Dosage patterns of antipsychotic drugs forthe treatment of schizophrenia in Swedishambulatory clinical practice �/ a highlyindividualized therapyKERSTIN BINGEFORS, DAG ISACSON, EVA LINDSTROM*

Bingefors K, Isacson D, Lindstrom E. Dosage patterns of antipsychotic drugs for the treatmentof schizophrenia in Swedish ambulatory clinical practice �/ a highly individualized therapy. NordJ Psychiatry 2003;57:263�/269. Oslo. ISSN 0803-9488.

Objective: To analyse the dosage pattern of antipsychotic drugs for schizophrenia in ambulatorycare in Sweden. Method: The study was based on a nationwide consecutive weekly randomsample of physicians during the period 1991�/98 comprising 265,331 visits. Results: In 515 visits(0.19%), antipsychotics were prescribed for schizophrenia. More than one antipsychotic (50different combinations) was prescribed in 20% of the visits. Patients received higher total dailydoses when prescribed more than one antipsychotic drug; mean dose in monotherapy was 210.7chlorpromazine equivalents (CPZeq) and in polytherapy 406.8 CPZeq. Conclusion: Antipsy-chotics, in contrast to current recommendations, were prescribed as highly individualizedtherapies in a wide variety of doses and with a high frequency of polypharmacy. Thecombinations used are often unsuitable and may lead to unnecessary adverse effects.� Antipsychotics, Polypharmacy, Pharmacoepidemiology, Prescribing, Schizophrenia.

Kerstin Bingefors, M.Sc., Ph.D., Departments of Neuroscience, Psychiatry, and Pharmacy,Uppsala University, Biomedical Centre, Box 580, SE-751 23 Uppsala, Sweden, E-mail:Chris.Bingefors@farmaci.uu.se; Accepted 26 March 2002.

Recently, the discussion on antipsychotic drug treat-

ment of schizophrenia in clinical practice has been

intensified in the light of studies showing poor con-

cordance with recommendations for achieving optimal

therapeutic effectiveness with as few adverse effects as

possible (1�/6).

Antipsychotic drug treatment is one of the corner-

stones in the treatment of patients with schizophrenia.

The first report published on the efficacy of neuroleptics

in the schizophrenic syndrome was published by Delay

& Deniker in 1952 (7) and even today, the most effective

treatment for schizophrenia is symptomatic and involves

the use of antipsychotic drugs. The efficacy of anti-

psychotic drugs in treatment of schizophrenia and

schizophrenia-like psychosis is well documented. How-

ever, antipsychotic drugs have also caused serious side-

effects including tardive dyskinesia (8).

Discussions concerning dose regimes have continued

since 1955, when the benefit of high-dose therapy,

‘‘neuroleptization’’ was presented (9). Others considered

that high doses were no more effective than moderate

doses, i.e. daily doses of about 400�/600 mg chlorpro-

mazine (10). The dangers of excessive dosing �/ more

side-effects, sedation and sudden death �/ have been

discussed in the literature since the early 1980s (11�/14).

Higher doses of neuroleptics have also been demon-

strated to worsen cognitive function (15). The majority

of studies with haloperidol show that there is no

advantage in exceeding standard doses (1, 2, 16).

Polypharmacy, i.e. the concomitant use of two or more

antipsychotics, is considered to increase adverse effects

due to higher total doses (17) and/or unpredictable

interaction effects.

Recommended, evidence-based use of antipsychotic

drugs in Sweden today, according to the Swedish

Council on Technology Assessment in Medicine (SBU)

(18), is for patients with severe psychosis only. Moreover,

when prescribing antipsychotic drugs to individuals with

a severe psychotic disorder, monotherapy is strongly

* Declaration of interest: Associate professor EvaLindstrom is the Swedish editor of the Nordic Journal ofPsychiatry.

# 2003 Taylor & Francis DOI: 10.108008039480310002066

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recommended. The dose prescribed should be the lowest

effective dose. The recommendations have been widelycommunicated to physicians.

Costs for antipsychotic treatment are rising with the

introduction of new drugs. In 1991, the total sales of

neuroleptic drugs in Sweden amounted to 178 million

SEK (1 GBP�/15.2 SEK 2001); in 1997, total sales had

increased to 251 million SEK, and in 2000 to 332 million

SEK (19, 20). It has been estimated that only two-thirds

of the sales is spent on antipsychotics prescribed topatients with a psychotic disorder, the rest (one-third) is

spent on antipsychotics given to patients with non-

psychotic disorders (21). Costs for antipsychotics to

psychotic patients in hospital treatment did not increase

during the period. The entire cost increase can be

attributed to sales in ambulatory care.

