1572
Registration is no more than a step in the regulatory process, although it is the most important. Efficient mechanisms are needed for reviewing registration in the light of new information or scientific developments. Such a review would require a commitment to developing various approaches to the evaluation of effectiveness and adverse drug reactions. Continuing vigilance should be part of the regulatory process, and will require efficient recording and evaluation of information on effectiveness and adverse effects. The existing British custom of renewing product licences every five years without requiring a proper scientific review seems designed to save staff time but not to protect consumers. All data that are not strictly related to the production process should be available to interested parties, and regulatory decisions and the reasons for them should be transparent and published. The summary basis of approval, which is issued in the USA, might be a suitable model for providing such information. It would also be desirable to provide open access to data on reported adverse events, as in Sweden. Members of committees dealing with drug regulation should declare any commitments that might involve them in a conflict of interest. Development of a united Europe creates an opportunity to consolidate the lessons learnt since the thalidomide affair and to raise regulatory norms within the Community as a whole. This goal cannot be attained unless the Treaty of Rome is amended to include public health as an area of central concern for the Community. If the shape of the EC regulatory system is determined before these amendments are considered, and is determined merely in the light of economic priorities, ground will be lost that can only be slowly and painfully regained-possibly at great human cost. European Community. Draft treaty articles with a view to achieving political union. Brussels, May, 1991. Document no Conf-up 1800/91. 2. Europe and health. Editorial and feature. The European Citizen, no 4. Brussels, October, 1990. 3. Commission of the European Communities. Future system for the free movement of medicinal products in the European Community. November, 1990. ISBN 92-77-66016-3. 4. Schönhöfer PS. Germany: effective drug regulations hampered by 1.
courts.
5.
Lancet 1991; 337: 904.
Payer L. Medicine and culture. Varieties of treatment in the United States, England, West Germany and France. New York: Henry Holt.
1988. 6. Offerhaus L. Pillen zonder grenzen? Tijdschr Geneeskd 1990; 134: 821-27.
(Pills without frontiers?)
Ned
Anonymous HIV testing: latest results Data from the programmes of anonymous testing for human immunodeficiency virus (HIV) antibodies supported by the UK Medical Research Council and the Department of Health are beginning to emerge. They provide vindication, earlier and more convincingly than could have been anticipated, of the approach that was adopted. In this issue (p 1562 and p 1565) we publish the results of two studies, one
conducted in Scotland and the other in three of the four Thames Regions of England, on testing for maternally transmitted HIV antibodies in blood samples from newborn infants. The findings complement those presented at a Department of Health press conference last month on a wider range of target populations, including pregnant women at antenatal clinics, male homosexuals at genitourinary medicine clinics, and drug users participating in needle exchange schemes or attending for treatment.! However, the results on pregnant women and newborn infants will have the more important repercussions for the great majority of the population. The main uncertainty in Britain and in many other countries is the extent to which HIV infection is penetrating the heterosexual population, and it is in this respect that the results are alarming. In inner London the rates of seropositivity among sexually active women are doubling every 12 months; if this rate of increase continues the figures will soon approach those of New York and other US cities. By identifying this surge in infection while it is happening, the opportunity is afforded for rapid public health action; creation of a London task force has already been announced by Mrs Bottomley at the Department of Health. Moreover, only 20% of positives were known to the obstetric services, even though named testing was being offered to women thought to be at risk. The danger of relying on voluntary testing programmes for essential epidemiological information is obvious. As a counter to the alarming results from inner London (and more controversy on this subject is aired in letters on p 1614), it is useful to observe a more stable overall geographic pattern of seroprevalence in women elsewhere, and in particular to know that in Scotland the early focus of infection among (drug using) women has