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Major Depression in Children

Child and adolescent psychiatry and behavioral sciences, what is major depression.

A type of mood (or “affective”) disorder, major depression, goes far beyond the typical feelings of sadness that a child might experience. Instead, major depression is a persistently sad or irritable mood that affects a child’s thinking and behavior at home, in school, and with peers.

The National Institute of Mental Health estimates that more than 10 percent of adolescents ages 12-17 experience major depression in a given year. It is on the rise in both children and adolescents. With early onset, childhood and adolescence depression can predict future episodes of depression into adulthood. Early and consistent treatment can help to lessen the risk of recurrence and reduce the severity of symptoms while improving functioning and well-being.  

Causes of major depression

There are a combination of causes, such as genetics, environment, and psychological factors.  Research suggests that major depression has a strong genetic component given that the illness can be passed on from one generation to the next.  However, it’s important to note that children don’t always develop depression simply because their parents have it. Many children develop depression even when there is no family history of the illness.  Children are also more likely to develop depression if they experience environmental stress such as abuse, neglect, or trauma, significant changes or losses, family and parental distress, or significant peer conflict such as bullying or romantic loss. In addition, children with chronic medical illnesses or other behavioral health disorders, such as anxiety, are at risk for developing depression.  

Signs and Symptoms of major depression

Each child may experience symptoms of major depression differently. To be diagnosed with major depression, a child needs to show at least one of the following two symptoms for most days of the week, for most of the day, during the same two-week period:

Persistent feelings of sadness or irritability

Loss of interest or pleasure in all or almost all activities once enjoyed

In addition, several of the following symptoms must also be present:

Feeling hopeless or helpless

Having low self-esteem

Feeling inadequate

Excessive guilt

Difficulty with relationships or social withdrawal

Sleep disturbances, whether sleeping too much or too little

Changes in appetite or weight

Decreased energy

Difficulty concentrating or a decline in school performance

Increased sensitivity to failure or rejection

Frequent physical complaints, such as a headache, stomachache, or fatigue

Thoughts of wishing to be dead

Suicidal thoughts or attempts

It’s crucial to remember that depression symptoms and suicidal thoughts and behaviors must be taken very seriously. 

Testing and Diagnosis of major depression

If you believe your child suffers from major depression, talk to your child’s pediatrician or seek out either a therapist or psychiatrist who specializes in children and adolescents. An accurate diagnosis and early treatment are keys to success in managing major depression. Depression can also occur alongside other behavioral health disorders, such as substance abuse or anxiety disorders. With the level of complexity often involved in diagnosing and treating depression, finding a highly trained professional, such as a pediatrician, licensed clinical social worker, a child psychologist, or a child and adolescent psychiatrist, is important. At Children’s Hospital of Philadelphia, a specialist will perform a comprehensive psychiatric evaluation. The evaluation may assess : 

Your child's age, overall health, and medical history

Extent of your child's current symptoms, behaviors, and functioning

Expectations for the course of the condition

Family dynamics and environmental stressors

Family psychiatric and medical history

Input from teachers and other care providers

Treatment for major depression

Early treatment is key to reducing distress, improving functioning, and preventing future depression episodes. Without treatment, your child’s depression could persist for longer and become increasingly more severe, leading to significant impairment in school, at home, and with friends and family.

At Children’s Hospital of Philadelphia, a specialist will design an individualized treatment plan based on your child’s symptoms and other personal factors. The treatment plan may include:

Evidence-based Individual Therapy

Cognitive-behavioral therapy: This treatment will help your child decrease depressive symptoms by changing distorted views of himself/herself and the world, engage in activities that promote positive mood, and utilize effective problem solving and coping skills.

Interpersonal therapy: This treatment will help your child decrease depressive symptoms by having him/her cope with and work through difficult relationship stressors by learning skills to improve communication, problem solving, and social interaction.

Family Therapy

A parent’s support is crucial in helping a child learn to manage his/her mood and life. Family therapy can also explore and address family dynamics or situational stressors contributing to your child’s depression.

An antidepressant medication can be very effective in treating moderate to severe depression, especially when it’s combined with individual and/or family therapy.

Outlook for major depression

Most children who receive early and effective treatment for major depression will improve and may even go on to experience complete resolution of symptoms. Children with more severe episodes of depression and children who have depression as well as other disorders (such as substance use, anxiety, or emotional dysregulation) may continue to work with treatment providers for a longer period of time. Some children will have a recurrent type of depression that can come and go over the course of their lifetime.  These children benefit from periodically re-engaging in treatment as symptoms arise.

Follow-Up Care

Depending on your child’s personalized treatment plan, your child and family may continue to meet with treatment providers until the symptoms of depression are in remission or under good control.  Periodic follow-up visits may be advised to monitor your child’s progress and ensure continued well-being.

Why Choose CHOP

An accurate diagnosis and early treatment are critical to helping a child recover from major depression and prevent later episodes. Treatment also allows your child to flourish at home, school, and in their relationships. Your child would be able to function at his/her best without depression interfering with his/her thoughts, feelings, and behavior. The team at Children’s Hospital of Philadelphia is specially trained to diagnose, treat, and manage major depression in children and adolescents. They have the skill set and experience to lead your child to long-term success.

Reviewed by Rhonda C. Boyd, PhD , Jason A. Lewis, PhD

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• Winter 2024 | VOL. 36, NO. 1 CURRENT ISSUE pp.A5-81

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The Links Between Stress and Depression: Psychoneuroendocrinological, Genetic, and Environmental Interactions

• Gustavo E. Tafet , M.D., Ph.D. ,
• Charles B. Nemeroff , M.D., Ph.D.

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The role of stress in the origin and development of depression may be conceived as the result of multiple converging factors, including the chronic effect of environmental stressors and the long-lasting effects of stressful experiences during childhood, all of which may induce persistent hyperactivity of the hypothalamic-pituitary-adrenal axis. These changes, including increased availability of corticotropin-releasing factor and cortisol, are also associated with hyperactivity of the amygdala, hypoactivity of the hippocampus, and decreased serotonergic neurotransmission, which together result in increased vulnerability to stress. The role of other monoaminergic neurotransmitters, genetic polymorphisms, epigenetic mechanisms, inflammatory processes, and altered cognitive processing has also been considered in the development of a comprehensive model of the interactions between different factors of vulnerability. Further understanding of the underlying mechanisms that link these factors may contribute significantly to the development of more effective treatments and preventive strategies in the interface between stress and mood disorders.

The link between stressful life events and the origin and development of depression has been widely investigated, providing an increasing body of evidence supporting this association. 1 – 3 Environmental factors likely affect individuals in somewhat different manners, therefore triggering an adaptive response to stress, which depends on both psychological and biological aspects in the interaction between stressors and individual resources. Psychological aspects include all of the cognitive processing related to incoming information; the subjective appraisal of different features related to stressors, such as magnitude and chronicity, predictability, and controllability; and potential resources to cope with them. Biological mediators include the activation of different neural structures underlying information processing, including sensory pathways, which convey environmental input to the CNS, and the resulting activation of neural and neuroendocrine cascades of molecular events, mediated by the subsequent activation of the sympathetic division of the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. 4 The efficacy of an adaptive response implies that it may be rapidly activated, to allow reacting in a successful and effective manner during stressful situations, and it should be efficiently controlled and concluded afterward. If it continues in a prolonged and excessive manner (e.g., during chronic stressful situations), it may lead to maladaptive changes, which in turn may contribute to the development of pathological conditions such as anxiety and mood disorders, including depression, particularly in individuals with increased genetic vulnerability. In this regard, various polymorphisms have been investigated as candidate genes, which are known to participate in important molecular pathways involved in the origin of depression. The presence of these genetic variations appears to be involved in the development of depression in response to stressful events, including adverse experiences during childhood and environmental stressors during adulthood. 5 – 10 Moreover, various studies have focused on the role of gene–environment interactions, including the search for these polymorphic variants and the role of transcriptional regulation by epigenetic mechanisms. 6 , 11 – 13 In addition, inflammatory processes associated with adaptive responses to stressful situations, with the consequent synthesis and release of proinflammatory cytokines, may lead to further maladaptive changes of neural and neuroendocrine systems, therefore contributing to the development of depressive symptoms, particularly in chronically stressed individuals.

This article aims to review the evidence for the role played by stress, associated with different converging factors, including a genetic diathesis, a history of adverse early life events, hyperactivity of the HPA axis, decreased monoamines, increased proinflammatory cytokines, and epigenetic mechanisms, such as those observed in response to environmental stressful conditions, and their potential interactions in the etiology of depression. An increased understanding of these factors and their potential interactions may lead to more effective strategies for the treatment of this disorder.

Processing of Environmental Stressors in the Brain

Environmental stressors are perceived and transmitted through sensory pathways to different structures in the CNS, such as the thalamus, which convey projections to the amygdala, and to sensory and association cortices, which in turn also project to different areas of the prefrontal cortex (PFC), including the orbitofrontal cortex, the medial PFC, and the anterior cingulate cortex (ACC). 4 , 7 Direct projections from the thalamus to the amygdala contribute to activate arousal and early alarm reactions, with the subsequent activation of the autonomic nervous system and the HPA axis, whereas indirect projections may reach the amygdala from sensory and association cortices as well as from transition cortices. The latter areas, including the entorhinal, perirhinal, and parahippocampal cortices, in turn project to the hippocampus, where sensory input is integrated with contextual cues, to convey more elaborated information to the amygdala. 14

The amygdala plays a critical role in emotional processing, including the assessment of the emotional relevance of environmental stimuli as well as internal stressors. It plays a key role in the regulation of autonomic and neuroendocrine responses, through projections to the lateral hypothalamus, which mediate the activation of the sympathetic branch of the autonomic nervous system; through direct projections to the paraventricular nucleus of the hypothalamus; or indirectly through the bed nucleus of the stria terminalis, which is involved in activation of the HPA axis. 14 In addition, the amygdala shares important connections with the orbitofrontal cortex and the medial PFC, 15 including Brodmann areas 10 and 32, and the subgenual ACC (Brodmann area 25). 16 The orbitofrontal cortex (Brodmann areas 11–14) has been associated with integration of multimodal sensory stimuli and primary appraisal of their positive or negative value, therefore participating in their affective assessment. 17 The medial PFC overlaps with the ACC, particularly in the subgenual ACC, 17 which regulates emotional responses generated by the amygdala. 18 These structures are in turn connected with the dorsolateral PFC (Brodmann areas 9 and 46) and the ventrolateral PFC (Brodmann areas 45 and 47), which participate in cognitive control and voluntary regulation of emotion. The dorsolateral PFC, which has been associated with executive aspects of cognitive processing 19 (most notably with conscious processing and working memory), receives input from the amygdala through the orbitofrontal cortex and ACC. 15 , 17 The dorsolateral PFC reciprocally projects back to limbic structures, mostly through indirect connections to the ventromedial PFC (Brodmann area 32), which projects to the subgenual ACC. 19 It has been proposed that projections from the ventromedial PFC and the subgenual ACC exert a modulatory effect on the amygdala, 19 , 20 which in turn sends excitatory output to the hypothalamus, 17 – 19 therefore regulating the activity of the HPA axis.

Decreased volume of the subgenual ACC has been described, together with hyperactivity of the amygdala, in individuals with mood disorders, 16 , 21 which has been associated with the role of the subgenual ACC in the top-down regulatory pathway between the dorsolateral PFC and the amygdala, allowing conscious down-regulation of negative emotions. These corticolimbic pathways may be dysfunctional in patients with depression, in which the dorsolateral PFC, dorsomedial PFC, orbitofrontal cortex, and ACC appear to be dysfunctional, particularly during cognitive-emotional tasks, with the consequent disruption of their top-down inhibitory effect expressed in the impaired cognitive modulation of emotions. 20 , 21 Recovery of conscious regulation of negative emotions has been associated with clinical recovery. In addition, decreased hippocampal volume has also been observed, along with increased activity of the amygdala and reduced activity of the dorsolateral PFC. 21 More recently, we documented changes in cortical thickness in patients exposed to child abuse and neglect, with the findings specific to the nature of the abuse. 22

Figure 1 illustrates the network of functional connections among different neural structures involved in adaptive responses to stress, including the processing of environmental stimuli through cortical and subcortical structures, and the activation of the HPA axis.

FIGURE 1. Schematic Representation of Neural Structures Involved in the Stress Response a

a Stressors are perceived by sensory receptors, which convey information to the thalamus, primary sensory cortices, association cortices, transition cortices, the hippocampus, and the amygdala. The amygdala also receives direct input from the thalamus. The orbitofrontal cortex and the medial prefrontal cortex are reciprocally connected and, together with the anterior cingulate cortex, convey information from sensory cortices and association cortices to subcortical structures, including direct connections to the hypothalamus and reciprocal connections with the amygdala. The amygdala participates in the activation of the HPA axis through stimulatory projections to the paraventricular nucleus of the hypothalamus, with consequent synthesis and release of CRF, which stimulates the release of ACTH from the pituitary. In turn, this stimulates the release of glucocorticoids from the adrenals, particularly cortisol. Cortisol exerts negative feedback at the level of the hypothalamus and the pituitary, as well as through the hippocampus, which exerts an inhibitory effect on the HPA axis. Activation of the HPA axis is also regulated by norepinephrine, through projections from the locus coeruleus, and serotonin, and through projections from the raphe nuclei. Both aminergic systems participate in regulation of the stress response through connections with the amygdala and the hippocampus, therefore exerting regulatory effects on both limbic structures. The amygdala is also involved in the activation of the autonomic component of the stress response through CRF inputs to the locus coeruleus. Solid lines indicate stimulatory inputs, whereas dotted lines indicate inhibitory inputs. ACC, anterior cingulate cortex; ACTH, adrenocorticotropin; CRF, corticotropin-releasing factor; DLPFC, dorsolateral prefrontal cortex; HPA, hypothalamic-pituitary-adrenal; MPFC, medial prefrontal cortex; OFC, orbitofrontal cortex.

