We are in the midst of a global mental health crisis, and mental illnesses are on the rise. But what causes mental illness? And why are mental health problems so hard to treat? Drawing on decades of research, Harvard psychiatrist Dr. Chris Palmer outlines a revolutionary new understanding that for the first time unites our existing knowledge about mental illness within a single framework: Mental disorders are metabolic disorders of the brain.
Brain Energy explains this new understanding of mental illness in detail, from symptoms and risk factors to what is happening in brain cells. Palmer also sheds light on the new treatment pathways this theory opens up—which apply to all mental disorders, including anxiety, depression, ADHD, alcoholism, eating disorders, bipolar disorder, autism, and even schizophrenia. Brain Energy pairs cutting-edge science with practical advice and strategies to help people reclaim their mental health.
This groundbreaking book reveals:
- Why classifying mental disorders as "separate" conditions is misleading
- The clear connections between mental illness and disorders linked to metabolism, including diabetes, heart attacks, strokes, pain disorders, obesity, Alzheimer's disease, and epilepsy
- The link between metabolism and every factor known to play a role in mental health, including genetics, inflammation, hormones, neurotransmitters, sleep, stress, and trauma
- The evidence that current mental health treatments, including both medications and therapies, likely work by affecting metabolism
- New treatments available today that readers can use to promote long-term healing
Palmer puts together the pieces of the mental illness puzzle to provide answers and offer hope. Brain Energy will transform the field of mental health, and the lives of countless people around the world. Brain Energy: A Revolutionary Breakthrough in Understanding Mental Health--and Improving Treatment for Anxiety, Depression, OCD, PTSD, and More
- Introduction
- Part I: Connecting the Dots
- Part II: Brain Energy
- Part III: Causes and Solutions
- Chapter 9: What’s Causing the Problem and What Can We Do?
- Chapter 10: Contributing Cause: Genetics and Epigenetics
- Chapter 11: Contributing Cause: Chemical Imbalances, Neurotransmitters, and Medications
- Chapter 12: Contributing Cause: Hormones and Metabolic Regulators
- Chapter 13: Contributing Cause: Inflammation
- Chapter 14: Contributing Cause: Sleep, Light, and Circadian Rhythms
- Chapter 15: Contributing Cause: Food, Fasting, and Your Gut
- Chapter 16: Contributing Cause: Drugs and Alcohol
- Chapter 17: Contributing Cause: Physical Activity
- Chapter 18: Contributing Cause: Love, Adversity, and Purpose in Life
- Chapter 19: Why Do Current Treatments Work?
- Chapter 20: Putting It All Together: Developing Your Metabolic Treatment Plan
- Chapter 21: A New Day for Mental and Metabolic Health
Introduction:
- Patient question about cause of mental illness
- Personal experiences: feeling like a fraud, lack of progress in treating mental illness
- Helping a patient lose weight leads to breakthrough in understanding the connection between diet and psychiatric symptoms
- Ketogenic diet's effect on schizoaffective disorder
- Discovery of ketogenic diet as an evidence-based treatment for epilepsy
- Expansion of research and collaboration with colleagues
- Unifying theory for mental illness: brain energy theory
Background:
- Problem in mental health field: understanding causes of mental illness, limited progress in treatments
- Personal experiences: feeling helpless, patients not making significant improvements
Breakthrough:
- Helping a patient lose weight with the ketogenic diet
- Dramatic changes in psychiatric symptoms and overall wellbeing
- Realization that ketogenic diet could be connected to epilepsy treatments used in psychiatry
Research:
- Diving deeper into medical literature
- Discovering the effectiveness of the ketogenic diet for various disorders: epilepsy, obesity, diabetes, Alzheimer's disease
- Uncovering connections between these different conditions and integrating new understanding with existing knowledge as a neuroscientist and psychiatrist.
Goals:
- Not a book about ketogenic diet or any specific treatment for mental illness
- Transformative understanding of mental health and illness
- Sharing the unifying theory: brain energy theory.
Understanding Mental Disorders: A New Perspective
Key Takeaways:
- Mental disorders are not distinct entities: Overlapping symptoms exist between various disorders like depression, anxiety, PTSD, etc. Many individuals are diagnosed with multiple mental disorders.
- Connections between mental and physical disorders: Explored connections between mental illnesses and conditions such as obesity, diabetes, heart attacks, strokes, pain disorders, Alzheimer's disease, epilepsy, etc.
- Mental disorders are metabolic disorders of the brain: Mental states, even normal ones, relate to metabolism; all known contributing factors impact metabolism and mitochondria.
Metabolism and Mitochondria:
- Key to understanding mental illness: Simple explanation with focus on mitochondria's role in metabolism.
- Normal mental states vs. mental disorders: Anxiety, depression, fear are normal but become problematic when occurring at wrong times or excessively.
Mechanisms of Action:
- Five broad mechanisms explained to understand clinical and neuroscientific observations in all mental disorders.
Contributing Factors:
- Genetics, inflammation, neurotransmitters, hormones, sleep, alcohol and drugs, love, heartbreak, meaning and purpose in life, trauma, loneliness, etc., linked to effects on metabolism and mitochondria.
Current Treatments:
- Psychological, social treatments may affect metabolism for healing rather than just symptom reduction.
New Understanding:
- Offers long-elusive answers and new solutions for mental illness treatment.
- Integrates existing biological, psychological, and social research into one unifying framework.
Mental Health Statistics
Prevalence of Mental Disorders (2017)
- Nearly 800 million people (10% of global population) suffered from mental health disorders
- Anxiety disorders affected about 3.8% of the world's population
- Depression affected about 3.4% of the world's population
- When substance use disorders are included, the number rises to 970 million people (13% of global population)
Mental Health Statistics in the United States
- Approximately 20% or one in five people diagnosed with a mental disorder
- Lifetime prevalence rates are much higher, with about 50% of the US population expected to meet criteria for a mental disorder at some point in their lives
- Mental illness rates are on the rise in the United States
Challenges in Estimating Prevalence Rates
- People often deny or minimize mental health problems due to stigma and shame
- Societal perceptions of certain disorders vary (e.g., psychotic disorders, substance use disorders)
- Stigma can lead to underreporting and underdiagnosis
- Data on mental health disorders is complex and difficult to obtain accurately
Rising Rates of Specific Disorders in the United States
- ADHD: Increasing 41% from 2003 to 2012 among children four through seventeen
- Depression: Increased by 68% in children ages twelve to seventeen and 49% in adults eighteen to twenty-five between 2006 and 2017
- Burnout: Not an official DSM diagnosis, but prevalence estimated at 23% among US employees based on a Gallup poll (higher than depression rates)
- Suicide: Increasing across most age groups in the United States with nearly 45,000 deaths in 2016 and over one million reported suicide attempts per year.
Conclusion: Mental health disorders remain widespread, and prevalence statistics may be underestimates due to stigma and other factors. The rates of specific mental health issues, such as ADHD, depression, burnout, and suicide, are increasing in the United States. Addressing these challenges requires continued efforts to destigmatize mental illnesses and improve access to accurate information and effective treatment.
Mental Disorders: Increasing Rates and Theories
Anxiety Disorders:
- More than doubled between 1999 and 2017
- Criteria for diagnosing evolve, making assessment difficult
- Some argue rates have not changed in recent years
- Annual household survey suggests increase from 2008 to 2018:
- 30% overall
- 84% for ages 18-25
Serious Mental Illness:
- Includes severe forms of depression, anxiety, schizophrenia, bipolar disorder, autism, etc.
- Increasing at an alarming rate:
- 21% increase between 2008 and 2017 for those over 18
- 100% doubling for ages 18-25 during the same period
Autism:
- Prevalence increased from 1 in 150 to 1 in 59 between 2000 and 2014
Bipolar Disorder:
- Prevalence increased from 0.4% to 7% between mid-1970s and early 2000s
- Increasingly common in children and adolescents
Theories on Increasing Mental Illness Rates:
- Pharmaceutical Companies: Trying to sell pills, leading to overdiagnosis
- Laziness: People want quick fixes, lack resilience
- New Generation of Kids: Pampered, lack discipline and perseverance
Conclusion:
- Assumptions about the causes of increasing mental illness rates are often oversimplified
- Real people behind statistics suffer from very real issues
Theories About the Increasing Rates of Mental Disorders (Second Category)
- Good thing:
- Reflects a broader understanding of mental disorders
- More awareness and identification
- Programs in schools, work environments to recognize symptoms
- Public service campaigns on suicide prevention
- Celebrities speaking out about their struggles
- Increased media coverage and reduced stigma
- Society:
- Increasing dependence on technology and screens
- Sedentary and isolated behavior
- Unrealistic expectations from social media
- Faster pace of life with busy schedules
- Lack of real-life connection
- Toxins, chemicals, and fake food:
- Exposure to toxins in everyday life
- Artificial ingredients in food
- New chemicals in personal care products and environment
- Unknown effects on health, including mental disorders
Additional Theories (Second Category)
- Genetics: Mutations leading to various disorders
- Trauma: Impact on mental health and disorders
- Lack of sleep: Role in mental disorder development
- Diet: Link between food choices and mental health
- Environment: Effects on mental wellbeing
Costs of Mental Disorders (Third Category)
- Financial toll: $2.5 trillion in 2010, expected to reach $6 trillion by 2030
- Direct costs: healthcare services and medications
- Indirect costs: lost productivity due to mental health issues
- Human suffering: misery, despair, ruined lives, social isolation, family chaos, domestic violence, homelessness, suicide
Mental Disorders and the COVID-19 Pandemic (Fourth Category)
- Increased rates of mental health struggles: 40% of US adults reporting issues in June 2020
- Financial costs to society: estimated $6 trillion by 2030.
Mental Health Suffering
Understanding Mental Disorders:
- People suffer alone in silence due to shame, lack of knowledge about symptoms, and belief that suffering is natural or unchangeable
- Example: Woman named "Mary" with a history of abuse and depression
Importance of Treatment:
- Can reduce suffering, prevent disability, restore dreams and potential, save lives
- Success stories exist, e.g., John's recovery from severe depression and anxiety
Challenges in Mental Health Treatment:
- Not effective for everyone or all the time
- Depression as a chronic, episodic illness:
- Only 10% of treated individuals fully recover
- Average of 59% symptom presence over 12 years
Conclusion:
- Mental health treatment is crucial, but its effectiveness is limited. Not every patient will achieve a full and lasting recovery.
Mental Health Treatment Effectiveness
Depression:
- Almost two-thirds of depressed patients don't experience remission
- Many suffer for years despite trying various treatments: medications, psychotherapy, group therapy, meditation, stress management, TMS, ECT
- Lack of long-term success with current treatments
Other Mental Disorders:
- OCD, autism, bipolar disorder, schizophrenia - Treatment success and chronicity similar to depression
- Many patients told they have lifelong disorders, lower expectations
Implications:
- Frustration among patients due to ineffective treatments
- Stigma and shame for those with mental disorders if they don't get better
- Importance of seeking help despite treatment limitations
- Encourage research on new solutions instead of relying solely on current methods.
Mental Health Research:
- Large financial investment in mental health research (NIH $3.2 billion)
- Lack of significant progress: no reduction in suicide, hospitalizations, or improvement for millions with mental illness
- Call for answering the question: "What causes mental illness?"
