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Neuroscience and Biobehavioral Reviews 49 (2015) 171–181

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

jou rn al h om epage: www.elsev ier .com/ locate /neubiorev

eview

iological determinants of depression following bereavement

melia A. Assareha,∗, Christopher F. Sharpleya,b, James R. McFarlanea,erminder S. Sachdevc

Collaborative Research Network for Mental Health and Well-being, University of New England, Armidale, AustraliaBrain-Behaviour Research Group, University of New England, Armidale, AustraliaCentre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia

r t i c l e i n f o

rticle history:eceived 10 July 2014eceived in revised form3 November 2014ccepted 7 December 2014vailable online 22 December 2014

eywords:ereavementrieftressful event

a b s t r a c t

There is considerable variability among people in their response to bereavement. While most peopleadapt well to bereavement, some develop exaggerated and/or pathological responses and may meetcriteria for a major depressive episode. Many studies have investigated the effect of psychosocial factorson bereavement outcome but biological factors have not received much attention, hence the focus ofthis paper. The biological factors studied to date in relation to bereavement outcomes include geneticpolymorphisms, neuroendocrine factors, and immunologic/inflammatory markers. In addition, animalstudies have shown the alterations of brain neurotransmitters as well as changes in the plasma levels ofthe neurotrophic growth factors under the influence of peer loss. Recent studies have also investigated thebiological basis of stress resilience, and have found a few genetic polymorphisms and potential biomark-ers as protective factors in the face of adversity. Longitudinal studies that include data collection prior

epressioneneticeuroendocrine immunologic

nflammatoryeurotransmitterseurotropic

to, and also after, bereavement and which chart both biological and psychological measures are neededto develop profiles for the prediction of response to bereavement and personalised interventions.

© 2014 Elsevier Ltd. All rights reserved.

esilience

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1722. Determinants of depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1723. Grief as a normal response to bereavement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1724. How is grief different from depression? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1735. Pathological and complicated grief . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1736. Longitudinal studies of grief . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1737. What determines whether a grief response becomes pathological? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1738. Biological determinants of a response to bereavement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

8.1. Genetic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1748.2. Interaction of genetics with environmental factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1748.3. Epigenetic regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1758.4. Neuroendocrine factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1758.5. Immunologic/inflammatory factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

8.6. Brain neurotransmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8.7. Neurotrophic growth factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8.8. The biology of resilience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Present address: Centre for Healthy Brain Ageing, Euroa Centrax: +61 2 9382 3774.

E-mail address: a.assareh@unsw.edu.au (A.A. Assareh).

ttp://dx.doi.org/10.1016/j.neubiorev.2014.12.013149-7634/© 2014 Elsevier Ltd. All rights reserved.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

e, Prince of Wales Hospital, Barker St., NSW 2031, Australia. Tel.: +61 2 9385 3840;

172 A.A. Assareh et al. / Neuroscience and Biobehavioral Reviews 49 (2015) 171–181

9. Biological model of depression following bereavement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17710. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17711. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

Depression is a major global public health issue due to a rela-ively high lifetime prevalence of up to 15% (Ustun and Chatterji,001). As a result of substantial comorbidity with chronic med-

cal diseases (Molteni et al., 2001, Moussavi et al., 2007) andssociation with high mortality (Mykletun et al., 2009), depres-ion has been considered as an important contributor to theotal disease burden (Üstün et al., 2004) and has been estimatedo be the second most common contributor to years lived withisability (Vos et al., 2013). Specific external causes have beeneported to promote the occurrence of depression, especiallyhose associated with loss (Ferster, 1973). Loss can take manyorms which include bereavement, romantic betrayal and rejec-ion, unexpected job loss, financial ruin, loss of possessions, naturalisasters, or negative medical diagnosis in oneself or a loved oneWakefield and First, 2012). However, it has been shown thatnterpersonal loss including bereavement, separations, endings orhreats of separation, has the most profound influence (Paykel,003). Bereavement usually has a profound effect and therefore

s understandable as one of the most prominent and consistentisk factors for depression (Cole and Dendukuri, 2003). Bereave-ent also leads to a grief reaction which may be regarded as a

ormative process. This raises some important questions: whenoes grief become pathological and should this be diagnosed asepression? Are there particular psychological and social factorshat predict depression in someone who is bereaved? Are thereiological factors that predispose a bereaved person to becomeepressed?

In this review, we address some of these questions and docu-ent the current state of knowledge on the biological determinants

f depression after bereavement. In particular, we attempt to showow the application of molecular biology and genetic techniques

s promoting the identification of biomarkers of major depressiveisorder (MDD) following bereavement. Finally, new strategies foruture research are proposed.

. Determinants of depression

Several factors have been identified as determinants of depres-ion. A review by Riso et al. (2002) classified the factors underlyinghronic depression into six putative categories: (1) develop-ental factors such as childhood adversity (early trauma oraltreatment), (2) personality and personality disorders like neu-

oticism and stress reactivity, (3) psychosocial stressors (lifevents), (4) comorbid disorders including anxiety and substancebuse, (5) biological factors such as dysregulation of the neu-oendocrine and/or immune systems, and (6) cognitive factorse.g. self-criticism). In studies of chronic depression, the strongestvidence of aetiology has been found for developmental factors,ith some support for environmental stressors and heightened

tress reactivity (Riso et al., 2002). The vast majority of researchn the association between stress and depression supports atrong relationship between stressful life events and depres-

ion (Kessler, 1997; Kendler et al., 1999; Pittenger and Duman,008), specifically the unique significance of depression follow-

ng a “loss” (Zisook and Shuchter, 1991; Biondi and Picardi,996).

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

3. Grief as a normal response to bereavement

“Grief” is a normal reaction to a major loss of any kind butwill be discussed herein in relation to the particular loss incurreddue to bereavement. Bereavement grief is multidimensional, withphysical, behavioural and meaning/spiritual components and ischaracterised by a complex set of cognitive, emotional and socialadjustments that follow the death of a loved one (Lobb et al., 2010).Although individuals vary in the type, intensity and duration ofthe grief they experience (Christ et al., 2003), most grieving peo-ple show similar patterns of intense distress, anxiety, yearning andsadness which usually settle over time.

