Guidelines for the dosage of antimvchotic drum I
U
H. Beckmann and G.Laux
Beckmann H, Laux C . Guidelines for the dosage of antipsychotic drugs. Acta Psychiatr Scand 1990; 82 (Supp1.358) : 63-66.
Department of Psychiatry, University of Wiirzburg, F.R.G.
Abstract: When commonly recommended guidelines for the dosage of neuroleptic drugs are critically reviewed, unanswered questions outnumber accepted rules. The relationship between dose and therapeutic efficacy remains far from clear, and despite lack of data there has been a trend in recent years to escalate dosage. Average clinical antipsychotic potency correlates closely with the affinity of the drug for dopamine (D2) receptors. Correlations of blood levels of neuroleptics with clinical efficacy are inconsistent. Assessments of immediate and follow-up treatment indicate that moderate doses are adequate for most psychotic patients and fail to support the use of high doses (more than the approximate equivalent of 300-600 mg chlorpromazine daily). Occasionally however, patients, perhaps because of idiosyncratic pharmacokinetics, require higher doses and do not conform to the statistical data for outcome. More precise results for determining the optimum dose of antipsychotic compounds in schizophrenics in the future, may be available from positron emission tomographic (PET) techniques.
One of the most pressing issues facing both clinicians and research workers from 1952 until the present is to determine the dosage of antipsychotic drugs that will provide maximal therapeutic benefit with minimal side effects. Table 1 shows the dose equivalents and recommended daily dose ranges for a variety of neuroleptics. However, the question of dosage equivalency,especially when comparing the so-called low-potency with the high-potency neuroleptics is still far from solved. The relationship between dose and therapeutic efficacy and the problem of appropriate dosage for acute and chronic treatment remain matters of debate. High-potency neuroleptics have traditionally been favoured for the acute treatment of psychotic disorders. During the past few years there has been a trend towards prescribing higher dosages for routine therapy (2,3). Nevertheless,outpatient data and the results of long-term treatment show that there is a preference for low dosage regimens in psychiatric practice on account of better compliance and increasing awareness of the risks of extrapyramidal side effects such as akathisia, parkin-
Drug Chlorpromazine Sulpiride Thioridazine FIuphenazine Haloperidol Pimozide
100 100 100 2-3 1.52.0 1-2
Recommended daily dose range (ms) 25800 100-1000 50-800 2-60 1-100 2-20
Key words: antipsychotic drugs schizophrenia- dopamine receptors H. Beckmann, M. D., Psychiatric Clinic of the University of Wurzburg, Fijchsleinstrasse 15, 0-8700 Wurzburg, F.R.G.
sonism,and tardive dyskinesias,as well as of incapacitating sedation (4)(Table 2).
Defining the optimal dosage Thus, the interest in defining optimal dosages is encouraged by a growing appreciation of the frequency and clinical importance of neurological reactions to antipsychoticagents. Dose-effectrelationship studies in the treatment of acute psychosis are few and vary in the quality of their design. Most have permitted flexible, poorly-controlled dosage regimens; controlled studies with randomized assignment of patients to one of several doses have been relatively rare (1). In the 1970sand early 1980s,“rapid neuroleptization” or “digitalization” using mega-/high-dose regimens to increase the degree and speed of therapeutic response was favoured. However, controlled, prospective, and blindly evaluated trials provided no evidence that addiTable 2. Dosage of antipsychotic drugs in psychiatric practice (n=105). Data from Schijssler (4). Haloperidol
Perazine
Average daily dose (mg)
5.5
195
90
29.6/2weeks
Patients on “IOW do.%” (“h)
59
50
70
43
Length of treatment (days)
714
1980
969
1809
Table 1. Antipsychotic drugs, dose equivalents, and recommendeddaily dose ranges. Data from Mclntyre and Gershon (1). Relative therapeutic potency
U
d
Thioridazine Fluphenazine decanoate
63
Beckmann & Laux tional clinical benefit was derived from dosing at more than the approximate equivalent of 600 mg chlorpromazineor 10-15mg haloperidol or fluphenazine in treating acutely psychotic patients (5). For example, Nedopil et al. (6) found no benefit from either continuous high dosage neuroleptic treatment or very high initial neuroleptization,only a greater frequency of extrapyramidal symptoms in the patients treated with higher doses (3 mg vs 12 mg, 6 mg vs 40 mg of benperidol) (Fig. 1) Previously, Davis et al. (7) had suggested that there was a dose-response relationship which indicated that moderate doses (600-900 mg chlorpromazine), seemed to be optimal for most patients. However, the dose ranges might differ from patient to patient.
