Low dose typical antipsychotics - a brief evaluation

Atypical antipsychotics have, according to some, revolutionisedthe treatment of schizophrenia. These drugs are claimed tobe better tolerated than older typical drugs largely becauseof 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 typicaldrugs. Many are claimed to improve, to a relatively greaterextent, negative and cognitive symptoms of schizophrenia. Inaddition, one atypical, clozapine, is unarguably more effectivethan typical drugs in the treatment of refractory schizophrenia.Atypical drugs are now sometimes recommended as first choicetreatment for schizophrenia (Lieberman, 1996; Taylor et al, 2000).

Set against these positive views are the draft recommendationsof the National Schizophrenia Guidelines Group of the RoyalCollege of Psychiatrists. This group apparently suggests thattypical drugs should be first choice agents (Donnelly, 1999)on the basis that atypical drugs have only been compared withmoderate or high doses of typical drugs and not with lowerdoses, which might be relatively better tolerated (Bebbington, 1999).The essence of this argument is that typical anti-psychoticsare effective and well-tolerated when used in low doses.

In order to evaluate properly this interesting proposition,it is necessary to define very carefully the terms used. Whatis meant, for example, by ‘low doses’? Most trialsof atypical drugs used for comparison fixed doses of haloperidolof 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 indicatea dose of less than 10 mg a day of haloperidol. ‘Effective’might be taken to mean unequivocally more effective than placeboas measured by recognised rating scales. ‘Well-tolerated’could be assumed to indicate placebo levels of EPSE, hyperprolactinaemiaand tardive dyskinesia. Thus, the central question is this- is there a dose of typical antipsychotic that is effective,but does not give rise to typical adverse effects?

Additional complications to this conundrum are the doses oftypical drugs used in practice and whether or not these reflectdoses used in clinical trials. Alongside this, it is also importantto consider the adverse effect burden induced by normal clinicaluse of typical drugs. That is, how toxic are atypicals whenused in clinician-determined doses?

Clinical dosing and adverse effect burden

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Clinical dosing and adverse...

A large number of studies have examined adverse effects inducedby typical drugs in clinical practice. For example, in a cohortof subjects given, on average, the equivalent of 24 mg/day haloperidol¹, Richardson and Craig (1982) noted high levelsof adverse effects despite the use of anticholinergic medication.Of 132 patients examined, 19.7% had parkinsonism-like symptomsand 28% tardive dyskinesia. In a Japanese cohort receivingthe equivalent of 64 mg/day haloperidol, 34.8% of patientsshowed signs of tardive dyskinesia and 40.5% had parkinsonism(Binder et al, 1987). Similar findings were reported for asample 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% withpersistent tardive dyskinesia. 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 medicationwas allowed. Although this might be expected to reduce theprevalence of EPSE, it clearly does not suppress symptoms inall cases. Prophylactic treatment with anticholinergics isalso, it seems, only partly effective (Keepers et al, 1983).

It is clear then that EPSE and tardive dyskinesia are commonlyseen in patients prescribed typical drugs at a wide range ofclinically determined doses. It is also likely that, in practice,the prevalence of these effects is underestimated: patientand prescriber experiences and expectations differ widely (Day et al, 1998),and training in detection of adverse effectseffectively doubles observed prevalence of some adverse effects (Chaplin et al, 1999).

Typicals and EPSE - inexorably linked?

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Typicals and EPSE -...

Clinical trials
Can typical drugs be prescribed such that EPSE do not occur?Surprisingly, there has been little work done specificallyto address this question, but a number of studies have examinedthe therapeutic and (less system-atically) adverse effectsof low dose typicals, particularly haloperidol.

An early study by Ayd (1972) evaluated haloperidol and fluphenazineat a mean dose of 3.4 mg/day. Both drugs were effective atthis dose, but 10/23 subjects suffered EPSE and six of themwere withdrawn from treatment. Later, Van Putten et al (1990)evaluated three doses of haloperidol (5 mg, 10 mg and 20 mg/day).The highest dose was marginally the most effective, but causedrelatively more severe akinesia and akathisia. The 10 mg/dayand 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 associatedwith clinical improvement and a high incidence of EPSE: thetwo outcomes could not be separated by dose. One further fixed-dosestudy (Rifkin et al, 1991) found haloperidol 10 mg/day tobe just as effective as 30 mg/day and 80 mg/day, but no bettertolerated.

In an unusual study, McEvoy and colleagues (1991) establishedthe mean threshold for EPSE in a cohort comprising first episodeand relapsed schizophrenia. Subjects were given haloperidol2 mg/day and the dose increased until rigidity appeared orworsened, or until 10 mg/day was reached. (The dose was reducedto 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 haloperidolrequired 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-naïvesubjects required only 2.1 mg/day (0.5-4 mg/day). These doseswere maintained and response was good (44% were rated as respondersafter 2 weeks) and was not improved by systematic dose increases.Of those maintained on threshold doses, only 4% withdrew becauseof severe EPSE. Overall, this study clearly showed that EPSEare induced by very low daily doses of haloperidol, but thatthese doses appeared to be optimally therapeutic. EPSE andtherapeutic effects could not be separated, since all subjectsexperienced EPSE according to the trial protocol.

The most recent fixed-dose uncontrolled study was that of Stoneand co-workers (1995). Subjects were given haloperidol 4 mg,10 mg or 40 mg/day and evaluated for 2 weeks (n=15). Subjectsgiven 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 therapeuticdose, but gives little information on toxicity on this dose(patient numbers were small and treatment duration only 2 weeks).

