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THE USEFULNESS AND USE OF SECOND-GENERATION
ANTIPSYCHOTIC MEDICATIONS - AN UPDATE
An update of the Review of Evidence and Recommendations
by a Task Force of the World Psychiatric Association
Norman Sartorius (Chair), Wolfgang W. Fleischhacker, Annette Gjerris, Ursula Kern,
Martin Knapp, Brian E. Leonard, Jeffrey A. Lieberman, Juan José López-Ibor,
Bas van Raay, Elizabeth Tornquist, Esther Twomey.
UPDATE
TO THE TECHNICAL REVIEW ON THE USEFULNESS AND USE OF
SECOND-GENERATION ANTIPSYCHOTIC MEDICATIONS.
Table of Contents
Preface
I
Introduction and review of issues discussed in national meetings
II
Critical review and summary of information about the effects and
safety of second-generation antipsychotic medications
Clinical data
Economic data
Drugs in development
III
Other developments relevant to the use of second-generation
antipsychotic medications
Recent meta-analyses
Recent large-scale investigations
Adjunctive therapy
Developments concerning regulatory procedures
IV
Recommendations
References
Appendices
1. List of Members of the Task Force
2. List of Experts Invited to Comment on the Drafts of the Technical Review
3. List of Organizations Consulted
4. List of National Meetings
5. Partial list of guidelines for the treatment of schizophrenia and related
psychotic states, 1991-2001, examined in the preparation of the Technical
Review and its Update
6. National Health Service National Institute for Clinical Excellence guidance on
the use of newer (atypical) antipsychotic drugs for the treatment of
schizophrenia
7. Resolution adopted by the General Assembly of the World Psychiatric
Association on 26 August 2002 in Yokohama, Japan and containing the
Consensus Statement on The Usefulness and Use of Second-Generation
Antipsychotic Medications.
Preface
Second-generation antipsychotics, as well as other new methods of treatment,
raise problems of equity. The costs involved in the development of drugs make
them expensive. Under the current circumstances new (and more expensive)
medications will not be available to many patients in developing countries; even
patients in developed countries might find it difficult to afford them. The lack of
knowledge about new medications and the fact that these medications may not
be fully covered by public or private reimbursement schemes further contribute
to their lesser use.
The proposals to limit the life time of patents to several years after which generic
medications are produced is not a satisfactory solution because patients who
need the medications now may get them only after many years. Limiting the
duration of patents may also be a disincentive to research investments and the
discovery of new and more effective drugs, and may increase the number of
orphan diseases for which few new medications will be developed.
To examine possible solutions to this type of problems in the case of secondgeneration antipsychotics, the World Psychiatric Association (WPA) appointed a
Task Force chaired by Prof. Norman Sartorius in order to: (1) review the evidence
of the efficacy, tolerability and costs of new medications in comparison with more
traditional medications, and to analyze the impact that the availability of these
medications has had on the way patients are treated; and(2) to propose to the
WPA some action concerning relevant health policy issues.
The WPA Task Force undertook an in-depth review of the published scientific
evidence on second-generation antipsychotics. This review included evidence on
the results of studies comparing second-generation antipsychotic medications
with other drugs in terms of efficacy and tolerability. It analyzed evidence about
the impact of the new medications on the way patients are treated, on the overall
cost of treatment and on the impact that the use of these drugs has (or could
have) on the burden of psychotic disorders and on the stigma associated with
them. In order to address such broad goals, the Task Force included experts
representing those concerned with the care of people with psychotic disorders
(psychiatrists, psychopharmacologists, care-givers, persons working for the
health care administration, and others) and consulted a large number of
individuals and organizations involved in work in this area in many countries.
A review of scientific data about a treatment can produce three levels of evidence.
When well designed, adequately powered randomized, controlled and blinded
studies show consistent results of clear superiority of a treatment over another, it
is possible to consider the use of such a treatment as a standard procedure. When
this is not the case, the scientific community may extrapolate from the evidence
base using less rigorous studies, case reports, clinical experience and expert
opinion to reach consensus and produce guidelines. In the absence of this, all
treatments become options.
Unfortunately the evidence on the usefulness of psychotropic medications,
specifically the newest ones, is limited. The Task Force thus did not produce
standards of psychiatric treatment but examined the evidence in the scientific
literature and the clinical experience available in many countries. Based on this
the Task Force produced recommendations to the World Psychiatric Association
and drafted a text of a policy for consideration and approval by consensus by the
General Assembly of the WPA. This document states general principles and
makes policy recommendations on areas of research which are needed, on
specific uses for the second-generation antipsychotics, on collaboration with
governmental (i.e., WHO) and nongovernmental organizations to address the
pricing problems, and on the education of professionals and the public about new
treatments.
This second document is an “update” to the first Consensus Statement published
in Current Opinion in Psychiatry in autumn 2001 and brings together new evidence
about the use and usefulness of the second-generation antipsychotic medications.
This evidence comes from a review of the literature undertaken to identify
scientific reports published in 2001 (the Technical Review of Evidence about The
Use and Usefulness of Second-Generation Antipsychotic Medications published
earlier did not include any publications that appeared after 31 December 2000).
The review of evidence also covered scientific reports published before January
2001 that had not been included in the previous Review. Some of these previous
reports were found by further searches made by the members of the WPA Task
Force; others were identified by readers of the Technical Review and by
participants in the national meetings held in the years 2000 and 2001.
In addition to the results of the review of evidence, the “update” reflects the
comments made during national review meetings that were held in 24 countries
(6 in South America, 8 in Asia and the Pacific Area, 1 in Africa, 8 in European
countries). These meetings were organized by the national psychiatric society
members of the WPA and involved psychiatrists, pharmacologists, neurologists
and other experts as well as representatives of patient and family organizations,
of the media, of the national governments and of the health industry. The
Technical Review that the WPA Task Force had drafted served as the background
document for the discussion at national level. It was translated into national
languages whenever it was expected that the use of English might hamper the
comprehension of the document or participation in the discussions. The review
was thus made available in Chinese, Croatian, Czech, German, Japanese, Korean,
Polish and Spanish. The comments and suggestions made during these meetings
and in their aftermath were most valuable, and it is my pleasant duty to thank all
those who prepared the meetings and participated in the discussions as well as
those who provided their comments in writing in the course of the consultation
process.
The Technical Review and its Update which is presented here served as
background documents for the consideration of a Consensus Statement on this
matter submitted to the General Assembly of the WPA in Yokohama in 2002.
The development of consensus statements is one of the constitutional functions of
the WPA. Their preparation not only serves to produce a document presenting
the views of the Member Societies of the WPA; it also serves a second objective,
that is, to link psychiatric societies and psychiatrists across national and
disciplinary boundaries and present opportunities to establish working
relationships with other partners in the mental health care enterprise – family and
patient organizations, governments, the industry and experts in disciplines
related to psychiatry. In this respect also, the preparation of the background
reviews has made a major contribution and I am thankful to the WPA Task Force
for having worked so hard and for having organized its work in a manner that
has allowed the achievement of both objectives mentioned above.
The use and usefulness of second-generation antipsychotics is not the only area of
treatment in psychiatry about which evidence should be assembled in order to
facilitate reaching consensus among psychiatrists and all others concerned with
the care of people with mental illness. I hope that, in the years to come, the WPA
will engage in similar endeavours concerning other possibilities of treating
mental illness.
Prof. Juan J. López-Ibor
President of the World Psychiatric Association
I
Introduction and review of issues discussed in national
meetings
Introduction
This paper aims to update the Technical Review presented in the recently
published supplement of Current Opinion in Psychiatry entitled The Usefulness and
Use of Second-Generation Antipsychotic Medications [1]. As mentioned in the Preface
it was produced using four types of material: (1) the results of studies about the
effects and side-effects of the second-generation antipsychotic medications
(SGAMs) that became available in the course of the year 2001 and in the first two
months of the year 2002; (2) relevant articles and information that, for one reason
or another, was not included in the recently published Technical Review of the
Use and Usefulness of the Second-generation Antipsychotic Meedications; (3) the
results of the discussions on the use and usefulness of SGAMs, organized in a
variety of countries by the World Psychiatric Association (WPA) member
societies; (4) the comments and suggestions received from individual experts and
from members societies that reviewed drafts of the Technical Review [1].
Structure of the Update
The contributions that were received from the sources mentioned above and from
the review of the literature have been used in three ways. Comments on the use
of the medications at national level and suggestions about future action, served to
produce sections II (Critical review and summary of the evidence base for the
therapeutic and side-effects of second-generation antipsychotic medications) and
IV (Recommendations). Appendix 2 gives a list of experts who were invited to
comment on the text of the Review, Appendix 3 lists the organizations and
associations to whom the document was sent for review, and Appendix 4 gives a
complete list of meetings convened to discuss the review.
Comments about the medications and about their effects and side-effects as well
as the new published evidence, were used to produce Section II and appendices 5
and 6. Appendix 5 presents a list of studies that were used in the development of
the review and those examined in the preparation of the Update. The way in
which the literature was searched and reviewed is described in the introduction
to the review. Appendix 5 (Partial list of guidelines and consensus statements
developed by institutions, governments or professional societies at national level)
is an updated version of Appendix 7 of the first review. Finally, Section III (Other
developments relevant to the use of second-generation antipsychotic
medications) was developed in response to specific suggestions concerning issues
not covered in the first review.
Issues, opportunities and concerns raised in the national meetings and by
individual experts
A major concern noted in most of the national meetings and expressed in many
individual comments is the fact that there are many people suffering from
schizophrenia and other psychotic conditions who do not have access to the
SGAMs. There was no disagreement about the fact that the SGAMs are at least as
effective as the previously used medications and that they have the advantage of
having significantly fewer extrapyramidal side-effects. The efficacy of the
SGAMs in the treatment of negative, affective and cognitive symptoms was seen
as less well proven than their efficacy in treating positive symptoms, despite
promising findings showing that some of the SGAMs are useful in dealing with
these. The side-effects (e.g. weight gain) of some of the SGAMs were seen as a
cause for concern, and avoidance of these side-effects was seen as a priority area
for further clinical and pharmacological research.
The reasons for the huge differences in the proportions of people with
schizophrenia who are currently being treated with SGAMs were discussed in
considerable detail. The prices of SGAMs in most countries are high and patients
in many countries simply do not have the money to acquire these medications. In
many developing countries only a minute proportion of the population is
covered by some form of insurance, and, even when people are covered,
insurance companies and governments are short of funds and reluctant to pay
prices that they consider too high.
The argument that the prices of the new medications are too high, however, was
also advanced in countries that have reserved considerable resources for the
improvement of health care. In those settings, the argument that the prices are
too high is not used with equal conviction for all types of medications. The
example given in national review meetings was the daily cost of new medications
used to deal with the nausea accompanying the treatment of tumours, which is
some 20 times higher than the cost of a daily dose of an SGAM. The stigma
attached to mental illness and the still-persisting perceptions of psychiatric
treatment as being of little use undoubtedly contribute to the difference in the
appreciation of the usefulness of this, or, for that matter, of other treatment
needed by a person suffering from mental illness.
Participants in national meetings stressed the positive role that the World Health
Organization could play in combating stigma and in presenting governments
with well-founded information about new methods of treatment. The World
Health Organization model list of essential drugs influences decision-making
concerning access to psychotropic and other medications: it was seen as
important, therefore, that the WPA and other professional organizations
participate actively in revisions of that list so as to ensure that it corresponds to
the best knowledge about psychiatric disorders and their treatment. The World
Health Organization could also play a very useful role as a partner to the WPA in
negotiations concerning the pricing of psychotropic medications at national level.
The use of generic preparations was discussed in several national meetings.
Participants recognized that the availability of generic medications can
significantly improve the services provided, particularly in developing countries.
The limitations of concentrating on this approach to the provision of better care,
to the exclusion of other approaches, were also discussed.
While the urgent need to take action concerning the costs of SGAMs was
generally recognized in these meetings, it was also made clear that other factors
play an important role in decisions about the type of treatment that will be
prescribed or taken. In two European countries – Spain and Austria – the healthinsurance regulations concerning reimbursement for the treatment of mental
illness are similar, yet Spanish psychiatrists prescribe SGAMs nearly twice as
often as their colleagues in Austria. The crucial importance of providing
unbiased information and in-service training (as well as updating undergraduate
and postgraduate training in psychiatry) for the best use of available treatments
and technology was stressed by a number of respondents. Such education is a
necessary part of the mandate that patients should at all times receive treatment
that is in their best interest rather than be exposed to interventions that are
designed to take mainly non-medical (e.g. economic) considerations into account.
Another subject commanding much attention was the fact that knowledge about
treatment in psychiatry in general is still insufficient. Numerous gaps in
knowledge were identified. Some of them were identified in the review and are
listed there, but many more were noted. Data about the effects (and side-effects)
of drugs given to patients in different populations are scarce. Several studies have
indicated that there might be differences between patients in terms of the optimal
initial and maintenance doses, but the existing evidence about these differences
does not allow the formulation of specific guidelines for treatment. There have
been no comparisons of effectiveness (or safety) among the first-generation
antipsychotic medications (FGAMs), and evidence about the differences between
the effects of high-dose and low-dose FGAMs is only now emerging. Evidence
about the effectiveness and safety of the SGAMs in the treatment of psychosis in
children, the elderly and pregnant women is also insufficient. Furthermore, few
studies have reliably measured the quality of life of patients and their families.
Understandably ( because the SGAMs have come into wider use only recently)
there are no solid findings on the long-term effects of these medications.
Even the evidence that is now available needs reconfirmation. Most of the studies
on SGAMs have been sponsored by the pharmaceutical companies that produced
the drugs being assessed. While these studies involved leading scientists in many
countries and were done with well-designed protocols, participants in national
review meetings agreed on the necessity to complement these studies with others
funded by agencies that could not be seen as having a conflict of interest in
sponsoring studies onpsycho-pharmacological medications. The major
collaborative study recently funded by the US National Institutes of Health
(Clinical Antipsychotic Trials of Intervention Effectiveness) was seen as a step in
the right direction and as a model that should be brought to the attention of other
agencies and governments.
