Understanding & Conquering Depression

Pleasure-​​Pain Balance

• Crucial for understanding mood disorders and motivation
• Pleasure system directly associated with psychological anguish and pain
• Pursuit of pleasure releases dopamine, increasing motivation and drive
• Balance shifts, causing less dopamine release and more craving each time
• Constant pursuit of pleasure leads to addiction and depression
• Resetting the balance requires entering states of boredom or non-pleasure-seeking

Real-​​Life Example

• 21-​​year-​​old man experiences depression due to disruption in pleasure-​​pain balance
• Ongoing pursuit of a particular activity led to less dopamine and more pain
• Treatment involves rebalancing the pleasure-​​pain pathway

Importance of Healthy Gut Microbiome

• Vital for a healthy immune system and gut-​​brain axis
• Proper probiotics facilitate a healthy gut microbiome
• Athletic Greens provides vitamins, minerals, and probiotics for a healthy gut

High-​​Quality Meat and Omega‑3 Fatty Acids

• Belcampo provides organic, grass-​​fed, and humanely raised meats
• High levels of omega‑3 fatty acids are vital for mood, cardiovascular health, and maintaining a healthy inflammatory response

Depression Types

• Major depression: distinguished from bipolar depression
  Bipolar Depression vs. Major Depression

• Bipolar depression: characterized by manic highs and lows 
  • Manic episodes: lack of sleep, fast talking, impulsive behavior
  • Depressive episodes: feeling low, lethargic
• Major depression (unipolar depression): characterized by lows 
  • Affects 5% of the population
  • Number four cause of disability

Diagnosing Major Depression

• Language and behavior are key tools for diagnosis
• Criteria for major depression: 
  • Presence of grief and sadness
  • Lower threshold to cry
  • Anhedonia: lack of ability to enjoy things previously enjoyed
  • Guilt: feeling guilty about past actions or general self-worth
  • Delusional thinking and anti-​​self confabulation: creating negative stories about oneself that don’t match reality
  • Vegetative symptoms: exhaustion, disrupted sleep patterns (early waking)

Important Note

• Accurate diagnosis should be done by a qualified healthcare professional
• Do not self-​​diagnose based on symptoms mentioned in this discussion 

Sleep and Depression

• Sleep architecture disrupted in depression< 
• Early in the night: more slow-​​wave sleep than REM sleep
• As night progresses: more REM sleep
• Disruptions in sleep patterns and brain activity during sleep in depression
• Waking up early and not being able to fall back asleep is a common symptom

Appetite and Depression

• Decreased appetite could be due to anhedonia (lack of pleasure from food)
• Hormones associated with appetite (hypocretin/​​orexin, ghrelin) could be disrupted

Depression and Anxiety

• Exhaustion and lethargy do not necessarily mean an absence of anxiety
• Anxiety about future, goals, and escaping depressive state can be present

Biology of Depression

• Early drugs for depression: tricyclic antidepressants and monoamine oxidase (MAO) inhibitors
• Worked by increasing levels of norepinephrine in the brain
• Side effects: blood pressure, libido, sleep, appetite, weight gain
• Pleasure pathways in the brain: nucleus accumbens and ventral tegmental area
• Rich with dopamine-​​producing neurons
• Disruption in dopamine pathway in depression
• SSRIs (selective serotonin reuptake inhibitors) discovered in the 1980s
• Prevent serotonin from being cleared from the synapse, increasing its efficacy
• Side effects vary among individuals and over time
• About a third of people don’t derive benefit from SSRIs, but they have saved and improved many lives
  Mysteries of SSRIs and Neuroplasticity
• SSRIs increase serotonin efficacy at the synapse 
  • Relief from depression symptoms usually occurs two weeks after starting SSRIs
• SSRIs may improve depression symptoms through neuroplasticity 
  • Changing neural circuits function
• Two main categories of studies on SSRIs and neuroplasticity: 
  1. SSRIs might trigger the production of more neurons in the brain, particularly in the hippocampus
  2. SSRIs have been shown to reopen critical periods of plasticity

Chemistry of Depression

• Norepinephrine, dopamine, and serotonin are major chemical systems related to depression 
  • Norepinephrine: related to psychomotor defects (lethargy, exhaustion)
  • Dopamine: related to anhedonia (lack of ability to experience pleasure)
  • Serotonin: related to grief, guilt, and emotional aspects of depression
• Pain is also involved in depression 
  • Substance P: manufactured by neurons, underlies sensation of pain
  • Substance P inhibitors have been used to treat depression

