Efficacy and safety of the new antipsychotics

withdrawal of moclobemide from 11 of 15 severely depressed and treatment-resistant depressed patients.2 Even the possibility that a few severely depressed patients

might

adversely to a new antidepressant is cause for Such concern is properly reflected in the Irish manufacturer’s data sheet: "If a depressive episode is treated in bipolar disorders, manic episodes can be provoked. Depressive patients with excitation or agitation as the predominant clinical feature should either not be treated with Manerix (moclobemide) or only in combination with a sedative (eg, a benzodiazepine) for not more than two to three weeks. Restlessness or agitation in depressive patients may occur".3 react

concern.

T J Fahy University College Hospital, Galway, Ireland 1

2

3

Danish University Antidepressant Group. Moclobemide; a reversible MAO-A inhibitor showing weaker antidepressant effect than clomipramine in a controlled multicenter study. J Affective Disord 1993; 28: 105-16. Fahy TJ. Side effects of moclobemide in depressed patients refractory to other treatments. Irish J Psychol Med 1993; 10: 24-27. Roche Products (Ireland) Limited. Manerix data sheet, 1993.

SiR-We believe that Freeman paints an unrealistic picture of the new antidepressant moclobemide. Efficacy data have indeed shown moclobemide to be, in the main, better than placebo and similar to other agents in depression.’ On the other hand, studies not cited by Freeman suggest that other treatments might be better than this drug/ Certain patients with endogenous depressionsocial phobia,4and possibly atypical depressions may respond better to tricyclics or older, non-selective MAOIs. With respect to tolerability, Freeman again portrays moclobemide in an unjustifiably positive light. Although most studies have favoured moclobemide when compared with other antidepressants, this is not always so,3 and clinical trial drop-outs due to worsened depression have been reported.:.! We found a surprising frequency of insomnia in 12 of 62 (19%) blindly-treated depressed patients6 and in 5 of 7 neuropathic pain patients-which is hardly the infrequent rate suggested by Freeman. On the other hand, New Zealand-wide monitoring (1990-93) has shown a reported adverse event rate of only about 8% in some 6000 moclobemide-treated patients (Coulter,

personal communication). Since moclobemide has only just been introduced in the UK, it is perhaps not surprising that its promise is yet to be seriously questioned. This compound has been available since 1989 in New Zealand and, although our experience has been generally positive,6 we have been disappointed by its lack of efficacy in 5 of our atypical depressive patients who were clearly responsive to older MAOIs. It remains an intriguing possibility that moclobemide’s limited efficacy in such cases might relate to its selectivity for the type-A isozyme. This property, in addition to contributing to its superior safety, may also confer a reduced risk of abuse and of provoking mania. The clinical place of moclobemide is still being defined, since its spectrum of activity may well be different from that of other antidepressants. We have found, for example, that it notably lacks the (co)-analgesic activity of the tricyclics (unpublished), but that it might be strikingly efficacious in menopausal flushing (unpublished). It remains to be seen why brofaromine, another new MAOII that is similar to moclobemide, has recently been abandoned by Ciba-Geigy. David B

Menkes, Kaaren Wood, David Woods

Department of Psychological Medicine, University of Otago, PO Box 913, Dunedin, New Zealand

1

Silverstone T. Moclobemide: placebo-controlled trials. Int Clin Psychopharmacol 1993; 7: 133-36.

476

Danish University Antidepressant Group. Moclobemide: a reversible MAO-A-inhibitor showing weaker antidepressant effect than clomipramine in a controlled multicenter study. J Affective Disord 1993; 28: 105-16. 3 Rossel L, Moll E. Moclobemide versus tranylcypromine in the treatment of depression. Acta Psychiatr Scand 1990; 360 (suppl): 61-62. 4 Versiani M, Nardi AE, Mundim FD, Alves AB, Liebowitz MR, Amrein R. Pharmacotherapy of social phobia. A controlled study with moclobemide and phenelzine. Br J Psychiatry 1992; 161: 353-60. 5 Larsen JK, Gjerris A, Holm P, et al. Moclobemide in depression: a randomized, multicentre trial against isocarboxazide and clomipramine emphasizing atypical depression. Acta Psychiatr Scand 1991; 84: 564-70. 6 Williams R, Edwards RA, Newburn GM, Mullen R, Menkes DB, Segkar C. A double-blind comparison of moclobemide and fluoxetine in the treatment of depressive disorders. Int Clin Psychopharmacol 1993; 7: 155-58.