The grief symptoms related to bereavement bear a close resem-blance to the symptoms of Major Depressive Disorder (MDD)as defined by the Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition, Text Revision (DSM-IV-TR) (AmericanPsychiatric Association, 2000). It has been argued that bereavedindividuals who have these symptoms are not experiencing a mooddisorder but rather an intense normal sadness in response to los-ing their loved ones, which should not be pathologized. However,a clinician evaluating a bereaved person is at risk of both over-andunder-diagnosis of MDD, either pathologizing a normal conditionor neglecting to treat an impairing disorder (Shear et al., 2011). Toprevent over-diagnosis of MDD in such individuals, the DSM-IV-TRused the ‘bereavement exclusion’ criterion where a bereavement-related depressive syndrome had to be either of a longer durationthan two months instead of the standard requirement of two weeks,be paired with specific symptomatic manifestations, or be asso-ciated with marked functional impairment (American PsychiatricAssociation, 2000). Although many other types of loss, such as mar-ital dissolution and unexpected job loss, can also trigger intensesadness that may meet the criteria for diagnosis of MDD, the con-cern about pathologizing grief has been restricted to the loss of aloved one and all depressive episodes following other major stress-ors were classified as MDD by the DSM-IV, irrespective of whetherthe response to those losses was complicated or not (Wakefield andFirst, 2012). There is ample evidence that stress caused by bereave-ment, like other stressors, has a negative effect on psychiatric andphysical morbidity and increases the risk and severity of depres-sive syndromes (Clayton and Darvish, 1979; Zisook et al., 2012a).The authors of DSM-IV focused primarily on the problem of over-diagnosis, and therefore the revision of DSM-IV-TR leading to thepublication of DSM-5, resulted in the removal of “BereavementExclusion” clause in the diagnosis of Major Depressive Disorderand has been one of the most contentious changes from DSM-IVto DSM-5, This has led to a lively controversy by grief and bereave-ment experts (Prigerson et al., 1995; Shear and Shair, 2005; Zisooket al., 2012a; Parker, 2013), and even resulted in some sensationalor misleading reports in the lay media; including headlines such as,“Psychiatrists want to make normal grief a mental disorder!” and“DSM-5 medicalizes mourning.” (Pies, 2014) (Table 1).

The DSM5 Mood Disorders Work Group believed that, althoughbereavement should not be ‘medicalised’, neither should the seri-ous risks of under-recognised MDD be normalised, since theseinclude suicide and cognitive dysfunction. Recognising major

depression following a recent bereavement requires careful clinicaljudgement and does not necessarily warrant psychopharmocologi-cal anti-depressant treatment (Pies, 2014). In reflection of this atti-tude, the DSM-5 itself warns clinicians that they need to distinguish

A.A. Assareh et al. / Neuroscience and Biobe

Table 1Symptomology of major depressive disorder following bereavement compared tonormal grieving.

Complicated grieving (majordepressive disorder)

Uncomplicated or normal grieving

Mood and ideation are mainlynegative

Painful feelings come in waves,often mixed with positivememories of the deceased

The agony of loss is relativelypersistent

Painful feelings of loss tend tocome in bursts or waves

Feelings of worthlessness andself-loathing are present

Self-esteem is usually preserved

Suicidal ideas, Anxiety, guilt,psychomotor retardation, andsevere impairment offunctioning might be present

These symptoms are not usuallypresent

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efs. Corruble et al. (2012) and Zisook et al. (2012a,b).

etween grief and a major depressive episode (MDE) by consideringhat, within grief, “the predominant affect is feelings of emptinessnd loss, while in MDE it is persistent depressed mood and thenability to anticipate happiness or pleasure” (APA, 2013, p. 126).

. How is grief different from depression?

As mentioned above in the quote from the DSM-5, there arelear differences between grief and major depression. However,t also should be emphasised that some individuals cannot copeffectively with bereavement-related distress and studies showhat up to 42% of bereaved people become clinically depressedithin 1 month after their loss, decreasing to 16% by one yearost-loss (Zisook et al., 2012a). Perhaps not unexpected, many cli-icians are uncertain about when to make the diagnosis of MDD

n bereaved individuals (Zisook et al., 2010). Although grief andajor depressive episodes have many features in common (such

s intense sadness, insomnia, loss of appetite and withdrawalrom customary activities) they are different in many importantspects, as suggested by the comment in the DSM-5 mentionedbove.

Some specific features that suggest the presence of MDD inddition to grief are: (i) in MDD, mood and ideation are mainlynd persistently negative whereas in uncomplicated grief, painfuleelings come in waves, often mixed with positive memoriesf the deceased; the individual may retain his or her sense ofumour; (ii) MDD is accompanied by feelings of worthlessnessnd self-loathing but in grief self-esteem is usually preserved; andiii) patients with MDD experience suicidal ideas, psychomotoretardation and severe impairment of functioning but these areess likely in grief (Corruble et al., 2012; Zisook et al., 2012b).herefore, it is important to note that some recently bereavedndividuals are not simply grieving, but are experiencing a full-lown MDD, which should be considered when making clinicalvaluations.

. Pathological and complicated grief

From the above, it may be concluded that, based on DSM-V criteria, a response to bereavement warrants a diagnosis of

DD if certain symptoms are present that are not characteristicf normal grief. These symptoms are entirely depressive symp-oms (e.g. feelings of worthlessness, suicidal ideation, psychotic

ymptoms and psychomotor retardation) and not grief-relatedymptoms (e.g. preoccupation with thoughts of the deceased)Prigerson et al., 1995). The DSM-IV uses the term “complicatedereavement” for bereavement that triggers MDD. However, this

havioral Reviews 49 (2015) 171–181 173

term has recently become widely used to also denote a non-depressive mourning-related condition. This syndrome, termed“complicated grief” (CG) (also known as “prolonged grief disor-der”) occurs when integration of the loss due to death does notoccur in the bereaved individual (Shear and Shair, 2005). Thebereavement-related depression consists of symptoms such ashypochondriasis, apathy, insomnia, anxiety, suicidal ideation, guilt,and depressed mood, while CG consists of symptoms such as pre-occupation with thoughts of the deceased, crying, searching forthe deceased, and disbelief over his or her death (Prigerson et al.,1995; Tomita and Kitamura, 2002). It is estimated that between10% and 20% of bereaved people experience CG (Middleton et al.,1996) and, although CG may share some symptoms and/or coexistwith depressive and anxiety disorders (Simon et al., 2007), it con-stitutes a distinct cluster of symptoms that can be distinguishedfrom depression (Prigerson et al., 1995; Shear et al., 2013) andshould be recognised as a distinct type of pathological response tobereavement.