Plasma levels Blood levels of neuroleptics have been estimated in more than 100 studies, but the results have been inconsistent and with no consensus on whether blood levels correlate with clinical effects (8). The problem has, however, been stimulated by the introduction of new techniques (high performance liquid chromatography, radioimmunoassay, neuroleptic radioreceptor assay) and improvements in the design of studies. In consequence, a "therapeutic window" for plasma haloperidol of between 4 and 14 ng/ml has been suggested (9-10). Furthermore, the incidence of extrapyramidal symptoms has been reported as being highly correlated to the concentrations of the drug in plasma and cerebrospinal fluid ( 1 1).
Dopamine receptor blockade Pharmacological studies have revealed a close correlation between average clinical potency and drug affinity for dopamine D2 receptors (r = -0.80) (12,13) (Fig. 2).
Recently, a well-defined curvilinear relationship between plasma level and dopamine receptor occupancy based on positron emission tomographic (PET) studies has been reported (14,15). At very low plasma haloperidol levels, receptor blockade increased rapidly with small increases in the level. The increase in blockade then tapered off at 5 - 15 ng/ml; above 20 ng/ml relatively little additional increase in receptor blockade could be measured, even with marked increases in plasma levels. This is in remarkable agreement with clinical experience that there is little added benefit as plasma haloperidol levels rise above 20 ngml(l6) and a strong argument for the clinical merit of measuring plasma neuroleptic drug levels. Interestingly, since comparable degrees of receptor blockade were found in both responders and non-responders ( 13, inconsistencies in clinical response at "therapeutic" plasma levels might reflect differences in biological features rather than variability in the pharmacokinetic relationship between plasma level and blockade. Among the factors that may have an important influence on the dosage regimen of antipsychotics are pharmacokinetic variables such as individual metabolism, bioavailability, age, and weight. Additionally, the relevance of the clinical subtypes of schizophrenia must be emphasized.
The concept of a neuroleptic threshold The concept of a neuroleptic threshold offers clinicians psychomotor and psychometric indicators for the operational definition of minimum effective dose (17) (Fig. 3). According to this hypothesis, which has not yet been adequately tested, the first appearance of slight hypokinesia-rigidityduring acute neuroleptic treatment heralds the achievement of an optimal neuroleptic dose (Fig. 3). This concept is limited to conventional neuroleptics, and is not valid for so-called atypical
:t -
1
1
0
1
2
4
I
I
7
14
I
0.1
21
Time (days)
Fig. I. Psychopathologicalchanges - Brief Psychiatric Rating Scale (BPRS) total score - during 20 days' treatment with high-dose (40 mg) versus low-dose (6 mg) benperidol in acute schizophrenic patients. (From Nedopil et al. 1985)
64
10
100
1000
Range and average clinical dose lor conlrol ot schizophrenia[mgday)
Fig. 2. Correlation of clinical dose with neuroleptic affinity for dopamine receptor binding. (Modified from Peroutka and Snyder
1980)
Dosage of antipsychotic drugs
!
I
I I
I I
100 -
0I
I
ME0 Dose
Fig. 3. The relationship between neuroleptic dose, therapeutic response, and hypokinesia-rigidity. MED = the minimum effective dose range. The solid line represents the dose-response curve.
antipsychotics such as clozapine or sulpiride. A linear relationship between the peak plasma concentration, the area under the concentration-versus-time curve, and the administered dose in the range 10-100mg has recently been found for remoxipride (1 8).
Pattern of dosage during treatment The regimen shown in Fig. 4 has been established. After reduction of the acute symptoms the dose is reduced to the critical point of the theoretical minimal effective dose. Too low a dose may increase the risk of relapse, too high a dose the risk of non-compliance due to discomfort and the risk of tardive dyskinesias. Deter12 14 100
12 10 \
Standard Low EE Standard \
'
\
\
\
\
4
c .
