In the diathesis-stress model, the diathesis refers to an and the stress refers to an

Genetics and Gene-Environment Interactions

The diathesis-stress model of depression suggests an individual's vulnerability to depression depends in part on their response to stress including ELS; this is largely genetically determined [60]. Several single-nucleotide polymorphisms have been identified that interact with early-life experience. Here, we review the data on CRHR1, brain-derived neurotrophic factor (BDNF), 5HTTLPR, monoamine oxidase A (MAOA), and FKBP5.

Two major subtypes of CRH receptors (CRH1 and CRH2) have been discovered [61]. Studies have implicated CRH1 in stress-induced activation of the HPA axis; the precise role of the CRH2 receptor is still less clear [62]. Notably, this finding is further supported by the predominance of CRH1 receptors in the corticolimbic pathways that are involved in fear- and anxiety-related emotional responses [63]. The importance of the CRH system in mediating the endocrine, autonomic, immune, and behavioral responses to stress has been well-documented in nonhuman rodent primate and human studies.

In humans, CRH concentrations are increased in the CSF in patients with depression and posttraumatic stress disorder [45]. CRH receptor antagonists have been shown to demonstrate anxiolytic properties in preclinical settings, as well as to decrease the effects of CRF administration [64,65]. Although clinical trial results are disappointing [66], many genetic variants of the components of HPA axis pathway have been implicated in the development of depression, particularly in the setting of ELS, as described below.

Increased activity of the HPA axis has been demonstrated in many psychiatric disorders, most notably including major depressive disorder. Thus, genes regulating the HPA axis in general and the CRH system in particular have been studied in the context of stress reactivity. Clinical studies of depressed patients reveal increased CSF CRH concentrations, as well as decreased CRF-R1 mRNA expression (a consequence of downregulation due to CRH hypersecretion) in the limbic system [67,68]. Moreover, a sex-specific association of increased sensitivity to CRF in females has been reported [69].

Genetic variants of the CRHR1 moderate the effect of child abuse on adult depressive symptoms especially depression with prominent anxiety [70]. This initial finding was expanded by the finding that having two copies of the CRHR1 TAT haplotype made the impact of childhood maltreatment on adult depression even more profound [71]. Other genetic variants of the CRHR1 gene have been implicated in regulating the impact of child abuse on adult pathology, strengthening the case that the genotype may be a useful predictor for depression risk in patients with a history of ELS.

Not surprisingly, there are gene × gene interactions between variants in different genes implicated in risk for development of depression. The CRHR1 genotypes interact with the 5-HTTLPR gene variants, noted below, to create a compounding risk for severe depression in the setting of child abuse [72]. However, this interaction was only significant when the amount and severity of child abuse was stratified, thus supporting a dose-response relationship between ELS and risk of syndromal mood disorders.

5-HTTLPR is the promotor region of a single gene (SLC6A4) that codes for the serotonin transporter (SERT) in humans. The variants of the 5-HTTLPR are denoted as short (s) and long (l). The “s/s” and “s/l” genotypes have been associated with reduced transcription of the SERT gene and thus reduced 5-HT uptake [73,74]. The s allele, associated with reduced transcription, has been shown to increase the predisposition for depression. Environmental factors, including ELS, have been reported to interact with SERT genotypes to increase the likelihood of developing depression [75]. A nonhuman primate study using foraging demand as ELS demonstrated that ELS leads to elevated CSF CRF concentrations, particularly in animals with the s/s or s/l 5-HTTLPR genotype [53].

There is indeed an association between the 5-HTTLPR genotype, ELS, and development of depression [75]. Individuals exposed to ELS and possessing the s/s genotype had the highest probability of developing depression and suicidality followed by the s/l genotype, to l/l carriers having no risk. Other studies and meta-analyses have supported these findings [76–78]. Lastly, studies have shown that early intervention in the form of a supportive childhood environment may protect children with an s/s genotype and history of ELS from developing depression [79].

