Treatment of schizophrenia

Frog.

Nemo-Psychopharmacol.

'~01.3, pp.47-52,

TREATMENT

1979. Perganon Press Ltd.

OF

Printed

in Great Britain

SCHIZOPHRENIA

B. BECKMANN, H. HIPPIUS and E. R?lHER Psychiatric

Hospital of the University Munich, West Germany

of Munich

Contents 1. 2. 3. 4. 5.

Abstract Introduction Therapeutic Side effects Theoretical Conclusions References

efficacy of neuroleptics of neuroleptics aspects. The neuroleptics

as tools

47 47 47 49 50 51 51

of research

Abstract 1. 2. 3. 4. 5.

Progress in 25 years' history of the neuroleptics is briefly reviewed. Development of certain butyrophenones more directly effective in "minus" symptoms of schizophrenia and introduction of depot neuroleptics is discussed. Extrapyramidal motor side effects (EPMS) are still a serious problem in the treatment. become the starting point of a Clozapine does not have EPMS. This drug could, therefore series of less hazardous antipsychotic drugs. The neuroleptics can be used as tools for exploration of the etiopathogenesis of schizophrenia. Some important pharmacological mechanisms, i.e. their antidopaminergic activity, are briefly outlined.

Key words: neuroleptics

clinical efficacy, neuroleptics, as pharmacological tools. 1.

side

effects,

pimozide,

penfluridol,

clozapine,

Introduction

After the introduction of chlorpromazine (Delay and Deniker, 1952) and reserpine (Kline, 1954) as effective antipsychotic drugs, further tricyclic derivatives more or less similar to The chemical differences chlorpromazine were used in the therapy of schizophrenic psychoses. between chlorpromazine and the majority of the following drugs were rather small and consisted mainly of changing the aliphatic side chain of the chlorpromazine molecule to a piperidyl side chain or a piperazinyl side chain thus arriving at drugs such as, e.g. thioridazine and fluphenazine, respectively. 2.

Therapeutic

Efficacy

of Neuroleptics

From the clinical point of view the results were differences in the neuroleptic potency and clinically between in the quantity of EPMS. Many attempts have been made to differentiate However, no clear-cut the neuroleptics and to find specific "target symptoms" for each drug. differences in the qualify of their therapeutic efficacy have yet been detected (Hollister, 1974).

47

48

B. Beckmann,

H. Hippius

and E. Riither

Thus, it seems widely accepted that these drugs all influence the same psychotic symptoms as psychomotor excitation, delusions and hallucinations and to a lesser degree the "minus affect, lack of initiatives and drive etc. Introduction of the symptoms" as autism, blunted thioxanthenes (chlorprothixen, clopenthixol) though clearly effective clinically did not show Investigation of the pharmacology of the remarkable progress in antipsychotic therapy. phenothiazines and the thioxanthenes showed several comon properties: a. all produce catalepsy b. they antagonize stereotyped behavior caused by amphetamine and apomorphine c. block the conditioned avoidance behavior. Using these pharmacologic actions for screening new and unknown drugs, the butyrophenones with their prototype haloperidol and later pimozide, penfluridol and fluspirilene were found. Consecutive clinical trials supported the conclusion that this class of neuroleptics were very potent antipsychotic drugs. None of them has remarkable vegetative side effects comparable with the phenothiazines. Sedation is relatively weaker. Another advantage is the long lasting efficacy of some of the butyrophenones which allows a single dose f.i. per week for penfluridol and fluspirilene. A limited number of clinical trials indicate that pimozide as well as penfluridol and fluspirilene have in addition to their antipsychotic property a somewhat more pronounced action against autism, social withdrawal and lack of initiatives; acute psychomotor excitation and most overt psychotic behavior seem to be less well counteracted by these drugs. However, more controlled studies with higher dosages are needed to decide on their efficacy in acute schizophrenia (Janssen et al., 1972). Taking chlorpromazine as a reference with moderate clincially in comparison to chlorpromazine into a. drugs with lower neuroleptic potency promazine thioridazine levopromazine etc. b. moderate neuroleptic potency chlorpromazine clopenthixol chlorprothixen etc. C. marked neuroleptic potency perphenazine butaperazine thiothixen etc. d. strong neuroleptic potency fluphenazine pimozide haloperidol trifluperidol etc.

potency,

all

neuroleptics

can be divided

The various members of this large family of drugs are still the most important drugs for treatment of schizophrenia, and it has to be admitted that there is not much progress in practical therapy in this field.

