write a 3 page double-spaced summary of the attached article" Depression"

DEPRESSION THE LANCET

Depression

David Meagher, Declan Murray

“Sex discrimination is not only a function of society, it is a function of disease”.’ This seems to be the case with depression, which is twice as common in women as in men. There are also differences between the sexes in clinical profile and course, and in treatment response- relevant to all branches of medicine. Depression is a major health concern not only because of personal distress, excess mortality, impaired interpersonal relationships, and restriction of work activities but also because of the economic burden it imposes. In 1990, the estimated cost to American society was $53 billion-comparable with that of diseases such as cancer, coronary heart disease, and AIDS.2

Prevalence The finding that depression is twice as prevalent in women as in men is not accounted for by different patterns of help-seeking behaviour since it has been consistently confirmed in general population studies.3 The female preponderance is evident from puberty onwards and is found across a range of cultures and countries. How can we account for this increased prevalence? Several factors are relevant.

The reproductive cycle In the month after childbirth there is a 22-fold increase in the incidence of affective psychosis4 and a less dramatic rise in non-psychotic depression.5 The affective psychoses are associated with primiparity, caesarean section, and perinatal death, but the main trigger is thought to be neurophysiological-possibly related to increased dopamine sensitivity. Non-psychotic postnatal depression is related more to psychosocial stressors,6 although oestrogen seems to be an effective treatment.7 Overall, childbirth does not fully account for the disproportionate expression of depressive disorders in women.

The association of depression with other aspects of the reproductive cycle-premenstrual syndrome,8 termination of pregnancy’-is less clearly demonstrated and remains controversial. With regard to the menopause, it now seems that neither hormonal nor psychosocial changes are aetiologically related to depression.‘o

Social factors Social factors undoubtedly contribute to the genesis and maintenance of depression in both sexes. Women may be at special risk because of gender-related stressors together with different coping styles; lack of a confiding relationship with a husband or lover is one of the most important vulnerability factors. In men, core relationships are less critical: vulnerability to depression only emerges when the bonds of intimacy come under great stress.”

Departmerd of Psychiatry, St Vincent’s Hospital, Dublin 4, &eland (D Meagher Mwssych) and St Ita’s Hospital, Portrane, Co Dublin (D Murray MRCPsych)

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What about work? Work outside the home is beneficial to women’s mental health except when it creates difficulties with housework and childcare.‘” Certain activities where women predominate-care of the elderly, mentally ill, mentally handicapped, and physically disabled-are linked with increased rates of depression.13 Women, it seems, are more likely than men to subordinate their needs to the needs of someone they look after.14

Another factor widely thought to increase psychiatric morbidity in adult life, which is much more frequent in women than in men, is childhood sexual abuse. 25% of depressed women report a history of such abuse compared with 6% of controls.” Women are also afraid of sexual and other violence in their present lives and some are described as having a virtual curfew after dark.16 However, most violence against women is domestic;17 often it goes undetected and it leads to health and social problems including depression.

Low self-esteem is a risk factor for depression,” and girls are more likely than boys to display poor self- confidence, to rely on the opinion of others, and to blame themselves for failure.18 Self-esteem is related to factors such as early parental loss, rearing style of parents, unemployment, and degree of social support, but a study of female twins indicates a strong genetic contribution.19 A similar study in men would be of great interest.

Melancolia I

By Albrecht Dhrer, 1471- 1528

THE LANCET DEPRESSION

Panel 1: JCD 10 symptoms of depression At least two (mild/moderate) or three (Severe), Of: Depressed mood LOSS of interest and enjoyment Increased fatiguabikty And at least two (mild), three (moderate), or four (severe) of: Reduced concentration and attention Reduced self-esteem and self-confidence Ideas of guilt and unworthiness Bleak and pessimistic views of the future Ideas or acts of self-harm or suicide Disturbed sleep Diminished appetite

We have referred to differences in coping style but the precise nature of these is unclear. One study indicated that women rate the degree of stress similarly to men but respond with a greater intensity of symptoms.” Another showed that women rate the impact of stressors more severely and that men are more insulated from depression by cognitive distortionzl Certain types of behaviour may enhance stress adaptation or act as a substitute for depression; for example, one suggestion is that a man might express distress through antisocial behaviour or alcohol abuse where a woman would become depressed. This notion is consistent with the finding that, although depression is commoner in women, overall rates of psychiatric morbidity are similar in the two sexes.