Another gene that has been studied in regard to diathesis for depression is BDNF, which plays a significant role in neural plasticity. The BDNF Met allele may serve as protective factor for individuals with the 5-HTTLPR s allele in healthy individuals. However, in individuals with a history of childhood maltreatment, having both the BDNF Met allele and the 5-HTTLPR s allele was associated with an increased risk of depression [80]. BDNF and ELS appear to interact alone as well; ELS may promote increased methylation of BDNF, leading to changes in expression of the BDNF gene later in life [81].

The MAOA enzyme metabolizes monoamine neurotransmitters including norepinephrine, serotonin, and dopamine. One early study tested the hypothesis that the MAOA genotype can moderate the influence of childhood maltreatment on neural systems implicated in destructive behavior. Evidence for this hypothesis was found, consistent across all measures of antisocial behavior studied [82]. Later studies confirmed and extended these findings. Using a birth cohort sample of 7-year-old boys, Kim-Cohen [83] reported that boys with a low-activity MAOA allele had significantly higher mental health problem scores than boys with a high-activity allele. Further, the association between maltreatment and mental health problems was significantly stronger in the low-activity group.

Adverse early experience as a vulnerability factor in depression-like syndrome

The stress diathesis model postulates the interaction between a genetic vulnerability or predisposition and adverse life events in the genesis of major depressive disorder. Considerable research supports the contribution of adverse early experience and/or exposure to a major trauma as precipitating factors in the onset of major depression (Dunner et al., 1979; Anisman and Zacharko, 1982; Ambelas, 1987; Brown et al., 1987; Nemeroff, 1991; Heim et al., 1997). While many theories of the primary defect leading to the onset of depression have been offered (Duman et al., 1997), much research in the current decade has been focussed on two theories: dysfunction of the central glucocorticoid receptor system (Holsboer et al., 1994, 1995) and dysregulation of central CRF systems (Nemeroff, 1996; Heit et al., 1997). These theories, of course, are not mutually exclusive.

The underlying etiology and pathophysiological adaptations in the central nervous system occurring during depression have been difficult to elucidate due to the lack of appropriate laboratory animal models (Kessler et al., 1994). Willner (1995) offered multiple criteria for the validation of animal models of depression including face and construct validity. Unfortunately, several of the proposed criteria require a priori knowledge of the etiology of the disease and, thus, cannot be fulfilled by any model. The chronic mild stress (CMS) model, consisting of daily exposure of adult rats to a variety of stressors over a prolonged period of weeks, has shown success in replicating much of the symptomology of depression and these effects can be reversed by antidepressant treatment (Papp et al., 1996; Willner, 1997). The model has good predictive validity, face validity, and construct validity; however, the duration of effects is variable and the model lacks a genetic component. Pucilowski and colleagues (1993) applied CMS to the hypercholinergic Flinders Sensitive Line (FSL) of rats, a putative genetic animal model of depression, and found that stress-induced anhedonia was increased in the FSL vs. the control Flinders Resistant Line (FRL) rats.

On the basis of our studies, we believe that the neonatal maternally separated rat provides a suitable model of at least a vulnerability to the development of a depression-like syndrome. These animals exhibit dysregulation of the HPA axis including CRF hypersecretion and dexamethasone-mediated negative feedback resistance, enhanced anxiety-like behavior, and anhedonia. Furthermore, many of the neurocircuits postulated to mediate the pathophysiology observed in major depressive disorder exhibit stable changes in function in the adult HMS180 animal. Finally, chronic treatment of these adult animals with antidepressants at least partially reverses all of the dysfunctions thus far observed.

