Review of Research Literature on Depression 10 minute read
Importance of symptom recognition in early stages of mental illness
O
riginally I conducted a study to identify links between a host of symptoms commonly associated with anxiety and depression. Research in the last 15 to 20 years has contributed much to our understanding of the causes of anxiety and depression. Further research is sorely needed to make informed decisions when best trying to manage these conditions
Young adults referred for mental health support frequently struggle with conditions and ailments that fall under the umbrella of affective disorders of which anxiety and depression are the most predominant. Concurrent symptoms and conditions cause additional distress. The scope and variety of these comorbid symptoms suggests that different neuronal pathways are involved. Careful exploration of symptoms can shed light on which pathways are involved and thus inform treatment decisions.
Functional Anatomy
For the purpose of discussion an understanding of basic systems and neuronal pathways is required. The systems involved in the pathophysiology of affective disorders include the emotional centers, the cognitive centers, neuroendocrine system and associated neuronal pathways that link the limbic and cognitive centers.
The limbic system consists of the hippocampus and amygdala. As it relates to mood the limbic system plays a key role in motivation and emotional life. The hippocampus provides a regulatory role for the hypothalamus, pituitary, adrenal axis (HPA) in modulating the fight or flight response. The amygdala is responsible for the expression of fear and aggression and defensive postures, and is instrumental in the formation and retrieval of emotionally laden memories.
Cognitive centers include the prefrontal cortex (PFC), the orbital frontal cortex and the ventromedial frontal cortex. The PFC is responsible for executive functions such as planning, decision making, predicting consequences for potential behaviors, processing speed and interpreting and moderating social behavior. The orbitofrontal cortex (OFC) codes information, controls impulses, and regulates mood. The ventromedial PFC is involved in reward processing and in the visceral response to emotions.
In addition to the activity of each brain region, it also is important to consider the neurotransmitters and their respective neuronal pathways providing communication between these regions. E.g. increased activity in emotion-processing brain regions in patients who have an anxiety disorder are associated with decreased inhibitory signaling by γ-amino-butyric-acid (GABA) or increased excitatory neurotransmission by glutamate.
Background
There a number of hypotheses proposed to explain the reasons for affective disorders.
1. Dysregulation of the hypothalamus pituitary adrenal axis.(Guerry & Hastings, 2011)
2. Changes in the endocrine and immune systems (Leonard, 2010)
3. Neurotrophic hypothesis
4. Imbalances in various neurotransmitters (Asberg, Thoren, Traskman, Bertilsson, & Ringberger, 1976)
5. An integrated view of depression involving a number of neural pathways(Müller & Schwarz, 2007)
From a biological perspective it is reasonable to assume there is a combination of neurotransmitters, hormones, neurotropic factors and enzymes involved in stress, anxiety and depression. Those most frequently targeted for research include; glutamic acid, GABA and the monoamine neurotransmitters; serotonin, dopamine, norepinephrine, acetylcholine quinolinic acid and more recently pro-inflammatory cytokines.
HPA dysregulation Hypothesis
Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis in adults with major depressive disorder
is among the most consistent and robust biological findings in psychiatry. It is noteworthy that the normative development of HPA axis activity results in both higher basal cortisol levels and stronger HPA axis responses to stressful events in late adolescence, when the frequency of life stressors and the prevalence of depression also increase markedly. The adjustments and expectations of young adulthood generate stress. This, along with inadequate or impaired ability to cope with the additional stressors is a sure fire way to hyper-activation of the HPA axis. Given the importance of a functional developmental transition from adolescence into adult hood and the recurrence of depressive phenomena over the lifespan, it is important to have an integrative approach to stress management in order to mediate the biochemical changes that occur in the HPA axis. (Guerry & Hastings, 2011)
In particular, when depression strikes during adolescence the condition is far more likely to be associated with a persistent, negative health outcomes (pathophysiology) over the lifespan.(Lewistohn, Rohde, Klein, & Seeley, 1999).
The pituitary and adrenal glands are reportedly enlarged in major depressive disorder (MDD). For example (Krishnan et al.1991) showed that MRI-based measures of cross-sectional area and volume of the pituitary were increased by 34 and 41%, respectively in depressives versus controls. This observation is consistent with evidence that the adrenal gland is also abnormally enlarged in MDD, (Drevets, Price, & Furey, 2008) putatively due to chronically elevated stimulation of the adrenal cortex by adrenocorticotropic hormone (ACTH).