There is some evidence that, where social roles are controlled for, gender differences in depression rates are absent. Among entrants to the teaching profession, when educational attainment, social class, marital status, and professional rank were matched, there was no difference in depression rates between men and women.22 In the Amish community, which strictly prohibits alcohol and antisocial behaviour, men and women have almost the same rates of depression.23 In matriarchal societies such as that in Papua New Guinea prevalence sex ratios may even be reversed.‘”

Ethology The study of behavioural patterns in other species has given rise to a “social competition hypothesis” which proposes that depressive states serve a useful evolutionary function.25 Social withdrawal and psychomotor inhibition are judged to represent a mechanism whereby an organism can adapt to failure in competitive situations and come to terms with low rank. Such a theory readily accommodates the social role commonly allocated to women in society and explains why where women have equal oppotunities the excess of female depression does not occur. Low rank has been linked to disturbances in indolamine metabolism, perhaps mirroring the neurochemical mechanisms of depression.

Neurobiology Gender differences are evident in the metabolism of noradrenergic and serotoninergic neurotransmitters implicated in depressive illness.z6 Moreover, the interaction of these systems with sex and stress hormones also varies according to sex. Morphologically, regions of the central nervous system involved in emotional or cognitive processing differ according to sex (hypothalamus, amygdala, and frontal cortex).” These neurobiological differences may be a source of altered vulnerability to various factors that precipitate mood disturbances. Although this has not been directly tested,

such a theory would account for the observed roles of both genetic and social factors in the genesis of depression.

A comprehensive theory of mood disorders must integrate findings from sociology, psychology, ethology, and the neurosciences. The potential overlap between these areas is illustrated by evidence that environmental complexity and social stimulation affect morphological development of the central nervous system.‘* The two sexes can experience quite different social environments even in the same classroom; for instance, teachers give more corrective feedback, individual instruction, praise, and encouragement to boys. Girls experience “relative deprivation” in the classroom.zy These and other variations in the social environment during development may contribute to neurobiological diiferences relevant to emotional processing.

Detection and diagnosis Panel 1 summarises internationally agreed diagnostic criteria for defiression.30 Depression is diagnosed where symptoms are present most of every day for 2 weeks or more. However, 50% of patients with depression do not consult their doctors and even in those who do the diagnosis is missed in around half.” Factors associated with reduced detection are listed in panel 2. Greater advantage could be taken of women’s contacts with health professionals in general practice, family planning services, and gynaecology clinics. An excellent example is the project in Edinburgh whereby health visitors were trained to detect postnatal depression and provide counselling.32

Course Depression has an earlier onset, higher rate of recurrence, longer duration, and lower rate of spontaneous remission in women than in men.33,34 This picture may result from a combination of the specific female stressors and the fact that, once the threshold for first episode of depression is crossed, “illness begets illness”.35 The course of depression is further complicated by the fact that depressed women have more concomitant medical and psychiatric disorders which are associated with lower detection rates and poorer prognosis.36 Depressed women are less likely than depressed men to commit suicide, and are six times less likely to commit suicide during the first postnatal year than during any other year, despite high rates of psychiatric morbidity during this time.37

Treatment Depression is a syndrome for which drug treatment is effective irrespective of aetiology. Doctors may be reluctant to prescribe antidepressants when symptoms are

Panel 2: Factors associated with decreased detection of depression

Patient factors Somatic symptoms of depression Physical disease Longstanding depression Atypical symptoms (eg, without overt depressed mood) Doctor factors: poor interview technique Less eye contact Early and frequent interruption Premature use of dosed questions (which can be answered yes/no) Poor listeners Fewer direct questions about psychological symptoms Fewer direct questions about social circumstances

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DEPRESSION THE LANCET

c1ear1y related to life circumstances but drug therapy should not be withheld for this reason.38 In addition to medication, psychotherapy is important. Specific Psychotherapies, including cognitive therapy and interpersonal psychotherapy, enhance the effect of antidepressants and in some circumstances (eg, pregnancy) may be an appropriate alternative to drugs.39 Attention to level of social support can be of enormous therapeutic value, especially in women with dependent children.

