Journal Pre-proof

Depression development: From lifestyle changes to motivational deficits

Daniela Schulz

PII: S0166-4328(20)30544-1
DOI: https://doi.org/10.1016/j.bbr.2020.112845
Reference: BBR 112845

To appear in: Behavioural Brain Research

Please cite this article as: { doi: https://doi.org/

This is a PDF file of an article that has undergone enhancements after acceptance, such as
the addition of a cover page and metadata, and formatting for readability, but it is not yet the
definitive version of record. This version will undergo additional copyediting, typesetting and
review before it is published in its final form, but we are providing this version to give early
visibility of the article. Please note that, during the production process, errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal
pertain.

© 2020 Published by Elsevier.

 of
Depression development:
From lifestyle changes to motivational deficits

ro
Daniela Schulz
Boğaziçi University
Institute of Biomedical Engineering,
Center for Life Sciences and Technologies -p
re
Istanbul, Turkey
lP
na

Correspondence
ur

Daniela Schulz, Ph.D.

Assistant Professor
Boğaziçi University
Jo

Institute of Biomedical Engineering

Center for Life Sciences and Technologies
Kandilli Campus
34684 ISTANBUL, Turkey
Phone +90 536 592-5514
daniela.schulz@boun.edu.tr
https://bme.boun.edu.tr/daniela-schulz

1
Abstract

Until now, depression research has taken a surprisingly narrow approach to modelling the

disease, mainly focusing on some form of psychomotor retardation within a mechanistic

framework of depression etiology. However, depression has many symptoms and each is

associated with a vast number of substrates. Thus, to deepen our insights, this SI (“Depression

Symptoms”) reviewed the behavioral and neurobiological sequelae of individual symptoms,

specifically, psychomotor retardation, sadness, low motivation, fatigue, sleep/circadian

of
disruption, weight/appetite changes, and cognitive affective biases. This manuscript aims to

ro
integrate the most central information provided by the individual reviews. As a result, a dynamic

model of depression development is proposed, which views depression as a cumulative process,

-p
where different symptoms develop at different stages, referred to as early, intermediate, and
re
advanced, that require treatment with different pharmaceutical agents, that is, selective serotonin

reuptake inhibitors early on and dopamine-based antidepressants at the advanced stage.

lP

Furthermore, the model views hypothalamic disruption as the source of early symptoms and site

of early intervention. Longitudinal animal models that are capable of modelling the different
na

stages of depression, including transitions between the stages, may be helpful to uncover novel

biomarkers and treatment approaches.

ur

Keywords: depression, animal model, symptomatology, hypothalamus, orexin, stress.

Jo

2
 Reductionism, no doubt, has been and continues to be useful for gaining an understanding of

molecular and behavioral functions. On the other hand, behavior is governed by an intricate

system of factors, such as stimulus-response contingencies, emotional, motivational, and

cognitive factors, and temporal context. Such a system will translate into an equally intricate

system of neural substrates, involving multiple brain regions and their connectivity and

molecular constituents.

From this perspective, the substrates of depression could be expected to have tremendous

of
complexity. After all, depression is defined by multiple symptoms and behavioral changes,

ro
ranging from crying behavior to sleeplessness and indecisiveness (American Psychiatric

Association, 2013). Even on their own, these behaviors are represented by highly complex

-p
neural systems (Newman, 2007; Brudzynski, 2019; Wirz-Justice and Benedetti, 2018; Rayner et
re
al., 2016). Yet, we have taken a surprisingly narrow approach to modelling depression, focusing

mostly on psychomotor retardation within a mechanistic framework of depression etiology.

lP

Perhaps not surprisingly, animal models are found wanting, patients are left unsuccessfully

treated, and clinical trials are failing.

na

To give food for thought, this Special Issue (“Depression Symptoms”) reviewed the

behavioral and neurobiological sequelae of depression symptoms, as defined by the Diagnostic

ur

and Statistical Manual of Mental Disorders (DSM)-5, in an effort to gain insights into their

commonalities and differences. The present manuscript aims to integrate the most central
Jo

information provided by the individual reviews. A dynamic model of depression development is

proposed as a result.

1. All behavior is activity.

3
 Behavioral activity can take on many forms. Exploratory movement, sitting, and sleeping are

a few examples. While it is a relatively simple task to measure a behavior, it can take decades to

discover what it means. A prime example is forced swim immobility, a form of psychomotor

retardation, generally defined as a lack of motion of the whole body except that required for

breathing and balancing to remain afloat (Porsolt et al., 1977). Immobility, as measured in the

forced swim test (FST), has long been interpreted to indicate a depression-like response, but this

notion has been challenged (Molendijk and De Kloet, 2019). As Unal and Canbeyli (2019) point

of
out, a reduction in physical activity occurs in many situations but for different reasons.

ro
The concept of learned despair, indexed by FST immobility, appears to have its origins in

learned helplessness theory, but it also differs in important ways. Learned helplessness is said to

-p
result from learning that escape from stress is impossible, where inescapability or
re
uncontrollability is defined as a lack of contingency between a response and a desired outcome

which, in turn, results in motivational, emotional, and cognitive changes resembling depression
lP

(Maier and Seligman, 1976). Motivational change typically consists of passive behavior, such as

not pressing a lever or not crossing over a barrier, even when active behavior would be adaptive
na

and result in control. In the FST, learned despair is said to result from learning that escape from

cold water stress is impossible (Porsolt et al., 1977). As a result, animals increasingly display
ur

passive as opposed to active escape behaviors, but they are also not given the opportunity to

escape. The FST has often been criticized for lacking a rationale or explanatory framework, but
Jo

because forced swim immobility is attenuated by certain antidepressants administered in the

clinic, it is generally viewed as a screening test for antidepressant compounds. The extinction-

induced despair (EID) model of depression also measures immobility as an index of despair, but

its mechanistic rationale is rooted in operant learning theory (Schulz et al., 2004; Schulz et al.,

4
2007a,b; Huston et al., 2009, 2013). In EID, animals learn two contingencies in succession.

First, they learn that a response results in reinforcement, such as negative reinforcement provided

by escape onto a hidden platform in the water maze (Schulz et al., 2004; Schulz et al., 2007a,b),

or positive reinforcement provided by food following a lever press (Huston et al., 2012).

Second, the animals learn that the previously reinforced response no longer results in

reinforcement, which is extinction. A resistance to extinction was found to be protective of

‘despair’, but with extinction of the previously reinforced response, water maze immobility and

of
active avoidance behaviors are observed (Schulz et al., 2004; Schulz et al., 2007a,b; Huston et

ro
al., 2012; Komorowski et al., 2012).

Thus, different contexts and rationales can be used to study ‘depression’ in rats. Many of our

-p
current models use indicators of psychomotor retardation as indexes of ‘depression’. While we
re
cannot be certain of the meaning of these behaviors in rats, interpretations of symptoms in

humans are also subject to continued debate (Treadway and Zald, 2011; Haskell et al., 2020;
lP

Tanriverdi et al., submitted). For example, psychomotor retardation, motivational deficits,

fatigue, and hypersomnia are all associated with reductions in physical activity, but are
na

considered distinct in DSM-5. To increase our understanding of the different symptoms, their

neurobiological substrates are discussed next (see Table 1 for a summary).

ur

------------------------------

Insert Table 1 about here

Jo

------------------------------

2. Psychomotor retardation

The substrates of psychomotor retardation are mainly studied in the context of Parkinson’s

disease. However, as Unal and Canbeyli (2019) point out, the same basal ganglia (BG) circuits,

5
in particular, those involving the medium spiny neurons of the striatum (STR) and nucleus

accumbens (NAc) are also directly relevant to depression (Pena, 2017; Francis and Lobo, 2017).

Neurochemically, dopamine (DA) D1 and D2 receptor antagonists decrease mobility, and so do

agonist neuromodulators with inhibitory effects on the DA-BG circuit, including cholinergic

histaminergic, and adrenergic agonists (Klemm, 1989, 2001). Furthermore, antidepressants with

high affinities to the serotonin transporter (SERT) and the DA transporter (DAT), like sertraline,

are the most effective in reducing psychomotor retardation, whereas drugs with high affinities to

of
the SERT but not DAT, like desvenlafaxine and fluoxetine, either have no effect or even increase

ro
psychomotor retardation in humans and EID models of depression (Schrijvers et al., 2009;

Mendhe et al., 2017; Schulz et al., 2007b; Huston et al., 2012). Taken together, psychomotor

-p
retardation belongs to a group of symptoms which manifest in reduced physical activity. It is
re
mediated by changes in the BG circuit and has enough molecular specificity that antidepressants

with a high affinity to the DAT alleviate it, whereas antidepressants with a high affinity to the
lP

SERT worsen it.

3. Sadness
na

According to DSM, either sadness or a loss of interest or pleasure have to be present for a

diagnosis to be warranted. Sadness is often expressed through crying. In this Special Issue,
ur

Brudzynski (2019) discusses the similarities and differences between rat 22 kHz ultrasonic

vocalizations (USV) and human crying. It is concluded that the rat calls represent an
Jo

evolutionary counterpart of human crying, despite some differences. Furthermore, the evidence

suggests that emission of 22 kHz USVs like human crying reflects anxiety, and not depression,

nor a symptom of depression, although depressed patients can have anxiety. Notably, rat 22 kHz

USVs are associated with behavioral inhibition, such as a decrease in motor and locomotor

6
activity. One reason might be that the ascending mesolimbic cholinergic system, which initiates

these calls, interacts mutually with the ascending mesolimbic DA system (Brudzynski, 2007).

