Asian Journal of Psychiatry 27 (2017) 101–111

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Asian Journal of Psychiatry

journal homepage: www.elsevier.com/locate/ajp

Review article

The neurobiology of depression: An integrated view

Jason Deana,* , Matcheri Keshavanb
a
Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02115, United States
b
Beth Israel Deaconess Medical Center, Massachusetts Mental Health Center, Harvard Medical School, 75 Fenwood Rd., Boston, MA, 02115, United States

A R T I C L E I N F O A B S T R A C T

Article history:
Received 18 July 2016 Major Depressive Disorder (MDD) is one of the most common and debilitating mental disorders;
Received in revised form 18 January 2017 however, its etiology remains unclear. This paper aims to summarize the major neurobiological
Accepted 21 January 2017 underpinnings of depression, synthesizing the findings into a comprehensive integrated view. A
literature review was conducted using Pubmed. Search terms included “depression” or “MDD” AND
Keywords: “biology”, “neurobiology”, “inflammation”, “neurogenesis”, “monoamine”, and “stress”. Articles from
Depression 1995 to 2016 were reviewed with a focus on the connection between different biological and
Biology psychological models. Some possible pathophysiological mechanisms of depression include altered
Neurobiology
neurotransmission, HPA axis abnormalities involved in chronic stress, inflammation, reduced neuro-
MDD
plasticity, and network dysfunction. All of these proposed mechanisms are integrally related and interact
Inflammation
Neurogenesis bidirectionally. In addition, psychological factors have been shown to have a direct effect on
Serotonin neurodevelopment, causing a biological predisposition to depression, while biological factors can lead
Psychology to psychological pathology as well. The authors suggest that while it is possible that there are several
Stress different endophenotypes of depression with distinct pathophysiological mechanisms, it may be helpful
Attachment to think of depression as one united syndrome, in which these mechanisms interact as nodes in a matrix.
Depressive disorders are considered in the context of the RDoC paradigm, identifying the pathological
mechanisms at every translational level, with a focus on how these mechanisms interact. Finally, future
directions of research are identified.
© 2017 Published by Elsevier B.V.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
1.1. Monoamine neurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
1.2. Hpa axis dysregulation and the stress response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
1.3. Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
1.4. Reduced neurogenesis and neuroplasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
1.5. Interaction between stress, inflammation, and neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
1.6. Neurocircuitry model of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
2. Discussion: a unified theory of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
3. Current state of the evidence and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

1. Introduction

Major depressive disorder (MDD) is one of the most prevalent

and debilitating psychiatric disorders. In 2014, 7% of Americans
over the age of 12 reported depression within the past two weeks
(Center for Disease Control and Prevention, 2014) and in 2003 the
* Corresponding author.
World Health Organization estimated a global lifetime prevalence
E-mail addresses: Jdean2@partners.org (J. Dean), mkeshava@bidmc.harvard.edu
(M. Keshavan). of roughly 16% (World Health Organization, 2003). Characterized

http://dx.doi.org/10.1016/j.ajp.2017.01.025
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by impairments in cognition, emotional regulation, memory, molecular, cellular, neurocircuitry, and behavioral levels) may be
motoric function, motivation, and neurovegetative symptoms, more fruitful than research based on the DSM categorical
MDD can cause severe disability. In addition to its primary effects, diagnosis. The recently formulated Research Domain Criteria
the disorder also causes secondary disability, as patients with (RDOC) paradigm (Insel and Cuthbert) emphasizes the analysis of
depression are more likely to develop chronic medical illnesses, each particular expression of a disorder, such as negative salience,
and depressed patients are less likely to comply with medical according to each translational level. This paper will follow the
treatment (World Health Organization, 2003). The combination of RDOC paradigm by discussing these different levels and their
the primary disability caused by depression and the secondary interactions in the production of a depressive phenotype.
disability of chronic medical illness makes MDD one of the most A discussion of the etiology or expression of MDD is beyond the
costly medical burdens in the world. The economic burden of MDD scope of this paper. Rather, this paper will focus specifically on
in the United States in the year 2000 was estimated to be 83.1 pathophysiology, showing that the various pathophysiological
billion dollars, with 26.1 billion dollars (31%) directly related to mechanisms at every level can be understood as an interactive
medical costs, 5.4 billion dollars (7%) related to suicide, and 51.5 matrix. Whereas an understanding of etiology is important for
billion dollars (62%) due to workplace costs including absenteeism prevention, an understanding of pathophysiology is most perti-
and reduced productivity (Greenberg et al., 2003). nent to treatment, as the different treatment modalities target
Despite tremendous progress in neuroscience research over the different pathophysiological mechanisms.
past few decades, the pathophysiology of MDD has not been fully Progress in this field has been hampered by the fact that there
elucidated. Research has implicated several mechanisms including are several schools of thought regarding the pathophysiology of
altered serotonergic, noradrenergic, dopaminergic, and glutama- depression that are often at odds with each other. There is an
tergic systems, increased inflammation, HPA axis abnormalities, ancient Indian parable of six blind men attempting to describe an
vascular changes, and decreased neurogenesis and neuroplasticity. elephant. Unable to see the giant animal as a whole, each describes
However, these findings are not present in every patient, and the elephant according to what he feels with his hands, as either a
treatments that target these mechanisms directly have only tree trunk, a wall, and so on. In a sense, MDD, and perhaps every
partially been explored. While the various biological mechanisms psychiatric disorder, is like the proverbial elephant. If we make the
implicated in depression may appear unrelated, indicating that mistake of equating one small part of a larger process with the
MDD may actually represent several biologically discrete illnesses, disease itself, we run the risk of missing the big picture, which is
research has shown that all of these pathways are related and that most psychiatric disorders probably represent an interactional
interconnected. A unified theory of depression that incorporates all matrix of many factors, and cannot be reduced to those factors
of these biological mechanisms would be helpful in several ways. alone.
First, an overly reductionistic approach that focuses on discrete The literature on the biological basis of depression is vast. As
biological pathways without recognizing the ways in which they this paper attempts to create an integrated framework in which
interact risks missing the true nature of the illness. Second, this multiple biological theories are synthesized, an emphasis was
model could explain the significant heterogeneity found in placed on papers that focused on an interaction between disparate
depressed patients; only a fraction of patients with MDD exhibit biological systems. A literature review was conducted using
each specific finding. Third, this framework would provide new Pubmed, with search terms including the term “depression”
research directions that would focus on understanding the coupled with the following search terms: “biology”, “neurobiolo-
complex interaction among these pathophysiological factors, gy”, “inflammation”, “neurogenesis”, “monoamine”, and “stress”.
rather than focusing on them in isolation. Articles from 1995 to 2016 were reviewed with a focus on the
This paper will suggest a unified theory of depression that connection between different biological and psychological models
conceptualizes the condition as resulting from an interactive of depression. A Pubmed search of the terms “biology” and
matrix of pathophysiological mechanisms. An alteration in the “depression” from 1995 to 2016 returns 5096 articles. A more
matrix at any one node has the ability to trigger the entire cascade limited search including the term “monoamine”, for instance,
of biological effects. As such, focusing on one biological factor in returns only 95 articles. Thus a series of more specific searches
isolation may totally miss the true nature of depression as an using the above terms made the review process more manageable.
illness in which these different factors interact and stimulate each Articles were selected for their relevance to an understanding of
other. Too narrow a focus risks mistaking a single part of a much the pathophysiology of depression, and many articles were
larger process as the cause of the illness itself. We wish to stress excluded due to their lack of direct relevance to the topic or lack
that this unified theory of depression is only one hypothesis among of generalizability. Finally, several important articles that the
several possibilities. It is also possible that depressive disorders authors wished to include but had been missed by the Pubmed
represent several subsyndromes or even numerous discrete search were added for their heuristic utility based on the authors’
disorders. own knowledge of the literature. A total of 66 papers are included
It is helpful to organize MDD according to its etiology, in our review. The distinction between the pathophysiology of
pathophysiology, and expression. MDD is an exceedingly complex MDD and bipolar depresion is beyond the scope of this paper and
disorder, with several etiologies, including genetic, epigenetic, and was not included in our review or discussion. For details, the reader
environmental factors, which together lead to the development of is referred to other recent reviews (Brady et al., 2014; Brady and
the disorder. The disorder itself has several pathophysiological Keshavan, 2015).
mechanisms, which can be organized according to the level of
neurochemistry, tissue and organ-level pathology such as inflam- 1.1. Monoamine neurotransmission
mation or an increased stress response, and altered neurocircuitry.
Finally, the disorder has numerous phenotypic expressions, A major hypothesis for the pathophysiology of depression, the
including depressive ideation, depressive affect, motor symptoms, monoamine hypothesis, posits that depression is caused by an
and neurovegetative symptoms which highly overlap between alteration in levels of one or more of the monoamines, including
several diagnostic entities, making categorical symptom-based serotonin (5-HT), norepinephrine (NE) and dopamine (DA).
distinctions problematic for the purpose of discovering patho- Evidence for the serotonergic theory includes the finding that
physiological substrates. For this reason, investigating pathophyi- serotonin metabolites are reduced in patients diagnosed with MDD
siological domains across translational units of analyses (i.e. and that antidepressants such as tricyclic antidepressants (TCA’s),

