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Classical antipsychotics in the treatment of negative symptoms
210
Not received
Classical antipsychotics in the treatment of negative symptoms
W.W. Fleischhacker and A.B. Whitworth lnnsbruck University Clinics, Department (4f Psychiato', 6020 lnnsbruck, Austria Key words: Negative symptoms; Neuroleptics; Schizophrenia; Antipsychotics; Dose; Parenteral application
Introduction
At the moment, two different research strategies are pursued concerning the treatment of negative symptoms of schizophrenic patients. New compounds with different pharmacological profiles are being developed, in the hope of finding a specific therapeutic approach for this form of schizophrenia. On the other hand there is renewed attention for the efficacy of well known, conventional antipsychotics in this indication. The following brief review will focus on the latter kind of studies. In the past, several large-scale, controlled studies have reported clinically relevant improvement in a significant proportion of schizophrenics, although a considerable diversity in the definition of negative symptoms and different inclusion criteria as well as a variety of rating instruments and study designs make it difficult to compare results of these trials. Phenothiazines and thioxanthenes
Among the first to address the issue of efficacy of neuroleptics in the treatment of negative symptoms were the authors of the National Institute of Mental Health Psychopharmacology Service Center Collaborative Study which was published in 1964. Assessing the response of 344 young, first-admission schizophrenics after 6 weeks of treatment with fluphenazine, chlorpromazine, thioridazine or placebo, they reported that phenothiazine treatment improved positive and negative symptoms with the exception of symptoms usually associated with affective disorders. The effects of neuroleptic treatment over a 26-week rather than a 6-week period were studied in the same group of patients by Goldberg et al. (1965). Negative symptoms (indifference to the environment, etc.) showed less improvement than did the symptoms classified as 'paranoid' (auditory hallucinations, delusions). In another study, Prien and Cole (1968) compared high (2000 mg/day) and low (300 mg/day) doses of chlorpromazine with placebo in a population of older, chronic schizophrenics and could show that younger patients with a hospitalization duration of less than 10 years responded best to high doses on all rating scales used for positive as well as negative symptoms. In a trial by Serafetinides et al. (1972) haloperidol, clopenthixol, chlorpromazine and placebo were compared in 57 schizophrenic patients over a 12-week period. The authors detected no significant drug versus placebo effects on BPRS items reflecting negative symptoms they even deteriorated over the course of the trial. Crow et al. (1980) compared the cis-isomer of flupenthixol with trans-flupenthixol and placebo in a double-blind trial of 45 acute schizophrenics and noticed after 4 weeks that the effect was limited to positive symptoms. Fluphenazine (range of 31 +_12 mg/day) was found to lead to a significant improvement of negative symptoms in a placebocontrolled study by Breier et al. (1987) in 19 chronic schizophrenics.
211 Diphenylbutylpiperidines Kolivakis et al. (1974) compared pimozide (2.5-21 rag/day, 26 patients) with cblorpromazine (75~450 mg/day, 25 patients) in 54 chronic schizophrenics. No difference could be detected on total BPRS scores, but pimozide significantly reduced emotional withdrawal. In 1975, Lapierre and Lavallee found no significant difference between pimozide (2 10 mg/day) and fluphenazine (3 21 mg/ day) in 32 chronic schizophrenic patients, although blind raters identified pimozide patients as less withdrawn and more communicative. Lacking sensitivity of rating scales is discussed by the authors in this context. Lapierre (1978) compared penfluridol (3 18 mg/day, 21 patients) with fluphenazine (20-120 rag/day, 20 patients) during a l-year period and found no overall differences. Haas and Beckmann (1982) again demonstrated no overall differences between haloperidol (40-60 rag/day) and pimozide (40 60 mg/day) in BPRS and CG1 scores. Pimozide treated patients showed a significant improvement in affective blunting, emotional withdrawal and anergy. Unfortunately there were also group differences in the incidence of extrapyramidal side effects and the use of anticholinergics, which makes the results difficult