Biological-determinants-of-depression-following-bereavement
Neuroscience and Biobehavioral Reviews 49(2015)171–181
Contents lists available at ScienceDirect
Neuroscience and Biobehavioral
Reviews
j o u r n a l h o m e p a g e :w w w.e l s e v i e r.c o m /l o c a t e /n e u b i o r e
v
Review
Biological determinants of depression following bereavement
Amelia A.Assareh a ,?,Christopher F.Sharpley a ,b ,James R.McFarlane a ,Perminder S.Sachdev c
a
Collaborative Research Network for Mental Health and Well-being,University of New England,Armidale,Australia b
Brain-Behaviour Research Group,University of New England,Armidale,Australia c
Centre for Healthy Brain Ageing,School of Psychiatry,University of New South Wales,Sydney,Australia
a r t i c l e
i n f o
Article history:
Received 10July 2014Received in revised form 13November 2014
Accepted 7December 2014
Available online 22December 2014
Keywords:Bereavement Grief
Stressful event Depression Genetic
Neuroendocrine immunologic In?ammatory
Neurotransmitters Neurotropic Resilience
a b s t r a c t
There is considerable variability among people in their response to bereavement.While most people adapt well to bereavement,some develop exaggerated and/or pathological responses and may meet criteria for a major depressive episode.Many studies have investigated the effect of psychosocial factors on bereavement outcome but biological factors have not received much attention,hence the focus of this paper.The biological factors studied to date in relation to bereavement outcomes include genetic polymorphisms,neuroendocrine factors,and immunologic/in?ammatory markers.In addition,animal studies have shown the alterations of brain neurotransmitters as well as changes in the plasma levels of the neurotrophic growth factors under the in?uence of peer loss.Recent studies have also investigated the biological 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 to,and also after,bereavement and which chart both biological and psychological measures are needed to develop pro?les for the prediction of response to bereavement and personalised interventions.
?2014Elsevier Ltd.All rights reserved.
Contents 1.Introduction (172)
2.Determinants of depression.........................................................................................................................172
3.Grief as a normal response to bereavement ........................................................................................................172
4.How is grief different from depression?............................................................................................................173
5.Pathological and complicated grief .................................................................................................................173
6.Longitudinal studies of grief ........................................................................................................................173
7.What determines whether a grief response becomes pathological?...............................................................................173
8.
Biological determinants of a response to bereavement ............................................................................................1748.1.Genetic factors ...............................................................................................................................1748.2.Interaction of genetics with environmental factors.........................................................................................1748.3.Epigenetic regulation ........................................................................................................................1758.4.Neuroendocrine factors......................................................................................................................1758.5.Immunologic/in?ammatory factors .........................................................................................................1768.6.Brain neurotransmitters .....................................................................................................................1768.7.Neurotrophic growth factors ................................................................................................................1768.8.The biology of resilience .....................................................................................................................
177
?Corresponding author.Present address:Centre for Healthy Brain Ageing,Euroa Centre,Prince of Wales Hospital,Barker St.,NSW 2031,Australia.Tel.:+61293853840;fax:+61293823774.
E-mail address:a.assareh@https://www.360docs.net/doc/ec2187085.html,.au (A.A.Assareh).
https://www.360docs.net/doc/ec2187085.html,/10.1016/j.neubiorev.2014.12.0130149-7634/?2014Elsevier Ltd.All rights reserved.
172 A.A.Assareh et al./Neuroscience and Biobehavioral Reviews49(2015)171–181
9.Biological model of depression following bereavement (177)
10.Future directions (177)
11.Conclusion (179)
References (179)
1.Introduction
Depression is a major global public health issue due to a rela-tively high lifetime prevalence of up to15%(Ustun and Chatterji, 2001).As a result of substantial comorbidity with chronic med-ical diseases(Molteni et al.,2001,Moussavi et al.,2007)and association with high mortality(Mykletun et al.,2009),depres-sion has been considered as an important contributor to the total disease burden(üstün et al.,2004)and has been estimated to be the second most common contributor to years lived with disability(Vos et al.,2013).Speci?c external causes have been reported to promote the occurrence of depression,especially those associated with loss(Ferster,1973).Loss can take many forms which include bereavement,romantic betrayal and rejec-tion,unexpected job loss,?nancial ruin,loss of possessions,natural disasters,or negative medical diagnosis in oneself or a loved one (Wake?eld and First,2012).However,it has been shown that interpersonal loss including bereavement,separations,endings or threats of separation,has the most profound in?uence(Paykel, 2003).Bereavement usually has a profound effect and therefore is understandable as one of the most prominent and consistent risk factors for depression(Cole and Dendukuri,2003).Bereave-ment also leads to a grief reaction which may be regarded as a normative process.This raises some important questions:when does grief become pathological and should this be diagnosed as depression?Are there particular psychological and social factors that predict depression in someone who is bereaved?Are there biological factors that predispose a bereaved person to become depressed?
In this review,we address some of these questions and docu-ment the current state of knowledge on the biological determinants of depression after bereavement.In particular,we attempt to show how the application of molecular biology and genetic techniques is promoting the identi?cation of biomarkers of major depressive disorder(MDD)following bereavement.Finally,new strategies for future research are proposed.
