C) 1997 Martin Dunitz Ltd
International Journal of Psychiatry in Clinical Practice 1997 Volume 1 Pages 261 -268
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Clozapine response in early treatment-resistant schizophrenia GRIGORI JOFFE', JURI RYBAK', MARK BUR KIN^, DMITRI BURKIN*, BJORNAPPELBERG', MARINA JOFFE', RAINER GADEKE' AND RANAN RIMON' 'Department of Psychiatry, University of Helsinki, Helsinki, Finland; and 'Department of Psychiatry, University of Petrozavodsk, Karelia, Russia Correspondence Address Grigori Joffe, Department of Psychiatry, University of Helsinki, Lapinlahdentie, 00180 Helsinki, Finland
Received 4 July 1997; accepted for publication 10 September 1997
Eleven consecutive schizophrenic patients with a mean duration of illness of 2.2 (range 0.9-3.8) years and early signs of resistance to conventional neuroleptics were studied prospectively in a 26-week open trial with clozapine (mean dose 192.5 mg at week 8 and 225.0 mg at end-point). Of the ten patients who completed the study, nine improved by 20% or more on total Brief Psychiatric Rating Scale (BPRS) scores; six (good responders) showed more than 30%, and four (fair responders) 21 -26% improvement on total Positive and Negative Syndrome Scale (PANSS) scores. The improvement was observed mainly within the first 8 weeks. Duration of illness correlated negatively @=0.047) with the decrease of positive PANSS scores. The duration of illness of the fair responders was more than twice that of the good responders. Clozapine appears to be a safe and effective treatment alternative for early treatment-resistant schizophrenic patients. These patients seem to respond to relatively low clozapine doses. Early rather than late transfer to clozapine in this population may be of benefit for later clinical outcome. (Int J Psych Clin Pract 1997 8: 261 - 268) Keywords clozapine time factor
INTRODUCTION
E
arly introduction of neuroleptics in schizophrenia appears to be associated with a need for lower doses' and better treatment However, up to 20% of schizophrenic patients fail to respond to conventional neuroleptic the rap^,^.^ which is then followed by prolonged psychotic illness. Since the schizophrenic process may, itself, be neurotoxic,6-" lack of adequate treatment in the beginning of the illness may lead to gradual worsening of the response. In addition, chronic treatment with conventional dopaminergic substances may be followed by persistent neural dysfunctionI2 and poor clinical outcome. 1.13.14 Clozapine is the first and only antipsychotic agent that has demonstrated efficacy in schizophrenic patients who are refractory to other antipsychotic d r ~ g s . ' ~ -Clozapine '~ may be superior to traditional antipsychotic drugs in terms of overall and time required for response. Thus, it could be postulated that the use of clozapine as a first-line treatment might lead to a better clinical outcome and fewer cases of chronic schizophrenia. However, due to the relatively high risk of
treatment resistance
a g r a n ~ l o c y t o s i s , ~clozapine ~-~~ has in most countries been reserved for patients with treatment-resistant schizophrenia. There is a wide range of grades between treatment re~istance'~.'~ and full response, i.e. rapid and complete remission on the first conventional neuroleptic In partial responders, we do not know what would be the ideal point for transfer from conventional neuroleptics to clozapine. Optimization of timing for such a transfer would be of great value, since the role of novel atypical neuroleptics in treatment-resistant schizophrenia still remains to be evaluated. The effect of clozapine in responders has been studied extensively. Recent clozapine investigations have mostly been performed in treatment-resistant schizophrenic patients, chronically psychotic for many year^.'^,'^.'^.^' To date, no clozapine studies have been reported in patients with early signs of emerging resistance to conventional neuroleptics and with a relatively short duration of illness. We studied prospectively 11 such patients in order to examine possible benefits and problems of clozapine treatment in this population.
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PATIENTS AND METHODS Male and female patients aged 18-55 years with schizophrenia defined according to DSM-III-RZ9were included in the study. The inclusion criteria required overt psychotic illness with a total score of at least 18 on the 18-item Brief Psychiatric Rating Scale (BPRS)30despite routine treatment with one or two conventional neuroleptics for 2-12 months. Furthermore, the current episode of illness had to be the first or second one, with a duration of less than one year. The patients had to have a level of understanding sufficient to communicate intelligently with the investigators. Exclusion criteria were serious medical diseases, a history of leukopenia or severe allergic adverse drug reactions, DSM-III-R psychoactive substance use or organic mental disorders, serious suicidal risk, pregnancy, lactation or absence of contraception (in women). Established therapy-resistant patients, i.e. those who had failed to show any significant clinical response to two neuroleptics of two different classes with a maximum daily dose of 800 chlorpromazine equivalents for at least 3 weeks each, were excluded. The study was conducted in the psychiatric hospital and the day treatment unit of the psychoneurological dispensary of the Karelian Republic, Petrozavodsk, Russia, in accordance with the guidelines of the Helsinki Declaration and good clinical practice. Before each patient entered the study their verbal consent was obtained. It was stressed that the patients could at any time withdraw their participation in the study without any negative consequence for their treatment. The protocol was approved by the Ethics Committee of the Petrozavodsk University and Ministry of Health of the Karelian Republic. The following information was obtained from hospital records and clinical interviews: sex, age, age at onset of the first psychotic symptoms, duration of the illness before clozapine, and number of conventional antipsychotics prior to clozapine. At the screening interview, pertinent physical and psychiatric examinations were performed. Psychiatric diagnoses were made by an experienced psychiatrist. A 1- 9 day wash-out from conventional orally used neuroleptic was conducted before base-line (week 0) evaluation (none of the patients had received depot neuroleptics). Assessments of treatment efficacy by BPRS, Positive and Negative Syndrome Scale (PANSS)13’ Clinical Global Impression (CGIy2 and Patient Global Impression (PGII3*were performed weekly for the first 8 weeks and thereafter bimonthly up to the end-point at week 26. In addition, assessment by CGI was performed at the screening preceding the wash-out period, and by the Quality of Life Scale (QLS)33 at base-line and end-point. The PANSS and BPRS scores were adjusted by subtracting 1 point from each item (ratings from 0 to 6 ) . In addition, the BPRS scores and changes to them were counted before adjusting for comparability with some earlier studies. Extrapyramidal side-effects were assessed by the SimpsonAngus Scale.34
The following clozapine dose regimen was recommended: A dose of 12.5-25 mg was to be given once or twice on the first day, followed by stepwise increases of 25-50 mg daily for 7- 14 days until a dose of 300450 mg (up to 600 mg) per day was reached. The protocol allowed an individual adjustment of the doses (not exceeding 900 mg per day). Use of the lowest effective dose during the maintenance period was strongly recommended. Concomitant use of medication with primarily central nervous system activity beyond prescription of short/ middle-acting benzodiazepines was not allowed. Complete blood counts were performed weekly during the first 18 weeks and monthly thereafter. Statistical probabilities when comparing subgroups were calculated using Kruskal-Wallis one-way ANOVA. Correlations were calculated with Spearman’s correlation coefficient (r). Descriptive statistical data are presented as means with ranges in brackets.