Further, studies have examined HPA axis functioning in asymptomatic children and adolescents of depressed parents and provide consistent evidence that parental depression, and particularly maternal depression, is associated with elevated HPA axis functioning in offspring.(Guerry & Hastings, 2011, p. 153) and (Van den Bergh, Van Calster, Smits, Van Huffel, & Lagae, 2007)
Immune System Dysfunction Hypothesis
Research in cytokine biology has revealed their role as messengers among inflammatory and immune cells, these proteins seem to interact with different tissues and organs and the central nervous system. Cytokines seem capable of acting as neuromodulators within the brain. As such, they affect important brain activities such as sleep, appetite, and neuroendocrine regulation.(Kronfol & Remick, 2000)
Cytokines are crucial for fighting off infections and in other immune responses. However, they can become dysregulated and pathological in inflammation, trauma and sepsis and have been linked to a number of diseases including schizophrenia and MDD. (‘Cytokine’, 2017)
In response to peripheral infection immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the immune system continues unabated, a similar phenomenon to HPA over-activation occurs, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression. (Dantzer, O’Connor, Freund, Johnson, & Kelley, 2008) These phenomena might account for the increased prevalence of depressive episodes and attending symptoms in a sub group of missionaries who are frequently physically ill.
Additionally, pro-inflammatory cytokines stimulate the HPA axis via hypothalamic neurons. The functional relationship between cytokines and HPA axis activity is generating interest in affective disorder research. Psychological stress together with an activation of the immune system may lead to an overwhelming stimulation of the HPA axis. (Konsman, Parnet, & Dantzer, 2002)
Beside the relationship between HPA axis hormones and cytokines, glucocorticoids stimulate the tryptophan metabolism through the KYN pathway in the liver, directly resulting in decreased CNS concentrations of serotonin with its cascading impact on a host of other systems. (Morón et al., 2003) Certain pro-inflammatory cytokines activate the tryptophan- and serotonin-degrading enzyme indole amine 2,3-dioxygenase (IDO). (Müller & Schwarz, 2007)Further, cytokines and their signalling pathways have been shown to enhance the re-uptake of dopamine neurotransmitters and thereby reduce their functionally important inter-synaptic concentrations in the brain (Zhu, Blakely, & Hewlett, 2006)
Neurotrophic hypothesis
Molecular and cellular studies have demonstrated opposing actions of stress and antidepressant treatment on the expression of neurotrophic factors, particularly brain-derived neurotrophic factor BDNF, in limbic structures of the brain. (Duman & Li, 2012)These changes in neurotrophic factor expression and function result in structural alterations in the hippocampus and prefrontal cortex PFC. Stress could contribute to the reduced volume of these brain regions in depressed patients.
The prefrontal cortex is capable of retraction and expansion in response to stress. Genetic, psychological and environmental factors constitute determinants of resiliency or pathophysiology.
Studies of the amygdala provide evidence of neuronal hypertrophy, including increased dendrite complexity of neurons in the basolateral nucleus. These changes could result from direct actions of stress on amygdala or from PFC hypofunction and reduced inhibitory control, highlighting the importance of dysfunctional circuits in depression.(Shansky & Morrison, 2009)
Monoamine Hypothesis
The monoamine hypothesis essentially postulates that deficiencies in particular neurotransmitters leads to depression and a number of symptoms commonly associated with affective disorders. The neurotransmitters most frequently targeted for research include monoamine neurotransmitters; serotonin 5 -HT, dopamine DA, norepinephrine NE, acetylcholine ACh, glutamic acid Glu, and gamma-aminobutyric acid GABA.
Serotonin deficiencies are the most studied and historically have been the most often implicated as the suspected mechanism of MD and associated symptoms. The relationship however appears to be correlational rather than causal. Simple biochemical theories that link low levels of serotonin with depressed mood are no longer tenable. However, experimental and computational accounts of how serotonin influences emotional processing is beginning to be elucidated.(Cowen & Browning, 2015)
There are other hypotheses for pathogenesis of affective disorders i.e. genetic factors, but the studies have been criticized for publication bias and data mining. This criticism points out that if the original finding was real, and not the result of publication bias, we would expect that those replication studies which are closest in design to the original are the most likely to replicate—instead we find the opposite. This suggests that authors may be data dredging analytic strategies which yield the results they want.(‘5-HTTLPR’, 2017)
An integrated view of depression
There is strong evidence for the view, that the interactions of the immune system, IDO (Indole amine 2,3-dioxygenase)and the serotonergic system, the HPA axis, glutamatergic and cholinergic neurotransmission play a key role in affective disorders.(Müller & Schwarz, 2007) This still nascent and heterogeneous literature underscores the importance of identifying and characterizing the intracellular signaling pathways that underlie the actions of antidepressants, as well as stress and depression. This hypothesis suggests mental illness and the problematic associated symptoms can be explained by the varied neuronal pathways involved and the cascade effect upon the downstream systems. This hypothesis aligns with the empirical evidence to best explain the numerous symptoms associated with affective disorders.