2.Determinants of depression
Several factors have been identi?ed as determinants of depres-sion.A review by Riso et al.(2002)classi?ed the factors underlying chronic depression into six putative categories:(1)develop-mental factors such as childhood adversity(early trauma or maltreatment),(2)personality and personality disorders like neu-roticism and stress reactivity,(3)psychosocial stressors(life events),(4)comorbid disorders including anxiety and substance abuse,(5)biological factors such as dysregulation of the neu-roendocrine and/or immune systems,and(6)cognitive factors (e.g.self-criticism).In studies of chronic depression,the strongest evidence of aetiology has been found for developmental factors, with some support for environmental stressors and heightened stress reactivity(Riso et al.,2002).The vast majority of research on the association between stress and depression supports a strong relationship between stressful life events and depres-sion(Kessler,1997;Kendler et al.,1999;Pittenger and Duman, 2008),speci?cally the unique signi?cance of depression follow-ing a“loss”(Zisook and Shuchter,1991;Biondi and Picardi, 1996).3.Grief as a normal response to bereavement
“Grief”is a normal reaction to a major loss of any kind but will be discussed herein in relation to the particular loss incurred due to bereavement.Bereavement grief is multidimensional,with physical,behavioural and meaning/spiritual components and is characterised by a complex set of cognitive,emotional and social adjustments that follow the death of a loved one(Lobb et al.,2010). Although individuals vary in the type,intensity and duration of the grief they experience(Christ et al.,2003),most grieving peo-ple show similar patterns of intense distress,anxiety,yearning and sadness 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 de?ned by the Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition,Text Revision(DSM-IV-TR)(American Psychiatric Association,2000).It has been argued that bereaved individuals who have these symptoms are not experiencing a mood disorder 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-and under-diagnosis of MDD,either pathologizing a normal condition or neglecting to treat an impairing disorder(Shear et al.,2011).To prevent over-diagnosis of MDD in such individuals,the DSM-IV-TR used the‘bereavement exclusion’criterion where a bereavement-related depressive syndrome had to be either of a longer duration than two months instead of the standard requirement of two weeks, be paired with speci?c symptomatic manifestations,or be asso-ciated with marked functional impairment(American Psychiatric Association,2000).Although many other types of loss,such as mar-ital dissolution and unexpected job loss,can also trigger intense sadness that may meet the criteria for diagnosis of MDD,the con-cern about pathologizing grief has been restricted to the loss of a loved one and all depressive episodes following other major stress-ors were classi?ed as MDD by the DSM-IV,irrespective of whether the response to those losses was complicated or not(Wake?eld and First,2012).There is ample evidence that stress caused by bereave-ment,like other stressors,has a negative effect on psychiatric and physical 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 the publication of DSM-5,resulted in the removal of“Bereavement Exclusion”clause in the diagnosis of Major Depressive Disorder and has been one of the most contentious changes from DSM-IV to DSM-5,This has led to a lively controversy by grief and bereave-ment experts(Prigerson et al.,1995;Shear and Shair,2005;Zisook et al.,2012a;Parker,2013),and even resulted in some sensational or misleading reports in the lay media;including headlines such as,“Psychiatrists want to make normal grief a mental disorder!”and “DSM-5medicalizes mourning.”(Pies,2014)(Table1).
The DSM5Mood Disorders Work Group believed that,although bereavement should not be‘medicalised’,neither should the seri-ous risks of under-recognised MDD be normalised,since these include suicide and cognitive dysfunction.Recognising major depression following a recent bereavement requires careful clinical judgement and does not necessarily warrant psychopharmocologi-cal anti-depressant treatment(Pies,2014).In re?ection of this atti-tude,the DSM-5itself warns clinicians that they need to distinguish
A.A.Assareh et al./Neuroscience and Biobehavioral Reviews49(2015)171–181173 Table1
Symptomology of major depressive disorder following bereavement compared to
normal grieving.
Complicated grieving(major
depressive disorder)
Uncomplicated or normal grieving
Mood and ideation are mainly negative Painful feelings come in waves, often mixed with positive memories of the deceased
The agony of loss is relatively persistent Painful feelings of loss tend to come in bursts or waves
Feelings of worthlessness and
self-loathing are present
Self-esteem is usually preserved
Suicidal ideas,Anxiety,guilt, psychomotor retardation,and severe impairment of functioning might be present These symptoms are not usually present
Refs.Corruble et al.(2012)and Zisook et al.(2012a,b).
between grief and a major depressive episode(MDE)by considering that,within grief,“the predominant affect is feelings of emptiness and loss,while in MDE it is persistent depressed mood and the inability to anticipate happiness or pleasure”(APA,2013,p.126).
4.How is grief different from depression?
As mentioned above in the quote from the DSM-5,there are clear differences between grief and major depression.However, it also should be emphasised that some individuals cannot cope effectively with bereavement-related distress and studies show that up to42%of bereaved people become clinically depressed within1month after their loss,decreasing to16%by one year post-loss(Zisook et al.,2012a).Perhaps not unexpected,many cli-nicians are uncertain about when to make the diagnosis of MDD in bereaved individuals(Zisook et al.,2010).Although grief and major depressive episodes have many features in common(such as intense sadness,insomnia,loss of appetite and withdrawal from customary activities)they are different in many important aspects,as suggested by the comment in the DSM-5mentioned above.
Some speci?c features that suggest the presence of MDD in addition to grief are:(i)in MDD,mood and ideation are mainly and persistently negative whereas in uncomplicated grief,painful feelings come in waves,often mixed with positive memories of the deceased;the individual may retain his or her sense of humour;(ii)MDD is accompanied by feelings of worthlessness and self-loathing but in grief self-esteem is usually preserved;and (iii)patients with MDD experience suicidal ideas,psychomotor retardation and severe impairment of functioning but these are less likely in grief(Corruble et al.,2012;Zisook et al.,2012b). Therefore,it is important to note that some recently bereaved individuals are not simply grieving,but are experiencing a full-blown MDD,which should be considered when making clinical evaluations.