For example, brief activation of muscarinic receptors led to hyperpolarization of DA neurons in

the substantia nigra pars compacta/ventral tegmental area (SNc/VTA; Fiorillo and Williams,

2000). And, DA D1/D2 receptor agonist R-(-)-apomorphine injected into the NAc decreased rat

22 kHz USVs induced by muscarinic agonist carbachol injected into the anterior hypothalamus-

medial preoptic area, a prominent target of the cholinergic projection originating in the

of
laterodorsal tegmental nucleus (LDT; Brudzynski, 2007; Silkstone and Brudzynski, 2019).

ro
Thus, even though crying has affective, cognitive and somatic components in addition to

behavioral sequelae, the latter involves a form a psychomotor retardation which might result

-p
from an inhibition of the mesolimbic DA system during crying.
re
4. Motivation

A second core symptom of depression, according to DSM, is a loss of interest or pleasure in

lP

previously rewarding activities. This definition is problematic because it lumps two very

different concepts with different neurobiological underpinnings into one symptom category. For
na

example, a cook, if depressed, might stop cooking because a) food is no longer enjoyable or b)

the action of cooking, which includes shopping for food, peeling the vegetables, thinking up
ur

recipes, washing up, and sharing the food with others, is just too demanding and therefore no

longer of interest to the person. The first case describes anhedonia, a loss of pleasure, whereas
Jo

the latter describes a decline in effortful motivation.

In rats, an objective measure of hedonia or ‘liking’ is mouth-licking behavior following

consumption of a palatable substance (Berridge and Robinson, 2003). ‘Liking’ involves opioid

receptor stimulation in the NAc and ventral pallidum (VP; Pecina and Berridge, 2000; Kelley et

7
al., 2002). Depressed patients appear to have normal hedonic experiences (Berlin et al., 1998;

Scinska et al., 2004; Swiecicki et al., 2009, 2015; Clepce et al., 2010), but might perceive

olfactory stimuli as more pleasant (Pause et al., 2001; Lombion-Pouthier et al., 2006) or crave

sweets and carbohydrates more (Moller, 1992).

By contrast, motivational deficits have been demonstrated in depression, as assessed with the

Efforts Expenditure for Rewards Task or EEfRT (Treadway et al., 2012; Yang et al., 2014). In

this task, participants choose to expend high or low physical effort, as indexed by speeded button

of
pressing, in exchange for different reward opportunities (Treadway et al., 2009). It was found

ro
that patients with major depression, and especially those with longer disease episodes, made

fewer high effort choices (Treadway et al., 2012). Originally developed for rats, the two-choice

-p
effort task has been instrumental in the discovery of the substrates of effortful motivation, that is,
re
DA neurotransmission in the NAc (Salamone et al., 1994; Salamone and Correa, 2012). For

example, blockade of DA receptors with haloperidol or depletion of DA in the NAc with 6-

lP

hydroxydopamine decreased the number of choices to climb over a large barrier in return for a

large food reward but did not impair approach and consumption of a small reward that did not
na

require any effort to obtain (Salamone et al., 1994).

Notably, a decrease in effortful motivation is not simply a reduction in physical activity but a
ur

reduction in effortful activity. Not pressing a lever or not crossing over a barrier to avoid foot-

shock, as is often measured in tasks designed to induce learned helplessness, or decreased

Jo

durations of swimming and struggling to escape the cold water in FST and EID could, among

other, also reflect decreases in effortful motivation (Maier and Seligman, 1976; Schulz et al.,

2016). One way to examine this hypothesis is to study the link between the measured behaviors

and their responsiveness to serotonergic and dopaminergic antidepressants. That is because

8
selective serotonin reuptake inhibitors (SSRIs), like fluoxetine and citalopram, are ineffective

and may even aggravate motivational deficits, whereas dopaminergic agents alleviate these

deficits (Padala et al., 2012; Randall et al., 2015; Yohn et al., 2016). In EID, the SSRI fluoxetine

increased immobility, whereas a noradrenergic reuptake inhibitor reduced it (Schulz et al.,

2007b). DA-based antidepressants like bupropion have not yet been tested in this paradigm. In

FST, immobility might be reduced by SSRIs, provided that a time-sampling technique is used for

scoring (Detke et al. 1995; Kirby & Lucki, 1997; Reneric & Lucki, 1998; Cryan et al., 2002,

of
2005). Using standard methods, others have found no effects or an increase in immobility

ro
(Gorka et al., 1979; Paul et al., 1990; Maj et al., 1992; Skrebuhhova et al., 1999; West & Weiss,

1998; Will et al., 2003; Thompson et al., 2004). By contrast, bupropion increased the release of

-p
DA in the NAc and reduced immobility in the FST (West & Weiss, 1998; Kitamura et al., 2010).
re
In the learned helplessness paradigm, failures to escape from foot-shock are attenuated by DA-

based antidepressants (Schulz et al., 2010), but also with SSRIs (Martin et al., 1990; Gambarana
lP

et al., 1995; Ferguson et al., 2000; Zazpe et al., 2007). SSRIs like fluvoxamine might at least

partially exert their effects through DA D1 and D2 receptor stimulation (Takamori et al., 2001).
na

5. Fatigue

Fatigue or a loss of energy is considered a somatic symptom of depression, along with sleep
ur

and appetite disturbances. Somatic symptoms can precede the development of depression. For

example, medically unexplained somatic symptoms that don’t warrant the diagnosis of
Jo

depression present a high risk for depression development in the medium term (Kapfhammer,

2006). Fatigue is also highly prevalent in depression, with rates up to 80% (Hamilton, 1989).

However, it is resistant to treatment with serotonergic antidepressants (Ghanean et al., 2018).

9
 Evidence suggests that fatigue and physio-somatic symptoms, and also fatigue in depression

(as opposed to depression per se) are associated with microglial activation and a resulting

inflammatory response which induces abnormal secretions of cytokines like interleukin (IL)-1β,

cytotoxic substances like reactive oxygen species and nitric oxide, and the tryptophan catabolites

kynurenine and quinolinic acid (Chaves-Filho et al., 2019). These changes do not occur

suddenly but are the consequence of a prolonged neuroprogressive process (Maes et al., 2012).

Possibly, they date back to early life adversity (Ganguly and Brenhouse, 2014).

of
A marked feature of chronic fatigue is abnormalities in pacemaker circuits (Chaves-Filho et

ro
al., 2019). Specifically, reduced circadian signals and altered cyclicity were found in patients

with chronic fatigue syndrome (Racciati et al., 2001). Pro-inflammatory cytokines could be

-p
responsible for this as receptors for IL-1β, tumor necrosis factor alpha, and interferons are
re
located on the master circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus,

and their activations suppress neural drive from the SCN onto its effector systems (Beynon and
lP

Coogan, 2010; Harrington, 2012).

6. Sleep/Rhythms
na

Sleeping and waking follows a circadian cycle, approximately 24 h long (reviewed by

Mendoza, 2019). This rhythm is orchestrated by the SCN, our internal clock, together with
ur

external Zeitgebers, such as daylight. Jet travel across time zones, shift work, light exposure at

night through devices emitting blue light, and staying up late on weekends or social jet lag can
Jo

lead to desynchronization, however. In turn, the chronic stress resulting from circadian

disruption poses a risk for depression development (Bass and Lazar, 2016).

In depression, sleep disturbances are also common (Franzen and Buysse, 2008). These

include difficulties initiating or maintaining sleep, early waking, and shortened rapid eye

10
movement sleep. Evidence suggests that these abnormalities are associated with blunted

circadian amplitudes and a decreased sensitivity to Zeitgebers (Souetre et al., 1989; Lyall et al.,

2018). Importantly, serotonin (5-HT), 5-HT agonists, and the SSRI fluoxetine can function as

Zeitgebers, similar to bright light, since their administration shifts the rhythms of the SCN, clock

genes, and behavior (Cuesta et al., 2008; Nomura et al., 2008; Mendoza, 2019).

It is interesting to observe that asynchronous activity is treatable with SSRIs, but fatigue is

not, though both are somatic symptoms of depression. The separation of somatic symptoms

of
(fatigue and sleep/appetite disturbances) is also evident in factor analysis of Beck’s Depression

ro
Inventory (BDI), a clinical tool used for the diagnosis of depression (Box 1). Thus, it is

conceivable that sleep disturbances manifest early in depression development, possibly resulting

-p
from lifestyle factors. Early on, these disturbances appear to be treatable with SSRIs (Franzen
re
and Buysse, 2008; Spulber et al., 2015; Bass and Lazar, 2016). However, the chronicity of the

stress resulting from desynchronization might lead to fatigue and exhaustion associated with
lP

neuroinflammation (Chaves-Filho et al., 2019), requiring a different treatment approach.

