Low dose typical antipsychotics - A brief evaluation

Abstract

Atypical antipsychotics have, according to some, revolutionised the treatment of schizophrenia. These drugs are claimed to be better tolerated than older typical drugs largely because of their lower propensity to cause acute extrapyramidal side-effects (EPSE). Some atypicals cause little or no hyperprolactinaemia. Some are suggested to cause less tardive dyskinesia than typical drugs. Many are claimed to improve, to a relatively greater extent, negative and cognitive symptoms of schizophrenia. In addition, one atypical, clozapine, is unarguably more effective than typical drugs in the treatment of refractory schizophrenia. Atypical drugs are now sometimes recommended as first choice treatment for schizophrenia (Lieberman, 1996; Taylor et al , 2000).

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Psychiatric Bulletin (2000), 24,465^468
DAVID TAYLOR
Low dose typical antipsychotics -- a brief evaluation
Atypical antipsychotics have, according to some, revolu-
tionised the treatment of schizophrenia. These drugs are
claimed to be better tolerated than older typical drugs
largely because of their lower propensity to cause acute
extrapyramidal side-effects (EPSE). Some atypicals cause
little or no hyperprolactinaemia. Some are suggested to
cause less tardive dyskinesia than typical drugs. Many are
claimed to improve, to a relatively greater extent, nega-
tive and cognitive symptoms of schizophrenia. In addi-
tion, one atypical, clozapine, is unarguably more effective
than typical drugs in the treatment of refractory schizo-
phrenia. Atypical drugs are now sometimes recom-
mended as first choice treatment for schizophrenia
(Lieberman, 1996; Taylor
et al
,2000).
Set against these positive views are the draft
recommendations of the National Schizophrenia Guide-
lines Group of the Royal College of Psychiatrists. This
group apparently suggests that typical drugs should be
first choice agents (Donnelly, 1999) on the basis that
atypical drugs have only been compared with moderate
or high doses of typical drugs and not with lower doses,
which might be relatively better tolerated (Bebbington,
1999). The essence of this argument is that typical anti-
psychotics are effective and well-tolerated when used in
low doses.
In order to evaluate properly this interesting propo-
sition, it is necessary to define very carefully the terms
used. What is meant, for example, by `low doses'? Most
trials of atypical drugs used for comparison fixed doses of
haloperidol of 10 mg or 20 mg a day. Where dose
titration was allowed, mean doses of haloperidol were
between 10 mg and 20 mg/day. `Low dose' therapy,
therefore, is assumed to indicate a dose of less than
10 mg a day of haloperidol. `Effective' might be taken to
mean unequivocally more effective than placebo as
measured by recognised rating scales. `Well-tolerated'
could be assumed to indicate placebo levels of EPSE,
hyperprolactinaemia and tardive dyskinesia. Thus, the
central question is this ^ is there a dose of typical anti-
psychotic that is effective, but does not give rise to
typical adverse effects?
Additional complications to this conundrum are the
doses of typical drugs used in practice and whether or
not these reflect doses used in clinical trials. Alongside
this, it is also important to consider the adverse effect
burden induced by normal clinical use of typical drugs.
That is, how toxic are atypicals when used in clinician-
determined doses?
Clinical dosing and adverse effect burden
A large number of studies have examined adverse effects
induced by typical drugs in clinical practice. For example,
in a cohort of subjects given, on average, the equivalent
of 24 mg/day haloperidol
1
, Richardson and Craig (1982)
noted high levels of adverse effects despite the use of
anticholinergic medication. Of 132 patients examined,
19.7% had parkinsonism-like symptoms and 28% tardive
dyskinesia. In a Japanese cohort receiving the equivalent
of 64 mg/day haloperidol, 34.8% of patients showed
signs of tardive dyskinesia and 40.5% had parkinsonism
(Binder
et al
, 1987). Similar findings were reported for a
sample of patients in Scotland (McCreadie
et al
,1992):
29% had tardive dyskinesia, 27% parkinsonism and 23%
akathisia (mean dose approximately equivalent to 10 mg/
day haloperidol). More recently, a large (
n
=1559) Italian
survey found 29.4% of patients suffering EPSE (mostly
parkinsonism) and 18.3% with persistent tardive dyski-
nesia. In that survey, more than 75% of patients were
prescribed doses equivalent to, or less than, 10 mg/day
haloperidol (Muscettola
et al
,1999).
In each of these surveys, free use of anticholinergic
medication was allowed. Although this might be
expected to reduce the prevalence of EPSE, it clearly does
not suppress symptoms in all cases. Prophylactic treat-
ment with anticholinergics is also, it seems, only partly
effective (Keepers
et al
, 1983).
It is clear then that EPSE and tardive dyskinesia are
commonly seen in patients prescribed typical drugs at a
wide range of clinically determined doses. It is also likely
that, in practice, the prevalence of these effects is
underestimated: patient and prescriber experiences and
expectations differ widely (Day
et al
, 1998), and training
in detection of adverse effects effectively doubles
observed prevalence of some adverse effects (Chaplin
et al
,1999).
Taylor Low dose typicals conundrum
1. In all cases,
haloperidol 2.5 mg
has been
assumed to be
equivalent to
100 mg/day
chlorpromazine
or chlorpromazine
equivalents.
465