5.Pathological and complicated grief
From the above,it may be concluded that,based on DSM-IV criteria,a response to bereavement warrants a diagnosis of MDD if certain symptoms are present that are not characteristic of normal grief.These symptoms are entirely depressive symp-toms(e.g.feelings of worthlessness,suicidal ideation,psychotic symptoms and psychomotor retardation)and not grief-related symptoms(e.g.preoccupation with thoughts of the deceased) (Prigerson et al.,1995).The DSM-IV uses the term“complicated bereavement”for bereavement that triggers MDD.However,this 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 not occur in the bereaved individual(Shear and Shair,2005).The bereavement-related depression consists of symptoms such as hypochondriasis,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 for the deceased,and disbelief over his or her death(Prigerson et al., 1995;Tomita and Kitamura,2002).It is estimated that between 10%and20%of bereaved people experience CG(Middleton et al., 1996)and,although CG may share some symptoms and/or coexist with depressive and anxiety disorders(Simon et al.,2007),it con-stitutes a distinct cluster of symptoms that can be distinguished from depression(Prigerson et al.,1995;Shear et al.,2013)and should be recognised as a distinct type of pathological response to bereavement.
6.Longitudinal studies of grief
Longitudinal studies of bereaved cohorts have shown that, although most people move through the stages of bereavement without signi?cant morbidity and mortality,many develop what resembles a MDE,which is present in approximately42%of bereaved people within a month of the death,decreasing consider-ably to nearly25%at two months,and16%at one year(Clayton and Darvish,1979;Zisook and Shuchter,1991).The rate of depression among the bereaved is reported to be7%by two years post-loss, which is no longer different from the rate of depression in the wider community(Parkes and Brown,1972;Zisook et al.,1994b). Bereavement studies that have been conducted prospectively from before to after the loss have also shown that the bereaved are characterised by emotional stability rather than exhibiting extreme affective reactions(Galatzer-Levy and Bonanno,2012).Two longi-tudinal studies reported that most bereaved individuals showed moderate disruptions in daily functioning during the?rst year after loss,which constituted a normal grief reaction,while more chronic symptoms were evidenced by a relatively small minority (Middleton et al.,1996;Bonanno and Kaltman,2001).Based on these?ndings,it has been argued that humans are more resilient in the face of loss than had been previously believed(Bonanno et al.,2001).In2002,these authors revisited the data using a more sophisticated analytic technique(https://www.360docs.net/doc/ec2187085.html,tent growth modelling)to address the methodological shortcomings of previous approaches (Galatzer-Levy and Bonanno,2012).That study revealed four dis-tinct and clinically meaningful trajectories similar in shape and proportion to the previous analyses:Resilience(characterised by little or no depression;66.3%),Chronic Grief(characterised by depression following loss,alleviated by4years post-loss;9.1%), Pre-existing Chronic Depression(ongoing high pre-through post-loss depression;14.5%)and Depressed-Improved(characterised by high pre-loss depression that decreased following loss;10.1%) (Galatzer-Levy and Bonanno,2012,p.1).These?ndings con?rmed previous data showing that,while some bereaved individuals suffer intense grief,many others adapt well over the course of bereavement.
7.What determines whether a grief response becomes pathological?
The published literature provides some information on the fac-tors that may increase the propensity for bereavement to become complicated or evolve into depression.Stroebe et al.(2006)pro-vided a systematic review of risk factors in bereavement outcome
174 A.A.Assareh et al./Neuroscience and Biobehavioral Reviews49(2015)171–181
in terms of situational risk factors(e.g.mode of death),personal risk factors(e.g.personality)and interpersonal risk factors(e.g.social support).Using this framework,we provide below more examples of each category based on some more recent research.
Situational factors related to the death include place of death,the time from diagnosis of a life-threatening illness to time of death, perceptions of the death being violent,lack of preparedness for the death,a pattern of high distress pre-death and persistent feelings of being stunned or shocked by the death(Lobb et al.,2010).Intrap-ersonal factors include low social and emotional support,?nancial strain(Galatzer-Levy and Bonanno,2012)and lack of death-related rituals(Castle and Phillips,2003).Personal factors include gen-der,poor physical health,past personal or family history of MDD, exposure to trauma(Zisook and Kendler,2007),low psycholog-ical resilience,and personality factors(insecure attachment style, excessive dependency,negative cognitions,and personal incompe-tence)(Wijngaards-de Meij et al.,2007;Lobb et al.,2010).However, although a number of studies have investigated the effects of per-sonal risk factors on the bereavement outcome,biological factors have not received much attention.Consequently,these are the focus of this review.
8.Biological determinants of a response to bereavement
8.1.Genetic factors
As development of depression(like any other psychiatric disorder)is under a degree of genetic in?uence,the variation in the response to bereavement and the reason some people develop MDD following bereavement while others experience normal grieving,might be due(at least in part)to genetic factors.Twin,family and adoption studies consistently show a moderate heritability of depression of up to40%(Sullivan et al.,2000),which is similar to that found for type2dia-betes mellitus.The most-studied genes include the serotonin transporter-linked polymorphic region(5-HTTLPR),brain-derived neurotropic factor(BDNF),dopamine transporter(DAT1),tryp-tophan hydroxylase(TPH),and catechol-O-methyl transferase (COMT),as well as some non-monoamine related genes;includ-ing variants in the genes encoding for apolipoprotein E(APOE), guanine nucleotide-binding protein beta3(GNB3),and methy-lene tetrahydrafolate reductase(MTHFR)(Lopez-Leon et al., 2007).However,many of these?ndings have failed replica-tion.
