Neurobiology of Depression – A Simplified Guide

PATHOPHYSIOLOGY OF DEPRESSION

Today, the neurobiology of depression can be visualised within a framework of monoamines, stress, inflammation, and neurogenesis. [Dean and Keshavan 2017]

There are converging lines of evidence that MDD is a matrix of pathophysiological mechanisms that encompass altered cellular neurochemistry and neurocircuitry as well as tissue- and organ-level pathology:

• Serotonergic, noradrenergic, dopaminergic, and glutamatergic systems
• Structural Abnormalities
• Increased inflammation and HPA axis abnormalities
• Decreased neurogenesis and neuroplasticity

The neurobiological interaction between stress, inflammation, and neurogenesis integrates several hypotheses to explain the spectrum of depressive symptoms. This is crucially all still within the matrix of a unified theory of depression.

NEUROTRANSMITTER ABNORMALITIES IN DEPRESSION

Monoamine Neurotransmission

Studies showed that successfully treated patients with antidepressants relapse if their tryptophan levels are depleted; however, tryptophan depletion has no effect in untreated patients. [Bell et al. 2001]

This data suggest that reduced 5-HT levels are not enough to cause depression, although increased 5-HT levels are necessary for antidepressant medications to be effective. Thus:

• There may not be any abnormality in 5-HT signalling in MDD.
• Multiple neuronal factors may regulate the synaptic concentration of 5-HT.

As previously stated, the monoamine hypothesis postulates that depression is caused by the depletion of serotonin (5-HT); however, research also implicates the brain’s other monoamines: noradrenaline (NA) and dopamine (DA). [Mulinari 2012]

It has been shown that these neurotransmitters are all interrelated and do not operate in isolation. [El Mansari et al. 2010]

• SNRIs inhibit the reuptake and subsequent catabolism of NA and serotonin, whereas antidepressants such as mirtazapine enhance NA and serotonin transmission.
• Tricyclic antidepressants and MAOIs are classified as broad-spectrum antidepressants as they increase NA, Serotonin and DA and are effective antidepressants in severe depression.
• Long term SSRI therapy enhances 5-HT transmission in the locus coeruleus; however, this also exerts an inhibitory action on NA neurons via sustained GABA release, thus dampening NE levels in the amygdala—this has been observed with citalopram, escitalopram, and paroxetine. [West et al. 2009]  Psychopharmacology of Selective Serotonin Re-uptake Inhibitors (SSRIs) – Mechanism of Action
• Serotonergic neurons also have an inhibitory influence on dopaminergic neurons in the ventral tegmental area, which again may be responsible for the absence of a therapeutic benefit with SSRIs in some patients. [Dremencov et al. 2009]
• Although less attention has been paid to purely blocking the reuptake of DA, data indicate that stimulants that enhance DA release or inhibit DA reuptake augment antidepressants.
• Bupropion, Methylphenidate, Dexamphetamine, Modafinil and Armodafinil increase dopamine and have antidepressant effects.

Role of Glutamate: 

• More recently, glutamate abnormalities have been observed in depression. Depressed patients show abnormal elevation of glutamate neurotransmission and glutamate levels in cortical/limbic brain areas. [Racagni & Popoli, 2008]
• Acute use of antidepressants increases glutamate in presynaptic terminals however chronic use is associated with synaptic reduction of NMDA receptor levels and function. This dampens glutamate transmission and enhances AMPA glutamate receptor-mediated transmission (vs NMDA receptor transmission).
• AMPA glutamate receptor activation increases BDNF levels and stimulates neurogenesis which is linked to antidepressant activity.
• Ketamine and Esketamine are NMDA antagonists at GABA-ergic interneurons (inhibitory). NMDA antagonism at GABA-ergic inhibitory neurons results in a rapid and transient rise in glutamate in the medial prefrontal cortex (mPFC), leading to the acute activation of AMPA receptors, which explains the rapid antidepressant effects of ketamine and esketamine. Ketamine and Esketamine in Depression – A Synopsis on Efficacy and Mechanism of Action

Therefore, in the context of antidepressant drugs, their potential efficacy relies on the drug interacting with different monoamines and the interactions between sympathetic nervous, immune, and endocrine systems. [Leonard 2001]

STRUCTURAL AND FUNCTIONAL BRAIN ABNORMALITIES IN DEPRESSION

Consistent abnormalities found in depression:

• Grey matter volume
• White matter tracts brain responses to emotional stimuli
• Functional brain responses to cognitive stimuli
• Functional connectivity across distant brain regions

Two main models have been proposed in the pathogenesis of depression: Dual Network and Triple Network Model.