not spread beyond the east of the country. The value of obtaining unbiased seroprevalence data over time, in selected target populations, is now firmly established. Two operational aspects of the reported studies merit comment-anonymity can be preserved in large-scale routine testing and the level of spontaneous opting out has been extremely low. Nevertheless, the existing anonymous testing programme has several imperfections, most of which reflect that fact that it is still a research programme at a developmental stage. First, nothing is known about the risk indicators of the women who are found to be positive. Were they injecting drug abusers? Had they had unprotected sexual intercourse in high-risk countries? Public health action could be far more precise if the relevant risk categories were known. In the high-risk areas of Scotland-Lothian and Tayside-the anonymous Guthrie card testing programme is being augmented to obtain simple risk factor information on everybody; this information is linked anonymously to the HIV result. Named testing is offered to those who declare risk behaviour. Similar adaptation of basic anonymous testing may be
1573
indicated for inner London but would require considerably greater resources. A benefit of the basic anonymous testing approach is that it shows where such extra resources should be applied. Second, the programme is seriously incomplete since many sexually active women at potentially increased risk of infection may never have had antenatal or Guthrie card specimens taken--eg, women who opt for early terminations or decide not to become pregnant. This lacuna was anticipated when the overall programme of anonymous testing was designed and samples from those undergoing pregnancy termination and from female hospital patients are also being tested to provide complementary information. The third criticism of the anonymous testing programme is more contentious-that it is unethical to test individuals for HIV in such a way that one cannot identify, and so cannot inform, the women who are positive. This criticism is misplaced. Named testing programmes, with the appropriate counselling services, are in operation and are the clinical responsibility of the obstetric services. All pregnant women can avail themselves of these. Rather than detracting from named testing services, the existence of an anonymous testing programme should improve their performance, since pregnant women and their obstetricians will be better informed as to local risks. Ultimately, named testing might be offered comprehensively in certain areas, as Ades and his colleagues (p 1562) suggest. Those responsible for anonymous testing can now be less defensive on the ethical issues. 1. The unlinked anonymous HIV
prevalence monitoring programme in England and Wales: preliminary results. Communicable Dis Rep 1991; 1: R69-76.
Melancholia and MRI "For more than 75 years the word has slithered innocuously the language like a slug, leaving little trace of its intrinsic malevolence and preventing, by its very insipidity, a general awareness of the horrible intensity of the disease when out of control".-William Styron; Darkness visible
through
(1990).
The word is depression and the disease, so graphically described by Styron, has long been the object of detailed study in mental and cognitive terms. More recently the search for a neurobiological explanation has intensified. The responsiveness of
depressed patients to pharmacotherapy, especially to tricyclic antidepressants and their later congeners, has also focused attention on possible neurotransmitter defects. To gain insight into these internal processes, various biological markers have been investigated; the resilient has been the cortisol response
the dexamethasone suppression test,! especially in its various psychiatric guises.2 In patients with depressive illness, most series have shown that a significant proportion (40-50%) do not suppress serum cortisol in response to dexamethasone. Although it remains unclear whether such resistance
most
to
is a state or trait marker for depression,3there is little doubt that hyperactivity of the hypothalamicpituitary-adrenal axis constitutes the most robust psychoneuroendocrine abnormality in this group of disorders.4 This increased activity is also manifest in terms of augmented total cortisol output,5 increased corticotropin concentrations,5 and adrenal gland hypertrophy as revealed by computed tomographic scanning.’ Many workers have attributed the increased activity to increased secretion of the
hypothalamic
corticotropin-releasing hormone, of these pituitary-adrenal changes CRH-41, may be mimicked by infusion of CRH-41 to normal subjects,8 while the blunted corticotropin responses to exogenous human7 or ovine9 CRH-41 in depressed patients may reflect potent corticosteroid feedback in some