8.2.Interaction of genetics with environmental factors
One possible explanation for poor replication of the psychi-atric genetic?ndings is inadequate attention to gene-environment interactions(‘GxE’).This means that often the vulnerability genes can be detected only when environmental impact has been objec-tively assessed.Possibly the best known example is the serotonin transporter gene(SLC6A4),in particular the length polymorphism known as5-HTTLPR,which occurs in“short”and“long”forms. The short allele is associated with lower transcription of the sero-tonin transporter mRNA and is therefore considered to be less ef?cient(Lesch et al.,1996).There have been over300published studies investigating the association of5-HTTLPR with anxiety-and depression-related phenotypes but the association of this gene with major depression has not been consistently reported (Clarke et al.,2010).A major development in the study of the5-HTTLPR occurred when it was reported that the association between stressful life events and depression was modi?ed by the5-HTTLPR polymorphism(Caspi et al.,2003).This was argued as explain-ing the varied results for the studies that simply investigated the5-HTTLPR and depression alone without taking into account the effects of stressful life events.Although many studies have investigated the effects on depressive status of the interaction between the5-HTTLPR polymorphism and a stressful life event, none has examined the effects of bereavement.Two meta-analyses recently synthesised the growing body of literature but failed to?nd consistent and replicable gene-by-environment effects (Munafòet al.,2009;Risch et al.,2009).However,these reviews have been criticised for overly restrictive inclusion criteria which resulted in the inclusion of only a small number of large studies that 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 con?rm the5-HTTLPR link between stress and depression(Zisook and Kendler,2007).Two subsequent,more inclusive meta-analyses sought to overcome the limitations of earlier meta-analyses and both found strong evidence that5-HTTLPR moderates the relation-ship between stress and depression,with the5-HTTLPR s allele being associated with an increased risk of developing depression under stress(Karg et al.,2011;Sharpley et al.,2014),although the later of those two reviews also revealed that almost26%of the81studies included in that meta-analysis failed to show any signi?cant association between the5-HTTLPR,stress and depres-sion(Sharpley et al.,2014).Although the5-HTTLPR has been the most examined gene for the GxE effects,the interaction of other gene variants with adverse life events has also been reported. Such genes include:serotonin transporter(SLC6A4)44BP Ins/Del (Eley et al.,2004),Serotonin1A receptor(HTR1A)(Brezo et al., 2009),dopamine receptor D2(DRD2)(Elovainio et al.,2007),BDNF (Gatt et al.,2009),and corticotropin-releasing hormone type1 receptor(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-in?ammatory cytokine SNPs in the Interleukin6(IL-6),IL-1ˇand TNF-?genes on the serum levels of the associated protein markers and also their interaction with bereavement severity(Schultze-Florey et al., 2012).Among the investigated polymorphisms,a GxE effect was observed for the IL-6?174SNP when IL-6?174G homozygotes were found to be protected against higher circulating levels of in?amma-tion resulting from bereavement exposure.However,those authors could not?nd a GxE effect for this SNP and depressive symptoms. An earlier study showed an association between depression and increased 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 modi?cation of signal trans-duction in these neurotransmitter systems(Shih and Thompson, 1999).As such,MAO-A activity is involved in the pathogenesis of major depression(Meyer et al.,2006).A functionally important30-bp variable number tandem repeat(VNTR)has been identi?ed in the promoter region of the MAO-A gene(Sabol et al.,1998),with the longer alleles increasing the transcription of the gene up to four times more than the shorter allele.The results of investigation of the association of this genetic polymorphism with depression have not been consistent,with two studies reporting the associa-tion(Schulze et al.,2000;Yu et al.,2005)while two other studies failed to do so(Kunugi et al.,1999;Syagailo et al.,2001).How-ever,one study that examined the effects of this genetic variation in the MAO-A gene in bereaved people showed a gender-speci?c association between the more active MAO-A VNTR variant and an increased vulnerability to complicated grief in females(Kersting et al.,2008).Those authors hypothesised that this could be due to the reduced serotonergic activity caused by elevated MAO-A
A.A.Assareh et al./Neuroscience and Biobehavioral Reviews49(2015)171–181175
activity as a primary monoamine-lowering process during major depression.
8.3.Epigenetic regulation
Research has shown that epigenetic regulation of gene transcription is a key mechanism for adaptation to external envi-ronmental stimuli at the molecular level(Feinberg,2007).The term‘epigenetic’refers to the reversible regulation of various genomic functions,which are independent of changes in the DNA sequence and principally include changes in DNA methylation and chromatin structure.Epigenetic mechanisms modify responses to environmental stimuli and contribute to tissue-speci?c gene expression pro?les during brain development involving pro-cesses such as neurogenesis and synaptic plasticity(Hsieh and Eisch,2010;Gr?ff et al.,2011).Therefore,epigenetic regula-tion might have a role in individual differences in response to environmental exposures to major stressors(Rutten et al., 2013).
On the other hand,it should be noted that the epigenetic modi?cations that differentiate individuals in their behavioural responses to environmental stresses might have been activated by experiencing stress during the early stages of life(Kim-Cohen and Turkewitz,2012).In other words,the relationship between epigenetic moderation and stress is reciprocal in that epige-netic processes can be activated by stress,and these long-lasting genetic imprints can later in?uence responses to environmen-tal stimuli.This might be one of the reasons that experiencing stressful life events early in life increases the risk of developing depression in adulthood when exposed to environmental adver-sity.