The initiative of the WPA in undertaking a review of the literature and preparing
technical materials to serve as the basis for discussion at national level was seen
as a useful method for obtaining information, and as a welcome stimulus for the
activation of national psychiatric societies in technical matters of particular
interest to the profession. It was felt that the evidence and experience assembled
and discussed in the national meetings would provide a useful background for
the consideration of the relevant Consensus Statement by the General Assembly
of the WPA. It was noted that the same model should be used in the preparation
of WPA consensus statements on other topics that are of practical importance but
which do not yet have sufficient evidentiary basis for the development of quality
control standards.
The participants in national meetings felt that the WPA is well placed to be
proactive in the evaluation of new methods of treatment and that its active
engagement in this area would enhance its usefulness to the member societies
and to the functioning of mental health services at national level.
The fact that a number of pharmaceutical companies provided support to the
WPA in order to review the evidence was also discussed at national meetings. In
this respect, three points were considered to be of particular importance: (1) all
the major companies (rather than only one, or a small number, of them) were
invited to make contributions, and these contributions were accepted in
accordance with the rules adopted by the General Assembly of the WPA; (2) no
representative of the industry participated in the work of the Task Force, and the
industry had no rights to veto any materials produced by the Task Force; and (3)
the Technical Review served as a background technical document to the
Executive Committee’s consideration of the text of the Consensus Statement
prepared for consideration by the General Assembly of the WPA. The companies
were invited to present published materials relevant to the review and were
given an opportunity to look at the text of the review. The Task Force examined
the materials and the suggestions in the same way in which it examined the
comments and suggestions offered by individual experts and institutions invited
to submit opinions during the preparation of the review.
The national meetings endorsed the recommendations of the Task Force
contained in the Technical Review. The meeting participants felt that the SGAMs
should be among the options considered for the initial treatment of people with
psychotic disorders. They were in agreement with the notion that the WPA
should become actively involved in negotiations and other actions necessary to
increase access to the new medications – through appropriate pricing, faster
review processes, improved distribution systems for medications, and other
measures. The notion that the WPA should work with the World Health
Organization in this context was seen as a particularly positive one..
The participants at national meetings also agreed with the recommendation that
health staff, as well as patients and their families, should be given opportunities
to upgrade and update their knowledge about psychiatric treatment in general
and about the use of new medications or other new treatments in particular. They
also stressed the difficulties in providing appropriate and unbiased training in
this respect. Information about new medications, for example, is usually only
available from companies that produce them and therefore possibly biased.
Governments seem to invest little in in-service training, and psychiatric societies
usually lack the resources to organize and provide it. In this respect, the activities
of the WPA were seen as being very useful, albeit insufficient. The WPA has
produced training materials about some disorders though not about many others;
many of the materials are available only in English, and it is not always easy to
find out that they exist or where to get them. Some national psychiatric societies
and institutions are also producing training materials, but these are distributed
only sporadically and are only rarely updated regularly.
The Task Force recommendation that psychiatric societies should support patient
and care-giver organizations and seek opportunities to collaborate with them was
generally endorsed. It was pointed out, however, that in many countries such
organizations do not exist and that there are numerous obstacles to their
establishment – ranging from prohibitive governmental policies to ignorance of
the steps that are useful in creating and managing them. The suggestion that the
leadership of an international professional organization might bring self-help or
user groups together was seen as unlikely to succeed since most such groups deal
with local problems and have only limited interest in international collaboration
on problems that are not directly related to their sphere of work. International
organizations that bring together user and care-giver associations operating in
different countries [such as the European Federation of Associations of Families
of Mentally Ill People (EUFAMI) and the World Schizophrenia Fellowship can
provide useful hints and help national associations much more. It was felt,
therefore, that the WPA should establish links with these organizations at the
international level and promote the idea that national psychiatric societies should
work with national patient or family organizations whenever possible and useful.
In these discussions, there was almost universal recognition of the difficulties that
arise, for any work in mental health, from the continuing stigmatization of mental
illnesses, of the patients who suffer from these illnesses, of their families, and of
any service or treatment method used to provide care. The WPA Global
Programme against Stigma and Discrimination because of Schizophrenia was
mentioned in a number of discussions, and its continuation and expansion to
countries not yet involved were recommended.
Numerous specific technical points were made in the course of national meetings.
They have been very useful in the development of this Update, and are reflected
in the texts of chapters 3, 4 and 5.
Options for further work, and lessons learned
The recommendations from national review meetings and the advice of experts
and organizations seem to converge on the following activities that the WPA
could undertake in the future.
(1)
(2)
(3)
(4)
(5)
(6)
The Executive Committee of the WPA could begin exploring the
possibilities for collaboration with the World Health Organization (and
possibly other agencies) in an effort to increase access to new medications
by using one or more of the strategies mentioned above.
Several versions of the Technical Review and its Update could be developed
for use by different categories of health personnel, care-givers and patients.
The documents could be translated into languages other than English. The
drafts of the Technical Review were translated into a number of local
languages to facilitate discussion in national review meetings, and
translation of the final version of the Technical Review and its Update could
therefore be completed relatively quickly.
Guidelines for the treatment of psychotic states using the SGAMs could be
produced. These guidelines would rely on the material in the Technical
Review and its Update and might be similar in style to some of the other
treatment guidelines produced at country level in recent years. Ideally, the
treatment guidelines should be related to quality-assurance programmes
and developed in parallel with them.
A training programme could be developed on the use of the SGAMs. The
training programme should include appropriate texts about the overall
management of psychoses and care for people who suffer from them.
The work could be continued on other groups of medications – e.g.
medications against anxiety and drugs used in dealing with cognitive
deficits. The strategy used in the production of the Technical Review and its
Update (and, in particular, the organization of a series of national meetings
to obtain first-hand experience and gain access to findings of studies
published in languages other than English, French and Spanish) could be
employed in this work.
These suggestions about future activities were submitted to the Executive
Committee of the WPA for consideration and for the inclusion of those in
harmony with the overall plans of the WPA in its submissions to the WPA
General Assembly.
II
Critical Review and summary of information about the
effects and safety of second-generation antipsychotic
medications
Clinical Data1
For this Update to the WPA Technical Review of Evidence and
Recommendations on the Use and Usefulness of Second-Generation
Antipsychotic Medications, the scientific literature from January 2000 to March
2002 was searched for clinical studies of antipsychotic drug treatment. As
mentioned earlier, suggestions concerning papers to reviewed, in both 2001/2002
and previous years, were also received from the institutions and experts
consulted individually and through the mechanisms of national review meetings.
Reports that were found to be relevant to the scope of this review and of
sufficient methodological rigour were selected for inclusion in this Update.
Clozapine
As a follow-up to a pivotal clozapine and chlorpromazine comparison (‘Study
30'), Kane; et al. [2,3] compared clozapine and haloperidol treatment used for 29
weeks in 71 community-based partially responsive but residually symptomatic
patients with schizophrenia. Those treated with clozapine had a significantly
lower dropout rate than those given haloperidol (35% versus 67%), and a higher
rate of response (57% versus 25%). Clozapine-treated patients had more sideeffects including salivation, dizziness, sweating and decreased appetite.
In a series of articles, Volavka et al. [4]2 reported the results of a 14-week
randomised double-blind trial comparing clozapine, olanzapine, risperidone and
haloperidol in 157 partially responsive but residually symptomatic patients with
schizophrenia. They found that the three SGAMs produced statistically
significant reductions in symptoms from baseline, while haloperidol did not, but
only clozapine and olanzapine were significantly better than haloperidol.
However, the doses of olanzapine and risperidone were higher than usual
(olanzapine mean, 30.4 mg/day; risperidmean, 11.4 mg/day). Although the
greater efficacy of the SGAMs was statistically significant, it was clinically
modest. EPSs were more common in patients treated with haloperidol and
risperidone, and weight gain was greater with clozapine and olanzapine
treatment. Using data from the same study, Citrome et al. [5] examined the
treatment effects on aggressive behavior. They found that clozapine was
The references to studies used in the review of evidence are listed in Table 1 on pages 22-28.
This paragraph is reprinted on pages 14 (for olanzapine) and 17 (for risperidone) since the Volavka
et al. study compared these three drugs and the chapters dealing with these drugs may be cited
separately.
1
2
significantly more effective in reducing hostility and aggression than haloperidol,
while olanzapine and risperidone were not.
In a novel study to evaluate the effects of treatment on suicidal behavior, Meltzer
[6] randomized 980 patients with schizophrenia or schizoaffective disorder at
high risk for suicidal behavior to open-label clozapine or olanzapine, and
followed them for up to 2 years. Results indicated that clozapine was associated
with significantly lower rates of suicidal events than olanzapine (24% versus
32%). However, there were no differences between the treatment groups in terms
of the number of completed suicides (five with clozapine and three with
olanzapine) or the reduction-of-symptom ratings.
Like olanzapine, clozapine has frequently been linked to weight gain,
hyperlipidaemia and diabetes. This is the subject of reports by Meyer [7], Liebzeit
et al. [8] and Wetterling [9]. A study by Lund et al. [10], who compared incidence
rates for diabetes, hyperlipidaemia and hypertension with medical and pharmacy
claims, found no differences in overall incidence rates for these disorders in
patients receiving clozapine or conventional antipsychotics. In younger patients,
however, clozapine administration was associated with an increased risk of
diabetes and hyperlipidaemia.
The topic of clozapine-related myocarditis has received considerable attention.
Hagg et al. [11], using cases submitted to the Swedish Adverse Drug Reaction
Advisory Committee and cases reported in the literature as a basis for their
analysis, came to the conclusion that myocarditis seems to be a rare though
potentially lethal side-effect of clozapine. This study corroborates an earlier
report from Australia by Killian et al.[12], which identified 15 cases of
myocarditis and 8 cases of cardiomyopathy associated with clozapine treatment
in physically healthy young adults with schizophrenia (all occurring within 3
weeks of starting clozapine).
Cohen et al. [13], when comparing heart-rate of patients on clozapine, haloperidol
and olanzapine with healthy subjects, found autonomic dysregulation and
cardiac depolarization changes occurring more frequently in patients treated with
antipsychotic medications, especially clozapine, than in healthy controls.
Olanzapine
In the first large clinical trial of olanzapine in Japanese patients, Ishigooka et al.
[14] randomized 182 patients with schizophrenia to olanzapine or haloperidol
under double-blind conditions for 8 weeks of treatment. Olanzapine was
comparable to haloperidol in reducing positive symptoms, and superior in
reducing negative symptoms. Olanzapine treatment caused significantly fewer
EPSs, but greater weight gain, than haloperidol.
Lindenmayer et al. [15] treated 43 patients determined to be resistant to treatment
with clozapine, risperidone or haloperidol prospectively with olanzapine doses
up to 40 mg/day; they found that 16.7% responded, particularly when treated
with higher doses. Olanzapine was also compared to clozapine in treatmentresistant schizophrenia patients, using a non-inferiority design [16]. The trial
showed both drugs to have comparable efficacy, with olanzapine having a
tolerability advantage. A mean of 20.5 mg olanzapine/day was compared with a
mean of to 303.6 mg clozapine/day over an 18-week double-blind therapy
period.
In a series of studies, the effects of olanzapine on mania were examined in
comparison with a placebo, lithium and divalproex sodium in separate
randomized double-blind trials. In a 3-week trial [17] and a 4-week trial [18],
olanzapine was superior to placebo. In a 4-week study [19], olanzapine appeared
to have antimanic effects comparable to those of lithium. In patients with acute
or mixed mania, olanzapine was superior to divalproex sodium and as effective
as haloperidol. Olanzapine was generally well tolerated but was associated with
significant weight gain.
In the series of articles mentioned earlier (in the section on clozapine), Volavka et
al. [4] reported the results of a 14-week randomized double-blind trial comparing
clozapine, olanzapine, risperidone and haloperidol in 157 partially responsive but
residually symptomatic patients with schizophrenia. They found that the three
SGAMs produced statistically significant reductions in symptoms from baseline,
while haloperidol did not, but only clozapine and olanzapine were significantly
better than haloperidol. However, the doses of olanzapine and risperidone were
higher than usual (olanzapine mean, 30.4 mg/day; risperidone mean, 11.4
mg/day). Although the greater efficacy of the SGAMs was statistically
significant, it was clinically modest. EPSs were more common in patients treated
with haloperidol and risperidone, and weight gain was greater with clozapine
and olanzapine treatment. Using data from the same study, Citrome et al. [15]
examined treatment effects on aggressive behavior. They found that clozapine
was significantly more effective in reducing hostility and aggression than
haloperidol, while olanzapine and risperidone were not.
Conley and Mahmoud [20] reported a study of 377 patients with schizophrenia or
schizoaffective disorder who were randomized to double-blind treatment with
risperidone or olanzapine for 8 weeks. The mean (sd) doses were 12.4 mg/day for
olanzapine and 4.8 mg/day for risperidone; 77.2% of the olanzapine-treated
patients and 71.8% of the risperidone-treated patients completed the study. Both
treatments produced significant symptom reductions; these did not differ in an
end-point analysis, but did differ at week 8, favouring risperidone with respect to
positive symptoms and anxiety/depression factors on the Positive and Negative
Sympsom Scale (PANSS). EPS symptoms were comparable between treatments,
but olanzapine was associated with more weight gain
Perry et al. [21] examined the relationship between plasma levels of olanzapine
and the therapeutic response. They found a threshold level of 23.2 ng/ml above
which a response was more likely. This suggests the potential benefit of higher
doses of olanzapine to maximize the likelihood of exceeding the therapeutic
threshold.
Weight gain and disturbances of the glucose and lipid metabolism have been the
focus of a number of reports about the safety of olanzapine. Wetterling [9], in his
review, calculated a monthly body weight gain of 2.3 kg. However, Kinon et al.
[22] found that weight gain associated with olanzapine treatment occurred early
and reached a plateau after approximately 9 months of treatment. Eder et al. [23],
who also reported a significant weight gain with olanzapine treatment, found this
attributable mainly to an increase in body fat rather than lean body mass. Serum
levels of leptin also increased two- to threefold over the 8-week study period.
Considerable weight gain in adolescent patients treated with olanzapine has also
been found by Kumra et al. [24], Haapasalo-Pesu and Saarijarvi [25], Selva and
Scott [26] and Domon and Webber [27].