Dr. Tom Insel's Assessment:
- Failed to move the needle in reducing suicide, hospitalizations, or recovery for those with mental illness despite spending $20 billion on research.
What Causes Mental Illness and Why Does It Matter?
Ancient Theories:
- Mental illnesses were largely thought to be caused by supernatural forces
- Punishment from God was a common belief
- Demonic possession and exorcism were treatment choices
Modern Approaches:
- Mental illness as a medical disorder was born
- Hippocrates: Postulated mental illnesses could be due to an imbalance of vital fluids (humors)
- Freud: Viewed mental disorders as due to unconscious desires or conflicts
- Biopsychosocial Model: Biological, psychological, and social factors contribute to mental illness
- Diathesis-Stress Model: A biological predisposition with environmental stress as the trigger
Risk Factors:
- Trauma, drug/alcohol use, hormonal issues, family history of mental illness, etc.
- However, these factors do not guarantee the development of a specific disorder
- Example: PTSD - trauma alone does not cause it, but it is a risk factor
Mental Illness and Depression:
- Mild depression is normal, but major depression requires more in-depth analysis
- Major depression involves sadness/depression most of the time with other symptoms like fatigue and disrupted sleep.
Major Depression: Causes and Theories
Symptoms:
- Robbing of ability to experience pleasure and enjoyment from life
- Overwhelming feelings of hopelessness, even suicidal thoughts
- At least 5 symptoms for 2 weeks required for diagnosis
Risk Factors:
- Genetics/family history
- Stress, loss of loved ones, relationship conflict
- Hormonal issues: low thyroid hormone, high cortisol, menstruation
- Gender: women are more susceptible
- Substance abuse and certain medications
- Social issues: bullying, loneliness, poverty
- Physical illnesses: chronic pain, diabetes, heart disease, arthritis
- Cancer: pancreatic cancer may precede depression
- Neurological disorders: strokes, MS, Parkinson's, Alzheimer's, epilepsy
- Other psychiatric disorders: anxiety, bipolar disorder, borderline personality disorder
Theories:
- Chemical Imbalance Theory: neurotransmitter imbalance causes depression
- Serotonin levels may be low in some cases
- Questions raised: cause of chemical imbalance, inconsistent treatment effects
- Learned Helplessness Theory: powerlessness leads to depression
- People give up after facing adverse circumstances.
Major Depression: Causes and Treatments
Treatment Approach:
- Based on cognitive behavioral therapy (CBT)
- Identify and change thoughts, emotions, behaviors
- Belief that people become clinically depressed due to thoughts influenced by past helplessness
- Empower patients to challenge negative thoughts
- Replace with less dire and hopeless ones
- Reinforces positive cycle
Theories about Causes:
- Biological: antidepressants target neurotransmitters, serotonin, dopamine, norepinephrine
- Psychological: relationships, thoughts, feelings, behaviors
- Social factors also contribute
Treatment Options:
- Medications: antidepressants, anxiety medications, mood stabilizers, antipsychotics, stimulants, antiepileptic medications, hormones, vitamins, supplements like St. John's wort
- Psychotherapy: relationship focused, thoughts and feelings, behaviors; present or past focus
- More aggressive treatments: TMS, ECT, surgery (brain or vagus nerve stimulation)
Variability in Treatments:
- Doesn't work for all people with depression
- Different causes for different individuals
- Some people do not receive treatment despite symptoms persisting
Physical Changes Associated with Major Depression:
- Inflammation: higher levels of inflammatory markers like C-reactive protein and interleukins
- Brain changes: atrophy or shrinkage of specific brain regions, potentially neurodegenerative disorder
Brain Changes and Inflammation:
- Inflammation may cause depression or be a result of it
- Not everyone with chronic depression experiences inflammation consistently
- Research ongoing to determine the relationship between the two.
Major Depression: Understanding Causes and Brain Changes
Biopsychosocial Model of Major Depression:
- Many causes: biological, psychological, social factors
- No single cause for all cases
- Different types or clusters of symptoms may exist
Risk Factors (Biological):
- Altered brain activity and communication in depressed individuals
- Brain changes found through functional MRI scans
- Decreased activity in some regions, increased activity in others
- Limitations: relative differences between groups, cause or consequence unclear
Risk Factors (Psychological):
- Social stressors and psychological factors contribute to depression
- Symptoms may vary among individuals
- Struggle for decades to identify causes
Gut Microbiome:
- Emerging role in various disorders, including depression and anxiety
- Play a role in producing hormones, neurotransmitters, and inflammatory molecules
- Research is still ongoing on specific organisms and their impact on mental health
Importance of Identifying Causes:
- Syndromes: clusters of signs and symptoms with unknown causes
- Diagnosis based on symptoms reported by patients (subjective experiences)
- No objective tests or laboratory diagnoses for mental disorders
- Unifying theory needed to connect all evidence in a logical and plausible way.
The Challenge of Mental Health Care: A Syndrome Approach
Background:
- Medical example of AIDS as a syndrome before its identification as a virus
- Psychiatry's reliance on syndrome diagnosis
Diagnosis Exclusion:
- Neurological illnesses, cancers, infections, autoimmune diseases can affect the brain but are not psychiatric disorders
- Mental symptoms from these conditions are not necessarily diagnosed as psychiatric disorders
Progress in Mental Health Care:
- Lack of clear cause hinders progress
- Treatments focus on symptoms rather than root causes
Treatment Models:
- Disease-modifying treatments: Address the root cause, cure illness
- Symptomatic treatments: Reduce symptoms, do not change course of illness
Mental Health Field Applications:
- Most psychiatric treatments are symptomatic
- Medications, ECT, TMS: Reduce symptoms but don't address root cause for some individuals
- Psychotherapy and social interventions: Addressing some root causes but not others
Circular Logic in Mental Health Field:
- Misconceptions about causes of mental illness based on symptom relief or treatment effects
- Flawed reasoning from fever example: Fever caused by brain disorder, Tylenol affects the brain as well
Conclusion:
- Proper understanding of mental illness causes is essential for effective treatments addressing root cause.
Correlations, Causes, and Common Pathways
Determining the Cause of an Illness
- Correlational research looks for relationships between variables (correlations) to identify potential causes
- Examples: brain scans identifying inflammation in individuals with depression, epidemiology studies examining heart attacks and obesity
- Correlation does not necessarily imply causation
- Misinterpreting correlational studies can lead to incorrect assumptions about cause and effect relationships
Understanding the Cause of Illness
- Complications arise when trying to define the cause of complex conditions like mental illness
- Multiple risk factors contribute to various illnesses, including genetics, lifestyle choices, environmental factors, etc.
- Correlations can reveal common pathways or root causes
Correlation vs. Cause and Effect
- Correlations may indicate a relationship between two variables (causation or consequence)
- Correlational studies do not definitively establish cause-and-effect relationships
- Misinterpreting correlations can lead to misunderstandings about the nature of causality in research findings
Common Pathways and Root Causes
- Correlations can reveal shared mechanisms underlying various symptoms or conditions
- Understanding these common pathways is essential for developing effective interventions and treatments
- Example: runny noses and sore throats could be caused by several factors, including the cold virus, allergies, etc.
Research on Runny Noses and Sore Throats
Background:
- Difficulty distinguishing runny noses from allergies vs. colds based on symptoms alone
- Researchers must identify common pathways or root causes to understand the disorders
Symptom Clusters:
- Runny Nose Disorder
- Sore Throat Disorder
Characteristics:
- Different treatments (Tylenol vs. pseudoephedrine)
- Comorbidity is common, bidirectional relationship
Common Pathway:
- Inflammation as a result of immune system activation
Potential Diagnoses:
- Tylenol deficiency disorder for sore throat group
- Pseudoephedrine deficiency disorder for runny nose group
Root Causes:
- Cold virus or allergies (different root causes, same symptoms)
- Inflammation as a common pathway
Simplification of Explanation:
- Identifying common pathways or root causes simplifies diagnosis and treatment
- Occam's razor: simpler explanations are more likely to be true.
Mental Health and Causation of Mental Disorders:
Understanding the Complexity
- Mental illness: defined by symptoms, varying degrees and preexisting conditions
- Differences in responses to same cause (flu virus)
- Healthy individual vs. person with asthma or advanced age
- Importance of understanding physiology for effective treatments
Challenges in Proving Causation:
- Mental health field deals with syndromes and symptomatic treatments
- Ethical concerns: unethical to expose people to causes of serious/life-threatening disorders
- Use of animal research and scientific theories
Proving Causation through Research:
- Randomized controlled trials: proving cause-effect relationship (cold virus causing runny nose)
- Challenges in human studies for serious disorders
- Studying risk factors and looking for evidence of cascade events leading to mental illness.
Current State of Research:
- No definitive proof of causation of mental disorders
- Evidence gathered but not put together (what this book aims to do).
Chapter 3: Searching for a Common Pathway
Defining Mental Illness:
- Involves changes or abnormalities in emotions, cognition, motivation, and behaviors
- Resulting in distress or problems functioning in life
- Context, duration, and appropriateness are essential factors
Normal vs. Abnormal:
- Symptoms of mental illness can resemble normal emotions under certain circumstances
- Intensity, duration, and impact on daily function determine whether it is an illness
- Controversies exist regarding depression diagnosis in the context of grief or stressful life events
DSM (Diagnostic and Statistical Manual):
- Defines mental disorders with clear criteria
- Diagnostic labels important for clinical care, research, funding, and treatment development
- Debates over how to diagnose mental disorders due to lack of objective tests
Bereavement Exception in DSM:
- Removed from DSM-5 after controversy
- Clinicians previously held off on diagnosing depression during bereavement period
- Controversy: Should clinicians offer support or medication treatment?
Distinctions between Mental Disorders:
- Some distinctions are obvious (e.g., schizophrenia vs. anxiety disorder)
- Diagnostic labels crucial for clinical care, research funding, and treatment development
Importance of Diagnostic Labels:
- Inform treatment plans
- Understand different treatment options
- Discontinue treatments after a defined period of time (e.g., John's case)
- Critical for FDA approval of medications and psychotherapy studies.
Heterogeneity and Comorbidity in Mental Health:
- Heterogeneity: People diagnosed with same disorder have varying symptoms, severity, impact on functioning, and courses of illness
- Examples:
- Major Depression: Different symptom presentations (depressed mood vs. excessive sleep), different approaches to treatment (sleeping pills for one, not for another)
- Anxiety and depression: Overlapping diagnoses, common treatments
Diagnostic Criteria:
- Lack of understanding and poor treatment outcomes in mental health field due to heterogeneity
- Calls for rethinking diagnostic criteria for major depression (e.g., inclusion of anxiety, irritability, pain)
Comorbidity:
- About half of people diagnosed with a mental disorder have more than one disorder simultaneously
- Examples: Major depression and anxiety, anxiety disorders and major depression
- Common treatments overlap (antidepressants for both depression and anxiety)
Diagnosis Changes Over Time:
- Symptoms can morph into different disorders, complicating treatment and diagnosis
- Example: Mike's case - ADHD > Social Anxiety Disorder > Major Depression > Bipolar Disorder > Schizoaffective Disorder > OCD > Opioid Addiction.