----------------------------
na

Insert Box 1 about here

----------------------------
ur

Other neurotransmitter systems are also involved in the control of the sleep-wake cycle. For

example, the SCN regulates, via orexin (ORX) neurons of the hypothalamus, the circadian
Jo

rhythm of DA neurons in the VTA, which show diurnal variations in accordance with rest-

activity levels (Luo and Aston-Jones, 2009; Moorman and Aston-Jones, 2010). Through

projections to ORX neurons, the SCN also modulates the activity of noradrenergic neurons in the

locus coeruleus, which mediate arousal and wakefulness (Gompf and Aston-Jones, 2008).

11
 ORX neurons have an interesting role in connecting the sleep-wake cycle with systems that

regulate appetite and metabolism (Bass and Lazar, 2016). For example, orexin overexpression

protected mice from diet-induced adiposity and metabolic impairments (Funato et al., 2009),

whereas orexin deficiency induced narcolepsy, inactivity, and obesity (Hara et al., 2001; Willie

et al., 2001; Arrigoni et al., 2019). Not surprisingly, sleep and appetite disturbances loaded on

the same factor in our analysis of BDI (Table 2).

------------------------------

of
Insert Table 2 about here

ro
------------------------------

7. Weight/Appetite

-p
Calorie dense, highly palatable cafeteria-style foods, which are high in fat and simple
re
carbohydrates, such as processed meats, chips, and cookies, quickly lead to weight gain,

adiposity, and metabolic syndrome (Sampey et al., 2011). Insufficient nutrition knowledge, low
lP

cost, and convenience may all contribute to choosing the cafeteria diet over healthy food choices.

A neurophysiological link, however, exists between social stress and the consumption of comfort
na

foods. Specifically, chronic social stress resulting from defeat and subordination, such as in

resident-intruder paradigms, disrupts the negative feedback inhibition of the hypothalamo-

ur

pituitary-adrenal (HPA) axis, induces comfort eating via glucocorticoid modulation of brain

reward circuits, and leads to storage of abdominal fats (Dallman et al., 2003; Coccurello et al.,
Jo

2009). Consumption of comfort food temporarily reduces stress and feelings of depression, but

can transition to recurrent comfort eating, weight gain, obesity, and inflammatory state (Dallman

et al., 2003; Sampey et al., 2011; Coccurello, 2019).

12
 Chronic social stress might achieve long-lasting changes in the brain through increased

plasticity and neuronal growth in the amygdala and onto hypothalamic systems (Dallman et al.,

2003; Patel et al., 2019). Enhanced arborization in the basolateral amygdala following chronic

social stress was associated with social avoidance (Patel et al., 2018). Moreover, decreased

plasticity in the ventral hippocampus, an area which regulates stress and emotions, and in the

prefrontal cortex, which mediates decision-making, working memory, and inhibitory control,

also impact the stress-regulating functions of the hypothalamus (Patel et al., 2018, 2019).

of
Coccurello (2019) hypothesizes that chronic social stress-induced eating leads to defective

ro
leptin signaling, which normally dampens appetite, and in structural remodeling of synaptic

inputs onto ORX neurons in the lateral hypothalamus (LH). This change is mediated by an

-p
increased production of endocannabinoids (eCB) and, thus, an increased inhibition of type-1
re
cannabinoid (CB1) receptor-mediated GABA release which, in turn, disinhibits ORX activity in

the hypothalamus (Cristino et al., 2013). Elevated ORX activity is proposed to increase food
lP

motivation through impacts on GABAergic projections from LH to the dopaminergic VTA

(Coccurello, 2019).
na

The lateral habenula (LHb), which appears to be overactive in animal models of depression

(Li et al., 2011; Mirrione et al., 2014), connects the LH and VTA indirectly, using glutamatergic
ur

projections. If LHb is inhibited, it increases the consumption of high calorie, palatable food

(Stamatakis et al., 2016). During stress, eCB-mediated long-term depression is abolished in

Jo

LHb, shifting plasticity towards potentiation (Park et al., 2017a,b). Thus, altered neuroplasticity

in LHb might underlie a change towards food aversion (Coccurello, 2019).

Serotonin influences energy homeostasis through impacts on the melanocortin system in the

hypothalamic arcuate and on ORX neurons in the LH, among other (Lam et al., 2010). Thus,

13
SSRIs could be expected to help with appetite disturbances in depression. However, the

evidence is not clear (Harvey and Bouwer, 2000). While SSRIs induced weight loss in obesity

without depression (Serralde-Zuniga et al., 2019), weights decreased or increased in depressed

patients depending on initial weights (Orzack et al., 1990), first decreased and then increased

depending on depressed state (Michelson et al., 1999), or increased unwantedly (Fisher et al.,

1995; Bouwer and Harvey, 1996; Bouchard et al., 1997).

of
8. Cognitive affective biases

Cognitive affective biases cause changes in the ways people think, because emotions impact

ro
their cognitions (Lewis et al., 2019). Biased ways of thinking can influence memory recall,

future expectations, decision-making, and judgment. Enhanced negative and reduced positive

-p
biases are hypothesized to play a causative role in the development and maintenance of
re
depression (Disner et al., 2011). In support of this hypothesis, negative biases were found in

individuals at risk for depression (Joormann et al., 2007; Romero et al., 2014), to predict relapse
lP

(Bouhuys et al., 1999), and precede the onset of depression (Rude et al., 2003).

Evidence strongly suggests that SSRIs and selective norepinephrine reuptake inhibitors
na

(SNRIs), given acutely, increase positive and decrease negative processing biases, both in

healthy people and depressed patients (Warren et al., 2015; Park et al., 2018). Indeed, the
ur

neurocognitive model of antidepressant treatment proposes that normalization of biases in

depression is the key action of antidepressants, which occurs early, preceding changes in other
Jo

symptoms (Warren et al., 2015). Moreover, the delay in antidepressant response may be due to

the time it takes for a more positive outlook to translate into new learning and the remodeling of

synaptic connections (Robinson, 2018; Lewis et al., 2019).

14
 Animal models of affective biases are not directly comparable to human tasks which use

emotional stimuli like faces and words to gauge unlearned emotional responses (Robinson,

2018). Animal tasks, by contrast, must rely on learning and memory processes. In the affective

bias test (ABT), biases are learned through pairing of drug effects with rewards, which then leads

to a preference of the reward or avoidance (Lewis et al., 2019). Consistent with human studies,

SSRIs and SNRIs induced a positive affective bias in healthy rats (Stuart et al., 2013). Negative

biases were induced, for example, by retinoic acid, which regulates gene expression and plays a

of
role in sleep and circadian rhythms, learning and memory, synaptic plasticity, and adult

ro
neurogenesis (Vilhais-Neto and Pourquie, 2008). Negative biases were also induced by stress,

eCB antagonist rimonabant, and immunomodulators like interferon alpha (Stuart et al., 2013,

-p
2017). Furthermore, lesions of the central nucleus of the amygdala prevented the formation of
re
positive biases induced by antidepressant treatment, and inactivation of the medial prefrontal

cortex prevented the expression of negative biases (Stuart et al., 2015).

lP

9. Dynamic Model of Depression Development

Based on information provided by the reviews for this SI, I propose a dynamic model of
na

depression development (Fig. 1).

-------------------------------
ur

Insert Figure 1 about here

-------------------------------
Jo

In this model, depression is defined as a cumulative process. It consists of an early stage in

which life style factors, such as repeated exposure to blue light and consumption of cafeteria-

style foods, but also social stress and negative attitudes cumulate and force a homeostatic system

to reorganize. In this early stage, sleep and appetite disturbances as well as cognitive biases are

15
treatable with traditional antidepressants, especially SSRIs. Without treatment or behavioral

change, depression continues to develop. The chronicity of stress resulting from early

disturbances now forces the system into an intermediate stage of depression development, where

fatigue and other physio-somatic symptoms are also present. The patient might seek medical

care, but will probably not be diagnosed with a depression, since traditional diagnostic systems

would not warrant the diagnosis. The current model predicts that, at this stage of depression

development, the patient would benefit from treatment with anti-inflammatory agents. Without

of
such a treatment, depression progresses further to the most advanced stage, in which

ro
motivational deficits are present and difficulties managing daily chores force the patient to seek

help from a psychotherapist or psychiatrist. At this point, the patient would likely benefit from

dopamine-based antidepressants.
-p
re
The implications of the current model are fairly obvious. 1) Depression starts early, long

before it is typically diagnosed. 2) Different pharmacological agents are capable of treating

lP

different symptoms and at different time points during depression development. 3) Future

scientific discovery might benefit from an understanding of the temporal dynamics of depression
na

development, including the mechanisms that mediate the transitions between stages. Clearly,

this will require the development of ‘longitudinal’ animal models that are capable of simulating
ur

early, intermediate, and advanced stages of depression development. In its core, the model is

simple and testable. It is also incomplete, since more symptoms could be addressed and
Jo

integrated in the future.