Role of the HPA Axis

Activation of the HPA axis is initiated in limbic structures, including direct projections from the central nucleus of the amygdala, or indirectly through the bed nucleus of the stria terminalis, which projects to the hypothalamic paraventricular nucleus, where corticotropin-releasing factor (CRF) is synthesized in parvocellular neurons and released to reach the anterior pituitary. There, CRF regulates the transcription of the proopiomelanocortin gene (a common precursor for adrenocorticotropin, β-endorphin, and related peptides) and stimulates the release of adrenocorticotropin into the systemic circulation. Adrenocorticotropin acts upon the adrenal cortex to stimulate the biosynthesis and release of glucocorticoids, particularly cortisol. 23

At the molecular level, cortisol binds to mineralocorticoid receptors (type I) and glucocorticoid receptors (GRs; type II), constituting a hormone-receptor complex, which in turn undergoes conformational changes to allow its recognition and binding to a glucocorticoid response element, in the promoter region of many target genes. 24 Cortisol regulates the activity of the HPA axis through multiple negative feedback loops, which require its binding to GRs located in the paraventricular nucleus and the pituitary, where it down-regulates the synthesis and release of CRF and adrenocorticotropin, respectively, and GRs in the hippocampus, which in turn activates GABAergic projections to the paraventricular nucleus that inhibit HPA axis activity. Hence, many of the effects of cortisol may be understood as a result of transcriptional regulation of various genes, including those involved in the negative feedback loops responsible for the regulation of the HPA axis. 24

In response to short-term exposure to environmental stressors, the amygdala stimulates the HPA axis with the consequent synthesis and release of cortisol, 14 which is self-regulated by negative feedback mechanisms mediated by the glucocorticoid. In addition, the HPA system interacts with CRF neurons in the amygdala, activating a positive feedback loop involved in fear and anger reactions; the HPA also activates catecholaminergic neurons, stimulating arousal and improving cognitive functions. Hence, upon exposure to acute or short-term stressors, cortisol is expected to exert widespread metabolic effects, which is mostly necessary to maintain or restore homeostasis. 25 Cortisol is actively involved in the mobilization of energetic resources, including the stimulation of gluconeogenesis with the resulting increased levels of circulating glucose, and the down-regulation of inflammatory processes, therefore contributing to coping with the stressful situation.

Chronic and persistent activation of the HPA system may disrupt physiological mechanisms, including negative feedback loops, resulting in persistent activation of the system. Circadian rhythms normally characterized by wide variations, with morning zeniths and evening nadirs, are markedly altered during chronic stress, with the consequent increase in plasma cortisol levels and blunted circadian rhythm, mostly due to increased levels of cortisol during the evening and mild changes in the morning. 25 Prolonged exposure to increased levels of cortisol may induce detrimental effects on hippocampal neurons, reducing dendritic branching and inhibiting neurogenesis. 26 Moreover, hypersecretion of CRF and cortisol was also associated with decreased hippocampal volume, particularly in individuals exposed to childhood trauma. 27 Because the hippocampus is involved in the regulation of the HPA axis, it is conceivable that patients with major depression and early life trauma who exhibit reduced hippocampal volume 28 , 29 may also exhibit decreased hippocampal function, therefore resulting in further sensitization of stress responses. 5 These observations support previous reports that associated the origin of depressive symptoms with decreased expression of GRs at the hypothalamic and hippocampal levels, 24 with the resulting hypercortisolism. Hence, an increasing body of evidence supports the association between chronic stress and depression at the molecular level, where hyperactivity of the HPA axis, with the consequent increase of cortisol, represents one of the most consistent findings in both syndromal mood and certain anxiety disorders. 23 , 26

Various studies have focused on genes involved in the regulation of the HPA system, including both the mineralocorticoid receptor and GR genes, resulting in the identification of different single-nucleotide polymorphisms (SNPs). Among these, two different SNPs in the GR gene (BclI and Asp363Ser) have been associated with increased vulnerability for depression in the general population, probably through increased glucocorticoid sensitivity. 30 More recently, various studies have focused on the FK506-binding protein FKBP5, a cochaperone of hsp-90 involved in the regulation of GR sensitivity, 31 which is also involved in HPA axis responsivity. This protein is a component of the GR heterocomplex, which, upon binding of cortisol, is replaced by FKBP4, which in turn facilitates the nuclear translocation of the hormone-receptor complex and its transcriptional activity. 32 Altered GR function may lead to impaired feedback regulation, with the resulting HPA hyperactivation commonly observed in chronic stress and depression. Therefore, various SNPs have been identified in the FKBP5 gene, some of them associated with increased FKBP5 protein expression, which in turn may lead to changes in GR, with the resulting effect on HPA axis regulation. 32 Increased FKBP5 protein expression may reduce hormone-binding affinity and may interfere with the translocation of the hormone-receptor complex. It is noteworthy that glucocorticoids may induce increased expression of this cochaperone, constituting an intracellular negative feedback loop to regulate GR activity. 33 One of the SNPs of the FBPP5 gene, defined as the substitution of a cytosine (C) by a thymine (T) and therefore identified as the high-induction allele T, was associated with increased FKBP5 protein expression and altered HPA response. Upon exposure to stressful stimuli, carriers of the T allele exhibited slower recovery of the cortisol response and homozygous carriers of the allele who experienced severe abuse during childhood presented increased vulnerability for the development of depression during adulthood, 34 which may also be associated with having an increased number of depressive episodes. 32

Role of CRF

CRF-containing circuits in the CNS play a critical role in the coordination of the stress response, both as a neuroendocrine factor regulating the HPA axis and through its function as a neurotransmitter, mediating behavioral, immune, and autonomic responses to stress. 35 CRF neurons are localized throughout different cortical areas, participating in neural pathways involved in cognitive responses, and limbic areas such as the central nucleus of the amygdala and the bed nucleus of the stria terminalis, where it participates in the regulation of emotional responses. 23 CRF projections from the amygdala have been shown to reach the hypothalamic paraventricular nucleus (therefore enhancing the activation of the HPA axis in response to stress) and the monoaminergic nuclei in the brainstem, including the locus coeruleus (LC) and the raphe nuclei (RN). 3 Moreover, CRF stimulates norepinephrine release in the LC, 36 with the consequent noradrenergic activation of the autonomic nervous system and the HPA axis, while mainly inhibiting serotonergic neurons in the RN, 37 which in turn may affect other structures through serotonergic projections to the amygdala, hippocampus, and paraventricular nucleus. 3 Therefore, through the regulation of these monoaminergic systems, CRF participates in neurobiological processes underlying mood and anxiety disorders, producing anxiogenic and depressogenic effects. 35 Increased CSF concentrations of CRF have consistently been reported in depressed and suicidal patients. 38 In addition, CRF may also be involved in anxiety and the encoding of emotional memories, 23 , 35 playing a critical role in the stress response not only during adulthood but also in mediation of the long-lasting effects of trauma and other early life stressful experiences. Moreover, increased levels of CRF may also be involved in neuroplastic changes induced by chronic stress, 39 and this effect may also be enhanced by glucocorticoids as a component of the stress response. 40

Various studies have focused on CRF, CRF-binding protein, and CRF type 1 receptor (CRHR1) genes, resulting in several important findings. 41 Indeed, several SNPs in the CRHR1 and haplotypes formed by certain SNPs involved in mediating the effects of early adverse experiences on the risk for adult depression have been identified. 42 Upon binding to CRF, this receptor participates in the activation of the HPA axis and plays a critical role in emotional and cognitive functions mediated by CRF in extrahypothalamic brain regions, including the amygdala and the LC, 35 therefore influencing arousal, attention, conscious perception of emotional experiences, and memory consolidation. Two haplotypes formed by different SNPs in the CRHR1 gene were associated with reduced symptoms of depression in subjects exposed to early stressful experiences. Because CRHR1 may be critically involved in the consolidation of emotionally charged memories, such as those produced by childhood aversive experiences, it was proposed that carriers of two copies of these haplotypes, which also exhibited overrepresentation of the protective alleles of the studied SNPs, 42 may have altered activation of memory consolidation processes. This may lead to decreased emotional influence in the cognitive processing of these memories, therefore protecting the individual from his or her potentially depressogenic and anxiogenic effects. 43

Role of Serotonin

The serotonergic hypothesis of depression posits deficient serotonergic activity in the CNS with increased vulnerability for the development of depression. The main groups of serotonergic neurons in the CNS are located within the boundaries of the RN, where an array of ascending projections arise from the dorsal RN (B6 and B7) and the medial RN (B8). The dorsal RN–forebrain tract projects to the PFC, amygdala, nucleus accumbens, and ventral hippocampus, among other forebrain structures, 44 and it participates in the state of anticipatory anxiety and thus plays an adaptive role during stressful situations. 45 The dorsal RN–forebrain tract has been associated with activation of the limbic structures (e.g., the amygdala) in the presence of environmental stressors associated with unpleasant experiences, and it is also involved in the regulation of potential emotional reactions. Alterations of this system, particularly involving dorsal RN–amygdala projections, may be associated with symptoms of anxiety. 45 The medial RN–forebrain tract projects to the dorsal hippocampus and hypothalamus, among other neural structures, 44 , 45 and it participates in conferring tolerance to unpleasant, unavoidable, and persistent aversive stimuli such as those perceived during chronic stressful situations. The medial RN–forebrain tract is also associated with adaptive control on negative emotional experiences. Therefore, alterations of this system, particularly involving medial RN–hippocampal projections, may be associated with decreased tolerance to aversive stimuli, learned helplessness, and subsequent depression. 45 , 46 Serotonergic neurons in the RN are also interconnected and are physiologically integrated with other monoaminergic systems in the brainstem, including noradrenergic and dopaminergic circuits. 47 It has been shown that both the dorsal RN and the medial RN receive noradrenergic projections, 48 which appear to be excitatory. The LC receives serotonergic projections from the RN reciprocally, 48 which appear to exert an indirect modulatory effect by inhibiting glutamatergic activation of the LC. The dorsal RN also modulates dopaminergic activity through projections to the ventral tegmental area, which appear to be excitatory, 49 and dopaminergic projections to the dorsal RN reciprocally exert an indirect inhibitory effect by increasing the activity of somatodendritic 5-hydroxytryptamine (serotonin [5-HT]) autoreceptors. 44

Figure 2 illustrates the network of functional connections between different neurotransmitter systems in the CNS, as well as their respective connections with different cortical and limbic structures involved in the stress response.

FIGURE 2. Schematic Representation of Neurotransmitter Systems Involved in the Stress Response and Regulation of Emotional and Cognitive Functions a

a The raphe nuclei send serotonergic projections from their medial component to the hippocampus and from their dorsal component to the amygdala and the DLPFC. The locus coeruleus sends noradrenergic projections to the hippocampus and the amygdala. The ventral tegmental area sends dopaminergic projections to the nucleus accumbens and the DLPFC. The nucleus accumbens is reciprocally connected with the amygdala and the OFC, which in turn is reciprocally connected with the medial prefrontal cortex and the ACC. All of these are reciprocally connected with the amygdala and with the DLPFC. Reciprocal connections between the raphe nuclei, the locus coeruleus, and the ventral tegmental area are also represented. ACC, anterior cingulate cortex; D, dorsal; DLPFC, dorsolateral prefrontal cortex; M, medial; OFC, orbitofrontal cortex.

At the molecular level, 5-HT is released into the synaptic cleft, where it binds to both presynaptic and postsynaptic receptors. A growing number of 5-HT receptors have been identified, including 14 different types, classified in seven families with various subtypes each. Each of the serotonin receptor subtypes exhibits a unique regional neuroanatomic distribution, conferring specificity on the effects of activation of this widespread and diffuse serotonergic innervation. Synaptic concentrations of 5-HT are regulated by the serotonin transporter (5-HTT), which is responsible for its reuptake, therefore regulating its availability to bind and activate specific 5-HT receptors. 47 The 5-HTT is believed to be the primary molecular target of selective serotonin reuptake inhibitors antidepressants. Hence, 5-HTT blockade by selective serotonin reuptake inhibitors is translated into higher 5-HT concentrations in the synaptic cleft, allowing increased activation of 5-HT receptors. 46 , 47 The clinical efficacy of antidepressants is not directly associated with this acute mechanism; instead, it is linked to more adaptive changes. Continuous administration of selective serotonin reuptake inhibitors leads to desensitization or down-regulation of somatodendritic 5-HT 1A autoreceptors in the RN after several days (which are known to moderate the release of 5-HT into the synaptic cleft) and up-regulation of postsynaptic 5-HT 1A and desensitization of 5-HT 2A receptors. 50

In addition to serotonergic projections directly involved in cognitive and emotional functions, projections from the RN have been shown to innervate CRF-containing neurons in the paraventricular nucleus. 51 There is evidence that these projections stimulate the HPA axis and the autonomic nervous system; glucocorticoids and catecholamines may reciprocally affect the serotonergic system during stressful situations. 46 Various studies have shown that postsynaptic 5-HT 1A receptors in different limbic structures may be down-regulated or desensitized by glucocorticoids or exposure to chronic stress. 52 , 53 In addition, it has been shown that cortisol may increase 5-HT uptake in vitro, an effect attributed to increased expression of the 5-HTT gene by the glucocorticoid, 54 therefore providing further support for the reciprocal regulation of the HPA and 5-HT systems and their potential interplay in the interface between stress and depression. 46

Various studies have also focused on the structure of the 5-HTT gene, in which a polymorphism was identified in its promoter region. 55 The promoter activity is regulated by sequence elements located in the upstream regulatory region, known as the 5-HTT gene-linked polymorphic region (5-HTTLPR), where a short (S) and a long (L) allele have been identified. 6 Hence, the short promoter variant (5-HTTLPR-S) was associated with decreased transcriptional efficiency compared with the long allele (5-HTTLPR-L), resulting in decreased expression of the 5-HTT gene, 55 which may affect the modulation of serotonergic activity in response to stress. This notion has been supported by multiple clinical and preclinical studies, 56 including evidence observed in functional brain imaging studies, in which carriers of the S allele (homozygous or heterozygous for the short allele) exhibited increased amygdala reactivity to fearful and threatening stressors compared with those homozygous for the L allele, 57 which suggests that variations in the 5-HTT gene may be involved in psychological responses to stress. 6 Although various studies have shown increasing evidence that this polymorphism moderates the relationship between stress and depression, 56 there are still other studies suggesting certain controversy around this hypothesis.

The amygdala participates in the regulation of emotional reactions to stressful events, and its increased reactivity was associated with anxiety and altered mood regulation. 14 Hence, a potential association between 5-HTT gene polymorphism and increased reactivity of the amygdala in response to negative stressors 58 may contribute to a better understanding of the potential effect of the molecular mechanisms underlying this association. Moreover, the amygdala also plays a critical role in the activation of the HPA axis, and hyperactivation of the amygdala may also lead to increased plasma levels of cortisol. Indeed, carriers of the S allele exhibit increased activation of the amygdala and elevated cortisol levels in response to a laboratory stressor. 11 The association between the 5-HTTLPR-S variation and a potentially decreased expression of the 5-HTT gene may appear paradoxical, considering the potential vulnerability attributed to 5-HTTLPR-S carriers. Therefore, it is conceivable that alterations in 5-HTT gene regulation (and consequent effects on synaptic 5-HT levels) may differ, with the former expressed as a result of constitutive conditions and the latter triggered by environmental factors. It has been proposed that 5-HTTLPR-S carriers may exhibit “essentially” increased concentrations of 5-HT, which may result in down-regulation of postsynaptic 5-HT receptors. This may lead to a relative desensitization of the serotonergic system, 58 providing a potential explanation for the vulnerability exhibited by 5-HTTLPR-S carriers. By contrast, up-regulation of the 5-HTT gene, associated with the effect of environmental stressors and the resulting hyperactivation of the HPA axis and hypercortisolism, may lead to increased 5-HT reuptake and decreased concentrations of 5-HT in the synaptic cleft, 54 which has been widely associated with the development of mood disorders.