An example of long lasting epigenetic modi?cation due to early life stress has been reported for the glucocorticoid recep-tor(McGowan et al.,2009).Several studies have also shown the role of epigenetic changes in the BDNF gene in risk for psy-chiatric disorders,(for a review see Boulle et al.,2011).Lasting epigenetic in?uence of early life adversity on the BDNF gene has also been reported(Roth et al.,2009).In addition,there is some evidence that the serotonergic system is under the in?u-ence of epigenetic changes(Lesch,2011).One study showed that higher5-HTT methylation,but not5-HTTLPR genotype,exacer-bated the effects of early life stress on behavioural reactivity in rhesus macaque infants(Kinnally et al.,2010).The authors therefore concluded that5-HTT methylation may be an impor-tant regulator of5-HTT expression early in development and may contribute to the risk for mood disorders observed in‘high-risk’5-HTTLPR carriers.In a series of studies on humans,Philibert and colleagues showed that methylation of the serotonin trans-porter gene was associated with reports of childhood abuse (Beach et al.,2010)and that product levels of the serotonergic system varied according to the level of methylation(Philibert et al.,2007)Another study of participants with experiences of loss or trauma found that the association between the5-HTTLPR genotype and poor response to psychological problems was sig-ni?cantly moderated by methylation patterns(van IJzendoorn et al.,2010).Those authors reported that higher methylation lev-els of the5HTT promoter were associated with increased risk of unresolved responses to loss or trauma in carriers of the usually protective5-HTTLPR ll variant.The5-HTTLPR ss variant predicted more unresolved loss or trauma only in the case of lower levels of methylation(van IJzendoorn et al.,2010).The observed association of the epigenetic regulation and the risk of depression in genetically high-risk individuals urged further investigation of the interaction of epigenetic changes and stress-ful events,which may lead to identi?cation of novel patterns of how epigenetic moderations of other vulnerability genes to depression in?uence stress responses in people with different risk genotypes.
8.4.Neuroendocrine factors
As noted,the experience of bereavement as an aversive envi-ronmental event could result in development of depression in those individuals who carry particular genes that are up-or down-regulated by their grief experience.Interactions between such environmental events and genetic predisposition to depression may lead to neurobiological and structural changes in the brain regions linked to depression.
A principal mediator of the impact of stress on brain and behaviour 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,leading to the eventual release of cortisol from the adrenal glands.Although short-term elevations of cortisol can be protective and may promote adaptation to environmental demand,long-term hyper-cortisolaemia is harmful because it is associated with impaired neurogenesis and cell apoptosis in the hippocampus and prefrontal areas,plus increased dendritic branching in the amygdala(McEwen and Milner,2007).On the other hand,glucocorticoids,released as a consequence of HPA axis activation interact with steroid receptors expressed throughout the brain.In particular,glucocorticoid recep-tors and mineralocorticoid receptors are expressed at high levels in the hippocampus,amygdala,prefrontal cortex(PFC)and other limbic and midbrain structures,where they modulate the neural circuitry and neuroendocrine systems that underlie behavioural responses to stress(Russo et al.,2012).The neurochemical alter-ations caused by high activation of the HPA axis,including excess release of cortisol and steroid receptors,lead to several changes to brain regions that are linked to depression.These structural changes include increased volume in amygdala,decreased volumes of the PFC and hippocampus,and alterations of the connectivity between amygdala and PFC,and between amygdala and hippocam-pus(Sharpley,2013).It is noteworthy to mention that increases in amygdala function and impairment of the PFC is directly linked to key symptoms of depression.The pathway between environmental stressor-induced hyper-activation of the HPA axis and depres-sion represents the neurobiological link between the stressors and the depressive symptomatology that is described in behavioural accounts of depression(Sharpley and Bitsika,2010).
Bereavement is associated with increased adrenocortical activ-ity,and elevated cortisol in the early period of bereavement has been con?rmed in several studies(Biondi and Picardi,1996; Buckley et al.,2012).Altered adrenocortical activity was not present in all bereaved individuals but rather in a subgroup with severe bereavement outcomes,and was associated with higher levels of anxiety,depressed mood or intense grief(Jacobs et 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-bereaved controls.Both cortisol and DHEAS are outputs of the HPA axis and a higher ratio of cortisol to DHEAS is observed in older age.As such,elevated cortisol in a group with reduced abil-ity to produce DHEAS is likely to have greater impact in the elderly bereaved,with greater potential for immune alteration (Khanfer et al.,2011).In addition,a small amount of evidence shows 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 isolated episode of stress(Jacobs et al.,1987;Biondi and Picardi,1996). Some individuals show an elevation in serum growth hormone in response to acute stress.One study showed that not only
176 A.A.Assareh et al./Neuroscience and Biobehavioral Reviews49(2015)171–181
the loss,but even the memory of the event,can trigger a neuroendocrine response as evidenced by the?nding that the recall of the lost loved-one can provoke a sharp increase in neu-roendocrine activity during an interview several months post-loss (Kosten et al.,1984).
8.5.Immunologic/in?ammatory factors
Activation of the in?ammatory immune system in response to stressors is also implicated in depression.Release of immune-signalling molecules(cytokines)such as interleukin-1?, interleukin-6,tumour necrosis factor-?and interferon-?,might in?uence many of the neurochemical changes provoked by stress-ors and thereby contribute to depression(reviewed by Anisman, 2009).
Changes in immune function have been reported in early bereavement and include reduced proliferation of T-cells(Bartrop et al.,1977;Schleifer et al.,1983;Gerra et al.,2003)and reduced activity of natural killer(NK)cells(Irwin et al.,1988;Gerra et al.,2003).Lower lymphocyte response(Linn et al.,1984),lower immunoglobulin-M levels(Lindstr?m,1997),absolute loss of sup-pressor/cytotoxic cells(Irwin et al.,1987)and reduced NK cells (Irwin et al.,1988)are also associated with higher depression scores in bereaved people.In addition,a well-designed,longitudi-nal study showed that,while no differences were observed between bereaved and control subjects in T-cell subpopulation,NK activity, and lymphocyte proliferation,the subgroup of bereaved subjects who met the criteria of major depression had a lower concentra-tion of CD8cells(a glycoprotein that serves as a co-receptor for the T cell receptor),lower NK activity,and a trend towards lower lymphocyte stimulation responses compared to a non-depressed bereaved group(Zisook et al.,1994a,b).
Stressful life events are linked to increased in?ammatory signalling and production of systemic markers of in?ammation. Schultze-Florey et al.(2012)investigated the impact of bereave-ment status on circulating levels of in?ammatory markers IL-6, IL-1RA as a marker of IL-1activity,and soluble tumour necrosis factor receptor II(sTNFRII)as a surrogate marker of TNF-?levels. Bereaved participants had higher levels of IL-1RA and IL-6com-pared to non-bereaved control participants but this was explained by either genotype differences or the severity of grief(Schultze-Florey et al.,2012).
