of adverse effects, and the like.
Table VII provides a selected overview of relevant self-report instruments that have been used in studies of patients with schizophrenia.
The development and use of the Verona Expectations for Care Scale (VECS) and the Verona Service Satisfaction Scale (VSSS) for measuring expectations and satisfaction with community-based psychiatric services in patients, relatives and professionals.
Illness Management and Measure (MHRM) in Outcomes Research. Ohio Department of Mental Health, Ohio Coordinating Center for Excellence for Illness and Recovery,
Columbus, Ohio2003
A self-rating to measure subjective effects of neuroleptic drugs, relationships to objective psychopathology, quality of life, compliance and other clinical variables.
Some scales take relatively little time to complete, making them amenable to being used in the waiting room of mental health clinics and doctor's offices. As always, the choice and interpretation of specific measures will be influenced by the goals of the study or data collection, the characteristics of the patient population, phase, and severity of illness.
Table VIISelected self-report measures scales for patients with schizophrenia.
The development and use of the Verona Expectations for Care Scale (VECS) and the Verona Service Satisfaction Scale (VSSS) for measuring expectations and satisfaction with community-based psychiatric services in patients, relatives and professionals.
Illness Management and Measure (MHRM) in Outcomes Research. Ohio Department of Mental Health, Ohio Coordinating Center for Excellence for Illness and Recovery,
Columbus, Ohio2003
A self-rating to measure subjective effects of neuroleptic drugs, relationships to objective psychopathology, quality of life, compliance and other clinical variables.
To establish the clinical relevance of treatment effects, clinicians should carefully assess and quantify efficacy and adverse effects using direct questioning of patients and, as much as is practical, also use rating scales. In research studies, validated scales should always be employed, both for therapeutic as well as for adverse effect outcomes. Moreover, adherence and attitudes toward medications that can be used to identify patients at high risk for nonadherence, such as the Drug Attitude Inventory,
should be considered, as nonadherence affects both efficacy and tolerability outcomes.
In addition to selecting the most appropriate assessment tools for the patient's condition and setting, a clinically meaningful display of the data beyond statistical significance should be mandatory in research reports. This includes the reporting of 95% confidence intervals or interquartile ranges around point estimates, as well as the calculation of effect sizes and numbers-needed-to-treat/harm. In general, effect sizes ≤0.2 are considered not clinically relevant, 0.5 is a medium effect size, and effect sizes ≥0.8 are considered large.
Point estimates with nonoverlapping 95% confidence intervals are considered significantly different. To establish clinically meaningful effect sizes for categorical outcomes of benefit or harm, numbers-needed-to-treat/harm should be calculated as the inverse of the absolute risk difference (ie, 1 divided by the delta between the proportion of patients having a certain outcome in one group compared with the other group). Numbers-needed-to-treat/harm of 1 to 3 represent a large effect size, 4 to 6 are medium, and 7 to 10 are small.
Furthermore, Likert-type scales that provide ordinal, rather than nominal, data are frequently used in psychiatry. Although each ordinal data point can be converted into a numeric value for ease of data entry (eg, the CGI scale goes from 1 to 7, and the PANSS or BPRS scales go from 0 to 6 or 1 to 7), it is important to note that these are not continuous data and that nonparametric, not parametric, statistical tests should be used in the analysis of such results.
Notwithstanding these general principles, the translation of such mathematical quantification into clinical relevance is not straightforward. This complication is due to the fact that effect sizes for certain efficacy or adverse effect outcomes might be weighted rather differently based on how critical the improvement or intolerability for a given individual is, that is, how much it affects subjective well-being, quality of life, functioning, health, and longevity. Such risk-benefit evaluation must be made on a case-by-case basis, and evaluations might change over time, even for the same physician or patient and his or her family.
Glick ID, Correll CU, Altamura CA, et al. Long-term efficacy and effectiveness of antipsychotic medications for schizophrenia: a data-driven, personalized, clinical approach. J Clin Psychiatry. In press.