Dual network model 

The dual network model of depression consists of a ventral and a dorsal network and was hypothesised to mediate different domains of depression. [Mayberg, 1997], [Phillips et al., 2003]

1. Ventral network:

• Mediates vegetative and somatic symptoms and consists of hyperactive brain regions
• Identification of the emotional significance of a stimulus
• Production of affective states
• Automatic regulation of emotional responses

2. Dorsal network:

• Mediates cognitive aspects of depression and consists of hypoactive brain regions.
• Mediates effortful regulation of affective states and behaviour.

Triple Network Model: [Menon, 2011]

Three functional brain networks

1. Default mode network (DMN) :

• Primarily active at rest
• Involved in emotional regulation, social cognition, future-oriented thinking and autobiographical memory
• Dysfunction in this network can give rise to alterations in cognitive processing of external information and relating it to self. (self-referential processing)

2. Central executive network (CEN) or Executive Central Network (ECN) 

• The seat of executive functioning
• Dysfunction in this network leads to cognitive dysfunction

3. Salience network (SN)

• Detection of salient internal and external stimuli to direct behaviour
• Dysfunction in this network can give rise to alterations in arousal

There has been a shift from the dual network model to the triple network model of depression postulating dysregulation between and within large-scale brain networks.

Following are correlates of symptoms with dysfunction in specific networks

Rumination 

• Dysfunction in parietal components of the DMN

Emotional disinhibition

• Dysfunction in the CEN

Emotional over-reactivity

• Dysfunction of the SN

The Prefrontal cortex (PFC) is a main cortical target of both NA and DA innervations, with both neuronal systems modulating PFC activity in addition to memory and attentional performance. [Xing B et al., 2016]

Functional Abnormalities: 

From a functional perspective, two connections stand out in their contribution to melancholic depression [Ichikawa N et al., 2020]

1.ECN-SN: Functional connections with left inferior frontal gyrus in the executive control network (ECN) and right Dorsal medial prefrontal cortex DMPFC/Frontal eye fields FEF/Supplementary motor area SMA in Salience network (SN)

2. DMN- ECN: Connections in Left DLPFC-IFG in ECN and Posterior cingulate cortex PCC/Precuneus in default mode network (DMN)

SSRIs did not improve the DMN-ECN connection but normalised the ECN-SN connection.

SSRIs do not act on the DMN-ECN, and evidence suggests that the mechanism of SSRIs maybe not due to the pharmacological properties of SSRIs in increasing synaptic serotonin but by the brain’s compensatory mechanisms in restoring energy homeostasis (explaining the lag effect of SSRIs). [Andrews P et al., 2015]

This suggests the need for combined treatment in melancholic depression for a broad spectrum effect. e.g. Combination antidepressants that target DLPFC (ECN) and /or neurostimulation and neurofeedback. Melancholic and Psychotic Depression – Review of Diagnosis and Management

HPA AXIS DYSREGULATION AND STRESS RESPONSE IN DEPRESSION

The concept of stress is defined as a disruption to homeostasis that induces adaptive reactions to reconstitute homeostasis.

The stress response can precipitate depression via abnormal HPA axis parameters (hypersecretion of CRH from the hypothalamus, hypercortisolaemia due to a hypersensitive HPA axis, and dysregulated negative feedback regulation of CRH) that are neurobiological biomarkers often associated with depressive episodes. [Dean and Keshavan 2017]

