(Aust Prescr 1998;21:87-91)
Letters, which may not necessarily be published in full, should be restricted to not more than 250 words. When relevant, comment on the letter is sought from the author. Due to production schedules, it is normally not possible to publish letters received in response to material appearing in a particular issue earlier than the second or third subsequent issue.
Editor, - The article by Professor B. Tonge, `Depression in young people' (Aust Prescr 1998;21:20-2), brought to the attention of your readers the recently published National Health and Medical Research Council (NHMRC) guidelines1 about the subject. We thank Professor Tonge for his scholarly summary of the guidelines and would like to make the following comments about physical treatments for this patient group.Professor B.J. Tonge the author indicates the lack of controlled studies of the newer antidepressants in young people. Since the NHMRC guidelines were released, a large placebo-controlled trial of fluoxetine in depressed children and adolescents has been published2, showing superior efficacy of antidepressant. Professor Tonge mentions the role of lithium, carbamazepine and sodium valproate in treating young persons with bipolar disorder. These drugs - particularly lithium - are sometimes also used to augment antidepressants in unipolar depression. Regrettably, studies of antidepressant augmentation in young people are scarce3,4,5 and restricted to reports of small series of cases. Finally, Professor Tonge makes no mention of electroconvulsive therapy (ECT) in his overview of treatments. Although information about ECT in young persons is limited and ECT is not commonly used in this age group, there is increasing evidence that ECT is a safe and effective treatment for severe depression in teenagers, as in adults.6,7 A total of 42 adolescents received ECT in New South Wales in the period 1990-1995.7 ECT was only given after other treatments had failed. The correlates of good outcome included the psychotic type of depression and absence of personality disorder.
Although some of the above treatments will only be given by specialist psychiatrists, we believe it is important that other practitioners are aware of them.
G. Walter and
J.M. Rey
Child and Adolescent Psychiatrists
Rivendell Unit, Sydney
and
University of Sydney
References
1. National Health and Medical Research Council. Depression in young people: clinical practice guidelines. Commonwealth Department of Health and Family Services, Canberra: Australian Government Publishing Service, 1997.
2. Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA, Hughes CW, Carmody T, et al. A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 1997;54:1031-7.
3. Ryan ND, Meyer V, Dachille S, Mazzie D, Puig-Antich A. Lithium antidepressant augmentation in TCA-refractory depression in adolescents. J Am Acad Child Adolesc Psychiatry 1988;27:371-6.
4. Strober M, Freeman R, Rigali J, Schmidt S, Diamond R. The pharmacotherapy of depressive illness in adolescence: II. Effects of lithium augmentation in nonresponders to imipramine. J Am Acad Child Adolesc Psychiatry 1992;31:16-20.
5. Walter G, Lyndon B, Kubb R. Lithium augmentation of venlafaxine in adolescent major depression. Aust NZ J Psychiatry. In press.
6. Rey JM, Walter G. Half a century of ECT use in young people.
Am J Psychiatry 1997;154:595-602.
7. Walter G, Rey JM. An epidemiological study on the use of
ECT in adolescents. J Am Acad Child Adolesc Psychiatry 1997;36:809-15.
Professor B.J. Tonge, the author of the article, comments:
I thank Dr G. Walter and Dr J.M. Rey for providing a pertinent elaboration
of my review of the NHMRC guidelines on depression in young people.
They bring attention to the recent study1 of the effectiveness of fluoxetine in the treatment of major depression in children and adolescents. This randomised (stratified for age and sex) double-blind placebo-controlled outpatient study of 96 young people aged 7-17 years with non-psychotic major depressive disorder found significant improvement at the end of the 8-week treatment period in depression rating scale scores and clinical assessment in the group treated with fluoxetine (20 mg morning dose) compared with the placebo group. However, there was no longer-term follow-up of these patients and there was no significant difference between the groups on general psychiatric symptoms (such as school attendance), global functioning and self-reports of symptoms.
Importantly, significant improvements were found for both the group of children aged 12 years and younger, as well as those aged 13 years and older. However, full recovery was unusual with only 31% of the fluoxetine and 23% of the placebo group having only minimal symptoms at the end of the 8-week period. About 8% of the young people receiving fluoxetine discontinued treatment due to the adverse effects of manic excitement for 6% and a severe rash in 2%.
Patients in this study were carefully screened and assessed to conform to strict diagnostic criteria for major depressive disorder (DSM-III-R criteria). The study then used an unusual procedure of placing all patients in a one-week single-blind course of placebo. Those young people who improved and no longer met diagnostic criteria after two weeks were excluded from the study (about 7% of the cohort). There is no discussion or justification offered on this procedure of excluding early placebo responders. It is possible that, if this step was omitted and this 7% of cases included in the double-blind placebo-controlled study, then the results may not have demonstrated a significant therapeutic effect compared to placebo.