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selective serotonin reuptake inhibitors (SSRI’s), and serotonin- dopaminergic mesolimbic pathway, and that these changes are
norepinephrine reuptake inhibitors (SNRI’s) have been shown to involved in altered expression of brain-derived neurotrophic factor
increase levels of serotonin in the brain. Furthermore, chronic (BDNF) and neuroplasticity (Nestler and Carlezon, 2006).
antidepressant treatment has been shown to down-regulate Serotonin, NE, and dopamine are all interrelated and effect each
inhibitory presynaptic 5-HT1A somatodendritic autoreceptors. other’s concentrations in the brain. For instance, dopamine has
As these presynaptic autoreceptors inhibit 5-HT release, their been shown to have an inhibitory effect on the release of NE from
down-regulation increases the probability of 5-HT release, which the locus ceruleus, while NE has a excitatory and inhibitory effect
has been associated with antidepressant response (Richelson, on dopamine release in the ventral tegmental area, through
2001). Similarly, depletion of tryptophan, an essential amino acid stimulation of a-1 and a-2 receptors respectively. Both NE and
needed for 5-HT synthesis, has been shown to induce depressive dopamine increase serotonin release from the dorsal raphe nucleus
symptoms in patients who were successfully treated for depres- through a-1 and D-2 receptors, respectively. These findings
sion with an antidepressant, though tryptophan depletion had no indicate that the monoamine neurotransmitters do not operate
effect on untreated depressed patients. These findings imply that in isolation, but rather that these neurotransmitter systems are
increased serotonin levels are necessary for antidepressant integrally interconnected. An alteration in one of these neuro-
medication effects, though depletion of serotonin alone may not transmitters likely effects the function of the other two (El Mansari
be sufficient to cause depressive symptoms (Bell et al., 2001). In et al., 2010).
addition, genetic abnormalities in serotonergic transmission have Gluatamate has also been implicated in mood regulation. The
been linked to depression. For instance, the serotonin-linked fact that ketamine, an NMDA receptor antagonist, acts as a potent
polymorphic region (5-HTTLPR), is a degenerate repeat in the gene and fast acting antidepressant has led to great interest in the
that encodes the serotonin transporter (SLC6A4). The s/s genotype glutamatergic system as a possible target for antidepressant
of this region is associated with a reduction in serotonin treatment. Clinical studies have shown that ketamine leads to a
expression, associated with increased vulnerability to depression rapid antidepressant effect, occurring in hours, rather than weeks,
(Caspi et al., 2010), though there is some controversy on this topic as is the case with traditional antidepressants (Machado-Vieira
(Fabbri et al., 2013). Similarly, the G(-1019) variant of the Htr1A et al., 2010). Ketamine has been hypothesized to act through the
promoter region which controls expression of the 5-HT1A antagonism of NMDA receptors in GABA-ergic interneurons, which
autoreceptor is associated with reduced 5-HT1A receptor expres- reduces inhibition of glutamate release in glutamatergic neurons.
sion. Both these polymorphisms have been associated with This disinhibition leads to a glutamate surge, with glutamate
impaired affective regulation and depressive symptoms (Caspi subsequently selectively binding to AMPA receptors. Increased
et al., 2010). stimulation of AMPA receptors leads to several second messenger
NE is also involved in mood regulation, as evidenced by the fact cascades, including eEF-2k inhibition, GSK-3 inhibition, and mTOR
that medications that inhibit NE reuptake, such as TCA’s, SNRI’s, activation, all of which lead to increased neuroplasticity. Ketamine
and norepinephrine-dopamine reuptake inhbitors (NDRI’s), and has also been shown to increase the release of BDNF in
those that increase NE secretion, such as mirtazapine, are effective hippocampal pyramidal neurons, which increases neuroplasticity
antidepressants (Leonard, 2001). Chronic stress is thought to alter as well (Iadarola et al., 2015). These findings imply that glutamate
the noradrenergic system, which is integrally related to the may be involved in mood regulation, possibly through the
neuroendocrine and immune systems. For instance, chronic stress maintenance of neuroplasticity.
leads to an increase in the activity of tyrosine hydroxylase, the
enzyme involved in NE synthesis, in the locus ceruleus. Stress also 1.2. Hpa axis dysregulation and the stress response
stimulates the production and release of NE by causing the
increased secretion of corticotropin-releasing factor (CRF) from the Stress and depression are often related. For instance, stressful
hypothalamus, which in turn triggers the release of ACTH from the life events can precipitate depressive episodes in vulnerable
pituitary gland, which subsequently stimulates the adrenal gland individuals (Kendler et al., 1999), and childhood stress in the form
to release NE and cortisol (Leonard, 2001). Increased levels of of abuse or neglect increases the risk of depression later in life
cortisol and NE subsequently increase sympathetic drive and the (Pechtel and Pizzagalli, 2011). Animal models have shown that
release of cytokines, which have been shown to have reciprocal chronic mild stress induces a spectrum of behavioral abnormalities
effects on the HPA axis, as well as neurotoxic effects, as discussed in rodents that parallel depressive symptoms including decreased
below. sucrose intake and mating (anhedonia), decreased motivation,
The mesolimbic pathway, consisting of dopaminergic neurons reduced grooming, and sleep changes (Willner, 2005). In recent
originating in the ventral tegmental area and projecting to the decades, several abnormalities in the HPA axis associated with a
nucleus accumbens, mediates the reward pathway and motivation. hyperactive response to stress have been found in depressed
There are several lines of evidence that implicate altered patients. Some of these alterations include hypersecretion of CRF
dopaminergic transmission and the mesolimbic pathway in the from the paraventricular nucleus of the hypothalamus, impaired
pathophysiology of depression. These include the fact that some negative feedback of the HPA axis, enlarged adrenal glands,
neurovegetative symptoms of depression, including anhedonia hypercortisolemia, and decreased suppression of cortisol in
and reduced motivation, are related to a malfunctioning of the response to dexamethasone (Pruessner et al., 2003). In a subset
reward system, as well as the recognition that primary neurologi- of depressed patients, a hypersensitive HPA axis results in cortisol
cal disorders of dopamine production, such as Parkinson’s Disease, release in response to lower levels of stress as well as chronically
can cause depression. Finally, the fact that antidepressant agents elevated cortisol levels.
such as bupropion increase dopamine levels in the brain provides What are the neurobiological ramifications of elevated cortisol
indirect evidence for the role of dopamine in mood regulation. levels in the brain? Studies on the effects of glucocorticoids have
Watt and Panksepp (Watt and Panksepp, 2009) have conceptual- elucidated some mechanisms which may explain the depressive
ized depression as a disorder of the mesolimbic system, in which consequences of hypercortisolemia. Three brain areas that have
an individual who has undergone significant stress or loss develops been shown to be altered by increased glucocorticoids are the
a shutdown of the reward pathway, which is experienced as medial prefrontal cortex (mPFC), the hippocampus, and the
anhedonia and despair. In line with this theory, studies have shown amygdala. The mPFC is involved in executive functioning and
that chronic stress causes neuroadaptive changes in the the processing of emotion, the hippocampus is involved in memory

