Introduction:
The old classification of depression into Reactive and Endogneous that are still observed in the clinical practice cannot all be accommodated under the current rubric of Major Depression. This is because psychiatric nosology under DSM and its latest 5th edition is still descriptive, and not etiologic. In this article both reactive and endogenous categories of depression are revisited from the perspective of today’s understanding of etiological pathways. From an epigenetic perspective, the old dichotomy of Reactive vs. Endogenous are inter-related through the impact of the environment (e.g. stress). This includes familial or prenatal depression, where the environmental impact is before birth, or childhood depression where the early life stress is the precipitating factor to the genetic susceptibility. In conclusion, searching for both environmental impact (e.g. stressors) and genetic predispositions in depression, even at a clinical level could help clinicians with better therapeutic decisions.
The differentiation of major depression into ‘reactive (stress-induced)’ vs. ‘endogenous (e.g. genetic)’ dates back to the German psychiatrist, Kurt Schneider (Schneider, 1920) who borrowed the term ‘endogenous’ from Emil Kraepelin. The differentiation was an early attempt at an etiological classification of depression (Mendels & Cochrane C, 1968). Despite the extensive use of these terms and despite the popularity of the catecholamine deficiency hypothesis of depression (Schildkraut, 1965) and the effectiveness of tricyclic antidepressants that began with the introduction of imipramine in the 1950’s, psychiatric nosology then gave up on the attempt of classifying depressions according to etiology.
Although the aim of DSM-III in 1980 was for psychiatry to do what the rest of medicine does, to classify disease according to cause, this proved impossible and a non-etiological, purely descriptive system was devised that relied on categories based on symptoms and their severity. DSM-III divided the depressions into major and minor (DSM-III, 1980). Almost four decades later, DSM5 continues to be descriptive and non-etiological (DSM5, 2013). This has continued despite research that points to distinguishable pathways leading to the symptoms of major depression (Ghaemi & Vohringer, 2011; Malki et al. 2014; Mizushima et al. 2013; Parker 2000).
In this article an attempt depression is reviewed on a pathophysiological basis through 1) the impact of stressful events and their timing 2) gene-environment interactions and 3) biological circuits affected by different kinds of depression. The generic term of “depression” that has been used in this paper, refers mostly to major or unipolar depression, though it can at times also applies to minor depression and dysthymia. This article also excludes the normal reaction of mood to stress below clinical level of severity and dysfunction.
The timing of the stress onset:
In reference to stress leading to depression, there is a major differentiation between an early childhood adversary or later in life (adulthood) stress. While these two types of depression, one with an early onset in childhood or adolescence, and the other one with a later onset in adulthood, could be referred to as “Reactive Depression”, they are fundamentally different. (Hazel NA., et al., 2008) This differentiation between reactive depression in the past decade has been recognized in the literature as “Juvenile” and “adult” onset with different pathophysiological pathways that perhaps demand different treatment pathways as well. (Jaffee SR, et al., 2002; Weissman MM, 2002)
Other than the age of onset differentiation of these two reactive subtypes of depression, the juvenile-onset depression is associated with increased risk for depression among the first-degree relatives of depressed probands in clinical and community samples, perhaps related to the shared stressful environment. (Weissman MM, et al., 1984; Kovacs M., et al., 1997; Neuman RJ., et al., 1997; Klein DN., et al., 2001) The children of depressed parents are also at higher risk for juvenile-onset depression compared with the children of non-depressed parents, and this association is explained by early parental age onset of depression. (Wickramaratne P., Weissman MM., 1998; Goodman SH Gotlib IH., 1999; Fergusson DM., et al., 1996)
The findings while show shared stressful environments such as poor parenting, family discord, parental psychopathology, losses and abuses, they also implicate genetic risk factors in juvenile-onset depression. There has been evidence also that juvenile onset depression before age 20 has been caused by early onset environmental stress, but not a later onset. (Kessler RC Magee WJ., 1993) Even it seems that the juvenile onset depression is heterogeneous as there is differentiation between pre-pubertal and post-pubertal age of onset. It has been shown that the pre-pubertal onset has been associated with higher risk of suicide attempts, alcohol dependence, and conduct disorder. (Harrington R., et al., 1997; Wickramaratne PJ., et al., 2000)
From an epigenetic model of gene-environmental interaction perspective, the so called endogenous/biological or familial/hereditary depression could have been also caused by an earlier, prenatal onset stress. It is well known that the early onset prenatal stress adversely affects the brain development with neuronal loss and behavioral dysfunction, not limited only to endogenous or biological depression. (Bernhardt LK., et al., 2017) There is also more recent appreciation of the significance of risk of polymorphism such as associated epigenetic risk factors of SNPs (Single Nucleotide Polymorphism) as environmental causes of depression. That is why most genetic studies have failed in concluding candidate genes for depression as there are many polymorphisms and genetic mutations as a result of prenatal or even earlier impact of stress on the genetic make-ups of parents. (Gonda X., et al., 2018)
Therefore the future classification of depression needs to go beyond the dichotomy of reactive/endogenous/melancholic/biological/familial, but by following a pathophysiologic pathway model to classify different types of depression. Starting with the gene-environmental interaction, the stress of different kinds start a cascade of pathophysiologic changes in the emotional circuit of the brain, causing different symptoms and severity of depressions, from minor to major depression and dysthymia. 