Meyer et al. [7] hypothesize a link between glucose and lipid metabolism changes
and structurally related antipsychotics such as clozapine, quetiapine and
olanzapine. Their report and a paper by Liebzeit et al. [8] agree that, among the
SGAMs, clozapine and olanzapine carry the highest risk of new-onset diabetes
[26].
In a study comparing intramuscular olanzapine with intramuscular haloperidol
and placebo [28], the advantage of olanzapine over haloperidol with regard to
extrapyramidal motor symptoms was substantiated. Patients treated with
haloperidol had a higher risk of developing acute dystonia or an ‘trapyramidal
syndrome’. They also received anticholinergic drugs sig-nificantly more often
than patients in the olanzapine and placebo groups.
Wudarsky et al. [29] found an increased prolactin level in seven out of ten young
patients treated with olanzapine for first-episode schizophrenia. Since this would
not be expected in an adult sample, this report lends additional support to the
hypothesis that the side-effect profiles of antipsychotic drugs may be age
dependent. Sholevar et al. [30] reported sedation as the main side- effect of
olanzapine among 15 patients with childhood schizophrenia.
As with other antipsychotic drugs, there have been a number of case reports
describing drug-induced neutropenia or agranulocytosis in patients receiving
olanzapine [31-37]. Taken together, all this information suggests that patients
who have developed blood dyscrasias on clozapine or other antipsychotic drugs
may be at higher risk of developing white blood count disorders during
olanzapine treatment. In contrast, a number of studies [38-44] that specifically
studied patients with clozapine-induced white-blood cell abnormalities did not
find any problems with white blood cell counts after switching these patients to
olanzapine. The findings on many of the reported cases are confounded by the
fact that patients were not on olanzapine monotherapy but received additional
psychotropic drugs, in many instances other antipsychotic medications. Kodesh
et al. [36] suggest that leucopenia may be a dose-dependent phenomenon, since
leucopenia disappeared with a dose decrease in the three patients they
described. An alternative explanation for these and other cases may be transient
neutropenia, a phenomenon well described for clozapine and other antipsychotic
medicatios [45]. In summary, it appears to be prudent to monitor white blood
cell counts in patients being treated with atypical antipsychotic drugs and who
have a history of drug-induced white blood cell count disorders, as well as in
patients who are treated with other drugs that bring a risk of white blood cell
aberrations.
Quetiapine
Purdon et al. [46] reported the response, in terms of clinical symptoms and
cognitive function, measured by neuropsychological tests in 25 patients with
schizophrenia randomized to treatment with quetiapine and haloperidol under
double-blind conditions for 6 months. They found that quetiapine produced a
greater improvement in psychotic, negative and mood symptoms and in six
cognitive domains. Quetiapine also produced fewer EPSs.
Copolov et al. [47] examined quetiapine and haloperidol in a multicentre,
international, 6-week, randomized controlled trial (RCT) study of patients with
acute exacerbations of schizophrenia. They found comparable reductions in
psychopathology with the two drugs, but fewer side-effects (in terms of EPS and
prolactin elevations) with quetiapine.
Emsley et al. [48] compared the effects of quetiapine and haloperidol in partially
responsive patients with schizophrenia in an 8-week RCT. They reported a
superior response for quetiapine-treated patients on PANSS and Brief Psychiatric
Rating Scale scores, but this did not reach statistical significance. In addition,
quetiapine-treated patients had fewer EPSs and less elevation of prolactin than
haloperidol-treated patients.
An open comparison of quetiapine (mean daily dose 253,9 mg) and risperidone
(4.4 mg) confirmed previous findings in which quetiapine showed good
tolerability with regard to EPSs [49]. Approximately half of the patients
suffering from schizophrenia or other disorders had EPSs at baseline. Motor
side-effects declined to a similar degree over the course of the 4-month open trial
in both groups, but quetiapine-treated patients required less anticholinergic
medication than patients in the risperidone group. Somnolence was the most
common adverse event in both groups, though it occurred at a significantly
higher rate in the quetiapine group. Dry mouth and dizziness were also more
common in patients treated with quetiapine.
The favourable EPS profile of quetiapine has also been found in patients with
Parkinson's disease who experienced psychosis. A number of small clinical trials
have consistently shown that quetiapine improved psychosis in these patients
without worsening motor functions; as a result, quetiapine is now a preferred
treatment for this clinical occurrence [50].
Whether or not quetiapine induces weight gain is still a contentious issue: while
Mullen et al.[49] and Brecher et al. [51] have not found this to be a problem,
Wetterling et al. [8], in a recent review, noted that a weight gain of 1.8 kg/month
is to be expected under short-term treatment with quetiapine. In this context, it is
of interest that two children successfully treated with quetiapine for Tourette’s
Syndrome [52] showed substantial weight loss while being treated with
quetiapine. On the other hand, Shaw et al. [53], who studied the efficacy and
tolerability of quetiapine in 15 psychiatric adolescents, found a weight gain of 3.4
kg (corrected for expected weight gain) over the 8-week period.
Two groups have presented case reports on neutropenia and agranulocytosis,
respectively, linked to quetiapine treatment [54,55]. Interestingly, two of the
three patients reported by Ruhe et al. [55] had a history of clozapine-induced
agranulocytosis. Only two out of four patients in these reports were on
quetiapine monotherapy; the other two received combination treatments of
quetiapine with olanzapine and lithium, or quetiapine with flupenthixol
decanoate. Ruhe et al. [55] also cite a number of other cases of agranulocytosis or
granulocytopenia associated with quetiapine that were reported to the Uppsala
Monitoring Center of the World Health Organization. While they note that these
data have to be interpreted with caution, they point to the structural similarity
between quetiapine and clozapine. In summary, as mentioned earlier, it appears
to be prudent to monitor white blood cell counts in patients being treated with
atypical antipsychotic drugs and who have a history of drug-induced white
blood cell count disorders, as well as in patients who are treated with other drugs
that bring a risk of white blood cell aberrations.
Risperidone
Conley and Mahmoud [20] reported a study of 377 patients with schizophrenia or
schizo-affective disorder who were randomized to double-blind treatment with
risperidone or olanzapine for 8 weeks. The mean (sd) doses were 12.4 mg/day for
olanzapine and 4.8 mg/day for risperidone; 77.2% of the olanzapine-treated
patients and 71.8% of the risperidone-treated patients completed the study. Both
treatments produced significant symptom reductions; these did not differ in an
end-point analysis but did at week 8, favouring risperidone on positive
symptoms and anxiety/depression factors on the PANSS. EPS symptoms were
comparable between treatments, but olanzapine was associated with more weight
gain.
As noted earlier, Volavka et al. [4] reported the results of a 14-week, randomized
double-blind trial comparing clozapine, olanzapine, risperidone and haloperidol
in 157 partially responsive but residually symptomatic patients with
schizophrenia. They found that the three SGAMs produced statistically
significant reductions in symptoms from baseline, while haloperidol did not, but
only clozapine and olanzapine were significantly better than haloperidol.
However, the doses of olanzapine and risperidone were higher than usual
(olanzapine mean, 30.4 mg/day; risperidone men, 11.4 mg/day). Although the
greater efficacy of the SGAMs was statistically significant, it was clinically
modest. EPSs were more common in haloperidol-treated and risperidone-treated
patients, and weight gain was greater with clozapine and olanzapine treatment.
Using data from the same study, Citrome et al. [5] examined treatment effects on
aggressive behavior. They found that clozapine was significantly more effective
in reducing hostility and aggression than haloperidol, while olanzapine and
risperidone were not.
Csernansky et al.[56] examined the efficacy of risperidone and haloperidol in
preventing relapse for a minimum of 1year in 397 patients with schizophrenia or
schizo-affective disorder in a randomized double-blind trial. The risk of relapse
was significantly lower in risperidone-treated patients (34%) than in haloperidol
patients (60%). Risperidone also produced fewer EPSs than haloperidol.
An open comparison of quetiapine (mean daily dose 253,9 mg) and risperidone
(4.4 mg) confirmed previous findings of quetiapine's good tolerability with
regard to EPSs [49]. Approximately half of the patients suffering from
schizophrenia or other disorders had EPSs at baseline. Motor side-effects
declined to a similar degree over the course of the 4-month open trial in both
groups, but quetiapine-treated patients required less anticholi- nergic medication
than patients in the risperidone group. Somnolence was the most common
adverse event in both groups, though it occurred at a significantly higher rate in
the quetiapine group. Dry mouth and dizziness were also more common in
patients treated with quetiapine.
Children and adolescents appear to be at higher risk for weight gain on
risperidone than adults. This was found by Hellings et al. [57] in mentally
retarded and autistic patients and by Martin et al. [58] in a retrospective chart
review of 37 child and adolescent in-patients. Over a 6-month observation period,
these authors found that weight increased at an average rate of 1,2 kg/month.
Markianos et al. [59], who studied the effects of a number of FGAMs and SGAMs
on prolactin levels, concluded that risperidone had a greater propensity to
increase prolactin levels than haloperidol. They also found that clozapine and
olanzapine (in that order) brought less risk of increased prolactin than
risperidone.
Sertindole
Pezawas et al. [60] have added to the available information on the propensity of
sertindole to prolong the QTc interval. In a drug-surveillance study of 34 comorbid and co-medicated sertindole-treated patients, they found a mean QTc
interval prolongation of 19.7 ms without any evidence of cardiac dysrhythmia.
The suspension for sertindole in Europe has been lifted, and the producers
(Lundbeck, Copenhagen, Denmark) of the medication have initiated two largescale, international, post-marketing surveillance studies which will include all
patients for whom sertindole is prescribed from mid-2002 onwards.
Ziprasidone
A recent study, as yet unpublished but available on the Food and Drug
Administration website (http://www.fda.gov), has produced evidence that
ziprasidone induces a mean prolongation of the QTc interval of 20.3 ms at the
time of maximum drug blood level. This is a larger increase than that induced by
haloperidol, risperidone, olanzapine or quetiapine, though thioridazine led to a
considerably larger QT prolongation (35.6 ms). Only 2 out of 2988 patients (0.06
%) who received ziprasidone in placebo-controlled clinical trials revealed QT
intervals above the threshold of 500 ms considered clinically relevant by the Food
and Drug Administration. One out of 440 (0.23 %) of the placebo-treated patients
crossed this threshold. To date there is no clinical correlate for propensity of
ziprasidone to prolong the QT interval, since none of the published studies have
found relevant increases in cardiac arrhythmias or an excess risk for unexplained
sudden death in patients receiving ziprasidone. None of the countries in which
ziprasidone has been licensed requires electrocardiogram monitoring, but all
package inserts provide a clear statement that ziprasidone is not to be used in
patients with a known history of QT prolongation, with recent acute myocardial
infarction or with uncompensated heart failure. Ziprasidone should not be taken
concomitantly with other medications that are known to influence the QT
interval, such as quinidine, pimozide, sotalol, thioridazine and sparfloxacin (this
is not a complete list).
A review on antipsychotic drugs, cardiac safety and sudden death was published
by Glassman and Bigger in 2001 [61]. This review and the report from a policy
conference of the European Society of Cardiology on the potential for QT
prolongation and proarrhythmia by non-antiarrhythmia drugs (clinical and
regulatory implications) [62] provide a useful framework within which to assess
the cardiac safety of antipsychotic drugs.
Three studies examined an acute intramuscular formulation of ziprasidone in
acutely agitated, psychotic patients, prior to transition to oral ziprasidone. All
found intramuscular ziprasidone to be rapidly effective and well tolerated at
therapeutic doses, extrapyramidal motor dysfunctions being conspicuously
absent [63]. Excessive sedation was also not reported.
Zotepine
Hwang et al. [64] reported the results of a randomized double-blind, 6-week trial
of zotepine and haloperidol in 70 patients with schizophrenia who had positive
symptoms. Both treatments were equivalent in their reduction of symptoms:
zotepine produced fewer EPSs but was associated with more dizziness, weight
gain and increases in pulse rate than haloperidol-treated patients.
Economic data
SGAMs offer patients, families and clinicians well-tolerated, effective treatments
[1]. Although there is now sufficient evidence on the comparative efficacy of the
SGAMs and conventional drugs to make meta-analyses possible, there are still
few good cost-effectiveness or similar studies, and many of the published
economic comparisons between FGAMs and SGAMs have been criticized for
methodological weaknesses [182-183]. A number of the earlier studies were
discussed in the Technical Review [181].
The wide-ranging economic impact of schizophrenia continues to be reported in
both longitudinal (Table 1) and cross-sectional studies (e.g. [184-186]. Yet almost
all of the cost-effectiveness studies on schizophrenia treatment have focused on
the important but narrow comparison of health-care impacts (on the cost side)
and symptom/functioning changes (on the effectiveness side). Wider cost
measures, assessment of patients’ quality of life, and an understanding of family
impacts are needed in order to gauge the full consequences of treatment with
SGAMs.
Cost-effectiveness evidence
New evidence on the cost-effectiveness of clozapine compared to usual care with
standard neuroleptic therapy is offered by Essock et al. [187] from a randomized
open-label study of patients in three large Connecticut state hospitals. Treatmentresistant schizophrenia patients who had been hospitalised for at least 4 months
(and who had spent at least 2 years in hospital in the previous 5 years) were
eligible for the trial. Data were collected every 4 months, over a 2-year period, on
the initial sample of 138 patients. There were no differences in the rates of
discharge from hospital, but, once discharged, members of the clozapine group
were less likely to be readmitted. Clozapine patients were significantly less
disruptive, required fewer ‘as-needed’ antipsychotic medications, and
experienced significantly fewer EPSs than the usual care group. There were no
differences between the groups with respect to weight gain or Brief Psychiatric
Rating Scale. Compared to the usual-care group, the clozapine sample had
US$1112 higher costs in the first year after randomization, but US$7149 lower
costs in the second year. These differences (and their sum) did not reach statistical
significance. It was therefore concluded that clozapine produced better outcomes
(on some, but not all measures, of effectiveness) at an equivalent cost, and was
consequently more cost-effective than usual care. This study by Essock et al. [187]
is unusual in this field for the breadth of its cost and effectiveness measurements,
and the rigour of its analytical methods.
