Thread by @Helios_Movement

If you have been depressed for a long time, focusing only on your psyche can be a big mistake.

So here are some things that can actually help you battle depression more effectively (most of which you've probably never been told before).

Thread 🧵

*Standard disclaimer that nothing in this thread should be used as a substitute for medical advice*

It's George.

First and foremost, in case the following are news to you:
-SSRIs have plenty of side effects
-Serotonin depletion does not cause depression

So before dismissing any alternative approaches, just be aware that most of the stuff you've been fed about depression for ages, was lies.

Disclaimer: Never quit SSRIs cold turkey.

Also, in case you are new here, i am not dismissing the impact that our psyche has on the way we feel.

At all.

After all, we still do not really understand the mental impact of modern upbringings, which are unnatural and flat-out insane from an evolutionary standpoint.

Most people were brought up malnourished, brainwashed by a tv, with absent parents because they had to work all day, detached from a tribe, no spiritual health and didn’t explore anything.

So they missed the key concepts that were a part of our development for TENS OF THOUSANDS OF YEARS.

And this is without even taking into consideration the traumatic events that some people faced.

So we can’t expect everything to go according to plan when certain key parts are missing.

This is a fact and how someone interprets it up to him.

All i'm saying is that it might be time to fix your body in order to fix your mind,

Now, if you are depressed, here are a few things that you might have to work on.

Number 1: Your circadian rhythm.

To put in perspective how crucial this is, eating breakfast is linked to lower suic*de rates.

Plus: Spending 1.5 h/day in outdoor light is associated with a lower risk of depression, REGARDLESS of genetic risk, and a 1-hour daily of morning walk outside showed a 48% reduction in HDRS.

Now if you are still not convinced, just having light in your bedroom while you sleep makes you more depressed (tap in the pics).

Of course, chronic circadian rhythm disruption is now shown to exacerbate or directly contribute to conditions such as:

-Gastrointestinal problems, including IBS
-ADHD, depression, bipolar disorders, anxiety and broader mental health issues
-Insulin resistance and metabolic disorders
-Immune system dysfunction
-Increased cancer risk
-Alzheimer’s disease
And more.

But it's no wonder why that's the case, since everything in the human body follows a circadian rhythm.

From liver enzyme activity to hormone production and gastric acid secretion, everything in the human body follows a circadian pattern.

Now circadian rhythms are 24-hour cycles that are part of the body’s internal clock and controlled by a combination of:
1. Internal molecular mechanisms
2. External environmental cues (aka zeitgebers)
3. Physiological processes
such as:

-The suprachiasmatic nucleus (SCN) (you can remember this more easily through the nickname “the pacemaker”)

The primary circadian clock in mammals is located in the suprachiasmatic nucleus (SCN), which is a cluster of approximately 20,000 neurons in the hypothalamus that integrates external cues (like light) and synchronizes peripheral clocks in organs like the liver, heart, and pancreas.

How?

Well it receives direct input through the retinohypothalamic tract, which connects the retina to the hypothalamus. and specialized retinal ganglion cells containing melanopsin detect light, particularly blue wavelengths (460–480 nm) and signal the SCN to reset the circadian clock daily (their signals follow a pathway called the retinohypothalamic tract).

So basically, the SCN takes the information on the lengths of the day and night from the retina, interprets it, and passes it on to things such as the pineal gland which in response to this secretes melatonin that peaks at night and ebbs during the day.

-Molecular feedback loops.

The circadian clock has a feedback loop in which genes are transcribed into mRNA, then into proteins and finally those proteins then regulate their own genes.

Some key genes and proteins when it comes to the topic of circadian rhythms include:

1. CLOCK (Circadian Locomotor Output Cycles Kaput)
2. BMAL1 (Brain and Muscle ARNT-Like 1)
3. PER
4. CRY
5. REV-ERB
6. ROR
7. DBP
8. E4BP4

When it comes to CLOCK and BMAL1, these transcription factors form a heterodimer that binds to E-box promoter regions, activating the transcription of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes.