6. Longitudinal studies of grief

Longitudinal studies of bereaved cohorts have shown that,although most people move through the stages of bereavementwithout significant morbidity and mortality, many develop whatresembles a MDE, which is present in approximately 42% ofbereaved people within a month of the death, decreasing consider-ably to nearly 25% at two months, and 16% at one year (Clayton andDarvish, 1979; Zisook and Shuchter, 1991). The rate of depressionamong the bereaved is reported to be 7% by two years post-loss,which is no longer different from the rate of depression in thewider community (Parkes and Brown, 1972; Zisook et al., 1994b).Bereavement studies that have been conducted prospectively frombefore to after the loss have also shown that the bereaved arecharacterised by emotional stability rather than exhibiting extremeaffective reactions (Galatzer-Levy and Bonanno, 2012). Two longi-tudinal studies reported that most bereaved individuals showedmoderate disruptions in daily functioning during the first yearafter loss, which constituted a normal grief reaction, while morechronic symptoms were evidenced by a relatively small minority(Middleton et al., 1996; Bonanno and Kaltman, 2001). Based onthese findings, it has been argued that humans are more resilientin the face of loss than had been previously believed (Bonannoet al., 2001). In 2002, these authors revisited the data using a moresophisticated analytic technique (i.e. latent growth modelling) toaddress the methodological shortcomings of previous approaches(Galatzer-Levy and Bonanno, 2012). That study revealed four dis-tinct and clinically meaningful trajectories similar in shape andproportion to the previous analyses: Resilience (characterised bylittle or no depression; 66.3%), Chronic Grief (characterised bydepression following loss, alleviated by 4 years post-loss; 9.1%),Pre-existing Chronic Depression (ongoing high pre- through post-loss depression; 14.5%) and Depressed-Improved (characterised byhigh pre-loss depression that decreased following loss; 10.1%)(Galatzer-Levy and Bonanno, 2012, p. 1). These findings confirmedprevious data showing that, while some bereaved individualssuffer intense grief, many others adapt well over the course ofbereavement.

7. What determines whether a grief response becomespathological?

The published literature provides some information on the fac-tors that may increase the propensity for bereavement to becomecomplicated or evolve into depression. Stroebe et al. (2006) pro-vided a systematic review of risk factors in bereavement outcome

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n terms of situational risk factors (e.g. mode of death), personal riskactors (e.g. personality) and interpersonal risk factors (e.g. socialupport). Using this framework, we provide below more examplesf each category based on some more recent research.

Situational factors related to the death include place of death, theime from diagnosis of a life-threatening illness to time of death,erceptions of the death being violent, lack of preparedness for theeath, a pattern of high distress pre-death and persistent feelingsf being stunned or shocked by the death (Lobb et al., 2010). Intrap-rsonal factors include low social and emotional support, financialtrain (Galatzer-Levy and Bonanno, 2012) and lack of death-relatedituals (Castle and Phillips, 2003). Personal factors include gen-er, poor physical health, past personal or family history of MDD,xposure to trauma (Zisook and Kendler, 2007), low psycholog-cal resilience, and personality factors (insecure attachment style,xcessive dependency, negative cognitions, and personal incompe-ence) (Wijngaards-de Meij et al., 2007; Lobb et al., 2010). However,lthough a number of studies have investigated the effects of per-onal risk factors on the bereavement outcome, biological factorsave not received much attention. Consequently, these are the

ocus of this review.

. Biological determinants of a response to bereavement

.1. Genetic factors

As development of depression (like any other psychiatricisorder) is under a degree of genetic influence, the variation

n the response to bereavement and the reason some peopleevelop MDD following bereavement while others experienceormal grieving, might be due (at least in part) to genetic

actors. Twin, family and adoption studies consistently show moderate heritability of depression of up to 40% (Sullivant al., 2000), which is similar to that found for type 2 dia-etes mellitus. The most-studied genes include the serotoninransporter-linked polymorphic region (5-HTTLPR), brain-derivedeurotropic factor (BDNF), dopamine transporter (DAT1), tryp-ophan hydroxylase (TPH), and catechol-O-methyl transferaseCOMT), as well as some non-monoamine related genes; includ-ng variants in the genes encoding for apolipoprotein E (APOE),uanine nucleotide-binding protein beta 3(GNB3), and methy-ene tetrahydrafolate reductase (MTHFR) (Lopez-Leon et al.,007). However, many of these findings have failed replica-ion.

.2. Interaction of genetics with environmental factors

One possible explanation for poor replication of the psychi-tric genetic findings is inadequate attention to gene-environmentnteractions (‘GxE’). This means that often the vulnerability genesan be detected only when environmental impact has been objec-ively assessed. Possibly the best known example is the serotoninransporter gene (SLC6A4), in particular the length polymorphismnown as 5-HTTLPR, which occurs in “short” and “long” forms.he short allele is associated with lower transcription of the sero-onin transporter mRNA and is therefore considered to be lessfficient (Lesch et al., 1996). There have been over 300 publishedtudies investigating the association of 5-HTTLPR with anxiety-nd depression-related phenotypes but the association of thisene with major depression has not been consistently reportedClarke et al., 2010). A major development in the study of the 5-