In contrast to these findings are the results of perhaps thebest designed, if inadvertent, study of low dose haloperidol (Zimbroff et al, 1997). Ironically, this trial was intendedto evaluate the efficacy of sertindole. Nearly 500 patientswith schizophrenia were enrolled and received one of threedoses 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 ClinicalGlobal Impression Scale and the positive sub-scale of the BriefPsychiatric Rating Scale. However, all three doses of haloperidolproduced similar levels of EPSE (about 40% required anticholinergicdrugs) and all doses, including 4 mg/day, produced substantiallyand significantly more EPSE than placebo. It can be seen then, that in this study 4 mg/day haloperidol was not convincinglyeffective, while producing levels of EPSE no different fromhigher doses. This strongly supports the contention that EPSEappear at essentially sub-therapeutic doses of haloperidoland is, for the most part, in accord with other data presented here.

Plasma level studies
Prescribed dose is an inexact predictor of drug plasma levelobtained because metabolism and distribution of antipsychoticsvary widely. Several trials have attempted to establish a thresholdplasma level for therapeutic response (Van Putten et al, 1992;Levinson et al, 1995; Volvavka et al, 1995; Palao et al, 1996), but none determined 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 EPSEmarked at plasma levels above 1.0 mg/ml, so clearly linkingthe 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 inthe striatum. Typical drugs appear to induce EPSE at striataloccupancies of D₂ receptors of around 75%, which are affordedby doses of around 4 mg/day haloperidol (Farde et al, 1992). Two small studies (total n=9) have reported clinical effectivenessat occupancies lower than 75% (Kapur et al, 1996; Hirschowitz et al, 1997).In the larger study (Kapur et al, 1996), fiveout of seven first-episode subjects responded to 2 mg haloperidoland showed mean striatal occupancies of 67%. Two subjects sufferedvery mild EPSE. In the smaller study, two subjects with ‘minimalprior antipsychotic treatment’ were given 2 mg/day and4 mg/day haloperidol. Both patients responded and showed receptoroccupancies of 51% and 72%, respectively. Only the subjectgiven 2 mg/day haloperidol showed any signs of EPSE - mild akathisia and reduced arm swing.

These studies tentatively suggest that there may be a dose ofhaloperidol that is effective but does not induce EPSE, andthat 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 D₂ occupancies below 75%. In addition, the precision and validity of neuroimaging studies have recentlybeen called into question (Seeman & Tallerico, 1999).

Hyperprolactinaemia
It has long been acknowledged that moderate doses of typicalantipsychotics (approximately equivalent to 15 mg/day haloperidol)cause symptomatic hyperprolactinaemia (Beumont et al, 1974).The dose required to engender a rise in plasma prolactin hasonly been superficially examined. Meltzer and Fang (1976) foundthat the equivalent of 100 mg chlorpromazine given twice daily(equivalent to approximately 5 mg/day haloperidol) caused prolactinto rise within 72 hours in all 27 subjects evaluated. On average,plasma prolactin increased almost fourfold and closely paralleledclinical response. Later, Nishikawa and co-workers (1985) showedthat pimozide 2 mg/day and thioridazine 75 mg/day were subtherapeuticbut clearly raised plasma prolactin (by about 25-100%). Higherdoses of pimozide (6 mg/day, equivalent to 6 mg/day haloperidol)were effective but increased plasma prolactin by approximately400%. More recent studies suggest that prolactin levels beginto rise after as little as 0.5-1.5 mg haloperidol and thathyperprolactinaemia is an unavoidable consequence of the therapeuticuse of typical drugs (Hamner & Arana, 1998).

Tardive dyskinesia
Tardive dyskinesia is a well-recognised long term adverse effectof typical antipsychotics. The risk of tardive dyskinesia seemsto be associated with drug dose (Morgenstern & Glazer, 1993;Chakos et al, 1996) and duration of treatment (van Os et al, 1997).There appears to be no trial that examined thethreshold dose at which the incidence of tardive dyskinesiais increased over that of placebo. However, a number of trialsin older patients have shown that tardive dyskinesia is apparentlyinduced by doses less than 4 mg/day haloperidol equivalents (Toenniessen et al, 1985; Caligiuri et al, 1997; Jeste etal, 1999). Thus, a ‘safe’ therapeutic dose of typical antipsychotics has not been established and, according to limitedevidence, may not exist.

Conclusions

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Conclusions

Typical antipsychotics appear to be widely used in moderatelyhigh doses, which are associated with high prevalences of acuteand chronic movement disorders. Trials of lower doses of typicaldrugs generally indicate that clinically relevant EPSE occurat daily doses that are not clinically effective or at thelower end of the effective dose range. Both hyperprolactinaemiaand, less convincingly, tardive dyskinesia appear to be engenderedby essentially sub-therapeutic doses of typical agents.

It should be noted, however, that this paper is a brief reviewbased 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: butyrophenonesare accepted to produce relatively high rates of movement disorder.

Nevertheless, the trials presented here indicate that, in relapsed schizophrenia, the effective dose of haloperidol is more than4 mg/day. Four very comprehensive reviews support this suggestion (Baldessarini et al, 1988; Kane & Marder, 1993, 1995;Bollini et al, 1994). It appears that EPSE occur at doses of4 mg haloperidol or less and that hyperprolactinaemia is inducedby doses even lower than this one. We can only conclude, therefore,that typical antipsychotics cannot be used effectively withoutgiving rise to typical adverse effects. Moreover, low but effectivedoses seem to cause as many ‘typical’ adverse effectsas higher doses such as those used in the trials of atypicaldrugs. Low-dose typical antipsychotics seem to offer littleor no advantage over higher doses.

References

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