As mentioned, studies from various countries have

shown that dosage regimens of particularly conventionalantipsychotics often are in excess of guidelines and that

patients receive combination therapy with more than

one antipsychotic (4, 22�/27). However, these studies are

often performed on selected patient groups from hospi-

tals, specified clinics, or insurance populations.

Recommendations are clear, but there are indications

that concordance in clinical practice is low. Therefore,

the aim of the present investigation was to study theprescription pattern of antipsychotic drugs for schizo-

phrenic patients in ambulatory care in Sweden with

respect to daily dose, type of antipsychotic drug, and the

use of monotherapy vs. combined therapies.

Material and MethodsThe Diagnosis and Therapy study is a nationwide study

of prescribing in Sweden (9 million inhabitants). A

consecutive random sample of all doctors each partici-

pate during 1 week. A copy of the prescription form

given to the patient provides information on the drug

prescribed, and certain patient and doctor characteris-tics. The reporting form also requires the physician to

state the diagnosis that led to the prescription. Partici-

pation is voluntary and 65�/70% of selected physicians

participated in the study until 1998; the participation

rate has since decreased considerably. The survey is

carried out in collaborations with the Swedish Medical

Association, the Medical Products Agency, Swedish

Pharmaceutical Data Inc., and the National Corpora-tion of Swedish Pharmacies (28). Due to the decreased

participation rate, the present study used information

collected from 1 April 1991 to 31 March 1998.

In the Diagnosis and Therapy Survey, diagnoses are

classified according to the Swedish version of the

International Classification of Diseases, 9th version

(ICD-9) (29). Medications prescribed are classified

according to the Anatomical-Therapeutical Classifica-tion (ATC) system recommended by the WHO (30). In

Sweden, a prescription can enable the patient to receive

drugs for up to 3 months, with an option to give up to 11repeats (before 1 January 1997) or three repeats (after 1

January 1997) covering drug use for a total of 1 year at

the same visit.

The database is based on individual prescriptions.

Since one patient may get two or more prescriptions in

one visit, we transformed the material into a visit-based

format where all prescriptions issued for antipsychotics

in one visit were summed up. Oral depot neurolepticswere analysed separately since the prescribed dose is not

given in the register. In these cases, the theoretical dose

made available for the patient was calculated from the

amount of drug prescribed. Unfortunately, we were not

able to calculate reliable doses prescribed for injectable

depot neuroleptics.

Statistical methodsAll statistical analyses were performed using the SAS

statistical analysis system (SAS Institute Inc., 1987). The

mean doses for each antipsychotic prescribed was

calculated using the daily dose prescribed by the

physician. The daily doses prescribed were also trans-

formed into chlorpromazine equivalents (CPZeq) (20).

Significance in differences between means was tested

using the t-test; when variances were unequal, theCochran approximation was employed.

ResultsDuring the study period 1990�/98, 265,331 patient-visitswere registered in the Diagnosis-Therapy Study. The

number of visits was higher during the start than during

the end of the study period, a mean of 38,000 visits

approximately the first 2 years compared with a mean of

27,000 visits approximately the last 2 years. At 515 visits

(0.19%), antipsychotic drugs were prescribed to patients

diagnosed as schizophrenics. Thus, the antipsychotic-

treated group consisted of 515 patients, diagnosed asschizophrenics according to ICD-9. The sex and age

distribution is shown in Table 1. The proportion of visits

due to schizophrenia, when antipsychotics were pre-

scribed, decreased during the study period, from 0.22%

in the first half of the study to 0.17% during the second

half of the study.

In total, 653 prescriptions for antipsychotics were

issued for the 515 patients with a diagnosis of schizo-phrenia. The majority of prescriptions for antipsychotics

(82.9%) were issued by psychiatrists. However, 6.4% of

the prescriptions were issued by specialists in internal

medicine, 4.3% by general practitioners (GPs) and 5.2%

by doctors in training (Table 1). The prescription

pattern, with respect to chemical compounds, changed

during the study period. In the first 2 years, 55.3% of the

prescriptions were for phenthiazines, compared with34,3% during the last 2 years. The prescribing of

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butyrophenones and thioxanthenes also decreased, from

10.6% to 4.9% and from 22.1% to 18.3%, respectively.