TTLPR occurred when it was reported that the association betweentressful life events and depression was modified by the 5-HTTLPRolymorphism (Caspi et al., 2003). This was argued as explain-

ng the varied results for the studies that simply investigated

havioral Reviews 49 (2015) 171–181

the 5-HTTLPR and depression alone without taking into accountthe effects of stressful life events. Although many studies haveinvestigated the effects on depressive status of the interactionbetween the 5-HTTLPR polymorphism and a stressful life event,none has examined the effects of bereavement. Two meta-analysesrecently synthesised the growing body of literature but failedto find consistent and replicable gene-by-environment effects(Munafò et al., 2009; Risch et al., 2009). However, these reviewshave been criticised for overly restrictive inclusion criteria whichresulted in the inclusion of only a small number of large studiesthat used retrospective, self-report measures of life stress (Parker,2013). Studies that used objective and interview-based assess-ments of stressful life events have been more likely to confirmthe 5-HTTLPR link between stress and depression (Zisook andKendler, 2007). Two subsequent, more inclusive meta-analysessought to overcome the limitations of earlier meta-analyses andboth found strong evidence that 5-HTTLPR moderates the relation-ship between stress and depression, with the 5-HTTLPR s allelebeing associated with an increased risk of developing depressionunder stress (Karg et al., 2011; Sharpley et al., 2014), althoughthe later of those two reviews also revealed that almost 26% ofthe 81 studies included in that meta-analysis failed to show anysignificant association between the 5-HTTLPR, stress and depres-sion (Sharpley et al., 2014). Although the 5-HTTLPR has been themost examined gene for the GxE effects, the interaction of othergene variants with adverse life events has also been reported.Such genes include: serotonin transporter (SLC6A4) 44 BP Ins/Del(Eley et al., 2004), Serotonin 1A receptor (HTR1A) (Brezo et al.,2009), dopamine receptor D2 (DRD2) (Elovainio et al., 2007), BDNF(Gatt et al., 2009), and corticotropin-releasing hormone type 1receptor (CRHR1) (Bradley et al., 2008). None of these genes,however, has been examined in the context of response to bereave-ment.

A recent work investigated the impact of pro-inflammatorycytokine SNPs in the Interleukin 6 (IL-6), IL-1 ̌ and TNF- ̨ geneson the serum levels of the associated protein markers and alsotheir interaction with bereavement severity (Schultze-Florey et al.,2012). Among the investigated polymorphisms, a GxE effect wasobserved for the IL-6−174 SNP when IL-6−174G homozygotes werefound to be protected against higher circulating levels of inflamma-tion resulting from bereavement exposure. However, those authorscould not find a GxE effect for this SNP and depressive symptoms.An earlier study showed an association between depression andincreased mortality risk only in IL-6-174GG homozygote patients(Cole et al., 2010).

Another interesting molecule, monoamine oxidase A (MAO-A),enzymatically degrades biogenic amines such as dopamine, nor-adrenaline, adrenaline and serotonin by oxidative deamination,and therefore plays a key role in the modification of signal trans-duction in these neurotransmitter systems (Shih and Thompson,1999). As such, MAO-A activity is involved in the pathogenesis ofmajor depression (Meyer et al., 2006). A functionally important 30-bp variable number tandem repeat (VNTR) has been identified inthe promoter region of the MAO-A gene (Sabol et al., 1998), withthe longer alleles increasing the transcription of the gene up tofour times more than the shorter allele. The results of investigationof the association of this genetic polymorphism with depressionhave not been consistent, with two studies reporting the associa-tion (Schulze et al., 2000; Yu et al., 2005) while two other studiesfailed to do so (Kunugi et al., 1999; Syagailo et al., 2001). How-ever, one study that examined the effects of this genetic variationin the MAO-A gene in bereaved people showed a gender-specific

association between the more active MAO-A VNTR variant and anincreased vulnerability to complicated grief in females (Kerstinget al., 2008). Those authors hypothesised that this could be dueto the reduced serotonergic activity caused by elevated MAO-A

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ctivity as a primary monoamine-lowering process during majorepression.

.3. Epigenetic regulation

Research has shown that epigenetic regulation of generanscription is a key mechanism for adaptation to external envi-onmental stimuli at the molecular level (Feinberg, 2007). Theerm ‘epigenetic’ refers to the reversible regulation of variousenomic functions, which are independent of changes in the DNAequence and principally include changes in DNA methylationnd chromatin structure. Epigenetic mechanisms modify responseso environmental stimuli and contribute to tissue-specific genexpression profiles during brain development involving pro-esses such as neurogenesis and synaptic plasticity (Hsieh andisch, 2010; Gräff et al., 2011). Therefore, epigenetic regula-ion might have a role in individual differences in responseo environmental exposures to major stressors (Rutten et al.,013).

On the other hand, it should be noted that the epigeneticodifications that differentiate individuals in their behavioural

esponses to environmental stresses might have been activatedy experiencing stress during the early stages of life (Kim-Cohennd Turkewitz, 2012). In other words, the relationship betweenpigenetic moderation and stress is reciprocal in that epige-etic processes can be activated by stress, and these long-lastingenetic imprints can later influence responses to environmen-al stimuli. This might be one of the reasons that experiencingtressful life events early in life increases the risk of developingepression in adulthood when exposed to environmental adver-ity.

An example of long lasting epigenetic modification due toarly life stress has been reported for the glucocorticoid recep-or (McGowan et al., 2009). Several studies have also shown theole of epigenetic changes in the BDNF gene in risk for psy-hiatric disorders, (for a review see Boulle et al., 2011). Lastingpigenetic influence of early life adversity on the BDNF geneas also been reported (Roth et al., 2009). In addition, there isome evidence that the serotonergic system is under the influ-nce of epigenetic changes (Lesch, 2011). One study showed thatigher 5-HTT methylation, but not 5-HTTLPR genotype, exacer-ated the effects of early life stress on behavioural reactivity

n rhesus macaque infants (Kinnally et al., 2010). The authorsherefore concluded that 5-HTT methylation may be an impor-ant regulator of 5-HTT expression early in development and mayontribute to the risk for mood disorders observed in ‘high-risk’-HTTLPR carriers. In a series of studies on humans, Philibertnd colleagues showed that methylation of the serotonin trans-orter gene was associated with reports of childhood abuseBeach et al., 2010) and that product levels of the serotonergicystem varied according to the level of methylation (Philibertt al., 2007) Another study of participants with experiences ofoss or trauma found that the association between the 5-HTTLPRenotype and poor response to psychological problems was sig-ificantly moderated by methylation patterns (van IJzendoornt al., 2010). Those authors reported that higher methylation lev-ls of the 5HTT promoter were associated with increased riskf unresolved responses to loss or trauma in carriers of thesually protective 5-HTTLPR ll variant. The 5-HTTLPR ss variantredicted more unresolved loss or trauma only in the case of

ower levels of methylation (van IJzendoorn et al., 2010). Thebserved association of the epigenetic regulation and the risk

f depression in genetically high-risk individuals urged furthernvestigation of the interaction of epigenetic changes and stress-ul events, which may lead to identification of novel patternsf how epigenetic moderations of other vulnerability genes to

havioral Reviews 49 (2015) 171–181 175

depression influence stress responses in people with different riskgenotypes.