to interpret. A double-blind comparison of pimozide (up to 20 mg/day) and chlorpromazine (up to 950 rag/day) over 1 year also yielded no differences between groups (Wilson et al., 1982). Feinberg et al. (1988) conducted an 8-week open trial with 10 neuroleptic refractory chronic schizophrenics. A 2-week baseline was established on a standard neuroleptic (chlorpromazine or haloperidol) and the patients were switched to pimozide in low but gradually increasing doses over the next 6 weeks. The negative scale of the PANSS, but not the positive, showed significant and progressive reduction over the investigation period. Substituted benzamides Wiesel et al. (1985) administered chlorpromazine (400 rag/day) and sulpiride (800 mg/day) to 50 schizophrenics and discovered a significant amelioration of the NOSIE factor 'retardation' in the sulpiride group. Another sulpiride study (Petit et al., 1987) compared doses of 150 and 1200 rag/day with each other, finding significant improvement of the BPRS items emotional withdrawal and affective fattening. Conclusion A review of the literature on the treatment of negative symptoms in schizophrenia makes it evident that we are currently far from a satisfactory treatment for this syndrome. Many studies suffer from the lack of a precise definition and description of negative symptoms. Two problems deserve special attention in future treatment trials: (1) are the negative symptoms of the primary or secondary type and (2) is the improvement noted independent of a concomitant amelioration of positive symptoms. If these questions are not accounted for, positive treatment outcomes can lead to undue optimism when for instance an alleviation of akinesia is mistaken for an improvement in negative symptoms. Another unexplored issue is the impression shared by many clinicians that low doses of typical antipsychotics improve negative symptoms. Even though it is clearly easier to treat hallucinations and paranoid ideas than affective blunting and anergy, psychiatrists should carefully study the options available and not let the paucity of reliable information discourage them from trying to treat negative symptoms. References Breier, A., Wolkowitz, O.W., Doran, A.R., Roy, A., Boronow, J., Hommer, D.W. and Pickar, D. (1987) Neuroleptic responsivity of negative and positive symptoms in schizophrenia. Am. J. Psychiatry 144, 1549 1555. Crow, T.J. (1980) Molecular pathology of schizophrenia: more than one disease process? Br. Med. J. 280, 66-68. Feinberg, S., Kay, S., Elijovich, L., Fiszbein, A. and Opler, L. (1988) Pimozide treatment of the negative schizophrenic syndrome: an open trial. J. Clin. Psychiatry 49, 235-241. Goldberg, S.C., Klerman, G.L. and Cole, J.O. (1965) Changes in schizophrenic psychopathology and ward behavior as a function of phenothiazine treatment. Br. J. Psychiatry I 11, 120-133. Haas, S. and Beckmann, H. (1982) Pimozide versus haloperidol in acute schizophrenia. A double blind controlled study. Pharmacopsychiatry. 15, 70-74. Kolivakis, T., Azian, H. and Kingstone, E. (1974) A double blind comparison of pimozide and chlorpromazine in the maintenance of chronic schizophrenic patients. Curr. Ther. Res. 16, 998-1004. Lapierre, Y.D. (1978) A controlled study of penfluridol in the treatment of chronic schizophrenia. Am. J. Psychiatry 135,956959. Lapierre, Y.D. and Lavallee, J. (1975) Pimozide and the social behaviors of schizophrenics. Curr. Ther. Res. 18, 181-188. National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group (1964) Phenothiazine treatment in acute schizophrenia. Arch. Gen. Psychiatry 10, 24~261. Petit, M., Zann, M., Lesieur, B. and Colonna, L. (1987) The effect of sulpride on negative symptoms of schizophrenia. Br. J.
212 Psychiatry 150, 270 271. Prien, R.F. and Cole, J.O. (1968) High dose chlorpromazine therapy in chronic schizophrenia. Report of NIMH Psychopharmacology Research Branch Collaborative Study Group. Arch. Gen. Psychiatry 18, 482~,95. Serafetinides, E.A., Collins, S. and Clark, M.I. (1972) Haloperidol, clopenthixol and chlorpromazine in chronic schizophrenia. J. Nerv. Ment. Dis. 154, 3142. Wiesel, F., Alfredson, G., Bjerkenstedt, L., H/irnryd, C., Oxenstierna, G. and Sedvall, G. (1985) Dogmatik in der Behandlung der Minussymptomatik bei schizophrenen Patienten. Semin. Hop. Paris 61, 1317 1321. Wilson, L., Roberts, R. and Gerber, C. (1982) Pimozide versus chlorpromazine in chronic schizophrenia: a 52 week doubleblind study of maintenance therapy. J. Clin. Psychiatry 43, 62 65.
