Genetic and Social Aetiology of Mood Disorders

Technical article

Topics covered:

  • Introduction
  • Genetic epidemiology of mood disorders
    • Adoption studies
    • Twin studies
    • Family studies
  • Molecular genetics in affective disorders
    • Chromosome 18
    • Chromosome 11
    • Chromosomes 4, 5, 12, and 21
    • X chromosome
    • Serotonin markers and affective disorders
    • Anticipation and expanded trinucleotide repeat sequences
  • Psychosocial factors in affective disorders
    • Impairment in social and familial relationships
    • Dysfunctional cognition
    • Gender
    • Socio-economic status
    • Temperament and behaviour
  • The gene–environment hypothesis
    • Gene–environment interactions
    • Molecular genetics and personality traits
  • Conclusion
  • References


Advances towards the understanding of the aetiological mechanisms involved in mood disorders provide interesting yet diverse hypotheses and promising models. In this context, molecular genetics has now been widely incorporated into genetic epidemiological research in psychiatry. Affective disorders and, in particular, bipolar affective disorder have been examined in many molecular genetic studies which have covered a large part of the genome; specific hypotheses such as mutations have also been studied. Most recent studies indicate that several chromosomal regions may be involved in the aetiology of bipolar affective disorder. Other studies have reported the presence of anticipation in bipolar affective disorder (1,2) and in unipolar affective disorder. (3) This phenomenon describes the increase in clinical severity and decrease in age of onset observed in successive generations. This mode of transmission correlates with the presence of specific mutations (trinucleotide repeat sequences) and may represent a genetic factor involved in the transmission of the disorder. (4,5) Large multicentre and multidisciplinary projects are currently under way in Europe and the United States and hopefully will improve our understanding of the genetic factors involved in affective disorders. In parallel to these new developments in molecular genetics, the classical genetic epidemiology, represented by twin, adoption, and family studies, has provided additional evidence in favour of the genetic hypothesis in mood disorders. Moreover, these methods have been improved through models to test the gene–environment interactions.

Recently publiched research has shown genetic links between 5 major psychiatric conditions (schizophrenia, bipolar disorder, autism, major depression and attention deficit hyperactivity disorder). Read more here.

In addition to genetic approaches, psychiatric research has focused on the role of psychosocial factors in the emergence of mood disorders. In this approach, psychosocial factors refer to the patient's social life context as well as to personality dimensions. Abnormalities in social behaviour such as impairment in social relationships (6,7and 8) and dysfunctional cognitions (9) have been observed during episodes of affective disorders, and implicated in their aetiology. Further, gender and socio-economic status emerged as having a possible impact on the development of affective disorders. Finally, the onset and outcome of affective disorders could also be explained by interactions between the social life context and the individual's temperament and personality. The importance of temperament and personality characteristics in the aetiology of depression has been emphasized in various theories, although disagreement exists with regard to terminology and the aetiology of the characteristics themselves.

While significant advances have been made in these two major fields of research, it appears that integrative models, taking into account the interactions between biological (genetic) factors and social (psychosocial environment) variables, offer the most reliable way to approach the complex mechanisms involved in the aetiology and outcome of mood disorders. This article will review some of the most promising genetic and psychosocial hypotheses in mood disorders that can be integrated in interactive models.

Genetic epidemiology of mood disorders

The various strategies available to investigate genetic risk factors in psychiatric disorders belong to the wider discipline of genetic epidemiology. This combines both epidemiological and genetic investigations and has the primary objective of identifying the genetic and non-genetic (environmental) causes of a disease. Genetic epidemiological data in affective disorders has come mostly from family, twin, adoption, and segregation (within families) studies. Family, twin, and adoption studies are the mainstay in establishing the genetic basis of affective disorders. These methods firstly demonstrated that genetic factors are involved in the aetiology of these disorders. (10) Twin and adoption data may also be used to investigate the relative contributions of genetic and environmental factors to the aetiology of a disease. (11) The exact contribution of these factors is not yet firmly understood for affective disorders but there have been some recent findings.

Adoption studies

The study of adoptees who are separated from their biological parents has consistently favoured the gene–environment hypothesis in the aetiology of diverse psychiatric disorders. One of the recent studies (12) show that major depression in females is predicted by an alcoholic diathesis only when combined with an environmental factor that is characterized by a psychiatrically ill adoptive parent. Other possible environmental factors were identified, such as fetal alcohol exposure, age at the time of adoption, and a family with an adopted sibling who had a psychiatric problem. These findings confirm the importance of the gene–environment interactions in the understanding of aetiological mechanism in mood disorders. The adoption study design is also used to validate clinical entities through the understanding of the gene–environment interactions as aetiological factors. The concept of depression spectrum disease has originally been developed from family studies (13) and further validated in adoption studies. In this model, depressions were divided into pure depressive disease (only depression in the family) and depression spectrum disease (characterized by a family history of alcoholism or antisocial personality). Different adoption studies confirmed this hypothesis, showing that daughters of alcoholics who where not adopted away showed significantly greater depression than control subjects and their female siblings who had been adopted away. (14) An excess of biological mothers with substance abuse was found among adoptees with depression (15) and more alcoholism was observed in the biological relatives of depressed adoptees than in the biological relatives of non-depressed adoptees. (16) These results confirm the significant role of gene–environment interactions in depression spectrum disease and further validate the concept.