Role of Dopamine

Dopamine has also been implicated in the neural mechanisms of stress responses, including stress-related regulation of the HPA axis, as well as in the pathophysiology of depression. 59 , 60 The main groups of dopaminergic neurons in the CNS comprise the retro-rubro field (A8), the substantia nigra pars compacta (A9), and the ventral tegmental area (A10), where the mesolimbic and mesocortical pathways arise. The mesolimbic pathway projects mainly to the nucleus accumbens and other limbic structures, including the amygdala, hippocampus, bed nucleus of the stria terminalis, and septum. This pathway is implicated in the processing and reinforcement of rewarding stimuli, motivation, and the subjective experience of pleasure. 59 The mesocortical pathway projects mainly to the PFC, ACC, and entorhinal cortex and is critically involved in cognitive functions such as concentration and working memory. 59

Environmental stressors provoke increased activity in the amygdala, which in turn may increase the concentrations of dopamine in the mesocortical pathway (particularly in the PFC), therefore conferring exaggerated salience to relatively mild negative stimuli 60 and contributing to the resulting negative bias in cognitive processing. Regarding the mesolimbic pathway, it has been shown that stressful events may induce opposite responses, depending on the potential controllability of the stimuli, 61 and the consequent subjective assessment. Therefore, exposure to acute and controllable stressors was associated with increased dopamine release in the ventral striatum, whereas exposure to chronic and uncontrollable stressful stimuli was associated with decreased dopaminergic activity 61 with resulting anhedonia. Moreover, it has been shown that unavoidable or uncontrollable stressors may lead to decreased dopamine release in the nucleus accumbens and impaired response to environmental stimuli, which may result in the expression and exacerbation of depressive symptoms induced by stress. 62 The inability to experience pleasure, associated with loss of interest and motivation in usual activities, constitutes the pathognomonic anhedonia exhibited by patients with depression, 59 , 60 and it has been shown that impaired dopaminergic function is critically involved in altered reward processing underlying anhedonia. 63 , 64 Moreover, the mesolimbic dopaminergic pathway, particularly the nucleus accumbens, participates in the processing of rewarding and hedonic experiences in association with the orbitofrontal cortex, which may be involved in the subjective assessments of hedonic and rewarding value. 65 The orbitofrontal cortex is connected with the ACC and dorsolateral PFC, where this emotional input participates in cognitive processes; by contrast, the nucleus accumbens receives dopaminergic projections from the ventral tegmental area, which may be enhanced by glutamatergic stimulation from the amygdala, to increase motivation. 65 Substantial interaction has also been described between the ventral tegmental area and the RN, 59 which may be critically involved in emotional processing.

Because increased dopamine release in the mesolimbic pathway has been observed not only in response to rewarding stimuli but also in the presence of aversive situations (particularly when these are perceived as controllable and escapable 61 ), it has been suggested that dopamine plays an adaptive role associated with motivation, increased arousal, and behavioral control in response to stress, including both appetitive and aversive conditions. 66

Role of Norepinephrine

Catecholamines (and more specifically norepinephrine) have long been posited to play a major role in the pathophysiology of affective disorders, forming the catecholamine hypothesis of depression. The main group of norepinephrine-containing neurons in the CNS is located within the LC (A6), where various projections arise to widely innervate cortical and subcortical areas, 48 including the amygdala, the hippocampus, and the paraventricular nucleus of the hypothalamus. 36 Projections from the LC to the ventral tegmental area have been described, in which norepinephrine has been shown to potentiate dopamine release. Projections from the LC to the RN have also been described, in which norepinephrine exerts regulatory effects on 5-HT release. 48 There is also evidence of reciprocal regulation between norepinephrine and 5-HT, not only through connections between both aminergic systems but also through limbic structures such as the hippocampus. 67 In addition, reciprocal connections between norepinephrine - and CRF-containing neurons suggest a critical role of the LC in the regulation of neural and neuroendocrine responses to stress. 36

In response to acute stressors, norepinephrine is released throughout different structures in the CNS, resulting in enhanced arousal and hypervigilance, in the context of adaptive responses to stress. Moreover, activation of the LC has been associated with subsequent stimulation of the lateral hypothalamus, which in turn participates in the activation of the sympathetic branch of the autonomic nervous system, therefore complementing the adaptive response to stress. 36 A potential dysfunction of the LC has been observed during chronic stress (particularly upon exposure to unavoidable or uncontrollable stressors), leading to altered norepinephrine release, which was associated with some features of learned helplessness as well as problems in cognitive functions such as attention and memory, which are frequently observed in depression. In addition, dysregulation of the norepinephrine system has also been described in altered states of arousal, 48 which is commonly observed in anxiety disorders as well as in depression.

Neuroplasticity and Neurogenesis: Role of Neurotrophic Factors

Several studies have focused on the potential role of neurotrophic factors in critical neural processes, with particular attention on the neurotrophin family, which is composed of nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3, neurotrophin-4/5, and neurotrophin-6. Among these neurotrophins, a growing body of research has focused on the role of BDNF in the regulation of brain development, neuroplasticity, and neurogenesis. 68 Various studies strongly suggest that decreased levels of BDNF may lead to depressive symptoms, whereas up-regulation of BDNF is associated with clinical recovery. 69 In vitro studies have demonstrated that BDNF may decrease 5-HT uptake, suggesting a potential role of the neurotrophin in regulation of 5-HTT. 70 Chronic stress, with the resulting activation of the HPA axis, may damage neurons in certain CNS structures (particularly in the hippocampus, where high levels of GRs have been found) and these changes have been associated with decreased availability of neurotrophic factors such as BDNF. 71 Moreover, it has been shown that increased levels of glucocorticoids, at least partially, may be involved in down-regulation of BDNF. 72 By contrast, it has been demonstrated that various antidepressants increase the expression of BDNF in the hippocampus 69 in a dose-dependent and time-dependent manner, which is consistent with the time dependency of therapeutic effects of antidepressants, therefore suggesting a role for BDNF in their mechanism of action. 73 The potential association between successful pharmacotherapy and the observed up-regulation of BDNF in the hippocampus suggests that BDNF may be involved in the long-lasting effects of antidepressants through neuroplastic changes in certain neural structures such as the hippocampus, amygdala, and PFC. 69 Moreover, it has been shown that BDNF and 5-HT may induce hippocampal neurogenesis. 74

Most neurons in the CNS are generated during early periods of development, although more recent studies have demonstrated that some neural structures, such as the dentate gyrus of the hippocampus, actually continue generating neurons later in life. 75 Therefore, neurogenesis in the adult CNS may be stimulated by special conditions, particularly those related to enhanced hippocampal activity and increased levels of 5-HT, 76 , 77 but it may be inhibited by stressful situations and increased levels of glucocorticoids. 78 Under chronic stress conditions, with increased activation of the HPA axis, inhibition of hippocampal neurogenesis may interfere with the formation of new cognitions, therefore contributing to provoking and sustaining ongoing depressogenic conditions. According to this hypothesis, successful therapeutic interventions may require recovery of the normal rate of hippocampal neurogenesis. This recovery may be associated with a direct effect of antidepressants through increasing levels of 5-HT 75 or indirectly through modulation of the HPA axis and increasing levels of BDNF, which was associated with up-regulation of neuroplasticity and increasing neurogenesis. This hypothesis remains quite controversial because of failure to confirm the increase in neurogenesis after long-term antidepressant treatment. 79

Various studies have focused on BDNF gene regulation and variations potentially involved in mood disorders, resulting in the identification of different SNPs. Among these, an SNP has been identified at nucleotide position 196 in the coding region of the BDNF gene, where a guanine (G) is replaced by an adenine (A), resulting in the substitution of valine (Val) by methionine (Met) at codon 66, which is thus termed Val66Met. This is where the presence of a Met allele has been associated with a functional alteration (i.e., abnormal intracellular trafficking and decreased secretion of BDNF). 73 , 76 Studies on carriers of the Met-BDNF allele revealed relatively smaller hippocampal volumes compared with those individuals who were homozygous for the Val-BDNF allele. 73 This was also associated with reduced hippocampal activation and deficient cognitive performance, 12 , 73 which have also been associated with lower emotional stability and increased vulnerability for the development of depressive symptoms.

Inflammatory Processes: Role of Cytokines

It has been demonstrated that acute and chronic psychosocial stress may activate inflammatory responses. 80 Increased blood concentrations of proinflammatory cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor-alpha, have been associated with the effect of diverse environmental stimuli, including psychosocial stress, 81 and this immune activation has also been observed in major depression. 82 Moreover, major depression may induce increased inflammatory responses to stress, and this has been observed mostly in patients exposed to adverse early life events, therefore suggesting a link between these and increased inflammatory responses to stress later in life. 80 To understand the role of proinflammatory cytokines in chronic stress and the subsequent development of depression, various studies have focused on their potential mechanisms of action. Environmental stressors activate the sympathetic branch of the autonomic nervous system, with the resulting release of catecholamines, which in turn activates their receptors on immune cells and thus stimulates the release of proinflammatory cytokines. 83 Chronic inflammatory responses in the CNS may result in excessive release of proinflammatory cytokines, which in turn may lead to decreased concentrations of neurotrophins (including BDNF), leading to impaired neuroplasticity 83 and decreased neurogenesis (particularly in the hippocampus 82 ), which have been associated with the origin of cognitive impairment and mood disorders. Proinflammatory cytokines have also been involved in regulation of the HPA axis, stimulating release of CRF with resulting hypercortisolism, 83 which has been associated with reduced sensitivity of GRs and glucocorticoid resistance. 81 , 83 Increased levels of cortisol, such as those observed during chronic stress, may lead to decreased synthesis of 5-HT due to reduced activity of the rate-limiting enzyme tryptophan hydroxylase. Hypercortisolism has been also associated with increased activity of tryptophan dioxygenase (indoleamine-pyrrole 2,3-dioxygenase), which is responsible for the degradation of tryptophan to kynurenine, with the resulting decreased synthesis and release of 5-HT. 83 Proinflammatory cytokines such as interferon have also been involved in the modulation of this pathway, stimulating indoleamine-pyrrole 2,3-dioxygenase and thus leading to reduced synthesis of 5-HT and increased synthesis of kynurenine. 84 Degradation of kynurenine leads to the formation of 3-hydroxykynurenine, which produces free radical species involved in oxidative stress, and kynurenic acid and quinolinic acid, which activate the glutamatergic system. This leads to neurotoxicity and neuronal apoptosis, which are also involved in the pathophysiology of depression. 83 , 84 In addition, certain proinflammatory cytokines, such as interleukin-1 and tumor necrosis factor, have been shown to affect serotonergic neurotransmission by stimulating the 5-HTT and thus reducing intersynaptic concentrations of 5-HT in the CNS. 83 , 85

Understanding the molecular mechanisms underlying neuroinflammatory processes in the CNS, particularly the role played by proinflammatory cytokines in mood disorders, has inspired various studies aimed at improving depressive symptoms by attenuating these processes. Preclinical studies have demonstrated the efficacy of certain anti-inflammatory cytokines to block the depressive-like state induced by proinflammatory cytokines in rodents. 83 Other studies have also approached the consequences of proinflammatory cytokines, antagonizing the activity of the glutamatergic system, activated by the kynurenine pathway. 81

Stress, Appraisal, and Coping: Role of Psychological Vulnerability

Psychological vulnerability depends on various features related to stressful life events (including strength, intensity, and length of the impact) and the availability of personal resources to cope with them. More remarkably, however, it may depend on cognitive appraisal, particularly the balance between stressors and individual resources, and the resulting coping strategies. 86 Chronic exposure to unavoidable and uncontrollable stressors may lead to decreasing cognitive and behavioral coping strategies to handle environmental events, mostly as a result of cognitive appraisals that personal resources are not enough, which has been associated with increasing feelings of helplessness. 86 According to the cognitive model of depression, 87 early life experiences provide the background to develop cognitive schemas, which in turn represent the basis to transform simple data into cognitions that are learned and stored in long-term memory. Adverse early life events, including childhood sexual or physical abuse 88 and peer victimization 89 (also known as bullying), may contribute to the formation of particular cognitive schemas. These schemas may be inactive during long periods and reactivated by new experiences at a later time, particularly those with strong emotional valence. In response to stressful situations in adulthood, activated dysfunctional schemas may induce negative biases during information processing, with consequent dysfunctional effects, including cognitive processing, emotional reactions, and behavioral responses, constituting the essential core of cognitive vulnerability. 87 Therefore, dysfunctional schemas shaped during childhood, with systematic negative biases, may lead to negatively biased appraisals, with consequent limitations in further processing of the resulting cognitions, therefore leading to feelings of helplessness and subsequent depression.

Epigenetics: Role of Gene–Environment Interactions

The term epigenetics refers to heritable characteristics that are not determined by structural changes in the underlying genetic sequence. At the molecular level, epigenetic mechanisms involve biochemical changes of nucleotides, without altering the DNA sequence, and the associated histone proteins, which constitute chromatin. Changes in the structure of chromatin may affect gene expression by allowing transcription factors to gain access to gene regulatory elements. Hence, environmental factors may induce changes in the chromatin state, which in turn may improve exposure of genes to the impact of different transcription factors, therefore increasing or decreasing gene expression while the original DNA sequence remains unaltered. 90 Potential changes include DNA methylation, which has been associated with down-regulation of gene expression; histone acetylation, which may induce up-regulation of gene expression; and histone methylation and phosphorylation, both of which may lead to activation or repression of transcriptional events. 90 Recent research has contributed to identifying epigenetic mechanisms in the context of stressful situations, which may induce long-lasting changes in gene expression in different neural structures. In turn, such changes have been associated with the development of stress-related conditions such as anxiety disorders and depression. Preclinical studies have revealed that chronic stress may regulate histone acetylation in the hippocampus, inducing transient increases and subsequent decreases; transient increases have also been observed in the amygdala. 91

In addition, preclinical studies also revealed that increased levels of CRF, observed during chronic stress conditions, have been associated with decreased DNA methylation at the promoter region of the CRF gene. 92 Moreover, a history of early adverse experiences has been associated with changes in histone markers and DNA methylation of the GR gene, particularly in the hippocampus, and changes in DNA methylation have also been observed in the GR and BDNF genes. 41 Therefore, chronic stress, including early stressful experiences, may induce diverse epigenetic changes in different neural structures, with a subsequent effect on their respective functions. This, in turn, may predispose individuals to increased vulnerability to stress and to the development of diverse clinical conditions such as depression.