the face of intense CRH-41 drive. Removal of this feedback with metyrapone, an 11-hydroxylase inhibitor, reveals the intensity of the overdrive,lO,l1 especially in dexamethasone non-suppressors. 12 There is also evidence that cerebrospinal fluid concentrations may be raised in depression. 13,14 Moreover, since central nervous system CRH-41 can cause behaviourals and autonomic16 changes that are compatible with its proposed role in organising the stress response, CRH-41 overdrive may be important in the pathogenesis of depression. If this theory is correct, the high CRH-41 drive should lead to hyperplasia of the corticotropic cells, and thus to enlargement of the pituitary. Krishnan et al 17 have now compared pituitary volumes computed by magnetic resonance imaging (MRI) in a group of 19 depressed patients and in normal age-matched and sex-matched controls. They found a slight, but statistically significant, increase in pituitary volume in the patients. Although the numbers are small and the findings need verification, the theory of CRH-41 overactivity in depression has so far withstood testing. It is still unclear whether such activation is central to the depressive process or a stress-related epiphenomenon,3and the links between such a neuropeptide theory and earlier concepts of neuroamine remain changes speculative. Nevertheless, humoral concepts seem to be leading to the roots of melancholia, and are among the strongest pointers so far to a fundamental biological dysfunction underlying this affliction. 1. Butler PWP, Besser GM. Pituitary adrenal function in severe depressive illness. Lancet 1968; i: 1234-36. 2. Carroll BJ. The dexamethasone suppression test for melancholia. Br J Psychiatry 1982; 140: 292-304. 3. Mullen PE, Linsell CR, Parker D. Influence of sleep disruption and calorie restriction on biological markers for depression. Lancet 1986; ii: 1051-54. 4. Gold PW, Goodwin FK, Chrousos GP. Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (2
parts). N Engl J Med 1988; 319: 348-53, 413-20. 5. Pfohl B, Sherman B, Schlecte J, Stone R. Pituitary-adrenal axis rhythm disturbances in psychiatric depression. Arch Gen Psychiatry 1985; 42: 897-903. 6. Amsterdam JD, Martinelli DL, Arger P, Winokur A. Assessment of adrenal gland volume by computed tomography in depressed patients
Registration is no more than a step in the regulatory process, although it is the most important. Efficient mechanisms are needed for reviewing registration in the light of new information or scientific developments. Such a review would require a commitment to developing various approaches to the evaluation of effectiveness and adverse drug reactions. Continuing vigilance should be part of the regulatory process, and will require efficient recording and evaluation of information on effectiveness and adverse effects. The existing British custom of renewing product licences every five years without requiring a proper scientific review seems designed to save staff time but not to protect consumers. All data that are not strictly related to the production process should be available to interested parties, and regulatory decisions and the reasons for them should be transparent and published. The summary basis of approval, which is issued in the USA, might be a suitable model for providing such information. It would also be desirable to provide open access to data on reported adverse events, as in Sweden. Members of committees dealing with drug regulation should declare any commitments that might involve them in a conflict of interest. Development of a united Europe creates an opportunity to consolidate the lessons learnt since the thalidomide affair and to raise regulatory norms within the Community as a whole. This goal cannot be attained unless the Treaty of Rome is amended to include public health as an area of central concern for the Community. If the shape of the EC regulatory system is determined before these amendments are considered, and is determined merely in the light of economic priorities, ground will be lost that can only be slowly and painfully regained-possibly at great human cost. European Community. Draft treaty articles with a view to achieving political union. Brussels, May, 1991. Document no Conf-up 1800/91. 2. Europe and health. Editorial and feature. The European Citizen, no 4. Brussels, October, 1990. 3. Commission of the European Communities. Future system for the free movement of medicinal products in the European Community. November, 1990. ISBN 92-77-66016-3. 4. Schönhöfer PS. Germany: effective drug regulations hampered by 1.
courts.
5.
Lancet 1991; 337: 904.
Payer L. Medicine and culture. Varieties of treatment in the United States, England, West Germany and France. New York: Henry Holt.
1988. 6. Offerhaus L. Pillen zonder grenzen? Tijdschr Geneeskd 1990; 134: 821-27.