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and learning, and the amygdala is involved in the processing of attachment figures is important for social functioning of the
emotion. Chronic stress has been shown to decrease the dendritic individual, and as such is a very powerful motivation of human
complexity of pyramidal neurons and increase the transcriptional behavior. An undisturbed attachment provides a sense of safety, a
activity of GABA interneurons in the mPFC, decreasing activity in threat to these relationships causes anxiety, reunion produces joy,
this area (Cerqueira et al., 2005). As the mPFC is implicated in the and separation causes distress and sorrow. In order to maintain
cognitive processing of emotions generated by subcortical regions these relationships, animals and humans employ attachment
such as the amygdala, reduced activity in this area leads to behaviors, which could be as simple as checking for the attachment
inadequate processing of negative affect. Furthermore, increased figure or involve following, clinging to, or calling for a caregiver.
cortisol levels impair the ability of the hippocampus to adapt to a When an animal or human is separated from an important
changing environment. Chronically stressed animals exhibit attachment figure, significant distress ensues, and the individual
reduced plasticity and long-term potentiation in CA1 hippocampal employs attachment behaviors in an attempt to find the lost
neurons mediated by the glucocorticoid receptor (GR) (Alfarez caregiver, which Bowlby terms a “protest.” Over time, if the lost
et al., 2002), leading to impaired adaptation and learning. object is not found, this protest gradually diminishes until the
In addition to the above cellular changes, high levels of cortisol individual “gives up.” An important aspect of this theory is the
also alter functional connections in the brain that deal with the concept that early loss may cause an individual to deviate
processing of emotion and adaptation. For instance, chronic stress developmentally to an insecure attachment type. These individuals
decreases long-term potentiation in the projections from the may be hypersensitive to loss, greatly magnifying the psychologi-
basolateral amygdala to the mPFC and increases excitability in the cal damage done by future losses (Bowlby, 1980). An inconsistent
amygdala in response to stress, resulting in increased reactivity to caregiver may elicit conflicted feelings from a child, leading to an
stress and decreased cognitive processing (Duvarci and Paré, insecure or anxious attachment style in which fear of abandon-
2007). Chronic stress also shifts functional memory from ment is inextricably mixed with love for the attachment figure. In
hippocampal-based learning to habitual striatum-based learning, this framework, depression can occur in the following way. An
as mineralocorticoid receptor (MR)-mediated glucocorticoid individual is abandoned by a key attachment figure and
effects cause an uncoupling of the amygdala from the hippocam- experiences significant anger towards this caregiver; however,
pus and increased connectivity to the striatum (Schwabe et al., due to an ambivalent relationship that combines both love and
2013). Taken together, glucocorticoids cause synaptic changes and anger, the patient spares the loved object his anger and instead
higher level alterations in emotional-cognitive circuitry that shift internalizes the object. This anger towards a beloved attachment
an organism from adaptive contextual learning and exploration to figure generates guilt as well, and depression can be seen as self-
habitual learning. In health, this mechanism allows an organism to punishment for feelings of forbidden anger (Holmes, 2013).
avoid exploration during chronic stress, relying on habit to safely Otto Kernberg (2009) summarized the psychodynamic theory
navigate external threats. However, when the external environ- of depression, which conceptualizes the condition as a response to
ment is misinterpreted as dangerous, this shift away from adaptive the loss of an ideal state of self (Bibring, 1953) due to the loss of an
learning may happen inappropriately, leading to disinterest in the internalized object (Freud, 1917) and the belief that one's own
external world, internal focus, and depressive symptoms (Myers aggression has destroyed the good internalized object (Klein,
et al., 2014). 1940). This state is more common in patients with a biological
The Diathesis-Stress Model provides a neurological basis for a predisposition, including temperament, hyperactive HPA axis, and
link between chronic psychological stressors and depression. This biologically amplified affects of rage and panic, as well as a
model views depression and many other psychiatric disorders as psychological predisposition, in which aggressive internalized
developmental derailments that evolve over time. A diathesis is a object relations predominate over libidinal internalized images of
predisposition, which could be either biological or psychological. self and other. Importantly, early deprivation and early life stress,
In this conception, depression is not caused by one biological or including insecure early attachment, can cause HPA axis hyperac-
psychological factor in isolation. Rather, in a vulnerable patient tivity, as well as pathological internalized object relations
who is predisposed to a negative response to stress, repeated (Kernberg, 2009).
stressors can cause that pre-existing vulnerability to manifest Cognitive theory, originally conceptualized by Aaron Beck,
itself. One example of this idea would be the genetic polymor- views depression as resulting from pathological cognition. In a
phisms in the serotonin transporter gene mentioned above. 2008 review, Beck summarized the developments in his theory and
Individuals with the s/s genotype of this polymorphism have explained them in the context of growing biological research. The
been shown to react more to stressful situations and to have main premise of cognitive theory is that negative cognitive biases
increased rates of depression. This diathesis or genetic predisposi- affect the way an individual perceives the external world. Early
tion is not sufficient to cause depression itself until it is brought out stress, loss, or trauma can lead to the development of negative
by environmental stressors (Beck, 2008; Scher et al., 2005). It is the cognitive schemata, which serve as a biased framework with which
combination of stressors and a pre-existing vulnerability, of nature to interpret future events. The development of these negative
and nurture, that causes disorder. The HPA axis may provide a biases confers a cognitive vulnerability to the patient, increasing
biological basis for this process, in which early stress leads to a the risk of developing depression in response to future stressors. In
functional “hyperactivation” of the HPA axis and a predisposition addition to cognitive vulnerability, which predisposes a patient to a
towards a maladaptive reaction to stress, rather than depressive full-blown depressive episode, Beck attributes milder acute
symptoms themselves. This biological diathesis is then brought out depressive symptoms to cognitive reactivity. Cognitive reactivity
by an acute stressor, leading to the entire cascade of effects denotes a negatively biased response to every-day stressors.
described above. Increased cognitive reactivity in depressed patients can lead to
When the concept of “stress” is extended from objective mild and transient depressive symptoms due to misinterpretation
external factors to internal psychological stress, the model of of everyday negative events. Furthermore, Beck discusses what he
chronic stress causing depression lends itself to several psycho- calls a depressive mode, which, in addition to a “hub” of negative
logical theories. In Attachment and Loss (1980), Bowlby presents his cognitive schemata, includes affective, motivational, behavioral,
Attachment Theory, which focuses on the strong emotional bonds and physiological schemata. External events are interpreted via
that animals and humans form as children with their caregivers these negative cognitive schemata which then activate the other
and as adults with other adults. Enduring emotional bonds with aspects of the depressive mode. Repeated activation of this mode