Stahl has suggested that it can be instructive to consider brain neuroanatomy in terms of specific functional centers and their neuronal pathways. (Stahl, Zhang, Damatarca, & Grady, 2003)
Serotonin 5-HT
It is an inhibitory neurotransmitter. Tryptophan is converted to L-tryptophan which is then converted to 5-hydroxytrptphan and finally serotonin. 5-Hydroxyindoleacetic acid is the main metabolite of serotonin. There is a significant correlation between the lower concentration of 5-HIAA and severity of depression.(Asberg et al., 1976) As 5-HT interacts with at least 5 brain centers it is no surprise of its preponderance in the pathophysiology of depression and why SSRIs have proven an effective mediator of depressive symptoms.
When serotonin is catabolized in the body, it does not break down into useful substrates in the way that dopamine is further degraded into epinephrine and norepinephrine. Instead, it breaks down into 5-hydroxyindoleacetic acid (5-HIA), an organic acid which may be harmful in high amounts. Tryptophan can further be catabolized into kynurenate, quinolinate, and picolinate, harmful substances that are generally regarded as markers of bodily inflammation.
Serotonin deficiencies and degradation manifest in the form of cravings, addictions, GI problems, sleep disruption, weight gain, gloomy thoughts and depressed mood.
Dopamine
Dopamine is an excitatory neurotransmitter. Deficiencies in this neurotransmitter are associated with symptoms frequently attached to depression; anxiety, fatigue, apathy, vacillating moods, difficulty concentrating, weight gain, social withdrawal, addictions and ADHD. Excessive dopamine serum levels are implicated in tremors, nervous ticks, restless leg and more serious mental health issues including schizophrenia and associated disorders. More frequent symptoms include; flat affect, loss of motivation, social withdrawal. Less frequent but also associated with low dopamine is suicidal ideations, ticks and tremors, weight gain, food cravings, fatigue and restless leg. ADHD is associated with excessive dopamine.
Dopamine excesses may contribute to states of confusion and delirium, which has been linked to concomitant acetylcholine decreases. Thus, acetylcholine and dopamine may be inversely related in cognitive pathogenesis. For example, D-amphetamine a dopamine agonist result in fronto-striatal abnormalities that correlate with delirium.(Wilkinson, 1997)
Acetylcholine
Acetylcholine was the first neurotransmitter to be identified in the early 1890’s and is essential in the mediation of a number of executive functions of the prefrontal cortex.(Turchi & Sarter, 2000) This includes; impulse control, processing speed, attention, working memory, visual motor functioning and word finding.
There is significant overlap of dopaminergic and cholinergic pathways, requiring homeostatic balance between these two neurotransmitters. The prefrontal cortex has six layers of distinct neurotransmitter receptors. The D2 receptor family (dopamine) inhibits acetylcholine synthesis. Dysfunctions in the D2 receptor have been associated with hallucinations, stereotypic behavior, and thought disturbances (Hshieh, Fong, Marcantonio, & Inouye, 2008). Impulse control issues associated with aggressive behaviours, addictions, ruminations all have links with acetylcholine deficiencies.