Tlme
Fig. 4. Maintenance antipsychotic drug treatment - clinical model and procedure.
mination of lowest effective dose must therefore be regarded as the critical factor. A closer look at the data in favour of high-dose strategies shows that an increased therapeutic effect was seen only in chronic patients who were resistant to standard doses. Thus, high doses may be useful for some patients who fail to achieve reasonable plasma levels on the standard dose. However, this point has not so far been fully explored. Studies of maintenance antipsychotic drug treatment conducted in recent years have focused on alternative strategies to reduce cumulative exposure to neuroleptics (19). Amongst these are intermittent strategies and low dose versus standard dose regimens. The overall results suggest that most chronic psychotic patients can be maintained on doses of neuroleptic as low as one-fifth of those commonly employed (20). Recently, this has been confirmed by Hogarty et al. (21) who compared fluphenazine decanoate 25 mg vs 3.8 mg every two weeks and in addition included familial expressed emotion as a co-factor (Fig. 5). However, patients in the minimal dosehigh expressed emotion category experienced more minor but aborted episodes in year 2. Side effects were fewer on the minimal dose and these recipients enjoyed significantly greater improvement in their instrumental and interpersonal performances.
Minimal,. High EE
I I
0
100
200
I
300
400
Days in Year 2 Fit?. 5. Survival in year 2 without minor episode according to dose of fluphenazine decanoate (standard =25 mg every two weeks, minimal = 3.8 mg every two weeks, average)and expressed emotion (EE) of household. Numbers on lines numbers of patients. (From Hogarty et al. 1988)
Conclusions The commonly recommended guidelines for the dosage of neuroleptics remain far from definitive. Assessment of immediate and follow-up treatment indicates that moderate doses are adequate for most psychotic patients. After the era of mega-doses the strategy nowadays is to treat with the minimal effective dose which must be titrated individually. The possibility of (extrapyramidal)side effects means that the benefit-risk 65
Beckmann & Laux ratio must always be kept in mind. In the long-term, most patients can be maintained successfully with doses as low as about one-fifth of the standard dose employed. However, the occasional patient, perhaps because of a pharmacokinetic idosyncrasy, requires a higher dose than standard. Monitoring of plasma levels in non-responders is to be recommended. More precise guidance for determining the optimum dose of antipsychotic drugs may in future be provided by PET techniques.
References 1. McINTRYRE, GERHSON S . Interpatient variations in anti-psychotic
therapy. J Clin Psychiatry 1985; 46: 3-5. 2. BALDESSARINI RJ, KA'IZ B, COTTON P. Dissimilar dosing with high-potency and low-potency neumleptics. Am J Psychiatry 1984; I4 I :748-752. 3. KONIG W, KUNOW J, KNIEHL R, REIMER F. Neuroleptics in the treatment of schizophrenia: Have there been changes in the dosage regimen'! Pharmacopsychiatr 1986; 19212-213. 4. SCHUSSLER G. Medikarnentase Behandlung von schizophrenen Patienten in der neweniztlichcn Praxis. In: Linden M, Lipski C, Pietzcker A, eds. Der schizophrene Patient in der Nervenarztpraxis. Stuttgart, New York: Thieme, 1985: 45-53. 5 . NEBORSKY R, JANKOWSKY D, MUNSON E, DEPRY D. Rapid treatment of acute psychotic symptoms with high- and low-dose haloperidol. ArchGen Psychiatry 1981; 38: 195-199. 6. NEDOPIL N, EBEN E, KLElN H, KRUGER R, RUTHER E, SCHMAUSS M. High-dosage neuroleptic therapy for acute schizophrenic patients - two double-blind studies with benperidol. Phannacopsychiah- 1985; 18: 63-66. 7. DAVIS JM, SCHAFFER CB, KILLIAN GA, KINARD C. CHAN C. Important issues in the drug treatment of schizophrenia. SchizophrBull 1980; 1: 70-84. 8. KO GN, KORPl ER, LINNOILA M. On the clinical relevance and methods of quantification of plasma concentrations of neuroleptics. J Clin P s y c h o p h m ~ o 1985: l 5: 253-262. 9. SMITH RC, VROULIS G, SHVARTSBURD A. RBC and plasma