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eventually causes it to become fixed and act autonomously, that it is only adaptive for acute illness. Chronic inflammatory
causing the patient to ignore positive external stimuli and focus conditions, which include chronic psychological stress, can lead to
internally. This process leads to anhedonia, lack of motivation, prolonged sickness behavior when it is no longer adaptive
increased rumination, and depression. (Rosenblat et al., 2014).
Beck (2008) proposes a neurobiological mechanism underlying It is worth stressing the overlap between inflammation and
what he calls the “depressive mode”. Genetic polymorphisms in many of the most prevalent chronic illnesses. Metabolic syndrome
the 5-HT transporter (see above) have been shown to lead to includes several conditions which are related to a proinflammatory
increased reactivity of the amygdala, which leads to increased state and vascular disease, including obesity, insulin resistance,
reactivity to negative events and a negative attentional bias. This hypertension, and dyslipidemia. Pro-inflammatory markers, such
attentional bias towards negative events leads to cognitive as TNF-alpha, IL-1, IL-2, and IL-6 may be elevated in patients with
distortions such as personalization, overgeneralization, and metabolic syndrome, which has recently been conceptualized as a
exaggeration, which in turn lead to dysfunctional attitudes neuroinflammatory disorder. Though the mechanism by which
regarding personal worth and acceptability. Repeated activation inflammatory molecules can induce metabolic syndrome remains
of these attitudes ultimately creates negative cognitive schemata, unclear, one possible mechanism includes TNF-alpha leading to
which in turn activate the HPA axis in response to a misinterpre- insulin resistance as well as altering the function of pro-
tation of external events (Beck, 2008). opiomelanocortin and neuropeptide Y neurons, which inhibit
In all of these psychological models, early life stress has a lasting and stimulate feeding, respectively (Singh et al., 2012). Inflamma-
effect on the HPA axis, causing a biologically determined sensitivity tion may also predispose to vascular disease, which has been
to later stressors, as well as pathological psychological factors that implicated in late-life depression. Late-life depression has been
predispose to depressive affect. Similarly, recent research has found to be associated with cognitive dysfunction and increased
shown that early life adversity leads to structural and functional white matter hyperintensities on MRI, representing ischemic
changes in structures such as the uncinate fasciculus (Hanson et al., damage to white matter tracts. These findings have been
2015), a white matter tract that connects the amygdala with medial conceptualized in a disconnection hypothesis in which ischemic
structures in the PFC that are involved in affect processing. Thus, damage to the white matter is thought to lead to altered
psychological stress may lead to neurodevelopmental changes in connection between affective and cognitive circuits. Increased
affective processing circuits, creating a biological predisposition to inflammation and hypoperfusion of the white matter are thought
depression in later life. These theories provide a powerful to cause ischemic damage, causing alterations in the connections
framework for the integration of biological and psychological between different circuits (Taylor et al., 2013). As the components
models of depression. of metabolic syndrome such as obesity, diabetes, hypertension, and
dyslipidemia can all lead to atherosclerosis, it is likely that these
1.3. Inflammation conditions could also cause or exacerbate depression through
vascular white matter disease. The same concern would apply to
Increased levels of inflammatory markers such as IL-1b, IL-2, IL- other chronic inflammatory conditions as well, including coronary
6, TNF-a, CRP, and PGE2 have been found in patients with artery disease, chronic obstructive pulmonary disease, and
depression (Felger and Lotrich, 2013). Studies have also shown that rheumatologic disorders.
inducing inflammation in research subjects causes depression. For
instance, Wright et. al showed that subjects who were vaccinated 1.4. Reduced neurogenesis and neuroplasticity
with S. Typhi subsequently developed depressed mood in
proportion to increased IL-6 levels (Wright et al., 2005). Similarly, The brain possesses remarkable plasticity, able to rapidly create
INF-a treatment of Hepatitis C causes depressed cognition related and eliminate synapses as well as to alter functional circuits in
to increased IL-2, IL-6, and TNF-a (Wichers et al., 2007). As adaptation and learning. One of the molecular factors needed for
psychological stress has been shown to increase the production of healthy neuroplasticity is brain-derived neurotrophic factor
cytokines such as IL-1b, IL-6, and TNF-a (Steptoe et al., 2007), there (BDNF). BDNF is a neurotrophin that promotes the survival of
exists a positive feedback between depression and inflammation in existing neurons and encourages the growth and differentiation of
which inflammation causes depression and psychological stress, new neurons and synapses (Acheson et al., 1995). The finding that
which in turn is pro-inflammatory. serum levels of BDNF are reduced in patients diagnosed with MDD
The bidirectional relationship between depression and inflam- (Monteleone et al., 2008) implies a possible role of BDNF in the
mation is paralleled by the clinical relationship between depres- pathophysiology of depression. Furthermore, a knock-out experi-
sion and inflammatory disorders. Depressed patients have an ment of BDNF in the dorsal dentate gyrus of the hippocampus was
increased rate of autoimmune disorders, and there are higher rates able to induce depressive behavior in rats (Taliaz et al., 2010)
of depression among patients with inflammatory diseases (Pasco suggesting that reduced production of BDNF and neuroplasticity
et al., 2010). In addition, anti-inflammatory agents have been used can lead to depression. In parallel, antidepressant effects have been
successfully as adjuncts to antidepressants. For instance, anti- shown to be associated with increased hippocampal neurogenesis
inflammatory treatment of psoriasis has been shown to reduce (Santarelli et al., 2003). Fluoxetine has been shown to increase
depressive symptoms independent of change in psoriasis symp- BDNF mRNA expression in the dentate gyrus of the hippocampus,
toms (Tyring et al., 2006). the ventral tegmental area (VTA), and the nucleus accumbens
The depressive symptoms of anhedonia, fatigue, and internal (Molteni et al., 2006). The VTA and the nucleus accumbens have
focus caused by inflammation are often termed “sickness been shown to be responsible for the reward circuit, which when
behaviors.” The mechanism by which inflammation causes altered can produce anhedonia in MDD, while the hippocampus is
depression is actually thought to be an adaptive response to essential for memory. Taken together, these findings suggest that
infection. Acute inflammatory illnesses and infections require a BDNF may be necessary for limbic and cortical circuits to adapt to a
great deal of energy expenditure, and exploration, mating, and changing environment (Castrén and Rantamäki, 2010).
other activities can lead to a dangerous expenditure of energy. The findings that neurogenesis and neuroplasticity are involved
Therefore, it is adaptive for inflammation to cause anhedonia and in antidepressant response has led to the suggestion of a network
fatigue, causing an organism to forego exploration and mating and hypothesis of depression. This hypothesis suggests that antide-
to focus on healing. The problem with this mechanism, of course, is pressants reinstate a juvenile-like plastic state in which a