There was an increase in the prescribing of clozapine,

from 5.5% to 23.0%. Risperidone was prescribed in

13.9% of visits during the last period.

In 421/515 visits, one antipsychotic drug was pre-

scribed; in 81 visits, two different antipsychotics were

prescribed; in 12 visits, three different antipsychotics;

and in one visit, four different antipsychotics. Since it

was not possible to calculate a mean daily dose for

patients on depot medication, these were excluded.

Separate analyses were carried out for antipsychotic

drugs prescribed as monotherapy and for drugs pre-

scribed as combination therapy. After the exclusion of

depot preparations, 353 visits with monotherapy (Table2) and 66 visits with polytherapy (Table 3) remained. In

19 visits with polytherapy, a depot preparation was one

of the drugs prescribed.

Table 2 shows the mean daily dose (mg/day and

CPZeq) for each drug at visits where monotherapy was

prescribed. There were large variations in dosage be-

tween different drugs; the mean daily dose was 210.7

CPZeq.Table 3 shows the mean daily dose (mg/day for each

substance and CPZeq) for each drug prescribed in visits

where two or more antipsychotic drugs were prescribed

at the same time and to the same patient. There was no

significant difference between the mean dose in patients

with monotherapy or combination therapy with respect

to mean dose for each substance. However, the mean

total daily dose in combination therapy, 406.8 CPZeq,was considerably higher than in monotherapy.

Further linear regression analyses (not shown) showed

that patient gender and age significantly influenced the

dose prescribed. Men received higher average doses (�/

66.5 CPZeq, P�/0.011) and doses decreased by age (�/

2.1 CPZeq/year, P�/0.028).

In all, 16 different substances were prescribed in 50

different combinations. At visits when more than oneantipsychotic drug were prescribed, two different anti-

psychotics were prescribed at 81 visits, three different

antipsychotics at 12 visits, and four different antipsy-

chotics at one visit. The combinations used in therapy

with two antipsychotics are shown in Table 4. The most

prescribed antipsychotic drugs in combination therapy

(with another antipsychotic drug) was levomeproma-

zine, 43.6%, followed by thioridazine, 29.8%, haloper-idol, 23.4%, perphenazine, 22.3% and zuklopenthixol,

22.3%.

DiscussionThe present study showed that antipsychotic drugs, in

contrast to current recommendations, are prescribed as

highly individualized therapies in a wide variety of doses

and with a high frequency of polypharmacy in ambula-

tory care in Sweden. In discussing the results, it is

important to emphasize that this study is based on

maintenance treatment in ambulatory care only.The prescription has been called the final common

pathway in therapeutic decision making (31). It has also

been shown that prescribing is influenced by several

non-medical factors, such as physician prescribing

habits, type of practice and patient load (32). The

main advantage of our study is that it covers a

consecutive nationwide sample of prescribers and thus

does not reflect local variations, which are relativelypronounced in Sweden (20).

Table 1. Visits for schizophrenia (n�/515) where antipsycho-tics were prescribed, Diagnosis-Therapy study 1990�/98.

Characteristic Number Proportion (%)

Physician specialty

Psychiatry 427 82.9

Internal Medicine 33 6.4

General practice 22 4.3

In training 27 5.2

Others 6 1.2

Patient gender

Women 234 45.4

Men 259 50.3

Missing 22 4.3

Patient age

0�/24 10 1.9

25�/44 247 48.0

45�/64 189 36.7

65�/74 42 8.2

75�/ 23 4.5

Missing 4 0.8

Drug delivery type

Tablets 395 76.7

Mixture 13 2.5

Injection 69 13.4

More than one 38 7.4

Type of antipsychotic drug*

Chlorpromazine 39 7.6

Levomepromazine 85 16.5

Dixyrazine 2 0.4

Fluphenazine 17 3.3

Perphenazine 87 16.9

Terfluzine 1 0.2

Thioridazine 68 13.2

Haloperidol 63 12.1

Melperon 2 0.4

Luvatrenxol 1 0.2

Flupenthixol 52 10.1

Chlorprothixene 11 2.1

Zuklopenthixol 64 12.4

Pimozide 14 2.7

Clozapine 39 7.6

Olanzapine 8 1.6

Remoxipride 31 6.0

Risperidone 27 5.2

Lithium 12 2.3

*Two or more antipsychotics were prescribed in 94 visits; the sum is

therefore more than 100%.