levels of haloperidol and clinical response in .xhizophrenia. Am J Psychiatry 1983; 139: 1054-1056. 10.MAVROlDIS ML, HIRSCHOWITZ J, KANTER D. Clinical response and plasma haloperidol levels in schizophrenia. Psychopharmacology 1983; 8 I: 354356. I 1 .SEDVALL G, GRIMM VE: Cerebrospinal fluid and plasma as tools for obtaining biochemical and phannacokinetic daVa in neuroleptic therapy. In: Burrows GD, Norman TR, eds. Psychotmpic drugs. Plasma concentrations and clinical response. New Yo&: Marcel Dekker, I98 1 : 33 1-360. 12.PEROUTKA SJ, SNYDER SH. Relationship of neuroleptic drug effects at brain dopamine, serotonin, a-adrenergic, and histamine receptors toclinical potency. Am J Psychiatry 1980; 137: 1518-1522. 13.RICHELSON E. Neuroleptic affinities for human brain receptors and their use in predicting adverse effects. J Clin Psychiatry 1984; 45: 331-336. 14.FARDE L, WIESEL FA, HALLDIN C, SEDVALL G. Central D2-dopunine receptor occupancy in schizophrenicpatients treated with antipsychotic drugs. Arch Gen Psychiatiy 1988; 45: 71-76. IS.WOLKIN A, BRODIE JD, BAROUCHE F, ROTROSEN J. Dopamine receptor occupancy and plasma haloperidol levels. Arch Gen Psychiatry 1989; 46:482483. I6.BALDESSARINI RJ,COHEN BM, TEICHER HM. Significance of neumleptic dose and plasma level in the phmiacological treatment of psychoses. Arch Gen Psychiatry 1988; 45: 79-88. 17.HAASE H J, JANSSEN PAJ. The action of neuroleptic drugs. Chicago: Year Book, 1965. 1X.GRIND M, NILSSON M-I, NILSSON L, OXENSTIERNA G, SEDVALL G, WAHLEN A. Remoxipride - a new potential antipsychotic compound. Tolerability and phmacokinetics after single oral and intravenous administration in healthy male volunteers. Psychopharmacology 1989; 98: 304-309. 19.KANE JM, LIEBERMAN JA. Maintenance pharmacotherapy in schizophrenia. Psychopharmacology 1987: 113: 1103-1109. 20.KANE JM, WOERNER M, SARANTAKOS S. Depot neuroleptics: comparative review of standard. intermediate and low-dose regimens. J Clin Psychiatry 1986; 47: 30-33. 21.HOGARTY GE, McEVOY JP, MUNETZ M, et al. Dose of fluphenazine, familial expressed emotion; and outcome in schizophrenia. Arch Gen Psychiatry 1988; 45: 797-80.5.
U
H. Beckmann and G.Laux
Beckmann H, Laux C . Guidelines for the dosage of antipsychotic drugs. Acta Psychiatr Scand 1990; 82 (Supp1.358) : 63-66.
Department of Psychiatry, University of Wiirzburg, F.R.G.
Abstract: When commonly recommended guidelines for the dosage of neuroleptic drugs are critically reviewed, unanswered questions outnumber accepted rules. The relationship between dose and therapeutic efficacy remains far from clear, and despite lack of data there has been a trend in recent years to escalate dosage. Average clinical antipsychotic potency correlates closely with the affinity of the drug for dopamine (D2) receptors. Correlations of blood levels of neuroleptics with clinical efficacy are inconsistent. Assessments of immediate and follow-up treatment indicate that moderate doses are adequate for most psychotic patients and fail to support the use of high doses (more than the approximate equivalent of 300-600 mg chlorpromazine daily). Occasionally however, patients, perhaps because of idiosyncratic pharmacokinetics, require higher doses and do not conform to the statistical data for outcome. More precise results for determining the optimum dose of antipsychotic compounds in schizophrenics in the future, may be available from positron emission tomographic (PET) techniques.
One of the most pressing issues facing both clinicians and research workers from 1952 until the present is to determine the dosage of antipsychotic drugs that will provide maximal therapeutic benefit with minimal side effects. Table 1 shows the dose equivalents and recommended daily dose ranges for a variety of neuroleptics. However, the question of dosage equivalency,especially when comparing the so-called low-potency with the high-potency neuroleptics is still far from solved. The relationship between dose and therapeutic efficacy and the problem of appropriate dosage for acute and chronic treatment remain matters of debate. High-potency neuroleptics have traditionally been favoured for the acute treatment of psychotic disorders. During the past few years there has been a trend towards prescribing higher dosages for routine therapy (2,3). Nevertheless,outpatient data and the results of long-term treatment show that there is a preference for low dosage regimens in psychiatric practice on account of better compliance and increasing awareness of the risks of extrapyramidal side effects such as akathisia, parkin-
Drug Chlorpromazine Sulpiride Thioridazine FIuphenazine Haloperidol Pimozide
100 100 100 2-3 1.52.0 1-2
Recommended daily dose range (ms) 25800 100-1000 50-800 2-60 1-100 2-20
Key words: antipsychotic drugs schizophrenia- dopamine receptors H. Beckmann, M. D., Psychiatric Clinic of the University of Wurzburg, Fijchsleinstrasse 15, 0-8700 Wurzburg, F.R.G.
sonism,and tardive dyskinesias,as well as of incapacitating sedation (4)(Table 2).