Therefore, although these findings are encouraging, further replication studies are needed with longer follow-up including measures of global functioning and self-report.
I agree that mood stabilisers such as lithium and sodium valproate have a
role in the augmentation of antidepressants in the treatment of severe unipolar
depression, but this polypharmacotherapy should be initiated with inpatients
or at least by specialist psychiatrists with outpatients. Similarly, ECT has
an important but limited role in the treatment of severe, usually psychotic,
depression in young inpatients.
Taking the above comments into account, the NHMRC guidelines should still remain
the foundation for the contemporary treatment of the majority of young people
in Australia who suffer from a depressive illness.
Reference
1. Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA, Hughes CW, Carmody T, et al. A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 1997;54:1031-7.
Corticosteroids in dermatology
Editor, - I refer to the article `The role of corticosteroids in dermatology' (Aust Prescr 1998;21:9-11). I am particularly interested in:• the role of corticosteroids in chloasma
• the use of high-dose corticosteroids in acute allergic contact dermatitis - benefit-risk analysis.
L.I. Mokhothu
Pharmacist
Maseru, Lesotho
Professor R. Marks, one of the authors of the article, comments:
There is no role for corticosteroids in the treatment of chloasma.
There is no formal benefit-risk analysis on the use of high-dose corticosteroids in acute allergic contact dermatitis. I am presuming that Mr Mokhothu is referring to high-dose corticosteroids given orally. However, there are plenty of data showing that high-dose corticosteroids, whether used topically or systemically, will reduce the inflammatory response of an acute allergic contact dermatitis. There are also data showing that short-term use of systemic corticosteroids is not normally associated with any major risk unless there are some other underlying conditions in which systemic corticosteroid use is contraindicated e.g. tuberculosis. In the absence of any contraindications, when the allergen is known and is able to be avoided, some people believe that the use of high-dose corticosteroids systemically is warranted to assist in rapid resolution of the acute inflammatory response.
Prevention of deep leg vein thrombosis
Editor, - I refer to the article `Prevention of deep leg vein thrombosis' (Aust Prescr 1998;21:37-9). The article puts the problems of deep vein thrombosis and pulmonary embolism into reasonable perspective, but one important aspect of this potentially lethal complication has been left out.Many years ago, when taking part in a symposium on this subject at St. George Hospital, I surveyed the admissions to St. George Hospital with deep vein thrombosis/pulmonary embolism. The exact figures escape me now, but one surprising finding was that a number of patients admitted with this complication merely had mild flu, common colds, etc., and had been put to bed by their local general practitioner. It seems that prevention should be thought of when patients become ill in their own home but do not require admission to hospital. It would depend on the illness and the risk factors, but precautions could range from advice not to lie or sit around all day doing nothing, to low-dose aspirin (although this has not been found to be of significant help, certainly in postoperative situations), to graded pressure stockings and even once-daily low molecular weight heparin in the high-risk patient.
K.B. Orr
Surgeon
Kogarah, N.S.W.
Dr A. Gallus, the author of the article, comments:
The important question of deep vein thrombosis and its prevention in medical
patients has received far too little attention.
In hospital-based surveys of pulmonary embolism, most pulmonary emboli arise in medical patients, not surgical patients. The attention paid to surgical prevention can be explained by the fact that surgery is a recognisable trigger and that prophylactic protocols can be built around this.
Deep vein thrombosis and pulmonary embolism in medical patients, in hospital
or at home, are far more difficult issues. Incidence, risk factors and the
effectiveness and cost-effectiveness of preventive measures have been so little
studied that there are no good answers to the questions asked by Dr Orr. Nevertheless,
his point is valid. At least as much attention should be given to deep vein
thrombosis prevention in medical patients as in surgical practice, and medical
admissions need great care with risk factor assessment. What studies are available
suggest that the methods known to work in surgery (standard heparin, low molecular
weight heparin, venous flow acceleration) are also effective in medical patients.
In his presentation I read that `Originally, it was thought that there was a long period of clinical and virological latency when very little was happening in an asymptomatic, but infected, patient ... we now know that there is no latent period in HIV disease.'
One of the regulatory genes of HIV, called nef (negative-regulatory factor), is a gene which slows down the transcription of the viral genome and may therefore be responsible for HIV remaining dormant in infected cells.
If so, is the presence of this gene and the analysis on latency period absence not contradictory?
I need further explanation on these two points.
