Nicholas Fabiano, MD Profile picture
Jun 4, 2024 18 tweets 4 min read Read on X
The neuroplasticity framework of depression has the potential to replace the serotonin deficit hypothesis.

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The serotonin deficit hypothesis explanation for depression has persisted among clinicians and the general public alike despite insufficient supporting evidence. 2/17 nature.com/articles/s4138…
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We must acknowledge that multiple biopsychosocial factors can interact with each other and converge on depression pathophysiology; these myriad of contributing factors converge in ways that are not yet fully understood to cause the symptoms of depression. 3/17 Image
Although heterogeneous and distinct for each patient, these symptoms share features of dysfunction in brain circuits that process emotional and cognitive information and regulate survival functions like energy and motivation. 4/17
These dysfunctional circuits leave individuals “stuck” in a state characterized by negativity bias, depressed mood, anhedonia, and dysfunction in several other behavioural domains, such as motivation, appetite, and sleep. 5/17
In particular, being stuck in a rut of negative information processing can be understood as an impairment in cognitive and emotional flexibility. 6/17
As such, people with depression are slower to adapt to changing rules in cognitive flexibility and remain stuck with a narrow or rigid repertoire of emotions. 7/17
Collectively, these findings result in a tendency to perseverate on negative information and an impaired ability to respond to positive input. 8/17
From a structural level, the behavioural symptoms of depression come from changes in the volume, activity, and connectivity of brain regions and networks involved in emotional salience, reward processing, motivation, and executive functioning. 9/17
Key brain regions involved in depression pathophysiology include the prefrontal cortex (PFC), hippocampus, nucleus accumbens (NAc), and amygdala; broadly speaking, the activity of these brain regions and their connectivity with each other are primarily dampened. 10/17
At the cellular level, there is evidence of dysfunction in synapses: the junctions between neurons where electrical signals and chemical neurotransmitters pass from the axon of a sending (presynaptic) neuron to the dendrites of a receiving (postsynaptic) neuron. 11/17 Image
Synaptic dysfunction is most evident in pyramidal neurons, a prevalent class of neurons that release glutamate, thereby activating target neurons that release other neurotransmitters, such as serotonin, norepinephrine, dopamine, and acetylcholine. 12/17
A growing body of evidence suggests that treatments for depression work by enhancing neuroplasticity, rewiring dysfunctional brain circuits and synapses in adaptive ways that allow patients to become “unstuck” from negative thoughts, emotions, and behaviours. 13/17
Monoamines are still essential for antidepressant effects, but rather than correcting a deficit, the serotoninergic, dopaminergic, and noradrenergic activity of typical antidepressants likely play two major roles in facilitating the therapeutic response. 14/17
(1) triggering downstream molecular cascades that result in neuroplasticity more chronically, and (2) changing emotional processing and behaviour more acutely. 15/17
Similar mechanisms involving neuroplasticity likely underlie the effects of novel “antidepressants” such as ketamine and psychedelics. 16/17
Overall, in this new model, although depression cannot accurately be considered a deficit in serotonin, serotonin still has a role to play through its interactions with mechanisms of neuroplasticity. 17/17
Read more from the full paper in @molpsychiatry here nature.com/articles/s4138…

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More from @NTFabiano

Apr 1
Bright light therapy is an effective adjunctive treatment for nonseasonal depressive disorders.

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These findings are from a study in @JAMAPsych which aimed to assess bright light therapy (BLT) effectiveness as an adjunctive treatment for nonseasonal depressive disorders. 2/8 jamanetwork.com/journals/jamap…Image
BLT is a low-cost adjunctive treatment option, however its efficacy has only previously been established in seasonal depressive disorders. 3/8
Read 8 tweets
Mar 31
This is the first map of human brain mitochondria.

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These findings are from a study in @Nature which created a map of mitochondria throughout the entire brain to bridge the scale gap between cognitive neuroscience and cell biology. 2/11 nature.com/articles/s4158…Image
The transformation of biochemical energy from food and oxygen into electricity, and then into molecules of ATP, one of the cell’s energy currencies, is done by organelles called mitochondria. 3/11 Image
Read 12 tweets
Mar 23
Daytime napping is associated with a larger total brain volume.

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These findings are from a study in @SleepHealthEiC which studied the relationship between habitual daytime napping and cognition and brain structure, using Mendelian randomization. 2/8 sleephealthjournal.org/article/S2352-…Image
Given that the most pronounced decline during aging occurs in reaction time and memory, and the high prevalence of cognitive impairment in the aging population, the identification of modifiable risk factors, such as sleep habits, is essential. 3/8
Read 8 tweets
Mar 22
Higher muscle mitochondrial oxidative capacity is associated with >10 years of preserved brain structure.

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These findings are from a study in @NatureComms which examined the association of muscle mitochondrial oxidative capacity with up to over a decade-long changes in brain atrophy and microstructure. 2/9 nature.com/articles/s4146…Image
The mitochondrial cascade hypothesis, centers on the key role of age-related mitochondrial decline in Alzheimer’s disease. 3/9 Image
Read 9 tweets
Mar 21
Creatine upregulates the mRNA content of genes and protein content of kinases in muscle - independent of exercise intervention.

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These findings are from a study in @PhysiologicalG which investigated the effect of short-term creatine supplementation on global and targeted mRNA expression and protein content in human skeletal muscle. 2/9 journals.physiology.org/doi/full/10.11…Image
Creatine supplementation has a number of biochemical and physiological effects and enhances muscle performance in humans. 3/9
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Mar 20
Ketones exhibit robust effects in restabilizing brain networks.

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These findings are from a study in @PNASNews which integrated human brain and physiological data to investigate underlying mechanisms. 2/9 pnas.org/doi/10.1073/pn…Image
Brain aging is associated with multiple degenerative processes, including glucose hypometabolism, atrophy, cerebrovascular disease, and deposition of beta-amyloid and tau proteins. 3/9
Read 9 tweets

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