Introduction
The key question concerning major depression is about difference--why do some people become depressed while others do not? There is an increasing consensus about etiology, with the proponents of genetic/ biological theories of causation acknowledging the inextricable links between these influences and social factors. Thus Plomin (1995) writes that 'the same genetic research that has demonstrated the important contribution of genetics also provides the best available evidence for the importance of environmental influence.'
Classification: Clarification Or Confusion?

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The study of the causation of major depression requires clear and sufficiently uncontroversial descriptions of the condition. Farmer points but the importance of this in relation to understanding genetics--we do have reliable definitions, but perhaps too many from which to chose, and the most appropriate for research purposes remain unclear. Studies on the genetics of unipolar major depression are only now coming to the fore--much work to date has focused on bipolar disorder. While the latter is easier to diagnose and classify, there is likely to be at best only a partial genetic overlap with the more common unipolar form. (Fombonne 1995)

Two aspects of classification are of particular importance. First, recognition of the value of a 'polydiagnostic' approach, and secondly, the acknowledgement of the heterogeneity of depressive states and in particular that much may be gained from studying individual symptom constellations. Brain imaging studies are helping to identify regions which subserve individual symptom clusters and we must be wary of over-zealous attempts at classification in light of the refinements which imaging studies may bring.

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There is controversy surrounding the diagnosis of dysthymia, as distinct from other 'neurotic' conditions, particularly if, as some contend, cothymia or the 'general neurotic syndrome' of mixed major depression and anxiety are in fact more accurate descriptions (Tyrer et al., 1993; Tyrer, 1989). Indeed, we may have to extend research to such syndromes. The question of quantity and quality clearly arise here--where does unhappiness become dysthymia, and dysthymia major depression, and where do apparently more restricted depressive syndromes sit--those for example of seasonal affective disorder and post-natal major depression?

Single causes or chains of events?
Genetic factors underlie major depression in a complex manner, but the biologists agree that we are looking at an inherited liability to develop major depression in response to environmental stressors rather than an entirely genetically determined condition. The biological basis of this vulnerability is being studied. Key possibilities include, perhaps most simply, a mutation disrupting, for example, some stage of amine neurotransmission--a likely candidate based on the empirical evidence of effective therapeutic drugs. But changes in the central control of corficosterold hormones in major depression also occur and may be paramount.

The work on the hypothalamic-pituitary axis, the stress response and cortisol brings us back towards basic mechanisms and treatments aimed at both the hypercortisolaemia which may underlie some depressive states and the defective negative feedback mechanisms which may cause or exacerbate this. Improved understanding of these systems may well have implications for refining both pharmacological and psychological treatments.

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More subtle links between genes and the propensity to become depressed have also been proposed, and we can start to conceive of a model whereby genetic factors influence people's behavior and cognitive style, leading in turn to a tendency to respond to certain environmental factors by becoming depressed. The extent to which our behavior--and thus our experiences and life-events, and indeed our interpretation of these, are genetically determined remains to be discovered. Inherited attributes may contribute to vulnerability and major depression through influences on people's exposure to environmental factors--'gene environment correlation', and effects on choices--those of partners, friends and lifestyle.

A complex chain of inherited predisposition to certain lifestyles coupled with the adverse effects of a vulnerability to some of the events arising as a result of these lifestyles could act together to determine a depressive reaction. In addition, the impact of events is mediated by their interpretation, and the extent to which they may be assimilated relatively painlessly.
It is also emphasized that the importance of factors which may mediate between, for example, childhood adversity and later major depression. Early unprocessed trauma, such as that of sexual abuse, may lead to chronic and recurrent major depression mediated by factors such as self-blame and bodily shame.

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It is believed that we must ascertain whether the course of a depressive illness is indeed critically determined by early childhood trauma and that trauma processing could thus have an important place in the cognitive therapy of major depression.
The involvement of economic circumstances in major depression is clear, and researchers must unravel the complex ramifications of seemingly straightforward problems such as poverty. For example, there is evidence that single mothers who try to cope with a spiral of poverty by finding full-time employment miss out on the protection against major depression, which this higher socioeconomic status should bring. Negative life-events may become more common and the mother's reactions to them can be detrimental--a mother whose child becomes delinquent may well feels guilty at the possibility that her job made her neglect her child. Here again we see life-events and cognitions conspiring together.

Poverty and deprivation worsen inter-personal relationships, but it is contended that it is essentially problems with the latter that cause major depression. What mechanisms underlie this at the neurochemical level? As mentioned, we have some empirical clues from the drugs effective at treating major depression, but our understanding of their mode of action remains fairly sketchy. Imaging studies, which allow identification of sites of action of labeled compounds with known receptor targets, compared in depressed and non-depressed subjects and during mood manipulation can help us to identify involved brain regions and what the drugs may be doing to modify them.

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Major Depression Across The Lifespan And Between The Sexes: Clues To Understanding The Etiology?

Given that the interplay of genetic and social factors conspires to cause major depression by determining our experiences and behavior, and the degree of support available to us, can we understand age and gender differences? The former are perhaps easier to consider--penetrance of genetic factors at different stages in the lifespan are not uncommon in disease, and social and environmental status clearly change with age.