Tadese Geleta
General Practitioner
Gimbie SDA Hospital
Ethiopia
Dr D. Smith, the author of the article, comments:
Dr Geleta questions the view that there is no period of virological latency
in people infected with HIV disease given that HIV carries a regulatory gene
(nef) that may be responsible for inducing latency in infected cells. This
apparent contradictory information can be explained if the dynamics of HIV
replication are considered. As HIV goes through its replication cycle, it must
be remembered that this process is happening slightly differently in the large
number of lymphocytes that are infected each day. The process is not perfect,
and errors are made at each step. In general, however, the majority of cells
that are infected are CD4 positive lymphocytes. The process of infection appears
to activate these cells and thereby activate the ongoing replication of HIV.
However, a small number of these T-cells become infected but fail to become
activated and contribute to the pool of long-lived, latently infected T-cells.
It is these cells that may rekindle HIV infection after discontinuing combination
antiviral therapy. It has been estimated that possibly 1:8000 or 1:10 000 infected
T-cells remains latently infected following infection with HIV.1
More recent information regarding the function of the nef gene seems to contradict its original role of a down-regulator of HIV replication. In fact, patients infected with HIV with a defective nef gene tend to show very low levels of viral replication and slow disease progression.2 Similarly, SIV with a defective nef gene seems to be less replication competent.3 These findings would imply that the nef gene is in fact important for up-regulating HIV replication.
This means that in an environment where hundreds of thousands of new virions are being produced and infecting cells, it is possible to see both high turnover replication rates and low levels of seeding inactivated cell lines giving both latency and acute active replication.
References
1. Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, Taylor H, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997;387:183-8.
2. Learmont J, Tindall B, Evans L, Cunningham A, Cunningham P, Wells J, et al. Long-term symptomless HIV-1 infection in recipients of blood products from a single donor. Lancet 1992;340:863-7.
3. Daniel MD, Kirchhoff F, Czajak SC, Sehgal PK, Desrosiers RC. Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science 1992;258:1938-41.
Editor, - We are writing to express our concern regarding several aspects of the recent `New drugs' comment on vinorelbine tartrate (`New drugs' Aust Prescr 1998;21:54).Firstly, the TGA-approved indications were not accurately stated. Vinorelbine has been approved for advanced breast cancer after failure of standard therapy (not `failure of other treatments') and for first-line treatment of advanced non-small cell lung cancer (and not for small cell lung cancer, as erroneously mentioned in the last paragraph).
Secondly, the statement `the drug is diluted and given by slow injection or infusion once a week' is an oversimplification. The product information gives specific recommendations for the preparation and administration of vinorelbine that have been found to reduce the occurrence of injection site reactions, and the readers' attention should be drawn to these. Further, dosage regimens can vary from weekly administration to a day 1 and day 5/8 schedule every 3 weeks when given in combination chemotherapy.
Thirdly, the clinically relevant features of the haematological toxicity of vinorelbine, i.e. that neutropenia is rapidly reversible and non-cumulative, and that the incidences of neutropenic sepsis, severe anaemia and thrombocytopenia are relatively low, were not mentioned.
Finally, the concluding two sentences in the comment, concerning survival, appear to reflect a value judgement on the part of the author. Any increase in survival in a disease with a poor prognosis may be relevant to the individual patient, and the questions of quality of life, improvement in performance status and relief of disease-related symptoms should also not be overlooked.
Maria Fallon
Manager, Regulatory Affairs
and Barry Dale
Medical Adviser, Oncology
ASTA Medica
Parramatta, N.S.W.
The Editor comments:
The intention of the `New drugs' section of Australian Prescriber is
to provide a brief description of the product and its role in therapy. This
section always carries the preface that the product information should be obtained
before prescribing a new drug. It is not possible, in a short comment, to give
detailed instructions about complicated regimens. However, the comment about
vinorelbine did state that the dose needs to be modified when there is haematological
toxicity. ASTA Medica is correct to point out that the `non' was missing from
one of the 4 mentions of non-small cell lung cancer.
While it is correct that vinorelbine can be given to women with breast cancer after the failure of standard therapy, is it the best option? There has been a study to compare vinorelbine with melphalan in anthracycline-resistant breast cancer. The time to progression of the disease was 12 weeks for vinorelbine and 8 weeks for melphalan.1 Questions remain as to the effect on quality of life and whether melphalan is the most appropriate comparison. Unless there has been a recent change, the Food and Drug Administration in the U.S.A. has not reversed its decision not to approve vinorelbine for breast cancer.