RESULTS Eleven patients were enrolled into the trial. One patient ceased participation at the very beginning of the study due to withdrawal of informed consent. Since no assessments were done after base-line for this patient, the scores of the last observations were not carried forward for the intentionto-treat analysis. Of the remaining 10 patients (six men and four women), seven had paranoid, one catatonic, and two undifferentiated schizophrenia. Four patients had previously received one (either haloperidol or trifluoperazine), and six patients consecutively two (haloperidol, trifluoperazine, chlorpromazine or sulpiride) conventional neuroleptics. At the screening phase all the patients were on either haloperidol (from 15 to 35 mg per day) or trifluoperazine (from 12.5 to 25 mg per day). In all 10 patients, the reason for the shift from conventional neuroleptics to clozapine was lack of response. In addition, seven patients suffered from considerable, mainly extra-pyramidal, side-effects. At the beginning of the study four patients were managed in open care, and six patients remained in hospital. None of the outpatients needed hospitalization, and five of the six inpatients became able to be discharged from the hospital during the study period. The sixth inpatient had been sentenced to hospital treatment by a court and therefore could not be discharged, regardless of his psychiatric condition. Some characteristics of the patients are presented in Table 1. The clozapine doses used during the study (mean 192.5, range 100.0-350.0 mg/day at week 8, and mean 225.0, range 50.0-450.0 mg/day at the end-point) tended to be lower, and their ascent somewhat slower than recommended by the study protocol (Figure 1).The main reasons for this were sedation and hypersalivation. On the other
Clozapine in early treatment-resistant schizophrenia
Table 1 Characteristics of 1 0 clozapine-medicated patients with early treatment-refractory schizophrenia
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Years, mean (range) Age at base-line Age at onset of illness Duration of illness before clozapine Duration of current episode of illness before clozapine Duration of the last neuroleptic treatment prior to clozapine
25.4 (18-44) 23.2 (1541) 2.2 (0.9-3.8) 0.61 (0.25-0.9) 0.42 (0.25-0.75)
hand, early improvement of the symptoms made a more aggressive dosage regimen unnecessary. None of the 10 patients deteriorated or improved during the wash-out period (mean 2.4, range 1 - 7 days). During clozapine treatment none of the patients remitted completely. However, all improved to some extent, as assessed by the scales used (with the exception of slight deterioration in PANSS negative scores in two patients). The changes in rating scale scores are presented in Figures 2, 3, 4 and 5. As can be seen in Table 2 and Figures 2, 3 and 4, the most prominent improvement was seen by week 8 of the study with only minimal changes thereafter. BPRS ratings before adjustment (range from 1 to 7, not included in Table 2) changed from 48.5 (45 - 53) at week 0
c 0
Figure I Changes in [he mean doses of clozapine
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to 38.2 (30-43) at week 8 and to 36.8 (33-43) at week 26. Thus, the percentage improvements from base-line in non-adjusted BPRS scores rose from 21% (13-36) at week 8 to 24% (19-31) at the end-point. Only one patient improved less (19%) than the 20% response which has been proposed as clinically significant.l 6 In six patients (defined below as good responders) the decrease in total PANSS scores (30-50%) exceeded 30%. The remaining four patients (fair responders) improved by 21% to 26%. For two of these patients the clozapine dose was able to be increased up to 300 mg/day after week 8 of treatment; however, this did not in fact lead to further clinical improvement; the reduction in total PANSS scores as compared to base-line rose from 18%at week 8 to 21%at the end-point in one patient, but declined from 28% to 23% in the other. There was no correlation between clozapine dose and improvement for the group as a whole. The duration of illness correlated negatively (r=- 0.639, P=0.047) with the reduction of positive PANSS scores*. Improvements in clinical rating scale scores did not show any correlation with the duration or sequence of the current illness episode, the duration or doses of the last neuroleptic, the number of previous conventional neuroleptic treatment efforts, or the actual age of the patients or their age at onset of the illness.
*Duration of illness also showed a tendency towards a negative correlation with improvement on total PANSS (r=-0.555, P=0.096) and a positive correlation on total QLS (r=0.612. P=0.060) scores. Since improvement corresponds with decrease on PANSS and increase on QLS scores, shorter duration of illness tended to correlate with better results on both scales.