Cholinergic deficits can occur in Illness and particular symptoms associated with Alzheimer’s disease and affective disorders. Illness generates physical stress typically activates the immune system and triggers cytokine release. Cytokines, which mediate inflammatory and immune responses to stress, may increase the risk of pathophysiology of executive functions including; attention, memory, processing speed, visual motor problems and concentration through multiple mechanisms, including increasing blood–brain barrier permeability and direct neurotoxic effects. (Herrero et al., 2008) Cytokines act as conduits between immune cells and the brain, modulating sleep, cognition, and appetite. Cytokines may also lead to cholinergic deficits. For instance, bacterial lipopolysaccharides and severe infection trigger a cascade of cytokine release in the brain that selectively reduces choline acetyltransferase (ChAT) immune-reactive neurons; ChAT is the key enzyme in biosynthesis of acetylcholine (Willard, Hauss-Wegrzyniak, & Wenk, 1999). One major cytokine triggered by stress, tumor necrosis factor-α (TNF-α), can play a role in neurodegeneration by inhibiting insulin-like growth factor-1 (IGF-1), a neurotrophic and neuroprotective peptide in injured brain (26). Cytokines may further contribute to cholinergic deficit by increasing blood–brain barrier permeability and modifying cerebral neurotransmission (29). Cholinergic neurotransmission is exquisitely balanced with other neurotransmitter systems. Cytokines can alter this equilibrium, increasing monoaminergic activity and ultimately reducing acetylcholine release. Cytokine production in healthy brains may cause minimal damage; but when coupled with neuronal damage in a vulnerable brain (e.g., chronic stress, infection), they can precipitate neurotoxic degeneration, especially in the sensitive cells of the cholinergic pathway (31)”
Anticholinergic medications reduce the availability of acetylcholine. First generation antihistamines are known to have anticholinergic effects. In my own practice I have noted a higher incidence of allergies amongst those referred for mental health support. With allergies comes the frequent use of antihistamines, i.e. dimetrapp. Allergies can be managed with newer antihistimines such as loratidine (Claratin) and or cetirizine (Allegro)
The cholinergic system has a key role in cognition and attention, and it is not surprising that there is extensive evidence to support a role for cholinergic deficiency in a confused state of mind and delirium.
Norepinephrine
Norepinephrine is both a hormone and a neurotransmitter. Evidence for the involvement of NE in depression is abundant, and recent studies on neuronal pathways and symptoms highlight the specific role of NE in this disorder. NE plays a determinant role in executive functioning regulating cognition and motivation.(Moret & Briley, 2011) Excessive amount of NE can explain why a number of executive functions are compromised during episodes of depression or anxiety. During periods of stress higher concentrations of NE alter specific sites in the limbic system resulting in symptoms associated with anhedonia, memory and motor impairment. (Tejani-Butt, Paré, & Yang, 1994)
NE primary role is arousal as part of the fight or flight response increasing blood pressure, respiration and muscle tension. Not surprisingly symptoms associated with physiological responses follow such as respiratory distress, dizziness, agitation and anger and the subsequent down swing as norepinephrine release subsides.
Glutamate
Glutamate is the major excitatory neurotransmitter in the nervous system. Glutamate pathways are linked to many other neurotransmitter pathways and glutamate receptors are found throughout the brain and spinal cord in neurons and glia. As an amino acid and neurotransmitter, glutamate has a large array of normal physiological functions. Consequently, glutamate dysfunction has profound effects both in disease and injury.
Tryptophan is not only the precursor to serotonin and melatonin but also quinolinic acid, QUIN acts as an intermediate to increase the activity of the glutamatergic neurotransmission. An increase of quinolinic acid is strongly associated with several prominent features of depression: progressive slowing of reaction time and cognitive deficits, in particular difficulties in learning.(Heyes et al., 1998)
In short, the glutamatergic system is over activated when serotonin is low. Several studies showed an increased activity of the glutamatergic system in the peripheral blood of depressive patients (Kim, Schmid-Burgk, Claus, & Kornhuber, 1982)
GABA
γ-Aminobutyric acid (GABA) is the chief inhibitory neurotransmitter in the brain and the major difference between glutamate and GABA is that the latter is synthesized from the former by the enzyme L-glutamic acid decarboxylase. Interestingly GABA in children is excitatory, but in adults it is inhibitory. This in part could explain why depression is more frequently diagnosed in late adolescence. In humans it is also the major contributor to muscle tone. Muscle tension, weakness and pain are symptoms commonly associated with affective disorders.
