Biology of TRD

Synaptic dysfunction in treatment-resistant depression

Major depressive disorder (MDD) is characterised by symptoms, burdens, and dysfunction. The highly heterogeneous nature of major depressive disorder is moreover associated with psychiatric and medical comorbidities¹. This variability is also reflected in responses to pharmacological treatment, most notably with treatment-resistant depression (TRD).

An understanding of the underlying pathophysiology of treatment-resistant depression is therefore essential for producing more efficacious treatments that leverage alternative mechanisms of action.

What is the pathophysiology of treatment-resistant depression?

The pathophysiology of major depressive disorder has yet to be fully elucidated due to its complexity and multiple potential aetiologies². The gene-environment interaction is essential to understand the onset of the disorder and its development according to the monoaminergic imbalance and the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis.

The most widely accepted hypothesis of antidepressant action is the monoaminergic hypothesis, which suggests that depression is due to an imbalance of the monoamine neurotransmitters: serotonin, norepinephrine, and dopamine.

Selective serotonin reuptake inhibitors, a first-line therapy for major depressive disorder, can however take weeks before seeing improvements in symptoms³.

A noteworthy development in the last several decades has been the investigation of rapid antidepressant agents, with an onset of action of hours, in treatment-resistant depressed patients^4,5.

The rapid mechanism of action of ketamine is associated with an induction of synaptogenesis and the reversal of the dendritic atrophy resulting from long-term stress exposure^6,7.

This has led to the recent hypothesis that major depressive disorder is caused by a disruption of the homeostatic mechanisms that control synaptic plasticity, leading to a consequential destabilisation and loss of synaptic connections⁸.

Why is synaptic plasticity important?

Synaptic plasticity is the activity-dependent modification of the strength or efficacy of synaptic transmission. It has been proposed as a mechanism that is central to some of the most important functions of the brain, including the formation of short- and long-term memory, and adaptive behaviour^9,10,11.

Various investigations have highlighted reduced levels of synaptic signalling proteins in patients with major depressive disorder, including glutamate receptor subtypes, pre-synaptic neurotransmitter vesicle as well as post-synaptic structural and functional proteins in the dorsolateral prefrontal cortex, hippocampus, and other forebrain structures^12–15.

From a macroscopic level, the most consistently observed disruption of this complex circuitry has been a reduction of prefrontal cortex and hippocampus volume^12,16,17. Cross sectional studies have also reported that smaller hippocampal volumes are correlated with¹⁷:

• Age of onset
• Length of untreated illness
• Burden of illness
• Time of treatment
• Non-responsiveness to treatment
• Depression severity
• History of childhood abuse
• Level of anxiety

There is also evidence of an association between small hippocampus volume and polymorphisms in the serotonin (5-HT) transporter gene 5-HTTLPR and in the brain-derived neurotrophic factor gene at position 66 (Val66Met)¹⁸.

A complex interaction of signalling pathways (Figure 1) influences the formation of synapses, the disruption of which could contribute to the loss of synapses and loss of brain volume in major depressive disorder¹⁹.

Figure 1: Signalling pathways that may contribute to the loss of synapses in major depressive disorder (Adapted from Duman et al19). ATP, adenosine triphosphate; Akt, protein kinase B; BDNF, brain-derived neurotrophic factor; ER, oestrogen receptor; GR, glucocorticoid receptor; GluR1/2, glutamate receptor 1/2, GSK3, glycogen synthase kinase 3; GFs, growth factors; LTD, long-term depression; LTP, long-term potentiation; mGlu, metabotropic glutamate; NtFs, neurotrophic factors; NMDA, N-methyl-D-aspartate receptor; mTOR, mechanistic target of rapamycin; PI3K, phosphatidylinositide 3 kinase; Pras40, proline-rich Akt substrate of 40 kDa; PSD95, postsynaptic density protein 95; TNFa, tumour necrosis factor alpha.

Neurotransmitters, such as glutamate; growth factors and neurotrophic factors; energy and metabolic factors; sex steroids, and the hypothalamic–pituitary–adrenal (HPA) axis all have an effect on various intracellular signalling cascades responsible for regulating neuronal function¹⁹.

Many of these pathways have been associated with major depressive disorder, such as the loss of neurotrophic factor support, oestradiol cycling disruption, and elevated inflammatory cytokines¹⁹.

Notably, glutamate neurotransmission also plays an important role in synaptic function and morphology^20,21. Stress and glucocorticoids via the glucocorticoid receptor inhibit mTORC1 signalling via induction of factors that inhibit mTORC1 stability. Activation of mTORC1 signalling leads to increased synthesis of proteins (e.g., GluA1 and PSD95) required for the maturation of existing synapses and the formation of new ones¹⁹.

How is glutaminergic neurotransmission involved in major depressive disorder?

Initial interest in glutamatergic transmission in major depressive disorder was sparked by the seminal study from Berman et al. that revealed the immediate and long-lasting antidepressant effects of ketamine in treatment-resistant depression⁴. This was further confirmed in follow-up studies that led to the use of ketamine in difficult-to-treat major depressive disorder patients²².

This research has led to novel insights into the pathogenesis of major depressive disorder and has led to the development of alternative treatment options for patients with treatment-resistant depression focusing on targets such as electroconvulsive therapy (ECT)-resistant depression²³ or suicidal ideation^24,25,26.

As a major excitatory neurotransmitter in the central nervous system, glutamate is one of the most abundant and versatile amino acids in the body²⁷. Stress and glucocorticoids have previously been shown to alter the expression and/or the activity of vesicular proteins in glutamate neurotransmission²¹, which can be altered by conventional antidepressant treatment²⁸ as well as ketamine²⁹.