A number of rating scales and assessment batteries have been validated that are used frequently in clinical pharmacology trials in schizophrenia. Although the use of efficacy rating scales is commonplace in research settings, there exists a big research-practice gap regarding the routine implementation of measurement-based principles in clinical care. As mentioned, this is due to a variety of factors, with time constraints and lack of familiarity and training among the most important ones. Thus, the field, administrators, and regulators need to decide which outcomes measures are most appropriate that can be realistically implemented in routine clinical practice. Ideally, abbreviated, pragmatic, but meaningful scales should be developed and field-tested to identify those that could become standard of care.
We propose that, at a minimum, the CGI severity and improvement scale
Clinical Global Impression in ECDEU Assessment Manual for Psychopharmacology, Revised (DHEW Publ No ADM 76-338). National Institute of Mental Health,
Rockville, MD1976
is likely not practical in most busy clinical settings, the assessment and documentation of the 8 items from the PANSS (or the equivalent items from the BPRS) that are used to define remission in patients with psychosis
is a reasonable expectation, as a clinical interview should focus on each of these items anyway (ie, delusions, hallucinations, social withdrawal/anhedonia), with 4 of these being merely observational (ie, formal thought disorder, bizarre behavior, alogia, and blunted affect) (Table III). Nevertheless, training on the anchored assessment needs to be provided.
Table VIIII. Commonly used rating scales to assess key efficacy and adverse effect outcomes in patients with schizophrenia.
Efficacy
Adverse Effects
Domain
Commonly Used Rating Scale
Domain
Commonly Used Rating Scale
Global outcome
Clinical Global Impressions (CGI) Severity and Improvement Scale
Clinical Global Impression in ECDEU Assessment Manual for Psychopharmacology, Revised (DHEW Publ No ADM 76-338). National Institute of Mental Health,
Rockville, MD1976
The UKU side effect rating scale A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients.
Clinical Global Impression in ECDEU Assessment Manual for Psychopharmacology, Revised (DHEW Publ No ADM 76-338). National Institute of Mental Health,
Rockville, MD1976
A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania.
Abnormal Involuntary Movement Scale (AIMS), ECDEU Assessment Manual for Psychopharmacology. National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs,
Bethesda, Md1976: 218-222
In addition, the clinical assessment should also include the specific PANSS (or BPRS) item “hostility,” as this item has been shown to be predictive of overt physical aggression (or violence) against other persons. For example, in schizophrenia patients in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE), for each unit increase on the 7-point rating of hostility, the odds of serious violence increased considerably, by a factor of 1.6.
Hostility and related violent behaviors are clinically relevant because they constitute a frequent reason for hospital admission (being reflected in some criteria for relapse), delay discharge, and increase the burden of illness for families and caregivers. Finally, assessing hostility and violence in schizophrenia has important treatment implications.
Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility in treatment-resistant patients with schizophrenia and schizoaffective disorder.
Although development of interventions to improve the cognitive deficits in schizophrenia has become a major target, antipsychotics have minimal effects and, to date, no selective treatment has been identified. Key areas of the cognitive deficits in schizophrenia include attention and vigilance, processing speed working memory, verbal memory, visual memory, reasoning and problem solving, executive functioning, and social cognition.
A comparison of the CogState Schizophrenia Battery and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery in assessing cognitive impairment in chronic schizophrenia.
The Schizophrenia Cognition Rating Scale: an interview-based assessment and its relationship to cognition, real-world functioning, and functional capacity.
However, these formal tests are usually labor- and time-intensive and require special training for the administration and scoring. Although the Mini-Mental Status Examination can be used to assess gross cognitive abnormalities, it is too crude to be useful for the assessment of deficits that are below the level of those observed in delirium or dementia. As part of the General Mental Status Examination, a number of attention, memory, and reasoning capabilities are crudely assessed by use of the serial 7 (or 3) subtraction, 5-minute 3-word recall, the request to link words through overarching categorical similarities and explain proverbs. Beyond this, few parent, teacher, and clinician reports or questionnaires are available
or under development (Opler M, Antonius D, Correll CU. New York Assessment of Adverse Cognitive Effects of Neuropsychiatric Treatment [NY-AACENT], unpublished rating scale) that could prove to be helpful to provide an office-based opportunity to assess cognitive deficits cross-sectionally and over time, which could include beneficial or adverse medication effects on clinically relevant, real-world cognitive functioning.