the

One important step forward is the introduction of long acting neuroleptics and of depotneuroleptics which are of advantage in the long-term treatment of chronic forms of schizophrenia. Several of these substances are available: For intramuscular injection

for

oral

25 mg 40 mg 6 mg application 20 mg

average dose fluphenazinedecanoate flupenthixoldecanoate fluspirilene (see above) penfluridol

interval of injection bi-weekly or longer bi-weekly or longer weekly

(see above)

With regard to the depot-neuroleptics or other long-term clear evidence of their ability to prevent the development chronic course of schizophrenia.

weekly neuroleptic therapy there is no of defectuous symptomatology in the

Treatment

with

neuroleptics

49

No comprehensive studies on dose response and response-time curves have been done as yet. Reviewing the literature, we studied the percentage of improved patients at different times from 2 to 12 weeks (Riither, 1977). It is obvious that in the second week 50 % of patients are improved (twelve studies) but that in the following weeks of treatment this percentage did not increase substantially. Seven studies lasted 10 weeks, four studies 12 weeks. However, different clinical assessment and different neuroleptic doses render a statistical evaluation impossible. High dosage neuroleptic therapy in patients resistant to standard dose is frequently discussed, in general the higher incidence of adverse effects should However, this method which includes reluctantly be considered. Definitive research on this issue is lacking (Donlon, 1976). Davis (1976) reviewing the literature found it necessary to administer at least 350 chlorpromazine units per day in order to get adequate clinical results. Lower dosages are usually without antipsychotic effects. 3.

Side Effects

of Neuroleptics

A serious problem in the 25 years' history of neuroleptic drugs has always been the occurrence of EPMS. They are defined as: a. Hyperkinetic-dystonic syndrome: Usually in the beginning of the treatment during the first 2-3 days. This condition is treatable by anticholinergic drugs. b. Parkinson syndrome and akathesia: Occurring during the first 2-3 months of neuroleptic treatment. Parkinson syndrome can also be counteracted by anticholinergic drugs. c. Tardive dyskinesia: These serious side effects develop after long-term administration of classical neuroleptics in 5-35 % of the patients (Crane, 1976). In our own investigations we found 34 % tardive dyskinesia in 531 patients (Hippius and Lange, 1970) and 9 % in another population of 1066 chronically treated patients (Riither, 1977). Reviewing the literature the percentage of tardive dyskinesia in neuroleptic treated patients varied between 5 and 53 %. The earliest appearance is after 3 months increasing up to 4 years. After this time the probability of developing tardive dyskinesia becomes rare. More than 90 % of these patients had received more than 100 mg chlorpromazine units per day. Successful treatment consists of the administration of neuroleptics, dean01 (Casey and Denney, 1975) or clozapine (Riither, 1977; Simpson and Varga, 1974). Latter results were not confirmed by Gerlach et al. (1975). Basic scientists (Janssen and Niemegeen, 1960) and many clinicians (Haase, 1961) regard the EPMS as a necessary condition for the antipsychotic efficacy. However, we and other investigators (Gross and Langner, 1966; Hippius and Klein, 1974; Ackenheil et al., 1974; Hippius, 1977) have demonstrated that the neuroleptic drug clozapine is an exception in 19'76; Riither, this regard. According to this it is possible to treat schizophrenic symptomatology without producing any EPMS. Up to now not one single case of tardive dyskinesia during long-term In regard to the EPMS of the neuroleptics clozatreatment with clozapine has been observed. pine is a drug of central interest. In our opinion this drug has a fundamental significance for theoretical discussion on relation of therapeutic and extrapyramidal efficacy. As to the practical use of clozapine there was the serious observation of agranulocytosis in some patients, first in 1975 in Finland. We have, therefore, analyzed firstly the literature and secondly population of the University Hospitals in Berlin and Munich. our own unselected patients' Both investigations show that the rare complication of an agranulocytosis is not restricted We have observed its occurrence to clozapine - it is a risk with all tricyclic neuroleptics. with perazine and thioridazine too - s,urprisingly only in patients of the Berlin Hospital, not in the more than 6000 carefully investigated patients of the Munich University Hospital. The most important result of our investigations (Helmchen et al., 1975) is that the manifestation of an agranulocytosis is not safely preventable - however, death by this fatal For the prevention of the fatal outcome of a drug-induced agranulocytosis the outcome is! systematical control of white blood cells is absolutely obligatory. During routine neglected.