Data from several studies suggest that the changes in the immune function of bereaved persons are more related to the depressive symptomatology accompanied by bereavement,rather the acute effect of loss per se(Biondi and Picardi,1996).Consis-tently,another study showed that,although changes in endocrine and immune parameters are signi?cantly more marked in the early phase of bereavement,they are still present in a number of bereaved persons6months after the acute phase,in association with in?ated anxiety and depression scores(Gerra et al.,2003). Those authors concluded that subjects who experienced a trau-matic event such as bereavement must still be considered at risk for the possible consequences of disruption in both the HPA and the immune system even six months post-loss.
8.6.Brain neurotransmitters
In addition to changes in the neuroendocrine and immuno-logic/in?ammatory systems,stressors also promote functional changes of classical neurotransmitter systems.Some of the neu-rotransmitter systems in?uenced by stressors include GABAergic (e.g.glutamate)and monoamine(e.g.dopamine,epinephrine,sero-tonin)pathways.The release of dopamine(Feenstra et al.,1995) and glutamate(Bagley and Moghaddam,1997)in response to stress has been shown in the PFC.Variation of brain levels and turn-over of serotonin(5-HT),5-HT transporter(5-HTT)and several sero-tonin receptors(5-HT1A,5-HT1B,5-HT2A,5-HT2C)has also been associated with stress-induced depression(Anisman et al.,2008; Anisman,2009).
As examining the modi?cation of brain neurochemicals in bereaved people is not currently possible,most of the knowledge regarding the alteration of brain neurotransmitters following a stressful life event is from animal studies.Non-human primate models share most of their genetic material with humans and therefore 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 after separation in monkeys,such as pituitary adrenal activation and reduced lymphocyte response to mitogen,are similar to neu-roendocrine and immune system changes in bereaved people. Therefore,the results of stress-induced neurotransmitter changes in non-human primates can also be applied to humans(Biondi and 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 CNS catecholamines and serotonin have been observed in the early acute phase of stress,resulting in an increase in CSF monoamine metabolite concentrations(Bayart et al.,1990).If the stress is prolonged,a chronic phase develops,with increased CSF levels of methoxy-hydroxyphenolglycol(a metabolite of norepinephrine degradation),and decreased levels of CSF homovanillic acid(Higley et al.,1991),the major dopamine metabolite.Another animal model of stress-induced depression is the exposure of male rats to a social defeat(Koolhaas et al.,1997).An important component of the dopaminergic system is the neuronal dopamine transporter (DAT),which regulates dopaminergic neurotransmission(Amara and Kuhar,1993).The stress-induced decrease of DAT binding sites has been shown in male rats after a single social defeat followed by social isolation(Isovich et al.,2001).
As opposed to mere social isolation,Bosch and colleagues introduced a model that selectively examined the effect of loss of a bonded partner on passive stress-coping behaviour(Bosch et al.,2008).Those authors suggested that,as the monogamous prairie vole forms enduring and selective pair bonds with its mat-ing partner,this rodent model can provide unique insights into the physiological consequences of pair bonding and the neurobiology of the loss of a bonded partner which may be relevant to grieving and bereavement in humans.
8.7.Neurotrophic growth factors
Depression has been associated with alterations of growth factors.Brain-derived neurotrophic factor(BDNF)is a secretory protein in the neurotrophin family which has been associated with both depression and anxiety(Martinowich et al.,2007).A num-ber of studies have demonstrated that blood levels of BDNF are decreased in depressed patients and can be normalised through antidepressant treatments(Shimizu et al.,2003;Schmidt and Duman,2010).Stressors were consistently shown to reduce the expression of BDNF in limbic regions that mediate mood states (Duman and Monteggia,2006).
Fibroblast growth factor-2(FGF-2)is a trophic molecule that has a critical role in the maturation and survival of a variety of neuronal phenotypes(Baird,1994).Stress-induced alterations of the FGF-2levels have been reported previously,and possibly occur through 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 model of early life stress leads to alterations in neurotrophins such as BDNF(Roceri et al.,2001;Marais et al.,2009),nerve growth factor
A.A.Assareh et al./Neuroscience and Biobehavioral Reviews49(2015)171–181177
(NGF)and neurotrophin-3(NT-3)(Marais et al.,2008).In addition, it has been shown that exposure to traumatic events(assessed by DSM-IV stem criteria for trauma)lowers the levels of BDNF in bipolar patients(Kauer-Sant’Anna et al.,2007).Another study showed that females who were genetically disposed to depression and were subjected to recent stressful life events(assessed by a previously published method in Kendler et al.,1995)had lower whole blood BDNF levels compared to genetically low-risk women or compared to men(Trajkovska et al.,2008).Those authors argued that the absence of such an association in men and women who were genetically protected against depression supports the notion that high-risk females are particularly vulnerable to depression (Kendler et al.,2006).However,no study to date has investigated the speci?c role of bereavement in serum levels of BDNF,although it could be assumed that this would show a similar pattern to other stressors and that the BDNF levels would be different in normal grief as in full-blown depression in bereaved people.
8.8.The biology of resilience
As discussed,personality factors such as insecure attachment style,excessive dependency,negative cognitions and personal incompetence may increase the risk of depression following bereavement(Wijngaards-de Meij et al.,2007;Lobb et al.,2010). Although a large body of empirical research has examined nega-tive psychological traits as determinants of a response to stressful life events,relatively little is known about how positive personal-ity characteristics such as self-system processes,ego resiliency and moderate ego over-control might modify the response to bereave-ment.