Defining the optimal dosage Thus, the interest in defining optimal dosages is encouraged by a growing appreciation of the frequency and clinical importance of neurological reactions to antipsychoticagents. Dose-effectrelationship studies in the treatment of acute psychosis are few and vary in the quality of their design. Most have permitted flexible, poorly-controlled dosage regimens; controlled studies with randomized assignment of patients to one of several doses have been relatively rare (1). In the 1970sand early 1980s,“rapid neuroleptization” or “digitalization” using mega-/high-dose regimens to increase the degree and speed of therapeutic response was favoured. However, controlled, prospective, and blindly evaluated trials provided no evidence that addiTable 2. Dosage of antipsychotic drugs in psychiatric practice (n=105). Data from Schijssler (4). Haloperidol
Perazine
Average daily dose (mg)
5.5
195
90
29.6/2weeks
Patients on “IOW do.%” (“h)
59
50
70
43
Length of treatment (days)
714
1980
969
1809
Table 1. Antipsychotic drugs, dose equivalents, and recommendeddaily dose ranges. Data from Mclntyre and Gershon (1). Relative therapeutic potency
U
d
Thioridazine Fluphenazine decanoate
63
Beckmann & Laux tional clinical benefit was derived from dosing at more than the approximate equivalent of 600 mg chlorpromazineor 10-15mg haloperidol or fluphenazine in treating acutely psychotic patients (5). For example, Nedopil et al. (6) found no benefit from either continuous high dosage neuroleptic treatment or very high initial neuroleptization,only a greater frequency of extrapyramidal symptoms in the patients treated with higher doses (3 mg vs 12 mg, 6 mg vs 40 mg of benperidol) (Fig. 1) Previously, Davis et al. (7) had suggested that there was a dose-response relationship which indicated that moderate doses (600-900 mg chlorpromazine), seemed to be optimal for most patients. However, the dose ranges might differ from patient to patient.
Plasma levels Blood levels of neuroleptics have been estimated in more than 100 studies, but the results have been inconsistent and with no consensus on whether blood levels correlate with clinical effects (8). The problem has, however, been stimulated by the introduction of new techniques (high performance liquid chromatography, radioimmunoassay, neuroleptic radioreceptor assay) and improvements in the design of studies. In consequence, a "therapeutic window" for plasma haloperidol of between 4 and 14 ng/ml has been suggested (9-10). Furthermore, the incidence of extrapyramidal symptoms has been reported as being highly correlated to the concentrations of the drug in plasma and cerebrospinal fluid ( 1 1).
Dopamine receptor blockade Pharmacological studies have revealed a close correlation between average clinical potency and drug affinity for dopamine D2 receptors (r = -0.80) (12,13) (Fig. 2).
Recently, a well-defined curvilinear relationship between plasma level and dopamine receptor occupancy based on positron emission tomographic (PET) studies has been reported (14,15). At very low plasma haloperidol levels, receptor blockade increased rapidly with small increases in the level. The increase in blockade then tapered off at 5 - 15 ng/ml; above 20 ng/ml relatively little additional increase in receptor blockade could be measured, even with marked increases in plasma levels. This is in remarkable agreement with clinical experience that there is little added benefit as plasma haloperidol levels rise above 20 ngml(l6) and a strong argument for the clinical merit of measuring plasma neuroleptic drug levels. Interestingly, since comparable degrees of receptor blockade were found in both responders and non-responders ( 13, inconsistencies in clinical response at "therapeutic" plasma levels might reflect differences in biological features rather than variability in the pharmacokinetic relationship between plasma level and blockade. Among the factors that may have an important influence on the dosage regimen of antipsychotics are pharmacokinetic variables such as individual metabolism, bioavailability, age, and weight. Additionally, the relevance of the clinical subtypes of schizophrenia must be emphasized.