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Table 2 Changes in rating scale scores and clozapine doses at weeks 8 and 26 vs. base-line
Rating scale scores
At week 0
At week 8
(change from base-line, %) PANSS positive
12.5 (8.16)
P A N S negative
14.1 (14-21)
PANSS general
29.9 (24-34)
PANSS total
54.5 (38-65)
BPRS
30.5 (27-35)
CGI (severity)
37.1 (21-79)
7 .5 (1-11) 40.8 (0.8-88.9) % 11.7 (5-16) 12.6 (-25.0-53.8) % 21.9 (15-29) 26.9 (12.1-51.6) % 39.7 (20-51) 27.1 (13.2-60.8) % 20.2 (12-25) 33.9 (21.4-58.6) % 4.0 (3-5) 20.5 (0.0-40.0 ) % 2.1 (2-3) 45.8 (25.0-50.0) % 2.2 (1-3) 44.4 (25.0-75.0) % NA
NA
192.5 (100-350)
5.0 ( 4 6 )
CGI (improvement) 4.0 ( 4 4 ) PGI QLS total
NA
Clozapine dose (mdday)
At week 26 (change from base-line, %)
7.4 (1-11) 42.3 (15.4-88.9) % 11.6 (6-14) 8.6 (-50.0-38.5) % 20.7 (16-26) 30.9 (13.3-46.7) % 37.6 (25-49) 31.0 (21 .O-51 .0) % 18.8 (15-25) 38.7 (18.6-48.4) % 3.8 (3-4) 23.3 (0.0-40.0) % 2.1 (2-3) 45.8 (25.0-50.0) % 2.0 (1-3) 50.0 (25.0-75.0) % 62.7 (33-89) 81.7 (181.0-6.3) % 225.0 (50-450)
The data are expressed as mean (range). The PANSS and BPRS scores were adjusted by subtracting 1 point from every item
Fipre 2 Changes in mean PANSS scores during clozapine. Sl=positive; S2=negative; S3=general; S4=total
In intergroup analysis (good responders versus fair responders), no significant differences in demographics or patient histories were found. However, the mean duration of illness in the fair responders was 3.25 (3.0-3.8) years, which was more than twice as long as the 1.5 (0.9-1.6) years in good responders. The side-effects of the study medication are shown in Table 3. None of the patients developed granulocytopenia
or agranulocytosis. At the end-point of the study, eight patients still showed a slight (1 point on the SimpsonAngus Scale) increase in salivation. The minor extrapyramidal symptoms, shown by all the patients at base-line, disappeared during clozapine treatment. The only exception was a slight (1 point on the Simpson-Angus scale) diminution in swing when walking, still seen at the endpoint in two patients.
Clozapine in early treatment-resistant schizophrenia
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Figure 3 Changes in BPR5 scores during clozapine treatment
Figure 4 Changes in the mean CGI and PGI scores. Sl=CGI improvement; SZ=PGI; S3=CGI severity
Figure 5 Mean QLS scores before and after 26-week treatment with clozapine. QLS items: 1 . Interpersonal relations; 2. lnstrumental role; 3. lntrapsychic foundations; 4. Common objects and activities; 5. Total. White=base-line score; blach=end-point score
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Table 3 Side-effects during clozapine treatment in 10 schizophrenic patients Side-effects
n
Hypersalivation
10 9
Sleepiness, sedation, fatigue Hyperthermia Considerable increase in weight Hypotension
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Dysarthria
4 2 1
1 1
Follow-up of nine of the 10 patients was continued for 6 - 15 months after the end-point of the study. Those six patients who continued treatment with Swiss-made clozapine were asymptomatic, and five of them were capable of work. Substitution of the original medication by Ukraineanproduced clozapine, tried in two of the six patients, failed in both cases; the symptoms deteriorated. Furthermore, one of the latter two patients twice developed a confusional state resembling toxic delirium. His condition rapidly improved after he went back on the original clozapine preparation. One patient, although not receiving neuroleptic treatment any more, was still asymptomatic and continued her studies at school. Two patients were shifted to conventional neuroleptics. This was partly due to problems of availability of the Swissmade clozapine in Russian Karelia. Other reasons were persistence of negative symptoms despite clozapine treatment in one patient and psychotic exacerbation and granulocytopenia during treatment with Ukrainean-made clozapine in another.
DISCUSSION Despite unusually low daily doses of clozapine, all our patients responded well, or at least fairly well, to the medication. The only difference between the good and the fair responders was that the latter had suffered from their illness for more than twice as long as the former. In the whole group, shorter duration of illness correlated (r= - 0.639, P=0.047) with better improvement, reflected also by the reduction of the positive PANSS subscale symptoms. The improvement was observed mainly within the first weeks of treatment, with only modest changes after week 8. The major methodological problems of the present study included the relatively small sample and the lack of a control group. Therefore, our results and conclusions should be taken as preliminary and with caution.