As we grow older, the influence of heritable factors in the etiology of major depression appears to increase for a time, taking over from the apparently predominating factor of shared environment in children, and then decreases again in the elderly. The twin studies which have shed such light on the relative importance of genetic and environmental factors become harder to conduct as people age, confounding our unraveling of the issues.

Evidence for biochemical and structural alterations in the brain associated with the ageing process, and for age-related physical and social changes has been presented. Together these may be responsible for maintaining the prevalence of major depression, despite the decrease in influence of heritable factors. We need to refine our instruments for assessing major depression in the elderly, recognize that it is not an inevitable consequence of the ageing process, and acknowledge that intervention can be successful and must be made available. Resolution of etiological subtypes of old age major depression is an important aim and will in turn have implications for therapeutic approaches.

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Cultural variations and societal beliefs are likely to be important and must be further investigated. The honor of looking after elderly relatives in India has made it virtually impossible to develop measures for burden of care for younger relatives and variations in the onset of depressive disorders may reflect culturally different views and treatment of older people. The 'Eurodep' survey (a BIOMED2 project bringing together old-age major depression researchers, coordinated by Professor John Copeland in Liverpool, UK) is using GMS internationally in a way that should shed light on this. Strong cultural determinants of major depression may emerge from such studies, which in turn will help to clarify the extent to which the biological correlates of old age--the neurochemical, neuroendocrinological and physical changes--are important etiological factors.

Major depression in children has its puzzles too. Social and environmental factors will be unique to this period of life and are clearly important, but again we have some more apparently biological determinants: the striking ineffectiveness of antidepressants in children highlights the possibility of developmental factors related to major depression and its nature at different ages. Other examples of age-related drug effects-perhaps the most striking that of methylphenidate in hyperactivity--suggest that this is not untenable. There are interesting leads to follow up on the cognitive side too---the efficacy of cognitive behavior therapy (CBT) in major depression in children is marked, but curiously, the cognitions, which this targets often, remain apparently untouched by the therapy (Spence, 1994). Taken together, the inefficacy of antidepressants and efficacy of CBT suggest that we are not simply dealing with a difference in terminology about feelings in children. Intervention at school age--which could help prevent the carrying through of both predisposing behaviors and interpretations, and major depression itself, into adult life, is clearly important.

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What of the gender difference? Twice as many women as men suffer from major depression during child-beating years, and we need to determine what underlies this and to consider it in all our attempts to understand the etiology of major depression as a whole. The causes of major depression must explain the gender difference but not all the causes may be involved, indeed a single one may be sufficient explanation.

Perhaps counter-intuitively, social causes of this imbalance are favored over biological ones. Nazroo and his colleagues (1996) report that the discrepancy pertains even in cases where male/female couples were selected for study because they shared a significant life experience predicted to impinge on both of them and to cause major depression. However, the events most obviously responsible for the gender difference in causing major depression were entirely those concerning reproduction, children and housing. There was no gender difference at all when other types of events were looked at, and most strikingly, the difference disappeared--the incidence of male major depression in-creased--in a small sub-group where men took a stronger role in more traditionally female activities.

The gender difference may be determined very strongly by role commitments, although differences in commitments themselves then demand explanation. It will be interesting to see what happens as more men became active partners, if indeed they do, and whether, as this study suggests, the overall burden of major depression will increase. Again though, unraveling cause and effect will become important: perhaps men enter this group because of difficulties, which could themselves increase a propensity to major depression.

Animal Models: Can We Trust Them?
The overall applicability of animal models of major depression in clarifying both biological and environmental etiologies is generally accepted, and their continued use is likely. There needs to be an awareness of the ways in which the neurochemistry of animals and man may differ, but this may not be such a great problem. We have seen how responses to both psychological and chemical anti-depressant interventions differ at different ages in humans. By the same token, despite variation, animals remain good general experimental models for some purposes.

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It must be borne in mind, however, that the animal models often seek to test out single etiological theories in the simplest possible ways. The need to consider the interplay between genetic and environmental theories of etiology in parallel exceeds the capacity of animal models.

Evolutionary Theories: Does Major Depression Help Us?
Why is major depression so common? Affecting perhaps as many as 10% of the population at any time, it has the hallmarks of a beneficial trait which has survived the processes of natural selection. Is it possible to view major depression as an adaptation to survival--perhaps prompting people to adopt passive responses to distressing life events and thereby maintaining, for example, relative equanimity within tight social groups?

Plorain is cautious about the value of focusing on the admittedly intriguing evolutionary perspective, which he fears may mislead more than it helps. Genetic selection tends to aim for a mid-point--against extremes and towards characteristics, which will be beneficial in the widest range of circumstances. If this is the case, investigating theories of adaptive advantage may not be very rewarding. Indeed, the hugely distressing and disruptive effects of major depression hardly support arguments that it is advantageous to the sufferer, so we must reconcile ourselves to the possibility that it is either an adaptive process gone much awry, or that any adaptive advantage it may once have had is now lost.