Those who respond to an antidepressant should continue on a full therapeutic dose, for a minimum of 4 months4’ Maintenance therapy may be necessary for those with recurrent illness;4* and sometimes long-term psychotherapy is also required to prevent symptom recurrence.

What other factors influence treatment response? Oral contraceptives induce liver enzymes and thus decrease concentrations of tricyclic antidepressants (the reverse is also true). There is some evidence that antidepressants work more slowly in women than in met-P and that women are more prone to side-effects from tricyclic compounds, monoamine oxidase inhibitors, and lithium.” Particular difficulties arise with use of medication around the time of conception, during pregnancy, and during breastfeeding. Group therapieP and problem-solving individual therapie? may suit women better than men.

A gap remains between what is agreed to be appropriate treatment and what happens in clinical practice.45Tricyclic antidepressants are often used in subtherapeutic doses, though this happens less with the serotonin-specific reuptake inhibitors which can usually be started at a therapeutic dose.45 Duration of treatment is often inadequate; most patients abandon medication in less than 2 months4h-not surprisingly, in the light of a MORI survey revealing that 78% of the public believe antidepressants to be addictive and only 16% think that depressed people should receive them.47 Effective psychological treatments may likewise also be underused. They languish, some say, because thay have not been developed and marketed by profit-making companies.48 Provision of inpatient treatment for women is difficult, since they are more likely than men to take early discharge from hospital for social or domestic reasons.36

In view of the consequences for the patient and her family, these shortfalls in delivery of effective treatments should be a major concern to health and social services.

Conclusion Development of mental health services and clinical practice should be informed by a better understanding of gender differences in clinical phenomena and service requirements. Clearly, diverse biological and social variables are interacting. From existing evidence, our judgment is that sex discrimination as much a function of depression as depression is a function of sex discrimination.

References 1 Roberts DF. Sex differences in disease and mortality. In: Carter CO,

Peel J, eds. Equalities and inequalities. London: Academic Press, 1976: 13.-34.

2 Greenberg PE, Kessler RC, Nells TL, Fink&rein SN, Bemdt ER. Depression in the workplace: a” economic perspective. In: Feighner JP, Bayer WF, et al. Selective serotonin x-e-uptake inhibitors, 2nd ed. New York: Wiley, 1996,

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4

5

6

7

8

9

11

12

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19

Paykel ES. Depression in women. BrJPsychiaty 1991; 158 (suppl 10): 22-29. Kendell RE, Chalmer, JC, Platz C. Epidemiology of puerperal psychoses. Br JPsychiaty 1987; 150: 662-73. Cox JL, Murray D, Chapman G. A controlled study of the onset, duration and prevalence of postnatal depression. BrJ Psychiaty 1993; 163: 27-31. Harris B. Biological and hormonal aspects of postpamm depressed mood. Working twva ds strategies for prophylaxis and treatment. Br Jl’sychiaty 1994; 164: 288-92. Greg&x AJ, Kumar R, Eve&t B, Henderson AF, Studd JW. Transdennal “estrogen for treatment of severe postnatal depression. Lancet 1996; 347: 930-33. Pearlstein TB. Hormn~~es and depression: what are the facts about premenstrual syndmw. menopause, and hormone replacement therapy? AmJ Obstej CT, ucol 1995; 173: 646-53. Gilchrist AC, Hannat~ Ed PC, Frank I?, Kay CR. Termination of pregnancy and psychs lric morbidity. B~JPsychiaty 1995; 167: 24348. Nicol-Smith L. Causa bly, menopause, and depression: a critical review of the literature. BM.9 1996; 313: 1229-32. Brow” GW. A psych,) axial view of depression. In: Bennett DH, Freeman HL, eds. C rnmunity psychiatry. London: Churchill Livingstone, 1991: 7 I 114. Parry G. Paid emplw tent, life events, social support and mental health in working claa mothers. J Health Sot Behav 1986; 27: 193-208. Twigg J, Aitken K. Caicrs perceived: policy and practice in informal care. Buckingham: Open University Press, 1994. Johnson S, Buszcwicz M. Women’s mental health in the UK. In: Abel K, Buszewicz M, Davison D, Johnson S, Staples E, eds. Planning community mental health services for women. London: Routledge, 1996: 6-19. Vize CM, Cooper PJ. Sexual abuse in patients with eating disorder, patients with depression and normal controls. A comparative study. BrJPsychiaty 1995; 167: 80-85. Mezey G, Stanko EA. Women and violence. In: Abel K, Buszewicz M, Davison D, Johnson S, Staples E, eds. Planning co”mm”ity mental health services for women. London: Routledge, 1996: 160-75. Home O&e. Criminal statistics of England and Wales. London: HMSO, 1992. Ruble DN, Greulich F, Pomerantz EM, Gochberg B. The role of gender-related processes in the development of sex differences in self- evaluation and depression. JAffect Disord 1993; 29: 97-128. Roy MA, Neale MC, Kendler KS. The genetic epidemiology of self esteem. BrJPsychiaty 1995; 166: 813-20.