Childhood Trauma: Role of Early Adverse Experiences

Early life stress, defined as adverse conditions and traumatic events experienced during childhood, represents a major factor of vulnerability in the origin and development of depression and bipolar disorder. 3 , 5 , 27 The association between a history of adverse and traumatic experiences during childhood and the development of mood disorders later in life has been observed particularly after additional stressful events during adulthood. 5 It has been shown that adverse early life events (including abuse, neglect, or loss) contribute to the formation of dysfunctional cognitive schemas, which may induce negative biases in response to stressful situations at a later time, therefore contributing to generating cognitive vulnerability. 56 This mechanism was also recently described in victims of bullying. 89 Moreover, it has been proposed that certain early life events, such as neglect, may lead to the formation of dysfunctional attitudes; this has also been associated with long-term hyperactivity of the HPA axis. 93 The effect of adverse early life events has been conclusively demonstrated to induce long-lasting changes in neural and neuroendocrine systems involved in adaptive responses to stress, particularly in CRF neurotransmission. 23 This, in turn, may be translated into persistent sensitization and increased responsiveness to stress. 3 , 5 Increased levels of CRF may lead to hyperactivity of the HPA axis and hypercortisolism, which may induce morphologic changes such as reduced hippocampal volume. 72 In this regard, various studies have focused on the role of hippocampal GRs, and increased levels of cortisol (in a sustained and prolonged manner) have been shown to induce down-regulation of GRs in certain areas of the hippocampus. 94 Moreover, additional research has suggested that the availability and efficacy of hippocampal GRs may be permanently affected as a result of early stressful experiences, 88 therefore contributing to glucocorticoid resistance and the consequent hyperreactivity of the HPA axis observed in response to additional stressful situations. In addition, increased concentrations of cortisol and decreased GR availability, induced by stressful situations during childhood, have been associated with decreased hippocampal volume and neural activity in adulthood as well as increased reactivity of the HPA axis, with the consequent functional alterations observed in adulthood. 88 , 95 A history of early life adverse experiences was also associated with hyperreactivity of neural and neuroendocrine responses to stress, which is reflected through increased CRF activity, hypercortisolism, and glucocorticoid resistance. 27 , 96

Klengel et al. 97 reported that a polymorphism in the FKBP5 gene increases the risk for the development of stress-related psychiatric disorders in adults by an allelic-specific, child abuse/neglect–dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. Thus, activation of a sensitized system in the presence of additional stressful situations later in life may result in an exaggerated and maladaptive activation of the stress response, therefore generating increased vulnerability to the development of depressive symptoms upon exposure to additional stressors in adulthood. 42 , 98

Conclusions

The role of stressful life events in the origin and development of depression may be conceptualized as the result of multiple interactions between the effect of environmental stressors and individual factors of vulnerability. Figure 3 illustrates the role of these factors and their potential interactions at the interface between chronic stress and depression. Genetic factors, including SNPs, may be associated with functional and structural alterations in certain neural structures, including increased reactivity of the amygdala and decreased function of the hippocampus. Adverse early life events have been shown to engender biological changes in the developing CNS, as well as psychological changes reflected in the formation of dysfunctional cognitive schemas, 99 with the resulting biased cognitive processing of environmental stimuli, which may be translated into cognitive and emotional vulnerability. 87 These may be further activated in response to stress in adulthood, contributing to increased vulnerability to depression. 27

FIGURE 3. Schematic Representation of Different Factors Involved in the Stress Response and Their Potential Role in Stress and Depression a

a Genetic polymorphisms (represented as genetic vulnerability) participate in the development of the CNS and, together with the influence of early environmental factors (represented by early life stress) and chronic stress, result in a particular CNS phenotype. Early life stress may also induce certain cognitive vulnerability, which in turn may result in emotional vulnerability. Upon the impact of traumatic events or chronic stress, a predisposed CNS responds with increased levels of CRF, hyperactivation of the HPA axis, and increased levels of cortisol, which may lead to molecular changes in different circuits (represented by molecular vulnerability), as well as altered cognitive and emotional responses (represented by emotional vulnerability). This, in turn, may result in increased vulnerability for the development of symptoms of anxiety and depression. CRF, corticotropin-releasing factor; HPA, hypothalamic-pituitary-adrenal.

The impact of abuse and neglect during childhood clearly leads to persistent changes in neural and neuroendocrine systems involved in the regulation of adaptive responses. Functional or structural alterations in the CNS, particularly in the cerebrocortical regions as well as in the amygdala and the hippocampus, along with cognitive biases, may induce biological changes such as increased levels of CRF. Upon exposure to environmental stressors, this mechanism may be translated into hyperactivity of the HPA system, with increased levels of CRF and cortisol, which in turn may lead to transcriptional events. Such molecular changes affecting different aminergic systems, particularly on the regulation of 5-HT together with altered cognitive processing, may result in emotional changes, thereby predisposing to symptoms of anxiety and depression. Therefore, multiple vulnerability factors (including psychological, biological, cognitive, genetic, and epigenetic factors) converge on different aspects of HPA regulation. This complex set of pathways likely links vulnerability to stress with the pathogenesis of depression. In addition, environmental stress has also been associated with inflammatory responses in the CNS with excessive release of proinflammatory cytokines, which may lead to further stimulation of the HPA axis, with resulting hypercortisolism and impaired 5-HT neurotransmission. Proinflammatory cytokines have also been associated with decreased neurotrophins, with resulting decreases in neuroplasticity and neurogenesis. Therefore, a better understanding of the molecular mechanisms underlying these processes may allow novel strategies aimed at improving depressive symptoms by attenuating neuroinflammation.

The observation that some individuals may exhibit stronger vulnerability to environmental stressors but others may be less sensitive, more resistant, or even resilient to similar experiences highlights the importance of further investigation of the nature of different risk factors. Future research should focus on further understanding the neurobiological background underlying these factors and should identify potential windows of intervention, including neural and molecular mechanisms involved in the interface between cognitive processing of environmental stressors and their potential effects in epigenetic processes. This may lead to the development of more successful treatments aimed at not only restoring altered neural and neuroendocrine mechanisms but also preventing the development of anxiety and mood disorders in vulnerable individuals.

This may be achieved either by identifying different vulnerability factors, which in turn may become targets for novel therapeutic interventions, or by increasing and promoting protective resources in individuals exposed to stressful conditions, particularly those exposed to traumatic events or adverse conditions during childhood.

Dr. Nemeroff has in the last 3 years consulted to Takeda, Xhale, Mitsubishi, Clintara, Taisho, Prismic, and Gerson Lehrman, has received grants/research support from NIH and the Agency for Healthcare Research and Quality, has served on the scientific advisory boards for Xhale, AFSP, the Brain and Behavior Research Foundation, Clintara, and the Anxiety and Depression Association of America, and holds stock in Celgene, Seattle Genetics, Abbvie, Titan, OPKO, and Xhale. Dr. Tafet reports no financial relationships with commercial interests.

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• Published: 29 March 2017

Parental separation in childhood as a risk factor for depression in adulthood: a community-based study of adolescents screened for depression and followed up after 15 years

• Hannes Bohman 1 , 2 , 3 , 4 ,
• Sara Brolin Låftman 5 ,
• Aivar Päären 1 &
• Ulf Jonsson 1 , 3  

BMC Psychiatry volume  17 , Article number:  117 ( 2017 ) Cite this article

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Earlier research has investigated the association between parental separation and long-term health outcomes among offspring, but few studies have assessed the potentially moderating role of mental health status in adolescence. The aim of this study was to analyze whether parental separation in childhood predicts depression in adulthood and whether the pattern differs between individuals with and without earlier depression.

A community-based sample of individuals with adolescent depression in 1991–93 and matched non-depressed peers were followed up using a structured diagnostic interview after 15 years. The participation rate was 65% (depressed n  = 227; non-depressed controls n  = 155). Information on parental separation and conditions in childhood and adolescence was collected at baseline. The outcome was depression between the ages 19–31 years; information on depression was collected at the follow-up diagnostic interview. The statistical method used was binary logistic regression.

Our analyses showed that depressed adolescents with separated parents had an excess risk of recurrence of depression in adulthood, compared with depressed adolescents with non-separated parents. In addition, among adolescents with depression, parental separation was associated with an increased risk of a switch to bipolar disorder in adulthood. Among the matched non-depressed peers, no associations between parental separation and adult depression or bipolar disorder were found.

Conclusions

Parental separation may have long-lasting health consequences for vulnerable individuals who suffer from mental illness already in adolescence.

Peer Review reports

Numerous cross-sectional studies have shown that children who do not live with two original parents in the same household report poorer mental health outcomes compared with their peers in nuclear families [ 1 – 3 ], although the overall effect sizes are rather small [ 4 ]. Prospective studies of the association between parental separation in childhood and later mental health have demonstrated that individuals with separated parents are more likely to suffer from adverse mental health outcomes in adulthood [ 5 – 10 ]. There are however also studies that do not show such a relationship. One Swedish prospective study demonstrated that individuals with divorced parents were more likely to appear in child and adolescent psychiatric care compared with their peers with non-divorced parents, but that there was no difference between the groups with regard to adult psychiatric care [ 11 ]. Another study by the same authors did not find any overall differences in depression and anxiety in adulthood between individuals whose parents had divorced in childhood and the comparison group of individuals with continuously married parents [ 12 ]. Thus, empirical findings concerning parental divorce in childhood and later mental health outcomes are not fully consistent. As underscored in a review by Hetherington and Stanley-Hagan [ 13 ], however, the effects of parental divorce in childhood may differ between individuals. Some children are more vulnerable while others are more resilient, where resilience is thought to be a function of several factors including the characteristics of the child, the family, and the surrounding environment. As a matter of fact, Di Manno et al. [ 14 ] call for more studies on moderating effects of parental divorce and offspring mental health and claim that “investigations of moderation are in their infancy and further research is needed to understand the varying trajectories of mental health outcomes, specifically depression and depressive symptoms, of children of divorced parents.” (Di Manno et al. [ 14 ], p. 78). We argue that one potentially important vulnerability factor to consider is whether the child suffers or has previously suffered from mental disorders like depression. Depressive disorders are common in adolescence with a one-year prevalence of 5–8% [ 15 ]. Depressive disorders are also a major contributor to the global burden of disease [ 16 ], and among 15- to 19-year-old males and females, depression is the most important cause of disability-adjusted life-years (DALYs) [ 17 ] and thus of major public health concern.

Any association between parental separation and poorer mental health (short- and long-term) among offspring could be caused by several mechanisms, including factors both preceding and following the actual separation. One potential mechanism is inter-parental conflict, and indeed, Olsson [ 15 ] demonstrated that the association between parental separation and adolescent depression was accounted for by inter-parental conflict. Analyses of large-scale survey data have shown that severe dissension in the childhood family is more commonly reported by individuals who experienced their parents’ separation than by those who grew up in nuclear families, and that it contributes to explaining the adverse mental health of the former group [ 18 ]. In addition, studies have shown that separated parents are more likely to have poorer relations with their children compared with those who are continuously married, supposedly as an effect of the stress linked with the separation as such or with single parenthood [ 4 ]. Poorer parental relations, in turn, have been linked to poorer mental health among offspring [ 19 ]. Furthermore, parental separation often involves a loss of resources for children, particularly for those who continue to live with only one parent. Accordingly, absolute poverty in terms of low income standard is more common among children in single-parent households than among those in two-parent families [ 20 ]. Studies have shown that economic strain following a divorce is linked to adverse outcomes among children [ 4 ]. Furthermore, parental separation can lead to residential moves, which for the children may entail entering a new school and having to make new friends in an already stressful situation [ 13 ]. Indeed, changing schools has been shown to be linked with an increased risk of adverse mental health [ 21 ]. Unsurprisingly, studies have shown that it is more common for individuals with separated parents to have moved during childhood [ 12 , 18 ]. Finally, the parents’ mental health should be considered. Marital distress and depression frequently co-occur, and it has been reported that the interaction of couples with a depressed partner is characterized by a higher frequency of negative communication and a lower frequency of positive communication [ 22 ]. Given that people with depression are more likely to divorce [ 23 ], and that parental psychopathology is a risk factor for mental disorders among offspring [ 24 ], any association between divorce and depression among offspring may partly be attributable to the heritability of depression. In addition, adults who have divorced tend to report poorer well-being compared with those who are continuously married [ 4 ]. This may negatively affect their ability to provide various kinds of social support to their children, with potentially negative implications for their children’s well-being. To conclude, as pointed out in the recent review by Di Manno et al. [ 14 ], it is important to investigate different types of moderating effects of parental separation on later depression. In the present study we focus on adolescent depression as a potential moderator.

Aim of the study

The aim of the present study was to analyze whether the experience of parental separation in childhood predicts major depression in adulthood; and more specifically whether the association between parental separation and later major depression differs among individuals with and without adolescent depression. To assess the extent to which any possible associations were accounted for by potential covariates, we adjusted for conflicts between and with parents, economic strain, family moves, and parental depression.

We formulated the following hypotheses:

H1. The experience of parental separation predicts adult depression.

H2. The association between the experience of parental separation in childhood and depression in adulthood is more prominent among individuals who had suffered from adolescent depression than among individuals without adolescent depression.

H3. The association between the experience of parental separation and adult depression is (at least partly) accounted for by major conflicts between parents, major conflicts with parents, economic strain, family moves, and parental depression.

Study population and procedure

The data come from a study of adolescent depression conducted in the town of Uppsala, Sweden, in 1991–1992. The purpose of the project was to investigate the prevalence of depression in a certain population and set up a case–control study based on a screening of a depression. Accordingly, all students in the first year of upper secondary school (ages 16–17 years) and school dropouts of the same age group were invited to participate in a screening for depression. Of 2,465 individuals, 2,300 (93%) participated in the screening. Two self-evaluations of depression were used: the Beck Depression Inventory-Child [ 25 ] and the Centre for Epidemiological Studies-Depression Scale for Children [ 26 ]. Adolescents with high scores (BDI-C ≥ 16 or CES-DC ≥ 30) or who reported a suicide attempt were interviewed diagnostically using the revised adolescent version of the Diagnostic Interview for Children and Adolescents (DICA-R-A) according to the DSM-III-R criteria [ 27 ]. From individuals with scores under the cut-off (i.e. BDI-C < 16 and CES-DC < 30), a control group was created from an equal number of peers who were matched for sex, age, and school class, and was also diagnostically interviewed in the same manner, using the DICA-R-A. In total, 307 adolescents with depressive symptoms and 302 non-depressed controls were interviewed and consented to be contacted for follow-up. All interviews were conducted face to face by in total six persons (specialists in child psychiatry and psychology students) [ 28 ]. Comorbidity was common among the depressed (87% had also other diagnoses than depression, the most common ones being anxiety disorders, specific phobia, and conduct disorders) but less common among the non-depressed (33% had a diagnosis, the most common diagnosis being specific phobia) [ 29 ].

The participants also completed the Children’s Life Events Inventory [ 30 ], which includes questions on life events related to the individual’s family and social situation. More information on the original baseline study, including characteristics of participants and of those who did not participate, can be found elsewhere [ 15 , 31 ].