8.4. Neuroendocrine factors

As noted, the experience of bereavement as an aversive envi-ronmental event could result in development of depression inthose individuals who carry particular genes that are up- or down-regulated by their grief experience. Interactions between suchenvironmental events and genetic predisposition to depressionmay lead to neurobiological and structural changes in the brainregions linked to depression.

A principal mediator of the impact of stress on brain andbehaviour is the activation of the Hypothalamus–Pituitary–Adrenal(HPA) axis, which results in widespread hormonal, neurochemi-cal and physiological alterations. Corticotropin-releasing hormone(CRH) is released by the hypothalamus in response to stress, leadingto the eventual release of cortisol from the adrenal glands. Althoughshort-term elevations of cortisol can be protective and maypromote adaptation to environmental demand, long-term hyper-cortisolaemia is harmful because it is associated with impairedneurogenesis and cell apoptosis in the hippocampus and prefrontalareas, plus increased dendritic branching in the amygdala (McEwenand Milner, 2007). On the other hand, glucocorticoids, released as aconsequence of HPA axis activation interact with steroid receptorsexpressed throughout the brain. In particular, glucocorticoid recep-tors and mineralocorticoid receptors are expressed at high levelsin the hippocampus, amygdala, prefrontal cortex (PFC) and otherlimbic and midbrain structures, where they modulate the neuralcircuitry and neuroendocrine systems that underlie behaviouralresponses to stress (Russo et al., 2012). The neurochemical alter-ations caused by high activation of the HPA axis, including excessrelease of cortisol and steroid receptors, lead to several changesto brain regions that are linked to depression. These structuralchanges include increased volume in amygdala, decreased volumesof the PFC and hippocampus, and alterations of the connectivitybetween amygdala and PFC, and between amygdala and hippocam-pus (Sharpley, 2013). It is noteworthy to mention that increases inamygdala function and impairment of the PFC is directly linked tokey symptoms of depression. The pathway between environmentalstressor-induced hyper-activation of the HPA axis and depres-sion represents the neurobiological link between the stressors andthe depressive symptomatology that is described in behaviouralaccounts of depression (Sharpley and Bitsika, 2010).

Bereavement is associated with increased adrenocortical activ-ity, and elevated cortisol in the early period of bereavementhas been confirmed in several studies (Biondi and Picardi, 1996;Buckley et al., 2012). Altered adrenocortical activity was notpresent in all bereaved individuals but rather in a subgroupwith severe bereavement outcomes, and was associated withhigher levels of anxiety, depressed mood or intense grief (Jacobset al., 1987; Weller et al., 1990). One study reported ele-vated blood levels of cortisol to dehydroepiandrosterone-sulphate(DHEAS) ratios in bereaved persons compared to non-bereavedcontrols. Both cortisol and DHEAS are outputs of the HPA axisand a higher ratio of cortisol to DHEAS is observed in olderage. As such, elevated cortisol in a group with reduced abil-ity to produce DHEAS is likely to have greater impact in theelderly bereaved, with greater potential for immune alteration(Khanfer et al., 2011). In addition, a small amount of evidenceshows that elevated adrenocortical activity and perhaps dys-regulation is more likely to be based on the persistency of

high levels of distress rather than a single high level isolatedepisode of stress (Jacobs et al., 1987; Biondi and Picardi, 1996).Some individuals show an elevation in serum growth hormonein response to acute stress. One study showed that not only

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he loss, but even the memory of the event, can trigger aeuroendocrine response as evidenced by the finding that theecall of the lost loved-one can provoke a sharp increase in neu-oendocrine activity during an interview several months post-lossKosten et al., 1984).

.5. Immunologic/inflammatory factors

Activation of the inflammatory immune system in responseo stressors is also implicated in depression. Release ofmmune-signalling molecules (cytokines) such as interleukin-1�,nterleukin-6, tumour necrosis factor-� and interferon-�, mightnfluence many of the neurochemical changes provoked by stress-rs and thereby contribute to depression (reviewed by Anisman,009).

Changes in immune function have been reported in earlyereavement and include reduced proliferation of T-cells (Bartropt al., 1977; Schleifer et al., 1983; Gerra et al., 2003) and reducedctivity of natural killer (NK) cells (Irwin et al., 1988; Gerrat al., 2003). Lower lymphocyte response (Linn et al., 1984), lowermmunoglobulin-M levels (Lindstrøm, 1997), absolute loss of sup-ressor/cytotoxic cells (Irwin et al., 1987) and reduced NK cellsIrwin et al., 1988) are also associated with higher depressioncores in bereaved people. In addition, a well-designed, longitudi-al study showed that, while no differences were observed betweenereaved and control subjects in T-cell subpopulation, NK activity,nd lymphocyte proliferation, the subgroup of bereaved subjectsho met the criteria of major depression had a lower concentra-

ion of CD8 cells (a glycoprotein that serves as a co-receptor forhe T cell receptor), lower NK activity, and a trend towards lowerymphocyte stimulation responses compared to a non-depressedereaved group (Zisook et al., 1994a,b).

Stressful life events are linked to increased inflammatoryignalling and production of systemic markers of inflammation.chultze-Florey et al. (2012) investigated the impact of bereave-ent status on circulating levels of inflammatory markers IL-6,

L-1RA as a marker of IL-1 activity, and soluble tumour necrosisactor receptor II (sTNFRII) as a surrogate marker of TNF-� levels.ereaved participants had higher levels of IL-1RA and IL-6 com-ared to non-bereaved control participants but this was explainedy either genotype differences or the severity of grief (Schultze-lorey et al., 2012).