As PER and CRY proteins accumulate in the cytoplasm (mainly at night), they form complexes, translocate to the nucleus, and inhibit CLOCK-BMAL1 activity, repressing their own transcription.

This creates a negative feedback loop with a 24-hour cycle.

Then, kinases like casein kinase 1 epsilon/delta phosphorylate PER, marking it for degradation via the ubiquitin-proteasome pathway, allowing the cycle to restart.

We also have some secondary feedback loops.
The nuclear receptors REV-ERBα/β and RORs regulate BMAL1 expression.

REV-ERBα/β represses BMAL1 for example while RORs activate it.

-External environmental cues (Zeitgebers).

External cues entrain the internal clock to the 24-hour day and are critical for aligning biological rhythms with the external world.

The main ones a person should focus on for starters are:

-Light
This is the most potent cue for resetting the SCN.

Blue light (460–480 nm) is particularly effective, as it activates melanopsin in intrinsically photosensitive retinal ganglion cells (ipRGCs).

This is why exposure to artificial light at night can desynchronize the SCN, leading to circadian misalignment with some studies suggesting that even low-intensity light (~100 lux) at night can suppress melatonin by up to 50%.

-Temperature
You might have read/heard advice such as "sleep in a slightly cold room" for example if you struggle with insomnia and the reason for this is that temperature influences peripheral clocks.

-Meal timing.
What's fascinating is that meal timing can reset peripheral clocks independently of the SCN.

For instance, eating during the night can desynchronize liver clocks, exacerbating and even leading to metabolic issues like insulin resistance.

-Physical activity.
Working out in the morning/early noon, can reinforce circadian rhythms by modulating clock gene expression and melatonin secretion.

However, intense exercise late at night may delay the clock.

Note in case it's unclear: we have peripheral clocks in organs such as the pancreas, liver, heart and even muscle tissues.

Now, here are some things you can do in order to improve the function of your CRs.

Number 1: Spend more time outside under natural light (if you don't have much time, try to at least do it at sunrise and sunset).

As it was stated: Light is the most potent cue for resetting the SCN.

"Should i try to spend time outside if it's cloudy?".

Of course.

Even if it's cloudy, you still need to spend time outside for multiple reasons and lux is one of them (there's a big difference between being indoors and outdoors).

Number 2: Block the artificial blue light especially after sunset.

Blue light may stimulate the SCN to promote alertness by increasing cortisol, vasopressin, vasoactive intestinal peptide and so on.

So ALAN will obviously mimic the effect of morning sunlight, signaling to the body that it’s daytime, even at night and disrupts the natural diurnal rhythm of cortisol, which should peak in the morning and decline by evening.

So:
-Use your electronic devices less when you really don't have to and spend more time outdoors.
-Get a pair of blue light blockers (most ones these days have studies on their sites).
-Install blue light blocking programs on your electronic devices.
-If you can get lightbulbs that have an R9 of 80 +, a CRI of 95+.

Number 3: Take care of your photoreceptors.
This means:
-Blocking the artificial blue light
-Sunset/RLT
-DHA
-Vitamin E
-B vitamins
-Vitamin C
-Taurine

Number 4: Eat and work out when we're supposed to (when possible (this is life and you can't be perfect all the time)).

This means eating breakfast for example, avoiding eating and working out late in the day and so on.

But once again prioritize whole nutrient dense foods.

FAD for example (in mice) controls the circadian rhythm in a light-independent manner.

So not enough B2 -> FAD is negatively affected -> Enhanced CRY degradation.

Number 5: Avoid using too many stimulants and obviously, go to bed when we're meant to for the most part.

Stimulation of nAChRs in the SCN through nicotine for example, can alter the expression of PER1 and PER2 potentially shifting the circadian phase.