After 15 years, the depressed and non-depressed adolescents who had participated in the diagnostic interview as well as consented to participate in a follow-up study were contacted for a follow-up evaluation. This evaluation included the structured diagnostic interview Mini International Neuropsychiatric Interview Plus (M.I.N.I.) [ 32 ]. The follow-up interviews were conducted by a clinical psychologist, a psychiatrist, and three students in clinical psychology, who did not know whether the participants belonged to the depressed or the non-depressed control group (free-marginal Kappa of 0.93). A total of 409 of the 609 participants were re-interviewed (67%). Of all interviews, 81% were conducted face to face and 19% by telephone. For more information on the follow-up study, including details on participants and reasons for non-participation, see Jonsson et al. [ 33 ].

The present analyses are based on the 409 participants who participated in the follow-up. Participants with no identified depressive disorder or elevated depressive symptoms in adolescence were grouped together, while participants with an identified depressive disorder or elevated depressive symptoms were grouped together. The diagnostic interview in adolescence identified a previous depressive disorder before age 16 in a total of 44 of the non-depressed controls that were followed up, and these controls were accordingly transferred to the depression group. Participants with mania or hypomania in adolescence ( n  = 27) were excluded from the analyses because the etiology and mental health trajectory of bipolar disorder can differ from that of depressive disorders. Thus, the present study included 382 individuals; more specifically 227 individuals with prior depression and 155 non-depressed controls without prior depression or depressive symptoms. Figure  1 provides a description of the data collection procedure at baseline and at follow-up.

Chart outlining the data collection procedure at baseline (in adolescence) and at follow-up (in adulthood)

The dependent variable was major depression in adulthood , based on information gathered at the follow-up diagnostic interview through M.I.N.I. [ 32 ]. Major depression was a dichotomous measure indicating whether or not the individual had suffered from one or more major depressive episodes between age 19 and approximately 31. We also conducted additional analyses of a number of other DSM-IV mental disorders assessed at follow-up through M.I.N.I.: bipolar disorder, anxiety disorder , somatoform disorder , alcohol abuse , drug abuse , and psychotic episodes (referring to the period from age 19 and until approximately 31, with the exceptions of somatoform disorders and some anxiety disorders which only covered the time at the follow-up).

The independent variables were constructed from information collected through the Children’s Life Events Inventory [ 30 ] in the baseline investigation. The main independent variable of interest was parental separation , based on questions asking whether the parents had moved apart and whether the parents had divorced. For both questions, the respondents were asked to reply whether this had happened during the past year or earlier in life. Participants who had reported that parents had moved apart or divorced (at any time point) were coded as having separated parents. Potential covariates that were included were major conflicts between parents; major conflicts with parents; family income reduced considerably; and family moved to another city. For each of these life events as well, participants were asked whether it had happened during the past year or earlier in life. We combined the answers to create binary measures of whether or not each life event had happened at all. Parental depression was recorded from the follow-up interview, more specifically from a constructed standardized interview that recorded different psychiatric diagnoses in close relatives, reported by the person interviewed and was coded as at least one parent having suffered from depression.

We also assessed the significance of parental remarriage , based on information from the Children’s Life Events Inventory [ 30 ] (whether, among individuals with separated parents, the mother and/or the father had remarried or had a new live-in partner). Long-term depression (depression most of the last year) and somatic symptoms (≥5 somatic symptoms according to the Somatic Symptom Checklist Instrument [ 34 ] – which from our earlier studies were shown to be important predictors of depression in adulthood [ 33 , 35 ] – were included as markers of severity of the depression in adolescence.

Statistical method

Chi-square tests were used to assess differences between groups. T -test was used to compare mean values. To adjust for potential confounders we conducted binary logistic regression models. To compare differences between individuals with and without separated parents, logit coefficients as well as odds ratios are presented. Since it is problematic to compare estimates from logistic regression analyses across models [ 36 ], as a sensitivity check we also conducted linear probability models (i.e. linear regression analyses of a dichotomous outcome), resulting in patterns similar to the ones presented (results available upon request).

Descriptives

Descriptive statistics of the data are presented in Table  1 , separately for the non-depressed control group and the depressed group (henceforth “non-depressed controls” and “depressed,” respectively). Differences between the two groups were assessed by chi-square tests. The shares of males and females were similar in both groups. Parental separation, major conflicts between parents and with parents, and having had a considerably reduced family income, were more commonly experienced by adolescents with depression than by the non-depressed controls. Parental depression was also more common among adolescents with depression. In adulthood, experiences of major depression were more common among individuals with adolescent depression than among non-depressed controls.

Next, the covariates at baseline and depression in adulthood among non-depressed controls and depressed respectively, are demonstrated by parental separation in childhood (Table  2 ). Among both non-depressed controls and depressed, major conflicts between parents in childhood were significantly more frequent among those with separated parents. Major conflicts with parents in childhood were also more frequent among those with separated parents than among those whose parents were not separated, although the difference was statistically significant only in the depressed group. Among both non-depressed controls and depressed, those with separated parents to a greater extent reported that their family income had been considerably reduced, compared with participants whose parents were not separated. Neither among non-depressed controls nor among depressed were there any significant differences in family moved to another city or in parental depression by parental separation. With regard to depression in adulthood, the prevalence among non-depressed controls did not differ by parental separation. Among participants who had suffered from adolescent depression, however, adult depression was significantly more common among those with separated parents in childhood (68.1%) than among those whose parents had not separated (53.4%). We also checked whether the severity of depression in adolescence, as indicated by long-term depression and by somatic symptoms, differed by parental separation among the individuals in the depressed group. This did not turn out to be the case, as 39.9% of those with non-separated parents and 40.4% of those with separated parents suffered from long-term depression ( p  = 0.931); and those with non-separated parents had on average 2.87 somatic symptoms compared with 2.97 symptoms among those with separated parents ( p  = 0.774) (data not shown).

Parental separation and depression at baseline

In Table  3 , associations between parental separation and adolescent depression (i.e., depression at baseline) are presented. Logit coefficients and their standard errors, p-values, and odds ratios with 95% confidence intervals from binary logistic regressions are displayed, with “group” as the dependent variable (0 = non-depressed controls; 1 = depressed). Model 1 shows an excess risk of adolescent depression for those with separated parents (OR = 1.90, p  = 0.004). When including potential covariates, it is seen that major conflicts between parents account for a rather substantial part of the association (Model 2). The association is attenuated somewhat also when including major conflicts with parents (Model 3), family income considerably reduced (Model 4), family moved to another city (although to a very minor extent) (Model 5), and parental depression (Model 6). When including all the potential covariates simultaneously (Model 7), the estimate of parental separation is attenuated and non-significant (OR 1.22, p  = 0.428). All the included covariates except for family moves were significantly associated with depression at baseline (Models 2–6) but in the fully adjusted model (Model 7) only major conflicts between and with parents remained statistically significant. While the baseline investigation does provide information on whether the separation occurred during the past year or earlier in life, the limited number of cases in the former category prevents any meaningful analyses of time since parental separation. For adolescents whose parents separated last year ( n  = 13), we cannot rule out that some adolescent depression with very short duration may partly capture reactions of grief. Accordingly, we conducted sensitivity analyses where we excluded these individuals. The results were similar to the ones presented but with somewhat attenuated estimates for parental separation in all models (data not shown).

Parental separation and depression at follow-up

Results from the analyses of the associations between parental separation in childhood and depression in adulthood are displayed in Table  4 . Among the non-depressed controls, there was no significant association between parental divorce and adult depression (Model 1) (reflecting the descriptive statistics in Table  2 ) and the estimates did not change considerably when the covariates were included (Models 2–6). Among individuals with adolescent depression, however, there was an excess risk of adult depression among those whose parents were separated compared with those whose parents were not (Model 1, OR = 1.99, p  = 0.016). The association was not accounted for more than marginally by any of the potential covariates (Models 2–6). When adjusting simultaneously for all the potential covariates (Model 7), the odds ratio was attenuated and reached statistical significance only at the 10% level (OR = 1.74, p  = 0.081). Again, we performed sensitivity analyses where we excluded the 13 individuals whose parents separated the year before the baseline investigation, with results very similar to the ones demonstrated in Table  4 , with no visible attenuation (data not shown). Additional analyses of individuals with adolescent depression and separated parents (not shown) tested whether parental remarriage was associated with depression in adulthood. Results indicated a tendency for parental remarriage to be associated with a decreased risk of depression, although this was statistically significant at the 10% level only (OR = 0.41, p  = 0.092).

The purpose of the study was to assess whether there was an association between parental separation and depression in adulthood within the two studied groups, i.e., among the depressed and among the non-depressed controls, respectively. The analyses in Table  4 showed that parental separation was associated with depression in adulthood among the depressed but not among the non-depressed controls. In order to assess whether the association between parental separation and depression in adulthood also differed between these two groups, additional analyses (not shown) were performed. We performed logistic regression analyses of the pooled sample (i.e., the depressed and the non-depressed merged together) and tested for the interaction between adolescent depression and parental separation. The interaction term was borderline significant at the 5% level ( p  = 0.052) (data not shown).

Parental separation and other mental disorders at follow-up

It is possible that the experience of parental separation predicts other mental illnesses than depression. Accordingly, we conducted additional analyses of parental separation in childhood and bipolar disorder, anxiety disorder, somatoform disorder, alcohol and substance abuse as well as the occurrence of psychotic episodes in adulthood, among non-depressed controls and depressed, respectively (Table  5 ). The only detected statistically significant association indicated that among individuals who had suffered from depression in adolescence, there was an excess risk for bipolar disorders in adulthood (OR 2.37, p  = 0.048). The association was slightly attenuated and turned non-significant when adjusting for all the potential confounders (OR 2.18, p  = 0.103) (data not shown). In addition, a separate analysis (not shown) of the non-depressed controls who suffered from anxiety disorder in childhood or adolescence showed that parental separation was associated with a statistically significant excess risk of continuation of anxiety in adulthood. In this particular subgroup, 14.3% of those with non-separated parents and 60.0% of those with separated parents met the criteria for an anxiety disorder in adulthood ( p  = 0.019). Among adolescents with depression and anxiety, parental separation was not significantly associated with anxiety in adulthood ( p  = 0.335) (data not shown).

The aim of this study was to investigate whether parental separation in childhood was associated with major depression in adulthood. In order to assess whether such an association was particularly prominent among individuals who had suffered from depression in adolescence, we utilized data from a community-based study of adolescents with depression and non-depressed controls followed prospectively 15 years after baseline. The results showed that parental separation was not associated with an excess risk of depressive disorder among the non-depressed controls. However, among individuals who had suffered from depression in adolescence, parental separation was linked with an excess risk of recurrence of depression in adulthood, albeit with a moderate effect size. Thus, while the negative effects of parental divorce are relatively small on average [ 4 ], the present study shows that they may be greater for specific vulnerable groups and smaller or even non-existent for others.

While earlier studies of Swedish data found that, overall, parental divorce was not associated with later mental illness [ 12 ] or adult psychiatric care [ 11 ], the present study adds to the previous literature by assessing whether the “effect” of parental separation may differ between groups, as has been suggested [ 13 ]. The association between parental separation and depression in adulthood in this vulnerable group was only to a limited extent accounted for by potential covariates: conflicts between and with parents, that the family’s income had been considerably reduced, that the family had moved to another city, or that one or both parents had suffered from depression. Thus, there are probably other mechanisms that we were not able to include in the present study. We found that inter-parental conflicts accounted for part of the association between parental separation and adolescent depression at baseline, but this did not contribute much to explaining the association between parental separation and depression in adulthood. This is in contrast to the findings reported by Gähler and Palmtag [ 18 ], who showed that the poorer mental health found among adults whose parents had divorced during their childhood was accounted for by economic difficulties and greater family dissension. A possible explanation of why our results differ from those of Gähler and Palmtag [ 18 ] may relate to the different designs of the data materials used. While the present study used a community-based sample of adolescents with depression and matched non-depressed peers who were followed-up prospectively and assessed with clinical mental health diagnoses, Gähler and Palmtag’s study was based on a representative sample of the adult population in Sweden, using retrospective data (implying the risk of recall bias), and with a self-reported mental health measure. Thus, it is possible that parental conflict accounts for the association between parental separation and less severe mental health problems but in case of major depression there seem to be also other mechanisms at work.

What, then, are the underlying reasons for the excess risk of depression in adulthood among individuals who had suffered from depression in adolescence and whose parents were divorced? One possible explanation may be that living in a single-parent family (which the majority of the individuals with separated parents had likely done for a shorter or longer period) often entails limited resources, both in terms of poorer socioeconomic resources but also with regard to less provision of social support and monitoring, which, in turn, are likely to be linked to poorer mental health outcomes among offspring. The finding that parental remarriage possibly seemed to be protective of relapse into depression (although only at the 10% level, data not shown) supports the interpretation that conditions associated with single parenthood may drive the associations between parental separation and later depression in the subgroup of depressed adolescents. The elevated risk of depression in adulthood among individuals with adolescent depression and separated parents could also potentially be an effect of a more severe adolescent depression in this subgroup. However, neither long depression nor somatic symptoms differed between these two subgroups, thus indicating that the adolescent depression was not more severe among individuals with separated parents than among those with non-separated parents. Other possible pathways in the association between parental separation and relapse into depression may include inflated self-concept and problematic interpersonal coping strategies. Assessing such potential mechanisms is a task for future research.

An incidental finding was that among individuals with adolescent depression, parental separation was linked with an excess risk not only of major depression but also of bipolar disorder in adulthood. This implies that parental separation seems to be associated with increased risk of chronicity of disorders already present in the individual, as well as with an increased risk of switching to a bipolar disorder. Future research is however needed to confirm this finding. Previous analyses of the same cohort have shown that a family history of bipolar disorder was a strong significant risk factor for bipolar disorder in adulthood [ 37 ]. The number of individuals in the data material with bipolar disorder in adulthood is however too small to disentangle relationships between parents’ bipolar disorder, parental separation, and the individual’s depression and bipolar disorder. Consequently, exploring the possible mechanisms using a larger data material is a promising task for future research.

Furthermore, the interpretation that parental separation is linked to a risk of chronicity in illnesses already present in the individual is supported by our analyses of anxiety disorder, which showed that among non-depressed controls with anxiety disorder in childhood or adolescence according to DICA-R-A, parental separation was linked with an excess risk of recurrence of anxiety in adulthood.