Hormones and Depression

• 20% of people with major depression have low thyroid hormone 
  • Low thyroid hormone leads to low energy and low metabolism
• Conditions that can impact thyroid hormone system and depression: 
  • Childbirth (postpartum depression)
  • Menstrual cycle
  • Menopause and postmenopausal women
• Cortisol hormone also plays a role in depression 
  • More stress is correlated with more bouts of major depression
  • Controlling stress system can help avoid depression

Genetics and Predispositions to Depression

• Genetic predispositions can play a role in susceptibility to depression
• Learning to control stress system can help reduce the risk of depression, regardless of genetic predisposition
  Stress, Depression, and Genetics
• Stress can lead to depression 
  • Stress system releases cortisol, impacting neuromodulators (dopamine, norepinephrine, serotonin)
  • Latent or longer-​​lasting impact on mood and well-being
• Importance of controlling stress to offset depression 
  • Genetic predisposition to depression 
    • 5‑HTTLPR gene: serotonin transporter
    • Polymorphism increases susceptibility to depression under stress
• Strong genetic component to depression 
  • Identical twins: 50% probability of depression if one twin has it
  • Fraternal twins: lower probability
  • Siblings: 25% probability
  • Half-​​siblings: 10% probability
• Mitigating stress is crucial for those with a genetic predisposition to depression

Tools to Alleviate Depression

• Behavioral tools can adjust levels of chemicals related to depression 
  • Cold showers: release norepinephrine and epinephrine
  • Exercise: increases norepinephrine, dopamine, and serotonin
• Prescription drugs and supplementation may be necessary for those who cannot access behavioral tools due to the severity of their depression
• Consult a physician before adding or subtracting any tools, supplements, or drugs

Inflammation, Immune System, and Depression

• Growing evidence linking depression to excessive inflammation 
  • Inflammation is important for wound healing and immune system function
  • Excessive inflammation may contribute to depression
    Inflammation and Depression
• Inflammation can lead to or exacerbate depression 
• Chronic stress can cause inflammation in the brain and body
• Inflammatory cytokines (e.g., IL‑6, TNF alpha, C‑reactive protein) are major players in creating chronic inflammation

Reducing Inflammation to Combat Depression

• Increasing intake of essential fatty acids (EPA) can help relieve depressive symptoms 
  • Studies show relief from depressive symptoms matches SSRIs
  • 1000 mg of EPA seems to be the critical threshold for benefiting from its effects
• Exercise also has a positive effect on reducing inflammation and combating depression

Serotonin and Tryptophan

• Serotonin is important for maintaining a healthy mood
• Tryptophan is an amino acid found in food and is a precursor to serotonin
• Inflammation can cause tryptophan to be diverted into a neurotoxic pathway, leading to depression

EPA and Exercise Impact on Serotonin

• Ingesting EPA limits inflammation, promoting the conversion of tryptophan into serotonin
• Exercise sequesters the neurotoxin that would lead to depression, promoting the conversion of tryptophan into serotonin

Recommendations

• Talk to a doctor about incorporating EPA and exercise into a depression treatment plan
• For those not suffering from depression, understanding these pathways can provide motivation for regular exercise and EPA intake
  EPA and DHA in Depression
• Debate about the ideal ratio of EPA and DHA 
• DHA may impact LDL (bad cholesterol)
• Positive effects of taking 1000–2000 mg of EPA per day
• Examine​.com lists 28 studies on EPA and major depression
• Study: “EPA but not DHA, appears to be responsible for the efficacy of omega‑3 long chain polyunsaturated fatty acid supplementation in depression” by Julian Martins (2009)

Creatine in Depression

• Creatine has important functions in the body, including increasing power output in muscles
• Phosphocreatine system in the brain involved in mood regulation and depression
• Creatine supplementation (3–5 grams per day) shown to improve mood and treat depression
• American Journal of Psychiatry (2012) study: Creatine monohydrate can enhance response to SSRIs in women with major depressive disorder
• Creatine may increase mania in people already experiencing mania

NMDA Receptors and Depression

• NMDA receptor is a key node for neuroplasticity and changing brain circuitry
• Creatine supplementation may affect NMDA receptor function, leading to changes in neural circuits and mood improvement
• NMDA receptor is a target for novel therapeutics in psychiatric clinics

Ketamine and PCP in Depression

• Both are known drugs of abuse, creating dissociative anesthetic states
• Clinicians are exploring their use for depression treatment
• More data needed to understand their effects on NMDA receptors and depression treatment
  Dissociative States and Depression Treatment
• Paper by Sam Vasuna and Dr. Carl Dysroff in Nature (2021)
  • Explored dissociative states in animals and humans
  • Found a common mechanism in layer five neurons of the neocortex
  • Activation of retrosplenial cortex after ketamine or PCP administration
• Dissociative states may help separate patients from their grief and emotions 
  • Possible neural circuitry shifts, reducing the burden of emotions
• Ketamine trials show promising results for depression treatment 
  • Relief from symptoms without many treatments
  • Works on NMDA receptor related to neuroplasticity