Glutamate binds to receptors on presynaptic and postsynaptic neurons as well as on glial cells³⁰. These receptors are divided into ionotropic N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate (KA) receptors and metabotropic glutamate receptors (mGluRs)³⁰.

The effect of glutamate receptor activation is determined primarily through the receptor subtype, localisation (synaptic, perisynaptic, and extrasynaptic), and interactions with various postsynaptic density proteins³⁰. This results in rapid ionotropic effects as well as synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD)³⁰, via signal transduction cascades³⁰.

Achieving synaptic homeostasis in treatment-resistant depression

The discovery that rapid-acting antidepressants, such as ketamine, quickly increase both the number and function of synapses has drawn attention to synaptogenesis as an important mechanism of action for the treatment of major depressive disorder and treatment resistance⁸. It has also highlighted that the disruption of synaptogenesis, loss of synapses, and neuronal atrophy are central to the pathophysiology of major depressive disorder⁸.

Synaptogenesis and treatment response

During normal brain activity, the number of synapses and their function is maintained through homeostatic mechanisms that govern regular mood (Figure 2), including the cycling of glutamate A1 (GluA1) receptors to and from the synapse⁸.

Chronic stress exposure, such as major depressive disorder, decreases synaptic density8. Stress also decreases brain-derived neurotrophic factor (BDNF), which may contribute towards the loss of synapses and neuronal atrophy⁸.

During depression, glycogen synthase kinase 3 (GSK3) is found to be increased and can be activated by protein phosphatase 1 (PP1)⁸. This could also be involved in synaptic destabilisation through the increase of GluA1 internalisation⁸.

Figure 2: Achieving synaptic homeostasis through ketamine-induced synaptogenesis (Adapted from Duman and Aghajanian⁸). Arc, activity-regulated cytoskeleton-associated protein; Akt, protein kinase B; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF, brain-derived neurotrophic factor; GluA1, glutamate A1; GSK3, glycogen synthase kinase 3; LTP, long-term potentiation; LTD, long-term depression; mTOR, mechanistic target of rapamycin; PP1, protein phosphatase 1; TrkB, tropomyosin-related kinase B.

Ketamine reduces excitation of subsets of cortico-limbic GABA interneurons, transiently increasing glutamate that stimulates postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors⁸. This leads to a local increase of BDNF, enhanced tropomyosin-related kinase B (TrkB) receptor stimulation, and activated protein kinase B / mechanistic target of rapamycin (Akt/mTOR) signalling⁸.

The result is an increase in the translation of synaptic proteins, such as GluA1 and activity-regulated cytoskeleton-associated protein (Arc)⁸, and a consequential rise in synapse number and function⁸.

The effects of ketamine are also dependent on GSK3 inhibition, occurring via the stimulation of Akt or the blocking of NMDA receptors and PP1⁸.

Relapse to the previous depressive state, following ketamine treatment, occurs after approximately 7 to 10 days⁸. This could be due to a failure of synaptic homeostasis caused by genetic mutations or environmental factors⁸.

New therapeutic targets for major depressive disorder

The most widely prescribed antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), can take weeks before there are improvements in symptoms and over a third of patients go on to develop treatment-resistant depression^31,32.

Investigations of the mechanisms underlying the mechanism of action of ketamine and the pathophysiology of major depressive disorder have provided newer targets for developing rapid-acting therapeutic agents.

NMDA receptors

Currently, esketamine is the only approved NMDA receptor antagonist for treatment-resistant depression^33,34. However, various studies have shown that selective NMDA receptor subtype 2B (NR2B) antagonists have antidepressant and synaptogenic effects^7,35. Further studies will be needed to assess their efficacy in treatment-resistant patients.

Glutamate receptors

Agents that increase synaptic levels of glutamate or enhance glutamate receptor signalling have also been investigated. Rapid responses have been seen from blocking metabotropic glutamate 2/3 receptors (mGluR2/3)^36,37.

AMPA receptors

AMPA receptor potentiators have also been shown to induce antidepressant responses in murine models and stimulate mTOR signalling in cultured cells^20,38.

GSK3 inhibition

Inhibition of the protein GSK3, which is required in the mechanism of action of ketamine, may also be a promising target for producing rapid-acting therapeutic agents similar to ketamine³⁹.

Exercise and treatment-resistant depression

Exercise in general is known to have a positive impact on emotional well-being⁴⁰. It also has beneficial effects in major depressive disorder^41,42 as well as depression in older people⁴³ and people with Alzheimer’s disease⁴⁴.

A study by Mota-Pereira previously found that a twelve week, home-based, exercise program consisting of 30–45 minutes per day of walking for five days a week improved in all depression and functioning parameters in major depressive disorder in patients with treatment-resistant depression (P < 0.05)⁴⁵. Towards the end of the study, 21% of participants showed response and 26% remission in the pharmacotherapy plus aerobic exercise group (N = 22) compared to 0% in the pharmacotherapy group (N = 11)⁴⁵.

Similarly, a Cochrane review concluded that exercise has a modest positive effect on major depressive disorder⁴⁶. Recent meta-analyses and systematic reviews have also found that treatment-resistant depression moderately benefits from exercise^47,48,49. One analysis specifically recommended exercise as an adjunctive therapy for treatment-resistant depression⁵⁰. While the evidence is insubstantial and clouded by a lack of consistent definitions for exercise type, there have yet to be trials that show exercise worsens major depressive disorder or treatment-resistant depression⁵¹. Exercise should therefore be safe to recommend to patients alongside medication or psychotherapy, as needed⁵¹.

Click here to learn more about the non-pharmacologic treatment options available for treatment-resistant depression

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