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Understanding & Conquering Depression

Key Takeaways

  • Pain and pleasure system is a scale: if you overwhelm the pleasure system, you will set yourself up for anhedonia (lack of enjoyment) and depression

  • Daily EPA above 1,000mg per day can be beneficial for mood and offset inflammatory pathways

  • Depression interventions to change biological function: exercise, ingesting EPAs, reducing inflammation, Selective serotonin reuptake inhibitors (SSRIs)

  • Ketamine and psilocybin take unique paths but focus on rewiring circuitry to function better in the future

  • The ketogenic diet has been explored for potential relief of depressive symptoms by modulating GABBA – particularly in those who do not respond to pharmaceutical treatment

Pleasure-Pain Scale

  • The pleasure system is the same pathway that modulates mental anguish and pain

  • When we pursue anything that we think will bring us pleasure, we experience a release of dopamine

  • Dopamine is the molecule of craving and drive

  • As we experience pleasure there’s a tilt on the scale of pain-pleasure and we crave more of the thing that brought us pleasure

  • If we remain in constant pursuit of pleasure, we’ll achieve less dopamine release every time while the amount of pain increases

  • To reset the balance, enter states of boredom which might even increase anxiety

  • Always be cautious of any state of mind or body that leads to any significant increase in dopamine release

  • Pain relievers can help people with emotional pain

  • A lot of people with depression are more sensitive to physical pain


  • Characterized by lows – in contrast to bipolar depression, which has a manic state followed by a crash

  • Depression affects us on a conscious level and subconscious (sleep, appetite, hormone)

  • Major depression impacts 5% of the population

  • Depression is the 4th largest cause of disability

  • There’s a significant challenge in diagnosing depression because the tool used to diagnose is language

  • Criteria of possible depression: grief, threshold to cry (when you didn’t previously cry), anhedonia (lack of enjoyment), guilt, confabulation, self-deprecation that doesn’t align with reality, vegetative symptoms, decreased appetite

  • At least three major chemical pathways in the brain relate to depression: norepinephrine, serotonin, dopamine

  • Norepinephrine relates to the lethargy and exhaustion

  • Dopamine relates to the anhedonia

  • Serotonin relates to the grief, guilt, and more cognitive effects of depression

Sleep & Depression

  • The architecture of sleep is disrupted during depression

  • The pattern of activity in the brain during sleep is disrupted

  • Sleep marker of depression: early waking without being able to fall back asleep

  • 9 pm peak in cortisol is signature of depression

Popular Pharmaceutical Treatments

  • Tricyclic antidepressants & MAO inhibitors increase norepinephrine in the brain

  • Side effects: impact libido, appetite, digestion, blood pressure

  • Selective serotonin reuptake inhibitor (SSRI): prevent serotonin from being wiped up by synapse; increase the efficacy of serotonin at the synapse not the amount of serotonin

  • Side effects: only works in about 1/3 of depression patients and can take about two weeks to kick in

Hormones & Stress

  • 20% of people with depression have low thyroid function

  • There are symptoms of hormonal dysfunction that can make people more susceptible to depression or make underlying depression worse

  • Women may experience symptoms of depression during the menstrual cycle, pre- and post-menopausal, post-partum

  • One of the best things you can do to stave off depression is control stress levels and particularly long term stress

  • There is a genetic disposition to stress – particularly a gene that regulates how much serotonin is in the brain under conditions of stress

  • Genetic disposition doesn’t mean you will get depression, but it will take far fewer bouts of intense stress to induce depression

  • The more closely related you are to someone with major depression, the more likely you are to get major depression

Exercise For Depression

  • Exercise increases the norepinephrine in the body

  • Regular exercise is a protective behavior of depression and can alleviate symptoms of depression

  • Double-edged sword of exercise & depression: exercise can be protective and alleviate symptoms but depending on how far along you are, apathy can take over and inhibit you from moving at all

  • People with depression can’t access circuits of happiness, motivation, movement, etc. in the same way people without depression can

  • Exercise has a positive effect on the tryptophan-serotonin pathway by sequestering pro-depressive effects on the pathway, essentially limiting bad pathway

  • Exercise dose: 150-180 minutes exercise per week

Inflammation, Nutrition & The Immune System

  • There is an abundance of evidence pointing to excessive inflammation as a precursor or exacerbator of depression

  • People who are depressed have more of an appetite for carbohydrates because they are trying to get more tryptophan which is eventually converted into serotonin

  • Supplement to limit inflammation and relieve some symptoms of major depression: increase intake of essential fatty acids – critical threshold level: 1,000 mg EPA (not DHA, read more here)

  • The phosphocreatine system in the brain has been shown to be involved in the regulation of mood pathways

  • Creatine (monohydrate): improve mood and symptoms of major depression (dose 1g – 5g)

  • A caveat with creatine supplementation: shown to increase mania in people who are already manic – but this same thing could be helpful for people with major depression (not bipolar)

  • Keto diet has been explored for potential relief of depressive symptoms by modulating gabba – particularly in those who do not respond to pharmaceutical treatment

NMDA Receptor As Therapeutic Target

  • Ketamine and PCP act as antagonists, blocking NMDA receptor

  • Dissociation induced by PCP and ketamine may lead to shifts in circuity and plasticity so depression doesn’t feel as heavy

  • Ketamine changes the spines of neurons in the prefrontal cortex

  • People who are depressed and take ketamine experience separateness from grief and emotions

  • Take ketamine with psychiatrist guiding experience

  • Ketamine may be increasing neuroplasticity through dissociative states

Psilocybin For Depressive Disorder

  • Significant improvement in depressive symptoms, mood, and affect in 50-70% of study participants who received psilocybin treatment

  • Read more: Recent study on the clinical use of psilocybin for the treatment of depression

  • It’s critical to have a highly trained guide and medical monitoring devices where relevant

  • There are common themes to psilocybin experience that lead to a therapeutic outcome, but people can have different experiences and still benefit

  • Microdosing effects don’t seem to be as impactful as bigger sessions given several weeks apart

  • Ketamine versus psilocybin: ketamine is about dissociating from oneself during the experience; psilocybin is about diving into oneself