Table IXCognitive test batteries and questionnaires.
Test
Cognitive Domains
Administration Time, min
Pros/Cons
Neuropsychological tests
Measurement and Treatment to Improve Cognition in Schizophrenia (MATRICS)
A comparison of the CogState Schizophrenia Battery and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery in assessing cognitive impairment in chronic schizophrenia.
The Schizophrenia Cognition Rating Scale: an interview-based assessment and its relationship to cognition, real-world functioning, and functional capacity.
Behavioral Regulation Index (BRI): Inhibit, Shift, and Emotional Regulation subdomains. Metacognition Index (MCI): Initiate, Working, Memory, Plan/Organize, Organization of Materials, and Monitor subdomains. Global Executive Composite (GEC) = BRI + MCI
10–15 (as per authors)
Scale consists of an 86-question real-world task-related Parent Form and 86-question Teacher Form. Questions are answered as “never,” “sometimes,” or “often”.
New York Assessment of Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) (unpublished scale)
Working memory Attention/vigilance Verbal learning/memory Visual learning/memory Reasoning and problem solving Speed of processing Social cognition
5–7
Clinician interview integrates informant data, patient self-report (separate forms) and indirect assessment based on real-life observations/impact. 7 probes/items rated “not present,” “a little bit bothersome,” “somewhat bothersome,” “quite bothersome,” “very bothersome” (Note: validation underway). Appropriate for clinical use
Regarding related psychopathology, such as depression and anxiety, at a minimum, a global, 2-item assessment of “observed” and “reported” severity of these domains should be ascertained and reported using a 10-point visual analogue scale or a Likert-like scale (none, mild, moderate severe, extreme). Neurovegetative signs (eg, appetite, sleep, activity level) should also be part of a regular clinical interview and should be quantified in the same way. Areas of high clinical importance for the safety of the patients and of others, such as suicidality and homicidality, should also always be inquired about. It is recommended that medical records be equipped with such simple rating tools and that clinicians be required to fill out these scales before being able to move on to another page when using electronic medical records. Obviously, in settings with more time and depending on the aim, formal rating scales can also be used for depression
Although quality-of-life and functional outcomes are increasingly relevant as treatment aims, there are currently no simple tools to measure these outcomes, as available interview-based scales are lengthy (eg, Heinrichs et al
) might lack detail and be too insensitive. Qualitative statements about who the patient lives and interacts with, how many times per week social contacts take place outside of the immediate family, whether the patient can provide self-care, and what the voluntary or paid employment status is should be inquired about and recorded at regular time intervals. These areas are useful to assess, as they overlap with the proposed psychosocial recovery criteria reviewed here.
Furthermore, to document treatment decisions, inefficacy in specific domains should be recorded as a justification to switch or augment any given treatment. Finally, adherence also needs to be inquired about and quantified, so that efficacy patterns can be evaluated more objectively.
Clinical Measurement of Adverse Effects in Schizophrenia
Antipsychotic treatment is associated with a wide range of acute and long-term side effects that can affect psychiatric and physical health, adherence, subjective well-being, and quality of life.
However, identifying side effects and attributing them to a particular drug can be difficult because patients are frequently on more than 1 medication and cannot always describe the onset and circumstances of their experiences in detail. Some patients with schizophrenia are not even aware that certain experiences can be a drug effect, requiring counseling when initiating treatment. Some domains, such as sexual side effects and constipation, are less readily volunteered, and patients may report these side effects only when directly questioned about them.
In addition, it can be difficult to distinguish some adverse effects from illness symptoms, for example, Parkinsonism from negative symptoms or depression, and akathisia from agitation.