Twin studies

The diagnostic validation and the structure of the genetic and environmental risk factors in mood disorders is also approached in twin studies. Using a prospective, epidemiologic, and genetically informative sample of adult female twins, Kendler et al. (17) have been able to identify and validate a typology of depressive syndromes characterized by mild typical depression, atypical depression (increased eating, hypersomnia, frequent, relatively short episodes, and a proclivity to obesity), and severe typical depression (comorbid anxiety and panic, long episodes, impairment, and help seeking). The members of twin pairs concordant for depression had the same depressive syndrome more often than expected by chance and this resemblance was greater in monozygotic than in dizygotic pairs. In order to clarify the interactions between genetic factors and stressful life events in the aetiology of depression, a population-based sample of female–female twin pairs including 2164 individuals where analysed in regard to stressful life events and onset of major depressive episodes in the past year. (18) For severe stressful events, the best-fitting model for the joint effect of stressful events and genetic liability on onset of major depression suggested genetic control of sensitivity to the depression-inducing effects of stressful life events. The authors concluded that genetic factors influence the risk of onset of major depression in part by altering the sensitivity of individuals to the depression-inducing effect of stressful life events.

In a more complex analysis of comorbidity among different psychiatric disorders, a large epidemiological survey of 1030 female–female twin pairs (19) investigated the influence of major genetic and environmental risk factors (separated in different domains: genes, family environment, and individual-specific environment) on comorbidity between different psychiatric disorders (phobia, generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism). Each major risk factor domain influenced comorbidity, but in a distinct manner according the disorders investigated and most of the genetic factors that influence vulnerability to alcoholism in women do not alter the risk for development of other common psychiatric disorders.

Family studies

Segregation analysis is used to determine the mode of genetic transmission of a disorder by describing the distribution of phenotypes in affected families. The two principal hypotheses which have emerged from these complex analyses in affective disorders are the single major locus model andthe polygenic model involving possible interaction between two or more loci. The exact mode of inheritance is not yet clear. (20) The situation is further complicated by the possible presence of anticipation in families with mood disorder. (1,2and 3) This mode of transmission, which involves dynamic mutations, fits better with the twin and family epidemiological data available in affective disorders and may explain their non-Mendelian pattern of inheritance.

Molecular genetics in affective disorders

The rapid advance in molecular genetic techniques over the last decade has generated a large database of DNA markers across the whole human genome and has enabled chromosomal regions throughout almost the entire genome to be studied in affective disorders. These studies have been performed mainly using linkage and association methodologies. Several markers and chromosomal regions are potentially interesting. Current linkage and association methods investigate heritable factors at a molecular genetic level, and enable genes to be mapped. (21) These approaches are mostly applied to bipolar affective disorder, which is considered to be the ‘core' phenotype in affective disorders. Linkage analysis tests the hypothesis that a linkage relationship exists between a known genetic marker and a trait which is known to be genetically determined but has not yet been mapped on a chromosome. (22) Two genetic loci are linked if they are located closely together on a chromosome. In linkage analysis, the distance between a marker locus and the gene under investigation is used for gene mapping. This method was originally designed to explore a major single genetic transmission and to evaluate the extent of co-segregation between genetic markers and the phenotype investigated in pedigrees. The major problems which linkage methodology faces when applied to affective disorders are the complex aetiology and inheritance patterns. More than one locus is probably involved in susceptibility to these disorders, and the exact mode of transmission is not known. Mis-specification of the genetic parameters of the phenotype may lead to errors in linkage studies. (22) Furthermore, the linkage approach fails to detect minor gene effects which contribute to genetic susceptibility to the disorder. (23)

The association method offers an alternative strategy of studying genetic factors involved in complex diseases in which the mode of transmission is not known. (24) The association strategy does not require genetic parameters to be known (non-parametric method). The purpose of association studies is to compare frequencies of genetic marker alleles in patient and control populations in order to detect linkage disequilibrium. Linkage disequilibrium between the disease locus and the marker tested is defined as a level of concordance between the two loci which is higher than would be expected by chance. The major reason for this is their proximity on a chromosome. The major advantage of association studies is that they can detect genes with minor effects other than a single major locus.