Then most stimulants will increase dopamine, yet dopamine levels follow a circadian pattern, peaking during daytine.

Number 2: Your nutrition matters, a lot.
More than you probably want to (just tap in the pics).

For example:
-A meatless diet increases the frequency of depressive episodes.
-Thiamine and B12 decrease depressive episodes

-Suic*de victims often show low levels of zinc, magnesium and myo-inositolsciencedirect.com/science/articl…

If you are still skeptical, see the effects of vitamin C and myo-inositol.

Keep in mind: These are just two nutrients. Two.

Number 3: Change the parts of your environment that you have control over.

Basically, try to hang out with better people and at better places.

Number 4: Spend time in nature.

Walking in nature for example:
-Reduces amygdala activity (especially in women).
-It reduces cortisol quite fast (even 30 minutes spent in nature can lower cortisol by 30%-50%).
-Is one of the most effective ways to destimulate.
-Can increase levels of DHEA and adiponectin, which support our cardiovascular and overall metabolic health.

Number 5: Cut out the junk food and alcohol.

These are the fastest ways to lower some of the existing inflammation.

Just do it.

Number 6: Go test your hormones (a thyroid panel, insulin/IGF01, an androgen panel and an estrogen panel).

Point blank: A basic TRT dose might do more than 20000 SSRI pills for plenty of men and underestimating the impact that low testosterone can have on the mood of men for example, is a common mistake and the question is why?

Because we know that hormonal issues can make someone VERY depressed.

So go and test your hormones (you can find tips for each hormone specifically in my profile).

Still skeptical?

Number 7: A lot of the time people with treatment resistance depression have SNPs in things such as the MTHFR or COMT (no one can have healthy neurotransmitter with poor methylation status or a poor ability to properly break down dopamine for example).

**Low folate levels impair methylation processes critical for neurotransmitter production, increasing depression risk. pmc.ncbi.nlm.nih.gov/articles/PMC18…

Number 8: Go and measure your vitamin D levels.

Number 9: Work on your gut.
All healthy people can become depressed through basic endotoxin infusions.

Still skeptical?

Number 10: Support neurotrophic factors.

Depression is often tied to reduced neuroplasticity and hippocampal atrophy.

BDNF and NGF counteract this by promoting synaptic connections and neurogenesis, potentially reversing structural brain changes.

These are proteins that act as growth factors, supporting the formation of new neural connections (synaptic plasticity), the growth of new neurons (neurogenesis), and the repair of damaged neural tissue.

There are three key ones that it’s a good idea to be familiar with:

1. Brain-derived neurotrophic factor (BDNF)

This one is the most abundant neurotrophin in the brain, being primarily expressed in the hippocampus, cortex and basal ganglia.

It is essential for consolidating memories and enhancing cognitive flexibility, mood regulation (low BDNF levels are linked to depression and anxiety and reduced BDNF in individuals with major depressive disorder is very common), increases dendritic spine density, protects neurons from oxidative stress, inflammation and apoptosis, it reduces beta-amyloid toxicity and supports dopaminergic neurons which are the primary mechanisms behind how it protects us against Alzheimer’s and Parkinson’s.

2. Glial-derived neurotrophic factor (GDNF)
GDNF is primarily produced by glial cells and is critical for the survival and function of dopaminergic neurons, particularly in the substantia nigra.

It modulates reward circuits in the ventral tegmental area, influencing addiction behaviors (higher levels = less addiction), plays a key role in motor control, axonal growth, protects dopaminergic neurons from oxidative stress and also interacts with NCAM (neural cell adhesion molecule) to support neural repair.

3. Nerve growth factor (NGF)
NGF is critical for the growth, maintenance, and survival of sensory and sympathetic neurons, particularly in the peripheral nervous system (PNS), supports cholinergic neurons in the basal forebrain (it also enhances acetylcholine release in it), cognitive functions like attention and memory, protects neurons from oxidative stress and inflammation, regulates sensory neuron function in the PNS, modulates stress

And now let's talk about tools you can use in order to support the function of the brain.

