- Email: [email protected]
FLUPHENAZINE DECANOATE
546 fluid
(1-1-55 g/1)
is
likely
to
reduce the risk of
hypoglycaemic
accidents. Service de Reanimation, Groupe Pitié-Salpétrière, Paris 75013
Hospitalier
Centre d’Hémodialyse Edouard Rist, 14 rue Boileau, Paris 75016
K. SAMII CH. CIANCIONI
J. ROTTEMBOURG Service de
Néphrologie, Groupe Hospitalier
Pitié-Salpétrière,
Paris 75013
F. BISSELICHES
C. JACOBS
DOUBLE-BLIND TRIALS
SIR,-We welcome and support the findings of Dr Hill and colleagues (Feb. 14, p. 352). Like them we have followed
her
periods of one day each, so carry-over effects could be serious. They were avoided by packing each treatment in foil packs of a distinctive colour and telling the patients that three different tablets were being tested. To preserve the clinicians’ blindness the correspondence between colour of the packs and their contents was varied from patient to patient. This approach may, however, encourage the development of bias as the trial progresses. Whichever way the problem of blindness is approached the measurement of bias and its implications still constitutes the core of uncertainty in the apple of the best-planned clinical trial. The benefits of the double-blind trial have been well demonstrated. Progress is likely to come from better methods to measure bias than from a return from double-blindness to the greater bias which preceded it. treatment
Joyce’s lead,but in two ways: (1) When a trial is still in the design stage, we always have a "placebo tasting session" when a "blind" group tries to distinguish drug from dummy. (2) During trials the observers, whether they be doctors making clinical observations or patients completing diary cards, are asked to try to break the code by noting which remedy they think is being provided at each clinic
Clinical Trials Unit, Department of Pharmacology and Therapeutics, London Hospital Medical College, E1 2AD
visit. The reason for the second procedure is that blindness can never be assumed, as Dr Hill and others show, so the trialist must either improve placebo matching until it is perfect, which is impossible, or measure its imperfection, which can be done. We therefore collect doctors’ or patients’ views on their medication and analyse them statistically. Inevitably the distribution of these views about the identity of the treatments is not completely random. Two important questions follow: how much bias is associated with a given degree of code breaking, and how will this bias alter the treatment outcome? We are still looking for the answers and for the moment content ourselves with accepting only small departures from randomness as likely to affect the trial adversely. These practices have led us into some amusing experiences, and have failed on some occasions. For example in one trial of injected gold for rheumatoid disease, a perfect placebo match was obtained at the start of the trial, but was lost a few weeks later when the gold solution turned yellow while the placebo remained white. In another trial a patient found that he could break a nearly perfect match by scratching the tablets lightly with his finger nail. One set developed a sheen when held up to the light, the other did not. An anaesthetist found that he could distinguish autoclaved from filtered dextrose solutions by listening as the needle went in; autoclaved bottles emit a soft hiss. One pharmaceutical company kindly supplied a beautifully matched set of drug and placebo ampoules, but the word "placebo" was printed on half of them! However, it is very satisfying to find that subjects cannot break a code; that is the final test. Even medical students seem unable to decode trinitrin set in the hollow of ’Polo’ mints with hard icing sugar. Perfectly matching treatments can also cause problems. In many diseases (especially those associated with pain) the patient’s expectations are important determinants of the treatment outcome. If the patient gets benefit from the first of a series of identical treatments the beneficial effect may carry over into successive treatment periods, the patient believing his therapy to be unchanged. This effect may be avoided by making the treatment distinctive and telling the patient that they are all different. This is in effect a "double dummy" approach, one dummy being for the drug, the other for the emotional impact of its appearance. In a recent trial (unpublished) of three antacids in duodenal ulceration it became clear that the taste of one of the treatments could not easily be disguised or matched in the placebo. Furthermore the trial consisted of 24