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depressed individual is able to alter networks in response to increase HPA axis activity and induce sickness behavior in order
external signals. While increased monoamine levels are essential to reduce energy expenditure while mobilizing distant energy
to antidepressants effects, increased neurotransmitter levels may sources (Straub et al., 2010). Another possible mechanism through
not directly improve mood. Instead, they increase plasticity in which inflammation could lead to depression lies in the relation-
dysfunctional limbic and cortical networks that allows an ship between inflammation and neuroplasticity, through mecha-
individual to adapt and change (Castrén, 2013). One notable study nisms such as synaptic pruning. Recent research in the field of
in support of this theory showed that fluoxetine was able to schizophrenia has shown that certain aspects of the complement
generate increased neuroplasticity in rats. When young rats are cascade, such as C4A, are located in synapses, dendrites, axons, and
deprived input to one of their eyes by suturing that eye shut during cell bodies (Sekar et al., 2016). This finding implies a possible
a critical period of development, they become blind in that eye, or explanation of the association of polymorphisms in certain
amblyopic, even when they are allowed to use that eye after the immune genes and an increased risk for schizophrenia, as the
critical period has ended. This blindness occurs because the visual immune system appears to be involved in the remodeling of
cortex that would ordinarily receive stimuli from that eye does not synapses that takes place in adolescence and early adulthood, a
develop if it is deprived of stimulus during the critical period. process called synaptic pruning. It is possible that increased
However, when these rats were treated with fluoxetine, and use of inflammation plays a role in depression in a similar fashion,
the bad eye was encouraged, their blindness was reversed. This through the reduction of dendritic complexity leading to reduced
reversal of blindness was associated with the reduction of GABA- functional connectivity in affect processing circuits. The effect of
ergic inhibition and increase in BDNF expression in the visual inflammation on the integrity of neurocircuitry will be discussed in
cortex. Interestingly, fluoxetine was only able to induce these more detail below.
changes when the amblyopic eye was used and the normal eye was The interaction between inflammation and the stress response
not (Vetencourt et al., 2008). Similarly, environmental enrichment, is bidirectional, with inflammation causing upregulation of the
defined as increased exploratory behavior and sensory-motor HPA axis, as above, and glucocorticoids and the sympathetic
stimulation, reverses amblyopia in rats by a similar mechanism nervous system increasing inflammation as well. Though gluco-
involving reduced GABA-ergic inhibition and increased plasticity corticoids are well-known for their anti-inflammatory properties
in the visual cortex (Sale et al., 2007). These findings suggest that in clinical practice, recent research has led to the growing
rather than improving mood directly, fluoxetine and other appreciation that glucocorticoids can actually be pro-inflammato-
antidepressants may provide the potential for change. It is ry as well. Glucocorticoids increase inflammation by permitting
noteworthy that cognitive remediation (Fisher et al., 2016), rTMS catecholamine activation of immune cells and by causing white
(Shang et al., 2016), and ECT (Rocha et al., 2016), all of which blood cells to leave circulation and travel to tissues (Sorrells et al.,
alleviate depression, increase neuroplasticity and lead to release of 2009). In addition, glucocorticoids have been shown to prime
BDNF. While depressed patients lack the normal ability to adapt cytokine release by macrophages. When given 12 or 24 h prior to
through neuroplasticity, effective treatment may entail reinstating lipopolysaccharides (LPS) inoculation, corticosterone caused
this plasticity. This conception implies that biological treatments macrophages to release increased levels of TNF-a, IL-1, and IL-6.
may not be sufficient alone, and that psychotherapy and/or efforts This increased immune response was associated with increased
on the part of the patient are necessary to induce change and activity of nuclear factor-kappa B, a transcription factor for many
clinical improvement (Castrén, 2013). cytokines (Smyth et al., 2004). The findings that glucocorticoids
enhance epinephrine’s ability to stimulate inflammation and
1.5. Interaction between stress, inflammation, and neurogenesis increase the activity of nuclear factor-kappa B suggest that stress
hormones potentiate a stronger immune response rather than
There is a strong interaction among the stress response, increasing inflammation directly. It is adaptive for the stress
inflammation, and neurogenesis in health. In a review of the response to prime the immune system as many sources of infection
neuroendocrine and immune regulation of energy in the inflam- are traumatic and related to “fight-or-flight” situations. An injury
matory response, Straub et al. (2010) describe the essential that could introduce a pathogen will stimulate an increase in
interaction between inflammation, the HPA axis, and the epinephrine and glucocorticoids which will in turn help the
sympathetic nervous system. Below is a summary of some of organism mount a robust immune response (Black, 2003).
the points most relevant to this discussion. An active immune In addition, inflammatory cytokines have been shown to reduce
response utilizes roughly 25%-30% of the basal metabolic rate, monoamine levels in depressed patients through increased
representing a very significant energy demand. In order to metabolism of tryptophan, which is an essential precursor of
conserve energy, inflammation causes sickness behavior including serotonin. Tryptophan, an essential amino acid needed for
reduced muscular, gastrointestinal, and mating activity. In health, synthesis of serotonin, is metabolized through the kynurenine
the circadian rhythm creates high levels of glucocorticoids during pathway to kynurenin (KYN) via the enzyme indoleamine 2,3-
the day to fuel activity. Conversely, at night glucocorticoid levels dioxygenase (IDO). Cytokines such as IFN-a, IFN-g, IL-1, TNF-a,
are low, whereas high levels of growth hormone provide glucose to and PGE2 induce IDO activity, leading to increased tryptophan
immune cells. Notably, “sickness behavior” induces increased metabolism (Weiss et al., 1999). As tryptophan is needed by
sleep, which in turn fuels an upregulated immune system, as bacteria for survival, the inflammatory response triggers the
immune cells are fueled primarily during sleep. These behavioral metabolism of tryptophan in order to control infection (Carlin
changes occur in response to increased cytokine levels. “Spillover” et al., 1989). However, as tryptophan is needed for serotonin
of cytokines, such as IL-6, in the context of a robust immune synthesis, its metabolism by IDO leads to reduced levels of
response activates the HPA axis and the sympathetic nervous serotonin and depressive symptoms as well. These findings
system, leading to increases in glucocorticoids, epinephrine, and provide an important connection between inflammation and
NE respectively. The activation of the HPA axis allocates energy serotonin depletion, providing a possible mechanism linking
from distant sources, such as glucose and ketones from the liver, inflammation with sickness behavior and depression (Müller
amino acids from muscle, lipids from fat, and calcium from bones. and Schwarz, 2007).
Similarly, stimulation of b2 adrenergic receptors by epinephrine Finally, cytokines and glucocorticoids have been shown to
increases glycogenolysis, gluconeogenesis, and lipolysis. As in- decrease monoamines and reduce neurogenesis. An important
flammation represents a high metabolic demand, cytokines experimental model of depression is the chronic unpredictable

