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How to Free Yourself from Depression with the Top Strategies for Depression: Part 2

The Antidepressant Strategies that can work for YOU!


[References to this Article]


[Related Article: Free Yourself From Depression Part 1 of 2]


“Old” Mood Disorder Explanation (Theory of Depression)


In pursuit of credibility with the mainstream medical community, psychiatrists and neuroscientists have sought biological depression causes using objectively measurable variables since the 1950s.

Heavily pharmaceutical industry-driven, the initial “low serotonin” depression theory focused on various serotonin level-raising types of antidepressants.

Easily the most commonly prescribed antidepressant drugs, selective serotonin reuptake inhibitors (SSRIs), inhibit or block serotonin reabsorption from presynaptic neurons, in favor of the postsynaptic neurons instead.

Recent studies pick apart this “low serotonin” theory as not being an adequate depression explanation, as a famous 2015 meta-analysis says, “don’t be sad, because your SSRI antidepressant medication is probably not working, anyway.”

Still, studies show despite SSRIs immediate serotonin level increase, weeks pass by before patients experience antidepressant effects from them.

Researchers now believe SSRI’s work in ways other than serotonin increase, such as brain-derived neurotrophic factor (BDNF), a protein we associate with brain growth.

Measuring BDNF levels are being offered as a more accurate measurement for the effectiveness of antidepressant treatments.

The problem with this is changes in BDNF levels are not uniform across all antidepressants.

The “low serotonin” theory has lost its favor in the scientific community, replaced by new biological depression theories.

At this point, it is safe to accept SSRI drugs are not the best antidepressants as we should explore other types of antidepressants.

Before reviewing the top science-backed lifestyle strategies for depression, let’s look at the future medications for depression and anxiety.

Best Antidepressants: New Medications for Depression and Anxiety in the Modern Era?

Along with the problem of side effects of antidepressants, the relative failure of SSRI drugs is leading us to explore other targets for medications for depression and anxiety.

These are the primary targets where researchers are exploring new types of antidepressants.

  • Circadian-rhythm Dysfunction (Sleep-Wake Cycle)
  • Gut Microbiome (Prebiotics/ Probiotics)
  • HPA Axis (Hypothalamic-pituitary-adrenal) Dysfunction
  • Low Monoamine Levels (COMT, MAO-A, MAO-B Enzymes)
  • Neuroinflammation and Impaired Neurogenesis (Excitotoxicity)


Mood and Cognition-Related Neurotransmitter Activities

A major flaw in the low serotonin model of depression theory is the ignoring of the role of the other primary neurotransmitters, such as dopamine, norepinephrine, and epinephrine.

And many decades later, despite serotonin being a “monoamine” metabolized in the MAO enzyme, we can say these other ignored monoamine neurotransmitters are at least equally important to serotonin, as we find them also as catecholamines metabolized within the COMT enzyme.

Besides insufficient GABA and/ or excessive glutamate, we also want to consider the role of endorphins in mood regulation, in consideration of the best antidepressants.


Drive, Motivation, Pleasure/ Reward


Energy, Focus, Wakefulness


Compulsions, Obsessiveness, Sleep

Dopamine + Serotonin

Aggressiveness, Appetite, Sex

Dopamine + Norepinephrine

Arousal, Attention, Energy

Norepinephrine + Serotonin

Anxiety, Impulsivity, Irritability

Symptoms of Depression


Agitation, crying, irritability, restlessness, social isolation.


Concentration and focus issues, repeatedly going over thoughts, slowed activity, suicidal thoughts.


Anxiety, apathy, discontent, guilt, hopelessness, loss of interest or pleasure in activities, mood swings, sadness.


Fatigue, insomnia, excessive sleep.


Excessive, low/no appetite, excessive hunger, weight gain, or weight loss.

Major Depression, Bipolar Depression, and the Other 7 Depression Types

1. Major Depression: (Classic or Unipolar Depression)

The most common type of depression, major depression involves a single episode or chronic ongoing severe despondency, doom, and gloom.

2. Chronic Depression: (Dysthymia)

Chronic depression or dysthymia, lasts at least two years, this is a chronic and often less intense feeling of sadness and hopelessness.

3. Bipolar Disorder: (Bipolar Depression or Manic Depression)

There are several types of bipolar depression or manic depression, which typically involves a mood shift rotation of manic and depressive episodes. Bipolar depression is generally more complicated in resolution over major depression.

4. Depressive Psychosis

Depressive psychosis is major depression along with delusions and hallucinations detaching from reality.

5. Perinatal Depression: (Postpartum Depression)

This is depression occurring within the month prior to or after childbirth. Women with a history of depression are more at risk.

6. Premenstrual Dysphoric Disorder: (PMDD)

PMDD is a severe form of premenstrual syndrome (PMS).