Many of the symptoms observed in major depressive disorder and in animal models can be elicited by central administration of exogenous CRF, a neuropeptide which coordinates the mammalian endocrine, autonomic, behavioral, and immunologic responses to stress (Heinrichs et al., 1995). Numerous preclinical and clinical studies have shown that both maternally separated rats and depressed patients exhibit an apparent increase in CRF neurotransmission, as evidenced by heightened HPA axis activity and increased CRF concentrations in the cerebrospinal fluid (CSF) (Heit et al., 1997). As a consequence of these observations, increased limbic and hypothalamic CRF activity has been linked to the psychopathology of affective disorders. Clinical studies have repeatedly shown that drug-free depressed patients exhibit elevated concentrations of serum cortisol, failure of cortisol suppression after the administration of the synthetic glucocorticoid dexamethasone (Evans et al., 1983a, b), increased concentrations of cerebrospinal fluid CRF (Nemeroff et al., 1984; Banki et al., 1987), decreased CRF receptor-binding in the frontal cortex (Nemeroff et al., 1988), a blunted ACTH response to exogenous CRF (Gold et al., 1986; Amsterdam et al., 1987), and hypertrophied pituitary and adrenal glands (Kathol et al., 1989; Nemeroff et al., 1992). These apparent increases in CRF neurotransmission and HPA axis activity are currently thought to represent a state rather than a trait marker of depression, since hypercortisolemia and elevated CSF CRF concentrations normalize after electroconvulsive therapy or following clinical recovery (Nemeroff et al., 1991; Amsterdam et al., 1998). However accumulating evidence suggests that there may be subtle trait markers in the function of these systems among populations with genetic or environmental loading for development of major depressive disorder (Holsboer et al., 1995; Lauer et al., 1998; Modell et al., 1998).

In addition to dysregulation of hypothalamic and extra-hypothalamic CRF neurocircuitry, HMS180 rats and depressed patients also appear to share dysregulation of noradrenergic and serotonergic systems (Owens and Nemeroff, 1994; Mongeau et al., 1997). Indeed, the pharmacological mechanism of action of most antidepressants is to increase NA and/or 5-HT neurotransmission. Antidepressant drugs are divided into several classes based on their pharmacological mechanisms of action. These classes include tri- and tetra-cyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and atypical antidepressants. However, the neurochemical cascade(s) initiated by antidepressants resulting in clinical efficacy remains to be determined. Antidepressants of these various classes have similar clinical efficacy (approximately 65%) and generally require 4–8 weeks of treatment to produce their full therapeutic activity.

Much research investigating chronic effects of antidepressant drugs has been conducted on normal, non-stressed animals. This approach, while convenient, will not likely provide much insight into the ultimate mechanisms of clinical recovery following antidepressant therapy. Antidepressants do not elevate the mood of non-depressed individuals (Sindrup et al., 1990). Therefore, it is unlikely that they will cause the same neurochemical cascade of events in normal rats as they might in those which have been exposed to early adverse experience. In support of this thesis, chronic antidepressant treatment has no consistent effects on basal CRF expression in normal rats but can prevent a stress-induced increase in CRF expression (Brady et al., 1992; Heilig M and Ekman, 1995; Stout et al., 1997). Furthermore, heightened pituitary-adrenal responses and CSF CRF concentrations are normalized by chronic antidepressant treatment in both depressed patients and maternally separated rats but are unaltered in control populations. Because antidepressants alter HPA axis activity and alter central components of the HPA axis, Barden and colleagues (Barden et al., 1995) have postulated that at least part of their mechanisms of action is via these changes.

We believe that the maternal separation model is suitable for investigating the pathophysiology of major depression and the mechanism(s) of action of antidepressant drugs. In support of this hypothesis, we have obtained preliminary evidence that various classes of antidepressant drugs attenuate or reverse the maternal separation phenotype. For example, we have found that increased regional CRF expression in maternally separated animals is attenuated by chronic treatment with the antidepressant paroxetine (Plotsky et al., unpublished communication). In addition, chronic treatment with paroxetine or the atypical antidepressant mirtazapine normalizes behavioral and endocrine stress responses in maternally separated rats (Plotsky et al., 1996; Ladd et al., 1997). These observations validate the maternal separation paradigm as a model of depression-like syndrome and, therefore, a means by which we can investigate the pathophysiology of this disease and the mechanism(s) of action of antidepressant drugs.

