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Acta Psychiatr Scand 2007: 115: 260–267
All rights reserved
DOI: 10.1111/j.1600-0447.2006.00982.x
Copyright 2007 The Author
Journal Compilation 2007 Blackwell Munksgaard
ACTA PSYCHIATRICA
SCANDINAVICA
Clinical overview
The case for long-acting antipsychotic agents
in the post-CATIE era
Nasrallah HA. The case for long-acting antipsychotic agents in the postCATIE era.
Objective: Long-acting antipsychotic agents were developed to
promote treatment compliance in patients requiring maintenance
treatment for schizophrenia.
Method: An analysis of the impact of non-compliance on treatment
outcomes in schizophrenia and the advantages and disadvantages of
long-acting antipsychotics.
Results: Partial or total non-compliance with oral antipsychotics
remains widespread and is associated with significant increases in the
risk of relapse, rehospitalization, progressive brain tissue loss and
further functional deterioration. Long-acting agents have the potential
to address issues of all-cause discontinuation and poor compliance.
The development of the first long-acting atypical antipsychotic, which
appears to be effective and well tolerated, should further improve the
long-term management of schizophrenia.
Conclusion: Long-acting agents represent a valuable tool for the
management of schizophrenia and merit wider use, especially in light of
emerging literature regarding the neuroprotective advantages of
atypical antipsychotics over conventional agents in terms of
regenerating brain tissue during maintenance therapy.
H. A. Nasrallah
Department of Psychiatry, University of Cincinnati
College of Medicine, Cincinnati, OH, USA
Key words: compliance; long-acting antipsychotic
agent; long-acting risperidone; schizophrenia
Henry A. Nasrallah, University of Cincinnati College of
Medicine, 231 Albert Sabin Way, Suite 7259, Cincinnati,
OH 45267-0599, USA.
E-mail: [email protected]
Accepted for publication November 10, 2006
Clinical recommendations
• Updating psychiatristsÕ knowledge about the high discontinuation rates observed with oral
antipsychotics may lead to more positive attitudes towards a greater reliance on long-acting
formulations.
• Clearly communicated advantages of long-acting agents, such as lower neurological adverse effects
and possibly enhanced neurotropic factors and neurogenesis may contribute to their broader
acceptance.
• Additional studies are required to further substantiate the positive impact of long-acting risperidone
on health-related quality of life and functioning.
Additional comments
• There are few published data on psychiatristsÕ and patientsÕ attitudes to long-acting medications.
• In the more recent literature there is a paucity of data on long-acting conventional antipsychotic
agents.
• The clinical and neurobiological effects of uninterrupted, prolonged medication compliance are
required since, as demonstrated by the Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE) study, few patients remain on oral atypical agents to reap long-term benefits such as
remission and possible neuroregeneration.
260
The case for long-acting therapy
Introduction
Long-acting antipsychotic agents were developed
in the 1960s as a novel method of drug delivery
aimed at enhancing treatment compliance in
patients with schizophrenia (thereby reducing the
risk of rehospitalization and subsequent Ôrevolving
doorÕ in-patients), as well as simplifying the
medication process (1, 2). It has been repeatedly
demonstrated that poor and partial compliance
with oral antipsychotic medication is high; more
than 35% of patients begin to demonstrate compliance problems during their first 4–6 weeks of
treatment, and only 25% are fully compliant
within 2 years (3). This has been further supported
by the results of the recent Clinical Antipsychotic
Trial of Intervention Effectiveness (CATIE), in
which 74% of patients (n ¼ 1493) who were
assigned to the conventional antipsychotic agent
perphenazine (up to 32 mg/day), or a range of oral
atypical antipsychotics (olanzapine up to 30 mg/
day, quetiapine up to 800 mg/day, risperidone up
to 6.0 mg/day or ziprasidone up to160 mg/day),
discontinued medication within a few months (4).
Non-compliance has been attributed to multiple
factors including lack of insight, cognitive dysfunction, negative symptoms such as apathy,
complicated treatment regimens, drug-related
side-effects and lack of patient education (5–7).
Aims of the study
This article provides an overview of the impact of
poor or partial compliance in schizophrenia and
discusses the possibility of significantly reducing
this problem by increasing the use of long-acting
agents. Advantages and disadvantages of longacting agents will be highlighted, along with a
Fig. 1. Illustration of the effect of compliance on patient
symptoms. A regression analysis from a 1-year naturalist study
of risperidone vs. conventional antipsychotics (n ¼ 565)
showed that a 20% increase in compliance predicts a 3.1
improvement in PANSS over 1 year (P < 0.0001) (27).