10. The special role of the hypothalamus

The hypothalamus regulates many vital functions, including sleep/wake rhythms, appetite,

and stress responsivity. In the present model, these are key systems that reorganize in early

16
depression development. Altered sleep and rhythmicity through disruptions of the SCN

(Mendoza et al., 2019), stress-induced changes in eating behavior that lead to the remodeling of

ORX neurons in LH (Coccurello et al., 2019), and structural changes in the amygdala, prefrontal

cortex, and hippocampus that impact the HPA-axis (Patel et al., 2019) appear central to the

manifestation of early symptoms. In this simplified view, hypothalamic disruption is the source

of early symptoms and, by inference, the site of early intervention.

of
11. Conclusion

This SI (“Depression Symptoms”) set out to review the neurobiological bases of individual

ro
symptoms as defined by DSM-5. It achieved its goal of elucidating the vast complexity of

substrates that govern different symptoms. An effort to integrate the different reviews resulted in

-p
the “Dynamic Model of Depression Development”, which predicts that different symptoms
re
develop at different stages, referred to as early, intermediate, and advanced, that require

treatment with different pharmaceutical agents, that is, SSRIs early on and DAergic
lP

antidepressants at the advanced stage. Furthermore, the model views hypothalamic disruption as

the source of early symptoms and site of early intervention. It may be beneficial to develop
na

longitudinal models of depression that can test the trajectory through different stages of

development.
ur

Acknowledgments
Jo

I would like to thank all authors who have contributed to the SI “Depression Symptoms”.

Conflicts of interest

None.

17
 of
References

ro
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders

(5th ed.). Washington, DC: Author; 2013.

-p
2. J.D. Newman, Neural circuits underlying crying and cry responding in mammals, Behav.
re
Brain Res. 182 (2007) 155-165. https://doi.org/10.1016/j.bbr.2007.02.011.
lP

3. S.M. Brudzynski, Emission of 22 kHz vocalizations in rats as an evolutionary equivalent of

human crying: Relationship to depression, Behav. Brain Res. 363 (2019) 1-12.
na

https://doi.org/10.1016/j.bbr.2019.01.033.

4. A. Wirz-Justice, F. Benedetti, Perspectives in affective disorders: Clocks and sleep, Eur. J.

ur

Neurosci. 51 (2020) 346–365. https://doi.org/10.1111/ejn.14362.

5. G. Rayner, G. Jackson, S. Wilson, Cognition-related brain networks underpin the symptoms

Jo

of unipolar depression: Evidence from a systematic review, Neurosci. Biobehav. Rev. 61

(2016) 53–65. https://doi.org/10.1016/j.neubiorev.2015.09.022.

6. R.D. Porsolt, M. Le Pichon, M. Jalfre, Depression: A new animal model sensitive to

antidepressant treatments, Nature 266 (1977) 730-732. https://doi.org/10.1038/266730a0.

18
7. M.L. Molendijk, E.R. de Kloet, Coping with the forced swim stressor: Current state-of-the-

art, Behav. Brain Res. 364 (2019) 1–10. https://doi.org/10.1016/j.bbr.2019.02.005.

8. G. Unal, R. Canbeyli, Psychomotor retardation in depression: A critical measure of the

forced swim test, Behav. Brain Res. 372 (2019) 112047.

https://doi.org/10.1016/j.bbr.2019.112047.

9. S.F. Maier, M.E. Seligman, Learned helplessness: Theory and evidence, J. Exp. Psychol.

Gen. 105 (1976) 3-46. https://doi.org/10.1037/0096-3445.105.1.3.

of
10. D. Schulz, B. Topic, M.A. De Souza Silva, J.P. Huston, Extinction-induced immobility in the

ro
water maze and its neurochemical concomitants in aged and adult rats: A possible model for

depression?, Neurobiol. Learn. Mem. 82 (2004) 128–141.

https://doi.org/10.1016/j.nlm.2004.05.010.
-p
re
11. D. Schulz, J.P. Huston, T. Buddenberg, B. Topic, “Despair” induced by extinction trials in

the water maze: Relationship with measures of anxiety in aged and adult rats, Neurobiol.
lP

Learn. Mem. 87 (2007a) 309–323. https://doi.org/10.1016/j.nlm.2006.09.006.

12. D. Schulz, T. Buddenberg, J.P. Huston, Extinction-induced “despair” in the water maze,
na

exploratory behavior and fear: Effects of chronic antidepressant treatment, Neurobiol. Learn.

Mem. 87 (2007b) 624–634. https://doi.org/10.1016/j.nlm.2006.12.001.

ur

13. J.P. Huston, D. Schulz, B. Topic, Toward an animal model of extinction-induced despair:

Focus on aging and physiological indices, J. Neural Transm. 116 (2009) 1029–1036.
Jo

https://doi.org/10.1007/s00702-009-0210-4.

14. J.P. Huston, M.A. De Souza Silva, M. Komorowski, D. Schulz, B. Topic, Animal models of

extinction-induced depression: Loss of reward and its consequences, Neurosci. Biobehav.

Rev. 37 (2013) 2059–2070. https://doi.org/10.1016/j.neubiorev.2013.02.016.

19
15. J.P. Huston, J. van den Brink, M. Komorowski, Y. Huq, B. Topic, Antidepressants reduce

extinction-induced withdrawal and biting behaviors: A model for depressive-like behavior,

Neuroscience 210 (2012) 249-257. https://doi.org/10.1016/j.neuroscience.2012.02.024.

16. M. Komorowski, J.P. Huston, I. Klingenhegel, J. Paulat, J. Sackers, B. Topic, Distance from

source of reward as a marker for extinction-induced “despair”: Modulation by the

antidepressants clomipramine and citalopram, Neuroscience 223 (2012) 152-162.

https://doi.org/10.1016/j.neuroscience.2012.07.064.

of
17. M.T. Treadway, D.H. Zald, Reconsidering anhedonia in depression: Lessons from

ro
translational neuroscience, Neurosci. Biobehav. Rev. 35 (2011) 537–555.

https://doi.org/10.1016/j.neubiorev.2010.06.006.

-p
18. A.M. Haskell, P.C. Britton, R.J. Servatius, Toward an assessment of escape/avoidance
re
coping in depression, Behav. Brain Res. 381 (2020) 112363.

https://doi.org/10.1016/j.bbr.2019.112363.
lP

19. D. Tanriverdi, G. Bilgen, D. Schulz, Cognitive effort, response accuracy, and perceived

energy: Different faces of the same coin? Submitted.

na

20. C.J. Peña, D1 and D2 Type Medium Spiny Neuron Contributions to Depression, Biol.

Psychiatry 81 (2017) 636–638. https://doi.org/10.1016/j.biopsych.2017.02.010.

ur

21. T.C. Francis, M.K. Lobo, Emerging role for nucleus accumbens medium spiny neuron

subtypes in depression, Biol. Psychiatry 81 (2017) 645-653.

Jo

https://doi.org/10.1016/j.biopsych.2016.09.007.

22. W.R. Klemm, Drug effects on active immobility responses – what they tell us about

neurotransmitter systems and motor functions, Prog. Neurobiol. 32 (1989) 403-422.

https://doi.org/10.1016/0301-0082(89)90030-0.

20
23. W.R. Klemm, Behavioral arrest: In search of the neural control system, Prog. Neurobiol. 65

(2001) 453-471. https://doi.org/10.1016/s0301-0082(01)00016-8.

24. D. Schrijvers, Y.J. Maas, M.P.B.I. Pier, Y. Madani, W. Hulstijn, B.G.C. Sabbe, Psychomotor

changes in major depressive disorder during sertraline treatment, Neuropsychobiology. 59

(2009) 34–42. https://doi.org/10.1159/000205516.

25. P.P. Mendhe, S.P. Shah, M.K. Desai, M.N. Parikh, Comparison of effect of antidepressants

on psychomotor functions, Indian J. Psychol. Med. 39 (2017) 69–75.

of
https://doi.org/10.4103/0253-7176.198946.

ro
26. S.M. Brudzynski, Ultrasonic calls of rats as indicator variables of negative or positive states:

Acetylcholine-dopamine interaction and acoustic coding, Behav. Brain Res. 182 (2007) 261–

273. https://doi.org/10.1016/j.bbr.2007.03.004.
-p
re
27. C.D. Fiorillo, J.T. Williams, Cholinergic inhibition of ventral midbrain dopamine neurons, J.

Neurosci. 20 (2000) 7855–7860. https://doi.org/10.1523/jneurosci.20-20-07855.2000.

lP

28. M. Silkstone, S.M. Brudzynski, Intracerebral injection of R-(-)-Apomorphine into the

nucleus accumbens decreased carbachol-induced 22-kHz ultrasonic vocalizations in rats,

na

Behav. Brain Res. 364 (2019) 264–273. https://doi.org/10.1016/j.bbr.2019.01.044.

29. K.C. Berridge, T.E. Robinson, Parsing reward, Trends Neurosci. 26 (2003) 507–513.
ur

https://doi.org/10.1016/S0166-2236(03)00233-9.

30. S. Pecina, K.C. Berridge, Opioid site in nucleus accumbens shell mediates eating and
Jo

hedonic ‘liking’ for food: Map based on microinjection Fos plumes, Brain Res. 863 (2000)

71-86. https://doi.org/10.1016/s0006-8993(00)02102-8.

21
31. A.E. Kelley, V.P. Bakshi, S.N. Haber, T.L. Steininger, M.J. Will, M. Zhang, Opioid

modulation of taste hedonics within the ventral striatum, Physiol. Behav. 76 (2002) 365-377.

https://doi.org/10.1016/s0031-9384(02)00751-5.