Typicals and EPSE ^ inexorably linked?
Clinical trials
Can typical drugs be prescribed such that EPSE do not
occur? Surprisingly, there has been little work done
specifically to address this question, but a number of
studies have examined the therapeutic and (less system-
atically) adverse effects of low dose typicals, particularly
haloperidol.
An early study by Ayd (1972) evaluated haloperidol
and fluphenazine at a mean dose of 3.4 mg/day. Both
drugs were effective at this dose, but 10/23 subjects
suffered EPSE and six of them were withdrawn from
treatment. Later, Van Putten
et al
(1990) evaluated three
doses of haloperidol (5 mg, 10 mg and 20 mg/day). The
highestdosewasmarginallythemosteffective,but
caused relatively more severe akinesia and akathisia. The
10 mg/day and 5 mg/day doses caused similar rates of
these adverse effects and were equally effective. A
similar study (Levinson
et al
, 1990) used three doses of
fluphenazine (10 mg, 20 mg and 30 mg/day) and found
that doses above 0.2 mg/kg were associated with clinical
improvement
and
a high incidence of EPSE: the two
outcomes could not be separated by dose. One further
fixed-dose study (Rifkin
et al
, 1991) found haloperidol
10 mg/day to be just as effective as 30 mg/day and
80 mg/day, but no better tolerated.
In an unusual study, McEvoy and colleagues (1991)
established the mean threshold for EPSE in a cohort
comprising first episode and relapsed schizophrenia.
Subjects were given haloperidol 2 mg/day and the dose
increased until rigidity appeared or worsened, or until
10 mg/day was reached. (The dose was reduced to
1.0 mg/day or 0.5 mg/day if severe rigidity occurred at
2 mg/day.) This `neuroleptic threshold' was, essentially,
the dose at which EPS appeared. On average, the dose of
haloperidol required to induce EPS was 3.7 mg/day
(range: 0.5 mg ^10 mg/day). Those previously exposed
to neuroleptics required 4.3 mg/day (0.5 mg ^10 mg/
day), whereas first episode neuroleptic-na|
«
ve subjects
required only 2.1 mg/day (0.5^4 mg/day). These doses
were maintained and response was good (44% were
rated as responders after 2 weeks) and was not
improved by systematic dose increases. Of those main-
tained on threshold doses, only 4% withdrew because of
severe EPSE. Overall, this study clearly showed that EPSE
are induced by very low daily doses of haloperidol, but
that these doses appeared to be optimally therapeutic.
EPSE and therapeutic effects could not be separated,
since all subjects experienced EPSE according to the trial
protocol.
The most recent fixed-dose uncontrolled study was
that of Stone and co-workers (1995). Subjects were given
haloperidol 4 mg, 10 mg or 40 mg/day and evaluated for
2weeks(
n
=15). Subjects given 4 mg/day did just as well
as those given higher doses, but no patient prescribed
4 mg or 10 mg/day haloperidol experienced `severe EPSE'.
This small short study provides some evidence to support
the use of 4 mg/day haloperidol as a therapeutic dose,
but gives little information on toxicity on this dose
(patient numbers were small and treatment duration only
2weeks).
In contrast to these findings are the results of
perhaps the best designed, if inadvertent, study of low
dose haloperidol (Zimbroff
et al
, 1997). Ironically, this trial
was intended to evaluate the efficacy of sertindole.
Nearly 500 patients with schizophrenia were enrolled and
received one of three doses of sertindole, one of three
doses of haloperidol (4 mg, 8 mg or 12 mg/day) or
placebo. Haloperidol 4 mg/day was not convincingly
effective in this study: compared with placebo, this dose
was not more effective as measured on the Clinical
Global Impression Scale and the positive sub-scale of the
Brief Psychiatric Rating Scale. However, all three doses of
haloperidol produced similar levels of EPSE (about 40%
required anticholinergic drugs) and all doses, including
4 mg/day, produced substantially and significantly more
EPSE than placebo. It can be seen then, that in this study
4 mg/day haloperidol was not convincingly effective,
while producing levels of EPSE no different from higher
doses. This strongly supports the contention that EPSE
appear at essentially sub-therapeutic doses of haloperidol
and is, for the most part, in accord with other data
presented here.
Plasma level studies
Prescribed dose is an inexact predictor of drug plasma
level obtained because metabolism and distribution of
antipsychotics vary widely. Several trials have attempted
to establish a threshold plasma level for therapeutic
response (Van Putten
et al
, 1992; Levinson
et al
,1995;
Volvavka
et al
, 1995; Palao
et al
, 1996), but none deter-
mined a level at which therapeutic effects occurred but at
which EPSE did not. In fact, one trial (Levinson
et al
,1995)
found therapeutic response to be optimal and EPSE
marked at plasma levels above 1.0 mg/ml, so clearly
linking the two effects.
Receptor binding studies
Neuroimaging techniques such as positron emission
tomography (PET) and single photon emission computed
tomography (SPECT) allow estimates to be made of drug
receptor occupancies in the striatum. Typical drugs appear
to induce EPSE at striatal occupancies of D
2
receptors of
around 75%, which are afforded by doses of around
4 mg/day haloperidol (Farde
et al
, 1992). Two small
studies (total
n
=9) have reported clinical effectiveness at
occupancies lower than 75% (Kapur
et al
,1996;
Hirschowitz
et al
, 1997). In the larger study (Kapur
et al
,
1996), five out of seven first-episode subjects responded
to 2 mg haloperidol and showed mean striatal occupan-
cies of 67%. Two subjects suffered very mild EPSE. In the
smaller study, two subjects with `minimal prior antipsy-
chotic treatment' were given 2 mg/day and 4 mg/day
haloperidol. Both patients responded and showed
receptor occupancies of 51% and 72%, respectively. Only
the subject given 2 mg/day haloperidol showed any signs
of EPSE ^ mild akathisia and reduced arm swing.
Taylor Low dose typicals conundrum
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information
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466