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stress (CUS) model. This model subjects rats to inescapable Several neuroimaging studies have lent support to this theory,
stressors, causing behavioral changes that parallel depressive and while it is beyond the scope of this paper to adequately review
symptoms in humans such as anhedonia, reduced motivation, and these findings here, it is helpful at this point to briefly mention
despair. One important finding is that CUS has been shown to some pertinent findings. In line with the theory of a top-down
decrease monoamine levels in rats (Ahmad et al., 2010). In turn, mechanism of depression, neuroimaging studies have found
low levels of serotonin have been shown to reduce neurogenesis. reduced volume in the prefrontal cortex, especially in the
The dorsal raphe, the primary site for serotonin synthesis, sends subgenual prefrontal cortex, as well as in the amygdala, basal
serotonergic projections to the hippocampus. Denervation of these ganglia, and hippocampus (Sheline, 2003). These volume losses
projections was shown to cause a reduction of newly generated may be due to chronic hypercortisolemia, induced by functional
granule cells in the dentate gyrus of the hippocampus, while hyperactivity of the HPA axis, which leads to neurotoxicity (
reinnervation by 5-HT fibers reversed these changes (Brezun and Sheline, 2003). In addition to reduced volume, studies of patients
Daszuta, 2000). Similarly, stimulation of 5-HT1A receptors has with depression have shown functional hypoactivity in the
been shown to increase granule cell proliferation in the subgenual prefrontal cortex, which is interconnected with the
subgranular layer and subventricular zone of the hippocampal basal ganglia, amygdala, lateral hypothalamus, and brainstem
dentate gyrus (Banasr et al., 2004). These findings indicate that seretonergic, noradrenergic, and dopaminergic nuclei (Drevets
there is an inherent connection between serotonergic neurotrans- et al., 1997). Other studies have found hyperactivity in the
mission and neuroplasticity in the hippocampus, in which reduced prefrontal cortex in some depressed patients. These seemingly
neuroplasticity in depressed patients may be caused or exacerbat- contradictory findings have been conceptualized in line with the
ed by reduced serotonin levels. theory of top-down inhibition, in which hypoactivity in the PFC
leads to depressive affect accompanied by apathy, psychomotor
1.6. Neurocircuitry model of depression retardation, and reduced executive functioning, while hyperactivi-
ty in these areas leads to psychomotor agitation and rumination (
In addition to the biological mechanisms described above, Mayberg, 2003).
neuroimaging studies of depressed patients have found changes in
functional connectivity in the neural circuits involved in affect 2. Discussion: a unified theory of depression
regulation. A neurological model of affect regulation involves a
neuroanatomical apparatus comprised of lower limbic centers that In thinking about a unified theory of MDD, an analogy to other
are reciprocally interconnected with higher cortical regions, as conditions that present with depressed mood is helpful. Among
shown in Fig. 1. While limbic areas, such as the amygdala, the many conditions that present similarly to MDD, two are
hippocampus, basal ganglia, and nucleus accumbens, mediate raw, relevant to this discussion: grief and adjustment disorder. In both
unprocessed emotion, areas of the prefrontal cortex (PFC), such as these conditions, patients may experience depressed mood and
the subgenual, medial, and dorsolateral PFC, as well as the neurovegetative symptoms, and their presentation may be
cingulate cortex, mediate cognitive processing of emotions and indistinguishable from that of a major depressive episode. The
top-down inhibition of the limbic system (Mayberg, 2003). When difference between MDD and these conditions is that the latter
strong emotion is generated in the limbic system, the cortex usually remit when the acute stressor or grief reaction has passed.
inhibits limbic activity and processes the emotion in a way that is Grief and adjustment disorder occur when there is an inability to
tolerable. In this conception, depression is viewed as a disruption tolerate and process an acute stressor or loss. While there exists a
in neurocircuitry. Rather than focusing on one biological factor or spectrum of vulnerability and resilience to stress (Fig. 2), it seems
lesion, researchers have described a “functional lesion," in which reasonable to assume that almost anybody could suffer depressive
there is a perturbation in the affect regulation system and an symptoms if placed under a sufficient level of stress. What is
associated attempt at compensation (Mayberg, 2003). Depression important in these disorders is that for a number of reasons the
can be caused by bottom-up phenomena, in which chronic normal capacity to tolerate stress or loss is overwhelmed, leading
hyperactivity of brainstem and limbic centers overwhelms the to depressive symptoms. As is depicted in Fig. 2, there exists a
cortex's capacity, or a top-down mechanism in which hypoactivity spectrum of depressive disorders, in which there is a continuum
or hypoconnectivity in the cortex precludes the necessary
inhibition of normal limbic activity (Mayberg, 2003).

Fig. 1. Affect regulation circuitry involving reciprocal connections between the Fig. 2. The stress-vulnerability model of depression. At increasing levels of
cortex and subcortical regions. biological vulnerability, even mild levels of stress can cause severe disorder.