2

Efficacy and safety of the new antipsychotics SiR-All first-generation antipsychotics have essentially equal efficacy and generally the same adverse effect profile. Newer antipsychotics, however, may well have better efficacy than their predecessors while being more or less dangerous than standard agents. In this context, Kerwin (Dec 11, p 1440) astutely comments that whereas standard drugs are often regarded as safe (ie, their dangers are forgotten), complications with newer drugs are usually reported with alarm (eg, the eight cases of aplastic anaemia among 50 000 patients who received remoxipride hydrochloride world wide). We would be less cautious than Kerwin, however, in describing the relative efficacy of the newer antipsychotics-ie, "as effective" "probably better", or "at worst they are equieffective"-in comparison with their predecessors. Our meta-analysis of six random-assignment, double-blind trials comparing clozapine with standard antipsychotics indicated that 57% of those on clozapine responded (versus only 36% on standard drug). This difference is highly significant (x2=42; df= 1), to about 10-10.1 The most carefully conducted trial was the large US multicentre study of treatment-resistant patients, which showed that 30% of those on clozapine were reponders (versus only 4% on standard drug).2 Similarly, several large, double-blind, controlled trials of risperidone reported at various scientific meetings showed that the 6 mg dose is better than typical doses of standard antipsychotics (eg, haloperidol, 10-20 mg daily). Indeed, our preliminary meta-analysis of these data showed that risperidone was more efficacious than these agents. Finally, remoxipride has also been carefully investigated, and we showed it to be equal in efficacy to standard antipsychotics.3 Since most of these drugs are taken as part of a long-term maintenance strategy, side-effects that interfere with the quality of life, such as sedation or akathisia, are important to most patients. Remoxipride is virtually free of most of these minor side-effects, whereas risperidone, especially at the 6 mg dose, has fewer of these than the standard antipsychotics. By contrast, clozapine has a substantial degree of minor sideeffects in addition to a 1-2% incidence of agranulocytosis-a potentially fatal complication. In addition, the more serious adverse effects associated with standard neuroleptics (eg, tardive dyskinesia, neuroleptic malignant syndrome, or falls due to postural hypotension) should be balanced against such possible problems as seizures and agranulocytosis, which are associated with clozapine, or aplastic anaemia, which is possibly associated with remoxipride. Finally, we do not know whether remoxipride or risperidone will cause tardive dyskinesia, a problem not yet recorded with clozapine. We strongly support concurrent postmarketing surveillance data on the incidence of serious adverse effects and the death rate for both recent and standard antipsychotics. Such data would

facilitate a rational choice of drug, given that the clinician now has qualitatively different alternatives to choose from. Our point is not so much that our meta-analysis is important but rather that clinicians should not use standard drugs merely because they are familiar or new drugs because they are newsworthy. Instead, they should make a deliberate clinical choice on the basis of an individual patient’s best interests. John M Davis, Philip G Janicak Illinois State Psychiatric Institute, University of Illinois at 1153 North Lavergne, Chicago, IL 60651, USA

Chicago,

previous experience, the patient asked for treatment with omeprazole. This was started 4 weeks later and again led to a full remission of colitis symptoms within 5 days. Omeprazole is effective in healing of peptic ulceration, and a few favourable reports exist for treatment of peptic ulcer in Crohn’s diseased To our knowledge, there are no reports of its use in ulcerative colitis. At present no pharmacological mechanism can be offered to explain our case; mechanisms may be speculatively proposed on the basis of the analogy of omeprazole interacting with Helicobacter pylori colonisation.2 Ute Heinzow, Tilman

1 Janicak PG, Davis JM, Preskorn SH, Ayd FJ Jr. Principles and practice of psychopharmacotherapy. Baltimore: Williams & Wilkins, 2

1993: 106-07. Kane J, Honigfeld

G, Singer J, Meltzer H. Clozaril collaborative study clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry

1

group:

1988; 45: 789-96. 3

Davis JM. Treatment of schizophrenia. Curr 28-33.

Opin Psychiatry 1991; 4:

Schlegelberger

Blücherplatz 11, D-24106 Kiel, Germany

2

Valori RM, Cockel R. Omeprazole for duodenal ulceration in Crohn’s disease. BMJ 1990; 300: 438-39. Bell GD, Powell KU, Bundge SM, et al. Omeprazole plus antibiotic combination for the eradication of metronidazole-resistant Helicobacter pylori. J Pharmacol Ther 1992; 6: 751-58.