The Gene-Environmental Interaction:
There is a clear difference between the onset time of stress on the brain, so that an early onset such as prenatal stress on the developing brain has a more severe damage than to a more developed and mature of an adult brain. Since the developing brain is less resistant to the oxidative toxicity of the stress, there is more alteration of the cellular homeostasis and damages to the young brain.(Gonda X., et al., 2018) Comparison studies of animal models of early vs. late onset depressions have shown each to have unique gene-expression profiles indicating divergent underlying molecular mechanisms. For example the early stress type shares 19%, while the late stress type share 11% gene overlap with the endogenous type. In fact the early stress or “chronic reactive depression” share more gene overlap with the endogenous type than with the late stress onset or “acute reactive type”. Gene pathway analysis has shown more neurodevelopmental impact by the early stress onset reactive depression, while the late stress onset reactive type being only associated with acute cell stress response and signaling. (Malki K., et al. 2014)
Most gene candidates in the pathophysiology of depression alone could be responsible for one third of major depression in the community. (Sullivan PF, et al., 2000) The gene candidates, e.g. BDNF, CRHE1, HTR2A, MAOA, NR3C1, SLC6A4 have been shown to be more causative when interact with early life stressful events such as childhood maltreatments, adversity and poor parenting. (Brown GW., et al., 2014; Bradley RG., et al., 2008; Jokela M., et al., 2007; Caspi A., et al., 2003; Karg K., 2011) There are differences among these gene polymorphisms in susceptibility to early or late onset stress to cause early or late onset depression. For example while the serotonin transporter gene length polymorphism (5-HTTLPR) in interaction with early life stress lead to early (juvenile) onset or endogenous depression, the BDNF may contribute in interaction with late life stress to adult onset depression. (Brown GW., et al., 2014)
Other than susceptible or mutated gene polymorphism in causing depression in interaction with destructive environments, there are protective genes and environments that prevent the causation of depression. For example low but not high MAOA gene activity, caused severe depressive symptoms in the face of early life maltreatments. Also sexual abuse and the 5-HTT short/short homozygote genotype, and not heterozygote or long/long alleles predicted higher depression, anxiety, and somatic symptoms. (Cicchetti D., et al., 2007) On a different account, carriers of the T/T or T/C genotype of the T102C polymorphism of the HTR2A gene were responsive to the protective aspects of nurturing mothering, and showed lower levels of depressive symptoms, opposed to the carriers of the C/C genotype. (Jokela M., et al., 2007)
Other than neurotransmitters gene polymorphism that contribute principally to the pathophysiology of depression through gene-environmental interactions, the hypothalamic-pituitary-adrenal (HPA)-axis related genes that regulate the response to stressful events, are contributing to the pathogenesis of depression. The gene polymorphism of glucocorticoid receptor (GR) that regulates the activity of the HPA-axis, in interaction with childhood adversity is also associated with increased risk for depression. For example the gene-environment interaction between the GR polymorphisms 22/23EK and 9beta and childhood adversity results in an increased risk of depression, while without childhood adversity there could be no such increased risk. (Bet PM., et al., 2009)
The Biological Impact:
The catecholamine deficiency hypothesis of depression, on which original and current antidepressants are largely based, was an early theory of the chemical chain of events that results from the pairing of susceptibility genes with an adverse environment. The pathophysiology of depression has now progressed to include the involvement of other neurotransmitters such as GABA and glutamate, neuromodulators, inflammatory markers, all in an interaction between the genetic predisposition and the environmental impact or adverse events.