The major limitation of this approach is that spurious associations between a genetic marker and a disorder may result from variations in allele frequency between cases and controls observed if the two populations are ethnically different (population stratification). It is important in this case to compare populations which are homogenous in their ethnic background. The haplotype relative risk strategy uses parental data for the control sample and reduces this type of bias. Non-transmitted alleles are selected from parents of the probands for the control population. (25) A further major difficulty in association studies is the interpretation of the precise meaning of the association observed. (26) The result may be interpreted as linkage disequilibrium between the disease locus and the associated marker allele(s). Alternatively, the associated marker may be interpreted as a susceptibility factor which is directly involved in the disease. The candidate gene approach in association studies is a useful method to investigate linkage between markers and diseases. A candidate gene refers to a region of the chromosome which is potentially implicated in the aetiology of the disorder concerned. The possibility of false-positive results must be taken into account, asa very large number of candidate genes now exist. The probability that each of these genes is involved in the aetiology of the disorder is relatively low.

Chromosome 18

Prominent findings with markers in the pericentromeric region of chromosome 18 have been recently published. Berrettini et al. (27) first reported linkage of bipolar affective disorder to chromosome 18 DNA markers in a systematic genome survey including 22 families. These authors' results suggest that a susceptibility gene is present in the pericentromeric region of this chromosome. Results of linkage analysis in individual families indicated possible linkage with some marker loci in this region (18p11). This result is of considerable interest, both because of its significance and also because it is at this location that one finds genes coding for the a unit of a guanosine triphosphate binding protein involved in neurotransmission and the corticotrophin receptor gene. Stine et al. (28) studied 28 nuclear families for markers on chromosome 18 and also found evidence for linkage with bipolar affective disorder. This study also demonstrated evidence of a parent-of-origin effect operating in bipolar affective disorder (an excess of paternally but not maternally transmitted alleles). Gershon et al., (29) on the other hand, observed linkage with chromosome 18 markers in affected sib-pair analysis only in pedigrees with mixed paternal–maternal transmission. Linkage was not found in pedigrees with exclusively maternal transmission. Chromosome 18 markers have been investigated in two large Belgian pedigrees with bipolar affective disorder. (30) Negative lod scores were found for a marker located in the pericentromeric region. Linkage and segregation analysis in one family suggested that a different region of chromosome 18 (18q21.33–q23) may contain a susceptibility locus for bipolar affective disorder. Freimer et al. (31) used both linkage and association strategies and also reported evidence of linkage with markers in this region (18q23). Despite slight allele sharing with two markers on chromosome 18 (D18S40 on 18p and D18S70 on 18q) in the National Institute of Mental Health genetics initiative bipolar affective disorder pedigrees, (32) these results were not confirmed in this large genome scan. A negative lod score was found for D18S40 in the study of De Bruyn et al. (30) on 18p markers, indicating exclusion of this region.

Chromosome 11

This region of the genome has been thoroughly investigated in affective disorders because of the presence of genes including those coding for tyrosine hydroxylase (11p15), tyrosinase (11q14–21), dopamine receptor D 2(11q22–23), dopamine receptor D 4 (11p15.5) and tryptophan hydroxylase (11p15). These proteins play an important role in catecholamine neurotransmission and their genes are considered to be candidate genes in bipolar and unipolar affective disorders. Overall results of linkage studies with tyrosine hydroxylase indicate that the tyrosine hydroxylase gene does not contribute a major gene effect to bipolar affective disorder. (33) Some studies, however, failed to exclude linkage with this gene and suggested that tyrosine hydroxylase should be further investigated using other methods such as allelic association. There are no linkage data for the tyrosine hydroxylase gene in pure unipolar affective disorder families. A possible role for the tyrosine hydroxylase gene was also examined in bipolar affective disorder association studies, all on moderate to small sample sizes. (34) Meta-analysis of the results do not support the tyrosine hydroxylase gene having a major role in the aetiology of bipolar affective disorder, while data suggest that this candidate gene should be examined in larger samples of unipolar affective disorder for which this marker may confer susceptibility to the disease. (34)

Chromosomes 4, 5, 12, and 21

Among the other autosomal DNA markers of interest are findings for chromosome 4, 5, 12, and 21 markers. Blackwood et al. (35) reported linkage between a locus on chromosome 4p (D4S394, 4p16) and bipolar affective disorder in a large family. Dopamine D5 receptor gene and the a2C -adrenergic receptor gene are located in the same region. Major candidate genes for the affective disorders are located on chromosome 5. Preliminary linkage data including three DNA markers on this chromosome (D5S39, D5S43, and D5S62) suggested linkage with bipolar affective disorder. (36) Two of these markers (D5S62 and D5S43) are located in the distal region of the long arm of chromosome 5 (5q35–q ter) and contain candidate genes contributing to the neurotransmitter receptors for dopamine, noradrenaline (norepinephrine), glutamate, and g-aminobutyric acid. These two markers, however, had exclusion lod scores in a previous study of 14 families. (37) Dopamine transporter gene (DAT1) is located in a different region of chromosome 5 (5p15). This marker has been investigated in an association study with bipolar affective disorder yet no association was found. (38) Kelsoe et al. (39) recently reported a possible linkage between a locus near the dopamine transporter (DAT) locus on chromosome 5 and bipolar affective disorder.