Strengths and limitations

The data used have several strengths. The data collected at baseline were community-based and included 2,300 adolescents of the same age with a high participation rate in the depression screening (93%). The non-depressed controls were matched to the depressed by sex, age, and school class. The data included clinical interview diagnoses both at baseline and at follow-up. One limitation is that only about two thirds of participants in the original investigation also took part in the follow-up. Still, the participation rate can be seen as reasonably high in relation to the follow-up period of 15 years. Furthermore, the attrition was evenly distributed between the non-depressed control and the depressed group. In addition, Jonsson et al. [ 33 ], using the same data, concluded that the studied baseline characteristics did not indicate that the attrition between baseline and follow-up resulted in biased findings. Their analyses using a multiple imputation approach showed overall similar results to those from analyses containing only complete cases. Nevertheless, Jonsson et al. [ 33 ] did not rule out the possibility that there could be bias due to other factors. Another limitation is that we lack proper measures of socioeconomic conditions in childhood. We also lack information on the time point of the parental separation, which may be relevant to include as a measure of time spent in a non-nuclear family. As recently highlighted in a review, earlier research has not been able to identify that experiencing parental separation at a particular age or development stage is especially critical for developing later depression [ 14 ]. Higher distress scores have been recorded for those who experienced separation at younger ages (0–16 years) than at older ages (17–33 years) [ 38 ] but it has also been shown that father absence in early childhood (child <5 years of age) predicted self-reported depressive symptoms at age 14, whereas father absence in middle childhood (child ≥5 years of age) did not [ 39 ]. As a sensitivity check, we performed additional analyses where we excluded individuals whose parents had separated the year before the baseline investigation. For the cross-sectional analyses of baseline data, it was shown that the “effect” of parental divorce on concurrent depression was somewhat weaker than in the analyses which included these individuals. For the prospective analyses of depression in adulthood, the results were however very similar irrespective of whether or not these individuals were included. Accordingly, our crude measure of the timing of parental separation did not seem to have a moderating role for the risk of depression in adulthood. Nevertheless, information on the timing of separation would indeed have been valuable in order to better distinguish between our covariates as confounders or as mediators. We believe this is important to consider in future inquiry about the links between parental divorce and later depression in different subgroups. Another limitation is the increased risk of type I errors stemming from multiple comparisons. However, we still judge that the general pattern of results is valid. Finally, even though we used community-based data, the generalizability of our findings to other populations than the one investigated is not straightforward and thus further studies are needed to corroborate the results in other contexts.

Adolescent depression appears to be a moderator in the association between parental separation and adult depression. Among depressed adolescents, parental separation seems to predict relapse into depression in adulthood. By contrast, among non-depressed adolescents, parental separation does not appear to be associated with an excess risk of suffering from future depression.

As a consequence, among adolescents with major depression, attention should be paid to those who also have separated parents. These adolescents in particular might benefit from qualified treatment and longer follow-up periods. Additionally to standard treatment like antidepressant medication and cognitive behavior therapy other treatment and supportive strategies might be added, for instance, family interventions and, if needed, cooperation with the social services. For example, previous studies have shown that parental sensitivity can be strengthened and work as a buffer against the risk of future depressive episodes among children [ 14 ].

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Acknowledgements

We are grateful to Hans Arinell for statistical advice and to Carina Mood for valuable comments on an earlier draft.

The Clas Groschinsky Memorial Foundation (SF14 10) and the Swedish Research Council for Health, Working Life and Welfare (Forte) (2012–1741) financially supported this work.

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Please contact the project manager Dr. Ulf Jonsson for any queries.

Authors’ contributions

HB and SL conceived the original idea for this study, had primary responsibility for the data analyses and for drafting the manuscript. UJ together with HB had primary responsibility for enrollment and outcome assessment in the follow-up study, and contributed to the analyses and interpretation of the data and to writing the manuscript. AP participated in the analytical framework of the study and contributed to writing the manuscript. All authors read and approved the final manuscript.

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Bohman, H., Låftman, S.B., Päären, A. et al. Parental separation in childhood as a risk factor for depression in adulthood: a community-based study of adolescents screened for depression and followed up after 15 years. BMC Psychiatry 17 , 117 (2017). https://doi.org/10.1186/s12888-017-1252-z

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DOI : https://doi.org/10.1186/s12888-017-1252-z

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Early Childhood Depression May Impact Brain Development in Later Years

Joan L. Luby, M.D.

Samuel and Mae S. Ludwig Professor of Psychiatry (Child)

Director and Founder, Early Emotional Development Program

Washington University School of Medicine in St. Louis

Scientific Council Member (Joined 2018)

2020 Ruane Prize for Outstanding Achievement in Child and Adolescent Psychiatric Research

2008, 2004 Independent Investigator Grant

2004 Klerman Prize for Exceptional Clinical Research

1999 Young Investigator Grant

Story highlights

Young adolescents who were diagnosed with depression in their preschool years have less gray matter in brain areas important for emotional processing than children unaffected by the disorder.

Research suggests early childhood depression can impact the course of brain development. Tweet >

From The Quarterly, May 2016

Over the past decade, it has become clear that even very young children can suffer from clinical depression . Now, research published December 16, 2015 in the journal JAMA Psychiatry suggests that early childhood depression can impact the course of brain development, underscoring the importance of identifying and treating children with the disorder.

According to the study, which followed children diagnosed with major depressive disorder between the ages of three and six, early childhood depression is associated with disruptions in brain development that continue into early adolescence. Periodic brain imaging revealed that in comparison with children unaffected by the disorder, children who had suffered from depression in their preschool years had lower volumes of gray matter—which contains the neural connections through which brain cells communicate—in the cortex of their brains. This change may have a lasting effect on emotional processing and make a child vulnerable to problems later in life, the researchers say.

Joan L. Luby, M.D. , a 2004 and 2008 Independent Investigator and Young Investigator in 1999, now at Washington University in St. Louis, has led research establishing that depression can occur in children as young as three years-old. Like adults with major depressive disorder, preschool-aged children with depression experience changes in sleep, appetite, and activity level and an inability to experience pleasure. These symptoms often continue later in childhood.

In the new study, Dr. Luby and her team, including 2013 Distinguished Investigator Deanna M. Barch, Ph.D. , (also a 1995 and 2000 Young Investigator, 2006 Independent Investigator), along with 1997 Young Investigator and 2005 Independent Investigator Kelly N. Botteron, M.D. , also at Washington University, wanted to understand whether those early experiences of depression impact brain development.

To find out, the researchers followed a group of 193 children, including 90 diagnosed with major depressive disorder during their preschool years, for up to 11 years. The scientists used magnetic resonance imaging (MRI) to watch how activity in each child’s brain changed as he or she aged. Up to three scans were collected for each child, beginning between the ages of six and eight and with the final scan occurring between the ages of 12 and 15.

The brain’s gray matter begins to form before birth, but continues to develop during childhood, reaching its greatest volume around puberty. After this peak, cells are pruned back to eliminate redundant connections, reducing gray matter volume. The research team observed this normal and expected decline in gray matter in all the children in their study, but it was most dramatic in those who had suffered depression. What’s more, the decline was steepest in those whose depression symptoms had been most severe.

The researchers stress that further research is needed to identify effective ways to treat depression in young children and to determine whether early intervention can restore normal patterns of brain development.

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Biological, Psychological, and Social Determinants of Depression: A Review of Recent Literature

Olivia remes.

1 Institute for Manufacturing, University of Cambridge, Cambridge CB3 0FS, UK

João Francisco Mendes

2 NOVA Medical School, Universidade NOVA de Lisboa, 1099-085 Lisbon, Portugal; ku.ca.mac@94cfj

Peter Templeton

3 IfM Engage Limited, Institute for Manufacturing, University of Cambridge, Cambridge CB3 0FS, UK; ku.ca.mac@32twp

4 The William Templeton Foundation for Young People’s Mental Health (YPMH), Cambridge CB2 0AH, UK

Associated Data

Depression is one of the leading causes of disability, and, if left unmanaged, it can increase the risk for suicide. The evidence base on the determinants of depression is fragmented, which makes the interpretation of the results across studies difficult. The objective of this study is to conduct a thorough synthesis of the literature assessing the biological, psychological, and social determinants of depression in order to piece together the puzzle of the key factors that are related to this condition. Titles and abstracts published between 2017 and 2020 were identified in PubMed, as well as Medline, Scopus, and PsycInfo. Key words relating to biological, social, and psychological determinants as well as depression were applied to the databases, and the screening and data charting of the documents took place. We included 470 documents in this literature review. The findings showed that there are a plethora of risk and protective factors (relating to biological, psychological, and social determinants) that are related to depression; these determinants are interlinked and influence depression outcomes through a web of causation. In this paper, we describe and present the vast, fragmented, and complex literature related to this topic. This review may be used to guide practice, public health efforts, policy, and research related to mental health and, specifically, depression.

1. Introduction

Depression is one of the most common mental health issues, with an estimated prevalence of 5% among adults [ 1 , 2 ]. Symptoms may include anhedonia, feelings of worthlessness, concentration and sleep difficulties, and suicidal ideation. According to the World Health Organization, depression is a leading cause of disability; research shows that it is a burdensome condition with a negative impact on educational trajectories, work performance, and other areas of life [ 1 , 3 ]. Depression can start early in the lifecourse and, if it remains unmanaged, may increase the risk for substance abuse, chronic conditions, such as cardiovascular disease, and premature mortality [ 4 , 5 , 6 , 7 , 8 ].

Treatment for depression exists, such as pharmacotherapy, cognitive behavioural therapy, and other modalities. A meta-analysis of randomized, placebo-controlled trials of patients shows that 56–60% of people respond well to active treatment with antidepressants (selective serotonin reuptake inhibitors, tricyclic antidepressants) [ 9 ]. However, pharmacotherapy may be associated with problems, such as side-effects, relapse issues, a potential duration of weeks until the medication starts working, and possible limited efficacy in mild cases [ 10 , 11 , 12 , 13 , 14 ]. Psychotherapy is also available, but access barriers can make it difficult for a number of people to get the necessary help.

Studies on depression have increased significantly over the past few decades. However, the literature remains fragmented and the interpretation of heterogeneous findings across studies and between fields is difficult. The cross-pollination of ideas between disciplines, such as genetics, neurology, immunology, and psychology, is limited. Reviews on the determinants of depression have been conducted, but they either focus exclusively on a particular set of determinants (ex. genetic risk factors [ 15 ]) or population sub-group (ex. children and adolescents [ 16 ]) or focus on characteristics measured predominantly at the individual level (ex. focus on social support, history of depression [ 17 ]) without taking the wider context (ex. area-level variables) into account. An integrated approach paying attention to key determinants from the biological, psychological, and social spheres, as well as key themes, such as the lifecourse perspective, enables clinicians and public health authorities to develop tailored, person-centred approaches.

The primary aim of this literature review: to address the aforementioned challenges, we have synthesized recent research on the biological, psychological, and social determinants of depression and we have reviewed research from fields including genetics, immunology, neurology, psychology, public health, and epidemiology, among others.

The subsidiary aim: we have paid special attention to important themes, including the lifecourse perspective and interactions between determinants, to guide further efforts by public health and medical professionals.

This literature review can be used as an evidence base by those in public health and the clinical setting and can be used to inform targeted interventions.

2. Materials and Methods

We conducted a review of the literature on the biological, psychological, and social determinants of depression in the last 4 years. We decided to focus on these determinants after discussions with academics (from the Manchester Metropolitan University, University of Cardiff, University of Colorado, Boulder, University of Cork, University of Leuven, University of Texas), charity representatives, and people with lived experience at workshops held by the University of Cambridge in 2020. In several aspects, we attempted to conduct this review according to PRISMA guidelines [ 18 ].

The inclusion and exclusion criteria are the following:

• - We included documents, such as primary studies, literature reviews, systematic reviews, meta-analyses, reports, and commentaries on the determinants of depression. The determinants refer to variables that appear to be linked to the development of depression, such as physiological factors (e.g., the nervous system, genetics), but also factors that are further away or more distal to the condition. Determinants may be risk or protective factors, and individual- or wider-area-level variables.
• - We focused on major depressive disorder, treatment-resistant depression, dysthymia, depressive symptoms, poststroke depression, perinatal depression, as well as depressive-like behaviour (common in animal studies), among others.
• - We included papers regardless of the measurement methods of depression.
• - We included papers that focused on human and/or rodent research.
• - This review focused on articles written in the English language.
• - Documents published between 2017–2020 were captured to provide an understanding of the latest research on this topic.
• - Studies that assessed depression as a comorbidity or secondary to another disorder.
• - Studies that did not focus on rodent and/or human research.
• - Studies that focused on the treatment of depression. We made this decision, because this is an in-depth topic that would warrant a separate stand-alone review.
• Next, we searched PubMed (2017–2020) using keywords related to depression and determinants. Appendix A contains the search strategy used. We also conducted focused searches in Medline, Scopus, and PsycInfo (2017–2020).
• Once the documents were identified through the databases, the inclusion and exclusion criteria were applied to the titles and abstracts. Screening of documents was conducted by O.R., and a subsample was screened by J.M.; any discrepancies were resolved through a communication process.
• The full texts of documents were retrieved, and the inclusion and exclusion criteria were again applied. A subsample of documents underwent double screening by two authors (O.R., J.M.); again, any discrepancies were resolved through communication.
• a. A data charting form was created to capture the data elements of interest, including the authors, titles, determinants (biological, psychological, social), and the type of depression assessed by the research (e.g., major depression, depressive symptoms, depressive behaviour).
• b. The data charting form was piloted on a subset of documents, and refinements to it were made. The data charting form was created with the data elements described above and tested in 20 studies to determine whether refinements in the wording or language were needed.
• c. Data charting was conducted on the documents.
• d. Narrative analysis was conducted on the data charting table to identify key themes. When a particular finding was noted more than once, it was logged as a potential theme, with a review of these notes yielding key themes that appeared on multiple occasions. When key themes were identified, one researcher (O.R.) reviewed each document pertaining to that theme and derived concepts (key determinants and related outcomes). This process (a subsample) was verified by a second author (J.M.), and the two authors resolved any discrepancies through communication. Key themes were also checked as to whether they were of major significance to public mental health and at the forefront of public health discourse according to consultations we held with stakeholders from the Manchester Metropolitan University, University of Cardiff, University of Colorado, Boulder, University of Cork, University of Leuven, University of Texas, charity representatives, and people with lived experience at workshops held by the University of Cambridge in 2020.

We condensed the extensive information gleaned through our review into short summaries (with key points boxes for ease of understanding and interpretation of the data).

Through the searches, 6335 documents, such as primary studies, literature reviews, systematic reviews, meta-analyses, reports, and commentaries, were identified. After applying the inclusion and exclusion criteria, 470 papers were included in this review ( Supplementary Table S1 ). We focused on aspects related to biological, psychological, and social determinants of depression (examples of determinants and related outcomes are provided under each of the following sections.

3.1. Biological Factors

The following aspects will be discussed in this section: physical health conditions; then specific biological factors, including genetics; the microbiome; inflammatory factors; stress and hypothalamic–pituitary–adrenal (HPA) axis dysfunction, and the kynurenine pathway. Finally, aspects related to cognition will also be discussed in the context of depression.