SIR,- Your editorial does less than justice to the advantages of slow-release injections in the maintenance treatment of schizophrenia. I am concerned lest young psychiatrists and others involved in the management of these patients infer that there is some special therapeutic benefit implicit in prolonged institutional care as opposed to current, albeit imperfect, community methods based upon chemotherapy. You seem to commend a lukewarm attitude towards discharge from hospital unless and until funds and other resources for hostels, sheltered workshops, and the like are forthcoming. I believe that such equivocation will not only cause patients, families, and staffto lose heart, but also, in the broader perspective, remove the stimulus necessary to elicit the funds needed for these community facilities. Few would wish to put the clock back to the asylum pattern of care. Surely the "quality of life" in the real world is preferable to that of an institution, however well-intentioned ? Many would agree that schizophrenia is a condition with social implications and that there have been considerable advances, notably by the Maudsley M.R.C. Social Psychiatry Unit, of our understanding of the ways in which these influence prognosis. Of course, such factors have to be considered before discharge of the patient. Nevertheless, schizophrenia is also a disease (or diseases) suffered by patients, and medical models of care are apposite. Good or bad outcome patients, irrespective of whether they are discharged on drugs or not, cannot yet be reliably predicted but only known post hoc. However, many patients with discrete psychoses of excellent outcome would be spared the inconvenience of long-term depot injections if a careful clinical distinction between affective illness and schizophrenia were made, and if this form of treatment were reserved for the second and subsequent admissions to hospital. Much about depot fluphenazine and flupenthixol is still unclear-especially, the duration and dose of maintenance therapy, whether they can ever safely be withdrawn, and the prevention and reversibility of extrapyramidal symptoms. Answers will appear in time, but meanwhile there is little doubt that over the ten years these preparations have been available, they have been overwhelmingly a force for good Certainly the many schizophrenics now maintained on them, who are reintegrated and resettled in society, would acknowledge this.
1.
Joyce, C. R. B. in Psychopharmacology Dimensions by M. Balint); p. 215. London, 1968.
and
D. W. VERE D. M. CHAPUT DE SAINTONGE
FLUPHENAZINE DECANOATE
Northwick Park Hospital and Clinical Research Centre, Watford Road, Harrow, Middlesex HA1 3UJ
Perspectives (edited 1. Lancet,
1975, ii, 1193.
M. W. P. CARNEY
(1-1-55 g/1)
is
likely
to
reduce the risk of
hypoglycaemic
accidents. Service de Reanimation, Groupe Pitié-Salpétrière, Paris 75013
Hospitalier
Centre d’Hémodialyse Edouard Rist, 14 rue Boileau, Paris 75016
K. SAMII CH. CIANCIONI
J. ROTTEMBOURG Service de
Néphrologie, Groupe Hospitalier
Pitié-Salpétrière,
Paris 75013
F. BISSELICHES
C. JACOBS
DOUBLE-BLIND TRIALS
SIR,-We welcome and support the findings of Dr Hill and colleagues (Feb. 14, p. 352). Like them we have followed
her
periods of one day each, so carry-over effects could be serious. They were avoided by packing each treatment in foil packs of a distinctive colour and telling the patients that three different tablets were being tested. To preserve the clinicians’ blindness the correspondence between colour of the packs and their contents was varied from patient to patient. This approach may, however, encourage the development of bias as the trial progresses. Whichever way the problem of blindness is approached the measurement of bias and its implications still constitutes the core of uncertainty in the apple of the best-planned clinical trial. The benefits of the double-blind trial have been well demonstrated. Progress is likely to come from better methods to measure bias than from a return from double-blindness to the greater bias which preceded it. treatment
Joyce’s lead,but in two ways: (1) When a trial is still in the design stage, we always have a "placebo tasting session" when a "blind" group tries to distinguish drug from dummy. (2) During trials the observers, whether they be doctors making clinical observations or patients completing diary cards, are asked to try to break the code by noting which remedy they think is being provided at each clinic
Clinical Trials Unit, Department of Pharmacology and Therapeutics, London Hospital Medical College, E1 2AD