The concept of a neuroleptic threshold The concept of a neuroleptic threshold offers clinicians psychomotor and psychometric indicators for the operational definition of minimum effective dose (17) (Fig. 3). According to this hypothesis, which has not yet been adequately tested, the first appearance of slight hypokinesia-rigidityduring acute neuroleptic treatment heralds the achievement of an optimal neuroleptic dose (Fig. 3). This concept is limited to conventional neuroleptics, and is not valid for so-called atypical
:t -
1
1
0
1
2
4
I
I
7
14
I
0.1
21
Time (days)
Fig. I. Psychopathologicalchanges - Brief Psychiatric Rating Scale (BPRS) total score - during 20 days' treatment with high-dose (40 mg) versus low-dose (6 mg) benperidol in acute schizophrenic patients. (From Nedopil et al. 1985)
64
10
100
1000
Range and average clinical dose lor conlrol ot schizophrenia[mgday)
Fig. 2. Correlation of clinical dose with neuroleptic affinity for dopamine receptor binding. (Modified from Peroutka and Snyder
1980)
Dosage of antipsychotic drugs
!
I
I I
I I
100 -
0I
I
ME0 Dose
Fig. 3. The relationship between neuroleptic dose, therapeutic response, and hypokinesia-rigidity. MED = the minimum effective dose range. The solid line represents the dose-response curve.
antipsychotics such as clozapine or sulpiride. A linear relationship between the peak plasma concentration, the area under the concentration-versus-time curve, and the administered dose in the range 10-100mg has recently been found for remoxipride (1 8).
Pattern of dosage during treatment The regimen shown in Fig. 4 has been established. After reduction of the acute symptoms the dose is reduced to the critical point of the theoretical minimal effective dose. Too low a dose may increase the risk of relapse, too high a dose the risk of non-compliance due to discomfort and the risk of tardive dyskinesias. Deter12 14 100
12 10 \
Standard Low EE Standard \
'
\
\
\
\
4
c .
Tlme
Fig. 4. Maintenance antipsychotic drug treatment - clinical model and procedure.
mination of lowest effective dose must therefore be regarded as the critical factor. A closer look at the data in favour of high-dose strategies shows that an increased therapeutic effect was seen only in chronic patients who were resistant to standard doses. Thus, high doses may be useful for some patients who fail to achieve reasonable plasma levels on the standard dose. However, this point has not so far been fully explored. Studies of maintenance antipsychotic drug treatment conducted in recent years have focused on alternative strategies to reduce cumulative exposure to neuroleptics (19). Amongst these are intermittent strategies and low dose versus standard dose regimens. The overall results suggest that most chronic psychotic patients can be maintained on doses of neuroleptic as low as one-fifth of those commonly employed (20). Recently, this has been confirmed by Hogarty et al. (21) who compared fluphenazine decanoate 25 mg vs 3.8 mg every two weeks and in addition included familial expressed emotion as a co-factor (Fig. 5). However, patients in the minimal dosehigh expressed emotion category experienced more minor but aborted episodes in year 2. Side effects were fewer on the minimal dose and these recipients enjoyed significantly greater improvement in their instrumental and interpersonal performances.
Minimal,. High EE
I I
0
100
200
I
300
400
Days in Year 2 Fit?. 5. Survival in year 2 without minor episode according to dose of fluphenazine decanoate (standard =25 mg every two weeks, minimal = 3.8 mg every two weeks, average)and expressed emotion (EE) of household. Numbers on lines numbers of patients. (From Hogarty et al. 1988)
Conclusions The commonly recommended guidelines for the dosage of neuroleptics remain far from definitive. Assessment of immediate and follow-up treatment indicates that moderate doses are adequate for most psychotic patients. After the era of mega-doses the strategy nowadays is to treat with the minimal effective dose which must be titrated individually. The possibility of (extrapyramidal)side effects means that the benefit-risk 65
Beckmann & Laux ratio must always be kept in mind. In the long-term, most patients can be maintained successfully with doses as low as about one-fifth of the standard dose employed. However, the occasional patient, perhaps because of a pharmacokinetic idosyncrasy, requires a higher dose than standard. Monitoring of plasma levels in non-responders is to be recommended. More precise guidance for determining the optimum dose of antipsychotic drugs may in future be provided by PET techniques.