20 Uhlenhuth EH, Paykel ES. Symptom intensity and life events. Arch Gen Psychiatry 1973; 28: 473-77.

21 Sowa CJ, Lustman PJ. Gender differences in rating stressful events, depression, and depressive cognition. J Clin Psycho1 1984; 40: 1334-37.

22 Wilhelm WI<, Parker Cr. Is sex necessarily a risk factor t” depression. Psychol Med 1989; 19: bOl-13.

23 Egeland JA, Hotstetter AM. Amish study I: affective disorder among the Amish, 1976-SO., !mJPsychiaty 1983; 140: 56-61.

24 Weissman MM, Klermann GL. Sex differences and the epidemiology of depression. Arch Gw Psychiaty 1977; 34: 98-111,

25 Price J, Sloman L, Gardner R, Gilbert P, Rohde I?. The social competition hypothesis of depression. BrJPsychiaty 1994; 164: 309-l 6.

26 Halbreich U, Lumley LA. The multiple interactional biological processes that might lead t” depression and gender differences in its appearance. JAffect Disord 1993; 29: 159-73.

27 Kelly DD. Sexual differentiation of the “erv”us system. 1”: Kandel ER, Schwartz JH, Jesse11 TM, eds. Principles of neural science, 3rd ed. New York: Elsevier, 199 1.

28 Heller W. Gender differences in depression: perspectives from neuropsychology. JAjfect Dtiord 1993; 29: 12943.

29 Kimball MM. A new perspective on women’s math achievement. Psycho2 Bull 1989; 105: 198-214.

30 World Health Organization. The ICD-10 classification of mental and behavioural disorders. Clinical descriptions and diagnostic guidelines. Geneva: WHO, 1992.

31 Bridges K, Goldberg D. Somatic presentation of depressive illness in primary care. In: Freeling I’, Downey LJ, Malkin JC, eds. The presentation of depression: current approaches. London: Royal College of General Practitioners, 1987.

32 Holde” JM, Sagovsky R, Cox JL. Counselling in a general practice setting: a controlled study og health visit& intervention in treatment of postnatal depression. BMJ 1989; 298: 223-26.

33 Yonkers KA, Chantilis SJ. Recognition of depression in obstetric/gynecology practices. Am J Obstet Gynecol 1995; 173: 632-38.

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34 Sargeant JK, Bruce ML, Florio LP, Weissman MM. Factors associated with one year wtcOme of major depression in the community. Arch Gen Psychiatry 1990; 41: 519-26.

35 Post RM. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. AmJ Psychiatry 1992; 149: 999-1009.

36 Pajer K. New strategies in the treatment of depression in women. J Clin Psychiaty 1995; 56 (suppl2): 30-37.

37 Appleby L. Suicide during pregnancy and in the first postnatal year. BMJ 1991; 302: 137-40.

38 Priest RG. Improving the management and knowledge of depression. BrJPsychiatry 1994; 164: 285-87.

39 Weissman M. Psychotherapy in the maintenance treatment of depression. BrJ Psychiatry 1994; 165 (suppl26): 42-50.

40 Paykel ES, Priest RG. Recognition and management of depression in general practice: consensus statement. BMJ 1992; 305: 1198-202.

41 Montgomery SA. Efficacy in long-term treatment of depression. J Clin Psychiatry 1996; 57 (suppl 2): 24-30.

42 Frank E, Carpenter LL, Kupfer DJ. Sex differences in recurrent

depression: are there any that are significant? Am J Psychiany 1988; 145: 41-45.