The Darier's disease region on chromosome 12q23–q24.1 has been investigated in several family studies in bipolar affective disorder, suggesting a possible linkage. (40,41,42and 43) Two of these studies have been able to report significant lod scores greater than 3. (42,43) To further test the hypothesis that genes containing expanded trinucleotide repeats may contribute to the genetic aetiology of bipolar affective disorder, loci within this region containing CAG/CTG repeat expansions have also been investigated, but no association was found with bipolar affective disorder. (44)

Straub et al. (45) detected linkage with the 21q22.3 locus on chromosome 21 in one bipolar family. Overall, however, the 47 families assessed for this genome do not support linkage with this marker.

X chromosome

Mendlewicz et al. (46) first reported possible genetic linkage between manic–depressive disorder and coagulation Factor IX (F9) at Xq27 in 11 pedigrees. Linkage with DNA markers on the X chromosome has been excluded, however, in other pedigrees. (33) More recently, Pekkarinen et al. (47) evaluated 27 polymorphic markers on the X chromosome (Xq25–28 region) in one large Finnish family. Linkage was found between a marker located on Xq26 (AFM205wd2) and bipolar affective disorder. This marker is located about 7 cM centrimeric to the F9 locus. These results are extremely suggestive of X linkage and confirm the need for further investigation of this region with other markers.

Serotonin markers and affective disorders

Dysfunction of the serotoninergic system has long been suspected in major depression and related disorders. Depression can successfully be treated with selective drugs which target serotonin receptors. The serotonin transporter may also be involved in susceptibility to affective disorders and in the response to treatment with these drugs. Allelic association has been suggested between the serotonin transporter gene (located on chromosome 17q11.1–12) and unipolar affective disorder. (48) The presence of one allele of this gene was significantly associated with a risk of unipolar affective disorder. This study also included a group of bipolar affective disorder patients, although no associations were found with this marker in this patient group compared to normal controls. This preliminary finding may add to our understanding of the possibility of polygenic inheritance in affective disorders. These findings were replicated in two different samples, again showing an association between this marker and unipolar affective disorder (major depression with melancholia) (49) and no association with a group of bipolar affective disorder patients. (50) A linkage study with the functional variant of the serotonin transporter gene in families with bipolar affective disorder could not exclude linkage. (51) More interestingly, a polymorphism within the promoter region of the serotonin transporter gene has been associated to treatment response to fluvoxamine, a typical selective serotonin reuptake inhibitor in major depression with psychotic features. (52) This promising preliminary finding requires to be confirmed. The tryptophan hydroxylase gene, which codes for the rate-limiting enzyme of serotonin metabolism, is also an important candidate gene for affective disorders and suicidal behaviour. Bellivier et al. (53) reported a significant association between genotypes at this marker and bipolar affective disorder; no association was found with suicidal behaviour. In a previous study in depressed patients, suicidal behaviour was associated with one variant of this gene. (54)

Anticipation and expanded trinucleotide repeat sequences

Anticipation implies that a disease occurs at a progressively earlier age of onset and with increased severity in successive generations. This may explain the non-Mendelian pattern of inheritance observed in some inherited diseases. This phenomenon has been observed in several neurological diseases including myotonic dystrophy, fragile X syndrome, Huntington's disease, and more recently in spinobulbar muscular atrophy, type 1 spinocerebellar ataxia, and spastic paraplegia. (55) Anticipation has been found to correlate with specific mutations in these syndromes: expanded trinucleotide repeat sequences. An expanded repeat sequence is unstable and may increase in size between family members, leading to increased disease severity of the disorder.

Anticipation has recently been described in bipolar affective disorder (1,2) and in unipolar affective disorder. (3) One recent study highlighted an association between cysteine–adenine–guanine (CAG) trinucleotide repeats and bipolar affective disorder in Swedish and Belgian patients. (56) CAG repeats have been detected by the repeat expansion detection method. This study, which was replicated in a different patient population, (57) demonstrated for the first time in a major psychiatric disorder that the mean length of CAG repeats was significantly higher in bipolar affective disorder patients compared to controls. More recently, an association between familial cases (but not sporadic cases) of bipolar affective disorder and CAG length has been observed. (58) This hypothesis has also been tested in a family sample of two-generation pairs with bipolar affective disorder. (59) A significant increase in CAG repeats between parents and offspring generations was observed, however, when the phenotype increased in severity, i.e. changed from major depression, single episode, or unipolar recurrent depression to bipolar affective disorder. A significant increase in CAG repeat length between generations was also found in female offspring with maternal inheritance, but not in male offspring. This is the first evidence of genetic anticipation in bipolar affective disorder families and should be followed by the identification of loci within the genome containing triplet repeats. CTG 18.1 on chromosome 18q21.1 and ERDA 1 on chromosome 17q21.3 are two repeat loci recently identified (60) which can be investigated in such study.