Not received
Classical antipsychotics in the treatment of negative symptoms
W.W. Fleischhacker and A.B. Whitworth lnnsbruck University Clinics, Department (4f Psychiato', 6020 lnnsbruck, Austria Key words: Negative symptoms; Neuroleptics; Schizophrenia; Antipsychotics; Dose; Parenteral application
Introduction
At the moment, two different research strategies are pursued concerning the treatment of negative symptoms of schizophrenic patients. New compounds with different pharmacological profiles are being developed, in the hope of finding a specific therapeutic approach for this form of schizophrenia. On the other hand there is renewed attention for the efficacy of well known, conventional antipsychotics in this indication. The following brief review will focus on the latter kind of studies. In the past, several large-scale, controlled studies have reported clinically relevant improvement in a significant proportion of schizophrenics, although a considerable diversity in the definition of negative symptoms and different inclusion criteria as well as a variety of rating instruments and study designs make it difficult to compare results of these trials. Phenothiazines and thioxanthenes
Among the first to address the issue of efficacy of neuroleptics in the treatment of negative symptoms were the authors of the National Institute of Mental Health Psychopharmacology Service Center Collaborative Study which was published in 1964. Assessing the response of 344 young, first-admission schizophrenics after 6 weeks of treatment with fluphenazine, chlorpromazine, thioridazine or placebo, they reported that phenothiazine treatment improved positive and negative symptoms with the exception of symptoms usually associated with affective disorders. The effects of neuroleptic treatment over a 26-week rather than a 6-week period were studied in the same group of patients by Goldberg et al. (1965). Negative symptoms (indifference to the environment, etc.) showed less improvement than did the symptoms classified as 'paranoid' (auditory hallucinations, delusions). In another study, Prien and Cole (1968) compared high (2000 mg/day) and low (300 mg/day) doses of chlorpromazine with placebo in a population of older, chronic schizophrenics and could show that younger patients with a hospitalization duration of less than 10 years responded best to high doses on all rating scales used for positive as well as negative symptoms. In a trial by Serafetinides et al. (1972) haloperidol, clopenthixol, chlorpromazine and placebo were compared in 57 schizophrenic patients over a 12-week period. The authors detected no significant drug versus placebo effects on BPRS items reflecting negative symptoms they even deteriorated over the course of the trial. Crow et al. (1980) compared the cis-isomer of flupenthixol with trans-flupenthixol and placebo in a double-blind trial of 45 acute schizophrenics and noticed after 4 weeks that the effect was limited to positive symptoms. Fluphenazine (range of 31 +_12 mg/day) was found to lead to a significant improvement of negative symptoms in a placebocontrolled study by Breier et al. (1987) in 19 chronic schizophrenics.
211 Diphenylbutylpiperidines Kolivakis et al. (1974) compared pimozide (2.5-21 rag/day, 26 patients) with cblorpromazine (75~450 mg/day, 25 patients) in 54 chronic schizophrenics. No difference could be detected on total BPRS scores, but pimozide significantly reduced emotional withdrawal. In 1975, Lapierre and Lavallee found no significant difference between pimozide (2 10 mg/day) and fluphenazine (3 21 mg/ day) in 32 chronic schizophrenic patients, although blind raters identified pimozide patients as less withdrawn and more communicative. Lacking sensitivity of rating scales is discussed by the authors in this context. Lapierre (1978) compared penfluridol (3 18 mg/day, 21 patients) with fluphenazine (20-120 rag/day, 20 patients) during a l-year period and found no overall differences. Haas and Beckmann (1982) again demonstrated no overall differences between haloperidol (40-60 rag/day) and pimozide (40 60 mg/day) in BPRS and CG1 scores. Pimozide treated patients showed a significant improvement in affective blunting, emotional withdrawal and anergy. Unfortunately there were also group differences in the incidence of extrapyramidal side effects and the use of anticholinergics, which makes the results difficult to interpret. A double-blind comparison of pimozide (up