Side effects are best assessed by using a standardized rating scale; a number of global and specific rating scales are available (Table VIII). Some measure specific side effects, such as the Barnes Aktathisia Ratings scale for assessing akathisia,
Abnormal Involuntary Movement Scale (AIMS), ECDEU Assessment Manual for Psychopharmacology. National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs,
Bethesda, Md1976: 218-222
Clinical Global Impression in ECDEU Assessment Manual for Psychopharmacology, Revised (DHEW Publ No ADM 76-338). National Institute of Mental Health,
Rockville, MD1976
The UKU side effect rating scale A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients.
Side effects are not simple dichotomous variables, and their presence differs among subjects. Therefore, rating scales should include thorough anchors for the score of each item. Moreover, the severity, attribution to a given medication, and onset and offset need to be captured. Rating scales generally assess the presence and severity of a side effect only, but not whether the side effect is subjectively bothersome or associated with functional impairment, although quality of life is more affected by the subjective feeling of a side effect than the number of side effects.
Some patients feel sedation as a bothersome side effect, whereas others are not particularly bothered by it and may even see this as a desired effect. Both past and present side effects have a negative impact on compliance, which should encourage psychiatrists to do their best to avoid, monitor, and manage adverse effects to optimize treatment outcomes.
In clinical trials, most frequently adverse effect are assessed by means of general, open-ended and unstructured questioning, rather than by rating scales. This is supposedly done to reduce the background noise of symptoms not associated with a given treatment or not reaching the level of subjective relevance. However, some symptoms might have been relevant and are not reported due to cognitive difficulties or feelings of shame or lack of knowledge that a symptom could be related to a medication. In addition, in many trials, the absence of rating scale-assessed side effects is used as a justification to solely report frequencies but not statistically analyze and compare them against control conditions. This has remained the case in regulatory trials performed to gain approval or indications. In addition, adverse effects are generally displayed as period incidence rates, rather than showing changes in severity or existence over time, which is standard in the analysis of efficacy measures and clinically relevant. This is an obvious bias against a state of the art assessment of adverse effects that are not treated the same way as efficacy outcomes. In fact, a recent systematic review of adverse effect reporting in 167 antipsychotic clinical trials in schizophrenia-spectrum disorder patients published in English between January 2002 and July 2007 with available efficacy and adverse effect reporting found that safety and tolerability data were collected and reported in mostly nonstandardized ways, which does not allow a fair and meaningful comparison of the relative risk profiles of individual antipsychotics.
Across these studies, extrapyramidal side effects (EPS) and weight gain were most frequently assessed, but a minority of studies included reporting of metabolic abnormalities, negative subjective experiences, and sexual dysfunction. Published rating scales were frequently used to evaluate EPS, but systematic methods were rarely applied to any other treatment-emergent problems. Moreover, the definition of individual adverse effects and the method of reporting were inconsistent.
We propose that, at a minimum, key adverse effect areas that should be inquired about in patients treated with antipsychotics (eg, sedation, EPS, dyskinesia, sexual functioning) should be quantified either along a 10-point visual analogue scale or using a Likert-like scale (none, mild, moderate severe, extreme). Furthermore, Parkinsonian side effects and abnormal involuntary movements should be measured directly at least twice per year, using the Simpson Angus Scale
(Table VIII). This takes less than 5 minutes when both the clinician and patient are familiar with this assessment. In addition, cardiometabolic indices, such as body weight, body mass index, waist circumference, and fasting glucose and lipids, should be measured and documented at currently recommended time intervals.
Physical illness in patients with severe mental disorders II. Barriers to care, monitoring and treatment guidelines, and recommendations at the system and individual level.
but low-cost, strategic, and administrative interventions can help increase guideline compliance. Finally, as for efficacy, to document treatment decisions, intolerability in specific areas should be recorded as a justification to switch or augment any given treatment.
