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

Aug 26
How to read an academic paper Image
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Read 4 tweets
Aug 4
Antidepressant efficacy is inflated by the cumulative impact of publication bias, outcome reporting bias, spin, and citation bias on the evidence base.

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This discussion is from a paper in @CambUP_Psych which analyzed the cumulative impact of biases on apparent efficacy for antidepressants. 2/12 cambridge.org/core/journals/…Image
Publication bias is the failure to publish the results of a study on the basis of the direction or strength of the study findings; oftentimes, studies which have statistically significant positive results get published and the negative studies do not. 3/12
Read 12 tweets
Jul 29
Our paper was just published in the Journal of Psychiatry & Brain Science.

5 grams of creatine per day saturates your muscles, but is likely too low for the brain.

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Given the constant energy supply required by the brain, there has been increasing interest in the potential of creatine for improving brain bioenergetics, health and function. 2/10 Image
Accumulating research indicates that creatine is capable of increasing brain creatine stores which may help explain improvements in cognitive functioning particularly during times of metabolic stress. 3/10
Read 12 tweets
Jul 17
Stronger legs are associated with larger brain volume & slower cognitive decline.

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These findings are from a study in @KargerPublisher which tested whether muscle fitness (measured by leg power) could predict cognitive change in a healthy older population over a 10-year time interval. 2/7 karger.com/ger/article/62…Image
There is consistent evidence from observational studies of a protective association between levels of physical activity and subsequent cognitive ageing within the healthy population. 3/7
Read 7 tweets
Jul 15
A common belief is that cognition arises from the brain.

This paper suggests that cognition is a complex multiscale information processing distributed across every single cell in the body.

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These findings are from a paper in @FrontNeurosci which argues that a promising way forward in understanding the nature of human cognition is to zoom out from the prevailing picture focusing on its neural basis. 2/10 frontiersin.org/journals/integ…Image
The idea that the mind is distinct from the body and somehow at home in the human brain has deep roots in a longstanding philosophical and scientific thinking, stretching from antiquity to the present day. 3/10 Image
Read 10 tweets
Jul 14
People with schizophrenia die 20 years prematurely, largely due to cardiovascular factors.

It’s time we incorporate exercise as a first-line treatment.

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These findings are from our paper in @jpahjournal which outlines practical strategies for exercise professionals and clinicians involved in the treatment of schizophrenia, informed by the latest evidence, to help prescribe exercise effectively. 2/12journals.humankinetics.com/view/journals/…
Schizophrenia is a chronic and disabling psychiatric disorder that affects approximately 1% of people. 3/12
Read 12 tweets

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