Psychosocial factors in affective disorders

Impairment in social relationships, dysfunctional cognition, gender, economic status, and temperament have been suggested as involved in the emergence of mood disorders. However, empirical studies on psychosocial factors of patients with affective disorders examine psychosocial features assessed after recovery from and/or at the time of episodes of affective disorder. These retrospective studies might not be able to distinguish between premorbid psychosocial patterns and those which result from previous episodes of illness. Further, longitudinal studies focusing on the role of psychosociological factors have involved predictions of recurrence or exacerbation of symptomatology in previously affected people, but not regarding the onset of the diseases. Thus, the demonstration of temporal antecedence to the initial onset of affective disorder is extremely difficult. (61) Thus, the conclusions in terms of aetiological psychosocial factor are limited.

Impairment in social and familial relationships

Difficulties in social functioning are concomitant to depressive disorders. (6,7,62) Previous research found that patients experienced a reduction of social relationships, with feeling of social discomfort, loneliness, and boredom. (6) Depressed patients seem lower in social self-confidence, they socialize less, and participate in social interaction less fully than do never-depressed persons. (62) In other words, depressed individuals do not make active effort to develop and sustain reciprocally supportive social relationships. The concept of social support has been widely used to predict general health and more specifically psychiatric symptoms. (63) Previous research revealed that the degree of integration in a social network, or structural support, have a direct positive effect on well being, reducing negative outcomes in both high- and low-stress life events. Among depressed individuals, dysfunctioning in social activities has been found to persist a long time after remission from the depressive episode. (6,64) The social dysfunctioning concerns more specifically marital, parental, and familial relationships.

The relationship between marital disturbance and affective disorder has received increased attention over the two past decades. First, descriptive studies have suggested that marital conflict correlates highly with concomitant depression, (65) and marital therapy has been found to be effective in reducing the symptoms of depression, alone (66) as well as in combination with pharmacotherapy. (67) Further, previous research found dysfunctional patterns of communication in couples with a depressed spouse. Specifically, compared with their non-depressed counterparts, depressed couples have been found to exhibit more friction, lack of affection, lower levels of constructive problem solving, mutual self-disclosure, and reciprocal support. (7,68,69) The lack of a confiding and intimate relationships leaves individuals vulnerable to depression. (7,70,71) Finally, marital distress may also exacerbate difficulties experienced in extramarital relationships, (72) thereby increasing introverted behaviour and social isolation. In a similar manner, the absence of a marital partner may hasten the onset of depression among vulnerable individuals. (73)

Parental relationshipsalso seem to have a great impact in the course of affective disorders. A variety of authors have emphasized the importance of the quality of early experiences with parents in the development of adult depression. Beck (74) explicitly attributed the development of negative cognition and negative schemata of self to critical disapproving parents, and later Blatt and collaborators (75) suggested that the vulnerability to depression arises from impairment in relationships with parents. In general, depressive individuals described both mother and father as lacking warmth and a caring attitude, and being overly controlling, which involves intrusiveness, overprotection, and control through guilt. (76,77) For example, Andrews and Brown (78) found that women who became depressed following occurrence of major life events were more likely to report lack of adequate parental care or hostility from their mothers than those who did not become depressed. In summary, perceived lack of parental warmth, acceptance, and affection has consistently been associated with depression, however the evidence for a relationship between parental negative control and affective disorders is less clear. Specifically, some investigators have found that depressed people perceive their mothers to have been overly protective and intrusive, and both parents to have used guilt and anxiety-provoking strategies to exercise control over them; however, contrary findings have also been reported. (79,80)

Studies on parental representation are generally retrospective, i.e. the parental representation of depressed patients is compared to those of non-depressed controls. Consequently, the depressed subjects' negative view of parents may be distortions due to the affective disorder rather than accurate recollections. Gotlib et al. (81) found that the perceptions of maternal caring and overprotectiveness experiences by moderately depressed individuals do not shift with remission of their depressed mood, and may be considered as stable perceptions. Thus, this study supports the notion that depressed adults had more negative relationships with their parents than have non-depressed persons.