visit. The reason for the second procedure is that blindness can never be assumed, as Dr Hill and others show, so the trialist must either improve placebo matching until it is perfect, which is impossible, or measure its imperfection, which can be done. We therefore collect doctors’ or patients’ views on their medication and analyse them statistically. Inevitably the distribution of these views about the identity of the treatments is not completely random. Two important questions follow: how much bias is associated with a given degree of code breaking, and how will this bias alter the treatment outcome? We are still looking for the answers and for the moment content ourselves with accepting only small departures from randomness as likely to affect the trial adversely. These practices have led us into some amusing experiences, and have failed on some occasions. For example in one trial of injected gold for rheumatoid disease, a perfect placebo match was obtained at the start of the trial, but was lost a few weeks later when the gold solution turned yellow while the placebo remained white. In another trial a patient found that he could break a nearly perfect match by scratching the tablets lightly with his finger nail. One set developed a sheen when held up to the light, the other did not. An anaesthetist found that he could distinguish autoclaved from filtered dextrose solutions by listening as the needle went in; autoclaved bottles emit a soft hiss. One pharmaceutical company kindly supplied a beautifully matched set of drug and placebo ampoules, but the word "placebo" was printed on half of them! However, it is very satisfying to find that subjects cannot break a code; that is the final test. Even medical students seem unable to decode trinitrin set in the hollow of ’Polo’ mints with hard icing sugar. Perfectly matching treatments can also cause problems. In many diseases (especially those associated with pain) the patient’s expectations are important determinants of the treatment outcome. If the patient gets benefit from the first of a series of identical treatments the beneficial effect may carry over into successive treatment periods, the patient believing his therapy to be unchanged. This effect may be avoided by making the treatment distinctive and telling the patient that they are all different. This is in effect a "double dummy" approach, one dummy being for the drug, the other for the emotional impact of its appearance. In a recent trial (unpublished) of three antacids in duodenal ulceration it became clear that the taste of one of the treatments could not easily be disguised or matched in the placebo. Furthermore the trial consisted of 24
SIR,- Your editorial does less than justice to the advantages of slow-release injections in the maintenance treatment of schizophrenia. I am concerned lest young psychiatrists and others involved in the management of these patients infer that there is some special therapeutic benefit implicit in prolonged institutional care as opposed to current, albeit imperfect, community methods based upon chemotherapy. You seem to commend a lukewarm attitude towards discharge from hospital unless and until funds and other resources for hostels, sheltered workshops, and the like are forthcoming. I believe that such equivocation will not only cause patients, families, and staffto lose heart, but also, in the broader perspective, remove the stimulus necessary to elicit the funds needed for these community facilities. Few would wish to put the clock back to the asylum pattern of care. Surely the "quality of life" in the real world is preferable to that of an institution, however well-intentioned ? Many would agree that schizophrenia is a condition with social implications and that there have been considerable advances, notably by the Maudsley M.R.C. Social Psychiatry Unit, of our understanding of the ways in which these influence prognosis. Of course, such factors have to be considered before discharge of the patient. Nevertheless, schizophrenia is also a disease (or diseases) suffered by patients, and medical models of care are apposite. Good or bad outcome patients, irrespective of whether they are discharged on drugs or not, cannot yet be reliably predicted but only known post hoc. However, many patients with discrete psychoses of excellent outcome would be spared the inconvenience of long-term depot injections if a careful clinical distinction between affective illness and schizophrenia were made, and if this form of treatment were reserved for the second and subsequent admissions to hospital. Much about depot fluphenazine and flupenthixol is still unclear-especially, the duration and dose of maintenance therapy, whether they can ever safely be withdrawn, and the prevention and reversibility of extrapyramidal symptoms. Answers will appear in time, but meanwhile there is little doubt that over the ten years these preparations have been available, they have been overwhelmingly a force for good Certainly the many schizophrenics now maintained on them, who are reintegrated and resettled in society, would acknowledge this.
1.
Joyce, C. R. B. in Psychopharmacology Dimensions by M. Balint); p. 215. London, 1968.
and
D. W. VERE D. M. CHAPUT DE SAINTONGE
FLUPHENAZINE DECANOATE
Northwick Park Hospital and Clinical Research Centre, Watford Road, Harrow, Middlesex HA1 3UJ
Perspectives (edited 1. Lancet,
1975, ii, 1193.
M. W. P. CARNEY