PANSS ¼ Positive and Negative Syndrome Scale.
discussion of long-acting risperidone, the only
atypical antipsychotic available in a long-acting
injectable formulation at this time.
Material and methods
An analysis of published data was undertaken to
examine: i) the impact of non-compliance on
treatment outcomes in schizophrenia; ii) the advantages and disadvantages of long-acting antipsychotic agents and iii) current data on the first
available long-acting atypical antipsychotic agent.
Results
Importance of consistent uninterrupted antipsychotic
pharmacotherapy
Antipsychotic agents are the major class of drugs
used in the treatment of schizophrenia. The
atypical antipsychotics represent an improvement
in both efficacy and tolerability over conventional
agents (8–15). Emerging literature has also suggested that the atypical agents may have the
potential to prevent or reverse the accelerated
frontotemporal cortical gray matter decline commonly observed in schizophrenia patients (16–19).
Indeed, several studies have demonstrated that the
atypical agents may offer greater levels of neuroprotection compared with conventional agents in
enhancing neurotropic growth factors and neurogenesis (20–22). However, despite these gains,
optimal pharmacotherapy for schizophrenia
remains problematic for a significant number of
patients. Besides the emergence of metabolic
adverse effects such as weight gain, hyperglycemia
and hyperlipidemia with the newer agents (23–25),
reliable and long-term disease control have often
been limited by patientsÕ total or partial compliance with therapy (26).
In the case of schizophrenia, non-compliance has
been shown to be highly correlated with inconsistent symptom control, relapse and rehospitalization, which in turn can lead to progressive brain
tissue loss, family discord, danger to self and others
and loss of autonomy, education or employment
possibilities. Results from a randomized study that
compared outcome measures of Ôhighly compliantÕ
patients (medication possession ration: MPR of
‡70) vs. Ôless compliantÕ patients (MPR of <70)
demonstrated that a 20% reduction in the degree
of treatment compliance predicts a 3.1 point
increase in total Positive and Negative Syndrome
Scale (PANSS) scores (Fig. 1) (27). Likewise, a
comprehensive review of five randomized studies
(28) demonstrated that there was an almost two261
Nasrallah
Fig. 2. Comparison of relapse rates in patients with schizophrenia following 1 year of continuous vs. intermittent maintenance therapy in five studies (28; 1996 Massachusetts
Medical Society).
fold increase in the risk of relapse in patients who
received intermittent treatment (Fig. 2) (29–34).
Finally, data from a cohort study of over 4000
patients with schizophrenia receiving antipsychotic
therapy demonstrated that a gap in medication
possession of as little as 1–10 days in a 1-year
period doubles the risk of hospitalization (35),
while another study which examined consecutive
admissions to an acute patient unit reported that
50% of hospitalizations were attributable to medication non-compliance (2).
Advantages of long-acting antipsychotic agents
Long-acting antipsychotic agents have several
advantages over oral agents, the major one being
assurance of uninterrupted medication access
(Table 1). Long-acting antipsychotic agents are
Table 1. Advantages and disadvantages of long-acting antipsychotic agents in the
maintenance therapy of chronic schizophrenia
Advantages
Improved treatment compliance, especially by overcoming
covert non-compliance
Easier early detection of relapse, improved relapse prevention and
reduced hospitalization rates
Enhanced antipsychotic efficacy with reduced drug exposure and tolerance
Less need to remind patients to take their medications
Lowest effective dose principle more safely achieved (step-wise reduction)
Minimal gastrointestinal absorption problems
Circumventing first-pass metabolism of the antipsychotic
More predictable and stable serum concentrations of the active drug
Reduced risk of accidental or deliberate overdose
Enriched patient–treatment team interaction
Increased opportunity for psychosocial support
Staff time savings within in-patient settings
Disadvantages
Delayed disappearance of distressing side-effects after
discontinuation of medication
Feeling of being ÔcontrolledÕ
Perception of stigma
Initial resistance to needles/injections
Occasional local tissue reactions at the site of injection
262
convenient for the patient and their family who no
longer have the burden of remembering to take
medication on a daily basis. In addition, patients
may also prefer the consistency that scheduled
treatment provides. Indeed, one study demonstrated that as many as 67% of patients preferred longacting agents because it afforded them a degree of
control over the timing of their treatment (36).