In addition to marital and parental relationships, the quality of the familial relationships, in general, has been shown to have a significant impact on mental health. (82,83) When the quality of the family relationships is evaluated, studies have consistently found that when family members are critical, unsupportive, or generally display negative attitudes towards the depressed member, these behaviours lead to less likelihood of recovery or greater likelihood of a relapse of depression for the depressed family member. (84,85 and 86)

In summary, the quality of social and familial relationships appear to set the stage of depression. Social maladjustment at recovery may represent a risk factor that predisposes to further recurrent episodes. Individuals who experienced negative parental and familial relationships may be vulnerable to depression, and children exposed to such experiences may become depressed. (87, 88) Most of the research to date is correlational, and cannot establish a causal link between negative relationships and the onset of affective disorders. Nevertheless, the associations are robust and well replicated, suggesting that disruption of social relationships may be a critical vulnerability factor for affective disorder.

Dysfunctional cognition

According to the helplessness model of depression, (89) vulnerability to depression derives from a habitual style of explaining the causes of life events, known as attributional style. A large body of research found that individuals suffering from depression think more negatively than healthy individuals. Specifically, depressed patients have a tendency to make internal, stable, and global causal attributions for negative events, and to a lesser extent, the attribution of positive outcomes to external, specific, and unstable causes. In other words, depressed patients have a low self-esteem. (90, 91) Thus, when thinking about the self, past, current, and future circumstances, depressed patients emphasize the negative, and this process is likely to contribute to the perpetuation of their depressed mood. However, the role of self-esteem in depression has not yet been well established. A controversy persists as to whether low self-esteem is a consequence of depression or a vulnerability factor of the disease. Lewinsohn et al. (92) assume that low self-esteem neither precedes nor follows depressive episode. Several studies have yielded no evidence of risk of depression associated with pre-depressive cognitions. (93, 94) To the contrary, Beck (74) has emphasized the aetiological significance of low self-esteem in depression. According to Beck, the low self-esteem should increase vulnerability to depression by existing in a latent state, to be activated by relatively minor experiences of deprivation or rejection. Brown and collaborators (95,96 and 97) have developed a psychosocial model of depression, similar to the Beck's model, in which the importance of the occurrence of both a negative life events and low self-esteem is highlighted. A number of prospective studies using college student samples support the predictive effect of negative attributions on the later development of depression following negative life events. (98) However, Haaga et al. (99) has reviewed five studies, and none of them indicate that negative cognitions added significantly to the prediction of later symptoms. More recently, Staner et al. (100) failed to support the predictive effects of self-esteem on later recurrence of depression in bipolar and unipolar patients. In summary, evidence supports the notion that depressed individuals have lower self-esteem, but less evidence is in favour of a causal role of negative thinking in the development of the disease.


Evidence for gender differences in responses to depression comes from a large number of studies. Women are consistently reported to have greater prevalence of affective disorders than men. (101,102,103,104and 105) The reasons for this gender difference are unclear, and are as likely to be social as biological.

Divergences in the number and quality of social and occupational roles have been proposed to explain the greater prevalence of affective disorders among women. (102) In the context of marital relationship, previous research has indicated that, for men, marriage confers a protection against illness, while it appears to be associated with higher rates of depression for women. (106) There has been some evidence that within the marriage the traditional female role is limiting, restricting, and even boring, which may lead to depression. (107,108) For example, the role of child caretaker has consistently been shown to be associated with both high levels of stress and a higher incidence of depression for women. (109) Women are found to have more depressive symptoms when they have young children in the home, and this tends to increase in an almost linear fashion according to the number of children in the household. (110) Further, since women who are employed outside the home also tend to be responsible for household chores, (111) the notion that differentiation in occupational roles partially explains the prevalence of depression for women is supported. Bracke (102) found validity of social role explanations by showing that the gender differences in depression chronicity can partially be explained by differences in employment status, marital status, and educational attainment. However, Weich et al. (105) refute the version of the occupational roles hypothesis, namely that women have a higher prevalence of common mental disorders by virtue of their tendency to be over- or underoccupied compared with men. Specifically, they did not find gender differences in the prevalence of common mental disorders when men and women are adjusted regarding the number or type of roles occupied. In other words, neither the number of social roles, occupancy of traditional ‘female' caring and domestic roles, nor socio-economic status explained the gender differences, in their study. In summary, the impact of social and occupational roles as explanation of gender differences in affective disorders is not yet obvious.

Further, to explain why women are more likely than men to manifest depression Nolen-Hoeksema has proposed the ‘response style theory'. (104,112) According to this theory, women are more likely than men to have a ruminative response style, which contributes to the perpetuation of their depressed mood. (113,114 and 115) Ruminative responses to depression refer to ‘behaviours and thoughts that focus one's attention on one's depressive symptoms and on the implications of these symptoms'. Nolen-Hoeksema argued that, when depressed, women are more likely to engage in these ruminative responses, thereby amplifying their depressive symptoms and extending the depressive episode. On the other hand, men are more likely to distract themselves from depressed mood, thereby dampening their symptoms.