• Chronic stress can cause pre-existing vulnerabilities to manifest themselves—known as the diathesis-stress model. This model states that a predisposition (possibly genetic or epigenetic) causes a neurodevelopmental issue that may not cause depression until an environmental factor elicits a maladaptive reaction. Epigenetic Mechanisms in Psychiatric Disorders – Major Depression, Psychosis and Addiction
• Chronic stress induces a neurobiological cascade that affects the hippocampus’ ability to adapt to stressful environments, thereby reducing neuroplasticity and the long-term potentiation of hippocampal neurons. Neurobiology of Stress and Resilience
• Research shows that chronic stress also reduces dendritic complexity in the medial prefrontal cortex (mPFC). The mPFC is involved in the cognitive reappraisal of negative emotions processed in the amygdala; these changes may be detrimental to the successful control of affect. [Banks et al. 2007]
• Hypercortisolaemia in the brain also changes the emotion-cognitive circuitry by uncoupling the amygdala from the hippocampus (adaptive learning) and increasing connectivity with the striatum (habitual learning), leading to anhedonia, rumination, lack of motivation, and depressive symptoms. [Myers et al. 2014]
• HPA axis dysfunction is not found in all patients with depression. There is no test for diagnosis or a drug that effectively targets specific HPA axis components. [Menke, 2019]

NEUROINFLAMMATION IN DEPRESSION

Inflammation

There is extensive data on the bidirectional relationship between depression and inflammation, whereby depressed patients have an increased rate of autoimmune disorders, and patients with inflammatory conditions are more likely to develop depression. [Pasco et al. 2010]

Inflammation and Depression – A Simplified Guide

• Stress can stimulate an inflammatory response, which can be explained as a legacy of evolution whereby interactions with predators and human rivals would elicit the fight-or-flight response and a suite of immunological responses to fight infection and heal wounds. [Raison and Miller 2013]
• Acute inflammation causes adaptive ‘sickness behaviours’ (e.g. anhedonia, fatigue, and internal focus) in response to an infection. However, chronic inflammatory conditions can prolong ‘sickness behaviours’ – cardinal features of depressive symptomatology. [Rosenblat et al. 2014]
• The pro-inflammatory markers TNF-alpha, IL-1, IL-2, and IL-6, the most reliable biomarkers of inflammation in depressed patients and anti-inflammatory treatments, can reduce depressive symptoms in patients with MDD and patients with rheumatoid arthritis and psoriasis. [Tyring et al 2006]; [Kohler et al 2014]
• Furthermore, infliximab (a monoclonal antibody directed against TNF) successfully treated patients with treatment-resistant depression that had a high baseline CRP level of >5 mg/L. [Raison et al. 2013] However, TNF-alpha antagonism does not work in patients with low levels of inflammation.
• There is increasing evidence of antidepressant efficacy being mediated through the modulation of neuroinflammation. Mechanism of Action of Selective Serotonin Reuptake Inhibitors (SSRIs) – The Latest

NEUROGENESIS AND NEUROPLASTICITY IN DEPRESSION

Neurogenesis and Neuroplasticity

There has been a steady increase in data over the last few years that describe maladaptive neuroplasticity in cortico-limbic regions of the brain. [Castren 2005]; [Castren 2013]

What is Neuroplasticity? – A Simplified Guide

The network plasticity hypothesis posits that circuits in the prefrontal cortex, amygdala and hippocampus cannot be appropriately activated and reorganised in response to the environment.

This hypothesis suggests that antidepressants increase monoamine levels, which then enhances neuroplasticity in cortico-limbic brain regions.

• BDNF is a neurotrophin that promotes neuronal survival and growth levels and is important in neuroplasticity.
• In patients with MDD, BDNF levels are reduced and research suggests that not only do reduced BDNF levels play a role in the pathophysiology of depression, but it may also be a risk factor for the development of depression.
• Part of fluoxetine’s efficacy is posited to be due to its ability to increase BDNF expression in the hypothalamus and nucleus accumbens. [Molteni et al 2006]
• With evidence of antidepressants mediating neuroplastic mechanisms, there is a case for antidepressant mechanisms to be relabelled as “hypothesis of neuroplasticity”. [Racagni & Popoli, 2008]
• Mechanism of Action of Selective Serotonin Reuptake Inhibitors (SSRIs) – The Latest

The efficacy of treatments such as rTMS [Shang et al 2016] and electroconvulsive therapy [Rocha et al 2016] have also been attributed, in part, to their ability to increase BDNF levels and increase neuroplasticity.

GUT-BRAIN AXIS

We have covered this important aspect in a stand-alone comprehensive article. 

SUMMARY

There are structural, functional and molecular alterations associated with the neurobiology of Depression that go beyond the 5-HT hypothesis.

Recent advances suggest a multi-faceted integration of different neurobiological models, including pathophysiological alterations to inflammation, stress, neurogenesis and monoamine neurotransmission.