Testing of blood donations for hepatitis C Aedes and dengue

virus

SiR-Freier (Nov 20, p 1281) mentions the recent spread of the efficient arboviral vector Aedes albopictus in North America. Introduced by international traffic in used tyres (Rogers and Packer, Nov 20, p 1282), A albopictus has reached other continents, including Europe, where most countries are within range of these cold-adapted strains from Japan.1-3 Current disturbances in the Balkans provide conditions similar to those that allowed a major European epidemic of dengue in 1926-27. The cold intolerance of the vector then involved, A aegypti, limited its spread. Cold-adapted strains of A albopictus would not be so limited. Severe cases of dengue (haemorrhagic fever; shock syndrome) can be fatal, and we have neither specific treatment nor a preventive vaccine.

SiR-The first commercial assay for hepatitis C virus (HCV) antibody available for screening donated blood in 1990 was based on a recombinant antigen from a single non-structural region of the genome, NS4.1 A second-generation assay, introduced in 1991, had recombinant antigens from the non-structural regions NS3 and NS4 and antigen from the core region. This much superior assay has dramatically reduced the incidence of post-transfusion hepatitis previously attributed to non-A, non-B hepatitis.3 Third-generation assays from Ortho and Abbott are now available in Europe additionally containing antigen from the NS5 region which codes an RNA polymerase. In theory, inclusion of antigens from further regions of the HCV genome should improve the ability of an assay to detect evidence of infection at any point in the time course of an HCV infection, but data are lacking on whether there is real benefit from these new assays. We report a donor whose HCV antibody detection required the presence of NS5 antigen in the test. An assay for HCV antibody already containing antigen from the NS5 region has been available from Murex Diagnostics for some years. In May, 1993, this test was adopted by the Edinburgh and South East Scotland blood transfusion service for HCV antibody screening. As part of our routine confirmatory procedure all repeat reactive samples were referred to the Scottish National Blood Transfusion Service (SNBTS) Microbiology Reference Unit for confirmation with Chiron third-generation recombinant immunoblot assay (RIBA) and, if positive or indeterminate, further referred to the SNBTS polymerase-chain-reaction (PCR) laboratory for PCR analysis and typing.4 In September, after 20 000 donations had been tested, a donation from a female was found to be repeat reactive on enzyme-linked immunosorbent assay (ELISA), RIBA-3 positive, PCR positive, and of HCV type 3a.4 This did not seem unusual. All samples referred to the Microbiology Reference Unit are screened by other ELISAs currently in use in the SNBTS as part of an investigation of the sensitivity of tests from different manufacturers. This sample was not detected on repeat testing by the Abbott 20, their

N R Grist, N R H Burgess Communicable Diseases and Environmental Health (Scotland) Unit, Ruchill Hospital, Glasgow G20 9NB, UK; and Department of Military Entomology, Royal Army Medical College, London

1 Grist NR. New mosquito in Africa. Lancet 1992; 339: 1363. 2 Grist NR. Aedes albopictus: the tyre-travelling tiger. J Infect 1993; 27: 1-4. 3 Ward MA. Burgess NRH. Aedes albopictus; a new disease Europe? J R Army Med Corps 1993; 139: 109-11.

vector

in

Omeprazole in ulcerative colitis SiR-We report an unexpected observation in a 34-year-old with biopsy-proven ulcerative colitis. He complained of flatulence since a teenager and, since 1983, had frequent bowel movements with bloody stools. In 1986 his symptoms became more serious and in 1991 active colitis localised to the rectum and sigmoid colon was diagnosed by sigmoidoscopy. He was initially treated with dietary exclusion of raw fruits and milk (the latter was found to be an irritant) and long-term sulphasalazine 500 mg twice daily. The severity of his bloody diarrhoea was reduced to three daily loose stools accompanied by mild abdominal cramps without full remission and symptom-free intervals during the past 2 years. In 1993 antrogastritis and oesophagitis were diagnosed by gastroscopy and treated with omeprazole 20 mg daily for 2 weeks. Within 4 days of commencing omeprazole, the colitis symptoms disappeared. Bowel movements became normal and milk products were again tolerated without bloody diarrhoea. 7 days after the successful omeprazole treatment of antrogastritis ended, his colitis symptoms recurred with several daily loose stools with blood. Because of the positive man

February 19, 1994

Manufacturer/type Abbott 2 0 Abbott 3 0 Ortho 2 5 Ortho 3 0 Murex VK48

Sample 1

Sample 2

OD/cut-offResult

OD/cut-off

0316 > 4 454 0 778 4 647 2 455

0278 > 5 076 0 942 4 752 > 3 324

*OD = optical density of sample; OD/cut-off Table: ELISA results

Negative Positive

Negative Positive Positive >

Result

Negative Positive

Negative Positive Positne

1 000 = pos!tivity.

477