Mike's Diagnoses
- Schizoaffective disorder
- Opioid use disorder
- Nicotine use disorder
- OCD
- Social anxiety disorder
- Previous diagnoses: ADHD, major depression, bipolar disorder, Asperger’s syndrome
Questions Raised by Mike's Case
- Why do people with mental disorders often have multiple diagnoses?
- Do some psychiatric disorders lead to others?
- Are different disorders merely different symptoms or phases of the same underlying problem?
- Is there a common pathway for mental disorders, despite varying symptoms and treatments?
Research on Psychotic Disorders: Schizophrenia, Schizoaffective Disorder, Bipolar Disorder
- Schizophrenia: Chronic psychotic symptoms like hallucinations or paranoia.
- Bipolar Disorder: Primary mood symptoms—manic and depressive episodes; psychotic symptoms during manic or depressive episodes.
- Schizoaffective Disorder: Combination of schizophrenia and bipolar disorder's symptoms.
- Researchers studied these disorders using the Bipolar Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study, including over 2,400 people:
- No significant differences found between diagnostic groups in terms of brain scans, genetic testing, EEGs, blood parameters, inflammation levels, or cognitive performance tests.
- Overlap in symptoms and treatments:
- Negative symptoms in schizophrenia overlap with depression symptoms
- Mood stabilizers used for bipolar disorder are frequently prescribed to people diagnosed with schizophrenia (despite the absence of significant mood symptoms)
- Antidepressants commonly used in both bipolar disorder and schizophrenia.
Mental Health Disorders: Overlaps and Spectrum of Symptoms
Antipsychotic Medications:
- Used for schizophrenia, bipolar disorder, and schizoaffective disorder
- Treat all symptoms of these disorders
- FDA approved as "antipsychotics" and "mood stabilizers" for bipolar disorder
Symptoms Overlap:
- Bipolar disorder, schizophrenia, and schizoaffective disorder may be the same illness on a spectrum of symptoms
- Major depression and anxiety disorders also have overlapping symptoms
Bipolar Disorder vs. Schizophrenia:
- Differences in symptom presentation
- Bipolar: Many people never experience psychotic symptoms or hospitalization, can function well
- Schizophrenia: Severe impairment, high rates of disability
- Symptomatically ill 47% of the time despite treatment for bipolar disorder
Possible Explanation:
- Multiple psychosis-causing disease processes with different biological pathways can lead to similar symptoms
- Fever as a symptom has one clear biological pathway (inflammation)
Diagnostic Overlap:
- Anxiety symptoms common across various mental diagnoses
- 26% of Americans meet criteria for at least one mental disorder in last twelve months
- 55% had only one diagnosis, 22% had two, and rest had three or more
Autism Spectrum Disorder:
- 70% have at least one other mental disorder, almost 50% have two or more
- Embedded criteria for obsessive-compulsive disorder (OCD)
- Longer term risk of developing additional mental disorders unknown.
Autism Spectrum Disorder and Mental Health Disorders
- Autism impairs social skills, increasing risk for mental disorders
- Autism puts people at higher risk for various mental disorders
- Mood disorders
- Psychotic disorders
- Behavioral disorders
- Eating disorders
- Substance use disorders
- Stress is a factor in developing mental disorders, but the relationship is complex
- Bidirectional relationships between mental disorders and eating disorders
- Eating disorders increase risk for other mental disorders
- Mental disorders increase risk for eating disorders
- Similar bidirectional relationships exist between all mental disorders
- Study on Danish health registry showed that any mental disorder dramatically increases chance of developing another mental disorder
- Strong correlations found among all mental disorders and their risk factors
- Possible existence of a common pathway (p-factor) to all mental illnesses.
Additional Information
- Dr. Benjamin Lahey et al., studied the symptoms and prognosis of eleven different mental disorders, finding tremendous overlap and possibility of "general factor" leading to all of them
- Avshalom Caspi and Terrie Moffitt reviewed research on epidemiological studies, brain imaging studies, and studies of risk factors for mental disorders, concluding strong correlations among all mental disorders.
Relationship Between Mental Disorders and Metabolic/Neurological Conditions
Common Pathway:
- Bidirectional relationships exist between mental disorders and various metabolic and neurological conditions
- Both mental symptoms (e.g., depression, anxiety) and physical symptoms can coexist
- Overlooked in clinical settings as normal reactions to diseases or underlying disorders
Metabolic Disorders:
- Obesity, diabetes, cardiovascular disease
- Strong association with mental illness
- People with schizophrenia: three times more likely to develop diabetes
- People diagnosed with depression: 60% more likely to develop diabetes
- Depression affects blood sugar levels in diabetics
- Higher rates of mood disorders, suicide attempts, psychiatrist visits among adolescents with diabetes
- Obesity and mental illness connection is complex
- People with mental disorders are more likely to be overweight or obese
- Schizophrenia: 50% increase in obesity after twenty years
- Autism: 40% higher risk of obesity
- Obesity may contribute to mental illness development, not just treatments causing weight gain.
- People with mental disorders are more likely to be overweight or obese
Diabetes:
- Historical connection between diabetes and mental illness since the late 1800s
- Increased risk for people with mental disorders to develop diabetes
- Schizophrenia: three times more likely
- Depression: 60% higher risk
- Depression has a negative impact on blood sugar levels in diabetics
- Higher rates of depression among people with diabetes (one in four)
Obesity:
- Mental disorders increase the likelihood of obesity development
- ADHD: even those not taking stimulants have higher obesity risk compared to non-ADHD individuals
- People with obesity are at increased risk for mental illness
Cardiovascular Disease:
- Further research needed on relationship between cardiovascular disease and mental disorders.
Obesity and Mental Disorders:
- Obese individuals are 25% more likely to develop depression or anxiety disorders
- 50% higher risk for bipolar disorder
- Weight gain during puberty increases risk of depression by fourfold
- Obesity affects brain function, leading to mental disorders
Cardiovascular Diseases:
- Depression increases risk of heart attack by 50-100% for those without a history
- Depression doubles chances of another heart attack in those who have already had one
- Schizophrenia and bipolar disorder linked to premature cardiovascular disease
- PTSD patients twice as likely to have transient ischemic attacks, 62% more likely to have a stroke
Mental Disorders and Early Death:
- Mentally ill people die an average of 13-30 years younger than expected
- Suicide not the primary cause; most early deaths due to heart attacks, strokes, and diabetes
- All mental disorders associated with shortened lifespans
Neurological Disorders:
- Neurological disorders affect brain function objectively
- Alzheimer's disease is most common form of dementia
- Risk factors: age, family history, head trauma, metabolic disorders, obesity, diabetes, heart disease, smoking, high blood pressure, low exercise.
Alzheimer's Disease:
- Most common form of dementia
- Symptoms: memory disturbances, personality changes, compromised judgment
- Hallmark findings: plaques and tangles in the brain
- Risk factors: age (doubles every five years after 65), family history, head trauma, metabolic disorders (obesity, diabetes, heart disease), smoking, high blood pressure, low exercise.
Obesity as a Risk Factor for Alzheimer's:
- Obesity in midlife increases risk of developing Alzheimer's disease
- Diabetes and heart disease also raise the risk
- APOE4 gene variant linked to early onset Alzheimer's.
Alzheimer's Disease and Psychiatric Disorders
- Study on Danish population found bidirectional relationships between various psychiatric disorders and Alzheimer's disease (organic mental disorder)
- Alzheimer's was included under organic mental disorders, which also include delirium and other dementias
- Every psychiatric disorder increased chances of developing an organic mental disorder: 50% to twentyfold
- Signs of Alzheimer's often begin with forgetfulness and "mental" symptoms (depression, anxiety, personality changes)
- Almost all patients with Alzheimer's develop psychiatric symptoms (97%)
- Common psychotic symptoms include hallucinations and delusions
Epilepsy and Psychiatric Disorders
- Epilepsy has a bidirectional relationship with mental disorders
- Can begin at any age, most often in childhood (1 in 150 children)
- Causes: brain abnormalities or unknown
- People with epilepsy more likely to experience mental symptoms even when not seizing
- Anxiety disorders common, three to sixfold higher rate than general population
- Depression high prevalence, one-third of all epileptics reported suicide attempts
- Suicide attempts often occurred before diagnosis
- Children with autism have a 16% chance of developing seizures
- ADHD children have a 16% chance of showing signs on EEGs
- Epileptic children more likely to be diagnosed with ADHD (two and a half times)
- Major depression increases chances of having unprovoked seizure sixfold
- Relationship between epilepsy and metabolic disorders: hypoglycemia can cause seizures, but people with diabetes are also more likely to have epilepsy
Common Pathway
- Bidirectional relationships suggest a possible common pathway for all these disorders
- Some believe the connection is due to stigma around mental and metabolic disorders.
Misconceptions about Mental Disorders and Metabolic Conditions
Neglect and Self-Destructive Behaviors:
- Many believe mental disorders lead to negligence and poor self-care (depression, obesity, diabetes)
- Overwhelming stress contributes to unhealthy habits (lack of motivation, energy)
The Conundrum:
- Rates of mental disorders, obesity, diabetes, cardiovascular disease have been skyrocketing over the past 50 years
- Why is this? What causes an "epidemic of laziness" or lack of self-discipline?
Possible Causes:
- Society: faster pace of life, constant distractions (emails, social media)
- Food supply: artificial ingredients, processed foods
The Missing Link:
- Inertia and lack of motivation may be symptoms of a metabolic problem rather than excuses for laziness or poor health behaviors
- People with mental disorders often don't have enough energy due to deficits in energy production inside cells (metabolic issues)
- Metabolism ties together various aspects of different disorders, such as risk factors, symptoms, and treatments.
Mental Disorders as Metabolic Disorders:
- All mental disorders lead to a greater probability of developing other mental disorders
- Mental disorders have bidirectional relationships with obesity, diabetes, cardiovascular disease, Alzheimer's disease, epilepsy, and other metabolic conditions
- Metabolism is the underlying common thread that explains causes, symptoms, and overlaps among these disorders. (Part Two will further explore this idea)
Mental Disorders as Metabolic Disorders
Theoretical Perspective:
- New theories should build upon existing knowledge
- The theory of brain energy suggests mental disorders are metabolic disorders of the brain
Implications for Mental Health Professionals:
- Incorporates biological, psychological, and social perspectives
- Offers new insights and potential treatments
Integration of Medical Disciplines:
- Connects psychiatry, neurology, cardiology, endocrinology, and more
- Encourages better cross-specialty collaboration and comprehensive care
Evidence for the Theory:
- Metabolic abnormalities found in mental disorders
- Shared risk factors for mental and metabolic disorders
- All symptoms of mental disorders tied to metabolism/mitochondria
- Current treatments affect metabolism
Metabolic Ripple Effect:
- Obesity, diabetes, cardiovascular disease, Alzheimer's, epilepsy, and mental problems are interconnected
- Increased risk for various other illnesses not usually viewed as metabolic disorders
Importance of the Theory:
- Simplistic views on causes may be misleading
- Understanding mental disorders as metabolic disorders can lead to more effective treatments.