Data from several studies suggest that the changes in themmune function of bereaved persons are more related to theepressive symptomatology accompanied by bereavement, ratherhe acute effect of loss per se (Biondi and Picardi, 1996). Consis-ently, another study showed that, although changes in endocrinend immune parameters are significantly more marked in thearly phase of bereavement, they are still present in a number ofereaved persons 6 months after the acute phase, in associationith inflated anxiety and depression scores (Gerra et al., 2003).

hose authors concluded that subjects who experienced a trau-atic event such as bereavement must still be considered at risk

or the possible consequences of disruption in both the HPA andhe immune system even six months post-loss.

.6. Brain neurotransmitters

In addition to changes in the neuroendocrine and immuno-ogic/inflammatory systems, stressors also promote functionalhanges of classical neurotransmitter systems. Some of the neu-otransmitter systems influenced by stressors include GABAergic

e.g. glutamate) and monoamine (e.g. dopamine, epinephrine, sero-onin) pathways. The release of dopamine (Feenstra et al., 1995)nd glutamate (Bagley and Moghaddam, 1997) in response to stressas been shown in the PFC. Variation of brain levels and turn-over

havioral Reviews 49 (2015) 171–181

of serotonin (5-HT), 5-HT transporter (5-HTT) and several sero-tonin receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C) has also beenassociated with stress-induced depression (Anisman et al., 2008;Anisman, 2009).

As examining the modification of brain neurochemicals inbereaved people is not currently possible, most of the knowledgeregarding the alteration of brain neurotransmitters following astressful life event is from animal studies. Non-human primatemodels share most of their genetic material with humans andtherefore there are many similarities in CNS organisation, develop-ment, and physiological function between monkeys and humans(Biondi and Picardi, 1996).

A number of neuroendocrine and immunological changes afterseparation in monkeys, such as pituitary adrenal activation andreduced lymphocyte response to mitogen, are similar to neu-roendocrine and immune system changes in bereaved people.Therefore, the results of stress-induced neurotransmitter changesin non-human primates can also be applied to humans (Biondiand Picardi, 1996). Separation of infants from their mothers,even in adulthood, is a deeply stressful event for most primates(Biondi and Picardi, 1996). Alterations in the concentration of CNScatecholamines and serotonin have been observed in the earlyacute phase of stress, resulting in an increase in CSF monoaminemetabolite concentrations (Bayart et al., 1990). If the stress isprolonged, a chronic phase develops, with increased CSF levelsof methoxy-hydroxyphenolglycol (a metabolite of norepinephrinedegradation), and decreased levels of CSF homovanillic acid (Higleyet al., 1991), the major dopamine metabolite. Another animal modelof stress-induced depression is the exposure of male rats to asocial defeat (Koolhaas et al., 1997). An important component ofthe dopaminergic system is the neuronal dopamine transporter(DAT), which regulates dopaminergic neurotransmission (Amaraand Kuhar, 1993). The stress-induced decrease of DAT binding siteshas been shown in male rats after a single social defeat followed bysocial isolation (Isovich et al., 2001).

As opposed to mere social isolation, Bosch and colleaguesintroduced a model that selectively examined the effect of lossof a bonded partner on passive stress-coping behaviour (Boschet al., 2008). Those authors suggested that, as the monogamousprairie vole forms enduring and selective pair bonds with its mat-ing partner, this rodent model can provide unique insights into thephysiological consequences of pair bonding and the neurobiologyof the loss of a bonded partner which may be relevant to grievingand bereavement in humans.

8.7. Neurotrophic growth factors

Depression has been associated with alterations of growthfactors. Brain-derived neurotrophic factor (BDNF) is a secretoryprotein in the neurotrophin family which has been associated withboth depression and anxiety (Martinowich et al., 2007). A num-ber of studies have demonstrated that blood levels of BDNF aredecreased in depressed patients and can be normalised throughantidepressant treatments (Shimizu et al., 2003; Schmidt andDuman, 2010). Stressors were consistently shown to reduce theexpression of BDNF in limbic regions that mediate mood states(Duman and Monteggia, 2006).

Fibroblast growth factor-2 (FGF-2) is a trophic molecule thathas a critical role in the maturation and survival of a variety ofneuronal phenotypes (Baird, 1994). Stress-induced alterations ofthe FGF-2 levels have been reported previously, and possibly occurthrough the elevation of glucocorticoid hormones, as demonstrated

in animal models (Riva et al., 1995; Molteni et al., 2001).

Animal studies indicate that maternal separation as a modelof early life stress leads to alterations in neurotrophins such asBDNF (Roceri et al., 2001; Marais et al., 2009), nerve growth factor

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NGF) and neurotrophin-3 (NT-3) (Marais et al., 2008). In addition,t has been shown that exposure to traumatic events (assessedy DSM-IV stem criteria for trauma) lowers the levels of BDNF

n bipolar patients (Kauer-Sant’Anna et al., 2007). Another studyhowed that females who were genetically disposed to depressionnd were subjected to recent stressful life events (assessed by areviously published method in Kendler et al., 1995) had lowerhole blood BDNF levels compared to genetically low-risk women

r compared to men (Trajkovska et al., 2008). Those authors arguedhat the absence of such an association in men and women whoere genetically protected against depression supports the notion

hat high-risk females are particularly vulnerable to depressionKendler et al., 2006). However, no study to date has investigatedhe specific role of bereavement in serum levels of BDNF, althought could be assumed that this would show a similar pattern to othertressors and that the BDNF levels would be different in normalrief as in full-blown depression in bereaved people.