Tool 1: Red light therapy

-It boosts ATP production in neurons.

-It decreases pro-inflammatory cytokines (IL-1β, TNF-α), protecting the blood-brain barrier (BBB) and neurons,.

-It stimulates the release of brain-derived neurotrophic factor (BDNF).

-It increases cerebral blood flow, supporting nutrient delivery and waste removal.

-It reduces secondary brain damage in TBI and stroke by decreasing inflammation, excitotoxicity, and neuronal apoptosis.

Tool 2: Curcumin (boosts BDNF and NGF, reduces oxidative stress, inhibits pro-inflammatory pathways and upregulates antioxidant enzymes).

Tool 3: Royal jelly (mainly for the BBB).

Tool 4: Lion's mane (Increases NGF and BDNF like few things do).

Tool 5: Any form of magnesium besides oxide and citrate (enhances BDNF, supports synaptic plasticity, blocks glutamate excitotoxicity and promotes BBB stability)

Tool 6: NAC (boosts glutathione, reduces oxidative stress, supports BBB integrity and enhances BDNF)

Tool 7: ALCAR (supports BDNF, enhances mitochondrial function and it may protect BBB by reducing oxidative stress).

Tool 8: CoQ10 (Enhances mitochondrial function, reduces oxidative stress, supports BDNF/GDNF and protects the BBB).

Tool 9: Gingko biloba (enhances BDNF, improves cerebral blood flow and supports BBB integrity.)

Tool 10: Bacopa (Increases BDNF and NGF).

Tool 11: PQQ (enhances BDNF and NGF, supports mitochondrial biogenesis, and protects BBB)

Tool 12: Gotu kola (increases BDNF and NGF)

Tool 13: Phosphatidylserine (supports BDNF and stabilizes BBB).

Tool 14: Selank (enhances GABA receptor activity and increasing brain-derived neurotrophic factor).

Tool 15: Semax (boosts BDNF and NGF).

Tool 16: Cerebrolysin (mimics endogenous neurotrophic factors).

Tool 17: Huperzine A (enhances NGF and BDNF)

Tool 18: Saffron (boosts BDNF and NGF, reduces oxidative stress, and supports BBB)

Tool 19: Creatine (increases phosphocreatine stores in neurons, reduces oxidative stress, upregulates BDNF, supports endothelial cell stability in the BBB).

"What about neurotransmitters?"

Neurotransmitters are chemicals that neurons use to communicate, influencing everything from mood to movement.

Imbalances can lead to issues like anxiety, depression, or poor focus.

Here’s a basic breakdown of these:
1. Glutamate
Glutamate, the primary excitatory neurotransmitter, is present in 90% of synapses and drives cognitive functions, neuroplasticity, and gut motility.
However, excess glutamate can cause excitotoxicity, leading to anxiety, migraines, or neurodegeneration.
To manage glutamate:
-Focus on GABA as it will be demonstrated down below.
-Avoid the regular consumption of foods that have free-form glutamate such as:
● MSG
● Monopotassium glutamate
● Soy sauce and soy products in general
● Wheat gluten
● Casein
● Maltodextrin
● Modified food starch
● Corn starch and corn syrup
● Barley malt
● Calcium caseinate
● Rice syrup and brown rice syrup
● Xanthan gum
● Carrageenan
● Bouillon
● Citric acid
-Avoid the daily usage of stimulants.
-Get enough magnesium and vitamin B6.
A lack of these two nutrients will lead to a glutamate excess through harming its conversion.
The enzyme glutamate decarboxylase that was mentioned prior for example, used B6 as cofactor.
-Consume enough bioavailable protein.
Consuming 1.8gr of bioavailable protein per pound of bodyweight which is shown to reduce serum glutamate.