7. Seasonal Depression: (Seasonal Affective Disorder or SAD)

SAD is officially called depressive disorder with a seasonal pattern which is depression triggered during winter months lacking sunlight. Light therapy is exceptionally effective for SAD, as the primary therapy. Light therapy machines are available in blue and white light.

8. Situational Depression

Also known as adjustment disorder with depressed mood, it is depression triggered by a specific event or situation such as a death in the family or financial struggles.

9. Atypical Depression

This is depression which resolves itself because of positive outcomes. It can come along with major depression and/or chronic depression. You might not even feel or seem depressed to yourself and others around you.

Types of Antidepressants: (The Sad News: SSRI Drugs and CBT)

Despite a lack of proven efficacy, along with benefits outweighing the risks, antidepressants (SSRIs) remain the first-line depression treatment for depression.

Even though SSRIs have been tremendously controversial for decades, with many researchers asserting SSRIs do not outperform placebo, and can have adverse short- and long-term effects, they are still prescribed.

While SSRIs were more effective over placebo against depression symptoms, their benefits were not clinically relevant as the symptom size reduction did meet the researchers’ guidelines.

Researchers claim SSRI risks are much higher with their benefits are much smaller than reported, with poor study design, poor statistical analysis method, and publication bias.

Cognitive-behavioral therapy (CBT), helpful in various studies, is the other first-line depression treatment, but is not a reliable treatment option because of cost and lack of access, along with uncertainty over its effectiveness.

Side Effects of Antidepressants: Anhedonia, PSSD, Tardive Dysphoria


With the various short- and long-term SSRI side effects, it is reasonable to ask if SSRIs worsen the course of depression in the long-term.


SSRIs may improve anhedonia, the loss of interest and pleasure, but SSRIs may also block emotions and make anhedonia worse.

Anhedonia may also occur because of an array of other causes such as the abuse of recreational drugs, stress, anxiety, and other medications, such as antipsychotics.


Only recently recognized as an official diagnosis, post-SSRI sexual dysfunction (PSSD), is the long term sexual dysfunction associated with long term SSRI use.

PSSD as a condition causes patients to experience sexual side effects after the termination of SSRI use.

Tardive Dysphoria

Tardive dysphoria is a treatment-resistant chronically depressive condition occurring in those exposed to SSRIs for prolonged periods of time.

Tardive dysphoria presents as a chronic dysphoric condition initially relieved by SSRIs in the short-term, only to become unresponsive to this chronically depressed state.

While more typical with antipsychotics, tardive dysphoria can still occur with some SSRIs.

18 Mood-Boosting Strategies and Treatments: (COMT and MAO-A Enzymes)

While CBT remains inaccessible to all, we should consider other depression strategies that may or may not offer greater accessibility and affordability worldwide.

1. Acupuncture

Increases: dopamine, GABA, opioid, serotonin. Decreases: glutamate, norepinephrine.

2. Catecholamine Foods

Citrus, caffeine, cocoa, coffee, black tea, green tea, berries, bananas, red wine, act to slow down the COMT enzyme. This might not be optimal for those with a slow COMT and/or anxiety.

3. Check Hormone Levels

Estrogen and testosterone can affect COMT and MAO-A enzymes and thus both depression and anxiety. DHEA and pregnenolone are effective for mood disorders when levels are low.

4. Chronotherapy (Sleep Deprivation)

Triple chronotherapy is more effective than exercise. Restores circadian rhythm along with dopamine and serotonin function.

5. Cold Therapy

Increases endorphins and norepinephrine. A 2 to 5 minute cold shower has shown benefit. Also effective for anxiety.

6. Dark Room at Night-Time

Blue-light-blockers and reduction of screen time.

7. Dietary Fiber

Dietary fiber can lower estrogen levels in men and women. Denser gut microflora is likely a bigger role player with lowering anxiety than depression, because of its believed effect on speeding up the COMT and MAO-A enzyme. It could still play a role in depression.

8. Exercise

Slows down COMT and MAO-A. Equally effective to medication and more effective than cognitive behavior therapy. The best combination appears as cardio with weight training. BDNF, dopamine, endorphins, norepinephrine, and serotonin. HPA axis and inflammation benefits.

9. High Protein Diet and/or Regular Protein Snacks

Tyrosine-rich protein increases dopamine, epinephrine, and norepinephrine. This serves to slow down the COMT and MAO-A enzymes. This may or may not be optimal as a strategy for those with anxiety.

10. Infrared Sauna

Heat therapy increases endorphins.

11. Improve Sleep Quality

Earlier and Regular Bedtime. Avoid evening alcohol, caffeine, and heavy meals. Cool and darkroom at night-time. Use a sleep tracking app or the Oura Ring.

12. Intermittent Fasting

Daily intermittent fasting inhibits the COMT enzyme, making it ideal for a fast COMT enzyme. This could speed up the MAO-A enzyme. If you experience carb cravings on the ketogenic diet, HIIT exercise, or intermittent fasting, this could indicate a fast MAO-A.

