Atypical neuroleptics: their contribution to the rehabilitation of schizophrenic patients

Eur Psychiatry 1996;1 I(Suppl 2):855-89s o Elsevier, Paris

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Atypical neuroleptics: their contribution to the rehabilitation of schizophrenic patients 1M Vanelle, T Brochier, F1 Bayle, H Loo Service Hospitalo-Universitaire de Santi Mental« et de Therapeutique, Centre Hospitalier Specialise Sainte-Anne, J rue Caban is. 75674 Paris cedex, France

Summary - Therapeutic effects of neuroleptics (NLP) in schizophrenia are well established in numerous international studies. Varying modalities of evolution under NLP treatment are described and require a clinical analysis. Neuroleptics are a necessary but insufficient condition for the therapy of schizophrenia. Via NLP treatment, other therapeutic approaches, such as psychotherapy, or sociotherapy become more effective. Consecutively, we present the effects of two compounds with dopaminergic selective activity (amisulpride, remoxipride) and of two other compounds with non-selective activity (risperidone, clozapine) regarding rehabilitation in schizophrenic patients. Data were collected from international studies with a medico-economic perspective and from French experience of clozapine in refractory schizophrenic patients. All these data stress the importance of several areas of study: clinical features, everyday life consequences and therapeutical effects observed with the atypical neuroleptics. schizophrenia I atypical neuroleptlcs I amlsulpride I rlsperidone I dozaplne

INTRODUCTION

Therapeutic effects of neuroleptic drugs (NLPS) in schizophrenia are well established. Davis et al (1986) reviewed 35 studies in which the efficacy of NLPs preventing relapse on the short term had been evaluated within each study different duration of follow-up. In these data. the average rate of relapse under placebo was 52% and only 17% under NLPs. Dollfus and Petit (1991), with all the caution regarding their methodology, tried to evaluate the evolution of schizophrenia in the long term before and after the neuroleptic era. Before the neuroleptic era the improvement rate averaged 25% (table I). Conversely an improvement and/or recovery rate of 60% to 80% is found for a similar duration of disease since the introduction of NLPs (table II). These results argue for the efficacy of NLPs, particularly regarding the symptomatic and social recovery of schizophrenic patients. As early as 1975, Prof By underlined that NLPs are a treatment which is necessary but insufficient for the therapy of schizophrenic patients. Therefore, other therapeutic approaches, such as psychotherapy, sociotherapy and institutional therapy, are made easier because of antipsychotic drugs. Behavioral therapists established a twelve step

program for social rehabilitation of schizophrenia (Liberman, 1989). As additional evidence of the NLP contribution to the treatment, they gave first priority, among them, to the educational step for NLP treatment. Furthermore, Achte (1967) compared two patient groups which differed by the first admission time in hospital. The follow-up begun for the first group having begun in the early 1950s and for the second group later in the 1960s. The authors found that the social impairment from recovery was 31% in the first group and 51% in the second group after the NLP era. However, Delay and Deniker (1961) reported that NLP treatment lead to the generalization of residual symptomatology. Finally, these authors concluded that caution should be taken with these residual core symptoms that constitute the long lasting impairment of treated schizophrenia. CLINICAL ASPECTS

Under NLP treatment the symptomatic expression and the steps of evolution differ. Beyond the evident split in the evolution, the symptomatology is attenuated with a reduction in positive symptoms. Despite numerous modalities (ie, pseudo-neurotic

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Table I. Comparison of studies conceming the follow-up before the neuroleptic era.

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Authors

B

A Number %

Follow-up < 12 years Stalker (1939) Hasting (1953) Rupp et Fletcher (1940) Langfeldt (1937) TOlal

65 73 74 77 73.5

55 183 386 102 726

Follow-up> 12 years Beck (1968) Rennie (1939) Total

Number

70 162 232

30 68 133 30 261

83.4 73 75.8

14 60 74

%

3S 27 26 23 26.4

16.6 27 24.2

A: no improvement; B: improvement or recovery.

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Table II. Comparison of studies conceming the follow-up during the neuroleptic era.

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A Authors

Number

Follow-up < 12 years Watt et al (1983) Prudo and Blum (1987) Bland et aI (1976) MOiler et aI (1982) Total Follow-up> 12 years Imlach and Murphy (1985) Bland and Om (1980) Total

%

B Number %

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46 36 29 34 145 10 7 17

43 41 33 45 40

2S 16 20.5

61 52 59 42 214 30 36 66

57 59 67 55 60 75 84 79.5

A: no improvement; B: improvement or recovery.

schizophrenia, pseudo-antisocial schizophrenia, pseudo-paranoiac schizophrenia) (Peron-Magnan, 1988). the hebephrenic evolution prevails either as a consequence of a first hebephrenic form or as a secondary consequence after a paranoid evolution. Thus. negative symptomatology constitutes the main difficulty in schizophrenic rehabilitation. Carpenter et al (1985) proposed a comprehensive model for negative symptoms and their treatment. The clinical analysis should try to differenciate: iatrogenic symptoms like secondary extrapyramidal disorders or "syndrome d'indifference psychomotrice" induced by NLP treatment; depressive states in which the psychomotor retardation prevails; and core negative symptoms (ie, autistic withdrawal, clinophilia, athymhormia). With such clinical pictures, different therapeutic approaches have been suggested (fig 1).