Ketamine and Neuroplasticity

• Study in Science (2019) by Liston 
  • Ketamine can relieve depressive symptoms rapidly by increasing spines on neurons in the prefrontal cortex
  • Spine formation is synonymous with neuroplasticity, circuit function changes, and changes in thoughts, feelings, and behaviors
• Layer five activity in the cortex may be important for rewiring the brain to alleviate depression symptoms 
  • Still experimental and cutting-​​edge research

Psilocybin and Depression Treatment

• Psilocybin, a psychedelic compound, is being actively pursued for its capacity to treat major depressive disorder
• Focuses on rewiring neural circuitry for better functioning and long-​​term remission from depression
  Psilocybin and Depression
• Clinical studies conducted in university settings and hospitals 
• Researchers include Matthew Johnson (Johns Hopkins), Patrick Finn, Roland Griffiths, etc.
• Psilocybin works on serotonin 5‑HT2A receptor and 5‑HT1 receptor 
  • Serotonin can have diverse effects on different cells and tissues due to the variety of receptors
• Study published in JAMA Psychiatry (May 2021): Effects of Psilocybin Assisted Therapy on Major Depressive Disorder 
  • Screened patients with major depressive disorder
  • Administered one or two rounds of psilocybin (dosages based on body weight)
  • Significant improvement in mood and relief from depressive symptoms in 50–70% of subjects
  • Psilocybin may soon become a treatment for various forms of depression

Psilocybin Experience and Relief from Depression

• Different people can have varied experiences and still receive benefit from psilocybin
• Psilocybin rewires neural circuitry in a common way despite the diversity of experiences
• 5‑HT1A receptor is enriched in layer 5 of the cortex, which has a lot of lateral connectivity 
  • Activation of serotonin system in 5‑HT1A receptor allows for broader engagement of lateral connections
• Psilocybin rewires associations between emotional events, past events, current events, and future events 
  • Allows people to gain relief or distance from depressive narratives and see new opportunities for optimism

Microdosing vs. Macrodosing

• Microdosing effects don’t seem to be as impactful as macrodosing (high amplitude sessions)
• Macrodosing involves dosages of 20mg per 70kg or 30mg per 70kg body weight, given a few weeks apart

Ketamine vs. Psilocybin

• Both involve neuroplasticity, layer 5 of the cortex, and rewiring of circuitry
• Ketamine: dissociating from experience during the session with the psychiatrist
• Psilocybin: immersing oneself in the experience and being fully present
• Both provide relief from major depression, but the exact differences are unclear
• Major depression likely involves serotonin, dopamine, and norepinephrine
  Psilocybin, MDMA, and Diet in Depression
• Psilocybin: most data on its use for major depression treatment 
• MDMA: mainly explored for trauma treatment, some trials for depression
• Diet and nutrition related to major depressive disorder 
  • Carbohydrates and tryptophan-​​rich foods can increase serotonin levels
  • Overeating any type of food is unhealthy

Vegan, Carnivore, and Ketogenic Diets

• Vegan diet: not much data on its effect on depression
• Carnivore diet: few controlled studies, some starting to emerge
• Ketogenic diet: most data available, can help maintain euthymia (balance between manic and depressive episodes) 
  • Originally used to treat epilepsy by increasing GABA transmission
  • Can help reduce depressive symptoms in people who don’t respond to classical antidepressants
  • May improve the ability for antidepressants to work at lower dosages

Summary of Tools for Depression

1. Don’t overwhelm pleasure centers: overindulgence in pleasurable activities or substances can lead to anhedonia and depression
2. Engage in norepinephrine-​​inducing activities: cold showers, breathing exercises, and regular exercise can help maintain a healthy norepinephrine system and improve mood
   EPAs and Mood
3. Essential fatty acids (EPAs) can be beneficial for mood 
4. 1000–2000 mg per day can help treat or offset major depressive disorder
5. Side effects vary; consult with a physician

Exercise and Inflammation

• Regular exercise and EPA intake can offset inflammatory pathways
• Inflammation can limit serotonin production

Fermented Foods

• 2–4 servings of fermented foods daily can maintain gut microbiome health
• Reduces inflammation and supports mood regulation
• Study by Sonnenberg Lab at Stanford published in Cell Press Journal

Creatine and Depression

• Creatine may provide relief from depression or prevent relapse
• Prescription compounds and study-​​based treatments include ketamine, PCP, psilocybin, and related compounds

Ketosis

• May not be suitable for everyone, but could benefit some individuals grappling with depression