2. GABA
GABA, an inhibitory neurotransmitter, calms the brain, reducing anxiety and promoting sleep. Low GABA is linked to insomnia and ADHD-like symptoms, while excess can cause fatigue.
To boost GABA:
-Get enough magnesium and vitamin B6 (there are other crucial nutrients that will be mentioned).
Remember the glutamine - glutamate -GABA cycle.
-Avoid chronic stress.
When glucocorticoid hormones are released, GABA has to counteract some of their signaling but if we are in a constant stressful state, GABA simply can’t keep up.
-Get enough dietary taurine and glycine.
Amino acids partly are building blocks for neurotransmitters so if we do not provide enough of them, we simply can’t have enough of them.
Now it is in fact very true that most people don’t consume nearly enough glycine and taurine from dietary sources. In order to fix that, go and get a grass fed beef gelatine and some quality seafood such as scallops.
-Cycle stimulants (nicotine, caffeine etc).
-Provide enough thiamine (vitamin B1), vitamin C, vitamin D, vitamin A, copper, zinc, magnesium, taurine and vitamin E.

3. Dopamine
Dopamine, a neuromodulator, drives motivation, reward, and focus. Low dopamine can cause apathy, low libido, or addiction, while excess may lead to insomnia or mania.
It’s produced in areas like the substantia nigra and VTA, and its receptors (D1–D5) influence conditions like ADHD and schizophrenia.
To optimize dopamine:
-Set small goals that will provide you with some positive feedback
-Get sunlight
-Go and measure your prolactin levels
-Get enough zinc, B6, B1, B12, vitamin C, taurine, animal protein, taurine and magnesium

4. Serotonin.
Serotonin regulates mood, sleep, and gut motility, but excess (from high tryptophan intake or stress) can cause anxiety, tinnitus, or hair loss.
To balance serotonin:
-Get full spectrum sunlight
-Get enough B2, B6 and magnesium
-Balance the amino acid profile of your diet
-Consider basic tools such as taurine and ginger

5. Acetylcholine.
Acetylcholine supports memory and learning. Low levels impair cognition, while excess may contribute to OCD-like symptoms.
To support acetylcholine:
-Consume enough choline, taurine, glycine and B vitamins
-Consider tools that can help you prevent the break down of acetylcholine such as: ginkgo biloba, bacopa, polygala, gotu kola and hyperzine

6. Histamine
Histamine influences alertness and drive. Too little can cause lethargy or erectile dysfunction, while excess may lead to addiction or overstimulation.
To balance histamine:
-Avoid consuming tons of the following foods.
Key word: Tons. You won't die if you eat a pickle.
●Fermented foods
●Foods with additives such as citric acid
● Aged cheeses
● Canned foods
●Too much cacao
● Cured meats
● Dried fruit
● Preservatives
● Vinegar
● Yeast
● Alcohol
-Consume enough zinc, C, B6, B12, B9 and bioavailable protein since they are DAO and HNMT cofactors.
-Optimize your gut health.
You can approach this from multiple angles.
A lot of histamine is stored in the ECL cell of the stomach for example, SIBO is known to cause histamine intolerance and things such as candida can produce oxalates and also cause histamine intolerance.
–Avoid exposure to mold and mycotoxins

7/8. Epinephrine/Norepinephrine
These neurotransmitters, part of the SNS, drive the fight-or-flight response.
Chronic elevation from stress or fasting can deplete dopamine, as adrenaline is synthesized from it.
To manage both:
-Get enough magnesium, zinc, potassium, B1, B5 and vitamin C
-Cycle all stimulants and never overuse them
-Keep your blood sugar stable.
-Avoid over-working or over-exercising (and especially working out too much in a fasted state).
-Stop “fasting” every day with black coffee.
-Monitor your alcohol intake.

That was it.
Improving depression can seem like a huge puzzle to be solved, but i hope that you found a couple of useful pieces in this thread.

If you did, make sure to leave a like/RT.