As far back as the early 1980s, GABA receptor agonists, e.g. progabide, had been suggested as capable of modifying the activity of several brain neurotransmitter systems, including noradrenaline and serotonin (Bartholini, 1985; Zivkovic et al., 1983) and both GABA and glutamate drugs are currently used as adjunct treatments in major depression (Krystal, 2002, Pande, 2003; Showraki, 2007). Glutamate N-methyl-d-aspartate (NMDA) receptor antagonists such as ketamine have been shown since 1990s to possess properties that can rapidly reverse depressive symptoms (Duman & Aghajanian, 2012; Trullas, 1990) Most recently, the mechanism of action of the glutamate antagonists have been hypothesized to lie in their ability to restore protein expression levels disrupted by chronic unpredictable stress (Zhang, 2018).
The roles of neuromodulators such as endorphins, enkephalins and oxytocin are also being researched. The impact of endorphins and non-opioid enkephalins such as alpha-MSH has been shown to have antidepressant effects in animal models (Kastin, 1978; Terenius, 1977). More recently, endorphins and other opioids have been more shown to alter the release of other neurotransmitters and to result in a decrease of oxytocin and an activation of GABA (Bali, 2015).
The placental oxytocin that had been known for long to be involved in the maternal milk secretion induced by the infant sucking, vital in ending the conception period and starting the lactation stage, has been studied in the depression field since late 1980s. This hormone or neuromodulator has been shown in the animal models of depression to improve physical mobility and reducing learned helplessness and escape failures with superior efficacy to Imipramine. (Arletti R, Bertolini A., 1987) Later on and in recent years, back to its role in lactation and sucking of the infant, Oxytocin’s significant role in attachment between the mother and infant has been demonstrated. Therefore maternal depression or childhood maltreatment and deprivation could disturb this relationship synchrony and lead to early childhood depression. (Priel A., 2019; Krause S., 2018) Most recently a preliminary study has also shown that cord plasma antidepressant levels are more strongly associated than maternal antidepressant dose or circulating blood antidepressant levels with increased DNA methylation of a specific unit within the promotor region of oxytocin receptor gene (OXTR). (Galbally M., et al. 2018)
Structurally it has also been shown how early prenatal stress impinges on the neurogenesis of the hippocampus, nucleus accumbens, dentate gyrus and amygdala through stress-induced oxidative damage to mitochondrial DNAs in neonates. (Kawamura T.,et al. 2006; Zhu Z.,et al. 2004) Repeated stress that is common in unfortunate home environments has also been shown to disrupt the neuroplasticity and dendritic architecture of the pyramidal neurons in amygdala and hippocampus, that could be protected by daily administration of agomelatine in animal studies. (Grillo CA. et al., 2015) Agomelatine that is a melatonin receptor agonist and a serotonin 5-HT2c receptor antagonist, has been shown in animal models to resynchronize circadian rhythm that is disturbed in many psychiatric conditions such as depression. (Racagni G. et al., 2011; Taylor D. et al., 2014) Circadian clock genes have been shown to regulate the release of the glucocorticoids that are so intimately linked to the stress response in humans (Landgraf et al., 2014).