A less well-recognized advantage of long-acting
agents is the more frequent contact between
patients and treatment teams. Schizophrenia
patients often live alone and have limited contact
with other people. The necessary regular visits to
the treatment center provide the opportunity for
more formal psychosocial support such as psychoeducation or social skills training. Moreover, from
a clinician’s point of view, a critical advantage of
long-acting antipsychotics is that if a patient does
become non-compliant, the clinical team will know
immediately and will be able to initiate efforts to
deal effectively with the problem before symptoms
re-appear (37).
Long-acting antipsychotic agents also have several pharmacological advantages over their oral
(immediate-release) counterparts. Administration
of a long-acting agent avoids the variability associated with absorption and first-pass metabolism,
and usually results in a better correlation between
the administered dose and the plasma levels
achieved (38, 39). Furthermore, once steady-state
is achieved, plasma levels remain relatively stable,
avoiding the daily peaks and troughs that occur
with oral agents (38, 39). Long-acting antipsychotics also facilitate the use of the lowest effective
dose principle, thereby reducing the frequency of
adverse events, including akathisia, dysphoria and
antipsychotic-induced deficit syndrome, and
enhancing patient’s quality of life (40, 41). The
risk of medication overdose with oral antipsychotics is also significantly reduced with long-acting
agents; this is of significant importance given that
suicide is a relatively common cause of death in
psychotic patients [10–20% lifetime risk in those
with schizophrenia (42, 43), and that most suicide
attempts are with medication overdose (44)].
Although long-acting agents are unable to prevent relapse completely, with a systematic metareview demonstrating that there is an irreducible
20–25% of patients who relapse despite receiving
long-acting agents (45), when all of the data from
individual trials and meta-analyses are taken
together, the findings are quite compelling, in
favor of long-acting agents. Results from a metaanalysis of six double-blind studies in 520 outpatients reported relapse rates to be significantly
reduced among patients treated with long-acting
The case for long-acting therapy
conventional agents (30.0%) vs. oral conventional
agents (47.1%) (1). Furthermore, an analysis of
data from mirror image studies in 613 out-patients
reported significant differences in the number of
hospitalization days between those on oral conventional medications (75 292 days) vs. longacting conventional agents (17 860 days) (1). In
addition, results from a prospective cohort study of
2230 consecutive adults with schizophrenia or
schizoaffective disorder reported that the use of
long-acting perhpenazine was associated with a
substantially lower risk of rehospitalization or
discontinuation (for any reason) of therapy than
the majority of the 10 most commonly used oral
antipsychotic agents. Such reductions in hospitalization translate into significant cost savings (46).
However, despite the attractiveness of this
treatment option, long-acting agents remain underutilized; in many countries throughout the
world fewer than 20% of patients with schizophrenia receive these medications. Interestingly, prescribing practices for long-acting antipsychotic
agents also differ significantly between countries,
with higher rates of prescribing in Denmark,
Sweden and the UK, and lower rates in France
and the USA (47). Indeed, anecdotal reports
indicate that only 10–20% of antipsychotic treatment in the USA involves long-acting formulations
compared with as much as 50% in the UK.
Disadvantages of long-acting antipsychotic agents
The main objective disadvantage of long-acting
agents is the rare occurrence of unexpected severe
side-effects, such as tardive dystonia, dyskinesia
and neuroleptic malignant syndrome (48–53). In
addition, there is a fear on the part of clinicians that
if adverse effects do occur, they will be more difficult
to manage because of the inability to rapidly
discontinue the medication. However, a review of
the literature undertaken by Glazer et al. (48),
which analyzed published data on neuroleptic
malignant syndrome, tardive dyskinesia and extrapyramidal symptoms (EPS), did not support the
assumption that long-acting conventional agents
are associated with a greater risk of major sideeffects than oral agents (54). As such, the authors
concluded that Ôthe obvious advantages of these
agents with regard to the problems of non-compliance, refractoriness and prevention of relapse need
not be lost because of unfounded fearsÕ (54).
Another potential disadvantage of the longacting esterifed oil-based conventional agents is
the occurrence of injection site pain (55). In some
cases the injection site can become edematous and
tender or pruritic with a palpable mass being
present for up to 3 months (56). In particular,
haloperidol, fluphenazine, zuclopenthixol, and flupenthixol injections are all associated with significant pain and discomfort to the patient (55). As
such, many physicians remain cautious about
prescribing a long-acting agent, wishing to save
the patient from the fear and pain of injections and
believing that injections are a psychological intrusion.