Treatment resistance has in earlier ~ t u d i e s ' ~ ~ been ''~'~~~~ defined as lack of response to three (or more) neuroleptics in high doses for a considerable period of time (usually 6 weeks or more). Unsuccessful long-term treatment with high doses of three or more conventional neuroleptics prior toclozapine was excluded in our study, and the number of episodes of prolonged illness was limited. Thus the patients, although not responding to their medication, were not treatment-resistant in the above-mentioned sense. They were also less chronically ill than most patients described in previous studies; for example, the patients of Singer and La$5 had a mean duration of illness of 2.5 years prior to clozapine, but in essence they were responders with an acute disease. The 17 neuroleptic-naive patients with acute paranoid schizophrenia in the series of Klieser et a136had been ill for an average of 4.9 years. Moreover, the median duration of illness in the study of Claghorn et alZ3 was 2.0 years, but their patients were intolerant of, rather than resistant to, conventional neuroleptics. Szymanski et alZBstudied a group of first-episode schizophrenic patients with a mean duration of illness of 4.4 years, which was considerably shorter than that in most other clozapine studies focusing on treatment-resistant schizophrenia. Nevertheless, the latter patients were well-established non-responders. Thus, it is obvious that our patients represent a population not investigated earlier. Nine (90%) of our patients showed a 20% or more reduction on the total BPRS score, and one patient a 19% reduction, which is considerably more than in the studies of Kane et al,I5Szymanski et a1,28Breier et all' and Schooler et al. In these studies the corresponding percentage varied from 30 to 54. However, direct comparison of these studies and the present one is difficult due to differences in study design. Relatively low doses of clozapine seemed to be effective in our patients. This is in agreement with earlier data on conventional neur~leptics,'*'~ showing that the doses of haloperidol required by first-episode patients were low, and tended to increase with time. Our patients also resembled the drug-naive ones in terms of side-effects, since all of them were prone to drug-induced sedation and hypersalivation, hindering further dosage increase. The patients of Klieser et al,36 who had never been medicated prior to clozapine but had been ill for longer, required and tolerated higher doses (mean 350 mg/day) of clozapine. The shorter duration of illness in the present study was associated (P=0.047) with a more noticeable improvement as measured by positive PANSS score. The same tendency, although not statistically significant, was observed on total PANSS (P=0.096) and QLS (P=0.060) scores. To date, there are no studies reporting statistically significant findings of this kind. However, some indirect data have been described.37 It is possible that such a correlation can be observed only within the first years of psychosis. Our term, 'early treatment-resistant schizophrenia', appears to describe adequately the population studied. Undoubtedly, the term needs further validation. It should
Clozapine in early treatment-resistant schizophrenia
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consider criteria defining in more detail the duration of illness and the treatment with conventional neuroleptics in terms of number, doses, and duration. In the present study no a priori response criteria were used. It is obvious that both ‘resistance’and ‘response’must be considered as continuous rather than yedno concepts. In our study we defined a 30% or more decrease in normalized total PANSS scores as a good, and 20 - 29%as a fair response. This classification is not yet accepted generally.
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KEY POINTS It can be concluded that: 0
0
0
0
There seem to be intermediate stages between treatment-responsive and treatment-resistant schizophrenia, which can be safely and successfully treated with clozapine Earlier rather than later transfer from conventional neuroleptics to clozapine in early treatmentresistant schizophrenia may be associated with favourable response Early treatment-resistant schizophrenic patients seem to be more sensitive to clozapine and require lower dosages of the drug than patients showing treatment resistance in the conventional sense The results of the present study should be replicated in a double-blind clozapine trial with a control group
REFERENCES 1. McEvoy J, Hogarty G, Steingard S (1991) Optimal dose of neuroleptic in acute schizophrenia. A controlled study of the neuroleptic threshold and higher haloperidol dose. Arch Gen Psychiatry 48: 739-45. 2. Wyatt R (1991) Neuroleptics and natural course of schizophrenia. Schizophr Bull 17: 325-351. 3. Loebel A, Lieberman J, Alvir J et al (1992) Duration of psychosis and outcome in first-episode schizophrenia. Am J Psychiatry 149: 1183-8. 4. Davis J, Schaffer C, Killian G et al (1980) Important issues in the drug treatment of schizophrenia. Schizophr Bull 6: 70-87. 5. Meltzer H (1992) Treatment of the neuroleptic-nonresponsive schizophrenic patient. Schizophr Bull 18: 515-42. 6. Lieberman J, Koreen A (1993) Neurochemistry and neuroendocrinology of schizophrenia. Schizophr Bull 19: 371 -429. 7. Olney J, Farber N (1994) Efficacy of clozapine compared with other antipsychotics in preventing NMDA-antagonist neurotoxicity. J Clin Psychiatry 55(suppl B): 43-46. 8. Nasrallah H, Skinner T, Schmalbrock P, Robitaille P (1994) Proton magnetic resonance spectroscopy (1H MRS) of the hippocampal formation in schizophrenia: a pilot study. B r ] Psychiatry 165: 481 -5. 9. Renshaw P, Yurgeluntodd D, Tohen M et al (1995) Temporal lobe proton magnetic resonance spectroscopy of patients with first-episode psychosis. Am J Psychiatry 152: 444-6. 10. StanleyJ, Williamson P, Drost D et a1 (1995) An in-vivo study of the prefrontal cortex of schizophrenic patients at different stages of illness via phosphorus magnetic resonance spectroscopy. Arch Gen Psychiatry 52: 399-406. 11. Horrobin D, Glen A, Vaddadi K (1994) The membrane hypothesis of schizophrenia. Schizophr Res 13: 195- 207. 12. Lieberman J, Kinon B, Koebel A (1990) Dopaminergic mechanisms in idiopathic and drug-indused psychoses. Schizophr Bull 16: 97- 110.
13. Lieberman J, Jody D, Geisler S et al (1993) Time course and biologic correlates of treatment response in first-episode schizophrenia. Arch Gen Psychiatry 50: 369-76. 14. Chouinard G (1991) Severe cases of neuroleptic-induced supersensitivity psychosis. Diagnostic criteria for the disorder and its treatment. Schizophr Res 5: 21-33. 15. Kane J, Honigfeld G, Singer J et al (1988) Clozapine for treatment-resistant schizophrenia. Arch Gen Psychiatry 45: 789-96. 16. Baldessarini R, Frankenburg F (1991) Clozapine: a novel antipsychotic agent. N Engl J Med 324: 746- 54. 17. Breier A, Buchanan R, Kirkpatrick B et a1 (1994) Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry 151: 20-26. 18. Kane J, Schooler N, Marder S et a1 (1996) Efficacy of clozapine versus haloperidol in a long-term clinical trial. Schizophr Res 18: 127. 19. Ekblom B, Haggstrom J (1974) Clozapine (Leponex@’) compared with chlorpromazine: a double-blind evaluation of pharmacological and clinical properties. Curr Ther Res 16: 945 - 57. 20. Gerlach J, Koppelhus P, Helweg E et al (1974) Clozapine and haloperidol in a single-blind cross-over trial: therapeutic and biochemical aspects in the treatment of schizophrenia. Acta Psychiatr Scand 50: 410-24. 21. Itoh H, Miura S, Yagi G et a1 (1977) Some methodological considerations for the clinical evaluation of neuroleptics comparative effects of clozapine and haloperidol on schizophrenics. Folia Psychiatr Neurol Japonica 31: 17- 24. 22. Shopsin B, Klein H, Aaronson M et a1 (1979) Clozapine, chlorpromazine and placebo in newly hospitalized, acutely schizophrenic patients: a controlled, double-blind comparison. Arch Gen Psychiatry 36: 657-64.