.8. The biology of resilience

As discussed, personality factors such as insecure attachmenttyle, excessive dependency, negative cognitions and personalncompetence may increase the risk of depression followingereavement (Wijngaards-de Meij et al., 2007; Lobb et al., 2010).lthough a large body of empirical research has examined nega-

ive psychological traits as determinants of a response to stressfulife events, relatively little is known about how positive personal-ty characteristics such as self-system processes, ego resiliency and

oderate ego over-control might modify the response to bereave-ent.One of the most powerful buffers against anxiety and depres-

ion disorders is the individual’s belief in their personal control ofow they will cope with adverse circumstances (Rutter, 1985). Thiselief has more recently been conceptualised as “resilience” in theace of major stressors (Rutter, 2006). Psychological resilience is aynamic process and has been defined as a measure of coping abil-

ty with stress (Connor and Davidson, 2003) that encompasses thettainment of positive adaptation within the context of exposure toignificant adversity that typically exerts major assaults on biologi-al and psychological developments (Cicchetti and Rogosch, 2012).he concept of resilience entails on one hand a process of sustaina-ility that prevents and attenuates disturbance of mental healthnd wellbeing after exposure to severe adversity, and on the otherand a process of rapid recovery from mental health disturbance

ollowing exposure to adversity (Rutten et al., 2013).Genetic factors may be important determinants of resilience

o major stressors that can lead to disorders such as depressionrising from bereavement. A few studies have investigated thessociation of candidate genes with stress resilience. The stud-ed genes included corticotrophin-releasing hormone receptor 1ene (CRHR1), FK506 binding protein 5 (FKBP5), which is a genehat codes for a ‘chaperone’ protein that regulates glucocorti-oid receptor sensitivity, SLC6A4, Catechol-O-methyltransferaseCOMT), Neuropeptide Y (NPY) and BDNF (Feder et al., 2009; Kim-ohen and Turkewitz, 2012). Most of these genes significantlyoderated the effect of the stressful life event on resilience.

ecently, a GxE study showed that polymorphisms in four genes,-HTTLPR, CRHR1, dopamine receptor (DRD4-521 C/T) and oxytocineceptor, all significantly moderated the impact of maltreatmentn the resilient functioning score, which the authors interpreted asupport for differential susceptibility to the environment perspec-ive (Cicchetti and Rogosch, 2012). According to the differential

usceptibility to environmental influence hypothesis profferedy Belsky and Pluess (2009), genes that confer risk in harshnvironments may also confer benefits in normal or nurturingnvironments. In other words, the characteristics of individuals

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(including their genotypes) that make them excessively more vul-nerable to experiencing adversity may also make them excessivelymore likely to benefit from supportive environments. In the caseof Ciccetti and Rogosch’s study (2012), maltreated children withtwo copies of the 5-HTTLPR short allele had lower resilient func-tioning, whereas non-maltreated children with the same 5-HTTLPRgenotype had higher levels of resilient functioning. Similar patternswere observed in children who had no copies of the CRHR1 TAT hap-lotype, the TT genotype of the DRD4 gene and the A allele carriersof the oxytocin receptor gene.

As significant individual differences in resilience to stress-induced neurochemical alterations have been reported (Feder et al.,2009), recent studies have investigated the biological basis of stressresilience with the aim of identifying novel protective factors topromote resilience in vulnerable individuals in the face of adver-sity. For instance, increased hippocampal BDNF levels have beenshown to mediate stress resilience in rodents (Taliaz et al., 2011)and administration of peripheral BDNF has shown to moderatelyreduce behavioural deficits caused by stress (Schmidt and Duman,2010), also in rodents. These results suggest that BDNF could serveas a potential marker for stress resilience.

Furthermore, a recently proposed biomarker for resilience isReelin (Fatemi, 2011), which is an extracellular protein responsi-ble for neuronal cell migration and normal brain lamination duringembryogenesis and has been shown to have a role in cell signallingand synaptic plasticity in adult life (Rice and Curran, 2001). Alteredexpression of Reelin and its isoforms has been shown in severalneuropsychiatric disorders, including major depression (Folsomand Fatemi, 2013). As over-expression of Reelin in a transgenicmouse model led to reversal of various behavioural abnormalities(Teixeira et al., 2011), this molecule has been suggested as a markerfor stress resilience. Genetic alterations of the RELN gene have beenshown in autistic (Persico et al., 2001) and schizophrenic patients(Goldberger et al., 2005) but no study has investigated the asso-ciation of RELN gene polymorphisms with MDD or resilience todate, leaving it as a good candidate for further research investi-gations.

9. Biological model of depression following bereavement

Based on the data reviewed in this paper, we represent a modelof stress-induced biological changes resulting in depression fol-lowing bereavement. As shown in Fig. 1, early life stress (e.g. lossof a parent, childhood maltreatment) leads to lasting epigeneticchanges, which result in modified gene expression, specificallywhen an individual is exposed to another stressful event later inadult life. Genetic factors can predict the risk or resilience to anadverse life event, based on different polymorphisms in the genesand whether they up- or down-regulate the gene expression levels.

Bereavement as a very stressful life event triggers biologicresponses in several pathways including neuroendocrine response,inflammatory/immune system, neurotropic growth factors andneurotransmitters. The responses in these systems, along withgenetic factors either directly or in an interaction with environment(bereavement) cause alterations in the level of related proteins,which finally affect brain regions involved in the development ofdepressive behaviour. (It is important to note that the genes or pro-teins shown in this model are some examples and by no meansdo they represent the range of molecules known to date that areinvolved in development of depression.)

10. Future directions

We have discussed that inadequate attention to the GxE inter-actions has made the results of genetic research in the field of

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Fig. 1. The role of biological factors in development of depression following a stressful life event (bereavement). Abbreviations: CRHR1: corticotropin-releasing hormonet kin 6n teract

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ype 1 receptor; GCC: glucocorticoids; GCCR: glucocorticoid receptors; IL-6: interleueurotropic factor; FGF-2: fibroblast growth factor-2; GxE: gene by environment in

epression inconsistent and non-replicable, as often the vulner-bility genes can be detected only when environmental impact haseen assessed. Meta-analyses have shown that robust findings inxE investigations are observed when a specific stressor is iden-

ified (Karg et al., 2011; Sharpley et al., 2014). The emerging GxEtudies in the past decade which resulted in identification of a fewenetic risk factors for developing depression following an adverseife event (Harro and Kiive, 2011) have mainly focused on child-ood trauma, while bereavement as the most stressful life eventas not received the attention it deserves in GxE studies for uncov-ring genetic factors underlying depression. Furthermore, the datao far indicate that multiple gene/biology systems are implicatedn determining an individual’s vulnerability to the negative conse-uences of an adverse environment (Kim-Cohen and Turkewitz,012) and therefore each of the known genetic factors imply amall effect for the risk of depression and it is the complex inter-lay between several mechanisms that make a person ‘at risk’ ofeveloping depression after bereavement. Genetic studies often

nvestigate not more than a few risk genes, either for their directssociation with depression or their interaction with stressful lifevents. The same scenario applies to epigenetic studies or studiesnvestigating stress-induced biological responses. Better insight iseeded regarding the mechanisms by which these many molecules

nteract with each other, urging the need for more comprehen-ive studies applying modern biotechnology techniques to collectenomic, epigenomic, transcriptomic, proteomic and metabolomicata, and use of sophisticated statistical software and computa-

ional packages for their analyses. Another step towards advancinghe field of GxE research is to consider resilience instead of focusingxclusively on mental disorders. Genome-wide studies can be con-ucted to explore genetic determinants of psychological resilience,