A different conclusion was reached by Sernyak et al. [188] in their matched
comparison of patients treated with clozapine or FGAM in a naturalistic setting
in the US. Clozapine patients had relatively more in-patient days in the three
years after discharge from the hospital (where the study commenced), leading the
authors to suggest that this treatment with this SGAM may actually be more
costly than treatment with conventional medications (although this proposition
was not actually tested).
Rehospitalisation rates were examined by Rabinowitz et al. [189] for patients with
schizophrenia who were discharged from in-patient psychiatric facilities in Israel.
Two years after discharge, half the patients discharged while taking a
conventional antipsychotic drug remained in the community, compared to twothirds of patients treated with risperidone or olanzapine.
Systematic reviews of evidence on depot preparations of conventional
antipsychotic drugs have been published recently. Although depot
administration has advantages over oral administration of conventional
treatments for patients who are not well engaged with services or do not take
their oral medication regularly, the international evidence on effectiveness is
mixed [190,191]. The cost-effectiveness evidence is very sparse indeed, and of
questionable quality, making it difficult to draw firm conclusions [192].
However, the non-concordance problem that may have led to the prescription of
a depot medication generates potentially major challenges for research in this
area: patients who do not take their oral medication may also be hard to recruit
into, or retain, in trials.
Table 1. Evidentiary Basis for Evaluation of Second-Generation
Antipsychotic Drugs
Drug
Amisulpride
Reference
Sechter et al., 2002 [65]
Type of study/report
RCT, double blind;
risperidone
Meta-analysis
Amisulpride
Leucht at al., 2002 [66]
Amisulpride
Colonna et al., 2000 [67]
Amisulpride
Mota Neto et al., 1999
[68]
Amisulpride
Danion et al., 1999 [69]
RCT, double-blind;
placebo-controlled
Amisulpride
Peuskens et al., 1999 [70]
RCT, double-blind;
risperidone comparator
Amisulpride
Puech et al., 1998 [71]
RCT, double-blind;
haloperidol comparator
Amisulpride
Wetzel et al., 1998 [72]
Amisulpride
Loo et al., 1997 [73]
Amisulpride
Speller et al., 1997 [74]
RCT, double-blind;
flupenthixol comparator
RCT, double-blind;
placebo controlled
RCT, double-blind;
haloperidol comparator
Amisulpride
Moller et al., 1997 [75]
RCT, double-blind;
haloperidol comparator
Amisulpride
Boyer et al., 1995 [76]
RCT, double-blind;
placebo-controlled
Amisulpride
Paillere-Martinot et al.,
1995 [77]
RCT, double-blind;
placebo-controlled
Clozapine
Volavka et al., 2002 [4]
RCT, double-blind;
risperidone, olanzapine,
haloperidol comparator
RCT, open randomized;
Haloperidol comparator
Meta-analysis
Clozapine
Citrome et al., 2001 [5]
Clozapine
Kane et al., 2001 [3]
Clozapine
Wahlbeck et al., 2000 [78]
RCT, double-blind;
risperidone, olanzapine,
haloperidol comparator of
hostility
RCT, double-blind;
haloperidol comparator
Meta-analysis
Clozapine
Meltzer et al., 1999 [6]
RCT, open label
Clozapine
Bondolfi et al., 1999 [79]
Clozapine
Buchanan et al., 1998 [80]
Clozapine
Martin et al., 1997 [81]
RCT, double-blind;
risperidone comparator
RCT, double-blind;
haloperidol comparator
Derivative analysis
Clozapine
Conley et al., 1997 [82]
Derivative analysis
Clozapine
Derivative analysis
Clozapine
Lindstrom and Lundberg
1997 [83]
Hong et al., 1997 [84]
Clozapine
Rosenheck et al., 1997 [85]
Clozapine
Kumra et al., 1996 [86]
Clozapine
Clozapine
VanderZwaag et al., 1996
[87]
Essock et al., 1996 [88]
Clozapine
Lieberman et al., 1994 [89]
Clozapine
RCT
Clozapine
Lindenmayer et al., 1994
[90]
Zito et al., 1993 [91]
Clozapine
Pickar et al., 1992 [92]
Clozapine
Mattes 1989 [93]
RCT, cross-over design;
fluphenazine comparator
Open study
Clozapine
Kane et al., 1988 [2]
RCT, double-blind;
chlorpromazine
comparator
RCT, double-blind;
haloperidol comparator
RCT, double-blind;
haloperidol comparator
RCT
RCT, open; continuation of
first-generation drugs
comparator
Derivative analysis
Derivative analysis
RCT, double-blind;
chlorpromazine
comparator
Clozapine
Small et al., 1987 [94]
Derivative analysis
Loxapine
Fenton et al., 2000 [95]
Meta-analysis
Molindone
Bagnall et al., 2000 [96]
Meta-analysis
Olanzapine
Bhana and Perry 2001
[97]
Olanzapine
Frazier et al., 2001 [98]
Olanzapine
Ishigooka et al., 2001 [14]
Olanzapine
Tollefson et al., 2001 16]
Olanzapine
Olanzapine
Lindenmayer et al., 2001
[15]
Perry et al., 2001 [21]
Olanzapine
Duggan et al., 2000 [99]
Review of RCT, doubleblind, placebo-controlled
studies on acute mania
Open study of mania in
children and adolescents
RCT, double-blind;
haloperidol comparator
RCT, double-blind;
clozapine comparator
Open study of treatmentresistant patients
RCT, double-blind;
haloperidol comparator
Meta-analysis
Olanzapine
Breier et al., 1999 [100]
Olanzapine
al Jeshi, 1998 [101]
RCT, double-blind;
haloperidol
Case report
Olanzapine
Allan et al., 1998 [102]
Open label
Olanzapine
Elian, 1998 [103]
Case report
Olanzapine
Kumra et al., 1998 [24]
Open label
Olanzapine
Case report
Olanzapine
O’Brien and Barber, 1998
[104]
Thomas and Labbate, 1998
[105]
Zarate et al., 1998 [106]
Olanzapine
Crawford et al., 1997 [107]
Derivative analysis
Olanzapine
Daniel et al., 1997 [108]
Case report
Olanzapine
Flynn et al., 1997 [109]
Case report
Olanzapine
Horrigan et al., 1997
[110]
Case report
Olanzapine
Case report
Chart review
Olanzapine
Littrell et al., 1997 [111]
Case report
Olanzapine
Case report
Olanzapine
Meil and Schechter, 1997
[112]
Ravindran et al., 1997 [113]
Olanzapine
Sheitman et al., 1997 [114]
Case report
Olanzapine
Tollefson et al., 1997 [115]
Derivative analysis
Olanzapine
Derivative analysis
Olanzapine
Tollefson et al., 1997
[116,117]
Weisler et al., 1997 [118]
Olanzapine
Beasley et al., 1999 [119]
Olanzapine
Conley et al., 1999 [120]
Olanzapine
Sanger et al., 1999 [121]
RCT, double-blind;
haloperidol comparator
RCT, double-blind;
chlopromazine
Derivative analysis
Olanzapine
Hamilton et al., 1998 [122]
Derivative analysis
Olanzapine
Tollefson et al., 1998 [116]
Derivative analysis
Olanzapine
Tollefson et al., 1998 [123]
Derivative analysis
Olanzapine
Beasley et al., 1997 [38]
Derivative analysis
Olanzapine
Glazer, 1997 [124]
Derivative analysis
Olanzapine
Martin et al., 1997 [81]
Open label
Olanzapine
Olanzapine
Tollefson and Sanger, 1997 RCT, double-blind;
[125]
haloperidol comparator
Tran et al., 1997 [126]
Derivative analysis
Olanzapine
Tran et al., 1997 [127]
Olanzapine
Beasley et al., 1996 [128]
Olanzapine
Beasley et al., 1996 [129]
Quetiapine
Purdon et al., 2001 [46]
Case report
Case report
RCT, double-blind;
risperidone comparator
RCT, double-blind; placebo
comparator
RCT, double-blind; placebo
and haloperidol
comparators
RCT, double-blind;
haloperidol comparator
Quetiapine
Emsley et al., 2000 [48]
Quetiapine
Copolov et al., 2000 [47]
Quetiapine
Srisurapanont et al., 2000
[130]
Parsa and Bastani 1998
[131]
Peuskens and Link 1997
[132]
Quetiapine
Quetiapine
RCT, double-blind;
haloperidol comparator
RCT, double-blind;
haloperidol comparator
Meta-analysis
Open label
RCT, double-blind;
chlorpromazine
comparator
Derivative analysis
Quetiapine
Hamner et al., 1996 [133]
Quetiapine
Borison, 1995 [134]
Quetiapine
Fabre et al., 1995 [135]
Quetiapine
Wetzel et al., 1995 [135]
Quetiapine
Arvanitis and Miller,
1997 [137]
Quetiapine
Small et al., 1997 [138]
Quetiapine
Hirsch et al., 1996 [139]
Risperidone
Csernansky et al., 2002 [56]
Risperidone
Risperidone
Conley and Mahmoud,
2001 [20]
Geddes et al., 2000 [140]
RCT, double-blind;
haloperidol comparator
RCT, double-blind;
olanzapine comparator
Meta-analysis
Risperidone
Gilbody et al., 2000 141]
Meta-analysis
Risperidone
Kennedy et al., 2000 [142]
Meta-analysis
Risperidone
Wirshing et al., 1999 [143]
Risperidone
Conley et al., 1999 [120]
Risperidone
Emsley, 1999 [144]
Risperidone
Bondolfi et al., 1998 [79]
Risperidone
Davies et al., 1998 [145]
RCT, double-blind;
haloperidol comparator
RCT, double-blind;
olanzapine comparator
RCT, double-blind;
haloperidol comparator
RCT, double-blind;
clozapine comparator
Pharmacoeconomic
study/analysis
RCT, double-blind; placebo
comparators
RCT, double-blind; placebo
comparators
Open label
RCT, double-blind; placebo
and haloperidol
comparators
RCT, double-blind; placebo
comparator
Derivative analysis
Risperidone
Risperidone
Risperidone
Muller-Siecheneder et
al., 1998 [146]
RCT, double-blind;
amitriptyline/haloperidol
comparator
Addington et al., 1997 [147] Open label
Risperidone
Chouinard and Albright,
1997 [148]
Marder et al., 1997 [149]
Pharmacoeconomic
study/analysis
Derivative analysis
Risperidone
Green et al., 1997 [150]
Risperidone
Moller et al., 1997 [151]
RCT, double-blind;
haloperidol comparator;
cognition outcome measure
Derivative analysis
Risperidone
Risperidone
Simpson and
Lindenmayer, 1997 [152]
Tran et al., 1997 [126]
Risperidone
Blin et al., 1996 [153]
Risperidone
Chouinard,1995 [154]
RCT, double-blind;
olanzapine comparator
RCT, double-blind;
haloperidol comparator
Derivative analysis
Risperidone
Czobor et al.,1995 [155]
Derivative analysis
Risperidone
Klieser et al., 1995 [156]
Risperidone
Moller, 1995 [157]
RCT, double-blind;
clozapine comparator
Derivative analysis
Risperidone
Lindstrom et al., 1995 [158]
Derivative analysis
Risperidone
Peuskens et al., 1995 [159]
Risperidone
Marder and Meibach,
1994 [160]
Risperidone
Kopala and Honer, 1994
[161]
McEvoy, 1994 [162]
RCT, double-blind;
haloperidol comparator
RCT, double-blind; placebo
and haloperidol
comparators
Open label
Risperidone
Risperidone
Risperidone
Ceskova and Svestka, 1993
[163]
Chouinard et al., 1993
[164]
Derivative analysis
Derivative analysis
RCT, double-blind;
haloperidol comparator
RCT, double-blind; placebo
and haloperidol
comparators
Risperidone
Borison et al., 1992
[165]
Risperidone
Claus et al., 1992 [166]
Sertindole
Lewis et al., 2000 [167]
Ziprasidone
Daniel et al.,1997 [108]
Ziprasidone
Lesem et al., 2001 [168]
Ziprasidone
Brook et al., 2000 [169]
Ziprasidone
Bagnall et al., 2000 [170]
Zotepine
Cooper et al., 2000 [171]
Zotepine
Cooper et al., 2000
[172]
Zotepine
Bagnall et al., 2000 [96]
Zotepine
Petit et al., 1996 [173]
Zotepine
Barnas et al., 1992 [174]
Zotepine
Harada et al., 1991 [175]
Zotepine
Klieser et al., 1991 [176]
Zotepine
Müller-Spahn et al., 1991
[177]
Wetzel et al., 1991 [178]
Zotepine
Zotepine
Fleischhacker et al., 1989
[179]
Zotepine
Fleischhacker et al., 1987
[180]
Zotepine
Sarai and Okada, 1987
[181]
RCT, Randomized controlled trial; PO, oral.
RCT, double-blind; placebo
and haloperidol
comparators
RCT, double-blind;
haloperidol comparator
Meta-analysis
RCT comparing 2 mg with
20 mg intramuscular
ziprasidone
RCT comparing 2 mg and
10 mg intramuscular
ziprasidone
Open label comparison of
ziprasidone intramuscular
+ PO and haloperidol
intramuscular + PO
Meta-analysis
RCT, double-blind;
placebo-controlled
RCT, double-blind;
placebo, chlorpromazine
comparators
Meta-analysis
RCT, double-blind;
haloperidol comparator
RCT, double-blind;
haloperidol comparator
Open label
RCT, double-blind;
haloperidol comparator
RCT, double-blind;
perazine comparator
RCT, double-blind;
perazine comparator
RCT, double-blind;
haloperidol-controlled
Open label
RCT, doube-blind;
thiothixene comparator
Comparisons between second-generation antipsychotic medications
Head-to-head economic evaluations of the SGAMs are still rare, they are often
based on research designs that are methodologically weak [186], and their
findings do not point consistently in any one direction.
Only one cost-effectiveness study using a RCT design has been published. On
the basis of an analysis of data for the 150 US patients included in a larger, multicountry RCT, Edgell et al. [193] concluded that medication and in-patient costs
were lower for patients treated with olanzapine than for those treated with
risperidone, though total costs did not differ significantly. Superior outcomes led
these authors to conclude that olanzapine was the more cost-effective treatment
for this group of patients.