Metabolism and Medications
Mark's Experience:
- Healthy, thin man developed multiple sclerosis (MS)
- Prescribed corticosteroid medication like prednisone
- Gained weight and developed pre-diabetes
- Struggled with cravings, lack of energy for exercise
- Developed cardiovascular risk factors and anxiety/depression
- Doctor's advice to "try yoga and diet" was unhelpful
Corticosteroid Medications:
- Known side effects include weight gain, high blood sugar, increased appetite, depression, anxiety
- Can cause metabolic disorders like diabetes and obesity
- Other medications can also cause these metabolic problems
Metabolism Complexities:
- Not avoidable through sheer willpower
- Altered levels of hormones or trauma history can lead to metabolic disorders
- Medications, environment, lifestyle factors all influence metabolism
What is Metabolism?:
- Process of turning food into energy or building blocks for cells
- Involves absorbing nutrients and managing waste products
- Determines cellular health, body/brain development, resource allocation
- Constantly adapting to environmental changes
Energy Imbalances:
- Problems with metabolism lead to energy imbalances in cells
- Affects all cells in the human body, including heart cells and pumping function.
Brain Cells and Metabolic Control
Importance of Brain Function Precision:
- Brain cells need precise control to be turned on/off at appropriate times
- Disruption of on/off processes can result in mental illness symptoms
Number of Brain Cells:
- Estimated 100 billion neurons and additional glial cells
- Some estimates suggest up to 806 billion total cells
Neurotransmitters and Cell Signaling:
- Neurotransmitters act as "go" or "stop" signals for cells
- Cells release neurotransmitters based on energy availability and other factors
Brain Energy Requirements:
- Brain uses about 20% of total body energy at rest
- Brain cells are sensitive to disruptions in energy supply
Metabolic Disruptions and Brain Function:
- Disruptions can cause various symptoms, from subtle to severe
- Severe cases can lead to heart attacks, strokes, or death due to cell failure
Chronic Metabolic Conditions:
- Diabetes as an energy shortage/deficit in insulin or cell responsiveness
- Cells have trouble converting glucose into energy, leading to impaired function
Diabetes and Metabolism:
Effect of Diabetes on the Body:
- Affects various parts of the body
- Symptoms range from mild to severe
- Can impact eyes, nerves, brains, heart, kidneys, and ability to fight infections
- Progression varies based on metabolism
Metabolism's Role in Diabetes:
- Affects functioning of cells throughout the body
- Complex factor influenced by numerous elements
- Controlled at multiple levels
Traffic Analogy for Understanding Metabolism:
- Body is like a city with organized traffic flow
- Traffic jams represent issues in specific parts of the body or brain
Factors Affecting Metabolism:
- Diet, light, sleep, exercise, drugs and alcohol, genes, hormones, stress, neurotransmitters, inflammation, and more.
Mental Disorders and Metabolism:
- All mental disorders relate to metabolism as it affects cell function
- Solvable through straightforward interventions.
Normal vs. Mental Disorder:
- Difference not clearly defined in the mental health field
- Focuses on functioning of mind versus adverse states or symptoms.
Chapter 6: Mental States and Mental Disorders
Normal Human Emotions vs. Mental Disorders:
- Distinguishing normal reactions from mental disorders important for treatment
- Both can lead to poor health outcomes
- Stressors cause mental illness when exposed to numerous or extreme stressors
Understanding Normal: Stress and the Stress Response
Stressors: psychological and social factors, interconnected with biological factors
Human Connections:
- We are meant to live in groups
- Seek attachment to others for safety and support
Challenges with Human Connections:
- People can be sources of psychological stress
- Stressors revolve around relationships, roles, resources, responsibilities
- Absence of humans (loneliness) is also a powerful stressor
Stress Response:
- Hypothalamic-pituitary-adrenal (HPA) axis: cortisol flow
- Sympathetic-adrenal-medullary (SAM) axis: adrenaline (epinephrine and norepinephrine) flow
- Inflammation
- Changes in gene expression, especially hippocampus
- Metabolic toll: energy used to produce changes, less available for other functions
- High alert state: heart pumps faster, blood pressure increases, blood glucose rises.
Effects of Stress on Body and Mind:
- Hormones flowing, inflammatory cytokines released
- Defense resources mobilized for body's protection
- Mild stress can be dealt with by resilient individuals (metabolically healthy)
- Extreme or prolonged stress can lead to mental and metabolic disorders
- Exacerbation of existing disorders: depression, alcoholism, schizophrenia, etc.
Psychosomatic Medicine/Mind-Body Connection:
- Field studying relationship between psychological factors and physical health
- Social determinants of health: poverty, abuse, high-crime neighborhoods
- Adverse Childhood Experiences (ACEs) studies: correlation between early experiences and long-term health outcomes
Impact of ACEs on Health:
- Increased risk for physical inactivity, obesity, diabetes
- Higher rates of smoking, poor self-rated health, cancer, heart disease, respiratory diseases
- Greater likelihood of sexual risk-taking, mental health issues, alcohol use, drug use
- Victim or perpetrator of violence, problematic drug use, suicide attempts
- Shortened lifespan: twenty years less compared to those with no ACEs
Biological Effects of Stress:
- Diversion of resources to fight-or-flight system
- Impairment of body's ability to maintain itself (autophagy)
- Inhibition by high cortisol levels
- Waste disposal and maintenance process affected in various disorders
- Delayed protein synthesis: stress granules formation, associated with neurodegenerative disorders
- Sleep disruption: insomnia, crucial for both physical and mental health.
Impact of Sleep Deprivation on Aging and Stress
Sleep Deprivation:
- Prioritizes maintenance functions are compromised when people aren't sleeping well
- Leads to higher levels of cortisol, which can make the problem worse
- Results in premature aging
Stress:
- Plays a role in human health and takes a metabolic toll
- Uses energy that could be used for proper cell function and maintenance
- Can lead to physical and mental disorders or just plain old aging
- Stress reduction practices can help, but may not be sufficient for everyone
- Stress may not be the cause of mental illness in some cases
New Definition of Mental Illness (RDoC):
- Focuses on symptoms rather than diagnostic labels
- Organizes symptoms into domains of functioning: emotion, cognition, motivation, social behavior
- Encourages exploration of these constructs without a focus on diagnostic criteria
Brain Functions and Mental Illness:
- Symptoms correspond to normal mental states or brain functions that are not working properly
- Includes emotions, cognition, behavior, and motivation
- Even bizarre symptoms like delusions and hallucinations can be tied to normal brain functions
Normal Brain Functions vs. Mental Illness:
Overactive or Underactive Brain Functions:
- Panic attacks: triggered for no clear reason, dysfunctional and maladaptive
- Memory impairment in dementia or lack of social skills in autism: brain functions fail to activate in the right situations
Symptoms of Mental Illness:
- Can seem unique and highly unusual
- Normal brain functions may perform at wrong times or with wrong intensity
- Can result in poor health outcomes
Analogy: Three Cars
- Car A: living the good life, no health problems
- Car B: living in harsh environment, more health problems, shorter lifespan
- Adaptations help navigate difficult conditions
- Car C: problem with the driver, not the car itself
- Prolonged or extreme stress: can lead to a disorder
- Normal brain functions: performing at wrong times or under wrong circumstances = disorder
- Societal factors: changing environments or helping people cope is ideal
- Brains of people with mental disorders: malfunctioning, doing things at the wrong times or with wrong intensity, or failing to do things they should be doing.
- Prolonged stress: can result in adaptive strategies no longer working (overactive or underactive functions)
- The driver of Car C: problem lies with the driver, not the car itself.
Understanding Pain as a Neural System: A Human Example
Function and Dysfunction of Pain System:
- Pain is controlled by neural pathways: pain receptors, spinal cord nerves, and brain regions
- Disorders in this system can be categorized into three types based on the function of the cells:
- Overactivity: People experience pain more frequently or intensely than necessary (e.g., diabetic neuropathy)
- Underactivity: People feel less pain than they should (e.g., reduced sensation in feet due to diabetes)
- Absence of function: People feel no pain despite an injury or condition (e.g., spinal cord injuries or strokes)
Chronic Pain Disorders:
- Difficulty distinguishing normal pain from a disorder
- Pain can become chronic, severe, and unprovoked, leading to a diagnosis of a pain disorder
Defining Mental Illness:
- Mental illness: Brain not working properly over a period of time, resulting in mental symptoms that cause suffering or impairment in functioning.
Components of the Definition:
- The brain is not working properly: Difficult to measure and assess with current technologies
- This results in mental symptoms: Indicators of abnormal brain function
- This malfunction occurs over a period of time: Cumulative effect of neural dysfunction
- The symptoms cause suffering or impairment in functioning: Direct impact on the individual's quality of life
Symptoms of Mental Illness: Overactive Brain Functions
- Hyperexcitability of brain cells and networks leads to mental disorder symptoms
- Fear and anxiety: Amygdala may malfunction, causing inappropriate or exaggerated responses
- Symptoms: Fear at wrong times or intensity
- Example: Phobias, panic attacks
- Obsessions and compulsions
- Hyperexcited cells and networks in brain regions responsible for grooming and checking behaviors
- Examples: Obsessive-Compulsive Disorder (OCD)
- Psychotic symptoms
- Hallucinations, delusions
- Found in various mental and neurological disorders
- Also common in people without diagnosed disorders.
Understanding Psychotic Symptoms
- Hyperexcitability of brain cells processing perceptions:
- Auditory hallucinations due to hyperexcitable sound perception neurons
- Neurosurgeons can induce hallucinations through electrode stimulation
- Abnormalities in cortical interneuron function, leading to overactivity in targeted neurons
- Psychotic symptoms related to sleep systems:
- Daytime hallucinations and delusions similar to dreams
- Brain areas responsible for creating dreams may be hyperexcitable during psychosis
- Capgras syndrome involves specific brain network overactivity/underactivity
Underactive Brain Functions in Mental Disorders
- Reduction in activity of certain neurons and brain networks:
- ADHD: Locus coeruleus neurons for focus, planning, and attention
- Cognitive impairment due to reduced neuron function for memory storage and retrieval
- Depression: Default mode network responsible for emotional regulation
- Symptoms wax and wane with underactive brain functions
Absence of Specific Brain Functions
- Permanent changes in brain cells and connections:
- Neurodevelopmental disorders (autism (missing or different neurons/connections))
- Neurodegenerative disorders (Alzheimer's disease, cell death leading to neuron loss)
- Symptoms are always present and don't change over time for these cases
- Additional symptoms may wax and wane despite permanent brain changes.
Multifaceted Brain Adaptations and Behavioral Disorders:
- Complex responses involving multiple brain functions:
- May not fit neatly into overactive, underactive, or absent categories.
Normal Responses and Mental Disorders:
- Depression: normal reaction to stressors, adversities, or losses; can last for more than two weeks and involve changes in mood, energy, appetite, and sleep
- Hypomania: opposite of depression; feeling great or euphoric, increased energy, productivity, and less need for sleep; can be a normal response
- Trauma response: flashbacks, nightmares, avoidance of situations reminding of event, negative effects on mood and thinking, trouble sleeping, being on edge; common after major life traumas
Behavioral Disorders:
- Substance use disorders and eating disorders deserve special attention as they show strong relationship with all mental disorders
- Overactive or underactive brain functions may drive people to engage in these behaviors, leading to problems
- Some people may use substances or change eating habits to cope with symptoms of other mental disorders (self-medication hypothesis)
- People can be perfectly fine and start engaging in these behaviors due to peer pressure or other reasons
- Effects on metabolism and brain function can lead to overactivity and underactivity of specific brain functions, creating vicious cycles.