3.1.1. Physical Health Conditions

Studies on physical health conditions—key points:

• The presence of a physical health condition can increase the risk for depression
• Psychological evaluation in physically sick populations is needed
• There is large heterogeneity in study design and measurement; this makes the comparison of findings between and across studies difficult

A number of studies examined the links between the outcome of depression and physical health-related factors, such as bladder outlet obstruction, cerebral atrophy, cataract, stroke, epilepsy, body mass index and obesity, diabetes, urinary tract infection, forms of cancer, inflammatory bowel disorder, glaucoma, acne, urea accumulation, cerebral small vessel disease, traumatic brain injury, and disability in multiple sclerosis [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. For example, bladder outlet obstruction has been linked to inflammation and depressive behaviour in rodent research [ 24 ]. The presence of head and neck cancer also seemed to be related to an increased risk for depressive disorder [ 45 ]. Gestational diabetes mellitus has been linked to depressive symptoms in the postpartum period (but no association has been found with depression in the third pregnancy trimester) [ 50 ], and a plethora of other such examples of relationships between depression and physical conditions exist. As such, the assessment of psychopathology and the provision of support are necessary in individuals of ill health [ 45 ]. Despite the large evidence base on physical health-related factors, differences in study methodology and design, the lack of standardization when it comes to the measurement of various physical health conditions and depression, and heterogeneity in the study populations makes it difficult to compare studies [ 50 ].

The next subsections discuss specific biological factors, including genetics; the microbiome; inflammatory factors; stress and hypothalamic–pituitary–adrenal (HPA) axis dysfunction, and the kynurenine pathway; and aspects related to cognition.

3.1.2. Genetics

Studies on genetics—key points:

There were associations between genetic factors and depression; for example:

• The brain-derived neurotrophic factor (BDNF) plays an important role in depression
• Links exist between major histocompatibility complex region genes, as well as various gene polymorphisms and depression
• Single nucleotide polymorphisms (SNPs) of genes involved in the tryptophan catabolites pathway are of interest in relation to depression

A number of genetic-related factors, genomic regions, polymorphisms, and other related aspects have been examined with respect to depression [ 61 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 ]. The influence of BDNF in relation to depression has been amply studied [ 117 , 118 , 141 , 142 , 143 ]. Research has shown associations between depression and BDNF (as well as candidate SNPs of the BDNF gene, polymorphisms of the BDNF gene, and the interaction of these polymorphisms with other determinants, such as stress) [ 129 , 144 , 145 ]. Specific findings have been reported: for example, a study reported a link between the BDNF rs6265 allele (A) and major depressive disorder [ 117 ].

Other research focused on major histocompatibility complex region genes, endocannabinoid receptor gene polymorphisms, as well as tissue-specific genes and gene co-expression networks and their links to depression [ 99 , 110 , 112 ]. The SNPs of genes involved in the tryptophan catabolites pathway have also been of interest when studying the pathogenesis of depression.

The results from genetics studies are compelling; however, the findings remain mixed. One study indicated no support for depression candidate gene findings [ 122 ]. Another study found no association between specific polymorphisms and major depressive disorder [ 132 ]. As such, further research using larger samples is needed to corroborate the statistically significant associations reported in the literature.

3.1.3. Microbiome

Studies on the microbiome—key points:

• The gut bacteria and the brain communicate via both direct and indirect pathways called the gut-microbiota-brain axis (the bidirectional communication networks between the central nervous system and the gastrointestinal tract; this axis plays an important role in maintaining homeostasis).
• A disordered microbiome can lead to inflammation, which can then lead to depression
• There are possible links between the gut microbiome, host liver metabolism, brain inflammation, and depression

The common themes of this review have focused on the microbiome/microbiota or gut metabolome [ 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 ], the microbiota-gut-brain axis, and related factors [ 152 , 162 , 163 , 164 , 165 , 166 , 167 ]. When there is an imbalance in the intestinal bacteria, this can interfere with emotional regulation and contribute to harmful inflammatory processes and mood disorders [ 148 , 151 , 153 , 155 , 157 ]. Rodent research has shown that there may be a bidirectional association between the gut microbiota and depression: a disordered gut microbiota can play a role in the onset of this mental health problem, but, at the same time, the existence of stress and depression may also lead to a lower level of richness and diversity in the microbiome [ 158 ].

Research has also attempted to disentangle the links between the gut microbiome, host liver metabolism, brain inflammation, and depression, as well as the role of the ratio of lactobacillus to clostridium [ 152 ]. The literature has also examined the links between medication, such as antibiotics, and mood and behaviour, with the findings showing that antibiotics may be related to depression [ 159 , 168 ]. The links between the microbiome and depression are complex, and further studies are needed to determine the underpinning causal mechanisms.

3.1.4. Inflammation

Studies on inflammation—key points:

• Pro-inflammatory cytokines are linked to depression
• Pro-inflammatory cytokines, such as the tumour necrosis factor (TNF)-alpha, may play an important role
• Different methods of measurement are used, making the comparison of findings across studies difficult

Inflammation has been a theme in this literature review [ 60 , 161 , 164 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 ]. The findings show that raised levels of inflammation (because of factors such as pro-inflammatory cytokines) have been associated with depression [ 60 , 161 , 174 , 175 , 178 ]. For example, pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-alpha, have been linked to depression [ 185 ]. Various determinants, such as early life stress, have also been linked to systemic inflammation, and this can increase the risk for depression [ 186 ].

Nevertheless, not everyone with elevated inflammation develops depression; therefore, this is just one route out of many linked to pathogenesis. Despite the compelling evidence reported with respect to inflammation, it is difficult to compare the findings across studies because of different methods used to assess depression and its risk factors.

3.1.5. Stress and HPA Axis Dysfunction

Studies on stress and HPA axis dysfunction—key points:

• Stress is linked to the release of proinflammatory factors
• The dysregulation of the HPA axis is linked to depression
• Determinants are interlinked in a complex web of causation

Stress was studied in various forms in rodent populations and humans [ 144 , 145 , 155 , 174 , 176 , 180 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 ].

Although this section has some overlap with others (as is to be expected because all of these determinants and body systems are interlinked), a number of studies have focused on the impact of stress on mental health. Stress has been mentioned in the literature as a risk factor of poor mental health and has emerged as an important determinant of depression. The effects of this variable are wide-ranging, and a short discussion is warranted.

Stress has been linked to the release of inflammatory factors, as well as the development of depression [ 204 ]. When the stress is high or lasts for a long period of time, this may negatively impact the brain. Chronic stress can impact the dendrites and synapses of various neurons, and may be implicated in the pathway leading to major depressive disorder [ 114 ]. As a review by Uchida et al. indicates, stress may be associated with the “dysregulation of neuronal and synaptic plasticity” [ 114 ]. Even in rodent studies, stress has a negative impact: chronic and unpredictable stress (and other forms of tension or stress) have been linked to unusual behaviour and depression symptoms [ 114 ].

The depression process and related brain changes, however, have also been linked to the hyperactivity or dysregulation of the HPA axis [ 127 , 130 , 131 , 182 , 212 ]. One review indicates that a potential underpinning mechanism of depression relates to “HPA axis abnormalities involved in chronic stress” [ 213 ]. There is a complex relationship between the HPA axis, glucocorticoid receptors, epigenetic mechanisms, and psychiatric sequelae [ 130 , 212 ].

In terms of the relationship between the HPA axis and stress and their influence on depression, the diathesis–stress model offers an explanation: it could be that early stress plays a role in the hyperactivation of the HPA axis, thus creating a predisposition “towards a maladaptive reaction to stress”. When this predisposition then meets an acute stressor, depression may ensue; thus, in line with the diathesis–stress model, a pre-existing vulnerability and stressor can create fertile ground for a mood disorder [ 213 ]. An integrated review by Dean and Keshavan [ 213 ] suggests that HPA axis hyperactivity is, in turn, related to other determinants, such as early deprivation and insecure early attachment; this again shows the complex web of causation between the different determinants.

3.1.6. Kynurenine Pathway

Studies on the kynurenine pathway—key points:

• The kynurenine pathway is linked to depression
• Indolamine 2,3-dioxegenase (IDO) polymorphisms are linked to postpartum depression

The kynurenine pathway was another theme that emerged in this review [ 120 , 178 , 181 , 184 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 ]. The kynurenine pathway has been implicated not only in general depressed mood (inflammation-induced depression) [ 184 , 214 , 219 ] but also postpartum depression [ 120 ]. When the kynurenine metabolism pathway is activated, this results in metabolites, which are neurotoxic.

A review by Jeon et al. notes a link between the impairment of the kynurenine pathway and inflammation-induced depression (triggered by treatment for various physical diseases, such as malignancy). The authors note that this could represent an important opportunity for immunopharmacology [ 214 ]. Another review by Danzer et al. suggests links between the inflammation-induced activation of indolamine 2,3-dioxegenase (the enzyme that converts tryptophan to kynurenine), the kynurenine metabolism pathway, and depression, and also remarks about the “opportunities for treatment of inflammation-induced depression” [ 184 ].

3.1.7. Cognition

Studies on cognition and the brain—key points:

• Cognitive decline and cognitive deficits are linked to increased depression risk
• Cognitive reserve is important in the disability/depression relationship
• Family history of cognitive impairment is linked to depression

A number of studies have focused on the theme of cognition and the brain. The results show that factors, such as low cognitive ability/function, cognitive vulnerability, cognitive impairment or deficits, subjective cognitive decline, regression of dendritic branching and hippocampal atrophy/death of hippocampal cells, impaired neuroplasticity, and neurogenesis-related aspects, have been linked to depression [ 131 , 212 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 ]. The cognitive reserve appears to act as a moderator and can magnify the impact of certain determinants on poor mental health. For example, in a study in which participants with multiple sclerosis also had low cognitive reserve, disability was shown to increase the risk for depression [ 63 ]. Cognitive deficits can be both causal and resultant in depression. A study on individuals attending outpatient stroke clinics showed that lower scores in cognition were related to depression; thus, cognitive impairment appears to be associated with depressive symptomatology [ 226 ]. Further, Halahakoon et al. [ 222 ] note a meta-analysis [ 240 ] that shows that a family history of cognitive impairment (in first degree relatives) is also linked to depression.

In addition to cognitive deficits, low-level cognitive ability [ 231 ] and cognitive vulnerability [ 232 ] have also been linked to depression. While cognitive impairment may be implicated in the pathogenesis of depressive symptoms [ 222 ], negative information processing biases are also important; according to the ‘cognitive neuropsychological’ model of depression, negative affective biases play a central part in the development of depression [ 222 , 241 ]. Nevertheless, the evidence on this topic is mixed and further work is needed to determine the underpinning mechanisms between these states.

3.2. Psychological Factors

Studies on psychological factors—key points:

• There are many affective risk factors linked to depression
• Determinants of depression include negative self-concept, sensitivity to rejection, neuroticism, rumination, negative emotionality, and others

A number of studies have been undertaken on the psychological factors linked to depression (including mastery, self-esteem, optimism, negative self-image, current or past mental health conditions, and various other aspects, including neuroticism, brooding, conflict, negative thinking, insight, cognitive fusion, emotional clarity, rumination, dysfunctional attitudes, interpretation bias, and attachment style) [ 66 , 128 , 140 , 205 , 210 , 228 , 235 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 , 280 , 281 , 282 , 283 , 284 , 285 , 286 , 287 , 288 , 289 , 290 ]. Determinants related to this condition include low self-esteem and shame, among other factors [ 269 , 270 , 275 , 278 ]. Several emotional states and traits, such as neuroticism [ 235 , 260 , 271 , 278 ], negative self-concept (with self-perceptions of worthlessness and uselessness), and negative interpretation or attention biases have been linked to depression [ 261 , 271 , 282 , 283 , 286 ]. Moreover, low emotional clarity has been associated with depression [ 267 ]. When it comes to the severity of the disorder, it appears that meta-emotions (“emotions that occur in response to other emotions (e.g., guilt about anger)” [ 268 ]) have a role to play in depression [ 268 ].

A determinant that has received much attention in mental health research concerns rumination. Rumination has been presented as a mediator but also as a risk factor for depression [ 57 , 210 , 259 ]. When studied as a risk factor, it appears that the relationship of rumination with depression is mediated by variables that include limited problem-solving ability and insufficient social support [ 259 ]. However, rumination also appears to act as a mediator: for example, this variable (particularly brooding rumination) lies on the causal pathway between poor attention control and depression [ 265 ]. This shows that determinants may present in several forms: as moderators or mediators, risk factors or outcomes, and this is why disentangling the relationships between the various factors linked to depression is a complex task.

The psychological determinants are commonly researched variables in the mental health literature. A wide range of factors have been linked to depression, such as the aforementioned determinants, but also: (low) optimism levels, maladaptive coping (such as avoidance), body image issues, and maladaptive perfectionism, among others [ 269 , 270 , 272 , 273 , 275 , 276 , 279 , 285 , 286 ]. Various mechanisms have been proposed to explain the way these determinants increase the risk for depression. One of the underpinning mechanisms linking the determinants and depression concerns coping. For example, positive fantasy engagement, cognitive biases, or personality dispositions may lead to emotion-focused coping, such as brooding, and subsequently increase the risk for depression [ 272 , 284 , 287 ]. Knowing the causal mechanisms linking the determinants to outcomes provides insight for the development of targeted interventions.

3.3. Social Determinants

Studies on social determinants—key points:

• Social determinants are the conditions in the environments where people are born, live, learn, work, play, etc.; these influence (mental) health [ 291 ]
• There are many social determinants linked to depression, such as sociodemographics, social support, adverse childhood experiences
• Determinants can be at the individual, social network, community, and societal levels

Studies also focused on the social determinants of (mental) health; these are the conditions in which people are born, live, learn, work, play, and age, and have a significant influence on wellbeing [ 291 ]. Factors such as age, social or socioeconomic status, social support, financial strain and deprivation, food insecurity, education, employment status, living arrangements, marital status, race, childhood conflict and bullying, violent crime exposure, abuse, discrimination, (self)-stigma, ethnicity and migrant status, working conditions, adverse or significant life events, illiteracy or health literacy, environmental events, job strain, and the built environment have been linked to depression, among others [ 52 , 133 , 235 , 236 , 239 , 252 , 269 , 280 , 292 , 293 , 294 , 295 , 296 , 297 , 298 , 299 , 300 , 301 , 302 , 303 , 304 , 305 , 306 , 307 , 308 , 309 , 310 , 311 , 312 , 313 , 314 , 315 , 316 , 317 , 318 , 319 , 320 , 321 , 322 , 323 , 324 , 325 , 326 , 327 , 328 , 329 , 330 , 331 , 332 , 333 , 334 , 335 , 336 , 337 , 338 , 339 , 340 , 341 , 342 , 343 , 344 , 345 , 346 , 347 , 348 , 349 , 350 , 351 , 352 , 353 , 354 , 355 , 356 , 357 , 358 , 359 , 360 , 361 , 362 , 363 , 364 , 365 , 366 , 367 , 368 , 369 , 370 , 371 ]. Social support and cohesion, as well as structural social capital, have also been identified as determinants [ 140 , 228 , 239 , 269 , 293 , 372 , 373 , 374 , 375 , 376 , 377 , 378 , 379 ]. In a study, part of the findings showed that low levels of education have been shown to be linked to post-stroke depression (but not severe or clinical depression outcomes) [ 299 ]. A study within a systematic review indicated that having only primary education was associated with a higher risk of depression compared to having secondary or higher education (although another study contrasted this finding) [ 296 ]. Various studies on socioeconomic status-related factors have been undertaken [ 239 , 297 ]; the research has shown that a low level of education is linked to depression [ 297 ]. Low income is also related to depressive disorders [ 312 ]. By contrast, high levels of education and income are protective [ 335 ].