13. Light Therapy

Seasonal Affective Disorder SAD. Possibly effective for all depression types within or separate from chronotherapy.

14. Lower Inflammation and Stress and Detoxification

Avoid simple carbohydrates and chronic stress and stressful situations. Have a regular detox routine.

15. Deep Breathing (Wim Hof)/ Meditation/ Self-hypnosis

Also effective for anxiety. Increases GABA. Lowers cortisol and norepinephrine. Moves body from “fight-or-flight” sympathetic nervous system to “rest-and-digest” parasympathetic nervous system response.

16. Neurofeedback/ DBS/ MST/ rTMS/ TMS/ PBM/ Vagus Nerve Stimulation (VNS)

Controversial and in the early stages of research. Increase of blood flow, HPA axis improvement, and improvement of neurotransmitter balance.

17. Sunlight

Increases dopamine, endorphins, serotonin. Also beneficial for bipolar depression. We find individuals with depression to have 1/8th lower vitamin D levels on average.

18. Yoga

Increases BDNF, GABA, endorphins, and serotonin. Lowers cortisol. Also effective for other mood disorders such as anxiety and PTSD.

***The best evidence exists to support light and sunlight therapy, sleep quality, meditation, yoga, and exercise for depression lifestyle strategies.

Psychedelic Therapy for Depression: (Ketamine and Psilocybin Mushrooms)

Treatment resistance along with the side effects of antidepressants is common with SSRI drugs, which lowers their more widespread use.

In response to the relative ineffectiveness of SSRI drugs, psychedelics continue emerging throughout the world as an exciting class of atypical types of antidepressants as medications for depression and anxiety.

Psychedelics continue trending in the news as new types of antidepressants for mood disorders, as we hear more and more about ketamine and psilocybin mushrooms for severe mood disorders.

The anesthetic dissociative ketamine is already in medical use in off-label use for treatment-resistant major depression.

Recently, the FDA granted approval for psilocybin mushrooms, a second breakthrough therapy designation for treatment-resistant depression.

MDMA, otherwise known as ecstasy, is in its last stages of clinical trials for PTSD.

Other psychedelics being studied as medications for depression and anxiety are as LSD, mescaline, 5-MeO-DMT, 5-MeO-DMT, ayahuasca, and ibogaine are also getting attention as mood disorder treatments.

While many discuss micro-dosing psychedelics, the research shows the “flood dose” or full dose under the guidance of a trained therapist, which is where things could likely head, as guided psychedelic therapy.

Conclusions on the Best Antidepressants


We discussed supplements in the first part of this series.

In part two, we looked at the theories of depression, the various treatment targets, and the best strategies.

Why do we spend so much time discussing these “targets”, and strategies?

The answer is simple.

As someone who has lived with what felt like dark depression, which would never end, the biggest realization is our mood can be looked at as a symptom of a cause.

I encourage people struggling with depression to do three things right now.

  1. Start Talking About It:

TALK about it publicly, or at least with those you trust. Most of them will not understand what you are experiencing, because how could they unless they have experienced it themselves. Acceptance is where healing can begin. Not their acceptance of you, but your acceptance of yourself. It is okay to fall into the river. It is not okay to not begin the process of getting yourself out.

2. Think in Root Cause or Causes:

WHAT is causing me to feel this way? We want to identify the root cause or causes and address the source of the problem, rather than crudely, and archaically manage the symptoms. This is the difference between taking dead aim at the bullseye versus firing arrows in the ocean blindfolded and hoping we “might” hit something. Now, this can be difficult with something as subjective as depression and mood disorders, but I can assure you, we can determine the actual cause. And if your doctor can’t tell you or even take an educated guess, then maybe getting a second opinion from a naturopathic or functional medicine specialist and/ or coach is something to consider.

3. Total Treatment:

Begin thinking in foundational depression treatment. If we eat a garbage diet, we are going to feel like garbage. Pretty simple connection here, right? Well, it can be more than just this. Yes, supplements and/ or medications can be helpful, but for many, only doing this can often lead to LIMITED results. Just as a table is supported by 4 legs, my depression protocol has 4 parts, and experience shows they are all equally important.

And if you are thinking how would I know what is causing this, then this is a good starting point.

What have you tried or what will you try doing next?

Have you tried serotonin raising supplements?

If you have and they have had little to no effect, then we can cross that target off of your list and move onto the next root cause explanation.

Why would one keep pushing on that same button?

Albert Einstein famously said, “the definition of insanity is doing the same thing over and over and expecting different results.”

[Related Article: My Favorite Mood and Cognitive Boosters]

[Related Article: My Favorite Biohacks]

Making sense?

“Breathe and Believe.”

“From the Ashes, We Rise!”

What’s your favorite depression strategy

Your Friend in Health

Mark Stein

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