Complexities of Mental Illness:
- Findings about reduced default-mode network activity are not consistent across people with the same disorder or even in the same person at different times
- Symptoms wax and wane, making it difficult to identify causes and develop diagnostic tests
- Developmental abnormalities affect a wide range of cell types and brain regions in different people, adding complexity to understanding mental disorders.
Mitochondria: The Drivers of Human Cells and Metabolism
Overview:
- Mitochondria are the "powerhouses" of human cells, responsible for energy production through ATP creation
- They are more than just powerhouses; they play a crucial role in cellular functioning and human evolution
Origin of Mitochondria:
- Ancestral mitochondrion was a bacterium that evolved into an independent living organism between 1-4 billion years ago
- Around the same time, archaea (single-celled organisms) engulfed this ancestral mitochondrion, resulting in symbiosis and the formation of the first eukaryotic cell with a nucleus
- Over time, this symbiotic arrangement led to multicellular life
Mitochondria's Role:
- Mitochondria evolved into organelles responsible for energy production in eukaryotic cells
- In plants and algae, some mitochondria became chloroplasts that facilitate photosynthesis
- Both mitochondria and chloroplasts are descended from the same ancient bacterium
- This merger occurred only once in evolution, and all eukaryotes share these organelles
Importance of Mitochondria:
- Being first matters in evolution; common genes are considered more essential to life
- Evolution tends to eliminate traits that aren't necessary or advantageous for survival and reproduction
- New genes must develop alongside existing ones to adapt and coexist
Mitochondria in Eukaryotic Cells
- Mitochondria: First appeared in eukaryotic cells as a single bacterium and an outside cell
- Over time, nucleus and other organelles developed
- Mitochondria likely influenced development of other cell parts and became indispensable
- Modern Mitochondria
- Can't replicate themselves outside of eukaryotic cells
- Most mitochondrial DNA transferred to cell's nucleus (human DNA)
- About 1,500 mitochondrial genes embedded within human DNA
- Each mitochondrion still has 37 genes for self-maintenance and independence
- 100% committed to eukaryotic cells: neither can survive without each other
- Size and Quantity
- Average human cell contains 3-400 mitochondria
- Total mitochondria in the body: about 10 million billion
- Make up about 10% of body weight despite small size
- Highly concentrated in metabolically demanding cells (brain cells)
- Function
- Produce lion's share of ATP, especially for brain cells
- Average human adult produces 9 × 10^20 ATP molecules per second
- Move around the cell using microtubules and filaments (cytoskeleton)
- Movement and Location
- Go to places in the cell where energy is needed
- Stay in places near factories (ribosomes) or synapses for brain function
- Mitochondrial Roles
- Rapid recyclers of ATP and ADP
- Provide ATP, recycle ADP simultaneously
- Interact with other organelles and each other for cell functions
- Critical role in almost all cell functions, including gene expression.
Mitochondria's Role in Cell Function
Ion Pumping:
- Cells require energy to set up ion pumps
- Triggered cells set off a cascade of events leading to cell function (e.g., neurotransmitter or hormone release)
- Ion pumping requires significant time and work to set up, but is easy to initiate
Calcium Regulation:
- Calcium levels act as an "on/off" switch for cells
- Mitochondria are directly involved in calcium regulation
- Dysfunctional mitochondria disrupt calcium regulation and the cell's "off" switch
Energy and Mitochondria:
- Mitochondria provide almost all the energy needed for ion pumping and cell function
- Mitochondrial dysfunction can lead to cells staying on too long or failing to work
Mitochondria's Other Roles:
- Metabolic Regulation: Mitochondria help regulate metabolism through mitochondrially derived peptides (e.g., humanin, MOTS-c, SHLP1–6)
- Neurotransmitter Production and Regulation: Mitochondria play critical roles in neurotransmitter production, secretion, reuptake, and regulation
Mitochondria's Role in Metabolism and Beyond
Mitochondria as Regulators of Metabolism and Mitochondria Themselves:
- Essential regulators of metabolism and mitochondrial function
- Help manage cellular stress and coordinate the integrated stress response
Mitochondria's Role in Immune System Function:
- Play essential role in immune system regulation
- Help regulate how immune cells engage with immune receptors
- Release components that serve as danger signals, activating chronic inflammation
Mitochondria's Role in Stress Responses:
- Control and coordinate stress response in the body (physical and mental)
- Initiate integrated stress response when cells are physically stressed
- Trigger death or "zombie" state if unable to manage stress
Mitochondria's Involvement in Hormone Regulation:
- Key regulators of hormones, as they synthesize, package, and release them
- Mitochondrial enzymes initiate production of certain hormones (e.g., cortisol, estrogen, testosterone)
- Some cells have mitochondrial receptors for these hormones, allowing them to travel between cell types
Mitochondria and Reactive Oxygen Species (ROS):
- Generate ROS during energy production process
- Small amounts of ROS serve a signaling function within the cell
- Large amounts of ROS are toxic, leading to inflammation, mitochondrial damage, and cellular damage
- Mitochondria also help clean up ROS through an elaborate system of enzymes and factors.
Mitochondria and Cellular Function
Detoxification Failure:
- ROS waste products can pile up and cause damage
- Leads to cellular dysfunction, aging, cell death, and disease
Mitochondrial Shapeshifting:
- Mitochondria change shape in response to environmental factors
- Can be long/thin or short/fat
- Interact through fusion (merging) and fission (division)
- Importance for cell function:
- Mitochondrial fusions impact fat storage, eating behaviors, and obesity
- Changes in shape send signals affecting the entire body
Mitochondria and Gene Expression:
- Nuclear DNA contains the human genome
- Genes control cell function, but epigenetics determines which genes are active
- Mitochondria regulate epigenetics by sending signals to nuclear DNA (retrograde response)
- ATP levels, ROS, and calcium impact gene expression and require mitochondrial function
Mitochondrial Role in Epigenetics:
- Mitochondria are required for the transport of epigenetic factors like histone H1
- Mitochondrial ROS inactivate enzymes regulating epigenetic gene expression (histone demethylase)
- Mitohormones, such as GPS2 and MOTS-c, released by mitochondria regulate nuclear DNA
Mitochondrial Biogenesis:
- Cells can produce more mitochondria under certain conditions
- More healthy mitochondria lead to healthier cells
Mitochondria in Cell Growth and Differentiation:
- Mitochondria are essential for cell growth, differentiation, and energy production
Mitochondria's Role in Cell Function
Mitochondria's Essential Functions:
- Regulate calcium levels and other signaling pathways
- Fusion with each other sends signals that activate genes in the nucleus
- Involved in autophagy process, generating signals like ROS and metabolic factors
- Interact with lysosomes during autophagy
- Provide energy (ATP) for cell maintenance and autophagy processes
Mitochondria and Apoptosis:
- Release cytochrome c when under high stress, activating "killing enzymes"
- Play a role in both apoptosis and autophagy
Mitochondria as Workers in the Cell:
- Provide various functions within cells: neurotransmitter production, hormone release, muscle function, etc.
- Communicate with and regulate other organelles (nucleus, endoplasmic reticulum, lysosomes)
- Interact with mitochondria in other cells through hormones and peptides
- Control the regulation of genes daily and during cell growth/differentiation
Mitochondria's History:
- Long overlooked due to focus on larger cell components (nucleus, membrane)
- Recent research has revealed surprising roles and interactions with other organelles
- Evidence suggests mitochondria may be the control center of the cell
Evidence of Metabolic Problems in Mental Disorders
- Previous chapter reviewed mitochondria's role and effects on cells, metabolism, neurotransmitters, hormones, inflammation, immune system function, gene expression, development, and cell health
- Link between mental disorders and metabolic disorders, such as diabetes, dating back to the 1950s
- Evidence of metabolic abnormalities in markers: ATP levels, redox balance, hormones, neurotransmitters, lactate (a marker of metabolic stress)
- Infusing lactate can precipitate panic attacks in people with panic disorder
- Cortisol dysregulation plays a role in some people with mental disorders
- Neuroimaging studies show metabolic differences in the brains of people with mental disorders
- Functional magnetic resonance imaging (fMRI), near-infrared spectroscopic imaging (NIRSI), positron emission tomography (PET), blood-oxygen-level-dependent imaging (BOLD), and single-photon emission computed tomography (SPECT) all measure metabolism in the brain
- Heterogeneity and inconsistent findings despite metabolic differences being known for decades
Mitochondrial Dysfunction and Mental Health
- Mitochondria play a large role in human health, and when they don't function properly, the body doesn't either
- Impairment in mitochondrial function is called mitochondrial dysfunction
- Widespread disorders associated with mitochondrial dysfunction include psychiatric disorders (schizophrenia to borderline personality disorder), metabolic disorders (obesity, diabetes, cardiovascular disease), neurological disorders (Alzheimer's disease, epilepsy, Parkinson's disease), and many cancers.
Mitochondrial Dysfunction and Mental Disorders
Background:
- Wide range of diagnoses linked to mitochondrial dysfunction
- Evidence exists for decades, but not widely recognized in psychiatry
- Importance of mitochondria in human health and disease has been studied extensively
Historical Research:
- Raymond Pearl: Published "The Rate of Living Theory" (1928), focusing on metabolic rate and aging
- Denham Harman: Proposed free radical theory of aging (1954) and mitochondrial theory of aging (1972)
- Increasing research on mitochondria in obesity, diabetes, cardiovascular disease, aging, and mental disorders since 1970s
Mitochondrial Dysfunction and Psychiatric Disorders:
- Dr. Douglas Wallace: Claimed all psychiatric disorders result from mitochondrial dysfunction (2017)
- Mitochondrial genetics play a role due to high mutation rate and lack of protection for mitochondrial DNA
- Brain is particularly affected as it's highly dependent on energy production by mitochondria
- Different parts of the brain may fail first depending on energy deprivation levels
Rebuttal:
- Psychiatric disorders are complex, requiring more than one factor for explanation
- Mitochondrial dysfunction cannot account for all symptoms in mental disorders or rare genetic mitochondrial diseases
- Different symptoms even among people with the same mitochondrial genetic mutation
- Mitochondria have multiple roles beyond energy production, affecting brain function and health
- Defining "dysfunction" is challenging due to various causes and outcomes
Measurement of Mitochondrial Function:
- Difficult to measure in scientific research context
- Can cause different problems for the mitochondria and cells they reside in, affecting overall brain function and health.