Conclusions
Quantification of treatment effects has relevance for patient management, research, and overall health care. Optimized treatment of schizophrenia aims for improvements in symptoms, subjective well-being, and functioning while minimizing adverse effects that interfere with treatment success. Clinical decision making requires the standardized definition of treatment goals and outcomes and the quantification of efficacy, adverse effects, and overall effectiveness to inform what degree of improvement in target domains is sufficient, what type and severity of adverse effects are still acceptable, and what functional outcomes are sought. Rational decisions about dose adjustments, when to stop a medication, when to switch or augment treatments, and the like require measurement-based approaches. Although rating scales are ubiquitous in schizophrenia research, time constraints and lack of familiarity with and training in validated assessment tools have limited their routine use in clinical practice. Easy to use but meaningful rating scales need to be developed and implemented to bridge the gap between lengthy rating scales used in research trials and mostly unstructured, qualitative assessments employed in clinical practice. Results from research trials providing the evidence base that guide practice need to be communicated in clinically meaningful ways. This includes going beyond the mere reliance on statistical significance. Pragmatic quantification should always include the reporting of effect sizes, numbers-needed-to-treat/-harm for meaningful categorical outcomes, confidence intervals, and absolute risk differences. Some important outcomes, such as treatment response, should be reported in escalating intervals using incrementally stringent psychopathology improvements. Nevertheless, even despite quantification, it remains a challenge to weigh individual efficacy and adverse effect outcomes against one another and to decide on the targeted maximum improvement or outcomes. Subjective, patient-based ratings and shared decision making need to be integrated with measurement-based approaches. Finally, beyond consensus about meaningful outcomes definitions, reporting strategies, and pragmatic tool development and implementation, the discovery of novel treatment mechanisms and bio-markers is hoped to further advance measurement based approaches in schizophrenia and improve patient outcomes in the near future.
Conflicts of Interest
Dr. Correll has been a consultant and/or advisor to or has received honoraria from Actelion, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, Eli Lilly, IntraCellular Therapies, Ortho-McNeill/Janssen/J&J, Merck, Novartis, Otsuka, Pfizer, and Sepracor/Sunovion. He has received grant support from the Feinstein Institute for Medical Research, the NIMH, the National Alliance for Research in Schizophrenia and Depression (NARSAD), and Ortho-McNeill/Janssen/J&J. Dr. Kishimoto has received speaker's honoraria from Banyu, Eli Lilly, Dainippon Sumitomo, Janssen, Novartis, Otsuka and Pfizer. He has received grant support from the Byoutaitaisyakenkyukai Fellowship (Fellowship of Astellas Foundation of Research on Metabolic Disorders) and Eli Lilly Fellowship for Clinical Psychopharmacology. Dr. Nielsen has received research grants from H. Lundbeck, Pfizer and Chempaq for clinical trials and received speaking fees from Bristol-Myers Squibb, Astra Zeneca, Janssen & Cilag, Lundbeck and Eli-Lilly. Dr. Kane has been a consultant to Astra-Zeneca, Janssen, Pfizer, Eli Lilly, Bristol-Myers Squibb, Dainippon Sumitomo/Sepracor/Sunovion, Johnson & Johnson, Otsuka, Vanda, Proteus, Takeda, Targacept, IntraCellular Therapies, Merck, Lundbeck, Novartis, Roche, Rules Based Medicine, Sunovion and has received honoraria for lectures from Otsuka, Eli Lilly, Esai, Boehringer-Ingelheim, Bristol-Myers Squibb, and Janssen. He has received grant support from The NIMH. The authors have indicated that they have no other conflicts of interest with regard to the content of the article.
Acknowledgments
This study was supported in part by the National Institute of Mental Health (NIMH) Advanced Center for Services and Intervention Research, The Zucker Hillside Hospital (P30MH090590). All authors contributed equally to the design of the paper and to the literature search. Dr. Correll provided the first full draft that included sections provided by each of the three co-authors. All authors contributed equally to the interpretation of the presented data and to the revision of the text. We would like to thank Susan Schiavi who assisted Dr. Kishimoto in numbering the references.
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For symptomatic remission, maintenance during a 6-month period of simultaneous ratings of mild or less on all items is required. Rating scale items are listed by item number.