Emerging evidence suggests the γ-aminobutyric acid (GABA) may also contribute to the treatment of depression. Sanacora provided the first evidence of abnormally low cortical GABA concentrations in the brains of depressed patients.(Sanacora et al., 1999)
L- Arginine
Arginine, a semi-essential amino acid and is an important initiator of the immune response. Arginine serves as a precursor in several metabolic pathways in different organs.(Wijnands, Castermans, Hommen, Meesters, & Poeze, 2015)
One of the critical pathways involves respiratory functioning. Decreased levels of arginine have been observed in individuals suffering from respiratory inflammation, asthmatics and some allergies. The respiratory distress activates the HPA axis exacerbating other hyper HPA related conditions.(Bratt, Zeki, Last, & Kenyon, 2011)
Methionine
Methionine is an essential amino acid and is important in angiogenesis (blood vessel growth). Methionine is also an intermediate in the biosynthesis of cysteine, carnitine, taurine, lecithin, phosphatidylcholine, and other phospholipids.(‘Methionine’, 2017) Methionine is required for the formation of S-adenosylmethionine, SAM a universal methyl donor for almost 100 different substrates, including DNA, RNA, hormones, proteins, and lipids.
Individuals with allergies, urinary tract infections consume more methionine. Hyperactivity of the HPA axis will encode traumatic events in memory generating epigenetic modifications. For example, maternal behaviour during development can have a powerful influence on stress levels of offspring later in life as a result of lasting epigenetic modifications. Methionine appears to have a reversal effect on the epigenetic programming and the possibility that diet could modify epigenetic programming in the brain not only during early development but also in adult life. (Weaver et al., 2005)
High levels of methionine can be found in eggs, sesame seeds, Brazil nuts, fish, meats and some other plant seeds; methionine is also found in cereal grains.
Chart A below lists the symptoms commonly associated with depression and anxiety taken from symptoms identified by 830 clients I have worked with. I subsequently conducted further research to determine which circuit(s) and the respective neurotransmitters, hormones and enzymes were involved in the symptoms noted. Recent advances in neuropharmacology and neuroimaging are mapping the topography of symptoms in affective disorders. What neuroimaging has provided is a clear delineation of the brain centers and systems affected by monoamine synaptic transmission. Upstream factors contribute to downstream system modulation and dysregulation.
Different malfunctioning neuronal circuits apparently generate clusters of symptoms commonly associated with chronic stress, anxiety and depressions. Since all clients with anxiety disorders and depression do not have the same symptoms, this implies that they do not have the same malfunctioning circuits. The idea is to to more accurately target and treat associated symptoms with strategies capable of boosting specific neurotransmitters in the dysfunctional circuits as a reduction in symptom distress would also reduce tge anxiety and or depression. Some dual-acting drugs, by extensively targeting both core and associated symptoms of major depression could offer some advantages, when compared with more selective antidepressants, in terms of clinical remission and improvement of quality of life (La Pia, 2009).
The prevalence of affective disorders amongst young adult population is 12.5% -13.5% in the U.S. and Canada. (Nguyen, Fournier, Bergeron, Roberge, & Barrette, 2005)
Studies of adolescents with depression have documented high rates of recurrence, of progression into chronic states, and of continuity into adult forms of affective disorder. (LEWINSOHN et al., 1999)The prospect of psychiatric illness lingering is reason for concern for those experiencing affective disorders during adolescence and young adulthood. Only one in every four of the 274 teenagers with depression in a study by Lewinsohn and colleagues remained free of illness by the time of their 24th birthday. (LEWINSOHN, ROHDE, KLEIN, & SEELEY, 1999)
In the study by Lewinsohn twenty percent of all depressed adolescents had a comorbid substance abuse disorder during the first episode of depression. During the next several years, the rate increased, with substance abuse disorders representing almost 80%. Given that over one-half of such non-mood outcomes represented new disorders that began after the age of 19, rather than the continuation of a pre-existing condition, the sequence and timing of these disorders seems critical. These data, consistent with previous reports that have suggested a window of over 4 years between onset of disorders. If the findings in normal population are an indication, young adults who experienced first onset in adolescence and relapse later are particularly at risk as depression and associated symptoms are correlated with much higher uses of both prescription and recreational drug abuse as a means of self- medication.
Conclusion
There is sufficient evidence to suggest similar metabolic pathways exist not only for affective disorders, but also a host of symptoms and conditions which are commonly associated with them. Significant progress has been made toward understanding the molecular and cellular signaling pathways generating the deleterious effects of stress, anxiety and depression. Yet it is the comorbid symptoms themselves that provide further understanding of the likely pathways involved and thus inform treatment protocols. Recognizing symptoms and understanding symptom roots can inform practice, expand treatment proceduress and reduce the likelihood of relapse. For the young adult, learning to navigate the challenges of affective disorders and associated symptoms instills a sense of control, engenders emotional resilience and enables wellbeing.
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