Mitochondrial Dysfunction
Causes of Mitochondrial Dysfunction:
- Problems with mitochondria themselves:
- Genetic mutations
- Shortage of mitochondria in the cell
- Mitrochondrial DNA is prone to mutations due to lack of protection
- Exposure to high levels of reactive oxygen species (ROS) can damage mitochondrial DNA and other parts, leading to defective mitochondria
- Inability for defective mitochondria to be disposed of and recycled, resulting in a "workforce shortage" for the cell
Aging and Mitochondrial Dysfunction:
- Number of mitochondria in cells decreases as we get older, reducing metabolic capacity
- This can lead to productivity decrease, cell death, and organ shrinkage
Mitochondrial Dysregulation:
- Factors that affect mitochondrial function come from outside the cell
- Includes neurotransmitters, hormones, peptides, inflammatory signals, and substances like alcohol
- Can cause impairment even when mitochondria were functioning fine before
Research Approaches:
- Measuring ATP production: can indicate impaired mitochondrial function
- Reduced ATP levels affect gene expression and cell function
- Found in various metabolic, neurological, and mental disorders
- Focusing on oxidative stress: buildup of ROS can damage cells, especially mitochondria
- Elevated in many metabolic, neurological, and mental disorders
Limitations of Mitochondrial Research:
- Failure to consider all diverse mitochondrial functions
- Differences between cell types in mitochondrial health and distribution
- Unclear causality: is illness causing mitochondrial dysfunction or vice versa?
Mitochondrial Dysfunction: Causes and Consequences
Causes of Mitochondrial Dysfunction:
- Not fully understood
- Feedback loops can lead to causes and consequences
Examples:
- Alzheimer's disease: Beta-amyloid accumulation can cause mitochondrial dysfunction (positive feedback loop)
- Research focuses on understanding the cause of beta-amyloid accumulation, overlooking potential role in mitochondrial dysfunction initiation
Consequences of Mitochondrial Dysfunction:
- Decreased cell maintenance: Impact on development, function, and maintenance of cells
- Overactive brain functions
- Underactive brain functions
- Developmental problems
- Cell shrinkage and cell death
Decreased Cell Maintenance:
- One-third of brain's ATP production used for cell maintenance (housekeeping functions)
- Mitochondria interact with other organelles, such as lysosomes and endoplasmic reticulum (ER), to facilitate routine maintenance functions
- Interactions between mitochondria and these organelles prevent waste accumulation and protein folding issues
Examples:
- Defects in myelin production or maintenance due to mitochondrial dysfunction
- Positive feedback cycle: Structural defects can make it harder for cells to work, leading to further metabolic issues
- Myelin is an outer protective coating for neurons that affects neuron function and signal transmission
- Mitochondrial dysfunction associated with myelin problems in various mental disorders (schizophrenia, major depression, bipolar disorder, etc.)
Mitochondrial Dysfunction and Its Impact on Brain Functions
Effects of Debris in Mitochondria:
- Impedes mitochondria movement, obstructing cell function
- Alzheimer's disease associated with protein accumulation (tau) that limits mitochondria's ability to move around the cell
- Interferes with cytoskeleton used for mitochondrial movement
- Results in trouble for the cell and potential cell death
Mitochondrial Dysfunction and Overactive Brain Functions:
- Ion pumping and calcium regulation impact:
- Proper functioning is crucial to turn cells off
- Mitochondrial dysfunction prolongs these processes, leading to hyperexcitability
- Dysfunction in cells meant to slow down other cells (e.g., GABA cells):
- Malfunctioning GABA cells result in uninhibited cells becoming hyperexcitable
- Maintenance problems causing hyperexcitability:
- Lack of myelin allows ions to leak into a cell and cause it to fire
- Demonstrated through deletion of sirtuin 3 protein essential for mitochondrial health, resulting in seizures and early deaths
- Mitochondrial abnormalities found in neurons from people with bipolar disorder:
- Lithium treatment reduces hyperexcitability
- Hyperexcitability's presence in various mental and neurological disorders
Mitochondrial Dysfunction and Underactive Brain Functions:
- Reduced cell function due to insufficient ATP production from mitochondria
- Impacts neurotransmitter release, hormone production, and brain cell function
- Dysregulated hormone levels if mitochondria are dysfunctional or dysregulated.
Mitochondrial Role in Brain Development:
- Critical for cell growth, differentiation, synapse formation during development from the womb to early adulthood
- Developmental windows exist for proper brain hardwiring
- Mitochondria's dysfunction or dysregulation can result in permanently absent brain functions.
Brain Energy Theory: Mitochondrial Dysfunction and Depression
Symptoms of Cell Shrinkage and Death:
- Symptoms don't wax and wane due to lack of necessary cells and connections
- Cells shrink due to mitochondrial dysfunction
- Reduced workforce leads to inability to maintain entire cell
- Dead parts absorbed by microglia, causing inflammation
- Brain regions affected differently based on risk factors and timing of onset
Mitochondria and Cell Function:
- Mitochondria provide energy for cell function and maintenance
- Dysfunction can result in various symptoms
- Impact on different parts of the cell leads to different symptoms
Evidence of Mitochondrial Dysfunction in Depression:
- Impaired ATP production: lower levels in brain, muscle cells, circulating immune cells, and animal models
- Abnormalities in mitochondrial proteins found in postmortem brain tissue of people with chronic depression
- Elevated levels of oxidative stress
- Biomarkers related to amino acid and lipid metabolism (mitochondrial function) identified through meta-analysis of forty-six studies
- Lower levels of acetyl-L-carnitine (ALC), a mitochondria-produced molecule important for energy production, in depressed individuals
- Improvement in ALC levels with effective antidepressant treatments and correlation to remission
- New strategies targeting mitochondia proposed to improve depression treatment.
Mitochondrial Dysfunction and Depression: Rats Study:
- Identification of rats exhibiting high anxiety and depression-like behaviors
- Researchers studied the nucleus accumbens, a specific brain region, for differences in mitochondrial function or development.
Anxious/Depressed Rats:
- Had fewer mitochondria per cell
- Differences in how mitochondria used oxygen to produce ATP
- Interaction between mitochondria and endoplasmic reticulum (ER) was different
- Neurons appeared abnormal due to mitochondrial dysfunction
Mitochondrial Dysfunction:
- Can lead to reduced metabolism, underactive functions, and depression symptoms like fatigue, anxiety, and depression
- Mitochondria's ability to fuse with each other and ER is impaired due to lower levels of mitofusin-2 (MFN2) protein
- Increasing MFN2 levels can restore normal mitochondrial function and improve behavior in rats
Depression vs. Mania:
- Depressive states are energy-deficient, while manic states involve increased energy production in the brain
- Manic states associated with increased glucose and lactate utilization, elevated neurotransmitters like glutamate and dopamine
- Mitochondrial dysregulation in bipolar disorder, leading to either too little or excessive energy production
Bipolar Disorder:
- Mitophagy disruption or mitochondrial biogenesis may occur throughout the body during disease states
- Higher calcium levels and neuronal excitability changes during manic episodes
- Manic episodes cause problems for hyperexcitable cells with poor maintenance and structure, leading to dangerous symptomatic responses.
Impact of Mitochondrial Dysfunction on Brain Function and PTSD:
- Two areas affected: amygdala & medial prefrontal cortex (mPFC)
- Amygdala: hyperexcitable in PTSD, sets off fear response
- mPFC: inhibits amygdala, underactive in PTSD, impaired panic reaction control
- Evidence of mitochondrial dysfunction in PTSD: abnormal gene expression, reduced mitochondria, increased oxidative stress, decreased ATP levels
Delirium and Mitochondrial Dysfunction:
- Serious mental disturbance with various psychiatric symptoms
- Can be caused by medical conditions (infections, heart attacks, cancer) or medication/substance withdrawal
- Onset of delirium may include normal responses to severe situations
- Progression: anxiety -> panic attacks -> confusion -> disorientation -> hallucinations
- Delirium diagnosis: lumping all symptoms under the diagnosis, regardless of mental disorder
- Gradual onset (UTI): can be difficult to recognize and diagnose, but treatment resolves symptoms.
Impact of Medical Conditions on Mitochondrial Function:
- Delirium: any psychiatric symptom can occur due to impaired mitochondrial function caused by various medical conditions or medication withdrawal.
Misconceptions about Delirium:
- Healthcare professionals attribute all symptoms under delirium diagnosis, even if they don't present with every mental disorder's full set of symptoms.
Recognition and Diagnosis of Delirium:
- Early stages: anxiety may be mistaken for normal reaction or given psychiatric medication without a formal delirium diagnosis
- Late stages: confusion, disorientation, hallucinations lead to delirium diagnosis.
Gradual Onset of Delirium (UTI):
- Symptoms look identical to Alzheimer's disease or other mental disorders but are due to a UTI and resolved by treating the infection.
Neurotransmitters, Stress Responses, Inflammation, and Delirium
- Experts examine various factors contributing to psychiatric symptoms (neurotransmitters, stress responses, inflammation)
- Brain energy theory offers a potential explanation for the connection between these factors and mental symptoms
Delirium: Causes and Treatment
- Proposed to be due to disturbed brain energy metabolism or "cerebral metabolic insufficiency" (Engel, 1959)
- PET imaging studies reveal decreased glucose metabolism in people with delirium (Engel, 2000)
- Treatment depends on underlying cause and specific symptoms; standard treatments for medical conditions are implemented
- Sedating medications may be used to control mental symptoms until the medical condition is resolved
Importance of Addressing Delirium Symptoms
- Mental symptoms can indicate more widespread or severe mitochondrial dysfunction
- Increased risk of mental disorders, dementia, cognitive impairment, and seizures (Engel, 2001; Kovak et al., 2003)
- Higher mortality rates for people with delirium during hospital admission and after discharge (Cournoyer et al., 2016; Dosemeci & Karademir, 2018)
Mental Symptoms as an Indicator of Mitochondrial Dysfunction
- Mental symptoms may signal metabolic and mitochondrial failure (Engel, 2001; Kovak et al., 2003; Roberts et al., 2009)
- Depression linked to higher rates of premature death and seizures in elderly patients with medical illnesses (Sandman et al., 2000; van den Akker et al., 2015)
Mental Disorders and Mitochondrial Dysfunction
Evidence for Mitrochondrial Role in Mental Disorders:
- People with mental disorders are more likely to develop "organic" mental disorders like delirium and dementia
- Chronic mental illnesses indicate metabolic or mitochondrial dysfunction
- Delirium is a common occurrence during the dying process, often preceding seizures, coma, and death
Implications for Diagnostic Labels:
- Current diagnostic labels provide useful information on symptom constellations
- However, they do not account for the underlying metabolic dysfunction
- A "metabolic brain dysfunction" diagnosis with symptom specifiers could be more informative
Brain Energy Theory Recap:
- Mental disorders are metabolic disorders of the brain
- Mitochondria regulate metabolism and can cause overactive, underactive, or absent brain functions
- Various mechanisms through which mitochondrial dysfunction can lead to mental illness symptoms
Contributing Causes of Mental Illness: Metabolism and Mitochondria
Metabolism and Mitochondria:
- Common pathway in mental disorders
- Brain energy theory links risk factors
- Traffic analogy: metabolism = flow of traffic, mitochondria = drivers and workers
- Mitochondria involved in metabolism but not always the cause of problems
Contributing Causes:
- Biological Factors:
- Genetic predisposition
- Epigenetics
- Inflammation
- Hormonal imbalances
- Nutritional deficiencies or excesses
- Allies related to metabolic disorders (obesity, diabetes, cardiovascular disease)
- Environmental Factors:
- Exposure to toxins and pollutants
- Trauma and stress
- Lifestyle Choices:
- Poor sleep habits
- Alcohol and substance abuse
- Malnutrition or disordered eating
- Psychological Stressors:
- Loss, grief, or trauma
- Financial problems
- Work-related stress
- Social Factors:
- Lack of social support
- Isolation and loneliness
- Viral Infections:
- HIV/AIDS
- COVID-19
- Physical Illnesses:
- Autoimmune disorders
- Cancer
- Medications and Drugs:
- Prescription medications (stimulants)
- Recreational drugs
Themes:
- All impact metabolism and mitochondria.