A recently completed European study which used an RCT design to collect data
prospectively over 6months found amisulpride and risperidone to be equally
cost-effective [194]. Interestingly, there were differences between Eastern and
Western European sites in terms of service-use pattern, relative costs, and the
balance between costs and outcomes, reinforcing the view that economic
evidence does not always ‘travel’ well across countries and health systems.
Economic studies with naturalistic designs have, to date, focused on the
comparison between olanzapine and risperidone. These studies collected data
either prospectively or retrospectively, and some used quite narrow measures of
cost. Some of the studies point to relative advantages for risperidone [195,196]
and some to relative advantages for olanzapine [197]. Calculating costs across a
wide range of services, Lewis et al. [198] found no significant cost differences for
patients on risperidone, olanzapine and clozapine. Methodological limitations –
some of which were quite substantial (such as a narrow focus solely on drug
costs) – and the draft status of some of these papers, however, make it impossible
to reach overall conclusions about the comparative cost-effectiveness of the
various SGAMs.
Incentives
The economic evidence on the SGAMs points to cost-effectiveness advantages
over conventional medications, and the possibility (as yet unproven) of some
cost-effectiveness differences between the newer drugs. However, none of the cost
advantages shown for the newer drugs with respect to the old medication has
been particularly large, and none is likely to accrue immediately because a large
part of the savings will come from the reduced need for hospitalization. Moreover, there are disincentives inherent in most health systems because the higher
acquisition costs (prices) of the SGAMs are often carried by one budget
(pharmacy) while the downstream savings fall elsewhere. Contractual and
managerial steps may need to be taken to ensure that narrow budgetary concerns
do not compromise the pursuit of overall cost-effectiveness improvements [199].
Drugs in Development
The role of serotonin receptor effects in the development of antipsychotic
medications
The improvement of the secondary negative symptoms, along with the
symptoms of depression often associated with schizophrenia, has been an
important feature of the SGAMs. Such findings may reflect the actions of the
SGAMs on serotonin (5-hydroxytryptamine, 5HT) sub-type 5HT2A and 5HT1A
receptors in addition to their actions on dopamine receptors. For example, all
these drugs have a high affinity for 5HT 2A and 5HT2C receptors and, to a lesser
extent, 5HT 1A, 5HT 6 and SHT 7 receptors [202]. For these reasons, several
compounds have been developed with a high affinity for 5HT2 receptors. Of
these, pipamerone, a highly selective 5HT2/dopamine (D)2 antagonist, has been
shown to have an antiautistic, disinhibiting and resocializing effect and a low
frequency of EPSs [203]. By contrast, MDL 100,907 (Hoest/Marion Roussel,
New Jersey, USA), a compound largely lacking D2 antagonism but which is a
potent 5HT 2A antagonist, while showing promising antipsychotic properties in
preclinical studies, was not found to be as effective as haloperidol in the
treatment of schizophrenia. Similarly, the D4/5HT2A antagonist fananserin
lacked clinical efficacy despite a promising experimental profile [204]. It is not
without interest that several selective D4 antagonists have failed to show clinical
efficacy in the treatment of schizophrenia, despite the evidence that some typical
(e.g. haloperidol) and atypical (e.g. clozapine) agents increase the density of these
receptors following chronic treatment [205]. Thus, it would appear that the
5HT2A antagonism, together with D2 antagonism, may contribute to the atypical
profile of the new antipsychotic drugs, but the 5HT2A antagonism alone does not
appear to confer antipsychotic effects.
Adrenergic receptors and antipsychotic action
While most schizophrenia research has focused on the importance of dopamine,
there is evidence that hyperactivity of the noradrenergic system also occurs in
these patients. There is clinical evidence that the alpha-2 adrenoceptor
antagonists can improve memory in patients with schizophrenia, and that
SGAMs are more effective than typical neuroleptics in normalizing the cognitive
deficits in these patients, presumably because of their actions on alpha-2
receptors [206]. There is also evidence that both alpha-1 adrenoceptors and
5HT2A receptor stimulation of the prefrontal cortex can cause cortical dysfunction
[207]. As many of the SGAMs are antagonists of both alpha-1 and 5HT2A
receptors, such actions could help to explain the improved cognitive function
seen with these drugs. So far, such clinical and experimenta1 findings have not
been extended to the development of novel antipsychotic drugs with a view to
enhancing the improved cognitive action of SGAMs.
Glutamatergic Receptors And Antipsychotic Action
Recent experimental and clinical evidence suggests that the glutamatergic system
plays a vital role in the pathophysiology of schizophrenia and may also
contribute to the efficacy of SGAMs [208]. In post-mortem brains from patients
with schizohrenia, changes in RNA expression of the kainate and ?-amino-3hydroxy-5-methyl-4-isoxa-zolepropionic acid (AMPA) metabotrophic receptors
and in the subtypes of the ionotrophic NMDA receptors have been reported.
Clozapine has been shown to decrease the densities of some of the NMDAreceptor subtypes, a change which correlates with an increase in the
metabotrophic receptors [200,201]. However, it would appear that other
subtypes of the NMDA receptor increase in response to effective therapies. Such
findings underpin the application of drugs that activate the NMDA receptors as
possible novel antipsychotic medications. Thus, glycine and d-serine, as NMDA
receptor agonists, have been studied for their potential antipsychotic effects.
High doses of glycine (30-60 g/day) have been shown to improve the negative
symptoms in schizophrenia [209]. d-Serine, a full agonist at the NMDA-receptor
glycine site, was also reported to improve the negative symptoms, psychosis and
cognitive functioning of patients with schizophrenia [210], while d-cycloserine, a
partial agonist of the glycine site, was shown to improve the negative symptoms
when added to conventional neuroleptic drugs, without improving cognitive
function [208]. These preliminary clinical findings support the possible value of
drugs that enhance glycine-receptor function, at least in the treatment of the
negative symptoms of schizophrenia.
Several compounds that act as positive modulators of the AMPA receptors have
also been studied. Of these, CX516 (AMPALEX, Novartis, Basel, Switzerland)
was shown to improve the attention, memory and distractibility of patients, and
also produced a significant improvement in cognitive function [211,212]. Thus, it
would appear that agonists of the glycine site on the NMDA receptor, and
modulators of the AMPA receptors, may prove to be novel antipsychotic
medications in the future.
Sigma receptors and antipsychotic action
Since the discovery that the psychotomimetic benzomorphans act on sigma
receptors in the brain, while some antipsychotic drugs such as haloperidol and
remoxipride act as sigma-receptor antagonists, attention has been directed
towards the development of sigma-receptor antagonists as potential
antipsychotic agents [213]. Several sigma antagonists have been clinically tested
over the past 17 years. However, most trials to date involve few patients; few
studies have been replicated and many of the first sigma agents to be tested were
also antagonists of 5HT2 receptors (e.g. rimcazole, tiosperone). Of the more
specific sigma antagonists, panamesine (EMD 57445) has been the subject of three
trials involving a small number of patients. Panamesine was found to exert acute
antipsychotic effect, at least in some patients [214]. Eliprodil (SL 820715) is also a
sigma ligand but, in addition, has NMDA-antagonistic properties that could limit
its efficacy. In an open trial, eliprodil was shown to improve the negative
symptoms in a small number of patients [215]. A potent selective sigma
antagonist, SR-31742, is also currently undergoing clinical trials in schizophrenia,
the results of which may provide conclusive evidence regarding the
antipsychotic potential of such drugs. Thus it appears that there is some evidence
that sigma antagonists may have antipsychotic potential, but more detailed
clinical studies are required to substantiate this.
GABAaergic receptors and antipsychotic action
Experimental studies have demonstrated that the y-aminobutyric acid (GABA)-A
receptors have an inhibitory action on the dopaminergic system while the GABAB receptors have an indirect stimulatory action on these receptors. Thus, it is
anticipated that GABA-A-receptor agonists might be of some value in the
treatment of schizophrenia. Of the drugs available, the benzodiazepines have
been reasonably well studied and have been shown to be beneficial in the
treatment of both positive and negative symptoms [216]. However, such drugs
are limited by their abuse potential and because tolerance of their therapeutic
effects develops. Valproate acts as a GABAmimetic by inhibiting the
metabolizing enzyme GABA transaminase, thereby enhancing central
GABAergic tone. The evidence for the efficacy of valproate has been reviewed
[217]: it is suggested that the drug is of limited value as sole therapy for the
treatment of schizophrenia, but it could be an effective medication for adjunctive
treatment. Thus, anticonvulsant drugs with GABAergic properties may be
promising candidates for the future.
Polyunsaturated fatty acids and antipsychotic action
There is evidence that patients with schizophrenia have a deficiency in omega- 3
fatty acids in their neuronal membranes [218]; clozapine has been shown to
increase the concentration of such fatty acids in red blood cell membranes,
suggesting that the SGAMs may contribute to the normalization of neuronal
membrane function by increasing their polyunsaturated fatty acid content. This
forms the basis of the phospholipid and membrane hypotheses of schizophrenia
[219]. Two open studies in which fish oils rich in omega-3 fatty acids were given
over a period of 6 weeks showed an improvement in both positive and negative
symptoms and a marked reduction in the Abnormal Voluntary Movement
scores; there was a strong correlation between the clinical improvement and the
increase in the omega-3 fatty acids in the red blood cell membranes [220]. These
studies have been extended to show a marked and sustained response to
treatment over a 1-year period [221]. However, recently two well-designed,
controlled, double-blind studies were reported, with differing results. Fenton et
al. [222] added omega-3 fatty acids or a placebo to the antipsychotic regimens of
87 patients with schizophrenia and schizoaffective disorder for 16 weeks and
found no difference between adjunctive treatments. Emsley et al. [223] added
omega-3 fatty acids or a placebo to the existing antipsychotic treatments of 40
patients with schizophrenia for 12 weeks and found that the patients taking
omega-3 fatty acid had significantly reduced PANSS positive and negative
scores. Thus, omega-3 fatty acids may provide an important and novel approach
to the development of antipsychotic drugs in the future.
Dopamine-receptor partial agonists
The need to develop novel antipsychotic drugs that have improved therapeutic
action and reduced side-effects has stimulated an interest in dopamine receptor
full antagonists and partial agonists. This approach has been stimulated by the
observation that dopaminergic neurons have autoreceptors that are sensitive to
the inhibitory action of dopamine [224]. In support of the view that dopamine
agonists and partial agonists exert antipsychotic action [225,226], studies have
shown that apomorphine and N-propyl-norapomorphine have modest activity;
more recently, the partial agonist preclamol [(-)-3PPP] has also been shown to
have some therapeutic activity. The potential advantage of partial dopamine
agonists lies in the fact that their activity can vary from that of a full agonist to
that of an antagonist depending on their intrinsic activity and the local
concentration of dopamine at the receptor sites. Despite the extensive
experimental and clinical studies undertaken on preclamol, recent work has
demonstrated that tachyphylaxis occurs in response to the action of the drug
following its chronic administration [227]. More recently, aripiprazole, a
quinolinone derivative, has received considerable attention [228]. Aripiprazole is
a partial dopamine agonist with a high affinity for D2 and D3 receptors and with
a moderate affinity for 5HT1A, 5HT2A and histamine-1 receptors. Experimental
studies have shown that it has low intrinsic activity, or partial agonist/antagonist
activity, at dopamine receptors. There is also experimental evidence that
aripiprazole acts as a full agonist at dopamine autoreceptors, but acts as a relative
antagonist at post-synaptic receptors. Its long half-life (60 h), preliminary clinical
evidence of its antipsychotic efficacy, its low cardiotoxicity and its favourable
safety profile [229,231] indicate that this approach to the development of novel
antipsychotic medications opens up new possibilities for the future.
Iloperidone is a new antipsychotic drug currently undergoing clinical
development. In radioligand studies, iloperidone shows a high affinity for D2 and
D4 receptors and, to a lesser extent, D1 and D2 receptors. In addition, it shows a
very high affinity for 5HT2A receptors and to a lesser extent, 5HT1A, 5HT1B,
5HT2C and 5HT6 receptors. The most unique pharmacological aspect of
iloperidone is its very high affinity for alpha-2 adrenoreceptors. This effect might
contribute to the increased release of adrenaline and dopamine from the
prefrontal cortex; clozapine has a somewhat similar effect. Results from a
randomized, double-blind, multicenter study show that iloperidone has an
efficacy comparable to that of haloperidol but with fewer EPSs and no elevation
of prolactin.
III
Other developments relevant to the use of secondgeneration antipsychotic medications
Recent meta-analyses
In an effort to gain a coherent and comprehensive view of the effectiveness of
SGAMs, statistical reviews using meta-analytic methods have been carried out.
Meta-analyses of a series of studies can be useful in aggregating the results of
individual studies and producing a summary statistic bearing on questions of
comparative effectiveness of treatments or classes of treatments. In the case of the
SGAMs, the comparisons have been between one SGAM and comparators (a
placebo and the antipsychotic drug), and between SGAMs and FGAMs. The
advantage of meta-analyses is that by aggregating studies they can enhance
statistical power. Thus, while some individual studies may be large enough (in
terms of numbers of subjects per treatment arm) to reach statistically significant
differences, the combining of studies enables small or moderate effects to be
detected. In addition, meta-analyses provide a measure of the consistency of
treatment effects and their magnitude. The major limitation of meta-analyses is
that they are wholly dependent on the quality of the constituent studies and the
data therein. They also can be subject to over-interpretation or misinterpretation.
The Register of Trials of the Cochrane Schizophrenia Group maintains a database
of trials on antipsychotic drugs, and periodically performs meta-analyses of their
results (http://www.cochranelibrary.com). They have performed reviews of all
of the SGAMs in comparison with placebos, FGAMs and other SGAMs. Overall,
these reviews have found that the SGAMs are clearly superior to placebos and
mostly equivalent to the FGAMs, with the exception of clozapine - which is
clearly superior to FGAMs, but there is insufficient evidence to evaluate the
comparative effectiveness of the current SGAMs. A brief review of the recent
meta-analyses of SGAMs follows.