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from a normal grief reaction through psychotic depression, based areas such as the amygdala, which are then processed in areas such
on the level of stress and vulnerability of the individual. as the cingulate cortex and the medial prefrontal cortex. Every
An analogy between these disorders and MDD, in which the stimulus is assigned meaning and affective valence as it is
ability to tolerate and process stress is overwhelmed, is helpful. In processed through cognitive schemata and psychological orga-
the former conditions, what is abnormal is the stress; in MDD, nizations that are described by the field of psychology and are
what is abnormal is the emotion-processing machinery. As represented in exquisitely complicated neural interconnections
described above, neuroimaging studies have found functional between numerous brain regions. For instance, a patient who has a
abnormalities in the affect regulation neurocircuitry in depressed cognitive schema that is organized according to a core belief of
patients, involving altered connectivity between cortical regions being inadequate or unlovable will process stimuli accordingly,
such as the PFC and subcortical regions such as the amygdala and triggering strongly negative emotional responses in the amygdala.
hippocampus. Combining the above notion of a spectrum of stress Similarly, an individual with disturbances in object relations or
and resilience with the neurobiological model of affect regulation, who harbors excessive intrapsychic conflict may also experience
we can suggest that depression results when the affect regulation many objectively neutral stimuli as subjectively painful and
system is not adequately able to process strongly negative or stressful. It is also significant that many stressors actually stem
depressive affect. This state is experienced by the individual as from internal sources, due to intrapsychic conflicts, an internalized
totally overwhelming and can lead to hopelessness and despair. sense of guilt or pathological object relations, etc. While stressors
While the common endpoint in this model is a tipping point, in experiments with animals usually relate to deprivation or pain,
beyond which affect regulation is overwhelmed, this endpoint can the near-infinite complexity of human psychology adds an
be reached through several different pathways. These include important dimension of meaning to psychosocial stressors.
psychological pathology, primary alterations in the neuroanatom- Accordingly, the psychological makeup of an individual is
ical regions themselves, and pathological changes in connectivity absolutely integral to an understanding of what stimuli will
between these areas. trigger strongly negative emotions, as well as how these emotions
A primary focus of this paper is the fact that all of the proposed are processed. For instance, negative emotions will be intolerable
biological pathophysiological mechanisms of depression, includ- to somebody with poor distress tolerance due to cognitive
ing inflammation, an increased stress response, and reduced distortions or impaired ego strength. In essence, these psychologi-
neuroplasticity, are reciprocally connected with each other and the cal mechanisms are really ways to organize processes that involve
neurochemical pathways, including the monoamines, glutamate, the interconnection between brain regions involving subcortical
and BDNF. All of these pathways can also lead to the alterations centers of affect and emotion and the cortical areas that process
found in the neurocircuitry of the affect regulation system, due to these emotions. These psychological theories explain the complex
direct damage or reduced neuroplasticity in white matter tracts, way in which these circuits work together to process affect, the
leading to the observed expression of the illness such as depressive concept of self and other, and to contextualize experience. These
ideation and affect, motoric symptoms, and neurovegetative psychological descriptions describe higher-order brain functions
symptoms (Fig. 3). that entail the complex collaboration of numerous neural circuits
This neurological system is strongly influenced by the working in tandem.
psychological makeup of the individual. When a stimulus is Primary biological derangements can also impair emotional
experienced, it is processed and assigned a valence according to its processing. It is important to recognize that a genetic predisposi-
psychological significance. Stimuli that are deemed meaningful tion to an excessive amygdalar response to stress, or a hyperactive
enough can then trigger strong emotional responses in subcortical HPA axis due to early life stress, may generate inappropriately

Fig. 3. A unified theory of depression. Numerous genetic and environmental etiological factors interact to cause one or more reciprocally interactive pathophysiological
mechanisms, which in turn cause symptomatic phenotypic expression in one or more R-DOC-like domains.

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strong affect that overwhelms an otherwise healthy psychological It is also significant that nearly all of the proposed pathophysi-
system. In an analogy to a computer, the biological substrate ological mechanisms of depression are integrally related and
represents the hardware, while the psychological mechanisms interconnected. Psychological stress causes HPA axis hyperactivity,
represent the software (Kendler, 2005). A defective software, or increased sympathetic outflow, and inflammation, which in turn
psychological pathology, can make even objectively mild experi- cause ischemic damage to white matter and reduced neurogenesis.
ences overwhelming. Defective hardware, in the form of a Inflammation causes HPA hyperactivity, which in turn has a
biological pathology, can overwhelm an otherwise healthy permissive effect on inflammatory processes, creating a vicious
software or psychological makeup. It is worth stressing that cycle. Inflammation, reduced neurogenesis, and monoamine
psychological mechanisms are just as biological as the primary depletion are all interrelated. All of these biological mechanisms,
biological mechanisms described. Psychopathology stems from the as well as a hyperactive amygdalar response, can also cause
maladaptive interconnections between emotional and cognitive secondary psychological issues as the patient creates maladaptive
circuitry. The distinction between a primary biological mechanism cognitive schemata or object relations to deal with such strong
and a psychological one lies in whether there is pathology is the negative emotions. Focusing on any one of these mechanisms as
pattern in which these systems are organized, observed as the main cause of depression is far too reductionistic. Rather, all of
psychological pathology, or in the brain centers or interconnec- these mechanisms occupy a position at a node in a complex
tions themselves, as manifested in diseased tissue and cells. To interactive matrix of pathophysiological factors. The functional
return to the analogy of a computer, the question is whether the alteration at any node in the system can lead to malfunction of the
computer has a functional hardware that was programmed entire matrix, with the end product being a depressive syndrome.
improperly, or whether the software itself is correct, but the The integrally interactive nature of the system dictates that
circuit-board has rusted. More often than not, there is a mixture of triggering any one of the nodes can ultimately activate the entire
these factors, which impact each other bidirectionally. The cascade. Disorder lies not at one or several nodes, but rather in the
biological findings in depressed patients, including monoamine interaction among them.
depletion, HPA axis hyperactivity, inflammation, impaired neuro- A unified theory of depression is useful for several reasons. First,
genesis, and ischemic damage, are all examples of malfunctioning such a conception shows that a dichotomy between psychology
hardware, as these mechanisms may cause reduced neurogenesis and biology as the mechanism behind depression is unfounded.
or white matter damage, which can impair the brain's ability to The preceding discussion makes it difficult to imagine a depression
physically transmit and process emotional stimuli. Even if the that could be purely biological or psychological without significant
individual's psychological makeup and affect regulatory centers overlap. Similarly, the notion of one biological factor as the main
are healthy, if the interconnections between these areas, consisting etiology of depression is also less likely. Even if the initial cause is
of white matter tracts, are damaged through inflammation, one psychological or biological mechanism, once the interactive
hypercortisolemia, or ischemic damage, the affect regulatory matrix is triggered most patients probably have multiple factors
pathway may be unable to adequately process negative emotions. contributing to their depression at once. Second, the description of
The above discussion shows how all of the proposed theories of MDD as several discrete conditions may represent a failure to
depression are really just different nodes in an interactive matrix. appreciate the illness in all its complexity due to an inappropri-
The psychological makeup of a person dictates how each stimulus ately narrow scope of focus. It may be more useful to view
will be interpreted and assigned an emotional valence. The depression as a final common pathway for many causative factors,
stimulus then triggers subcortical brain regions, generating an acting singly or in combination. Third, this model could explain
emotional reaction that is then relayed to higher cortical why different patients have such varying responses to antidepres-
processing regions. This relay of information must traverse the sant therapy, as well as why targeting some of the biological
brain's rich interconnecting networks whose functional utility is mechanisms involved has had limited success. Targeting the
dependent on the biological integrity of the tissue. Any significant monoamine system alone with antidepressants without address-
biological abnormality could damage these information processing ing the other nodes in the system may simply be inadequate in
highways, leaving strongly negative emotions inadequately some patients with strong biological or psychological predis-
processed. Finally, as the information reaches cognitive centers positions to depression. Finally, a unified theory of depression
in the cortex, they must be interpreted and processed according to could dramatically shift the focus of future research. A reduction-
the individual's psychological structure. It is also important to note istic approach to finding the sole biological cause of depression can
that this psychological processing occurs via near-infinite inter- entirely miss the essence of the condition, which lies in the
connections between numerous cortical and subcortical regions, interconnection of the various factors. Future research into how
and as such, the psychological organization itself is subject to the nodes in the matrix are connected could elucidate the complex
primary biological insults as well. interactions involved.
This highly complex neurological apparatus allows most people While attractive, a unified theory of depression as a syndrome is
to deal with everyday stress with relative ease and functionality. not proven. It could well be that there are several dimensions of
However, when an acute stressor overwhelms the system, an what we call depression that may or may not be related. In fact,
otherwise healthy individual may develop an adjustment disorder. there are at least several possible ways to conceptualize this
An objective loss that overwhelms the system may lead to grief. In disorder. The hypothesis presented here, that the pathophysiologi-
these cases, the nodal problem lies in the external stimulus. cal mechanisms of depressive disorders represent one unified
However, when the dysfunctional node of the matrix is in the matrix, is one possibility. Another possibility is that there are
biological information relay system itself, mild stress or even several different subsyndromes of depression. For instance, there
normal stimuli can totally overwhelm a crippled brain. In these are patients who only have anhedonia, and nothing else, while
cases the brain simply cannot process the information adequately. there are others who may only have motoric underactivity or
Similarly, a biological predisposition to an excessive emotional depressive ideation. In this conception, each subsyndrome may
response to stress, either through genetic factors or HPA axis consist of a grouping of pathophysiological mechanisms into
hyperactivity due to early life stressors, slides a patient along the discrete groups that have little or no overlap. Finally, each
spectrum, so to speak, causing even objectively mild stressors to pathophysiological mechanism may represent a discrete disorder.
overwhelm the patient in a way that much more severe stressors Thus, the pathophysiology of depression may represent one
would do to a healthy patient. disorder comprised of an interactive matrix of mechanisms, a

