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Second generation antipsychotics:
a role in South Africa?
Prof Dave Swingler
Second generation antipsychotic medications are now the preferred choice in
treating conditions such as bipolar disorder and schizophrenia. Despite their
effectiveness, their cost reduces their ready availability to patients in South
Africa. Prof Dave Swingler examines the benefits of the SGAMs vs traditional
medication and poses the question: Can we afford to use SGAMs in South Africa? More pertinently, can we afford
not to?
Charpentier's synthesis of chlorpromazine in 1950 and subsequent discovery of
its effectiveness in treating severe agitation and psychosis opened the doors of
psychiatry. Along with the development of agents such as haloperidol and
fluphenazine decanoate, previously custodial care could be expanded into the
community. The modern era of mental health was born.
While effective in treating conditions such as schizophrenia, the
neurological side effects (tremor, muscle rigidity, late-onset motor dyscontrol)
of these agents limit their acceptability to patients, and compliance with
treatment. The excitement surrounding the introduction of clozapine - which
lacks these 'extra-pyramidal' motor side effects - was short-lived due to the
emergence of new adverse effects - a risk of bone marrow suppression. Kane and
colleagues' pivotal 'Study 30', published in 1988, proved its superiority over
chlorpromazine and it re-entered clinical use, combined with blood monitoring.
Anti-psychotic drug discovery has, over the past two decades, concentrated on
developing agents without either motor or bone marrow effects. Olanzapine,
risperidone, quetiapine, amisulpride, ziprasidone, and zotepine and, more
recently, aripiprazole, have all since come to the global market. Sertindole is
re-emerging now that initial safety concerns have been reviewed. While they each
have one or other side effect profiles that needs to be taken into account when
individualising treatment, they offer significant advances in terms of
tolerability over the old or 'typical' drugs.
Being relatively new products of expensive development, these medications
still enjoy patent-protection and their acquisition costs are high. Their
clinical indications have also expanded beyond schizophrenia and now include
bipolar disorder (acute mania and relapse prophylaxis) and behavioural
disturbances in children and dementia. As a result, South African health care
funders are reticent to adopt them in their various formularies and generally
restrict usage until there is sufficient 'evidence' of their superiority. Save
for discrete scenarios (suicidal and aggressive patients, clozapine for
treatment-resistant schizophrenia, risperidone for first-episode schizophrenia),
it is extremely difficult (and costly) to 'prove' that one agent is more
effective than another. But they have fewer side effects, are better tolerated,
and are more acceptable to patients.
A further obstacle to their entry into formularies is the heterogenous nature
of this group of new agents, which makes them challenging for decision makers
(and even psychiatrists) to understand. Clozapine was so unusual (in terms of
structure, mode of action, side effect profile) at the time that its discovery
spawned the term 'atypical' for this new generation of anti-psychotics. Now,
with several agents as different from each other as they are similar, the only
thing atypical about them is each from the other.
'Atypicality' was initially defined as the inability to induce catalepsy in
laboratory animals (as the old, 'typical', conventional agents can do). This was
developed to include clinical observations such as limited motor or endocrine
effects, improvement of negative symptoms and regional specificity of action in
the limbic areas of the brain. More recent attempts to delineate the group rests
with their similarities of 'stickiness' to dopamine receptors - a 'fast
dissociation' or dopamine 'K' > 1.75nM/L. Kasper and Zohar, writing in The
World Journal of Biological Psychiatry, even question whether or not the term 'antipsychotic'
is still justified. They contend that 'the old term "neuroleptic",
meaning to treat the neuron, might be more realistic, practical and - from a
patient's point of view - non-discriminating'. This review accords with the
World Psychiatric Association's (WPA) moniker of 'second-generation
antipsychotic medications' (SGAMs).