Leucht et al. [235] reviewed studies that evaluated the efficacy and tolerability of
olanzapine, risperidone, quetiapine and sertindole. The results of their metaanalysis indicated that the SGAMs were superior to placebos; quetiapine and
sertindole were as effective as haloperidol, and olanzapine and risperidone were
slightly more effective than haloperidol in the treatment of global schizophrenic
symptoms. With respect to negative symptoms, olanzapine and risperidone were
slightly superior to haloperidol. All the SGAMs were associated with less
frequent use of antiparkinsonian medication than haloperidol.
Geddes et al. [140] reported, for the National Schizophrenia Guideline
Development Group, the results of a meta-analysis comparing all SGAMs and
FGAMs on overall symptom scores and rates of drop-out, which they considered
a proxy for tolerability, particularly of EPSs. They found substantial
heterogeneity in the results, which was partially accounted for by the dose of the
SGAM comparator used: when the dose used was up to 12 mg/day in
haloperidol equivalents, FGAMs and SGAMs were equivalent on symptom
reduction and tolerability. Based on this, they concluded that the FGAMs should
be used as the initial treatment unless a patient has not responded to, or
tolerated, an FGAM. However, the National Institute for Clinical Excellence
Guidelines on the use of newer (atypical) antipsychotic drugs for the treatment of
schizophrenia (www.nice.org.uk) - an evidence-based appraisal - included the
following in its guidance recommendations: “It is recommended that the oral
atypical antipsychotic drugs amisulpiride, olanzapine, quetiapine, risperidone
and zotepine are considered in the choice of first-line treatments for individuals
with newly diagnosed schizophrenia” (see Appendix 6).
Chakos et al. [236] reviewed studies that compared the efficacy and tolerability of
FGAMs and SGAMs in treatment-resistant schizophrenia. The results of this
meta-analysis indicated that clozapine was superior to FGAMs in efficacy on
measures of psychopathology and compliance and in terms of EPSs. However,
the magnitude of this effect was not consistently robust. The data on efficacy of
other SGAMs in the treatment of patients with refractory schizophrenia was
inconclusive.
Leucht et al. [66] reviewed 18 studies that compared the efficacy and tolerability
of amisulpride with placebos and FGAMs. The results indicated that amisulpride
was consistently more effective than placebos and FGAMs on global
schizophrenic symptoms and negative symptoms. Amisulpride also had lower
rates of antiparkinsonian medication usage and fewer drop-outs due to adverse
events.
Recent large-scale investigations
The need to obtain relevant data on treatments for mental illness is so great that
large-scale investigations of treatment effectiveness have been undertaken by
governments and industry. The Clinical Antipsychotic Trials of Intervention
Effectiveness, a major research initiative in the US by the National Institute of
Mental Health, are assessing the effectiveness of the SGAMs in a broad range of
patients with schizophrenia and in patients with Alzheimer’s disease. In
Germany, Medical Networks in Medicine has undertaken significant research. A
consortium of pharmaceutical companies supports the European First Episode
Treatment Study in Schizophrenia. Novartis has recently completed a large
international study of suicidal behavior in schizophrenia (InterSePT) [234]. In the
US, Pfizer is conducting a large post-marketing cardiac surveillance study
(Zodiac).
Adjunctive therapy
Despite the relative lack of study of the use of adjunctive medications to augment
the effects of antipsychotic drugs, the practice of combining medications is very
common. This includes the use of mood-stabilizers, antidepressants, anxiolytics,
cholinomimetics or marketed experimental agents (e.g. guanfacine, glycine) with
FGAMs and SGAMs and the combination of multiple antipsychotic drugs
[212,235].
One of the few controlled studies of combined treatments with SGAMs was
recently reported by Casey et al.[236]. This was a 4-week RCT under double
blind conditions in which valproate or a placebo was combined with either
risperidone or olanzapine in patients with acutely exacerbated schizophrenia
patients. Valproate plus the SGAM were found to produce a significantly faster
rate of improvement than the SGAM plus the placebo.
Experimental data also have been developed on the potential adjunctive efficacy
of agents (including glycine, serine and d-cycloserine) that allosterically
modulate the NMDA receptor and enhance its activity. The best evidence exists
for glycine, and the therapeutic effects appear to be reflected predominantly in
negative symptoms [237].
Two meta-analyses of adjunctive treatments have recently been carried out on
adjunctive treatment with carbamazepine [66] and beta blockers [238].
Developments concerning regulatory procedures
Since the time that the Technical Review was published, there have been a
number of regulatory changes in various countries. Indications and safety
warnings outlined in package inserts continue to vary considerably from country
to country, mostly because of different licensing procedures and legal
requirements. Some countries have added new indications for drugs already on
the market, and some have added warnings to the package inserts. Thus, for
example, the intramuscular preparation of ziprasidone is now licensed in Europe
but not in the US, while olanzapine has an indication for bipolar mania in the US
and many European countries but not in Asia. Similarly, the long-acting
injectable form of risperidone is licensed in parts of Europe but not yet in the US.
The same is true for warnings in the package inserts. In the US, the labelling
language for ziprasidone has been modified by the specification of additional
medications that prolong the electrocardiographic QT interval and should not be
co-administered with ziprasidone. In Japan, the package insert for olanzapine has
been modified to include a warning about patients experiencing marked
increases in blood glucose levels, a recommendation that observations such as
measurement of blood glucose may be indicated for patients with diabetes or
with risk factors for diabetes, and a contra-indication for the use of olanzapine in
patients with diabetes mellitus and those who have a history of diabetes. In the
US, new package labelling language has been added to indicate that clozapine is
associated with an increased risk of myocarditis, particularly in the first month of
the clozapine therapy. The company producing the medication provided
information on appropriate clinical monitoring. The revised label notes that
clozapine should be promptly discontinued in patients in whom myocarditis is
suspected.
The scope of this document does not permit a detailed and full description of all
the regulatory changes, so it is recommended that readers consult the specific
regulations in the countries of interest to them.
IV
Recommendations
Having reviewed the additional evidence and the comments and suggestions
made during the national meetings, the Task Force re-examined the ideas and
recommendations included in the Technical Review and agreed that no changes
to these recommendations are necessary. The recommendations are therefore
reprinted here, with only very minor changes, for ease of reference.
( 1)
The currently available evidence indicates that the SGAMs have significant
effects in reducing the positive symptoms of schizophrenia. They also
appear to improve negative symptoms, affective symptoms and cognitive
deficits, which are prominent in patients treated with conventional
antipsychotic medications. Although evidence from controlled clinical
trials is less firm for the latter types of symptoms than for positive
symptoms, clinical experience, post-hoc analyses of controlled studies, and
reports from uncontrolled studies support this view. In addition, the
available evidence suggests potential advantages for the SGAMs, both
individually and as a class, for suicidal and aggressive behavior, and for
relapse prevention and treatment adherence. The available evidence also
strongly demonstrates that the SGAMs have lower side-effect risks in terms
of EPSs, TD and, in most cases, the elevation of prolactin and its consequent
endocrine effects. At the same time, clinical experience with some of the
SGAMs demonstrates increased risks for weight gain and suggests possible
risks for elevations in blood glucose, cholesterol and triglycerides.
However, the extent of these risks and their potential medical consequences
in terms of morbidity and mortality are not yet known. As additional
information about the side-effects of the SGAMs is developed, it is likely
that new standards of care will be developed that include monitoring ofthe
potential for medical morbidity. Clinical experience and preliminary
evidence indicate that the SGAMs are better received by patients, who are
willing to take them more regularly and report that their quality of life
improved after they started treatment with the medications [239].
Thus, the evidence to date indicates that the SGAMs represent a useful
addition to the array of treatment options for persons with psychotic states,
primarily schizophrenia, and should be among the options of initial
treatment. More scientific evidence on their effectiveness would be
welcome, but patients should have access to these medications now.
Furthermore, the use of SGAMs should be the first choice of treatment for
certain groups of patients, including those with Parkinson’s disease, those
with histories of EPS sensitivity, and perhaps those with tardive
dyskinesia. A change from a FGAM to a SGAM should be made for
patients who experience mild akathisias with a therapeutic dose of a
conventional drug, as well as for women with menstrual irregularities, due
to elevated prolactin levels, on conventional antipsychotics. It also seems
that these drugs are more likely to be tolerated by more drug-sensitive,
younger and first-episode patients and the elderly.
(2)
More scientific information from controlled trials and clinical observations
is urgently needed in several areas. First, more comparisons between the
SGAMs are needed to establish their differential risk/benefit profiles.
Also, more comparisons of SGAMs with FGAMs, particularly at low and
equivalent doses, are needed.
Research is needed on the use of the
SGAMs in children and adolescents with psychotic and other disorders,
and on the effects of these substances on women, elderly patients and
patients with other concurrent physical and mental disorders. More
information is also needed on the long-term effects of treatment (in terms
of safety and effectiveness) and the effects of these medications on people
belonging to different geographically, culturally and genetically defined
groups. It is of particular importance to ensure that developing countries
participate in studies assessing these therapeutic agents.
The pharmaceutical industry contributes significant funding for research
leading to the development of new medications, and on the assessment of
the effects of the medications. The need to obtain relevant data on
treatments for mental illness is so great that these efforts will not be
sufficient: governments must find ways to make similar investments in
research on treatment and service-organization.
(3)
The emerging body of information on the efficacy and safety of the
SGAMs, and their increasing use, does not mean that the FGAMs have no
role in the treatment of schizophrenia and other disorders for which their
use is indicated. There are clearly indicated continued uses in the
management of patients with acute agitation, in floridly psychotic
patients, in patients needing long-acting medication forms in which
SGAMs are not widely available, and in patients who are stable and
effectively tolerating treatment with FGAMs.
(4)
The cost of SGAMs is often mentioned as the main reason for restricting
their use. Although the costs of these medications on “per tablet”, daily
and annual-ized bases are significantly higher than those of classical
antipsychotic drugs, it should be remembered that the cost of medications,
at least in developed countries, represents only a small proportion of the
total cost of health care for these populations (particularly if the treatment
is provided on an in-patient basis). Thus, while medication costs may be
higher, the total cost of treatment with the SGAMs could well be lower
than that of treatment using the FGAMs. Furthermore, according to an
increasing number of reports, improvement of quality of life is greater
when the disease is treated with the SGAMs {240]. Unfortunately, this
feature often does not enter into the calculation of the benefits of
treatment. Indeed, the use of cost as the basis for restricting treatment
with SGAMs is a reflection of the stigma of mental illness: the cost of other
medications, e.g. immunosuppresive drugs or antibiotics, is not viewed in
this manner, because societies consider the transplantation of organs and
the treatment of infectious diseases very important.
In developing countries, despite the growing prevalence of mental
disorders, the financial resources provided by governments for the
treatment of mental illness are extremely low, and most patients have very
low incomes, making it almost impossible for them to purchase SGAMs.
At the same time, however, by adopting UN Resolution 119, governments
of both developed and developing countries have recognized that
appropriate treatment of mental illness is a human right which should be
respected.
Thus, the provision of effective treatment is not simply a medical matter,
nor is it a proposition that should be decided purely on the basis of
economic arguments. Ensuring that people with mental illness receive
treatment that will help them is an ethical imperative of any society,
regardless of the level of its industrial development. At the same time, the
current trend toward extending the responsibility for health care from
health professionals to governments, patients, and patients’ families, as
well as the health-care industry and health-care professionals, means that
the resolution of the issue of the cost of medications cannot be left solely to
any one of these agencies. Governments, the health-care industry and the
pharmaceutical industry will all have to consider increasing their
contributions to the provision of mental health care. This is especially true
in countries with severely restricted resources, for example in Eastern
Europe and large parts of the developing world.
(5)
Improved education and refresher training about the SGAMs for
physicians of all types, as well as for other health-care workers, are among
the obvious tasks of health -care authorities and non-governmental
organizations, along with an emphasis on quality of care. In particular, it is
important for physicians to know what to expect from the SGAMs; this
may prevent unnecessary prescriptions and ease the process of
authorizing the use of these medications. In addition, as greater awareness
of their therapeutic benefits and side effect profiles develops, specific uses
and new standards of care will be developed about which clinicians will
need to be educated.
(6)
Care-givers also need information and support, and psychiatrists can help
by referring people with mental illnesses and their care-givers to self-help
organizations. Well-informed, responsibly assertive family members and
other care-givers and well-informed patients could significantly improve
the outcome of mental illness. Thus, the strengthening of groups of
patients and family organizations presents significant potential for better
use of available treatments, better monitoring of their effects, and overall
improvement of care for people with mental illness.
(7)
The World Health Organization can play a key role in improving the
quality of care and in optimizing the use of antipsychotic medications. In
particular, it is important for this unique intergovernmental organization
in the field of health to strengthen its ties with professional and nonprofessional organizations in the area of mental health in order to provide
the best advice to governments about mental health programme
development. The recommendations that the World Health Organization
makes concerning the list of essential drugs are of special importance for
health-care policies and programmes worldwide. Review, and updating,
of the list should be carried out in consultation with organizations
specializing in the field of mental health, and should take into account new
developments in the field. The list of essential drugs for the treatment of
mental disorders has remained almost unchanged over the two decades
since its first publication, despite the considerable advances of
psychopharmacotherapy in the same period. A regular review of this list
of drugs with professional and non-professional non-governmental
organizations is therefore a matter of priority. The World Health
Organization can also play an important role in the training of health
professionals about mental health matters and new treatments, in
collaboration with non-governmental organizations.
(8)
Action by international organizations (whether inter-governmental or
non-governmental), however, cannot replace the initiative and
engagement of national governments and national professional
organizations and agencies. If the opportunities offered by the advent of
the SGAMs are to be utilized, it is essential that, at the national level, all
concerned - patient and family organizations, governments, the industry,
health professionals, the media and the general public – together examine
this and other key statements affecting care, and join hands in building
programmes that will ensure that people with mental illness receive the
best possible care and retain, or find, their place in the community in
which they live.