Finally, there is some evidence to suggest that the post-partum and the premenstrual periods, with their associated biological and psychological changes, represent periods of increased risk of depression among women. However, the extent of the risk imparted by endocrine factors has not yet been determined. (116)

In summary, at similar levels of stress women are probably more vulnerable to affective disorders than men. One explanation of this finding is that women may be more willing than men to admit symptoms and/or men may express their symptoms in different ways through alcohol abuse or ‘acting out', for example.

Socio-economic status

Many studies have reported that low socio-economic status is associated with high prevalence of mood disorders. (117) For a long time in social psychiatry, ‘social causation' and ‘social selection' hypotheses have been accepted explanations of the role of the low socio-economic status in affective disorder. The causation hypothesis suggests that the stress associated with low social position, i.e. exposure to adversity and lack of resource to cope with difficulty, may contribute to the development of the affective disorder, (118, 119) while the social selection hypothesis argues that genetically predisposed persons drift down to or fail to rise out of such positions. (120, 121)Thus, the social selection hypothesis emphasizes the genetic interpretation of cause, while social causation hypothesis focuses on the aetiological role of the environment. Few longitudinal data sets are available to test the causal hypothesis. Nevertheless, there is evidence that disadvantaged socio-economic status, poverty, or education and occupation can be considered as risk factors for mood disorders. (122, 123) Bruce and Hoff (124) found that the effect of poverty is substantially reduced when controlling for degree of isolation from friends and family, suggesting that social isolation mediates some of the relationships between economic status and mood disorders.

In summary, a positive relationship has been found between socio-economic status and vulnerability for affective disorders, with higher rates of vulnerability found among individuals with lower educational and social achievement levels.

Temperament and behaviour

Temperament has been defined in terms of differences in the adaptative systems, i.e. differences in reactivity and self-regulation within the social context. (125,126and 127) According to Derryberry and Rothbart, (126,127) self-regulation refers to the relatively enduring biological make-up of the individual, influenced over time by heredity, maturation, and experience. Reactivity is defined as the functional state of somatic, endocrine, autonomic, and central nervoussystems reflecting the response parameters of threshold, latency, intensity, rise time, and recovery time. Self-regulation is a higher-level process functioning to modulate (enhance or inhibit) the reactive state of these systems. Self-regulation was approached in terms of emotion or affective–motivational processes. Indeed, the construct of temperament has traditionally focused upon individual differences in emotionality. When viewed as regulatory, however, affective–motivational processes can be seen to extend beyond the traditional response-oriented domain of emotion, influencing a variety of perceptual and cognitive processes. For example, an emotion such as sadness regulates somatic, autonomic, and endocrine response systems, while at the same time modulating sensory channels converging upon these response system. Thus, the regulatory system of temperament plays a high-level role in co-ordinating attention and response to social context and influences nearly every aspect of experience and behaviour. Many authors (127,128 and 129) postulate, to some degree, a stable association between biogenetic dispositions to specific mood and observable temperament traits. Affective disorders are likely to emanate from specific temperament which increases vulnerability to mood disturbances. The relevant literature is vast, and we necessarily limit our coverage to the more influential models.

The model of temperament developed by Eysenck (128) approaches temperament in terms of cortical arousal. Eysenck suggested that individuals differ in their basic arousability and therefore in their optimal level of stimulation. These physiological differences give rise to the primary personality dimension of introversion–extraversion. Introverts are said to possess relatively reactive reticular systems, and thus to attain their optimal level of cortical arousal at relatively low level of stimulation. As a result of their low optimal arousal level, introverts are expected to prefer and seek out mild formsof stimulation and to avoid more intense and novel form of stimulation. In contrast, extraverts are said to possess relatively unreactive reticular systems, to have correspondingly high optimal levels of cortical arousal, and to therefore approach more intense and novel forms of stimulation. While this central form of arousal is seen to influence the affective quality of experience, Eysenck (128) proposed a complementary form of limbic activation influences the intensity of behaviour. Variability in the functioning of the limbic activation system underlies a personality dimension referred to as ‘neuroticism–stability'. Individuals with reactive limbic systems (i.e.neurotics) are said to be prone to intense autonomic discharges, while those with less reactive limbic systems (i.e. non-neurotics) are thought to demonstrate autonomic lability. On the basis of their reticular and limbic reactivity, individuals are classified into four basic types: neurotic extravert, stable extravert, neurotic introvert, and stable introvert. In general, neuroticism correlates positively with depressive symptoms while extraversion is inversely related to depression. (129,130) Neuroticism has been shown to be mood dependent, (131) decreasing as depressive symptoms abate. Given the high correlation between neuroticism and anxiety, (132) the decrease in neuroticism may simply reflect the amelioration of anxiety symtoms associated with depressive illness. Although there is some evidence that remitted patients remain abnormally neurotic following recovery from depression, this finding is not consistent across studies, and additional research is required. (133,134 and 135) The evidence linking the extraversion–introversion personality dimension with previous dimensions is more consistent. In general it has been found that extraversion scores are not significantly affected by recovery from depression (136) and depressives remain less extraverted than never-depressed people. (137)