43 Leibenluft E. Women with bipolar illness: clinical and reasearch issues. AmJPsychiaty 1996; 153: 163-73.

44 Thase ME, Reynolds CF, Frank E, et al. Do depressed men and women respond similarly to cognitive behaviour therapy? Am J Psychiaty 1994; 151: 500-05.

45 Donoghue J, Tylee A, Wildgust H. Cross sectional database analysis of antidepressant prescribing in general practice in the United Kingdom, 1993-95. B&I’3 1996; 313: 861-62.

46 MacDonald TM, MacMahon AD, Reid IC, Fenton GW, McDevitt DG. Antidepressant drugs use in primary care: a record linkage study in Tayside Scotland. BMJ 1996; 313: 860-61.

47 Priest RG, Vize C, Roberts A, Roberts M, Tylee A. Lay people’s attitudes to the treatment of depression: results of an opinion poll for the Defeat Depression Campaign just before its launch. BMJ 1996; 313: 858-59.

48 Andrew G. Talk that works: the rise of cognitive behaviour therapy. BMJ 1996; 313: 1501-02.

Hormones and bones

Rent? Rizzoli, Jean-Philippe Bonjour

Of the various hormones that can affect the metabolism and structural integrity of bone, oestrogen is undoubtedly the most important in women, at least after puberty. Observations in disorders associated with low oestrogen production or inadequate oestrogen action, and in delayed puberty, suggest that sex hormones are a key factor in acquisition of bone mass. However, we do not yet know whether differences in sex hormone secretion or action during pubertal maturation in healthy adolescents contribute to the large biological variability in bone mass gain observed at sites at special risk of osteoporotic fractures such as lumbar spine and proximal femur.

After puberty, males have larger bones with greater cortical thickness than females, and the main reason for this gender difference seems to be the longer bone maturation period in males. Puberty affects bone size much more than volumetric mineral density; indeed, at the end of pubertal maturation males and females differ very little in volumetric trabecular density. In healthy Caucasian females with adequate intakes of energy and calcium, bone mass accumulation in both lumbar spine and femoral neck seems virtually complete before the end of the second decade.“’

Once peak bone mass has been achieved, the amount of bony tissue remains constant throughout reproductive life except possibly in the femoral neck, where a slight decrease has been reported in cross-sectional studies from the third decade on. Female sex hormones, physiologically integrated in a regular menstrual cycle, seem crucial not only to acquisition of maximum bone mass after menarche but also to maintenance of this mass by control of bone

Division of Bone Diseases, WHO Collaborating Centre for Osteoporosis and Bone Diseases, Department of Internal Medicine, University Hospital, 1211 Geneva 14, Switzerland (R Rizzoli MD, Prof J-P Bonjour !m)

remodelling during reproductive life.3 Even a shortening of the luteal phase may be associated with abnormal bone loss.4

The susceptibility of bone to sex hormone deprivation was recognised more than 50 years ago by Albright, who noticed an association between osteoporosis and menopause.s Since then, the concept of a causal link between oestrogen deficiency and accelerated bone loss has been supported by observations in various states of premature oestrogen deficiency, such as anorexia nervosa, secondary amenorrhoea due to strenuous exercise, and use of gonadotropin inhibitors.6J Some might object that, in exercise-induced amenorrhoea, eating disorders are a likely factor in the low bone mass, but in female marathon runners we observed that bone loss was essentially attributable to oestrogen deficiency rather than alterations in calorie, calcium, or protein intake (Gremion G, Rizzoli R, Slosman D, et al, unpublished).

Whereas in the mid-nineteenth century female life expectancy was under 50 years, a western woman today can expect to reach age 80 or more. This phenomenon is predicted to progress and the world projection for the year 2050 is a five-fold increase in the population aged 65 and over.* Since the age of menopause has not greatly changed, today a woman can anticipate spending about 30 years, one-third of her life, in a postmenopausal state.

Pathophysiology of bone loss in oestrogen deficiency Oestrogen deficiency increases the rate of bone remodelling and leads to an imbalance between bone resorption and formation, resulting in a net bone loss and possibly osteoporosis.9 Cytokines such as interleukin-1 (IL-l), tumour necrosis factor-a (TNF-a), interleukin-6, interleukin-I 1, and macrophage colony-stimulating factor may be involved in bone resorption by facilitating the recruitment and maturation of osteoclast precursors.

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