The review of evidence presented here, as well as any consensus statements
developed on the basis of it, should be reviewed at national level in the light of
socio-economic and cultural specificities, health-care policies and their
implementation, and other locally relevant facts. This review will undoubtedly
lead to the development of country-specific additions and recommendations for
the development of teaching materials relevant to the use of these medications,
research that should be undertaken on matters relevant to the situation in each
country, and legal and administrative measures that will be necessary to
optimize the treatment of mental illness. The results of such reviews at national
level should be made available to other countries in which the Statement is to be
reviewed, so that they can learn from the experience that has been obtained
elsewhere.
Acknowledgements
The WPA gratefully acknowledges the generous contributions by AstraZeneca,
Bristol-Myers Squibb, Eli Lilly and Company, Janssen Pharmaceutica, Knoll AG,
H. Lundbeck A/S, Pfizer, Sanofi-Synthelabo and Servier, which greatly
facilitated the development of this Technical Review.
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APPENDIX 1
LIST OF MEMBERS OF THE TASK FORCE
Dr W. Wolfgang Fleischhacker, Professor of Psychiatry, Department of
Psychiatry, Innsbruck University Clinics, Anichstrasse 35, A-6020 Innsbrück,
Austria
Dr Annette Gjerris, Professor and Chair, Department of Psychiatry, Gentofte
University Hospital, Niels Andersens Vej 65, 2900 Hellerup, Denmark
Dr Ursula Kern, Director and Professor, Head of Neurology, Psychiatry,
Anaesthesiology,Addiction, Clinical Pharmacology II, Federal Institute for
Drugs and Medical Devices Seestrasse 10, D-13353 Berlin, Germany
Dr Martin Knapp, Professor, Personal Social Services Research Unit, London
School of Economics and Political Sciences, Houghton Street, London WC2A
2AE, United Kingdom
Dr Brian E. Leonard, Professor of Pharmacology, National University of
Ireland, Galway, Ireland
Dr Jeffrey Lieberman, Thad and Alice Eure Distinguished Professor of
Psychiatry, Pharmacology and Radiology University of North Carolina
School of Medicine, 7025 Neurosciences Hospital, CB7160 Chapel Hill, NC
27599-7160, USA
Dr Juan J. López-Ibor, Professor of Psychiatry, President, World Psychiatric
Association,Clinica Lopez-Ibor, C./Nueva Zelanda, 44, E-28035 Madrid,
Spain
Mr Bas van Raay, President, EUFAMI, Siegersteeg 2, 7734 PG Vilsteren, The
Netherlands
Dr Norman Sartorius, Professor, HUG Hôpitaux Universitaires de Genève,
Belle-Idée, Bâtiment Le Salève, 2 chemin du Petit-Bel-Air, CH-1225 ChêneBourg/Geneva, Switzerland (Chairman of the Task Force)
Ms Elizabeth Tornquist, University of North Carolina at Chapel Hill, Campus Box #
7160, Chapel Hill, NC 27599-7160, USA
Mrs Esther Twomey, Vice-President EUFAMI, Effoldstown Farm Lusk, IreCounty Fingal, Ireland.
APPENDIX 2
LIST OF EXPERTS INVITED TO COMMENT ON THE DRAFTS
OF THE STATEMENT3_
ACKENHEIL, Manfred
Ludwig-Maximilians-Universität München
Klinikum Innenstadt
D-80336 München, Germany
ALTAMURA, A. Carlo
University of Milan
Istituto di Scienze Biomediche
Ospedale L. Sacco
I-20157 Milano, Italy
AZORIN, Jean-Michel
F-13274 Marseille Cedex 09, France
BAUMANN, Pierre
Unité de Biochimie et Pharmacologie Clinique
CH-1008 Prilly-Lausanne, Switzerland
BELFORT G., Edgard
Presidente, Sección Infantil de APAL
Caracas 1010, Venezuela
BERNER, Peter
14, rue Mayet
F-75006 Paris, France
BITTER, István
Semmelweis University of Medicine
H-1083 Budapest, Hungary
CASSANO, Giovanni
Istituto Clinica Psichiatrica
Universiti degli Studi di Pisa
Ospedale Santa Chiara
I-56100 Pisa, Italy
3
For editorial reasons experts are listed by name and surname without an indication of their
academic title
_
CASSAY, Daniel E.
VA Medical Center
Portland, OR 97201, USA
CHANG, Wen-Ho
Laboratory of Biological Psychiatry
Taipei City Psychiatric Center
Taipei, Taiwan 10510, Republic of China
CHRISTODOULOU, George N.
Department of Psychiatry
Eginition Hospital
11528 Athens, Greece
CROW, Timothy J.
Department of Psychiatry
University of Oxford
Oxford OX3 7JX, UK
CUNNINGHAM OWENS, David G.
University of Edinburgh
Royal Edinburgh Hospital
Edinburgh EH10 5HF, UK
DAVIDIAN, Harmik
Iranian Psychiatric Association
P.O.Box 13185-734
Tehran, I. R. Iran
DEN BOER, Johan A.
Academic Hospital Groningen
NL-9700 RB Groningen, The Netherlands
DICKSON, Ruth
University of Calgary
Calgary, Alberta, Canada T1Y 6J4
DOLLFUS, Sonia
CHU Côte de Nacre
F-14033 Caen Cedex, France
ECONOMOU, Marina
Department of Psychiatry
Eginition Hospital
1528 Athens, Greece
EMSLEY, Robin A.
University of Stellenbosch
Cape Town, South Africa
FALKAI, Peter
Psychiatrische Klinik der Universität
D-53105 Bonn
FARDE, Lars
Karolinska Institute
Stockholm, Sweden
FOLNEGOVIC-ŠMALC, Vera
Psihijatrijska Bolnica
41090 Vrap_e - Zagreb, Croatia
FÜREDI, Jan
Postgraduate Medical University
Department of Psychiatry and Clinical Psychology
H-1281 Budapest, Hungary
GAEBEL, Wolfgang
Direktor, Psychiatrische Klinik
Postfach 12 05 10
D-40605 Düsseldorf, Germany
GERLACH, Jes
St. Hans Hospital
DK-4000 Roskilde, Denmark
GLAZER, William
Harvard Medical School
Massachusetts General Hospital
New York, NY 10013, USA
HELMCHEN, Hahnfried
Reifträgerweg 30A
D-14129 Berlin, Germany
HENN, Fritz A.
Central Institute of Mental Health
POB 12 21 20
J 5, 68159 Mannheim, Germany
HSIAO John
Adult Geriatric Treatment and Preventive
Intervention Research Branch
DSIR/NIMH
Bethesda, MD 20892-9635, USA
JAREMA, Marek
Head, Department of Psychiatry (III)
Institute of Psychiatry and Neurology
02-957 Warszawa, Poland
JOHANNESSEN, Jan Olav
Racoland Psychiatric Services
4004 Stavanger, Norway
JOHNSTONE, Eve C.
Department of Psychiatry
The University of Edinburgh
Edinburgh EH10 5HF, Scotland
KANE, John M.
Hillside Hospital
Department of Psychiatry
Glen Oaks, NY 11004, USA
KASPER, Siegfried
Department of General Psychiatry
University of Vienna
A-1090 Vienna, Austria
KATSCHNIG, Heinz
Vorstand der Universitätsklinik für Psychiatric Psychiatrie
Währinger Gürtel 18-20
A-1090 Vienna, Austria
KRASNOV, Valery N.
Moscow Research Institute of Psychiatry
Poteshnaya 3
107258 Moscow, Russia
KULHARA, Parmanand
Postgraduate Institute of Medical Education and Research
Chandigarh-160 012, India
LAMBERT, Tim
Centre for Cultural Studies in Health
University of Melbourne
Level 2, Bolte Wing
St Vincent’s Hospital
Fitzroy, Victoria 3065, Australia
LECRUBIER, Yves
INSERM U 302
Hôpital La Salpêtrière
F-75651 Paris Cedex, France
LEGGATT, Margaret
President, World Schizophrenia Fellowship
for Schizophrenia and Allied Disorders
29, Mary Street
North Carlton 3054, Victoria, Australia
LEHMANN, Anthony F.
Center for Mental Health Services Research
685 West Baltimore Str. MSTF 300
Baltimore, MD 21201, USA
LIBIGER, Jan
Psychiatric Clinic of
Charles University Medical School
University Hospital
CZ-500 05 - Hradec Králove, Czech Republic
LINDSTRÖM, Leif
Psykiatriska forskningsenheten Centrallasarettet
S-721 89 Vasteras, Sweden
LOGA, Slobodan
Psychiatric Association of Bosnia-Herzegovina
ul. Bolnicka 25
Sarajevo, Bosnia & Herzegovina
LÖNNQVIST, Jouko
National Institute of Mental Health
Mannerheimintie 166
FIN-00300 Helsinki, Finland
MAJ, Mario
Clinica Psichiatrica
1a Facoltà di Medicine e Chirurgia
Policlinico Universitario
I-80138 Napoli, Italy
MARDER, Stephen
Director, Mentall Illness Research,
Education and Clinical Center of the
VA Desert-Pacific Healthcare Network
West Los Angeles
Los Angeles, CA 90073, USA
McEvoy, Joseph
Duke University Medical Center
Division of Biological Psychiatry
John Umstead Hospital
Butner, NC 27509, USA
MELLE, Ingrid
Division of Psychiatry
Ullevaal Hospital
N-0407 Oslo, Norway
MOSOLOV, S. N.
Chief, Department of Psychopharmacology
Moscow Research Institute of Psychiatry
107258 Moscow, Russia
MOUSSAOUI, Driss
Centre Psychiatrique Universitaire Ibn Rushd
Casablanca, Morocco
MURRAY, Michael C.
The Keri Neale Foundation
Mariazell, 5 Castle Was
Stafford, ST16 1BS, UK
MURTHY, Dr R. Srinivasa
Department of Psychiatry
National Institute of Mental Health and Neuro Sciences
Bangalore-560 029, India
NABER, Dieter
Klinik für Psychiatrie und Psychotherapie
der Universität Hamburg
Martinistrasse 52
D-20246 Hamburg, Germany
ODEJIDE, A. Olabisi
Department of Psychiatry
University College Hospital
PMB 5116
Ibadan, Nigeria
OKASHA, Ahmed M.F.
Ain Shams University
3, Shawarby Street
Kasr-el-Nil, Cairo, Egypt
OLIE, Jean-Pierre
Hôpital Sainte Anne
Pavillon Cabanis
4, rue Cabanis
F-75004 Paris, France
PHILLIPS, Michael
Beijing Hui Long Guan Hospital
Beijing 100096, P.R.China
PICHOT, Pierre
24, rue des Fossés Saint-Jacques
F-75005 Paris, France
REMINGTON, Gary
The Clark Institute of Psychiatry
Schizophrenia Division
Toronto, Ontario
Canada M5T 1RS
RYBAKOWSKI, Janusz
Department of Adult Psychiatry
University of Medical Sciences Poznan
60572 Poznan, Poland
SARACENO, Benedetto
Director, Department of Mental Health
World Health Organization
CH-1211 Geneva, Switzerland
SCHÖNY, Werner
Head, Section of Psychiatry
Österreischischer Nervenärzte und Psychiater
Wagner-Jauregg-Krankenhaus
A-4020 Linz, Austria
SEDVALL, Goran
Department of Clinical Neurosciences
Psychiatry Section
Karolinska Hospital
S-17176 Stockholm, Sweden
SHARMA, Tonmoy
Senior Lecturer in Psychiatry
Head, Section of Cognitive Psychopharmacology
Institute of Psychiatry
De Crespigny Park, Denmark Hill
London SE5 8AF, UK
SLACK, Joel
Respect International, Inc.
Montgomery, Alabama 36124, USA
SLOOF, C. J.
Dutch Schizophrenia Foundation
Postbus 130
NL-3769 ZJ Soesterberg
STAHL, Steven M.
Director, Clinical Neuroscience Research Center
8899 University Center Lane,
Suite 130
San Diego, CA 92122, USA
STEFANIS, Costas N.
Department of Psychiatry
Eginition Hospital
Athens University Medical School
11528 Athens, Greece
TAMMINGA, Carol
University of Maryland
Maryland Psychiatric Research Center
P.O.Box 21247
Baltimore, Maryland 21228, USA
TIGANOV, A.
National Mental Health Research Centre
Academy of Medical Sciences
113152 Moscow, Russia
VAN OS, Jim
Department of Psychiatry and Neuropsychology
European Graduate School of Neuroscience
Maastricht University
NL-6200 MD Maastricht, The Netherlands
WADDINGTON, John
Department of Clinical Pharmacology
Royal College of Surgeons in Ireland
St. Stephanis Green
Dublin 2, Ireland
WHITEFORD, Harvey
The World Bank
Health, Nutrition and Population
Human Development Network
Washington, DC 20433, USA
WILDSCHUT, Glenda
9 Wembley Avenue
Plumstead 7800, Republic of South Africa
APPENDIX 3
LIST OF ORGANIZATIONS CONSULTED
Member Societies of WPA
Argentinean Association of Psychiatrists
Foundation for Interdisciplinary Investigation of Communication
Armenian Association of Psychiatrists & Narcologists
Royal Australian and New Zealand College of Psychiatrists
Austrian Society of Neurologists & Psychiatrists
Azerbaijan Psychiatric Association
Bangladesh Association of Psychiatrists
Barbados Association of Psychiatrists
Byelorussian Psychiatric Association
Royal Society of Mental Medicine of Belgium
Society of Flemish Neurologists & Psychiatrists (Belgium)
Bolivian Society of Psychiatry
Psychiatric Association of Bosnia-Herzegovina
Brazilian Association of Psychiatry
Psychiatric Association of Rio de Janeiro State
Society of Psychiatry of Rio Grande do Sul (Brazil)
Bulgarian Psychiatric Association
Canadian Psychiatric Association
Society of Neurology, Psychiatry & Neurosurgery (Chile)
Chinese Society of Psychiatry
Hong Kong College of Psychiatrists
Colombian Association of Psychiatry
Costa Rican Psychiatric Association
Croatian Psychiatric Association
Cuban Society of Psychiatry
Cyprus Psychiatric Association
Czech Psychiatric Society
Danish Psychiatric Association
Dominican Society of Psychiatry
Ecuadorian Association of Psychiatry
Egyptian Psychiatric Association
Salvadorean Association of Psychiatry
Estonian Psychiatric Association
Finnish Psychiatric Association
French Association of Psychiatrists in Private Practice.