Second generation antipsychotic medications increasingly recommended
A review of the scientific literature yields increasing evidence for the
superiority of SGAMs. Leucht and colleagues' 1999 meta-analysis found that
risperidone and olanzapine were more effective in treating global and negative
symptoms of schizophrenia and that, along with sertindole and quetiapine, caused
less motor side effects. They followed this up in 2003 with the finding that the
new drugs were better than conventional ones for all doses equivalent to >
300mg chlorpromazine. Geddes and colleagues' controversial conclusion in 2000
that there was no clear evidence that atypical antipsychotics were more
effective or better tolerated than conventional ones, was tempered in 2002 with
the view that 'the preponderance of evidence now supports the use of risperidone
as a first-line treatment for… schizophrenia'. Supporting the notion that not
all SGAMs are equal, Davis, Chen and Glick's recent meta-analysis carried in the
Archives of General Psychiatry concluded that clozapine, olanzapine, risperidone
and amisulpride were superior to older drugs as well as, by comparison, their
SGAM peers. Csernansky's group elegantly showed that risperidone was superior to
haloperidol in reducing the risk of (and thus preventing) relapse over one year,
in 2002.
Professional bodies have been cautious but are now increasingly emphatic in
supporting these findings. The WPA task team concluded its 2001 review of the
data with the opinion that 'the evidence to date indicates that the second
generation anti-psychotics represent a useful addition to the… treatment
options for… schizophrenia and should be among the options for first-line
treatment'. By 2002 it stated 'the scientific evidence… and the experience
from many countries justify… these medications among the options for the
initial treatment of schizophrenia and related psychotic disorders'. The
recommendations of its 2003 update take a stronger line still: 'More scientific
evidence on their effectiveness would be welcome, but patients should have
access to these medications now.' Further, 'SGAMs should be the first choice of
treatment for certain groups of patients'.
The WPA is not alone. The London-based National Institute of Clinical
Excellence (NICE) issued evidence-based guidelines in 2002 that recommended oral
'atypical' antipsychotic drugs be considered in the choice of first-line
treatments for newly diagnosed schizophrenia, and for patients with unacceptable
adverse effects caused by 'typical' agents. The World Federation of Societies of
Biological Psychiatry incorporated SGAMs into its Bipolar Depression (2002) and
Mania (2003) treatment guidelines. The prestigious American Psychiatric
Association revised its influential practice guideline for treating bipolar
disorder in 2002 to take into account the new evidence supporting the use of
SGAMs in these conditions.
Costs
If SGAMs are indeed the preferred choice of treatment for schizophrenia and
bipolar disorder, why are they not readily available to patients in South
Africa? Cost. As Professor JJ Lopez-Ibor, WPA President, puts it: 'SGAMs raise
problems of equity.' Development costs make them expensive, putting them out of
reach of many patients in developing countries.
Pharmacoeconomic studies -
designed to test the premise of 'pay today, save tomorrow' - are fraught with
difficulty. Concepts of cost effectiveness, cost-efficiency and cost-equity are
not identical, neither are modes of evaluation such as cost-benefit,
-effectiveness or -utility. Studies in schizophrenia - 'a battleground'
according to David Taylor, lead author of The Maudsley 2003 Prescribing
Guidelines - suggest SGAMs are cost neutral, with savings accruing due to
reduced readmission. The WPA argues that almost all the cost-effectiveness
studies on schizophrenia treatment have focussed on the important but narrow
comparison of health-care impacts (cost) and symptom/functioning changes
(effectiveness). It proposes that considering wider cost measures, including
patient quality of life and family impacts, would better gauge the full
cost-effectiveness of SGAM treatment.
Affordability
Can we afford to use SGAMs in South Africa? More pertinently, can we afford
not to? As the National Department of Health reviews its far-reaching Essential
Drug List and as the private third party reimbursement industry begins to
accommodate legislative requirements of compulsory and unlimited benefits for
Prescribed Minimum Benefits for chronic conditions - that include schizophrenia
and bipolar disorder - a window of opportunity exists. One in which to bring the
latest science supporting modern treatments to the attention of policy makers,
to enlighten them regarding the implications of sub-optimal management and
'silo-budgeting' (assessing drug procurement costs out of context with other
health care delivery costs), and to cogently motivate for the availability of
acceptable, contemporaneous clinical treatments. A responsibility that patients,
their families and support groups, the mental health professions, the
pharmaceutical industry and the government cannot afford to abdicate.
More information:
Article by Prof Dave Swingler, Fort England Hospital & Rhodes University
(The author writes in his personal capacity. The opinions expressed herein
are solely those of the author and are not necessarily shared by his employer,
Fort England Hospital or Rhodes University. References available on request.)
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