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The survey had a nearly 35% non-participation rate.

Some non-participation could influence the results;

physicians prescribing inadequately, and who are aware

of that, might choose not to participate to a greater

extent. Furthermore, due to methodological difficulties,

we were not able to include dosages of injectable depot

antipsychotics in the calculations, which lead to an

underestimation of the actual dosages prescribed. Stu-

Table 2. Prescribed doses (mg/day) at visits for schizophrenia where one antipsychotic was prescribed, Diagnosis-Therapy Study1990�/98.

CPZeq

Type of antipsychotic n n w. doses Mean (mg) CPZeq Mean Min Max s

Chlorpromazine 25 24 174.8 50/50 174.8 30 450 26.4

Levomepromazine 44 43 52.4 50/50 52.4 5 200 6.6

Dixyrazine 2 2 60.0 50/30 100.0 75 125 25

Fluphenazine 7 7 4.0 50/2 100.0 25 250 30.3

Perphenazine 45 44 13.9 50/4 173.6 25 550 17.4

Thioridazine 40 40 163.9 50/50 163.9 20 800 27.6

Haloperidol 30 30 8.7 50/1 435.3 25 4000 135.3

Melperon 2 2 25.0 50/40 31.3 25 38 6.3

Luvatrenxol 1 1 40.0 * �/ �/ �/ �/

Flupenthixol 28 26 3.9 50/1 194.7 25 750 34.1

Chlorprothixene 6 6 82.5 50/50 82.5 45 150 15.7

Zuklopenthixol 20 20 16.3 50/5 163.0 20 500 27.7

Pimozide 13 13 4.2 50/1 207.7 50 500 37.1

Clozapine 32 30 273.3 50/50 273.3 25 600 27.1

Olanzapine 8 7 8.6 50/2 214.3 63 375 47.0

Remoxipride 24 24 370.8 50/40 463.5 94 1563 79.3

Risperidone 22 20 4.2 50/1 211.3 75 400 22.1

Lithium 4 4 110.3 * �/ �/ �/ �/

All 353 338 �/ �/ 210.7 5 4000 15.8

*No CPZeq.

s, standard error.

Prescriptions for injectable antipsychotics are excluded.

Table 3. Prescribed doses (mg/day) per antipsychotic drug at visits where two or more antipsychotics were prescribed, Diagnosis-Therapy Study 1990�/98.

CPZeq

Type of antipsychotic n n w. doses Mean (mg) CPZeq Mean Min Max s

Single prescriptions

Chlorpromazine 14 14 201.8 50/50 201.8 25 800 58.9

Levomepromazine 41 39 48.1 50/50 48.1 3 200 7.7

Fluphenazine 6 6 4.7 50/2 116.7 25 500 76.8

Perphenazine 21 16 18.6 50/4 233.1 50 813 42.4

Terfluzine 1 1 14.0 50/3 233.3 233 233 �/

Thioridazine 28 28 203.0 50/50 203.0 20 1065 41.6

Haloperidol 22 17 5.3 50/1 266.2 25 1000 63.9

Flupenthixol 14 12 5.7 50/1 286.5 25 1300 93.1

Chlorprothixene 5 5 96.0 50/50 96.0 25 200 34.3

Zuklopenthixol 20 15 19.3 50/5 192.7 20 750 47.9

Pimozide 1 1 3.0 50/1 150.0 150 150 �/

Clozapine 7 7 289.3 50/50 289.3 50 600 76.3

Remoxipride 7 7 450.0 50/40 562.5 63 1500 185.0

Risperidone 5 5 5.3 50/1 265.0 25 600 99.9

Lithium 8 8 152.3 * �/ �/ �/ �/

Total prescribed doses at one visit

Excl. visits with 66 66 �/ 406.8 25 2300 48.2

missing

*No CPZeq.

s, standard error.

Prescriptions for injectables are excluded.

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dies have shown that patients receiving depot antipsy-

chotics are at high risk of excessive total dosage (4).