Vinorelbine is approved in the U.S.A. for advanced non-small cell lung cancer. It can be helpful to some patients with inoperable cancers. The decision to prescribe vinorelbine in this situation does indeed require a value judgement. The patients have to judge if their quality of life will be improved by a toxic treatment which, if they are in the minority who respond, will extend their lives for, at best, a few months. As our sister journal Prescrire International concluded, `Vinorelbine does not appear to influence the grim prognosis of this cancer.'
Reference
1. Jones S, Winer E, Vogel C, Laufman L, Barlogic B, O'Rourke M, et al. for the Navelbine Breast Cancer Working Group. A multicenter, randomized trial of i.v. Navelbine vs. i.v. Alkeran in patients with anthracycline-refractory advanced breast cancer (ABC). American Society of Clinical Oncology (ASCO) proceedings 1994;13:103 (abstr. 216).
Assessing the safety of drugs and breast-feeding
Editor, - Christine Jenkins' letter (Aust Prescr 1998;21:31) concerning budesonide and other corticosteroids, whilst breast-feeding, epitomises the health professional's perennial dilemma in this area of health information. Indeed, budesonide is a classic case of a valuable drug used for the management of a medical condition, where negligible quantities are excreted into breast milk, but where, because of actual or perceived medico-legal restraints, the manufacturer warns against using the drug whilst breast-feeding. Meanwhile, we promote public awareness of the need for optimum medication management of asthma! Susan Parker's reply that Astra Pharmaceuticals would be happy to include a (TGA-approved) statement for those drugs where it is clear that `transfer into breast milk is unlikely' is a refreshing and welcome approach which could be explored by other manufacturers.In my 1996 Drugs and breast-feeding booklet1, I identified some 70 drugs where studies had measured the quantities transferred in milk, and, uniquely, for this type of booklet, estimated the mg/kg dose that the infant would receive. I believe that this approach, in addition to, where applicable, clinical experience suggesting that a drug may be used whilst breast-feeding, would be of great practical assistance to health practitioners.
The problem in assessing safety during lactation, compared to the drugs and pregnancy situation, is that we lack a categorisation system. In the late 1980s, the Scandinavian countries developed a categorisation system for drugs used in breast-feeding, whilst in the U.S.A., the Pediatric Academy periodically publishes safety recommendations for drugs used during lactation. In Australia, however, neither systematic nor peer-reviewed evaluation of drug safety during lactation exists. In my view, they are long overdue.
R. Batagol
Pharmacy and Drug Information Consultant
Nunawading, Vic.
Reference
1. Batagol R. Drugs and breast-feeding. Melbourne: C.S.L. Ltd, 1996.
Editor, - I refer to previous correspondence on this matter (`Letters' Aust Prescr 1998;21:32-3).The key issue in prescribing prophylactic antibiotics for arthroplasty patients undergoing dental procedures is not the choice of antibiotic, but the decision to prescribe at all. Bearing in mind the millions of potential episodes, the production of infection by dental bacteraemia, if it ever occurs, must be an extreme rarity and only a tiny number of cases provide any evidence for such a connection.1 Earlier reports proposing a link are seriously flawed, not least because staphylococci, the predominant pathogens in late prosthesis infection, are almost never found in dental bacteraemia.
The British Society for Antimicrobial Chemotherapy Working Party on Prophylaxis (assisted by orthopaedic input) considered the matter in 1992 and concluded that wide exposure of patients to antibiotics for this purpose was unjustified.2 No new information has since come forward to persuade us to change this view. The Americans have recently agreed.3 Some have argued - as a counsel of safety - that immunosuppressed patients or insulin dependent diabetics warrant extra protection4, but there is no evidence that even these patients are at risk from dentistry.
Optimum dental health and the prompt and effective treatment of dental sepsis will benefit any patient regardless of other considerations and is the true basis of prevention of distant infection.
David A. McGowan
Professor of Oral Surgery
Glasgow Dental School
University of Glasgow
Glasgow, Scotland
References
1. Bartzokas CA, Johnson R, Jane M, Martin MV, Pearce PK, Saw Y. Relation between mouth and haematogenous infection in total joint replacements. Br Med J 1994;309:506-8.
2. Simmons NA, Ball AP, Cawson RA, Eykyn SJ, Hughes SP,
McGowan DA, et al. Case against antibiotic prophylaxis for dental treatment
of patients with joint prostheses [letter]. Lancet 1992;339:301.
3. American Dental Association; American Academy of Orthopaedic
Surgeons. Advisory statement: Antibiotic prophylaxis for dental patients with
total joint replacements. J Am Dent Assoc 1997;128:1004-8.
4. Field EA, Martin MV. Prophylactic antibiotics for patients
with artificial joints undergoing oral and dental surgery: necessary or not?
Br J Oral Maxillofac Surg 1991;29:341-6.
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