Finally, some physicians believe that patients
have negative attitudes toward receiving continual
injections, particularly with regard to feeling overly
controlled and losing their independence and freedom by receiving continual injections (57–59).
However, the perceived loss of control is often
more imagined than real and there are many other
areas of everyday life where patients have ample
opportunity to become autonomous without risking psychotic relapse. Furthermore, results from a
systematic review of patient preference reported
that in five of the six studies analyzed, the majority
of patients preferred to receive their medication via
a long-acting formulation than in tablet form (60).
In reality, it is often the practitioners who have their
own biases, resistances and negative thoughts about
long-acting agents. Indeed, this was confirmed by
the results of a recent cross-sectional postal survey
of psychiatrists, which demonstrated that a substantial minority believed long-acting agents to be
old fashioned (40%), stigmatizing (48%) and less
acceptable to patients (69%) and relatives (66%).
Some physicians may also associate long-acting
agents with Ônon-compliantÕ or ÔbadÕ patients and,
therefore, be reluctant to prescribe them (61).
The development of the first long-acting atypical antipsychotic
agent
Risperidone is the first atypical antipsychotic to
become available in long-term injectable form.
Controlled trials demonstrate its efficacy, safety
and tolerability (64, 65). Long-acting risperidone is
unique among currently available long-acting antipsychotics because it is an aqueous suspension
containing risperidone in a biodegradable matrix
of glycolic acid–lactate polymer. In contrast with
oil-based solutions, the aqueous nature of longacting risperidone is associated with minimal pain,
induration and inflammation at the injection site
(62). The pharmacokinetic profile of long-acting
risperidone exhibits less peak-trough variability
(56–71% vs. 118–129% for oral risperidone), and
25–32% lower peak plasma concentrations than
oral risperidone, due to the delayed release of
active agent from the vehicle microspheres (63).
These factors have been associated with both a
263
Nasrallah
clinical improvement in symptom severity and a
decrease in EPS vs. oral risperidone (33, 39).
Controlled clinical trials of long-acting risperidone
The clinical benefits of long-acting risperidone, vs.
placebo and in the long term, have been explored
in two large clinical trials, in which long-acting
risperidone was administered at doses of 25, 50 and
75 mg every 2 weeks (64, 65). In a 12-week,
randomized, controlled trial by Kane et al. (64),
long-acting risperidone was associated with significantly greater improvements in PANSS total and
factor (positive and negative symptoms) scores at
endpoint compared with placebo (P < 0.01) (64).
Statistically significant improvements in total
PANSS scores (P < 0.01), positive symptoms
(P < 0.01) and negative symptoms (P < 0.001)
were also seen in the international, 1-year, openlabel trial conducted by Fleischhacker et al. (65) in
patients with schizophrenia who were switched to
long-acting risperidone from oral or long-acting
conventional or oral atypical antipsychotics. In the
study by Kane et al. (64) similar proportions of
patients in the placebo and long-acting risperidone
groups (80–83%) reported adverse events, while
long-acting risperidone was also well tolerated in
the long-term trial by Fleischhacker et al. (65),
with 65% of patients completing the trial.
A number of studies have also demonstrated that
patients can be switched from other oral and longacting antipsychotic agents with minimal transition
complications (66–68). In addition, long-acting
risperidone has been shown to reduce episodes of
hospitalization, an indicator of reduced relapse
(69). Finally, preliminary data have demonstrated
improvements in health-related quality of life and
social functioning following treatment with longacting risperidone (70, 71).
Of particular note, neither of the studies by
Kane et al. (64) or Fleischhacker et al. (65) demonstrated significant differences in clinical outcomes for doses ranging from 25 mg/2 weeks or
75 mg/2 weeks, thereby suggesting that the optimal
dose of long-acting risperidone may be less well
established than that of oral risperidone (72).
Furthermore, the observation that the lowest
dose of long-acting risperidone gives rise to mean
active moiety plasma levels of only 32.9 nmol/l, has
lead to some debate as to whether a dose of 25 mg/
2 weeks is truly effective in clinical practice (73).