Also, the study is based on physician visits and

prescriptions issued at one visit, therefore we were not

able to estimate the total amount of drugs received by a

patient. However, prescriptions issued at one visit are

highly likely to be used concomitantly, therefore the

polypharmacy seen in the study is intentional. The

prescribing of newer ‘‘atypical’’ antipsychotics increased

during the study period but since risperidone and

olanzapine did not enter the market until the mid-

1990s we were not able to study differences in therapy

with the newer compounds.

Not all prescriptions for antipsychotic schizophrenia

therapy were issued within psychiatry; 17% were from

other doctors. In sparsely populated areas, psychiatric

patients are often treated by GPs. However, the main

reason is probably that physician services in nursing

homes are provided by GPs or geriatric departments.

A wide variety of daily doses was prescribed to the

patients in our study. Combination therapies with more

than one antipsychotic drug was found in approximately

20% of the visits. Doses used in monotherapy in our

study were not alarmingly high, whereas patients treated

with several concomitant antipsychotics were at risk of

excessive dosing and/or interaction effects. Studies on

hospitalized as well as ambulatory patients in different

countries have shown similar patterns to that seen in our

study (6, 17, 25, 27, 33) and the risk of excessive dosing

of antipsychotics has been discussed (4, 16).

Elderly patients are more sensitive to antipsychotic

drugs than are younger patients and they more easily

develop side-effects (34). This sensitivity is caused by

factors such as interaction with concomitant medica-

tions and reduced metabolic activity (35). This indicates

that when antipsychotics are prescribed to elderly

people, doses should be decreased. Our study showed

that elderly patients did receive lower doses on average.

Gender differences in schizophrenia are also well estab-

lished (36). Differences in age of onset, symptomatology

and psychosocial factors, as well as body weight,

metabolism and other biological factors may influence

antipsychotic drug therapy. Men received on average

higher doses than women in our study. Similar patterns

have been shown in other studies (25, 37, 38).

It has been shown that co-medication with more than

one substance may have negative clinical consequences

and may induce unexpected side-effects and/or a differ-

ent therapeutic response than expected since the same

enzyme (cytochrome P450) is involved in the metabo-

lism. Levomepromazine, the most prescribed drug to

patients receiving more than one antipsychotic drug, is a

strong inhibitor of the P450 isoenzyme CYP2D6 and

should not be used concomitantly with other antipsy-

chotics, although it is commonly used in the evenings

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ANTIPSYCHOTIC DOSAGE PATTERNS

NORD J PSYCHIATRY �VOL 57 �NO 4 � 2003 267

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due to its sedative effects. Thioridazine, haloperidol,

perphenazine and zuklopenthixol, also commonly pre-scribed during co-medication, are all metabolized by the

same P450 isoenzyme (39).

Polypharmacy in general is associated with a high risk

of hospitalization due to adverse effects of the drug

treatment, particularly among older patients (40) and

has been shown to be associated with reduced survival in

schizophrenia (41). As mentioned earlier, research has

shown that an optimal antipsychotic effect of antipsy-chotics may be achieved at lower doses than earlier

recommended (42). High doses of antipsychotics and/or

interaction effects have been shown to lead to con-

sequences in several areas such as negative subjective

cognitive effects (15), and increased side-effects with

subsequent non-compliance and relapse (43). Sudden

death in connection with high doses of antipsychotics

has been reported repeatedly (5, 13, 16, 44, 45).

ConclusionAntipsychotic treatment of schizophrenia in ambulatory

care is still a highly individualized therapy. The large

variations in prescribing for schizophrenia patients in

ambulatory care, particularly the high frequency of

combination therapies seen in this study, as well as in

others, are causes for concern and are not based on

scientific evidence. In spite of more than a decade ofprofessional debate on high-dose therapy and polyphar-

macy, and widespread communication of the current,

clear guidelines, there seems to be a lack of desired effect

on prescribing in actual clinical practice.

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Kerstin Bingefors, M.Sc., Ph.D., Departments of Neuroscience,Psychiatry, and Pharmacy, Uppsala University, Biomedical Centre,Box 580, SE-751 23 Uppsala, Sweden.Dag Isacson, M.Sc., Ph.D., Department of Pharmacy; UppsalaUniversity, Biomedical Centre, Box 580, SE-751 23 Uppsala, Sweden.Eva Lindstrom, MD, Ph.D., Department of Neuroscience, UppsalaUniversity, Biomedical Centre, Box 580, SE-751 23 Uppsala, Sweden.

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