Stress, Inflammation and Depression:
Over the past couple of decades, the pathophysiology of depression has evolved to include an inflammatory and metabolic processes. (Rohleder N, Miller GE., 2008) It has long been known that depression could trigger and/or exacerbate medical comorbidities, which recently has been partly explained through inflammatory/metabolic pathophysiologic processes. This association have been hypothesized and shown to be facilitated through different inflammatory markers such as Interleukins such as 1 & 6, CRP (C-reactive protein), and Cytokines. (Douglas KM. et al., 2004; Miller AH. et al., 2009; Valkanova V. et al., 2013)
In explaining the chain reaction of inflammation triggering or causing depression then comorbid medical conditions, the initial precipitating factor has been hypothesized and shown to be early life stress and adversity. (Slavich GM. Et al., 2010; Miller GE. et al., 2012; Slopen N. et al., 2012) This association and pathophysiologic process has been shown in depressed adults with a history of childhood maltreatment who exhibited larger stress-related increases in plasma IL-6 than healthy controls, with an enhanced DNA binding of the pro-inflammatory transcription factor nuclear factor-kappa B. (Pace TW. Et al., 2006) It has also been shown that depressed subjects with history of early adversity having low-grade inflammation indexed by a composite of CRP, fibrinogen, and leukocyte counts, while depressed subjects with no history of early life stress were statistically indistinguishable from controls. (Danese A. et al., 2008)
The pathophysiologic hypothesis of early life stress triggering inflammation and in turn leading to depression and comorbid medical conditions has been extended to include even late life morbidities and mortalities. It is thought that children reared in unfavorable socioeconomic circumstances show increased susceptibility to the chronic diseases of aging in the fifth and sixth decades of life, through up-regulation of genes conveying adrenergic signals to leukocytes, and down-regulation of genes signaling the glucocorticoid receptor, causing cortisol secretion and transducing anti-inflammatory reactions in the immune system. The subjects from low-SES (Socio- Economic Status) with higher frequency of early life stress have been shown to have more output of cortisol in daily life, and greater production of the pro-inflammatory cytokine interleukin 6. Although this inflammatory and anti-inflammatory reaction to stress could serve adaptive functions during acute stress, over the long term they might cost an allostatic toll on the body that ultimately contributes to depression and the chronic diseases of aging. (Miller GE. et al., 2009)
Conclusion:
In summary “Reactive Depression” that used to be applied as reaction to stress, loss, adjustment and alike, is not purely psychological and non-biological. The epigenetics remind us of the significance of the interaction between genetics (susceptibility) and environment (insults, adversaries, stress, etc.) that result to a phenomenological by-product such as depression. By the same token, the other old term, “Endogenous Depression” is not purely biological, but has also the impact of environmental stress on its genetic predisposition to evolve to its symptomatic manifestation. From this perspective, therefore any types of depression could be both reactive while biological and the only differentiation of the importance is the timing, or the time of impact of the environmental factor or insult on the genetic make up of the individual.
Is it all Reactive?
The old dichotomy of Reactive vs. Endogenous Depression throughout the recent decades’ research have been shown to be in fact inter-related. What seemed to be reactive depression in response to stress of any types (loss, adjustments, etc.), it seems nowadays to be biological as well, through causing a cascade of neurochemical reactions, involving alterations in the mood neurotransmitters, neuromodulators, inflammatory processes and more. Endogenous or familial depression as well, have been shown in the recent decades to be in fact an early response to an early life stress, as early as prenatal through maternal depression.
So if all unipolar depressions are in reality epigenetic, or the byproduct of early or late life stresses, causing imbalance in the neurochemical/anatomical architecture of the brain, then what are the depressions caused secondary to comorbid medical and mental conditions? It has been known for long that depression is a common comorbidity in many medical conditions such as MS (Multiple Sclerosis), Parkinson’s Disease, and cardiovascular diseases such as myocardial infarction. (Sadovnick AD. et al., 1996; Starkstein SE. et al., 1990; Forrester AW. et al., 1992) Although some of these conditions could be argued to be neurological, hence brain conditions affecting the limbic system, white matter and other components of emotional neuro-circuitry, there are other non-neurologic conditions such as cardio-vascular’s associated and causing depression. This causality of depression secondary to medical conditions could also be explained as “reactive” to physical/medical stress to the neuro-homeostasis of the body, through a cascade of metabolic/inflammatory processes causing alterations in the mood neurotransmitters and neuromodulators.
The final dilemma would be within psychiatry itself and the relationship between depression and other mental conditions, such as the common comorbidity of depression and anxiety. Anxiety e.g. in GAD (Generalized Anxiety Disorder), as intrinsic stress without external triggers, specially in early life when untreated, it could be complicated with depression as well. (Showraki M., 2018)
In closing remark, Reactive Depression, an old diagnostic category, long abandoned by the DSM, may come to a new light when the epigenetic of depression, or the environmental impact on the genetic susceptibility is appreciated. Therefore from this new perspective, all unipolar depressions (Major, Minor and Dysthymic) are endogenous and reactive. Endogenous in having a genetic predisposition and reactive in having an environmental impact such early or late life stress on the genetic susceptibility.
Hereby the difference between different subtypes of unipolar depression at a symptomatic level observed clinically, depends on the timing of the environmental impact or stress. Stress or insult could be as early as prenatal, then postnatal, childhood, and as late as in adulthood and thereafter. Based on the timing of stress/insult there are different reactions of the mood neuro-circuitry to cause different types and severity of unipolar depressions. Based on the timing of the impact, the earlier development of depression leads to more chronic and refractory to treatment type of the illness. But the later in life impact and development of later life or acute types of depression are more responsive to interventions.
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