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23. Claghom J, Honigfeld G, Abuzzahab FS et a1 (1987) The risks and benefits of clozapine versus chlorpromazine. J Clin Psychopharmacol 7: 377- 84. 24. Gelenberg A, Doller JC (1979) Clozapine versus chlorpromazine for the treatment of schizophrenia: preliminary results from a double blind study. j Clin Psychiatry 40: 238-40. 25. Amsler H, Teerenhovi L, Barth E et a1 (1977) Agranulocytosis in patients treated with clozapine: a study of the Finnish epidemic. Acta Psychiatr Scand 56: 241 -48. 26. Idanpaan-HeikkilaJ, Alhava E, Olkinuora M et al (1977) Agranulocytosis during treatment with clozapine. Eur j Clin Pharmacol 11: 193-8. 27. May P, Dencker S, Hubbard J et a1 (1988) A systematic approach to treatment resistance in schizophrenic disorders. In: Treatment resistance in schizophrenia (eds S Dencker, F Kulhanek) 22 - 33. Vieweg, BraunschweigNiesbaden. 28. Szymanski S, Masiar S, Mayerhoff D et a1 (1994) Clozapine response in treatment-refractory first-episode schizophrenia. Bid Psychiatry 35: 278-80. 29. American Psychiatric Association (1987) DSM-111-R. Diagnostic and Statistical Manual of Mental Disorders. 3rd edn., revised. APA, Washington, DC. 30. Overall J, Gorham D (1962) The Brief Psychiatric Rating Scale. Psycho1 Rep 10: 799-812.
31. Kay S, Fiszbein A, Opler (1987) The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 13: 261 - 76. 32. Guy W (1976) ECDEU assessment manual for psychopathology (revised). 217 - 222. US Department of Health, Education and Welfare, Washington, DC. 33. Heinrichs D, Hanlon T, Carpenter W, Jr (1984) The Quality of Life scale: an instrument for rating the schizophrenic deficit syndrome. Schizophr Bull 10: 388-98. 34. Simpson G, Angus J (1970) A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 45(Suppl. 212): 11- 12. 35. Singer K, Law S (1974) A double-blind comparison of clozapine (Leponex) and chlorpromazine in schizophrenia of acute symptomatology.j Int Med Res 2: 433-5. 36. Klieser E, Straws WH, Lemmer W (1994) The tolerability and efficacy of the atypical neuroleptic remoxipride compared with clozapine and haloperidol in acute Schizophrenia.Acta Psychiatr Scand 89: 68 - 73. 37. Joffe G, Vendainen E, Tupala J et a1 (1996) The effect of clozapine on the course of illness in chronic schizophrenia: focus on treatment outcome in outpatients. Int Clin Psychopharmacol 11: 265-72.
International Journal of Psychiatry in Clinical Practice 1997 Volume 1 Pages 261 -268
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Clozapine response in early treatment-resistant schizophrenia GRIGORI JOFFE', JURI RYBAK', MARK BUR KIN^, DMITRI BURKIN*, BJORNAPPELBERG', MARINA JOFFE', RAINER GADEKE' AND RANAN RIMON' 'Department of Psychiatry, University of Helsinki, Helsinki, Finland; and 'Department of Psychiatry, University of Petrozavodsk, Karelia, Russia Correspondence Address Grigori Joffe, Department of Psychiatry, University of Helsinki, Lapinlahdentie, 00180 Helsinki, Finland
Received 4 July 1997; accepted for publication 10 September 1997
Eleven consecutive schizophrenic patients with a mean duration of illness of 2.2 (range 0.9-3.8) years and early signs of resistance to conventional neuroleptics were studied prospectively in a 26-week open trial with clozapine (mean dose 192.5 mg at week 8 and 225.0 mg at end-point). Of the ten patients who completed the study, nine improved by 20% or more on total Brief Psychiatric Rating Scale (BPRS) scores; six (good responders) showed more than 30%, and four (fair responders) 21 -26% improvement on total Positive and Negative Syndrome Scale (PANSS) scores. The improvement was observed mainly within the first 8 weeks. Duration of illness correlated negatively @=0.047) with the decrease of positive PANSS scores. The duration of illness of the fair responders was more than twice that of the good responders. Clozapine appears to be a safe and effective treatment alternative for early treatment-resistant schizophrenic patients. These patients seem to respond to relatively low clozapine doses. Early rather than late transfer to clozapine in this population may be of benefit for later clinical outcome. (Int J Psych Clin Pract 1997 8: 261 - 268) Keywords clozapine time factor
INTRODUCTION
E
arly introduction of neuroleptics in schizophrenia appears to be associated with a need for lower doses' and better treatment However, up to 20% of schizophrenic patients fail to respond to conventional neuroleptic the rap^,^.^ which is then followed by prolonged psychotic illness. Since the schizophrenic process may, itself, be neurotoxic,6-" lack of adequate treatment in the beginning of the illness may lead to gradual worsening of the response. In addition, chronic treatment with conventional dopaminergic substances may be followed by persistent neural dysfunctionI2 and poor clinical outcome. 1.13.14 Clozapine is the first and only antipsychotic agent that has demonstrated efficacy in schizophrenic patients who are refractory to other antipsychotic d r ~ g s . ' ~ -Clozapine '~ may be superior to traditional antipsychotic drugs in terms of overall and time required for response. Thus, it could be postulated that the use of clozapine as a first-line treatment might lead to a better clinical outcome and fewer cases of chronic schizophrenia. However, due to the relatively high risk of
treatment resistance
a g r a n ~ l o c y t o s i s , ~clozapine ~-~~ has in most countries been reserved for patients with treatment-resistant schizophrenia. There is a wide range of grades between treatment re~istance'~.'~ and full response, i.e. rapid and complete remission on the first conventional neuroleptic In partial responders, we do not know what would be the ideal point for transfer from conventional neuroleptics to clozapine. Optimization of timing for such a transfer would be of great value, since the role of novel atypical neuroleptics in treatment-resistant schizophrenia still remains to be evaluated. The effect of clozapine in responders has been studied extensively. Recent clozapine investigations have mostly been performed in treatment-resistant schizophrenic patients, chronically psychotic for many year^.'^,'^.'^.^' To date, no clozapine studies have been reported in patients with early signs of emerging resistance to conventional neuroleptics and with a relatively short duration of illness. We studied prospectively 11 such patients in order to examine possible benefits and problems of clozapine treatment in this population.