to 20 mg/day) and chlorpromazine (up to 950 rag/day) over 1 year also yielded no differences between groups (Wilson et al., 1982). Feinberg et al. (1988) conducted an 8-week open trial with 10 neuroleptic refractory chronic schizophrenics. A 2-week baseline was established on a standard neuroleptic (chlorpromazine or haloperidol) and the patients were switched to pimozide in low but gradually increasing doses over the next 6 weeks. The negative scale of the PANSS, but not the positive, showed significant and progressive reduction over the investigation period. Substituted benzamides Wiesel et al. (1985) administered chlorpromazine (400 rag/day) and sulpiride (800 mg/day) to 50 schizophrenics and discovered a significant amelioration of the NOSIE factor 'retardation' in the sulpiride group. Another sulpiride study (Petit et al., 1987) compared doses of 150 and 1200 rag/day with each other, finding significant improvement of the BPRS items emotional withdrawal and affective fattening. Conclusion A review of the literature on the treatment of negative symptoms in schizophrenia makes it evident that we are currently far from a satisfactory treatment for this syndrome. Many studies suffer from the lack of a precise definition and description of negative symptoms. Two problems deserve special attention in future treatment trials: (1) are the negative symptoms of the primary or secondary type and (2) is the improvement noted independent of a concomitant amelioration of positive symptoms. If these questions are not accounted for, positive treatment outcomes can lead to undue optimism when for instance an alleviation of akinesia is mistaken for an improvement in negative symptoms. Another unexplored issue is the impression shared by many clinicians that low doses of typical antipsychotics improve negative symptoms. Even though it is clearly easier to treat hallucinations and paranoid ideas than affective blunting and anergy, psychiatrists should carefully study the options available and not let the paucity of reliable information discourage them from trying to treat negative symptoms. References Breier, A., Wolkowitz, O.W., Doran, A.R., Roy, A., Boronow, J., Hommer, D.W. and Pickar, D. (1987) Neuroleptic responsivity of negative and positive symptoms in schizophrenia. Am. J. Psychiatry 144, 1549 1555. Crow, T.J. (1980) Molecular pathology of schizophrenia: more than one disease process? Br. Med. J. 280, 66-68. Feinberg, S., Kay, S., Elijovich, L., Fiszbein, A. and Opler, L. (1988) Pimozide treatment of the negative schizophrenic syndrome: an open trial. J. Clin. Psychiatry 49, 235-241. Goldberg, S.C., Klerman, G.L. and Cole, J.O. (1965) Changes in schizophrenic psychopathology and ward behavior as a function of phenothiazine treatment. Br. J. Psychiatry I 11, 120-133. Haas, S. and Beckmann, H. (1982) Pimozide versus haloperidol in acute schizophrenia. A double blind controlled study. Pharmacopsychiatry. 15, 70-74. Kolivakis, T., Azian, H. and Kingstone, E. (1974) A double blind comparison of pimozide and chlorpromazine in the maintenance of chronic schizophrenic patients. Curr. Ther. Res. 16, 998-1004. Lapierre, Y.D. (1978) A controlled study of penfluridol in the treatment of chronic schizophrenia. Am. J. Psychiatry 135,956959. Lapierre, Y.D. and Lavallee, J. (1975) Pimozide and the social behaviors of schizophrenics. Curr. Ther. Res. 18, 181-188. National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group (1964) Phenothiazine treatment in acute schizophrenia. Arch. Gen. Psychiatry 10, 24~261. Petit, M., Zann, M., Lesieur, B. and Colonna, L. (1987) The effect of sulpride on negative symptoms of schizophrenia. Br. J.
212 Psychiatry 150, 270 271. Prien, R.F. and Cole, J.O. (1968) High dose chlorpromazine therapy in chronic schizophrenia. Report of NIMH Psychopharmacology Research Branch Collaborative Study Group. Arch. Gen. Psychiatry 18, 482~,95. Serafetinides, E.A., Collins, S. and Clark, M.I. (1972) Haloperidol, clopenthixol and chlorpromazine in chronic schizophrenia. J. Nerv. Ment. Dis. 154, 3142. Wiesel, F., Alfredson, G., Bjerkenstedt, L., H/irnryd, C., Oxenstierna, G. and Sedvall, G. (1985) Dogmatik in der Behandlung der Minussymptomatik bei schizophrenen Patienten. Semin. Hop. Paris 61, 1317 1321. Wilson, L., Roberts, R. and Gerber, C. (1982) Pimozide versus chlorpromazine in chronic schizophrenia: a 52 week doubleblind study of maintenance therapy. J. Clin. Psychiatry 43, 62 65.