- Associated with a wide variety of symptoms in mental disorders.
- Connected to physical disorders like obesity, diabetes, cardiovascular disease, Alzheimer's disease, and epilepsy.
- Variability in symptoms is due to the combination of contributing causes and their impact on different individuals.
Metabolism and Mental Illness:
Two Primary Answers to Differences in Vulnerabilities
- Preexisting vulnerabilities:
- All people are unique, even identical twins
- Genetic code doesn't guarantee uniformity
- Biological blueprint (genetics) + past experiences and environmental exposures influence metabolism and mitochondria health
- Weakest link determines overall metabolic strength
- Muscles analogy: different symptoms due to varying vulnerabilities
- Differences in inputs:
- Cells respond differently to various inputs
- Different brain regions need different amounts of energy
- Contributing causes impact specific cells, leading to diverse symptoms
Relationship between Mental and Metabolic Disorders
- Understanding individual vulnerabilities helps explain the connection
- Metabolism is interconnected: traffic analogy
- Traffic jam spreads if not addressed (symptoms)
- Long-term problems can cause metabolic deterioration over time
Treatments and Success Stories
- Strategies to address contributing causes: remove/reduce dysregulators, correct imbalances, improve metabolism
- Treatments for dysregulating factors: diet, sleep, stressors, etc.
- Correcting metabolic imbalances: neurotransmitter or hormonal adjustments
- Metabolism enhancement techniques: mitochondrial biogenesis, mitophagy, autophagy
- Chapter Twenty will provide an overall approach and strategies for treatment plans
- Implement treatments after understanding all contributing causes and approaches fully
- Real people's success stories using metabolic interventions will be shared throughout the book.
Genetics and Epigenetics
Mental Disorders and Families:
- Mental disorders have been observed to run in families
- Conclusion: Genetic information is transmitted from parents to children, implying a genetic cause
The Human Genome Project (HGP):
- 1990-2003: Researchers began sequencing and mapping all human genes
- Initial hope that the HGP would lead to cures for inherited illnesses, including mental disorders
Genetics of Mental Illness:
- Genome-wide association studies (GWAS): Scanned the entire genome for genes related to mental illness
- Found no meaningful relationships between genes and mental illness
- Most risk genes are not specific to individual disorders, but confer risk for many psychiatric, metabolic, and neurological disorders
Genes Related to Mitochondria and Metabolism:
- DISC1 gene: Confers risk for schizophrenia, bipolar disorder, depression, and autism; related to mitochondrial function and neuron development
- CACNA1C gene: Plays a major role in oxidative stress and mitochondrial integrity and function
- APOE gene: Increases risk for Alzheimer's disease; codes for a protein related to fat and cholesterol transportation and metabolism
Mitochondria and Mental Illness:
- Many risk genes are directly related to mitochondria and metabolism
- The APOE gene strongly impacts both metabolism and mitochondria
APOE4 and Alzheimer's Disease:
- APOE4 increases risk for some metabolic and mental disorders
- Increases risk for cardiovascular disease, certain mental disorders, epilepsy
- Decreases risk for obesity and type 2 diabetes due to complexity of metabolism
- Affects brain cells (astrocytes and microglia) in specific ways
- Gradual decline in function leads to cognitive symptoms
- Other mental symptoms appear once complete failure occurs
- Metabolism and mitochondria play a role as common pathway
- Mitochondrial genetics are complicated, influenced by both nuclear and mitochondrial genes
- Genes within mitochondria more susceptible to mutations
- Mitochondrial genes impact brain function, behavior, cognition, food intake, stress response
- Research on mitochondrial genes under-explored due to assumptions they don't matter significantly
Epigenetics:
- Field studying what causes genes to turn on or off
- Most people have similar genes but expression varies
- Epigenetics responsible for making cells different from each other
- Genes get turned on and off based on environmental circumstances and body needs
- Long-lasting epigenetic changes provide memory of the body's experiences
- Traits, both physical and mental, linked to specific patterns of gene expression
- Methylation, histones, micro-RNAs, hormones, neuropeptides influence gene expression
- Factors that impact epigenetics revolve around metabolism and mitochondria.
Epigenetics as Metabolic Blueprints
- Epigenetics reflect gene patterns for cell survival and coping with environment
- Maladaptive patterns or lack of appropriate signals can become problematic
Mitochondria's Role in Epigenetics
- Regulators of epigenetics
- Influence gene expression through ROS, glucose/amino acids, ATP levels
- Control essentially all genes for a cell
Transmission of Metabolic and Mental Disorders through Epigenetics
Womb Environment:
- Fetus is bathed in metabolic signals from mother
- Mother's hormones, neuropeptides, alcohol, drugs, prescription meds affect fetus
- Dutch winter famine study: babies born during famine more likely to develop metabolic and mental disorders later in life
Early Life:
- Caregiver neglect/deprivation profound effects on children's metabolic and mental health
- Epigenetic mechanisms play a role
- NAD cofactor transfer from mother to baby via breast milk impacts mitochondria, metabolism, and epigenetics in offspring
Intergenerational Transmission of Trauma:
- Parental trauma linked to poor mental health outcomes in children and grandchildren
- Not just psychological or social cause; physiological mechanisms involved (e.g., cortisol sensitivity)
Genetics and Epigenetics:
- Revolution in understanding that mental disorders may not be solely due to specific "abnormal" genes
- Transmission of mental illness: more likely through epigenetic mechanisms, which are reversible
- Epigenetics playing a significant role in transmission from parents to children and even grandchildren
Discoveries:
- Differences in methylation patterns of glucocorticoid receptor and other DNA regions associated with stress response system
- Fathers passing on traumatic experiences through epigenetic mechanisms, such as miRNA molecules in sperm
- Studies show sperm in both mice and men transmit offspring miRNAs affected by early childhood stress
- Low levels of specific miRNAs (449 and 34) found in men with highest levels of stressful life events
- Timing of stress can influence brain function differently: fetal exposure to maternal stress, childhood separation, severe abuse
Implications:
- Fetal exposure to mother's stress results in higher rates of learning impairment, depression, anxiety
- Early childhood separation leads to higher cortisol levels throughout life; severe abuse can result in lower cortisol levels
- Epigenetic mechanisms likely responsible for mental illness transmission rather than "abnormal" genes
Hopeful Aspects:
- Most epigenetic mechanisms are reversible through lifestyle interventions alone
- People are not usually born with permanent, fixed genetic defects that make it impossible to be healthy
- Mental illnesses not caused by genetic defects but rather environmental factors or dysfunctional mitochondria
Mitochondria Dysfunction:
- Primary causes of mental illness often in our environments or mitochondrial function
- Even those with APOE4 gene allele, which impairs mitochondrial function over time, have hope for healing through treatments that improve autophagy.
Chemical Imbalances, Neurotransmitters, and Medications
Chemical Imbalance Theory:
- Does not challenge observations of neurotransmitter imbalances playing a role in mental disorders
- Does not challenge clinical trials demonstrating improvement in symptoms using medications that affect neurotransmitters
- Does not challenge the real-world experience of people helped or saved by psychiatric medications
Limitations of Chemical Imbalance Theory:
- Leaves many questions unanswered
- Fails to restore lives for far too many people
- Brain energy theory offers new ways to understand neurotransmitter imbalances and the effects of medications
Mitochondria and Metabolism:
- Explain the underactivity and overactivity/hyperexcitability of specific brain cells that result in neurotransmitter imbalances
- Neurotransmitters produce their own effects in target cells, resulting in a "chain of dominoes" of metabolic disruption
Neurotransmitters and Mitochondria:
- Mitochondria play a key role in the production of many neurotransmitters
- Mitochondria have receptors for important neurotransmitters on their membranes (e.g., benzodiazepine, GABA receptors)
- Mitochondria have an enzyme involved in the degradation and regulation of some key neurotransmitters (e.g., dopamine, epinephrine, norepinephrine)
Serotonin:
- Not just a "simple on/off signal" between cells
- Neurotransmitter with a prominent and complex role in metabolism and mitochondrial function
- Serotonin increases mitochondrial function and biogenesis, which can improve metabolic function
- Serotonin is a product of the kynurenine pathway, which involves the fate of the amino acid tryptophan and the production of NAD, a molecule important for energy production and electron management
GABA:
- Neurotransmitter with a wide range of functions
- Mitochondria directly influence and sometimes control GABA activity
- GABA can sequester inside mitochondria, directly controlling its release
- GABA plays a role in metabolic disorders like obesity
Dopamine and Mitochondria
- Dopamine is released from neurons, binds to receptors, and can be taken up into the releasing neuron for another round
- Some dopamine ends up inside cells, which is managed by mitochondria through monoamine oxidase enzyme
- This process directly stimulates mitochondria to produce more ATP
Dopamine's Role in Regulation of Glucose and Metabolism
- Dopamine D2 receptors are found not only in the brain but also in the pancreas, playing a critical role in insulin release and glucagon regulation
- Antipsychotic medications can affect weight, diabetes, and metabolism due to their impact on dopamine D2 receptors
Neurotransmitters, Mitochondria, and Metabolism Connections
- Serotonin, GABA, or dopamine levels are affected by psychiatric medications, which have impacts on mitochondria and metabolism
- Medications like Valium activate the ventral tegmental area (VTA), increasing dopamine in the nucleus accumbens (NAc) and enhancing mitochondrial function, resulting in reduced anxiety and enhanced social dominance
Mitochondrial Effects of Psychiatric Medications
- Monoamine oxidase inhibitors increase epinephrine, norepinephrine, and dopamine levels near mitochondria, stimulating mitochondrial activity
- Lithium enhances ATP production, antioxidant capacities, and calcium signaling within cells, all related to mitochondria
- Antipsychotic medications like lithium can impair mitochondrial function, leading to neurological side effects such as tremors, muscle rigidity, and tardive dyskinesia (TD)
- Mitochondrial dysfunction is the most likely explanation for these neurological side effects.
Mitochondrial Function and Medication Use
Background:
- Researchers study specific cells in the brain, not all cells
- Importance of considering consequences of not treating certain conditions
- Hyperexcitability can be toxic to the brain
Medications and Mitochondria:
- Some medications impair mitochondrial function broadly
- Balancing risks vs benefits in dangerous or life-threatening situations
- Example: Seizures require immediate treatment
- Epilepsy treatments like Depakote can impair mitochondrial function
Complexities:
- Different situations require various interventions
- Brain energy theory offers explanations for medication effects on mental health
- Metabolic problems can spread and impact other brain regions
Medications and Mitochondria Connection:
- SSRIs enhance mitochondrial function, taking time to work
- Serotonin's impact on metabolism restores energy health over time
- Antipsychotic medications suppress hyperexcitability in various cell types
Metabolic Medications in Psychiatry:
- Blood pressure medications (clonidine, prazosin, propranolol)
- Used for ADHD, PTSD, anxiety disorders, substance use disorders, Tourette’s syndrome
- Statins (hydroxylmethyl glutaryl coenzyme A reductase inhibitors)
- Reduce inflammation and impair mitochondrial function
- L-type calcium channel antagonists
- Decrease hyperexcitability by limiting calcium in cells
- Metformin (biguanides)
- Plays a role in mitochondrial function, dose-dependent effects
Complexities of Medication Use:
- Stopping psychiatric medications requires medical professional supervision
- Symptoms can worsen quickly and new symptoms may emerge.