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PATIENTS AND METHODS Male and female patients aged 18-55 years with schizophrenia defined according to DSM-III-RZ9were included in the study. The inclusion criteria required overt psychotic illness with a total score of at least 18 on the 18-item Brief Psychiatric Rating Scale (BPRS)30despite routine treatment with one or two conventional neuroleptics for 2-12 months. Furthermore, the current episode of illness had to be the first or second one, with a duration of less than one year. The patients had to have a level of understanding sufficient to communicate intelligently with the investigators. Exclusion criteria were serious medical diseases, a history of leukopenia or severe allergic adverse drug reactions, DSM-III-R psychoactive substance use or organic mental disorders, serious suicidal risk, pregnancy, lactation or absence of contraception (in women). Established therapy-resistant patients, i.e. those who had failed to show any significant clinical response to two neuroleptics of two different classes with a maximum daily dose of 800 chlorpromazine equivalents for at least 3 weeks each, were excluded. The study was conducted in the psychiatric hospital and the day treatment unit of the psychoneurological dispensary of the Karelian Republic, Petrozavodsk, Russia, in accordance with the guidelines of the Helsinki Declaration and good clinical practice. Before each patient entered the study their verbal consent was obtained. It was stressed that the patients could at any time withdraw their participation in the study without any negative consequence for their treatment. The protocol was approved by the Ethics Committee of the Petrozavodsk University and Ministry of Health of the Karelian Republic. The following information was obtained from hospital records and clinical interviews: sex, age, age at onset of the first psychotic symptoms, duration of the illness before clozapine, and number of conventional antipsychotics prior to clozapine. At the screening interview, pertinent physical and psychiatric examinations were performed. Psychiatric diagnoses were made by an experienced psychiatrist. A 1- 9 day wash-out from conventional orally used neuroleptic was conducted before base-line (week 0) evaluation (none of the patients had received depot neuroleptics). Assessments of treatment efficacy by BPRS, Positive and Negative Syndrome Scale (PANSS)13’ Clinical Global Impression (CGIy2 and Patient Global Impression (PGII3*were performed weekly for the first 8 weeks and thereafter bimonthly up to the end-point at week 26. In addition, assessment by CGI was performed at the screening preceding the wash-out period, and by the Quality of Life Scale (QLS)33 at base-line and end-point. The PANSS and BPRS scores were adjusted by subtracting 1 point from each item (ratings from 0 to 6 ) . In addition, the BPRS scores and changes to them were counted before adjusting for comparability with some earlier studies. Extrapyramidal side-effects were assessed by the SimpsonAngus Scale.34
The following clozapine dose regimen was recommended: A dose of 12.5-25 mg was to be given once or twice on the first day, followed by stepwise increases of 25-50 mg daily for 7- 14 days until a dose of 300450 mg (up to 600 mg) per day was reached. The protocol allowed an individual adjustment of the doses (not exceeding 900 mg per day). Use of the lowest effective dose during the maintenance period was strongly recommended. Concomitant use of medication with primarily central nervous system activity beyond prescription of short/ middle-acting benzodiazepines was not allowed. Complete blood counts were performed weekly during the first 18 weeks and monthly thereafter. Statistical probabilities when comparing subgroups were calculated using Kruskal-Wallis one-way ANOVA. Correlations were calculated with Spearman’s correlation coefficient (r). Descriptive statistical data are presented as means with ranges in brackets.