One of the most powerful buffers against anxiety and depres-sion disorders is the individual’s belief in their personal control of how they will cope with adverse circumstances(Rutter,1985).This belief has more recently been conceptualised as“resilience”in the face of major stressors(Rutter,2006).Psychological resilience is a dynamic process and has been de?ned as a measure of coping abil-ity with stress(Connor and Davidson,2003)that encompasses the attainment of positive adaptation within the context of exposure to signi?cant adversity that typically exerts major assaults on biologi-cal and psychological developments(Cicchetti and Rogosch,2012). The concept of resilience entails on one hand a process of sustaina-bility that prevents and attenuates disturbance of mental health and wellbeing after exposure to severe adversity,and on the other hand a process of rapid recovery from mental health disturbance following exposure to adversity(Rutten et al.,2013).
Genetic factors may be important determinants of resilience to major stressors that can lead to disorders such as depression arising from bereavement.A few studies have investigated the association of candidate genes with stress resilience.The stud-ied genes included corticotrophin-releasing hormone receptor1 gene(CRHR1),FK506binding protein5(FKBP5),which is a gene that codes for a‘chaperone’protein that regulates glucocorti-coid receptor sensitivity,SLC6A4,Catechol-O-methyltransferase (COMT),Neuropeptide Y(NPY)and BDNF(Feder et al.,2009;Kim-Cohen and Turkewitz,2012).Most of these genes signi?cantly moderated the effect of the stressful life event on resilience. Recently,a GxE study showed that polymorphisms in four genes, 5-HTTLPR,CRHR1,dopamine receptor(DRD4-521C/T)and oxytocin receptor,all signi?cantly moderated the impact of maltreatment on the resilient functioning score,which the authors interpreted as support for differential susceptibility to the environment perspec-tive(Cicchetti and Rogosch,2012).According to the differential susceptibility to environmental in?uence hypothesis proffered by Belsky and Pluess(2009),genes that confer risk in harsh environments may also confer bene?ts in normal or nurturing environments.In other words,the characteristics of individuals (including their genotypes)that make them excessively more vul-nerable to experiencing adversity may also make them excessively more likely to bene?t from supportive environments.In the case of Ciccetti and Rogosch’s study(2012),maltreated children with two copies of the5-HTTLPR short allele had lower resilient func-tioning,whereas non-maltreated children with the same5-HTTLPR genotype had higher levels of resilient functioning.Similar patterns were observed in children who had no copies of the CRHR1TAT hap-lotype,the TT genotype of the DRD4gene and the A allele carriers of the oxytocin receptor gene.
As signi?cant individual differences in resilience to stress-induced neurochemical alterations have been reported(Feder et al., 2009),recent studies have investigated the biological basis of stress resilience with the aim of identifying novel protective factors to promote resilience in vulnerable individuals in the face of adver-sity.For instance,increased hippocampal BDNF levels have been shown to mediate stress resilience in rodents(Taliaz et al.,2011) and administration of peripheral BDNF has shown to moderately reduce behavioural de?cits caused by stress(Schmidt and Duman, 2010),also in rodents.These results suggest that BDNF could serve as a potential marker for stress resilience.
Furthermore,a recently proposed biomarker for resilience is Reelin(Fatemi,2011),which is an extracellular protein responsi-ble for neuronal cell migration and normal brain lamination during embryogenesis and has been shown to have a role in cell signalling and synaptic plasticity in adult life(Rice and Curran,2001).Altered expression of Reelin and its isoforms has been shown in several neuropsychiatric disorders,including major depression(Folsom and Fatemi,2013).As over-expression of Reelin in a transgenic mouse model led to reversal of various behavioural abnormalities (Teixeira et al.,2011),this molecule has been suggested as a marker for stress resilience.Genetic alterations of the RELN gene have been shown 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 to date,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 model of stress-induced biological changes resulting in depression fol-lowing bereavement.As shown in Fig.1,early life stress(e.g.loss of a parent,childhood maltreatment)leads to lasting epigenetic changes,which result in modi?ed gene expression,speci?cally when an individual is exposed to another stressful event later in adult life.Genetic factors can predict the risk or resilience to an adverse life event,based on different polymorphisms in the genes and whether they up-or down-regulate the gene expression levels.
Bereavement as a very stressful life event triggers biologic responses in several pathways including neuroendocrine response, in?ammatory/immune system,neurotropic growth factors and neurotransmitters.The responses in these systems,along with genetic factors either directly or in an interaction with environment (bereavement)cause alterations in the level of related proteins, which?nally affect brain regions involved in the development of depressive behaviour.(It is important to note that the genes or pro-teins shown in this model are some examples and by no means do they represent the range of molecules known to date that are involved 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?eld of
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171–181
Fig.1.The role of biological factors in development of depression following a stressful life event (bereavement).Abbreviations :CRHR1:corticotropin-releasing hormone type 1receptor;GCC:glucocorticoids;GCCR:glucocorticoid receptors;IL-6:interleukin 6;5-HTTLPR :serotonin transporter gene length polymorphism;BDNF:brain-derived neurotropic factor;FGF-2:?broblast growth factor-2;GxE:gene by environment interaction.