French Association of Psychiatry
French Scientific Association of Psychiatrists in Public Service
International Society of Psychopathology of Expression (France)
Medical Psychologic Society
The Psychiatric Evolution (France)
Georgian Psychiatric Association
German Society of Psychiatry, Psychotherapy and Neurology
Ghana Psychiatric Association
Hellenic Psychiatric Association
Hellenic Society of Neurology and Psychiatry
Guatemalan Psychiatric Association
Honduran Society of Psychiatry
Hungarian Psychiatric Association
Iranian Psychiatric Association
Icelandic Psychiatric Association
Indian Association for Social Psychiatry
Indian Psychiatric Society
Indonesian Psychiatric Association
Iraqi Society of Psychiatrists
Israeli Psychiatric Association
Italian Association for Research in Schizophrenia
Italian Psychiatric Association
Japanese Society of Psychiatry & Neurology
Jordan Association of Psychiatrists
Kazakh Association of Psychiatrists & Narcologists
Korean Neuropsychiatric Association
Kuwait Psychiatric Association
Kyrgyz Science and Practical Community of Psychiatrists
Latvian Psychiatric Association
Lebanese Psychiatric Association
Lithuanian Psychiatric Association
Luxembourguese Society of Psychiatry, Neurology & Psychotherapy
Psychiatric Association of Macedonia (FYROM)
Malaysian Psychiatric Association
Mauritius Psychiatric Association
Mexican Psychiatric Association
Mexican Society of Neurology & Psychiatry
Moroccan Society of Psychiatry
Netherlands Psychiatric Association
Nicaraguan Psychiatric Association
Association of Psychiatrists in Nigeria
Norwegian Psychiatric Association
Pakistan Psychiatric Society
Papua New Guinea Psychiatric Association
Paraguayan Society of Psychiatry
Peruvian Psychiatric Association
Philippine Psychiatric Association
Polish Psychiatric Association
Portuguese Association of Psychiatry
Portuguese Society of Psychiatry and Mental Health
Panamanian Society of Psychiatry
Association of Free Psychiatrists of Romania
Romanian Psychiatric Association
Independent Psychiatric Association of Russia
Russian Society of Psychiatrists
Society of Psychopathology and Mental Hygiene of Dakar (Senegal)
Singapore Psychiatric Association
Slovak Psychiatric Association
Psychiatric Association of Slovenia
South African Society of Psychiatrists
Spanish Association of Neuropsychiatry
Spanish Society of Psychiatry
Swedish Psychiatric Association
Swiss Society of Psychiatry
Syrian Arab Association of Psychiatrists
Taiwanese Society of Psychiatry
Psychiatric Association of Thailand
Tunisian Society of Psychiatry
Turkish Neuro-Psychiatric Association
Ukraine Scientific Society of Neurologists, Psychiatrists & Narcologists
Ukrainian Psychiatric Association
The Royal College of Psychiatrists
American Psychiatric Association
Society of Psychiatry of Uruguay
Venezuelan Society of Psychiatry
Yemen Psychiatrists & Neurologists Association
Yugoslav Association of Psychiatric Institutions (YUKO)
Yugoslav Psychiatric Association
WPA Affiliated Associations
Danubian Psychiatric Association
Francophone International Federation of Psychiatry
Global Alliance of Mental Illness Advocacy Networks (GAMIAN)-Europe
International Association of Ethnopsychologists & Ethnopsychiatrists
Latin American Psychiatric Association (APAL)
Romanian League for Mental Health
Society for Settlement of Physically & Mentally Disabled
World Association for Dynamic Psychiatry
Other Nongovernmental Organizations:
Collegium Internationale Neuro-Psychopharmacologicum (CINP)
European College of Neuropsychopharmacology (ECNP)
Federación Latinoamericana de Psiquíatria Biológica
World Association for Psychiatric Rehabilitation (WAPR)
World Federation of Societies of Biological Psychiatry (WFSBP)
International Union of Users of Psychiatric Services
European Network of (Ex-)Users and Survivors of Psychiatry
Global Alliance of Mental Illness Advocacy Networks (GAMIAN)
Governmental Organizations:
World Health Organization
Pharmaceutical Companies:
AstraZeneca
Bristol-Myers Squibb
Eli Lilly and Company
Janssen Pharmaceutica
Knoll AG
H. Lundbeck A/S
Pfizer
Sanofi-Synthelabo
Servier
APPENDIX 4
LIST OF NATIONAL MEETINGS
National meetings that have reviewed the second draft of the Consensus
Statement are listed:
Berlin, Germany, 10 March 2000
Madrid, Spain, 25 April 2000
Prague, Czech Republic, 26 May 2000 (also included Slovak Republic
representatives)
Buenos Aires, Argentina, 18 September 2000
Jakarta, Indonesia ,11 October 2000
Bucaramanga, Colombia, 15 October 2000
Ipoh, Malaysia, 15 October 2000
Melbourne, Australia, 16 October 2000
Caracas, Venezuela ,17 October 2000
Singapore, 21 October 2000
Hong Kong, China, 30 October 2000; Beijing, China, 28 February 2001
Asunción, Paraguay, 15 November 2000
Seoul, Korea, 16 November 2000
Montevideo, Uruguay, 20 November 2000
Tartu, Estonia ,25 November 2000
Sao Paulo, Brazil, 27 November 2000
Santiago, Chile, 28 November 2000
Copenhagen, Denmark, 18 January 2001
Warsaw, Poland, 17 May 2001; follow-up meeting, 5 June 2002
Helsinki, Finland, 18 May 2001
Johannesburg, South Africa , 20-21 August 2001
Brijuni, Croatia, 18 October 2001
Tokyo, Japan, 29 February 2002
The following meetings of presidents of psychiatric societies were
convened for the purpose of planning national meetings:
Kyoto, Japan, 10 April 2000 (presidents of psychiatric societies in Asia)
Madrid, Spain, 25 April 2000 (presidents of psychiatric societies in Latin
America)
Copenhagen, Denmark, 22 August 2000 (presidents of psychiatric
societies in Nordic countries)
APPENDIX 5: Partial list of guidelines for the treatment of
schizophrenia and related psychotic states, 1991-2001, examined
in the preparation of the Technical Review and its Update
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3
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Gournay K, Beadsmoore A. The report of the clinical standard advisory
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5
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6
Zarate CA Jr. Algorithms for the diagnosis and management of
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8
Zarate Jr CA, Daniel DG, Kinon BJ, et al. Algorithms for the treatment of
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9
Frances A, Docherty JP, Kahn DA, et al., editors. The Expert Consensus
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la schizophrénie, 1999. De Boeck & Larcier s.a., 2000
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Guidelines Series.
30 Consensus Conference della Società Italiana di Psicopatologia. Linee Guida
per la Farmacoterapia della Schizofrenia. Rome, 14-15 April 2000. Giornale
Italiano di Psicopatologie 2000 ; 6 (Suppl) :
31 Taylor D et al.. The Bethlem and Maudsley NHS Trust, 2001 prescribing
guidelines, 6th edn. Martin Dunitz 2001.
32 Katschnig H, Donat H, Fleischhacker W, et al. 4x8 Empfehlungen zur
Behandlung von Schizophrenie der Österreichischen Gesellschaft für
Psychiatrie und Psychotherapie. Edition Pro Mente, Linz 2002. English: 4x8
Recommendations for the Treatment of Schizophrenia. Cambridge
University Press. On behalf of the Austrian Society of Psychiatry and
Psychotherapy (in preparation).
33 VHA Clinical Practice Guideline for the Management of Persons with
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newer (atypical) antipsychotic drugs for the treatment of schizophrenia.
Technology Appraisal Guidance, No. 43. National Institute for Clinical
Excellence; Issue Date: June 2002; Review Date: May 2005.
APPENDIX 6: National Health Service National Institute
for Clinical Excellence guidance on the use of newer
(atypical) antipsychotic drugs for the treatment of
schizophrenia
(1)
The choice of antipsychotic drug should be made jointly by the individual
and the clinician responsible for treatment based on an informed discussion
of the relative benefits of the drugs and their side effect profiles. The
individual's advocate or carer should be consulted where appropriate.
(2)
It is recommended that the oral atypical antipsychotic drugs amisulpride,
olanzapine, quetiapine, risperidone and zotepine are considered in the
choice of first-line treatments for individuals with newly diagnosed
schizophrenia.
(3)
The oral atypical antipsychotic drugs listed in Section 3.3 should be
considered as treatment options for individuals currently receiving typical
antipsychotic drugs who, despite adequate symptom control, are
experiencing unacceptable side-effects, and for those in relapse who have
previously experienced unsatisfactory management or unacceptable sideeffects with typical antipsychotic drugs. The decision as to what are
unacceptable side-effects should be taken following discussion between the
patient and the clinician responsible for treatment.
(4)
It is not recommended that, in routine clinical practice, individuals change
to one of the oral atypical antipsychotic drugs if they are currently
achieving good control of their condition without unacceptable side-effects
with typical antipsychotic drugs.
(5)
In individuals with evidence of treatment-resistant schizophrenia (TRS),
clozapine should be introduced at the earliest opportunity. TRS is suggested
by a lack of satisfactory clinical improvement despite the sequential use of
the recommended doses for 6 to 8 weeks of at least two antipsychotics, at
least one of which should be an atypical.
(6)
A risk assessment should be performed by the clinician responsible for
treatment and the multidisciplinary team regarding concordance with
medication, and depot preparations should be prescribed when
appropriate.
(7)
Where more than one atypical antipsychotic drug is considered
appropriate, the drug with the lowest purchase cost (taking into account
daily required dose and product price per dose) should be prescribed.
(8)
When full discussion between the clinician responsible for treatment and
the individual concerned is not possible, in particular in the management of
an acute schizophrenic episode, the oral atypical drugs should be
considered as the treatment options of choice because of the lower potential
risk of extrapyramidal symptoms (EPS). In these circumstances, the
individual's carer or advocate should be consulted where possible and
appropriate. Although there are limitations with advanced directives
regarding the choice of treatment for individuals with schizophrenia, it is
recommended that they are developed and documented in individuals' care
programmes whenever possible.
(9)
Antipsychotic therapy should be initiated as part of a comprehensive
package of care that addresses the individual's clinical, emotional and social
needs. The clinician responsible for treatment and key worker should
monitor both therapeutic progress and tolerability of the drug on an
ongoing basis. Monitoring is particularly important when individuals have
just changed from one antipsychotic to another.
(10) Atypical and typical antipsychotic drugs should not be prescribed
concurrently except for short periods to cover changeover of medication.
APPENDIX 7: Resolution adopted by the General
Assembly of the World Psychiatric Association on 26
August 2002 in Yokohama, Japan, and containing the
Consensus Statement on
THE USEFULNESS AND USE OF SECOND-GENERATION
ANTI-PSYCHOTIC MEDICATIONS
The General Assembly of the World Psychiatric Association,
Having considered the evidence on the effectiveness, side-effects, use and
usefulness of the second generation antipsychotic medications presented to it by
the WPA Task Force that assembled the relevant material in the Technical
Review of such evidence and in its Update;
Having taken note of the fact that the Technical Review of the evidence has been
presented to all of its Member Societies and that discussions of this document
have been organized by more than twenty of its Member Societies and involved,
not only psychiatrists but also other relevant specialists, and representatives of
governments and patient and family organizations;
Recognizing that these meetings and the correspondence with Member Societies
have made it possible to take into account the experience obtained in using these
medications in many countries as well as the relevant evidence in preparing the
Technical Reviews submitted to the WPA;
Aware of its constitutional mandate to do all that is within its power to improve
the care for people with mental disorders;
(1) Expresses its satisfaction with the intensive process of consultation used in
the preparation of the relevant documents and commends the Executive
Committee of the WPA for its leadership and the WPA Task Force for its
efforts in developing the relevant documentation, coordinating national and
international consultations and presenting the materials for discussion
during WPA official meetings;
(2) Thanks the Member Societies, individual experts, professional associations
and governmental and nongovernmental organizations for the contributions
they have made in the process of reviewing the evidence and experience with
this group of medications;
(3) Thanks academic institutions for their support and the pharmaceutical
companies for the unrestricted educational grants that have greatly
facilitated the work on this matter;
(4) Adopts the following conclusions concerning the use of this group of
medications, by consensus:
I.
The World Psychiatric Association should give high priority to ensuring
that antipsychotic medications of the first and second generations and
other treatments of proven efficacy become available to all people who
need them, worldwide. In pursuing this goal the WPA should collaborate
with the health industry, including pharmaceutical companies, and with
governments aiming to ensure appropriate treatment of people with
mental illness as specified in the UN Resolution 119 of 1991.
II.
The scientific evidence about the effectiveness and side-effect profiles of
the second-generation antipsychotic medications, and the experience
from many countries justify the placement of these medications among
the options for the initial treatment of schizophrenia and related
psychotic disorders.
III. The efforts to secure the availability of effective antipsychotic
medications should go hand in hand with educational programmes for
mental health personnel and with measures that will ensure the delivery
of high quality mental health services.
IV. The World Psychiatric Association should work with the World Health
Organization on the development of the model list of drugs essential for
psychiatric treatment to ensure that an appropriate array of medications
is made available for the treatment of mental disorders.
V. Member Societies as well as national and international research
organizations in developed and developing countries should undertake
or continue research that will produce currently lacking data on
i.
ii.
iii.
iv.
v.
The differential risk/benefit profiles of each of the medications
in this group
The comparison of second-generation antipsychotics with firstgeneration antipsychotics given at low doses
The effects of second-generation antipsychotic medications in
children with psychotic disorders
The effects of these drugs in the treatment of psychotic states in
women, elderly patients and patients with concurrent physical
disorders
The long-term effects of these medications and their effects on
different geographical, cultural and ethnic groups
vi. The use of second-generation antipsychotic medications for the
treatment of disorders other than schizophrenia and related
psychotic states.
vii. The World Psychiatric Association should advocate an increase in the
allocations for research on psychiatric treatment methods at national
and international levels.
viii. The Executive Committee of the WPA should continue its efforts to
develop consensus statements on other matters of importance for the
practice of psychiatry and seek resources to continue this line of
work.