(Pills without frontiers?)
Ned
Anonymous HIV testing: latest results Data from the programmes of anonymous testing for human immunodeficiency virus (HIV) antibodies supported by the UK Medical Research Council and the Department of Health are beginning to emerge. They provide vindication, earlier and more convincingly than could have been anticipated, of the approach that was adopted. In this issue (p 1562 and p 1565) we publish the results of two studies, one
conducted in Scotland and the other in three of the four Thames Regions of England, on testing for maternally transmitted HIV antibodies in blood samples from newborn infants. The findings complement those presented at a Department of Health press conference last month on a wider range of target populations, including pregnant women at antenatal clinics, male homosexuals at genitourinary medicine clinics, and drug users participating in needle exchange schemes or attending for treatment.! However, the results on pregnant women and newborn infants will have the more important repercussions for the great majority of the population. The main uncertainty in Britain and in many other countries is the extent to which HIV infection is penetrating the heterosexual population, and it is in this respect that the results are alarming. In inner London the rates of seropositivity among sexually active women are doubling every 12 months; if this rate of increase continues the figures will soon approach those of New York and other US cities. By identifying this surge in infection while it is happening, the opportunity is afforded for rapid public health action; creation of a London task force has already been announced by Mrs Bottomley at the Department of Health. Moreover, only 20% of positives were known to the obstetric services, even though named testing was being offered to women thought to be at risk. The danger of relying on voluntary testing programmes for essential epidemiological information is obvious. As a counter to the alarming results from inner London (and more controversy on this subject is aired in letters on p 1614), it is useful to observe a more stable overall geographic pattern of seroprevalence in women elsewhere, and in particular to know that in Scotland the early focus of infection among (drug using) women has not spread beyond the east of the country. The value of obtaining unbiased seroprevalence data over time, in selected target populations, is now firmly established. Two operational aspects of the reported studies merit comment-anonymity can be preserved in large-scale routine testing and the level of spontaneous opting out has been extremely low. Nevertheless, the existing anonymous testing programme has several imperfections, most of which reflect that fact that it is still a research programme at a developmental stage. First, nothing is known about the risk indicators of the women who are found to be positive. Were they injecting drug abusers? Had they had unprotected sexual intercourse in high-risk countries? Public health action could be far more precise if the relevant risk categories were known. In the high-risk areas of Scotland-Lothian and Tayside-the anonymous Guthrie card testing programme is being augmented to obtain simple risk factor information on everybody; this information is linked anonymously to the HIV result. Named testing is offered to those who declare risk behaviour. Similar adaptation of basic anonymous testing may be
1573
indicated for inner London but would require considerably greater resources. A benefit of the basic anonymous testing approach is that it shows where such extra resources should be applied. Second, the programme is seriously incomplete since many sexually active women at potentially increased risk of infection may never have had antenatal or Guthrie card specimens taken--eg, women who opt for early terminations or decide not to become pregnant. This lacuna was anticipated when the overall programme of anonymous testing was designed and samples from those undergoing pregnancy termination and from female hospital patients are also being tested to provide complementary information. The third criticism of the anonymous testing programme is more contentious-that it is unethical to test individuals for HIV in such a way that one cannot identify, and so cannot inform, the women who are positive. This criticism is misplaced. Named testing programmes, with the appropriate counselling services, are in operation and are the clinical responsibility of the obstetric services. All pregnant women can avail themselves of these. Rather than detracting from named testing services, the existence of an anonymous testing programme should improve their performance, since pregnant women and their obstetricians will be better informed as to local risks. Ultimately, named testing might be offered comprehensively in certain areas, as Ades and his colleagues (p 1562) suggest. Those responsible for anonymous testing can now be less defensive on the ethical issues. 1. The unlinked anonymous HIV
prevalence monitoring programme in England and Wales: preliminary results. Communicable Dis Rep 1991; 1: R69-76.