RESULTS Eleven patients were enrolled into the trial. One patient ceased participation at the very beginning of the study due to withdrawal of informed consent. Since no assessments were done after base-line for this patient, the scores of the last observations were not carried forward for the intentionto-treat analysis. Of the remaining 10 patients (six men and four women), seven had paranoid, one catatonic, and two undifferentiated schizophrenia. Four patients had previously received one (either haloperidol or trifluoperazine), and six patients consecutively two (haloperidol, trifluoperazine, chlorpromazine or sulpiride) conventional neuroleptics. At the screening phase all the patients were on either haloperidol (from 15 to 35 mg per day) or trifluoperazine (from 12.5 to 25 mg per day). In all 10 patients, the reason for the shift from conventional neuroleptics to clozapine was lack of response. In addition, seven patients suffered from considerable, mainly extra-pyramidal, side-effects. At the beginning of the study four patients were managed in open care, and six patients remained in hospital. None of the outpatients needed hospitalization, and five of the six inpatients became able to be discharged from the hospital during the study period. The sixth inpatient had been sentenced to hospital treatment by a court and therefore could not be discharged, regardless of his psychiatric condition. Some characteristics of the patients are presented in Table 1. The clozapine doses used during the study (mean 192.5, range 100.0-350.0 mg/day at week 8, and mean 225.0, range 50.0-450.0 mg/day at the end-point) tended to be lower, and their ascent somewhat slower than recommended by the study protocol (Figure 1).The main reasons for this were sedation and hypersalivation. On the other
Clozapine in early treatment-resistant schizophrenia
Table 1 Characteristics of 1 0 clozapine-medicated patients with early treatment-refractory schizophrenia
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Years, mean (range) Age at base-line Age at onset of illness Duration of illness before clozapine Duration of current episode of illness before clozapine Duration of the last neuroleptic treatment prior to clozapine
25.4 (18-44) 23.2 (1541) 2.2 (0.9-3.8) 0.61 (0.25-0.9) 0.42 (0.25-0.75)
hand, early improvement of the symptoms made a more aggressive dosage regimen unnecessary. None of the 10 patients deteriorated or improved during the wash-out period (mean 2.4, range 1 - 7 days). During clozapine treatment none of the patients remitted completely. However, all improved to some extent, as assessed by the scales used (with the exception of slight deterioration in PANSS negative scores in two patients). The changes in rating scale scores are presented in Figures 2, 3, 4 and 5. As can be seen in Table 2 and Figures 2, 3 and 4, the most prominent improvement was seen by week 8 of the study with only minimal changes thereafter. BPRS ratings before adjustment (range from 1 to 7, not included in Table 2) changed from 48.5 (45 - 53) at week 0
c 0
Figure I Changes in [he mean doses of clozapine
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to 38.2 (30-43) at week 8 and to 36.8 (33-43) at week 26. Thus, the percentage improvements from base-line in non-adjusted BPRS scores rose from 21% (13-36) at week 8 to 24% (19-31) at the end-point. Only one patient improved less (19%) than the 20% response which has been proposed as clinically significant.l 6 In six patients (defined below as good responders) the decrease in total PANSS scores (30-50%) exceeded 30%. The remaining four patients (fair responders) improved by 21% to 26%. For two of these patients the clozapine dose was able to be increased up to 300 mg/day after week 8 of treatment; however, this did not in fact lead to further clinical improvement; the reduction in total PANSS scores as compared to base-line rose from 18%at week 8 to 21%at the end-point in one patient, but declined from 28% to 23% in the other. There was no correlation between clozapine dose and improvement for the group as a whole. The duration of illness correlated negatively (r=- 0.639, P=0.047) with the reduction of positive PANSS scores*. Improvements in clinical rating scale scores did not show any correlation with the duration or sequence of the current illness episode, the duration or doses of the last neuroleptic, the number of previous conventional neuroleptic treatment efforts, or the actual age of the patients or their age at onset of the illness.
*Duration of illness also showed a tendency towards a negative correlation with improvement on total PANSS (r=-0.555, P=0.096) and a positive correlation on total QLS (r=0.612. P=0.060) scores. Since improvement corresponds with decrease on PANSS and increase on QLS scores, shorter duration of illness tended to correlate with better results on both scales.
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Table 2 Changes in rating scale scores and clozapine doses at weeks 8 and 26 vs. base-line
Rating scale scores
At week 0
At week 8
(change from base-line, %) PANSS positive
12.5 (8.16)
P A N S negative
14.1 (14-21)
PANSS general
29.9 (24-34)
PANSS total
54.5 (38-65)
BPRS
30.5 (27-35)
CGI (severity)
37.1 (21-79)
7 .5 (1-11) 40.8 (0.8-88.9) % 11.7 (5-16) 12.6 (-25.0-53.8) % 21.9 (15-29) 26.9 (12.1-51.6) % 39.7 (20-51) 27.1 (13.2-60.8) % 20.2 (12-25) 33.9 (21.4-58.6) % 4.0 (3-5) 20.5 (0.0-40.0 ) % 2.1 (2-3) 45.8 (25.0-50.0) % 2.2 (1-3) 44.4 (25.0-75.0) % NA
NA
192.5 (100-350)
5.0 ( 4 6 )
CGI (improvement) 4.0 ( 4 4 ) PGI QLS total
NA
Clozapine dose (mdday)
At week 26 (change from base-line, %)
7.4 (1-11) 42.3 (15.4-88.9) % 11.6 (6-14) 8.6 (-50.0-38.5) % 20.7 (16-26) 30.9 (13.3-46.7) % 37.6 (25-49) 31.0 (21 .O-51 .0) % 18.8 (15-25) 38.7 (18.6-48.4) % 3.8 (3-4) 23.3 (0.0-40.0) % 2.1 (2-3) 45.8 (25.0-50.0) % 2.0 (1-3) 50.0 (25.0-75.0) % 62.7 (33-89) 81.7 (181.0-6.3) % 225.0 (50-450)
The data are expressed as mean (range). The PANSS and BPRS scores were adjusted by subtracting 1 point from every item
Fipre 2 Changes in mean PANSS scores during clozapine. Sl=positive; S2=negative; S3=general; S4=total
In intergroup analysis (good responders versus fair responders), no significant differences in demographics or patient histories were found. However, the mean duration of illness in the fair responders was 3.25 (3.0-3.8) years, which was more than twice as long as the 1.5 (0.9-1.6) years in good responders. The side-effects of the study medication are shown in Table 3. None of the patients developed granulocytopenia
or agranulocytosis. At the end-point of the study, eight patients still showed a slight (1 point on the SimpsonAngus Scale) increase in salivation. The minor extrapyramidal symptoms, shown by all the patients at base-line, disappeared during clozapine treatment. The only exception was a slight (1 point on the Simpson-Angus scale) diminution in swing when walking, still seen at the endpoint in two patients.