thereapy

the interaction

of neuroleptics

with

other

drugs

is too often

B. Beckmann,

50

H. Hippius

and E. Riither

Most experienced clinicians agree that the basic therapy with neuroleptics should be a After this time the drug may be changed or a combination monotherapy for at least 2-4 weeks. The reason for combined neuroleptic therapy is mostly of different neuroleptics can be used. For example in our own supposed to be the different therapeutic properties of neuroleptics. experiments we have compensated successfully the haloperidol induced parkinsonism with clozapine. It is worthwhile to note that in addition to the reduced parkinsonian side effects, The combination of the akathesia was improved during this drug combination (Riither, 1978). neuroleptics with anticholinergics may be used very cautiously because anticholinergics reduce The the plasma level of neuroleptics by decreasing the intestinal uptake of neuroleptics. combination of neuroleptics with antidepressants is sometimes useful in treating the depressive syndromes after long-term neuroleptic treatment. 4.

Theoretical

Aspects.

The Neuroleptics

as Tools

of Research

A large body of evidence suggests that most of the neuroleptics, i.e. the phenothiazines, thioxanthenes and the butyrophenones, block selectively noradrenergic and dopaminergic receptors of postsynaptic neurones in catecholaminergic structures of the brain. Clinically this can be demonstrated by measuring the homovanillic acid in cerebrospinal fluid (CSF) either by additive administration of probenecid or by measuring the baseline levels during neuroleptic treatment. Increase of HVA in CSF can be noticed after all neuroleptics (including clozapine) (Ackenheil et al., 1974), especially during the first 5-15 days. After this time tolerance develops (Bowers, 1974; Riither, 1977). Controversial findings have been reported regarding the correlation between the improvement of psychopathology and the decrease in central dopaminergic activity as one condition for neuroleptic action (Sedvall et aZ., 1976; van Praag, 1976; Riither, 1977). Further support for the hypothesis that dopaminergic activity is involved in the pathomechanism of schizophrenia are the following findings: a. After administration of a-methyl-pam-tyrosine (AMPT) an inhibitor of dopamine and noradrenaline synthesis in addition to phenothiazines to schizophrenic patients, the antipsychotic effects were significantly potentiated (Carlsson et al., 1972; 1973). b. Amphetamine releases dopamine and noradranaline from the presynaptic neuron onto the postsynaptic neuron, thus leading to excitation of the neuron. The evidence that the psychoses of chronic amphetamine abusers have great similarity with the paranoid form of schizophrenia gives an unique possibility to explore the biochemical conditions of psychotic symptoms. The amphetamine psychoses are promptly counteracted by the neuroleptics. c. Disulfiram and fusaric acid, both inhibit the dopamine-S-hydroxylase (DBH) and thus, presumably, increase the dopaminergic activity in brain: administered to schizophrenic patients they increase psychotic behavior specifically (Heath et al., 1965; Goodwin and Sack, 1974). This and other findings strongly suggest that overactivity of central dopaminergic structures is somehow involved in the etiopathogenesis of at least certain forms of schizophrenia. Another strategy to evaluate the proposed mode of action of the neuroleptics is to reduce the central dopaminergic activity by increasing the concentration of gamma amino butyric acid (GABA) in brain. GABAergic neurons have an inhibitory influence on dopaminergic activity in the central nervous system (Fuxe et aZ., 1975). However, trials with the GABAergic drug baclofen have failed to improve the acute or chronic schizophrenic symptomatology, possibly because of lack of specific GABAergic action of this drug (Beckmann et aZ., 1970). Coincidence of antipsychotic effects and EPMS has led to the hypothesis that dopaminergic structures (mainly the striatum) are the site of neuroleptic action. However, evidence has been presented by several investigators that structures as limbic forebrain and the cortex itself may be the preferential topographical targets of these drugs (And& and Stock, 1973). Whereas tolerance develops to the antipsychotic drugs in the striatum none such is detected in dopaminergic structures of the cortex (Laduron et aZ., 1977). As to specificity, it is generally thought that blocking of dopaminergic receptors is responsible for the therapy of most of the positive symptoms as delusions, hallucinations psychotic excitement. However, administration of pimozide, a rather selective dopamine-

and

Treatment

with

51

neuroleptics

receptor blocking agent is - at least in lower doses -more effective in symptomatology as blunted affect, lack of energy and drive and loss of initiatives. Conversely, neuroleptics with both noradrenergic and dopaminergic receptor blocking properties are better in counteracting overt psychotic behavior. However, other aminergic neuronal systems have to be taken into consideration for the explanation of antipsychotic activity. The serotonergic system seems to be of some importance. For instance, it has been shown by Wyatt et al. (1973) that S-hydroxy-tryptophan has some antipsychotic properties in chronic schizophrenic patients. 5.