depression inconsistent and non-replicable,as often the vulner-ability genes can be detected only when environmental impact has been assessed.Meta-analyses have shown that robust ?ndings in GxE investigations are observed when a speci?c stressor is iden-ti?ed (Karg et al.,2011;Sharpley et al.,2014).The emerging GxE studies in the past decade which resulted in identi?cation of a few genetic risk factors for developing depression following an adverse life event (Harro and Kiive,2011)have mainly focused on child-hood trauma,while bereavement as the most stressful life event has not received the attention it deserves in GxE studies for uncov-ering genetic factors underlying depression.Furthermore,the data so far indicate that multiple gene/biology systems are implicated in determining an individual’s vulnerability to the negative conse-quences of an adverse environment (Kim-Cohen and Turkewitz,2012)and therefore each of the known genetic factors imply a small effect for the risk of depression and it is the complex inter-play between several mechanisms that make a person ‘at risk’of developing depression after bereavement.Genetic studies often investigate not more than a few risk genes,either for their direct association with depression or their interaction with stressful life events.The same scenario applies to epigenetic studies or studies investigating stress-induced biological responses.Better insight is needed regarding the mechanisms by which these many molecules interact with each other,urging the need for more comprehen-sive studies applying modern biotechnology techniques to collect genomic,epigenomic,transcriptomic,proteomic and metabolomic data,and use of sophisticated statistical software and computa-tional packages for their analyses.Another step towards advancing the ?eld of GxE research is to consider resilience instead of focusing exclusively on mental disorders.Genome-wide studies can be con-ducted to explore genetic determinants of psychological resilience,
which requires a large cohort of participants with reliable resilience scores.
Another gap in the literature is regarding the use of bio-markers in early detection of bereavement-related depression.The role of stress has received much attention in the depression litera-ture but its study using biological markers has not been extended to bereavement and depression.The commonly-used measures of physiological stress states are salivary cortisol (as an index of the HPA axis)and salivary alpha-amylase (as an index of the sympathetic-adrenal-medullary (SAM)axis).These two indicators of psychophysiological stress responses can complement paper-and-pencil tests of anxiety and depression and provide additional ways of validating the state of the participants vis-à-vis their reac-tions to bereavement.Although cortisol levels have been assessed in relation to the severity of participants’response to bereavement (Jacobs et al.,1987;Gerra et al.,2003),their utility in predicting MDD following bereavement has not been examined.Moreover,no study has yet investigated the association of alpha-amylase with depression following bereavement.
As some in?ammatory markers (lower lymphocyte response,lower immunoglobulin-M levels,and higher NK cells)have been shown to be associated with higher depression scores in bereaved people (Buckley et al.,2012),they can serve as biomarkers of depression once their association with MDD in bereaved people is replicated in other cohorts.In addition to in?ammatory mark-ers,growth factors in speci?c plasma levels of BDNF are proposed as 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 examined bereavement in the context of neurobiological changes follow-ing an environmental stressor.Therefore,the data from other general stressors have been presented and discussed where no bereavement-speci?c data were available in the literature.Consid-ering the fact that the similarities between bereavement-related depression and depression related to other stressful life events sub-stantially outweigh their differences(Kendler et al.,2008),similar patterns of biological changes are expected following bereave-ment.In addition,the biological responses triggered by perceived loss are shown to be stronger than responses to other stressors (Gail et al.,1997),with unexpected loss of a loved one but not anticipatory bereavement,being associated with increased adreno-cortical activity(Irwin et al.,1988).However,individuals with bereavement-related depression are reported to have lower lev-els of neuroticism,and guilt and higher levels of fatigue and loss of interest compared to individuals with depression related to other stressful life events(Kendler et al.,2008).Therefore,although the neurobiological changes due to general life stressors could be extended to bereavement,caution must be taken in generalising such results.
Apart from the lack of information on neurobiological features underlying bereavement-related depression,it is also important to note that multiple grief trajectories exist and,with either com-plicated grief or bereavement-related depression,the symptoms are characterised as pathologic if:(1)they last for a long dura-tion;(2)reach a threshold for a psychiatric diagnosis;(3)impact negatively on functioning;or(4)cause marked distress.However, the differing manifestations of these trajectories have not been examined consistently in the same study.More importantly,there is a high non-normal variability among depression scores follow-ing loss.Variability following such a distribution level may not be successfully captured in statistical models that sample from the mean,as is commonly the case in bereavement studies,because such models assume homogeneity characterised by a single nor-mal distribution.A number of approaches(e.g.Hierarchical Linear Modelling)have been developed to model patterns with high lev-els of variability.However,these modelling techniques assume a common pattern that individuals?t better or worse.For variables such as the stress response for which there is a true heterogene-ity,such models may be inadequate(Galatzer-Levy and Bonanno, 2012).A recent set of analytic techniques that has emerged to response to limitations of previous methods is Latent Growth Modelling,which allows for the empirical exploration of the under-lying heterogeneity within the data,while also allowing for the modelling of covariates as predictors(Galatzer-Levy and Bonanno, 2012).
A similar heterogeneity exists for the de?nition of depression itself.With nine diagnostic criteria for MDD,and two key criteria, the possible number of required symptoms for a diagnosis of MDD is nearly1500(Ostergaard et al.,2011).Based upon this wide vari-ety in depressive symptomatology for MDD and the relatively poor outcomes of standard?rst-line treatments(i.e.about50%effec-tiveness)(Rush et al.,2006),the notion of‘depressive subtypes’has been recommended as a potential way of identifying and explaining the lack of general treatment ef?cacy for MDD(Insel,2013,2014). One model of four subtypes of MDD based upon clustering of simi-lar symptoms has been described(Sharpley and Bitsika,2013),with validity and reliability data reported(Sharpley and Bitsika,2014). These four subtypes of depression have been observed in prostate cancer patients(Sharpley et al.,2013),who experience a form of bereavement in their loss of function that may be similar to that experienced by persons who have lost a loved-one.Further inves-tigation of the ways in which MDD may present could represent a potential method for diagnosing bereavement-related MDD as distinct from CG.11.Conclusion
Examining biological risk and protective factors for the develop-ment of depression after bereavement is a nascent?eld of research. Results from such investigations would considerably contribute to advancing the knowledge in both?elds of bereavement and depres-sion.Bereavement offers an excellent opportunity to study the antecedents of depression longitudinally,considering the relatively high number of people who develop depression after bereavement. These?ndings may have applications to depression in other con-texts and major depression in general.
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