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few disorders representing separate groups of pathophysiological by identifying domains that run across different diagnoses and
mechanisms, or numerous discrete biological mechanisms. then identifying the various factors involved on every level of
The interactive nature of each biological mechanism involved in detail, from genes and molecules to neural circuits and behaviors.
depression lends support to the hypothesis that the phenotypic The weakness of this approach is that it reduces what could be a
expression of depression stems from an underlying interactive complicated network of factors into isolated mechanisms. If, as we
matrix of factors. It seems less likely, though definitely possibly, suggest here, the various biological mechanisms involved in MDD
that each biological mechanism exists as a separate disorder. It is represent different nodes in a complex interactive matrix, then
certainly possible that there are several discrete subsyndromes of focusing on the elaboration of each individual factor may miss the
depression. At this point, our lack of understanding of each entire essence of the disorder. Despite an increasingly sophisticat-
biological mechanism limits our ability to directly test these ed understanding of each mechanism, if we do not learn how these
hypotheses. Studying each of these domains and their neurobio- factors interact in overarching patterns, we may not come closer to
logical correlates across translational (R-DoC) levels will help us understanding the disorder in a way that will inform treatment. It
understand each biological mechanism in its detail, after which a is reasonable to continue along the path of elucidating each
study of how these mechanisms interact will be possible. Thus, one individual factor in more detail, for without understanding each
way in which these hypotheses could be tested would be to mechanism in depth it will be impossible to understand how
continue the R-DoC project, with the ultimate goal of grouping various mechanisms interact. However, we must not make the
patients according to the underlying pathophysiology of their mistake of being too reductionistic, searching for understanding in
disorder, subsequently mapping out the relationship between the pieces of the puzzle without understanding how they fit
pathophysiology and its phenotypic expression. together.
Future research will need to focus on working out the specific
3. Current state of the evidence and future directions molecular mechanisms for the various interactions between the
different systems. Increased understanding of any of the factors
If so much is known about the various biological causes of would likely be beneficial; however, it may be helpful to highlight
depression and their interactions, why have therapeutic inter- one specific area that may be the most fruitful. Among the strictly
ventions on these factors been either ineffective or incompletely biological pathophysiological factors in depression, the common
utilized? Why is it that despite our understanding of so many end pathway appears to be reduced neurogenesis, leading to
aspects of the neurobiology of depression, our antidepressant functional hypoconnectivity in higher cortical regions and hyper-
therapies target increasing levels of serotonin, NE, and dopamine, connectivity in limbic areas, as described by the network
without addressing all of the other factors? The answer to these hypothesis; yet, the precise way in which these biological factors
questions may be that while research has increased our lead to reduced neurogenesis or the way reduced neurogenesis
understanding of which biological factors are involved in depres- leads to depression remains unclear. Targeting this common
sion and that they interact with each other, it remains very unclear pathway with the goal of understanding how a hyperactive HPA
exactly how they do so on a molecular level. Without an axis, inflammation, and alterations in neurotransmitters cause
understanding of the molecular mechanisms involved, creating reduced neurogenesis would be of paramount importance, as
effective therapies is close to impossible. intervention at this level may hold great promise for good clinical
Through what mechanism do cytokines activate the HPA axis, outcomes. Since triggering any node of the matrix can lead to the
and how do glucocorticoids potentiate the immune system? How stimulation of the entire cascade, it seems reasonable to target a
exactly do both stress and inflammation reduce monoamine common end pathway, as intervening at this level could be
levels? The induction of tryptophan metabolism by IDO is one effective regardless of the original etiological factors involved.
proposed mechanism, but this process remains incompletely Such developments may ensure that the wealth of knowledge
understood. Reduced serotonin levels have been shown to reduce acquired over the past few decades will be translated into new
neurogenesis, but the precise mechanism remains unknown. The therapies and ultimately into better patient outcomes.
precise way in which genetic factors, such as a polymorphism in
the 5-HT transporter gene, cause increased amygdalar reactivity is References
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