The differences between Cloninger's model and other models are that Cloninger assumes relationships between biogenic amine neurotransmitters (noradrenaline, serotonin, and dopamine) and personality dimensions. Specifically, Cloninger defined temperament dimensions in terms of individuals differences in associative learning in response to novelty, danger, or punishment, and reward. Further, he hypothesized a positive correlation between serotoninergic activity and harm avoidance, dopaminergic activity and novelty seeking, and finally between noradrenergic activity and reward dependence. According to this author, these aspects of personality denote traits that are usually considered temperament factors because they are heritable, manifest early in life, and apparently involved in learning. The possible tridimensional combinations of extreme (high or low) variants on these basic stimulus–response characteristics correspond closely to the traditional descriptions of personality disorders. The specific relationship between temperament and mood disorder is not yet understood satisfactorily. Few studies have been done regarding the Tridimensional Personality Questionnaire scores in relation to mood disorder, the data available suggest that depressed patients have elevated harm avoidance scores. (138,139,140and 141)

The study of the aetiological role of temperament in mood disorder requires longitudinal research beginning with subjects who have not yet developed the disease. To our knowledge, such issues have not yet been investigated.

The gene–environment hypothesis

Gene–environment interactions

The current relevant data on gene–environment interactions are derived from twin and adoption studies, both providing powerful tools to predict the different ways genetic and environment factors interact. Tree models are commonly used to describe the possible gene–environment relationships. (142) The classical additive models infer that individuals inherit the susceptibility genes for the disease from their parents and that environmental experiences act as an additive effect to cause the disease. In this model, the probability of being exposed to the environmental risk factor is unrelated to the genetic inheritance. In other models, the relationship between genetic factors and environmental factors is more interactive. The ‘genetic control of exposure to the environment' refers to possible role of genes conferring a vulnerability to the pathogenic effect of the environment. Genetic factors influence the risk of onset of major depression inpart by altering the sensitivity of individuals to the depression-inducing effect of environmental factors. The ‘genetic control of exposure to the environment' assumes that genetic factors influence the exposure to the pathogenic environmental factor. Many environmental factors can be considered within these models but very few have been included in twin and adoption studies.

The availability of molecular genetic findings in affective disorders offers new directions in this research field. It is now possible to consider the gene–environment hypotheses using DNA markers as the genetic liability variable. However, it remains difficult to test these hypotheses using classical linkage and association methods.

Molecular genetics and personality traits

Molecular genetics has recently been incorporated into genetic epidemiological research on behavioural traits. Some recent findings in this field may be relevant considering the genetic aspects of psychiatric disorders, particularly affective disorders. The possible role of candidate genes has been investigated in personality traits, in particular dopamine receptor D 4 in novelty-seeking and serotonin transporter in anxiety.

The results of these studies are very interesting since different personality questionnaires and ethnically distinct populations were used. The exact nature of the relationship between behavioural traits and mental disorders has never been investigated using the combined genetic (DNA) determinants. Hence, personality dimensions and their genetic determinants should be considered in future research on genetic aspects of psychiatric disorders in integrative models of gene–environment interactions.


The complexity of affective disorders is a major limitation when their genetic bases are being studied. This could be attributed to their non-Mendelian mode of inheritance. Bipolar affective disorder and unipolar affective disorder are, in fact, phenotypes which do not appear to exhibit classic Mendelian recessive or dominant inheritance involving a single major locus. The presence of both environmental as well as genetic factors and phenotypic heterogeneity also represents important problems when dealing with these disorders. Genetic studies in affective disorder represent a powerful tool for investigating non-genetic factors involved in the aetiology of bipolar affective disorder and unipolar affective disorder. If one or more genes contribute to susceptibility to these common diseases it is reasonable to assume that these will be identified in the near future. Several consistent hypotheses are currently being tested and will, hopefully, lead to major advances. Potential genetic markers have been localized; some of these are directly linked to neurobiological hypotheses of the aetiology of affective disorders. A number of these chromosomal regions actually contain candidate genes for bipolar affective disorder and unipolar affective disorder. Specific mutations and modes of inheritance (trinucleotide repeats and anticipation) have also been implicated in recent studies. Future genetic studies will need to either confirm or refute these findings but should also investigate environmental factors which may be important in affective disorders.


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