; 5-HTTLPR: serotonin transporter gene length polymorphism; BDNF: brain-derivedion.

which requires a large cohort of participants with reliable resiliencescores.

Another gap in the literature is regarding the use of bio-markersin early detection of bereavement-related depression. The roleof stress has received much attention in the depression litera-ture but its study using biological markers has not been extendedto bereavement and depression. The commonly-used measuresof physiological stress states are salivary cortisol (as an indexof the HPA axis) and salivary alpha-amylase (as an index of thesympathetic-adrenal-medullary (SAM) axis). These two indicatorsof psychophysiological stress responses can complement paper-and-pencil tests of anxiety and depression and provide additionalways of validating the state of the participants vis-à-vis their reac-tions to bereavement. Although cortisol levels have been assessedin relation to the severity of participants’ response to bereavement(Jacobs et al., 1987; Gerra et al., 2003), their utility in predictingMDD following bereavement has not been examined. Moreover,no study has yet investigated the association of alpha-amylase withdepression following bereavement.

As some inflammatory markers (lower lymphocyte response,lower immunoglobulin-M levels, and higher NK cells) have beenshown to be associated with higher depression scores in bereavedpeople (Buckley et al., 2012), they can serve as biomarkers ofdepression once their association with MDD in bereaved peopleis replicated in other cohorts. In addition to inflammatory mark-ers, growth factors in specific plasma levels of BDNF are proposedas predictive biomarkers of vulnerability to depression (Blugeot

et al., 2011; Schmidt et al., 2011). However, no study has yet exam-ined BDNF levels in association with the severity of participants’response to bereavement, or their power to predict depression fol-lowing bereavement.

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As noted in the previous section, few studies have examinedereavement in the context of neurobiological changes follow-

ng an environmental stressor. Therefore, the data from othereneral stressors have been presented and discussed where noereavement-specific data were available in the literature. Consid-ring the fact that the similarities between bereavement-relatedepression and depression related to other stressful life events sub-tantially outweigh their differences (Kendler et al., 2008), similaratterns of biological changes are expected following bereave-ent. In addition, the biological responses triggered by perceived

oss are shown to be stronger than responses to other stressorsGail et al., 1997), with unexpected loss of a loved one but notnticipatory bereavement, being associated with increased adreno-ortical activity (Irwin et al., 1988). However, individuals withereavement-related depression are reported to have lower lev-ls of neuroticism, and guilt and higher levels of fatigue and lossf interest compared to individuals with depression related tother stressful life events (Kendler et al., 2008). Therefore, althoughhe neurobiological changes due to general life stressors could bextended to bereavement, caution must be taken in generalisinguch results.

Apart from the lack of information on neurobiological featuresnderlying bereavement-related depression, it is also important toote that multiple grief trajectories exist and, with either com-licated grief or bereavement-related depression, the symptomsre characterised as pathologic if: (1) they last for a long dura-ion; (2) reach a threshold for a psychiatric diagnosis; (3) impactegatively on functioning; or (4) cause marked distress. However,he differing manifestations of these trajectories have not beenxamined consistently in the same study. More importantly, theres a high non-normal variability among depression scores follow-ng loss. Variability following such a distribution level may not beuccessfully captured in statistical models that sample from theean, as is commonly the case in bereavement studies, because

uch models assume homogeneity characterised by a single nor-al distribution. A number of approaches (e.g. Hierarchical Linearodelling) have been developed to model patterns with high lev-

ls of variability. However, these modelling techniques assume aommon pattern that individuals fit better or worse. For variablesuch as the stress response for which there is a true heterogene-ty, such models may be inadequate (Galatzer-Levy and Bonanno,012). A recent set of analytic techniques that has emerged toesponse to limitations of previous methods is Latent Growthodelling, which allows for the empirical exploration of the under-

ying heterogeneity within the data, while also allowing for theodelling of covariates as predictors (Galatzer-Levy and Bonanno,

012).A similar heterogeneity exists for the definition of depression

tself. With nine diagnostic criteria for MDD, and two key criteria,he possible number of required symptoms for a diagnosis of MDDs nearly 1500 (Ostergaard et al., 2011). Based upon this wide vari-ty in depressive symptomatology for MDD and the relatively poorutcomes of standard first-line treatments (i.e. about 50% effec-iveness) (Rush et al., 2006), the notion of ‘depressive subtypes’ haseen recommended as a potential way of identifying and explaininghe lack of general treatment efficacy for MDD (Insel, 2013, 2014).ne model of four subtypes of MDD based upon clustering of simi-

ar symptoms has been described (Sharpley and Bitsika, 2013), withalidity and reliability data reported (Sharpley and Bitsika, 2014).hese four subtypes of depression have been observed in prostateancer patients (Sharpley et al., 2013), who experience a form ofereavement in their loss of function that may be similar to that

xperienced by persons who have lost a loved-one. Further inves-igation of the ways in which MDD may present could represent

potential method for diagnosing bereavement-related MDD asistinct from CG.

havioral Reviews 49 (2015) 171–181 179

11. Conclusion

Examining biological risk and protective factors for the develop-ment of depression after bereavement is a nascent field of research.Results from such investigations would considerably contribute toadvancing the knowledge in both fields of bereavement and depres-sion. Bereavement offers an excellent opportunity to study theantecedents of depression longitudinally, considering the relativelyhigh number of people who develop depression after bereavement.These findings may have applications to depression in other con-texts and major depression in general.

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