32. I. Berlin, L. Givry-Steiner, Y. Lecrubier, A.J. Puech, Measures of anhedonia and hedonic

responses to sucrose in depressive and schizophrenic patients in comparison with healthy

subjects, Eur. Psychiatry 13 (1998) 303-309. https://doi.org/10.1016/S0924-9338(98)80048-

5.

of
33. A. Scinska, H. Sienkiewicz-Jarosz, W. Kuran, D. Ryglewicz, A. Rogowski, E. Wrobel, A.

ro
Korkosz, A. Kukwa, W. Kostowski, P. Bienkowski, Depressive symptoms and taste

reactivity in humans, Physiol. Behav. 82 (2004) 899-904.

https://doi.org/10.1016/j.physbeh.2004.07.012.
-p
re
34. L. Swiecicki, P. Zatorski, D. Bzinkowska, H. Sienkiewicz-Jarosz, J. Szyndler, A. Scinska,

Gustatory and olfactory function in patients with unipolar and bipolar depression, Prog.
lP

Neuropsychopharmacol. Biol. Psychiatry 33 (2009) 827-834.

https://doi.org/10.1016/j.pnpbp.2009.03.030.
na

35. L. Swiecicki, A. Scinska, D. Bzinkowska, J. Torbinski, H. Sienkiewicz-Jarosz, J.

Samochowiec, P. Bienkowski, Intensity and pleasantness of sucrose taste in patients with

ur

winter depression, Nutr. Neurosci. 18 (2015) 186-191.

https://doi.org/10.1179/1476830514Y.0000000115.
Jo

36. M. Clepce, A. Gossler, K. Reich, J. Kornhuber, N. Thuerauf, The relation between

depression, anhedonia and olfactory hedonic estimates—A pilot study in major depression,

Neurosci. Lett. 471 (2010) 139-143. https://doi.org/10.1016/j.neulet.2010.01.027.

22
37. B.M. Pause, A. Miranda, R. Göder, J.B. Aldenhoff, R. Ferstl, Reduced olfactory performance

in patients with major depression, J. Psychiatr. Res. 35 (2001) 271-277.

https://doi.org/10.1016/S0022-3956(01)00029-2.

38. S. Lombion-Pouthier, P. Vandel, S. Nezelof, E. Haffen, J.-L. Millot, Odor perception in

patients with mood disorders, J. Affect. Disord. 90 (2006) 187-191.

https://doi.org/10.1016/j.jad.2005.11.012.

39. S.E. Moller, Serotonin, carbohydrates, and atypical depression, Pharmacol. Toxicol. 71

of
(1992) 61-71. https://doi.org/10.1111/j.1600-0773.1992.tb01630.x.

ro
40. M.T. Treadway, N. Bossaller, R.C. Shelton, D.H. Zald, Effort-Based Decision-Making in

Major Depressive Disorder: A Translational Model of Motivational Anhedonia, J. Abnorm.

-p
Psychol. 121 (2012) 553–558. https://doi.org/10.1037/a0028813.
re
41. X.-H. Yang, J. Huang, C.-Y. Zhu, Y.-F. Wang, E.F.C. Cheung, R.C.K. Chan, G.-R. Xie,

Motivational deficits in effort-based decision making in individuals with subsyndromal

lP

depression, first-episode and remitted depression patients, Psychiatry Res. 220 (2014) 874–

882. https://doi.org/10.1016/j.psychres.2014.08.056.
na

42. M.T. Treadway, J.W. Buckholtz, A.N. Schwartzman, W.E. Lambert, D.H. Zald, Worth the

“EEfRT”? The effort expenditure for rewards task as an objective measure of motivation and
ur

anhedonia, PLoS One. 4 (2009) 1–9. https://doi.org/10.1371/journal.pone.0006598.

43. J.D. Salamone, M.S. Cousins, S. Bucher, Anhedonia or anergia? Effects of haloperidol and
Jo

nucleus accumbens dopamine depletion on instrumental response selection in a T-maze

cost/benefit procedure, Behav. Brain Res. 64 (1994) 221-229. https://doi.org/10.1016/0166-

4328(94)90108-2.

23
44. J.D. Salamone, M. Correa, The Mysterious Motivational Functions of Mesolimbic

Dopamine, Neuron. 76 (2012) 470–485. https://doi.org/10.1016/j.neuron.2012.10.021.

45. D. Schulz, F.A. Henn, D. Petri, J.P. Huston, Rats bred for helplessness exhibit positive

reinforcement learning deficits which are not alleviated by an antidepressant dose of the

MAO-B inhibitor deprenyl, Neuroscience. 329 (2016) 83–92.

https://doi.org/10.1016/j.neuroscience.2016.04.049.

46. P.R. Padala, K.P. Padala, V. Monga, D.A. Ramirez, D.H. Sullivan, Reversal of SSRI-

of
associated apathy syndrome by discontinuation of therapy, Ann. Pharmacother. 46 (2012).

ro
https://doi.org/10.1345/aph.1Q656.

47. P.A. Randall, C.A. Lee, S.J. Podurgiel, E. Hart, S.E. Yohn, M. Jones, M. Rowland, L. Lopez-

-p
Cruz, M. Correa, J.D. Salamone, Bupropion increases selection of high effort activity in rats
re
tested on a progressive ratio/chow feeding choice procedure: Implications for treatment of

effort-related motivational symptoms, Int. J. Neuropsychopharmacol. 18 (2015) 1–11.

lP

https://doi.org/10.1093/ijnp/pyu017.

48. S.E. Yohn, S.L. Collins, H.M. Contreras-Mora, E.L. Errante, M.A. Rowland, M. Correa, J.D.
na

Salamone, Not All Antidepressants Are Created Equal: Differential Effects of Monoamine

Uptake Inhibitors on Effort-Related Choice Behavior, Neuropsychopharmacology. 41 (2016)

ur

686–694. https://doi.org/10.1038/npp.2015.188.

49. M.J. Detke, M. Rickels, I. Lucki, Active behaviors in the rat forced swimming test
Jo

differentially produced by serotonergic and noradrenergic antidepressants,

Psychopharmacology 121 (1995) 66-72. https://doi.org/10.1007/BF02245592.

24
50. L.G. Kirby, I. Lucki, Interaction between the forced swimming test and fluoxetine treatment

on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the rat, J.

Pharmacol. Exp. Ther. 282 (1997) 967-976.

51. J.P. Reneric, I. Lucki, Antidepressant behavioral effects by dual inhibition of monoamine

reuptake in the rat forced swimming test, Psychopharmacology 136 (1998) 190-197.

https://doi.org/10.1007/s002130050555.

52. J.F. Cryan, A. Markou, I. Lucki, Assessing antidepressant activity in rodents: Recent

of
developments and future needs, Trends Pharmacol. Sci. 23 (2002) 238-245.

ro
https://doi.org/10.1016/s0165-6147(02)02017-5.

53. J.F. Cryan, M.E. Page, I. Lucki, Differential behavioral effects of the antidepressants

-p
reboxetine, fluoxetine, and maclobemide in a modified forced swim test following chronic
re
treatment, Psychopharmacology 182 (2005) 335-344. https://doi.org/10.1007/s00213-005-

0093-5.
lP

54. Z. Górka, E. Wojtasik, H. Kwiatek, J. Maj, Action of serotoninmimetics in the behavioral

despair test in rats, Commun. Psychopharmacol. 3 (1979) 133-136.

na

55. I.A. Paul, G.E. Duncan, C. Kuhn, R.A. Mueller, J.S. Hong, G.R. Breese, Neural adaptation in

imipramine-treated rats processed in forced swim test: assessment of time course, handling,
ur

rat strain and amine uptake, J. Pharmacol. Exp. Ther. 252 (1990) 997-1005.

56. J. Maj, Z. Rogóz, G. Skuza, The effects of combined treatment with MK-801 and
Jo

antidepressant drugs in the forced swimming test in rats, Pol. J. Pharmacol. Pharm. 44 (1992)

217-226.

25
57. T. Skrebuhhova, L. Allikmets, V. Matto, Effects of anxiogenic drugs in rat forced swimming

test, Methods Find. Exp. Clin. Pharmacol. 21 (1999) 173-178.

https://doi.org/10.1358/mf.1999.21.3.534826.

58. C.H. West, J.M. Weiss, Effects of antidepressant drugs on rats bred for low activity in the

swim test, Pharmacol. Biochem. Behav. 61 (1998) 67-79. https://doi.org/10.1016/s0091-

3057(98)00076-8.

59. C.C. Will, F. Aird, E.E. Redei, Selectively bred Wistar-Kyoto rats: an animal model of

of
depression and hyper-responsiveness to antidepressants, Mol. Psychiatry 8 (2003) 925-932.

ro
https://doi.org/10.1038/sj.mp.4001345.