A group of determinants touched upon by several studies included adverse childhood or early life experiences: ex. conflict with parents, early exposure to traumatic life events, bullying and childhood trauma were found to increase the risk of depression (ex. through pathways, such as inflammation, interaction effects, or cognitive biases) [ 161 , 182 , 258 , 358 , 362 , 380 ].

Gender-related factors were also found to play an important role with respect to mental health [ 235 , 381 , 382 , 383 , 384 , 385 ]. Gender inequalities can start early on in the lifecourse, and women were found to be twice as likely to have depression as men. Gender-related factors were linked to cognitive biases, resilience and vulnerabilities [ 362 , 384 ].

Determinants can impact mental health outcomes through underpinning mechanisms. For example, harmful determinants can influence the uptake of risk behaviours. Risk behaviours, such as sedentary behaviour, substance abuse and smoking/nicotine exposure, have been linked to depression [ 226 , 335 , 355 , 385 , 386 , 387 , 388 , 389 , 390 , 391 , 392 , 393 , 394 , 395 , 396 , 397 , 398 , 399 , 400 , 401 ]. Harmful determinants can also have an impact on diet. Indeed, dietary aspects and diet components (ex. vitamin D, folate, selenium intake, iron, vitamin B12, vitamin K, fiber intake, zinc) as well as diet-related inflammatory potential have been linked to depression outcomes [ 161 , 208 , 236 , 312 , 396 , 402 , 403 , 404 , 405 , 406 , 407 , 408 , 409 , 410 , 411 , 412 , 413 , 414 , 415 , 416 , 417 , 418 , 419 , 420 , 421 , 422 , 423 , 424 , 425 , 426 , 427 , 428 ]. A poor diet has been linked to depression through mechanisms such as inflammation [ 428 ].

Again, it is difficult to constrict diet to the ‘social determinants of health’ category as it also relates to inflammation (biological determinants) and could even stand alone as its own category. Nevertheless, all of these factors are interlinked and influence one another in a complex web of causation, as mentioned elsewhere in the paper.

Supplementary Figure S1 contains a representation of key determinants acting at various levels: the individual, social network, community, and societal levels. The determinants have an influence on risk behaviours, and this, in turn, can affect the mood (i.e., depression), body processes (ex. can increase inflammation), and may negatively influence brain structure and function.

3.4. Others

Studies on ‘other’ determinants—key points:

• A number of factors are related to depression
• These may not be as easily categorized as the other determinants in this paper

A number of factors arose in this review that were related to depression; it was difficult to place these under a specific heading above, so this ‘other’ category was created. A number of these could be sorted under the ‘social determinants of depression’ category. For example, being exposed to deprivation, hardship, or adversity may increase the risk for air pollution exposure and nighttime shift work, among others, and the latter determinants have been found to increase the risk for depression. Air pollution could also be regarded as an ecologic-level (environmental) determinant of mental health.

Nevertheless, we have decided to leave these factors in a separate category (because their categorization may not be as immediately clear-cut as others), and these factors include: low-level light [ 429 ], weight cycling [ 430 ], water contaminants [ 431 ], trade [ 432 ], air pollution [ 433 , 434 ], program-level variables (ex. feedback and learning experience) [ 435 ], TV viewing [ 436 ], falls [ 437 ], various other biological factors [ 116 , 136 , 141 , 151 , 164 , 182 , 363 , 364 , 438 , 439 , 440 , 441 , 442 , 443 , 444 , 445 , 446 , 447 , 448 , 449 , 450 , 451 , 452 , 453 , 454 , 455 , 456 , 457 , 458 , 459 , 460 , 461 , 462 , 463 , 464 , 465 , 466 , 467 , 468 , 469 ], mobile phone use [ 470 ], ultrasound chronic exposure [ 471 ], nighttime shift work [ 472 ], work accidents [ 473 ], therapy enrollment [ 226 ], and exposure to light at night [ 474 ].

4. Cross-Cutting Themes

4.1. lifecourse perspective.

Studies on the lifecourse perspective—key points:

• Early life has an importance on mental health
• Stress has been linked to depression
• In old age, the decline in social capital is important

Trajectories and life events are important when it comes to the lifecourse perspective. Research has touched on the influence of prenatal or early life stress on an individual’s mental health trajectory [ 164 , 199 , 475 ]. Severe stress that occurs in the form of early-life trauma has also been associated with depressive symptoms [ 362 , 380 ]. It may be that some individuals exposed to trauma develop thoughts of personal failure, which then serve as a catalyst of depression [ 380 ].

At the other end of the life trajectory—old age—specific determinants have been linked to an increased risk for depression. Older people are at a heightened risk of losing their social networks, and structural social capital has been identified as important in relation to depression in old age [ 293 ].

4.2. Gene–Environment Interactions

Studies on gene–environment interactions—key points:

• The environment and genetics interact to increase the risk of depression
• The etiology of depression is multifactorial
• Adolescence is a time of vulnerability

A number of studies have touched on gene–environment interactions [ 72 , 77 , 82 , 119 , 381 , 476 , 477 , 478 , 479 , 480 , 481 ]. The interactions between genetic factors and determinants, such as negative life events (ex. relationship and social difficulties, serious illness, unemployment and financial crises) and stressors (ex. death of spouse, minor violations of law, neighbourhood socioeconomic status) have been studied in relation to depression [ 82 , 135 , 298 , 449 , 481 ]. A study reported an interaction of significant life events with functional variation in the serotonin-transporter-linked polymorphic region (5-HTTLPR) allele type (in the context of multiple sclerosis) and linked this to depression [ 361 ], while another reported an interaction between stress and 5-HTTLPR in relation to depression [ 480 ]. Other research reported that the genetic variation of HPA-axis genes has moderating effects on the relationship between stressors and depression [ 198 ]. Another study showed that early-life stress interacts with gene variants to increase the risk for depression [ 77 ].

Adolescence is a time of vulnerability [ 111 , 480 ]. Perceived parental support has been found to interact with genes (GABRR1, GABRR2), and this appears to be associated with depressive symptoms in adolescence [ 480 ]. It is important to pay special attention to critical periods in the lifecourse so that adequate support is provided to those who are most vulnerable.

The etiology of depression is multifactorial, and it is worthwhile to examine the interaction between multiple factors, such as epigenetic, genetic, and environmental factors, in order to truly understand this mental health condition. Finally, taking into account critical periods of life when assessing gene–environment interactions is important for developing targeted interventions.

5. Discussion

Depression is one of the most common mental health conditions, and, if left untreated, it can increase the risk for substance abuse, anxiety disorders, and suicide. In the past 20 years, a large number of studies on the risk and protective factors of depression have been undertaken in various fields, such as genetics, neurology, immunology, and epidemiology. However, there are limitations associated with the extant evidence base. The previous syntheses on depression are limited in scope and focus exclusively on social or biological factors, population sub-groups, or examine depression as a comorbidity (rather than an independent disorder). The research on the determinants and causal pathways of depression is fragmentated and heterogeneous, and this has not helped to stimulate progress when it comes to the prevention and intervention of this condition—specifically unravelling the complexity of the determinants related to this condition and thus refining the prevention and intervention methods.

The scope of this paper was to bring together the heterogeneous, vast, and fragmented literature on depression and paint a picture of the key factors that contribute to this condition. The findings from this review show that there are important themes when it comes to the determinants of depression, such as: the microbiome, dysregulation of the HPA axis, inflammatory reactions, the kynurenine pathway, as well as psychological and social factors. It may be that physical factors are proximal determinants of depression, which, in turn, are acted on by more distal social factors, such as deprivation, environmental events, and social capital.

The Marmot Report [ 291 ], the World Health Organization [ 482 ], and Compton et al. [ 483 ] highlight that the most disadvantaged segments of society are suffering (the socioeconomic context is important), and this inequality in resources has translated to inequality in mental health outcomes [ 483 ]. To tackle the issue of egalitarianism and restore equality in the health between the groups, the social determinants need to be addressed [ 483 ]. A wide range of determinants of mental health have been identified in the literature: age, gender, ethnicity, family upbringing and early attachment patterns, social support, access to food, water and proper nutrition, and community factors. People spiral downwards because of individual- and societal-level circumstances; therefore, these circumstances along with the interactions between the determinants need to be considered.

Another important theme in the mental health literature is the lifecourse perspective. This shows that the timing of events has significance when it comes to mental health. Early life is a critical period during the lifespan at which cognitive processes develop. Exposure to harmful determinants, such as stress, during this period can place an individual on a trajectory of depression in adulthood or later life. When an individual is exposed to harmful determinants during critical periods and is also genetically predisposed to depression, the risk for the disorder can be compounded. This is why aspects such as the lifecourse perspective and gene–environment interactions need to be taken into account. Insight into this can also help to refine targeted interventions.

A number of interventions for depression have been developed or recommended, addressing, for example, the physical factors described here and lifestyle modifications. Interventions targeting various factors, such as education and socioeconomic status, are needed to help prevent and reduce the burden of depression. Further research on the efficacy of various interventions is needed. Additional studies are also needed on each of the themes described in this paper, for example: the biological factors related to postpartum depression [ 134 ], and further work is needed on depression outcomes, such as chronic, recurrent depression [ 452 ]. Previous literature has shown that chronic stress (associated with depression) is also linked to glucocorticoid receptor resistance, as well as problems with the regulation of the inflammatory response [ 484 ]. Further work is needed on this and the underpinning mechanisms between the determinants and outcomes. This review highlighted the myriad ways of measuring depression and its determinants [ 66 , 85 , 281 , 298 , 451 , 485 ]. Thus, the standardization of the measurements of the outcomes (ex. a gold standard for measuring depression) and determinants is essential; this can facilitate comparisons of findings across studies.

5.1. Strengths

This paper has important strengths. It brings together the wide literature on depression and helps to bridge disciplines in relation to one of the most common mental health problems. We identified, selected, and extracted data from studies, and provided concise summaries.

5.2. Limitations

The limitations of the review include missing potentially important studies; however, this is a weakness that cannot be avoided by literature reviews. Nevertheless, the aim of the review was not to identify each study that has been conducted on the risk and protective factors of depression (which a single review is unable to capture) but rather to gain insight into the breadth of literature on this topic, highlight key biological, psychological, and social determinants, and shed light on important themes, such as the lifecourse perspective and gene–environment interactions.

6. Conclusions

We have reviewed the determinants of depression and recognize that there are a multitude of risk and protective factors at the individual and wider ecologic levels. These determinants are interlinked and influence one another. We have attempted to describe the wide literature on this topic, and we have brought to light major factors that are of public mental health significance. This review may be used as an evidence base by those in public health, clinical practice, and research.

This paper discusses key areas in depression research; however, an exhaustive discussion of all the risk factors and determinants linked to depression and their mechanisms is not possible in one journal article—which, by its very nature, a single paper cannot do. We have brought to light overarching factors linked to depression and a workable conceptual framework that may guide clinical and public health practice; however, we encourage other researchers to continue to expand on this timely and relevant work—particularly as depression is a top priority on the policy agenda now.

Acknowledgments

Thank you to Isla Kuhn for the help with the Medline, Scopus, and PsycInfo database searches.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/brainsci11121633/s1 , Figure S1: Conceptual framework: Determinants of depression, Table S1: Data charting—A selection of determinants from the literature.

Appendix A.1. Search Strategy

Search: ((((((((((((((((“Gene-Environment Interaction”[Majr]) OR (“Genetics”[Mesh])) OR (“Genome-Wide Association Study”[Majr])) OR (“Microbiota”[Mesh] OR “Gastrointestinal Microbiome”[Mesh])) OR (“Neurogenic Inflammation”[Mesh])) OR (“genetic determinant”)) OR (“gut-brain-axis”)) OR (“Kynurenine”[Majr])) OR (“Cognition”[Mesh])) OR (“Neuronal Plasticity”[Majr])) OR (“Neurogenesis”[Mesh])) OR (“Genes”[Mesh])) OR (“Neurology”[Majr])) OR (“Social Determinants of Health”[Majr])) OR (“Glucocorticoids”[Mesh])) OR (“Tryptophan”[Mesh])) AND (“Depression”[Mesh] OR “Depressive Disorder”[Mesh]) Filters: from 2017—2020.

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions(R)

• exp *Depression/
• exp *Depressive Disorder/
• exp *”Social Determinants of Health”/
• exp *Tryptophan/
• exp *Glucocorticoids/
• exp *Neurology/
• exp *Genes/
• exp *Neurogenesis/
• exp *Neuronal Plasticity/
• exp *Kynurenine/
• exp *Genetics/
• exp *Neurogenic Inflammation/
• exp *Gastrointestinal Microbiome/
• exp *Genome-Wide Association Study/
• exp *Gene-Environment Interaction/
• exp *Depression/et [Etiology]
• exp *Depressive Disorder/et
• or/4-16   637368
• limit 22 to yr = “2017–Current”
• “cause* of depression”.mp.
• “cause* of depression”.ti.
• (cause adj3 (depression or depressive)).ti.
• (caus* adj3 (depression or depressive)).ti.

Appendix A.2. PsycInfo

(TITLE ( depression OR “ Depressive Disorder ”) AND TITLE (“ Social Determinants of Health ” OR tryptophan OR glucocorticoids OR neurology OR genes OR neurogenesis OR “ Neuronal Plasticity ” OR kynurenine OR genetics OR “ Neurogenic Inflammation ” OR “ Gastrointestinal Microbiome ” OR “ Genome-Wide Association Study ” OR “ Gene-Environment Interaction ” OR aetiology OR etiology )) OR TITLE ( cause* W/3 ( depression OR depressive )).

Author Contributions

O.R. was responsible for the design of the study and methodology undertaken. Despite P.T.’s involvement in YPMH, he had no role in the design of the study; P.T. was responsible for the conceptualization of the study. Validation was conducted by O.R. and J.F.M. Formal analysis (data charting) was undertaken by O.R. O.R. and P.T. were involved in the investigation, resource acquisition, and data presentation. The original draft preparation was undertaken by O.R. The writing was conducted by O.R., with review and editing by P.T. and J.F.M. Funding acquisition was undertaken by O.R. and P.T. All authors have read and agreed to the published version of the manuscript.

This research was funded by The William Templeton Foundation for Young People’s Mental Health, Cambridge Philosophical Society, and the Aviva Foundation.

Conflicts of Interest

The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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