Despite its proven efficacy in schizophrenia,
many physicians continue to manifest a reluctance
to adopt long-acting risperidone for its association
with several ÔobstaclesÕ. These primarily relate to
the fact that some physicians feel long-acting
264
risperidone is too complicated and time consuming
to obtain, involving much paperwork, and is
cumbersome to store and administer (74). However, although obtaining long-acting risperidone
can take considerable personal time and effort,
which can be a daunting task for those practitioners who are not surrounded by a team of nurses
and administrative staff, it has become easier over
time, and after the initial startup, paperwork is
minimal (74). Long-acting formulations of other
antipsychotics such as olanzapine and aripiprazole
are also currently in development, but no data are
as yet available.
Cost-effectiveness of long-acting risperidone
A number of studies and pharmacoeconomic
models have demonstrated that long-acting risperidone decreases direct healthcare costs largely by
reducing the rates of relapse and hospitalization
(69, 75–79). Indeed, results from a 1-year international, open-label trial of long-acting risperidone in
in-patients and out-patients with stable schizophrenia or schizoaffective disorder reported that
the number of patients requiring hospitalization
decreased continuously and significantly from 37%
in the 3 months before treatment to 12% during
the last 3 months of treatment (69). Of note,
preliminary data from a Swedish multicenter
study in 92 patients have demonstrated that for
patients treated with long-acting risperidone, the
total number of hospitalizations was reduced by
38% (P ¼ 0.0004) compared with the same observational period when treated with their previous
antipsychotic therapy (80). Using an empirical
economic model, based on Swedish costs, the mean
annual cost savings were estimated to be US$3600–
6900 per patient following a switch to long-acting
risperidone within the recommended dose range
(80). However, in contrast to the various studies
cited above, results from a recent study indicated
that switching to long-acting risperidone was
associated with a continuation of the trend for
increased bed-stay and use of healthcare resources.
In fact, the mean number of days per patient spent
in hospital increased from 31 in the 3 years before
initiation with long-acting risperidone to 141
following 1-year treatment with long-acting risperidone (81). Direct healthcare costs also rose
accordingly. As such, further studies are required
to clarify the cost-effectiveness of long-acting
risperidone, and to determine the optimal dose
and adjunctive psychosocial therapy required to
achieve pharmacoeconomic advantages.
Long-acting risperidone costs about twice a
comparable dose of oral risperidone, and that is
The case for long-acting therapy
due in part to the cost of the prepackaged kit of
vials, syringes, needles, and related items that come
with each dose of injectable long-acting risperidone. However, the hidden cost of unused and
wasted oral medication because of poor
compliance is circumvented with full adherence to
injectable medication.
Discussion
The introduction of long-acting antipsychotic
agents was a major advance in the maintenance
treatment of chronic schizophrenia. However, their
use has declined in recent years, perhaps owing to
the introduction of the oral atypical antipsychotic
agents. Although long-acting agents have several
advantages over oral medication, including
improved treatment compliance and consistent
drug delivery, an unjustified stigma in some, but
not all countries, remains attached to their use
which has been reinforced by required visits to
specialized clinics at regular intervals. To address
this, the advantages of long-acting agents, such as
reduced relapse rates, improved tolerability and
enhanced patient quality of life, should be
clearly communicated to ensure wider future
acceptance of these drugs by psychiatrists, patients
and payers.
Parenteral and uninterrupted administration of
long-acting risperidone should reduce hospitalization and the overall cost of care in a manner similar
to that demonstrated by both the long-acting
conventional agents and the atypical agents. However, long-term trials, which specifically address
functional outcomes and relapse rates, as well as
the development of emergent adverse outcomes,
are required to further characterize the full impact
of long-acting risperidone on the course of the
illness and on treatment outcomes in schizophrenia
and other recurrent psychoses including bipolar
disorder.
In summary, long-acting antipsychotic agents
that ensure continuous drug delivery and the
provision of appropriate psychosocial therapy
have the potential to address issues of all-cause
discontinuation and poor compliance. Furthermore, it has been reported that some patients
prefer long-acting formulations, thereby suggesting
that physicians should more often recommend and
prescribe a long-acting agent when antipsychotic
maintenance therapy is indicated (58).
Acknowledgements
This study was supported by an unrestricted education grant
from Johnson & Johnson. The author would like to thank
Frances Gambling, Medicus International, for her editorial
assistance. Editorial assistance was funded by Johnson &
Johnson.
Declaration of interest
Dr Henry Nasrallah has received research grants from
AstraZeneca, Forest, Lilly, Janssen and Pfizer, and has
received honoraria for consultations, advisory boards and
speaker’s bureau from Abbott, AstraZeneca, Bristol-Myers
Squibb, Janssen, Pfizer and Shire.
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