Clozapine in early treatment-resistant schizophrenia
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Figure 3 Changes in BPR5 scores during clozapine treatment
Figure 4 Changes in the mean CGI and PGI scores. Sl=CGI improvement; SZ=PGI; S3=CGI severity
Figure 5 Mean QLS scores before and after 26-week treatment with clozapine. QLS items: 1 . Interpersonal relations; 2. lnstrumental role; 3. lntrapsychic foundations; 4. Common objects and activities; 5. Total. White=base-line score; blach=end-point score
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Table 3 Side-effects during clozapine treatment in 10 schizophrenic patients Side-effects
n
Hypersalivation
10 9
Sleepiness, sedation, fatigue Hyperthermia Considerable increase in weight Hypotension
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Dysarthria
4 2 1
1 1
Follow-up of nine of the 10 patients was continued for 6 - 15 months after the end-point of the study. Those six patients who continued treatment with Swiss-made clozapine were asymptomatic, and five of them were capable of work. Substitution of the original medication by Ukraineanproduced clozapine, tried in two of the six patients, failed in both cases; the symptoms deteriorated. Furthermore, one of the latter two patients twice developed a confusional state resembling toxic delirium. His condition rapidly improved after he went back on the original clozapine preparation. One patient, although not receiving neuroleptic treatment any more, was still asymptomatic and continued her studies at school. Two patients were shifted to conventional neuroleptics. This was partly due to problems of availability of the Swissmade clozapine in Russian Karelia. Other reasons were persistence of negative symptoms despite clozapine treatment in one patient and psychotic exacerbation and granulocytopenia during treatment with Ukrainean-made clozapine in another.
DISCUSSION Despite unusually low daily doses of clozapine, all our patients responded well, or at least fairly well, to the medication. The only difference between the good and the fair responders was that the latter had suffered from their illness for more than twice as long as the former. In the whole group, shorter duration of illness correlated (r= - 0.639, P=0.047) with better improvement, reflected also by the reduction of the positive PANSS subscale symptoms. The improvement was observed mainly within the first weeks of treatment, with only modest changes after week 8. The major methodological problems of the present study included the relatively small sample and the lack of a control group. Therefore, our results and conclusions should be taken as preliminary and with caution.
Treatment resistance has in earlier ~ t u d i e s ' ~ ~ been ''~'~~~~ defined as lack of response to three (or more) neuroleptics in high doses for a considerable period of time (usually 6 weeks or more). Unsuccessful long-term treatment with high doses of three or more conventional neuroleptics prior toclozapine was excluded in our study, and the number of episodes of prolonged illness was limited. Thus the patients, although not responding to their medication, were not treatment-resistant in the above-mentioned sense. They were also less chronically ill than most patients described in previous studies; for example, the patients of Singer and La$5 had a mean duration of illness of 2.5 years prior to clozapine, but in essence they were responders with an acute disease. The 17 neuroleptic-naive patients with acute paranoid schizophrenia in the series of Klieser et a136had been ill for an average of 4.9 years. Moreover, the median duration of illness in the study of Claghorn et alZ3 was 2.0 years, but their patients were intolerant of, rather than resistant to, conventional neuroleptics. Szymanski et alZBstudied a group of first-episode schizophrenic patients with a mean duration of illness of 4.4 years, which was considerably shorter than that in most other clozapine studies focusing on treatment-resistant schizophrenia. Nevertheless, the latter patients were well-established non-responders. Thus, it is obvious that our patients represent a population not investigated earlier. Nine (90%) of our patients showed a 20% or more reduction on the total BPRS score, and one patient a 19% reduction, which is considerably more than in the studies of Kane et al,I5Szymanski et a1,28Breier et all' and Schooler et al. In these studies the corresponding percentage varied from 30 to 54. However, direct comparison of these studies and the present one is difficult due to differences in study design. Relatively low doses of clozapine seemed to be effective in our patients. This is in agreement with earlier data on conventional neur~leptics,'*'~ showing that the doses of haloperidol required by first-episode patients were low, and tended to increase with time. Our patients also resembled the drug-naive ones in terms of side-effects, since all of them were prone to drug-induced sedation and hypersalivation, hindering further dosage increase. The patients of Klieser et al,36 who had never been medicated prior to clozapine but had been ill for longer, required and tolerated higher doses (mean 350 mg/day) of clozapine. The shorter duration of illness in the present study was associated (P=0.047) with a more noticeable improvement as measured by positive PANSS score. The same tendency, although not statistically significant, was observed on total PANSS (P=0.096) and QLS (P=0.060) scores. To date, there are no studies reporting statistically significant findings of this kind. However, some indirect data have been described.37 It is possible that such a correlation can be observed only within the first years of psychosis. Our term, 'early treatment-resistant schizophrenia', appears to describe adequately the population studied. Undoubtedly, the term needs further validation. It should
Clozapine in early treatment-resistant schizophrenia
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consider criteria defining in more detail the duration of illness and the treatment with conventional neuroleptics in terms of number, doses, and duration. In the present study no a priori response criteria were used. It is obvious that both ‘resistance’and ‘response’must be considered as continuous rather than yedno concepts. In our study we defined a 30% or more decrease in normalized total PANSS scores as a good, and 20 - 29%as a fair response. This classification is not yet accepted generally.
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KEY POINTS It can be concluded that: 0
0
0
0
There seem to be intermediate stages between treatment-responsive and treatment-resistant schizophrenia, which can be safely and successfully treated with clozapine Earlier rather than later transfer from conventional neuroleptics to clozapine in early treatmentresistant schizophrenia may be associated with favourable response Early treatment-resistant schizophrenic patients seem to be more sensitive to clozapine and require lower dosages of the drug than patients showing treatment resistance in the conventional sense The results of the present study should be replicated in a double-blind clozapine trial with a control group
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