60. M.R. Thompson, K.M. Li, K.J. Clemens, C.G. Gurtman, G.E. Hunt, J.L. Cornish, I.S.

-p
McGregor, Chronic fluoxetine treatment partly attenuates the long-term anxiety and
re
depressive symptoms induced by MDMA ('Ecstasy') in rats, Neuropsychopharmacology 29

(2004) 694-704. https://doi.org/10.1038/sj.npp.1300347.

lP

61. Y. Kitamura, T. Yagi, K. Kitagawa, K. Shinomiya, H. Kawasaki, M. Asanuma, Y. Gomita,

Effects of bupropion on the forced swim test and release of dopamine in the nucleus
na

accumbens in ACTH-treated rats, Naunyn. Schmiedebergs. Arch. Pharmacol. 382 (2010)

151–158. https://doi.org/10.1007/s00210-010-0521-x.
ur

62. D. Schulz, M.M. Mirrione, F.A. Henn, Cognitive aspects of congenital learned helplessness

and its reversal by the monoamine oxidase (MAO)-B inhibitor deprenyl, Neurobiol. Learn.
Jo

Mem. 93 (2010) 291–301. https://doi.org/10.1016/j.nlm.2009.11.003.

63. P. Martin, P. Soubrié, A.J. Puech, Reversal of helpless behavior by serotonin uptake blockers

in rats, Psychopharmacology (Berl). 101 (1990) 403–407.

https://doi.org/10.1007/BF02244061.

26
64. C. Gambarana, O. Ghiglieri, I. Taddei, A. Tagliamonte, M.G. De Montis, Imipramine and

fluoxetine prevent the stress/induced escape deficits in rats through a distinct mechanism of

action, Behav. Pharmacol. 6 (1995) 66-73.

65. S.M. Ferguson, J.D. Brodkin, G.K. Lloyd, F. Menzaghi, Antidepressant-like effects of the

subtype-selective nicotinic acetylcholine receptor agonist, SIB-1508Y, in the learned

helplessness rat model of depression, Psychopharmacology 152 (2000) 295-303.

https://doi.org/10.1007/s002130000531.

of
66. A. Zazpe, I. Artaiz, L. Labeaga, M.L. Lucero, A. Orjales, Reversal of learned helplessness by

ro
selective serotonin reuptake inhibitors in rats is not dependent on 5-HT availability,

Neuropharmacology, 52 (2007) 975-984. https://doi.org/10.1016/j.neuropharm.2006.10.014.

-p
67. K. Takamori, S. Yoshida, S. Okuyama, Repeated treatment with imipramine, fluvoxamine
re
and tranylcypromine decreases the number of escape failures by activating dopaminergic

systems in a rat learned helplessness test, Life Sci. 69 (2001) 1919-1926.

lP

https://doi.org/10.1016/s0024-3205(01)01279-6.

68. H.P. Kapfhammer, Somatic symptoms in depression, Dialogues Clin. Neurosci. 8 (2006)
na

227–239. https://doi.org/10.1016/s0924-9338(99)80453-2.

69. M. Hamilton, Frequency of symptoms in melancholia (depressive illness), Br. J. Psychiatry

ur

154 (1989) 201-206. https://doi.org/10.1192/bjp.154.2.201.

70. H. Ghanean, A.K. Ceniti, S.H. Kennedy, Fatigue in Patients with Major Depressive Disorder:
Jo

Prevalence, Burden and Pharmacological Approaches to Management, CNS Drugs 32 (2018)

65–74. https://doi.org/10.1007/s40263-018-0490-z.

27
71. A.J.M. Chaves-Filho, D.S. Macedo, D.F. de Lucena, M. Maes, Shared microglial

mechanisms underpinning depression and chronic fatigue syndrome and their comorbidities,

Behav. Brain Res. 372 (2019) 111975. https://doi.org/10.1016/j.bbr.2019.111975.

72. M. Maes, M. Berk, L. Goehler, C. Song, G. Anderson, P. Gałecki, B. Leonard, Depression

and sickness behavior are Janus-faced responses to shared inflammatory pathways, BMC

Med. 10 (2012) 1–19. https://doi.org/10.1186/1741-7015-10-66.

73. P. Ganguly, H.C. Brenhouse, Broken or maladaptive? Altered trajectories in

of
neuroinflammation and behavior after early life adversity, Dev. Cogn. Neurosci. 11 (2015)

ro
18–30. https://doi.org/10.1016/j.dcn.2014.07.001.

74. D. Racciatti, M.T. Guagnano, J. Vecchiet, P.L. De Remigis, E. Pizzigallo, R. Della Vecchia,

-p
T. Di Sciascio, D. Merlitti, S. Sensi, Chronic fatigue syndrome: Circadian rhythm and
re
hypothalamic-pituitary-adrenal (HPA) axis impairment, Int. J. Immunopathol. Pharmacol. 14

(2001) 11–15. https://doi.org/10.1177/039463200101400103.

lP

75. A.L. Beynon, A.N. Coogan, Diurnal, age, and immune regulation of interleukin-1β and

interleukin-1 type 1 receptor in the mouse suprachiasmatic nucleus, Chronobiol. Int. 27

na

(2010) 1546–1563. https://doi.org/10.3109/07420528.2010.501927.

76. M.E. Harrington, Neurobiological studies of fatigue, Prog. Neurobiol. 99 (2012) 93–105.
ur

https://doi.org/10.1016/j.pneurobio.2012.07.004.

77. J. Mendoza, Circadian insights into the biology of depression: Symptoms, treatments and
Jo

animal models, Behav. Brain Res. 376 (2019) 112186.

https://doi.org/10.1016/j.bbr.2019.112186.

78. J. Bass, M.A. Lazar, Circadian time signatures of fitness and disease, Science 354 (2016)

994-999. https://doi.org/10.1126/science.aah4965.

28
79. P.L. Franzen, D.J. Buysse, Sleep disturbances and depression: Risk relationships for

subsequent depression and therapeutic implications, Dialogues Clin. Neurosci. 10 (2008)

473–481.

80. E. Souetre, E. Salvati, J.-L. Belugou, D. Pringuey, M. Candito, B. Krebs, J.-L. Ardisson, G.

Darcourt, Circadian rhythms in depression and recovery: Evidence for blunted amplitude as

the main chronobiological abnormality, Psychiatry Res. 28 (1989) 263-278.

https://doi.org/10.1016/0165-1781(89)90207-2.

of
81. L.M. Lyall, C.A. Wyse, N. Graham, A. Ferguson, D.M. Lyall, B. Cullen, C.A. Celis Morales,

ro
S.M. Biello, D. Mackay, J. Ward, R.J. Strawbridge, J.M.R. Gill, M.E.S. Bailey, J.P. Pell, D.J.

Smith, Association of disrupted circadian rhythmicity with mood disorders, subjective

-p
wellbeing, and cognitive function: A cross-sectional study of 91105 participants from the UK
re
Biobank, Lancet Psychiatry 5 (2018) 507-514. https://doi.org/10.1016/S2215-

0366(18)30139-1.
lP

82. M. Cuesta, J. Mendoza, D. Clesse, P. Pévet, E. Challet, Serotonergic activation potentiates

light resetting of the main circadian clock and alters clock gene expression in a diurnal
na

rodent, Exp. Neurol. 210 (2008) 501–513. https://doi.org/10.1016/j.expneurol.2007.11.026.

83. K. Nomura, O. Castanon-Cervantes, A. Davidson, C. Fukuhara, Selective serotonin reuptake

ur

inhibitors and raft inhibitors shorten the period of Period1-driven circadian bioluminescence

rhythms in rat-1 fibroblasts, Life Sci. 82 (2008) 1169-1174.

Jo

https://doi.org/10.1016/j.lfs.2008.03.024.

84. S. Spulber, M. Conti, C. DuPont, M. Raciti, R. Bose, N. Onishchenko, S. Ceccatelli,

Alterations in circadian entrainment precede the onset of depression-like behavior that does

29
 not respond to fluoxetine, Transl. Psychiatry. 5 (2015) e603-10.

https://doi.org/10.1038/tp.2015.94.

85. A.H. Luo, G. Aston-Jones, Circuit projection from suprachiasmatic nucleus to ventral

tegmental area: A novel circadian output pathway, Eur. J. Neurosci. 29 (2009) 748–760.

https://doi.org/10.1111/j.1460-9568.2008.06606.x.

86. D.E. Moorman, G. Aston-Jones, Orexin/hypocretin modulates response of ventral tegmental

dopamine neurons to prefrontal activation: Diurnal influences, J. Neurosci. 30 (2010) 15585–

of
15599. https://doi.org/10.1523/JNEUROSCI.2871-10.2010.

ro
87. H.S. Gompf, G. Aston-Jones, Role of orexin input in the diurnal rhythm of locus coeruleus

impulse activity, Brain Res. 1224 (2008) 43–52.

https://doi.org/10.1016/j.brainres.2008.05.060.
-p
re
88. H. Funato, A.L. Tsai, J.T. Willie, Y. Kisanuki, S.C. Williams, T. Sakurai, M. Yanagisawa,

Enhanced Orexin Receptor-2 Signaling Prevents Diet-Induced Obesity and Improves Leptin
lP

Sensitivity, Cell Metab. 9 (2009) 64–76. https://doi.org/10.1016/j.cmet.2008.10.010.

89. J. Hara, C.T. Beuckmann, T. Nambu, J.T. Willie, R.M. Chemelli, C.M. Sinton, F. Sugiyama,
na

K.I. Yagami, K. Goto, M. Yanagisawa, T. Sakurai, Genetic ablation of orexin neurons in

mice results in narcolepsy, hypophagia, and obesity, Neuron 30 (2001) 345–354.

ur

https://doi.org/10.1016/S0896-6273(01)00293-8.