Approximately 50% of patients who discontinue pharmacological antidepressant therapy during the first few months relapse into a depressive episode (Hirschfeld, 1996). This observation suggests that antidepressant therapy is required not only to reach clinical recovery but also to maintain it. Cessation of therapy removes the stabilizing effects of the drug, increasing the frequency and severity of relapse. It is our hypothesis that the neurochemical cascade of events underlying this relapse parallels that initiating the primary affective episode. Thus, we will attempt to elucidate the pathophysiology of depression by investigating the neurochemical cascade(s) associated with antidepressant withdrawal. Preliminary data from our laboratory has revealed that normalization of the maternal separation phenotype following paroxetine administration is reversed upon drug withdrawal in adult HMS180 rats, suggesting that the maternal separation paradigm is suitable for investigating the pathophysiology of affective states.

Precipitating factors

Recent prospective studies of the diathesis-stress model of insomnia have shown that stressful life events often trigger the onset of insomnia disorder (Drake et al., 2014a). Apart from stress, there are several other precipitating factors that may contribute to sleep disturbance, such as high caffeine intake close to bedtime (Drake et al.,2013), certain sleep-disrupting medications, consumption of alcohol (Ebrahim et al., 2013), and smoking. The interruption of sleep due to altered circadian rhythms can also trigger insomnia, particularly in individuals transitioning to night shift work (Kalmbach et al., 2015; Wickwire et al., 2017). Treatments for sleep disorders, such as the use of continuous positive airway pressure (CPAP) for obstructive sleep apnea, improves sleep disordered breathing but can also be disruptive to sleep in some vulnerable patients (Wickwire and Collop, 2010). Normal life processes such as aging and the onset of menopause can also be triggers for insomnia. Once a trigger for significant sleep disturbance occurs, individuals may engage in a variety of maladaptive cognitions and behaviors known as perpetuating factors in response to their sleep disturbance. These perpetuating factors serve to maintain the sleep disruption, which over time can become chronic and produce a vicious cycle resulting in insomnia disorder.

How Does Insomnia Become a Comorbid Condition?

Etiology in insomnia is often thought of in a diathesis-stress model, with insomnia exceeding a clinical threshold when a predisposing factor is present. An expansive array of predisposing factors are possible, including but not limited to, environmental changes, physical or mental health conditions, positive or negative life events, interpersonal conflict, and travel across multiple time zones. Once a predisposing factor happens, the subsequent insomnia is then maintained by perpetuating factors. This may include heightened awareness of threats to maintaining sleep that were not as much of an issue beforehand (e.g., muscle tension, ticking of a clock, light from outside, bed partner who moves during sleep), negative thoughts about sleep (e.g., “if I don't sleep tonight, I won't be able to function tomorrow”), and coping behaviors (e.g., spending more time in bed trying to catch up on sleep, napping, caffeine, alcohol before bed, prescription, and over-the-counter medication).

Although the initial predisposing condition may be well controlled with treatment, the insomnia does not always remit. It is the perpetuating thoughts about sleep and maladaptive coping behaviors that began with the sleep disruption that are thought to turn the insomnia into a comorbid condition, taking on a separate ‘life of its own’ from the initial predisposing factor.

For example, a patient who has a new onset of a major depressive disorder may indeed find that depression led to a disruption in the sleep–wake process. If no perpetuating factors were present, one would expect the sleep problem to remit with the successful treatment of the anxiety disorder. However, if maladaptive coping behaviors and negative thoughts about sleep are activated, chronic insomnia is likely to result as a comorbid condition. These perpetuating thoughts and actions then become the target cognitive behavioral therapy for insomnia (CBT-I), a nonpharmacologic intervention, considered by many to be the gold standard treatment for insomnia.

What does the diathesis

What is the diathesis

When is the diathesis

What's the meaning of diathesis?