References 1. McINTRYRE, GERHSON S . Interpatient variations in anti-psychotic
therapy. J Clin Psychiatry 1985; 46: 3-5. 2. BALDESSARINI RJ, KA'IZ B, COTTON P. Dissimilar dosing with high-potency and low-potency neumleptics. Am J Psychiatry 1984; I4 I :748-752. 3. KONIG W, KUNOW J, KNIEHL R, REIMER F. Neuroleptics in the treatment of schizophrenia: Have there been changes in the dosage regimen'! Pharmacopsychiatr 1986; 19212-213. 4. SCHUSSLER G. Medikarnentase Behandlung von schizophrenen Patienten in der neweniztlichcn Praxis. In: Linden M, Lipski C, Pietzcker A, eds. Der schizophrene Patient in der Nervenarztpraxis. Stuttgart, New York: Thieme, 1985: 45-53. 5 . NEBORSKY R, JANKOWSKY D, MUNSON E, DEPRY D. Rapid treatment of acute psychotic symptoms with high- and low-dose haloperidol. ArchGen Psychiatry 1981; 38: 195-199. 6. NEDOPIL N, EBEN E, KLElN H, KRUGER R, RUTHER E, SCHMAUSS M. High-dosage neuroleptic therapy for acute schizophrenic patients - two double-blind studies with benperidol. Phannacopsychiah- 1985; 18: 63-66. 7. DAVIS JM, SCHAFFER CB, KILLIAN GA, KINARD C. CHAN C. Important issues in the drug treatment of schizophrenia. SchizophrBull 1980; 1: 70-84. 8. KO GN, KORPl ER, LINNOILA M. On the clinical relevance and methods of quantification of plasma concentrations of neuroleptics. J Clin P s y c h o p h m ~ o 1985: l 5: 253-262. 9. SMITH RC, VROULIS G, SHVARTSBURD A. RBC and plasma
levels of haloperidol and clinical response in .xhizophrenia. Am J Psychiatry 1983; 139: 1054-1056. 10.MAVROlDIS ML, HIRSCHOWITZ J, KANTER D. Clinical response and plasma haloperidol levels in schizophrenia. Psychopharmacology 1983; 8 I: 354356. I 1 .SEDVALL G, GRIMM VE: Cerebrospinal fluid and plasma as tools for obtaining biochemical and phannacokinetic daVa in neuroleptic therapy. In: Burrows GD, Norman TR, eds. Psychotmpic drugs. Plasma concentrations and clinical response. New Yo&: Marcel Dekker, I98 1 : 33 1-360. 12.PEROUTKA SJ, SNYDER SH. Relationship of neuroleptic drug effects at brain dopamine, serotonin, a-adrenergic, and histamine receptors toclinical potency. Am J Psychiatry 1980; 137: 1518-1522. 13.RICHELSON E. Neuroleptic affinities for human brain receptors and their use in predicting adverse effects. J Clin Psychiatry 1984; 45: 331-336. 14.FARDE L, WIESEL FA, HALLDIN C, SEDVALL G. Central D2-dopunine receptor occupancy in schizophrenicpatients treated with antipsychotic drugs. Arch Gen Psychiatiy 1988; 45: 71-76. IS.WOLKIN A, BRODIE JD, BAROUCHE F, ROTROSEN J. Dopamine receptor occupancy and plasma haloperidol levels. Arch Gen Psychiatry 1989; 46:482483. I6.BALDESSARINI RJ,COHEN BM, TEICHER HM. Significance of neumleptic dose and plasma level in the phmiacological treatment of psychoses. Arch Gen Psychiatry 1988; 45: 79-88. 17.HAASE H J, JANSSEN PAJ. The action of neuroleptic drugs. Chicago: Year Book, 1965. 1X.GRIND M, NILSSON M-I, NILSSON L, OXENSTIERNA G, SEDVALL G, WAHLEN A. Remoxipride - a new potential antipsychotic compound. Tolerability and phmacokinetics after single oral and intravenous administration in healthy male volunteers. Psychopharmacology 1989; 98: 304-309. 19.KANE JM, LIEBERMAN JA. Maintenance pharmacotherapy in schizophrenia. Psychopharmacology 1987: 113: 1103-1109. 20.KANE JM, WOERNER M, SARANTAKOS S. Depot neuroleptics: comparative review of standard. intermediate and low-dose regimens. J Clin Psychiatry 1986; 47: 30-33. 21.HOGARTY GE, McEVOY JP, MUNETZ M, et al. Dose of fluphenazine, familial expressed emotion; and outcome in schizophrenia. Arch Gen Psychiatry 1988; 45: 797-80.5.