Conclusions

Twenty-five years after the introduction of the first effective antipsychotic drug the progress made is remarkable, but not overwhelming. The neuroleptics clearly abolish many forms of psychotic behavior, however, it is questionable whether they can cure or protect prophylactically against schizophrenia. The problem of tardive dyskinesia persists to be a serious one. Clozapine which does not produce EPMS involves some risk of agranulocytosis. This drug may only be the starting point for a new and less hazardous series of antipsychotic drugs. Theoretically the neuroleptics yielded some insight into the basic pathomechanisms of They may be very useful tools in experimental psychiatry to explore schizophrenic syndromes. the etiopathogenesis of this mental disorder. Future research should aim at developing antipsychotic drugs which counteract the "minus" symptoms and the defectuous state of schizophrenia, possibly by influencing other neurotransmitter systems than the dopaminergic one in the central nervous system. Acknowledgement The authors

thank

Mrs.

Grade for

carefully

arranging

and typing

the manuscript.

References ACKENHEIL, M., BECKMANN, H., GREIL, W., HOFFMANN, G., MARKIANOS, E. and RAESE, J. (1974). Antipsychotic efficacy of clozapine in correlation to changes in catecholamine metabolism The Phenothiazines and Structurally Related Drugs, J. S. Forrest, C. J. Carr in man. In: and E. Usdin (eds.), pp. 647-657. Raven Press, New York. Effect of clozapine on the turnover of dopamine in the ANDEN, N. E. and STOCK, G. (1973). corpus striatum and in the..limbic system. J. Pharm. Pharmacol. 25: 346-348. BECKMANN, H., FRISCHE, M., RUTHER, E. and ZIMMER, R. (1970). Baclozn (para-chlorphenyl-GABA) in Schizophrenia. Pharmakopsychiat. 10: 26-31. Central dopazne turnover in schizophrenic syndromes. Arch. Gen BOWERS, M. B. JR. (1974). Psychiat. 31: 50-54. CARLSSON, A.,PERSSON, T., ROOS, B.-E. and W&INDER, J. (1972). Potentiation of phenothiazines by a-methyltyrosine in treatment of chronic schizophrenia. J. Neural Trans. 33:83. CARLSSON, A., ROOS, B.-E., WbINDER, J. and SKOTT, A. (1973). Further studies onthe mechanism of antipsychotic action: potentiation by a-methyltyrosine of thioridazine effects in chronic schizophrenics. J. Neural Trans. 34-125. Eanol in treatment of tardive dyskinesia. Am. J. Psychiat. CASEY, D. E. and DENNEY, D. (1975). 132: 864-867. Risks of long-term therapy with neuroleptic drugs. In: Antipsychotic Ca, G. E. (1976). G. Sedvall, B. Uvnls and Y. Zotterman (eds.), Drugs: Pharmacodynamics and Pharmacokinetics, pp. 411-419. Pergamon Press, Oxford. DAVIS, J. M. (1976). Comparative clinical studies on antipsychotic drugs. In: Antipsychotic Drugs: Pharmacodynamics and Pharmacokinetics, G. Sedvall, B. Uvngs and Y. Zotterman (eds.), pp. 397-410. Pergamon Press, Oxford. DELAY, J. and DENIKER, P. (1952) 38 cas de psychoses trait6s par la cure prolongge et continue de 4568 RP. Ann. Med.-Psychol. -110: 364.

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B. Beckmann,

H. Hippius

and E. RUther

DONLON, P. T. (1976). High dosage neuroleptic therapy - a review. Int. Pharmacopsychiat. 11: 235-245. FE, K., H&FELT, A., LJUNDAHL, L., AGNATI, L., JOHANSSON, 0. and PEREZ de la MORA, M., (1975). Evidence for an inhibitory gaberic control of the meso-limbic dopamine neurons: possibility of improving treatment of schizophrenia by combined treatment with neuroleptics and gaberic Medical Biol. 53: 177-183. drugs. GERLACH, J., THORSEN, K.
and reprint

requests

should

be addressed

Prof. Dr. H. Hippius Direktor der Psychiatrischen Klinik der Universitlt Nussbaumstr. 7, D-8000 Munich 2, West Germany

to: Munchen