Melancholia and MRI "For more than 75 years the word has slithered innocuously the language like a slug, leaving little trace of its intrinsic malevolence and preventing, by its very insipidity, a general awareness of the horrible intensity of the disease when out of control".-William Styron; Darkness visible
through
(1990).
The word is depression and the disease, so graphically described by Styron, has long been the object of detailed study in mental and cognitive terms. More recently the search for a neurobiological explanation has intensified. The responsiveness of
depressed patients to pharmacotherapy, especially to tricyclic antidepressants and their later congeners, has also focused attention on possible neurotransmitter defects. To gain insight into these internal processes, various biological markers have been investigated; the resilient has been the cortisol response
the dexamethasone suppression test,! especially in its various psychiatric guises.2 In patients with depressive illness, most series have shown that a significant proportion (40-50%) do not suppress serum cortisol in response to dexamethasone. Although it remains unclear whether such resistance
most
to
is a state or trait marker for depression,3there is little doubt that hyperactivity of the hypothalamicpituitary-adrenal axis constitutes the most robust psychoneuroendocrine abnormality in this group of disorders.4 This increased activity is also manifest in terms of augmented total cortisol output,5 increased corticotropin concentrations,5 and adrenal gland hypertrophy as revealed by computed tomographic scanning.’ Many workers have attributed the increased activity to increased secretion of the
hypothalamic
corticotropin-releasing hormone, of these pituitary-adrenal changes CRH-41, may be mimicked by infusion of CRH-41 to normal subjects,8 while the blunted corticotropin responses to exogenous human7 or ovine9 CRH-41 in depressed patients may reflect potent corticosteroid feedback in some
the face of intense CRH-41 drive. Removal of this feedback with metyrapone, an 11-hydroxylase inhibitor, reveals the intensity of the overdrive,lO,l1 especially in dexamethasone non-suppressors. 12 There is also evidence that cerebrospinal fluid concentrations may be raised in depression. 13,14 Moreover, since central nervous system CRH-41 can cause behaviourals and autonomic16 changes that are compatible with its proposed role in organising the stress response, CRH-41 overdrive may be important in the pathogenesis of depression. If this theory is correct, the high CRH-41 drive should lead to hyperplasia of the corticotropic cells, and thus to enlargement of the pituitary. Krishnan et al 17 have now compared pituitary volumes computed by magnetic resonance imaging (MRI) in a group of 19 depressed patients and in normal age-matched and sex-matched controls. They found a slight, but statistically significant, increase in pituitary volume in the patients. Although the numbers are small and the findings need verification, the theory of CRH-41 overactivity in depression has so far withstood testing. It is still unclear whether such activation is central to the depressive process or a stress-related epiphenomenon,3and the links between such a neuropeptide theory and earlier concepts of neuroamine remain changes speculative. Nevertheless, humoral concepts seem to be leading to the roots of melancholia, and are among the strongest pointers so far to a fundamental biological dysfunction underlying this affliction. 1. Butler PWP, Besser GM. Pituitary adrenal function in severe depressive illness. Lancet 1968; i: 1234-36. 2. Carroll BJ. The dexamethasone suppression test for melancholia. Br J Psychiatry 1982; 140: 292-304. 3. Mullen PE, Linsell CR, Parker D. Influence of sleep disruption and calorie restriction on biological markers for depression. Lancet 1986; ii: 1051-54. 4. Gold PW, Goodwin FK, Chrousos GP. Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (2
parts). N Engl J Med 1988; 319: 348-53, 413-20. 5. Pfohl B, Sherman B, Schlecte J, Stone R. Pituitary-adrenal axis rhythm disturbances in psychiatric depression. Arch Gen Psychiatry 1985; 42: 897-903. 6. Amsterdam JD, Martinelli DL, Arger P, Winokur A. Assessment of adrenal gland volume by computed tomography in depressed patients