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Fig 1. Model for assessment and treatment of negative symptoms (Catpenten et al, 1985).

Antidepressive compounds have shown their efficacy on depressive states in schizophrenia and also on negative symptomatology. Deniker and Ginestet (1973) reported the existence of a disinhibitory effect induced by NLPs. In the last years, the pharmacological development of new neuroleptics follows a guideline in which two main targets are defined: i) to try to obtain a better efficacy (20% of schizophrenic patients are evaluated as NLP refractory); and ii) to reach a better tolerance. particularly for the neurological side-effects. New compounds have been developed with mesocortical and mesolimbic specific affinity without nigrostriatal affinity or a specific receptors affinity like dopaminergic receptors. Other compounds with a non-selective pharmacological activity have been proposed, like clozapine. This drug shows an efficacy both on negative and positive symptomatology for the same dosage. Those drugs characterized by few extra pyramidal side-effects lead to the atypical neuroleptic concept. One of the five criteria of NLP effects as defined by Delay and Deniker (1961) is missing.

Atypical neuroleptics and the rehabilitation of schizophrenic patients

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Table m. Controlled studies on negative symptoms in schizophrenia with amisulpride.

Study

Picho~Boyer(J988)

Clerc(1989)

Boyer et al (1988)

Reference compound (number of patients)

Amisulpride (34) SQ-3OOmg versus Fluphenazine (28) 2-12mg

Amisulpride (6) cp20 mg versus Arnisulpride (6) cp 100

Amisulpride (34) 100 mglday versus Amisulpride (36) 300 mglday

VS Diagnostic

DSM-llI

wash-out Duration Evaluation Drop-out

8 days 6 weeks CGI, BPRS, NOSIE A: 10 F: 10

Results

Global efficacy A = F Anergia Ab F Activation A > F Anxiety-depression A>F

PLB (34) DSM-ID

DMS-llI ICD-9 ? 1 month BPRS 0

6 weeks

Negative correlation between efficacy and dosage

6 weeks SANS. SAPS A loomg:4 A300mg:6 PLB:9 Aloo>PLB A 300 > PLB A ioovx soo

BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression; PLB : Placebo; NOSIE: nurses' observation scale for inpatient evaluation; SANS: Scale for the Assessment of Negative Symptoms; SAPS: Scale for the Assessment of Positive Symptoms.

THE ATYPICAL NEUROLEPTICS

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In the following we present the activity in the rehabilitation of schizophrenic patients of two compounds with dopaminergic selective activity (amisulpride, remoxipride) and two compounds with a non-selective activity (risperidone, clozapine). Amisulpride is characterized by a bipolar therapeutic effect. The antipsychotic dosage on active positive symptoms is about 600 mg and up, whereas the desinhibitory activity is obtained with a dosage of 50 to 300 mg. The efficacy of amisulpride on negative symptomatology has been shown in controlled studies (Pichot and Boyer. 1988; Boyer et al, 1988; Clerc, 1989) (table III). In particular, Boyer et al (1988) in a randomised study compared three groups of schizophrenic patients. The first group received placebo, the second and the third group were treated, respectively by a daily dose of 100 mg and 300 mg amisulpride. The Scale for Assessment of Negative Symptoms (SANS) score was over 75, the Scale for the Assessment of Positive Symptoms (SAPS) score was under 60 after a six-week wash-out period. As shown in figure 2, the authors found a significant decrease in the total mean SANS score of the two treated groups compared to placebo (respectively 41%, 48% and 23%). Similar results were found for the overall assessment of anhedoniaand social withdrawal. The benzamide remoxipride is now marketed in

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some European countries but its development will probably be stopped because of haematological toxicity. Controlled studies versus haloperidol do not find differences in efficacy and remoxipride seems to be well tolerated. An activity in negative symptoms is advocated. Risperidone, a potent dopaminergic and scrotoninergic antagonist has a potential activity on both positive and negative symptomatology, Numerous international studies regarding the schizophrenic population are now available. Among them 19 are