90. J.T. Willie, R.M. Chemelli, C.M. Sinton, M. Yanasigawa, To eat or to sleep? Orexin in the
Jo

regulation of feeding and wakefulness, Annu. Rev. Neurosci. 24 (2001) 429-458.

https://doi.org/10.1146/annurev.neuro.24.1.429.

30
91. E. Arrigoni, M.J.S. Chee, P.M. Fuller, To eat or to sleep: That is a lateral hypothalamic

question, Neuropharmacology. 154 (2019) 34–49.

https://doi.org/10.1016/j.neuropharm.2018.11.017.

92. B.P. Sampey, A.M. Vanhoose, H.M. Winfield, A.J. Freemerman, M.J. Muehlbauer, P.T.

Fueger, C.B. Newgard, L. Makowski, Cafeteria diet is a robust model of human metabolic

syndrome with liver and adipose inflammation: Comparison to high-fat diet, Obesity. 19

(2011) 1109–1117. https://doi.org/10.1038/oby.2011.18.

of
93. M.F. Dallman, N. Pecoraro, S.F. Akana, S.E. La Fleur, F. Gomez, H. Houshyar, M.E. Bell, S.

ro
Bhatnagar, K.D. Laugero, S. Manalo, Chronic stress and obesity: A new view of “comfort

food,” Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 11696–11701.

https://doi.org/10.1073/pnas.1934666100.
-p
re
94. R. Coccurello, F.R. D’Amato, A. Moles, Chronic social stress, hedonism and vulnerability to

obesity: Lessons from Rodents, Neurosci. Biobehav. Rev. 33 (2009) 537–550.

lP

https://doi.org/10.1016/j.neubiorev.2008.05.018.

95. R. Coccurello, Anhedonia in depression symptomatology: Appetite dysregulation and

na

defective brain reward processing, Behav. Brain Res. 372 (2019) 112041.

https://doi.org/10.1016/j.bbr.2019.112041.
ur

96. D. Patel, M.J. Kas, S. Chattarji, B. Buwalda, Rodent models of social stress and neuronal

plasticity: Relevance to depressive-like disorders, Behav. Brain Res. 369 (2019) 111900.
Jo

https://doi.org/10.1016/j.bbr.2019.111900.

97. D. Patel, S. Anilkumar, S. Chattarji, B. Buwalda, Repeated social stress leads to contrasting

patterns of structural plasticity in the amygdala and hippocampus, Behav. Brain Res. 347

(2018) 314–324. https://doi.org/10.1016/j.bbr.2018.03.034.

31
98. L. Cristino, G. Busetto, R. Imperatore, I. Ferrandino, L. Palomba, C. Silvestri, S. Petrosino,

P. Orlando, M. Bentivoglio, K. Mackie, V. Di Marzo, Obesity-driven synaptic remodeling

affects endocannabinoid control of orexinergic neurons, Proc. Natl. Acad. Sci. U. S. A. 110

(2013) 2229–2238. https://doi.org/10.1073/pnas.1219485110.

99. B. Li, J. Piriz, M. Mirrione, C. Chung, C.D. Proulx, D. Schulz, F. Henn, R. Malinow,

Synaptic potentiation onto habenula neurons in the learned helplessness model of depression,

Nature. 470 (2011) 535–541. https://doi.org/10.1038/nature09742.

of
100. M.M. Mirrione, D. Schulz, K.A.B. Lapidus, S. Zhang, W. Goodman, F.A. Henn,

ro
Increased metabolic activity in the septum and habenula during stress is linked to subsequent

expression of learned helplessness behavior, Front. Hum. Neurosci. 8 (2014) 1–8.

https://doi.org/10.3389/fnhum.2014.00029.
-p
re
101. A.M. Stamatakis, M. Van Swieten, M.L. Basiri, G.A. Blair, P. Kantak, G.D. Stuber,

Lateral hypothalamic area glutamatergic neurons and their projections to the lateral habenula
lP

regulate feeding and reward, J. Neurosci. 36 (2016) 302–311.

https://doi.org/10.1523/JNEUROSCI.1202-15.2016.
na

102. H. Park, J. Rhee, K. Park, J.S. Han, R. Malinow, C.H. Chung, Exposure to stressors

facilitates long-term synaptic potentiation in the lateral habenula, J. Neurosci. 37 (2017)

ur

6021–6030. https://doi.org/10.1523/JNEUROSCI.2281-16.2017.

103. H. Park, J. Rhee, S. Lee, C.H. Chung, Selectively Impaired Endocannabinoid-Dependent

Jo

Long-Term Depression in the Lateral Habenula in an Animal Model of Depression, Cell Rep.

20 (2017) 289–296. https://doi.org/10.1016/j.celrep.2017.06.049.

32
104. D.D. Lam, A.S. Garfield, O.J. Marston, J. Shaw, L.K. Heisler, Brain serotonin system in

the coordination of food intake and body weight, Pharmacol. Biochem. Behav. 97 (2010) 84–

91. https://doi.org/10.1016/j.pbb.2010.09.003.

105. B.H. Harvey, C.D. Bouwer, Neuropharmacology of paradoxic weight gain with selective

serotonin reuptake inhibitors, Clin. Neuropharmacol. 23 (2000) 90–97.

https://doi.org/10.1097/00002826-200003000-00006.

106. A.E. Serralde-Zúñiga, A.G. Gonzalez Garay, Y. Rodríguez-Carmona, G. Melendez,

of
Fluoxetine for adults who are overweight or obese, Cochrane Database Syst. Rev. 2019

ro
(2019). https://doi.org/10.1002/14651858.CD011688.pub2.

107. M.H Orzack, L.M. Friedman, Weight changes on fluoxetine as a function of baseline

-p
weight in depressed patients, Psychopharmacol. Bull. 26 (1990) 327–330.
re
108. D. Michelson, J.D. Amsterdam, F.M. Quitkin, F.W. Reimherr, J.F. Rosenbaum, J.

Zajecka, K.L. Sundell, Y. Kim, C.M. Beasley, Changes in weight during a 1-year trial of
lP

fluoxetine, Am. J. Psychiatry. 156 (1999) 1170–1176. https://doi.org/10.1176/ajp.156.8.1170.

109. S. Fisher, T.A. Kent, S.G. Bryant, Post-marketing surveillance by patient self-monitoring:
na

preliminary data for sertraline versus fluoxetine, J. Clin. Psychiatry 56 (1995) 288–296.

110. C.D. Bouwer, B.H. Harvey, Phasic craving for carbohydrate observed with citalopram,
ur

Int. Clin. Psychopharmacol. 11 (1996) 273–278. https://doi.org/10.1097/00004850-

199612000-00009.
Jo

111. J.M. Bouchard, N. Strub, R. Nil, Citalopram and viloxazine in the treatment of depression

by means of slow drop infusion. A double-blind comparative trial, J. Affect. Disorders 46

(1997) 51–58. https://doi.org/10.1016/s0165-0327(97)00078-5.

33
112. L.R. Lewis, A. Benn, D.M. Dwyer, E.S.J. Robinson, Affective biases and their

interaction with other reward-related deficits in rodent models of psychiatric disorders,

Behav. Brain Res. 372 (2019) 112051. https://doi.org/10.1016/j.bbr.2019.112051.

113. S.G. Disner, C.G. Beevers, E.A.P. Haigh, A.T. Beck, Neural mechanisms of the cognitive

model of depression, Nat. Rev. Neurosci. 12 (2011) 467–477.

https://doi.org/10.1038/nrn3027.

114. J. Joormann, L. Talbot, I.H. Gotlib, Biased processing of emotional information in girls at

of
risk for depression, J. Abnorm. Psychol. 116 (2007) 135-143. https://doi.org/10.1037/0021-

ro
843X.116.1.135.

115. N. Romero, A. Sanchez, C. Vazquez, Memory biases in remitted depression: The role of

-p
negative cognitions at explicit and automatic processing levels, J. Behav. Ther. Exp.
re
Psychiatry 45 (2014) 128-135. https://doi.org/10.1016/j.jbtep.2013.09.008.

116. A.L. Bouhuys, E. Geerts, M.C. Gordijn, Depressed patients’ perceptions of facial
lP

emotions in depressed and remitted states are associated with relapse: A longitudinal study, J.

Nerv. Ment. Dis. 187 (1999) 595-602. https://doi.org/10.1097/00005053-199910000-00002.

na

117. S.S. Rude, C.R. Valdez, S. Odom, A. Ebrahimi, Negative cognitive biases predict

subsequent depression, 27 (2003) 415-429. https://doi.org/10.1023/A:1025472413805.

ur

118. M.B. Warren, A. Pringle, C.J. Harmer, A neurocognitive model for understanding

treatment action in depression, Philos. Trans. R. Soc. B Biol. Sci. 370 (2015).
Jo

https://doi.org/10.1098/rstb.2014.0213.

119. C. Park, Z. Pan, E. Brietzke, M. Subramaniapillai, J.D. Rosenblat, H. Zuckerman, Y. Lee,

D. Fus, R.S. McIntyre, Predicting antidepressant response using early changes in cognition:

34
 A systematic review, Behav. Brain Res. 353 (2018) 154–160.

https://doi.org/10.1016/j.bbr.2018.07.011.