These studies tentatively suggest that there may be
a dose of haloperidol that is effective but does not induce
EPSE, and that dose might be guided by neuroimaging
trials. However, the studies presented here were small
and uncontrolled and, more importantly, subjects showed
clear signs of EPSE even at low doses associated with D
2
occupancies below 75%. In addition, the precision and
validity of neuroimaging studies have recently been called
into question (Seeman & Tallerico, 1999).
Hyperprolactinaemia
It has long been acknowledged that moderate doses of
typical antipsychotics (approximately equivalent to
15 mg/day haloperidol) cause symptomatic hyperprolac-
tinaemia (Beumont
et al
, 1974). The dose required to
engender a rise in plasma prolactin has only been super-
ficially examined. Meltzer and Fang (1976) found that the
equivalent of 100 mg chlorpromazine given twice daily
(equivalent to approximately 5 mg/day haloperidol)
caused prolactin to rise within 72 hours in all 27 subjects
evaluated. On average, plasma prolactin increased almost
fourfold and closely paralleled clinical response. Later,
Nishikawa and co-workers (1985) showed that pimozide
2 mg/day and thioridazine 75 mg/day were subthera-
peutic but clearly raised plasma prolactin (by about 25^
100%). Higher doses of pimozide (6 mg/day, equivalent
to 6 mg/day haloperidol) were effective but increased
plasma prolactin by approximately 400%. More recent
studies suggest that prolactin levels begin to rise after as
little as 0.5^1.5 mg haloperidol and that hyperprolactin-
aemia is an unavoidable consequence of the therapeutic
use of typical drugs (Hamner & Arana, 1998).
Tar di v e dy skinesia
Tardive dyskinesia is a well-recognised long term adverse
effect of typical antipsychotics. The risk of tardive dyski-
nesia seems to be associated with drug dose (Morgen-
stern & Glazer, 1993; Chakos
et al
, 1996) and duration of
treatment (van Os
et al
, 1997). There appears to be no
trial that examined the threshold dose at which the
incidence of tardive dyskinesia is increased over that of
placebo. However, a number of trials in older patients
have shown that tardive dyskinesia is apparently induced
by doses less than 4 mg/day haloperidol equivalents
(Toenniessen
et al
, 1985; Caligiuri
et al
, 1997; Jeste
et al
,
1999). Thus, a `safe' therapeutic dose of typical antipsy-
chotics has not been established and, according to
limited evidence, may not exist.
Conclusions
Typical antipsychotics appear to be widely used in
moderately high doses, which are associated with high
prevalences of acute and chronic movement disorders.
Trials of lower doses of typical drugs generally indicate
that clinically relevant EPSE occur at daily doses that are
not clinically effective or at the lower end of the effective
dose range. Both hyperprolactinaemia and, less convin-
cingly, tardive dyskinesia appear to be engendered by
essentially sub-therapeutic doses of typical agents.
It should be noted, however, that this paper is a
brief review based on a simple Medline search conducted
in January 2000. As such, it may represent a selective
review of relevant literature. In addition, the use here of
haloperidol as the `standard' typical may also be partly
misrepresentative: butyrophenones are accepted to
produce relatively high rates of movement disorder.
Nevertheless, the trials presented here indicate that,
in relapsed schizophrenia, the effective dose of haloper-
idol is more than 4 mg/day. Four very comprehensive
reviews support this suggestion (Baldessarini
et al
,1988;
Kane & Marder, 1993, 1995; Bollini
et al
,1994). Itappears
that EPSE occur at doses of 4 mg haloperidol or less and
that hyperprolactinaemia is induced by doses even lower
than this one. We can only conclude, therefore, that
typical antipsychotics cannot be used effectively without
giving rise to typical adverse effects. Moreover, low but
effective doses seem to cause as many `typical' adverse
effects as higher doses such as those used in the trials of
atypical drugs. Low-dose typical antipsychotics seem to
offer little or no advantage over higher doses.
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London SE5 8AZ
468