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1M Yanelle et al

open label trials with a mean duration of four weeks exc~pt for four wh!ch are one year long follow-up studies. Other studies are double-blind trials, seven v~rsus haloperidol (2-20 mg/day), one versus clozapine (400 mg/day), and one versus perphenazine (16-48 mg/day) (Chouinard et al, 1993). The review concluded for a 4-8 mg/day optimal dose and for an effic~cy on ~ll. different aspects of schizophrenia, ?egative~ postuve and affective symptoms. A large international study confirmed these results. The authors compared different risperidone doses versus 10 mg .halope~idol .dose/day in five groups of 225 schizophrenic patients. For the total Positive and Negative Symptom Scale (PANSS) and total Brief Psychiatric Rating Scale (BPRS) scores, the risperidone 4 mg dose/day showed a significant improvement in efficacy over the 10 mg haloperidol dose/day. No significant difference was found on the ~cgative symptoms PANSS subscale between risperIdone. and haloperidol. Conversely, on the BPRS anergra cluster (ie, emotional withdrawal motor retardation, blunted affect, disorientation) rlsperidone (4-:"8 mg/day) s~owed a better efficacy than haloperidol. Regarding tolerance, risperidone (4-8 mg/day) showed significantly improved results over haloperid.ol (10 mg/day) on the Extrapyramidal ~ymP.tom Rating Scale (ESRS) total score. With a risperidone ~eatm~nt, the number of patients requiring antiparkinsonian medication was significantly less important, The efficacy of clozapine is now well-established. Clozapine has a better efficacy than chlorpromazine on both paranoid and anergia clusters of BPRS (Kane et al, 1989). This activity on positive and negative s~ptoms is also demonstrated by the improvement of SIX of the seven actors on the Nurse's Observation Scale for Inpatient Evaluation (NOSIE 30) scale. Nevertheless clozapine's ability to reduce positive and ~egative symptoms does not necessarily imply that It produces comparable improvement in social functioning. The effect of six months of treatment with clozapine on the quality of life of 38 treatmentresistant schizophrenic patients was prospectively studied in an open trial by Meltzer et al (1990). They reported that mean quality of life scale scores improved by 59.9% over the 6-month period (fig 3). After a six-month treatment, 14 of them were back to work and 21 after 19 months. For only one patient, hospitalisation needed to be continued. After one year the rehospitaIisation rate was 83% less than the rate during the year before the clozapine treatment, Among the first 600 patients treated in France the paranoid form is prevalent with a 63% rate . Actually the data does not allow the evaluation of the improvement rate in different schizophrenia

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Fig 3. Ratings on the Quality of Life Scale (QLSI) at baseline and six months after cJozapine treatment began. for 38 patients.

subtypes (Pere et al, 1992). However, the global clinical appreciation does not show a difference in the improvement of hebephrenic (60.4%) and paranoid subtypes (69%) . Interestingly, the mean clozapine daily dose used is equivalent in the different schizophrenic groups. In fact, the clozapine activity on positive and negative symptoms is not dependent on the dose range. The suggested underlying mechanisms of the therapeutical effect observed by psychiatrists are: sedative effect (41.4%); effect on positive symptoms (73%); and effect on negative symptoms (33.3%) (non exclusive answers). In a retrospective study concerning 43 treatment refractory schizophrenic patients, Reine et al (1992) evaluated the efficacy of clozapine on negative and positive symptoms and also on social rehabilitation (ie, leaving hospital, restarting work or studies, improving social performance). The authors found a positive effect on social rehabilitation, with 67% of the patients showing an improvement in social performance. Moreover regarding the improvement in social performance, a dose effect (optimal dose 500 rng) and a time effect (6 months and longer) were noted. DISCUSSION All these data lead to the question of the most relevant criteria in clinical evaluation of schizophrenia. Among the psychopathological scales, the Andreasen (SAPS and SANS) and Kay (PANSS) scales have the advantage of taking more into account the negative symptoms . The PANSS scale has a better face validity than the SANS and the SAPS scale which

I Differences between scores at baseline and six months were sign ificant at the .0001 level for the total, intrapsychic foundations, and interpersonal relations scores ; at the .02 level for the instrumental role score ; and at the .006 level for the common objects and activities score .

Atypical neuroleptics and the rehabilitation of sch izophrenic patients

are based on more hypothetical constructs with poor specificity and therefore have less validity (Dollfus et al, 1991). Other scales complete the measurement of the psychotic process in terms of affective, environmental and socio-occupational evaluation. Although very close to what the social adaptation scale measures, the concept of quality of life measurement is the subject of many controversies. Future studies should take into account the medico-economic impact of therapy. The clozapine treaunent seems to have an economical advantage for society as well as a therapeutic advantage for the patient (Revicki et al, 1990). A prospective randomised open-labeled international study is in process with the aim to compare on the basis of 400 schizophrenic patients, the oral administration of risperidone versus usual neuroleptic treatment. An economical evaluation will be made with two quality of life scales in addition to clinical measurement by cm and BPRS. Souetre et al (1992) compared the compliance of amisulpride versus haloperidol. The authors found an improvement in the relapse rate and decrease of medical costs with the amisulpride treatment. Thus a better therapeutical evaluation is needed in such a polysymptomatic disease as schizophrenia. Clinical aspects, everyday life consequences and induced therapeutical effects are the three main focuses on which studies should concentrate. The atypical neuroleptics (amisuIpride, clozapine, risperidone) confirm the importance of NLPs in the global therapeutic strategy for schizophrenia.

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