120. E.S.J. Robinson, Translational new approaches for investigating mood disorders in

rodents and what they may reveal about the underlying neurobiology of major depressive

disorder, Philos. Trans. R. Soc. B Biol. Sci. 373 (2018).

https://doi.org/10.1098/rstb.2017.0036.

121. S.A. Stuart, P. Butler, M.R. Munafò, D.J. Nutt, E.S.J. Robinson, A translational rodent

of
assay of affective biases in depression and antidepressant therapy,

ro
Neuropsychopharmacology. 38 (2013) 1625–1635. https://doi.org/10.1038/npp.2013.69.

122. C. Vilhais-Neto, O. Pourquie, Retinoic acid, Curr. Biol. 18 (2008) 191–192.

https://doi.org/10.1016/j.cub.2007.12.042.
-p
re
123. S.A. Stuart, C.M. Wood, E.S.J. Robinson, Using the affective bias test to predict drug-

induced negative affect: implications for drug safety, Br. J. Pharmacol. 174 (2017) 3200–
lP

3210. https://doi.org/10.1111/bph.13972.

124. S.A. Stuart, P. Butler, M.R. Munafò, D.J. Nutt, E.S.J. Robinson, Distinct
na

Neuropsychological Mechanisms May Explain Delayed-Versus Rapid-Onset Antidepressant

Efficacy, Neuropsychopharmacology. 40 (2015) 2165–2174.

ur

https://doi.org/10.1038/npp.2015.59.

125. I. Mori, The olfactory bulb: A link between environmental agents and narcolepsy, Med.
Jo

Hypotheses. 126 (2019) 66–68. https://doi.org/10.1016/j.mehy.2019.03.017.

35
 of
ro
-p
re
lP

Figure 1. Dynamic Model of Depression Development. In this model, depression symptoms

na

are sorted across time, with changes in sleep and appetite as well as cognitive affective biases

representing early symptoms in depression development. At this time point, the symptoms are
ur

treatable with selective serotonin reuptake inhibitors (SSRIs). Exposure to blue light devices,

consumption of the cafeteria diet, stress, and even viruses may have led to the remodeling of
Jo

synaptic inputs to the hypothalamus, resulting in early symptoms (Coccurello, 2019; Mendoza,

2019; Mori, 2019; Patel et al., 2019). Without treatment or behavioral change, depression

continues to develop, where fatigue and other physio-somatic symptoms are also present that are

accompanied by microglial activation and a resulting inflammatory response (Chalves-Filho et

36
al., 2019). Psychomotor retardation and motivational deficits have a well-established

dopaminergic (DAergic) basis (Unal and Canbeyli, 2019; Lewis et al., 2019). In the present

model, their presence indicates the most advanced stage of depression development. At this

stage, the individual is most likely to seek help from a mental health professional and to receive a

traditional diagnosis of depression.

of
ro
-p
re
lP
na
ur
Jo

37
Box 1. Factor analysis of Beck’s Depression Inventory (BDI-IA)

The inventory was administered to 294 participants (176 males, 114 females, mean age ±
S.D. = 33.58 ± 14.56, range = 63) that were part of a larger study (publication in
preparation). They were recruited from the streets of Istanbul, in 6 different city centers, to
represent the general city population.
The mean (± SD) BDI score was 10.54 (± 7.86). The Cronbach’s alpha was 0.865. Item 19
was removed to increase the alpha to 0.868. Principal component analysis was conducted

of
with varimax rotation. The 20 items loaded onto 4 factors with Eigenvalues > 1, explaining
13.75%, 12.37%, 11.22%, and 11.08% of the variance, respectively. The largest loadings
for each item are shown in Table 2.

ro
The first component appears to encode psychological pain. The second component
reflects cognitive-emotive changes, such as indecisiveness, health worries, and irritation,
so not surprisingly, fatigue was also associated with this factor. The third component

-p
appears to imply feelings of insufficiency. The fourth component compiles somatization
items, most notably, changes in sleep and appetite. Fatigue, a somatic symptom, also
loaded on the fourth dimension. However, the fact that it most strongly loaded on the
re
cognitive factor and is known to associate with neuroinflammatory processes (Chaves-Filho
et al., 2019), might indicate some separation from other somatization symptoms.
lP
na
ur
Jo

38
Table 1. Summary of biological systems mediating symptoms of depression
Behavior/ Key brain areas/ Key biological Possible link

of
Symptom(s) Concept(s)
syndrome circuits systems with depression Author(s)
acc to DSM-V studied

ro
insomnia or circadian sleep, circadian disruption
SCN 5-HT, DA, ORX Mendoza
hypersomnia rhythms wakefulness poses
risk for depression
development

-p
weight loss or reward, leptin, ORX, eCB, stress-induced
eating behavior HPA-axis, Coccurello
weight gain aversion, CB1-R, comfort eating

re
or changes in food GABA, GLU, DA leads to structural
LH-VTA, LHb, VP
appetite motivation D1-R, D2-R remodeling
and altered
appetite regulation

diminished
ability to think
cognitive
affective
biases
lP
digging for
reward in a
mPFC, AMYG 5-HT, NE, DA,
enhanced negative
and reduced
Lewis, Benn,
Dwyer,
na
drug-induced positive biases may
or concentrate retinoic acid, Robinson
affective state play a
eCB, GABA, causative role in
immunomodulators depression
development
ur

resident- GLU, AMPA-R, stress induces Patel, Kas,

N/A social stress HPA-axis,
intruder models NMDA-R, structural Chattarji,
Jo

AMYG, PFC, HIPP TrkB, BDNF, tPA reorganization Buwalda

Chaves-
fatigue or loss fatigue and high risk for
chronic fatigue SCN immune pathways, Filho,
of energy other depression,
Macedo,
physio- high prevalence de Lucena,
syndrome DMH-LC microglia, IL-1,
somatic during depression, Maes

39
 oxidative &
symptoms VTA residual symptom
nitrosative stress,

of
bacterial
translocation

ro
passive immobility in infralimbic mPFC- if persisting, Molendijk,
N/A GR activation,
coping FST STR, enhances de Kloet
with
extended AMYG- parasympathetic vulnerability to
inescapable
PVN, vlPAG, activation, depression

-p
stress
VTA eCB, DA

re
psychomotor behavioral immobility in basal ganglia psychomotor Unal,
GABAergic MSN,
retardation despair FST, circuit, retardation Canbeyli
reduced afferents to, DA D1-R, D2-R
in depression
physical activity efferents from BG, antagonism,

lP STR, FC
dynorphin,
substance P,
neuromodulators of
DA BG circuit,
nACh, mACh, H1,
na
α1, α2, agonism,
BDNF

effortful
ur

DA, A2A-R, mACh- low motivation in Lewis, Benn,

loss of interest motivation decision- NAc, VP
R, GABAA-R depression Dwyer,
making
Robinson
Jo

ascending
could suggest
sadness crying 22 kHz USV mesolimbic mACh Brudzynski
anxiety state
cholinergic
system originating in depressed
in LDT patients

40
 of
5-HT = serotonin; A2A-R = adenosine 2A receptor; α1 = alpha-1 adrenergic receptor; α2 = alpha-2 adrenergic receptor; AMPA-R =
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AMYG = amygdala; BDNF = brain-derived neurotrophic factor; BG
= basal ganglia; CB1-R = type-1 cannabinoid receptor; D1-R = dopamine D1 receptor; D2-R = dopamine D2 receptor; DA =

ro
dopamine; DMH = dorsomedial hypothalamus; eCB = endocannabinoid; FC = frontal cortex; FST = forced swim test; GABA =
gamma aminobutyric acid; GLU = glutamate; GR = glucocorticoid receptor; H1 = histamine H1 receptor; HIPP = hippocampus; HPA
= hypothalamo-pituitary-axis; IL = interleukin; LC = locus coeruleus; LH = lateral hypothalamus; LHb = lateral habenula; mACh =

-p
muscarinic acetylcholine receptor; mPFC = medial prefrontal cortex; MSN = medium spiny neuron; NAc = nucleus accumbens;
nACh = nicotinergic acetylcholine receptor; NE = norepinephrine; NMDA-R = N-methyl-D-aspartate receptor; ORX = orexin; PVN =
paraventricular nucleus of the hypothalamus; SCN = suprachiasmatic nucleus; STR = striatum; tPA = tissue plasminogen activator;
TrkB = tyrosine receptor

re
lP
na
ur
Jo

41
Table 2. Factor analysis of Beck’s Depression Inventory (BDI-IA).

Rotated Component

Item # Type 1 2 3 4

BDI1 Sad .636

BDI2 Hopeless .565

BDI3 Failure .542

of
BDI4 Dissatisfaction .381

BDI5 Guilty .656

ro
BDI6 Punished .678

BDI7 Self-dislike .627

BDI8

BDI9
Self-blame

Suicidal thoughts
-p .674

.523
re
BDI10 Crying .360

BDI11 Irritation .498

lP

BDI12 Social withdrawal .452

BDI13 Indecisiveness .576

na

BDI14 Appearance .505

BDI15 Work difficulty .616

ur

BDI16 Sleep .609

BDI17 Fatigue .498 .488

Jo

BDI18 Appetite .673

BDI20 Health worries .649

BDI21 Loss of libido .578

42