Impact of Abruptly Stopping Psychiatric Medications
- Patients may become acutely depressed, suicidal, manic, or psychotic when medications are stopped abruptly or decreased too rapidly
- Discontinuing medications is not something to undertake on one's own
Brain Energy Theory and Understanding Medications
- Psychiatric medications have helped countless people with mental disorders
- Brain energy theory offers new ways to understand how and why medications work
- Importance of understanding impact on metabolism and mitochondria
Mitochondrial Function and Medications
- Medications that increase metabolism and improve mitochondrial function can improve symptoms of underactive cells, but may exacerbate symptoms related to overactive or hyperexcitable cells
- Medications that impair mitochondrial function should be used cautiously
- May interfere with healing and recovery in the long run
- Could potentially cause symptoms
- Can be lifesaving in dangerous situations
Success Story: Jane's Case
- 81-year-old woman with Alzheimer's, experiencing agitation and delirium after prolonged use of psychiatric medications
- Delirium likely caused by the sedating effects of the medications
- Stopping most of the medications led to improvement in Jane's symptoms
- Importance of understanding potential long-term effects on mitochondrial function, especially in elderly individuals and those with dementia.
Hormones and Metabolic Regulators
Hormones:
- Chemical messengers produced in one cell and impacting other cells
- Numerous hormones in the human body, affecting mitochondrial function and causing epigenetic changes
- Change metabolism of cells, playing a role in mental and metabolic disorders
- Mitochondria supply energy for hormone production and release
Factors Affecting Hormone Levels:
- Biological, psychological, and social factors
- Hormones respond to stress and environmental opportunities
Hormonal Imbalances:
- Caused by various factors including autoimmune disorders, stress, aging, and mitochondrial dysfunction
Regulators of Metabolism and Mitochondrial Function:
- Hormones (e.g., cortisol, insulin, estrogen, thyroid hormone)
- Neuropeptides, mitokines, adipokines, myokines, RNA molecules, and other messengers
Cortisol:
- Plays an important role in the stress response
- High levels associated with metabolic disorders and mental symptoms
- Begins and ends with mitochondria, which initiate its production and bind to receptors
Insulin:
- Regulates glucose metabolism and sensing of glucose availability
- Mitochondrial dysfunction linked to both types 1 and 2 diabetes
- Plays a significant role in brain function, regulating metabolism, appetite, and neurotransmitter activity
Mitochondrial Dysfunction and Neurotransmitter Imbalances:
- Mitochondrial dysfunction can result from insulin receptor issues on neurons and support cells (astrocytes)
- Changes in brain energy metabolism, anxiety, and depressive behaviors linked to insulin receptor removal in animals
- Insulin resistance may have similar effects
- Animal study showed mitochondrial dysfunction and behavioral abnormalities with genetic removal of brain-specific insulin receptors
Insulin Resistance and Psychosis:
- Studies suggest insulin resistance might come before mitochondrial dysfunction, leading to psychosis
- Brain scans in people with schizophrenia and bipolar disorder revealed insulin resistance in patients and their siblings
- Mitochondrial function differences found between patients and siblings
Insulin Resistance and Alzheimer's Disease:
- Insulin resistance linked to mitochondrial dysfunction in Alzheimer's disease
- Brain's energy supply from glucose affected by insulin resistance
- Areas of the brain with plaques and tangles have the most significant impact
Historical Use of Insulin in Psychiatry:
- Insulin coma therapy used for mental disorders treatment from 1927 to 1960s
- Effective results reported but fell out of favor due to psychiatric medications
- Insulin making a comeback in Alzheimer's disease research using intranasal insulin delivery method
Measuring Insulin and Glucose Levels:
- Identifying problems like insulin resistance, hypoglycemia, and other issues important for treatment
- Fasting glucose and insulin levels, oral glucose tolerance tests, continuous glucose monitoring devices are available tools
- Collaborate with healthcare provider to get these tests.
Estrogen's Role in Mental Health
Estrogen as a Hormone:
- Plays an important role in mental health, obesity, diabetes, cardiovascular disease, and brain metabolism
- Affects mood, cognition, and other brain functions
- Mitochondria produce and bind to estrogen receptors
Fluctuations in Estrogen Levels:
- Women experience mental and metabolic symptoms related to monthly estrogen fluctuations (PMDD)
- Hormonal changes around menstruation, pregnancy, postpartum period, and menopause can affect mental health
- Estrogen levels decrease broadly during menopause, increasing risk for Alzheimer's disease
Estrogen as a Treatment:
- Oral contraceptives contain estrogen and progesterone with mixed effects on mood symptoms
- Thyroid hormone acts as the master regulator of metabolism, revving up mitochondria
Thyroid Hormone's Impact on Mitochondria
- Thyroid hormone stimulates mitochondria to produce ATP or heat
- Mitochondria have thyroid hormone receptors, allowing direct signaling
- Thyroid hormone acts through genes in the nucleus, impacting mitochondria
- Induces mitochondrial biogenesis, increasing cellular mitochondria count
- Stimulates mitophagy - mitochondrial repair process
Effects of Hypothyroidism
- Underactive thyroid gland produces less thyroid hormone than body requires
- Autoimmune disorder is most common cause, but there are others
- Can lead to weight gain, obesity, heart disease, fatigue, brain fog, depression
- Linked to bipolar disorder, schizophrenia, dementia when occurring during development (cretinism)
Thyroid Hormone as a Treatment
- Used for decades in treatment-resistant depression and bipolar disorder
- Increases metabolism and mitochondrial health and number
- Can cause unwanted symptoms due to cell overstimulation
Success Story: James' Case
- Fifty-four-year-old man with thirty-year history of bipolar disorder
- Depression recurred every fall until spring despite trying numerous medications
- Diagnosed with hypothyroidism, high blood pressure, cholesterol, and sleep apnea
- High-dose thyroid hormone treatment drastically improved symptoms
- Normal doses of thyroid medication were ineffective for depression treatment
- Continued to use low-dose antidepressant and sleep medication occasionally but hasn't experienced a severe depression in many years.
Inflammation's Role in Metabolism, Mental Health, and Mitochondrial Function
Observations about Inflammation:
- Many people consider inflammation as a bad thing
- Low-grade inflammation is often found in metabolic and mental disorders
- Neuroinflammation may be the root cause of some mental and neurological disorders
- Cytokine storms can kill people with COVID-19
- Lingering inflammation causes long COVID symptoms
- Autoimmune disorders are caused by inflammation and the immune system attacking the body's own cells
- A "leaky gut" can cause chronic inflammation
Beneficial Roles of Inflammation:
- Inflammation is involved in fighting off infections and healing injuries
- It serves important signaling functions
- Involved in the normal stress response
- Inflammatory cytokines send stress signals throughout the body and brain
- Microglial cells, the brain's immune cells, play a role in brain development, learning, and memory
Inflammation and Metabolism:
- Inflammation affects metabolism by allocating and using metabolic resources
- When inflammatory cytokines are released, more blood flows to the affected area, bringing oxygen, glucose, amino acids, and fats
- Inflammation triggers the production of immune cells and antibodies, which take energy and resources
- High levels of inflammation can change emotions, thoughts, motivations, and behaviors, conserving metabolic resources
Mental States Causing Inflammation:
- Loneliness increases the stress response and induces a specific pattern of immune cell activation, leading to chronic, low-grade inflammation
- Lonely people and monkeys were more vulnerable to viral infections
- Mental symptoms can cause inflammation, which can trigger or exacerbate mental and metabolic disorders
Examples of Inflammation's Impact on Disorders:
- Rhinitis (runny nose) increases the risk of depression by 86%
- Infections can lead to subsequent mental disorder diagnoses, including schizophrenia, OCD, personality disorders, and more
Mitochondria and Inflammation
Feedback Loop:
- Mitochondria involved in normal inflammatory response
- Inflammation can impair mitochondrial function
- Mitochondrial dysfunction can lead to inflammation
Mitochondria in Immune Response:
- Mitochondria play role in immune cell death when response should turn off
- Dysfunctional mitochondria can lead to overactive or underactive immune/inflammatory responses
Inflammation's Impact on Mitochondria:
- Tumor necrosis factor (TNF) directly inhibits mitochondrial function
- Interferon production influenced by mitochondria, can directly suppress ATP production and mitochondrial genes
Mental Disorders and Mitochondria:
- Medications like interferon can cause psychiatric symptoms due to mitochondrial dysfunction
- Inflammation during pregnancy linked to increased autism risk
- Mitochondrial dysfunction in other cells can lead to chronic inflammation
Mitochondria and Inflammatory Response:
- Mitochondria are powerful "damage-associated molecular patterns" (DAMPs) that trigger inflammation when released from struggling cells
- Inflammation is a normal response, not the primary problem, to metabolic dysfunction
Treatment Approaches:
- Suppressing inflammation with medications like antioxidants and anti-inflammatory agents has been disappointing for various disorders
- Addressing metabolic dysfunction directly, rather than just inflammation, may be more effective
Inflammation's Impact on Mental and Metabolic Health
Lifestyle Factors and Inflammation:
- Many lifestyle factors can cause widespread metabolic dysfunction, leading to chronic inflammation
- Addressing these lifestyle factors is powerful in decreasing inflammation and addressing metabolic and mental disorders
- Antioxidants alone do not counteract the negative effects of these lifestyle factors
Autoimmune Disorders and Inflammation:
- Autoimmune disorders are associated with high levels of inflammation, contributing to mental and metabolic disorders
- Addressing these may require anti-inflammatory treatments or addressing hormone deficiencies
Chronic Infections and Inflammation:
- Chronic infections (e.g., HIV, chronic Lyme disease, hepatitis) take a metabolic toll and can lead to problems
- Work with healthcare provider for optimal care
Allergies and Inflammation:
- Allergens can lead to chronic inflammation
- Sometimes allergens can be avoided; other times, treatments may be needed
Dental Hygiene and Inflammation:
- Dental hygiene affects inflammation, which in turn impacts metabolic and mental disorders
- Regular brushing, flossing, and dental checkups are important to reduce a source of inflammation
Summing Up:
- Inflammation plays a powerful role in mental and metabolic health
- Inflammation affects metabolism, and metabolic problems increase inflammation
- Poor diet, lack of exercise, sleep issues, smoking, alcohol/drug use are primary causes of low-grade inflammation
- Inflammation impacts mental states and vice versa
- Mitochondria's role in inflammation and immune cell function is complex and important for metabolic and mental health.
Sleep, Light, and Circadian Rhythms:
Interconnections and Impact on Health
Impact of Sleep on Metabolism and Disorders:
- Role in "rest and repair" state
- Decline in metabolic rate and body temperature during sleep
- Brain undergoes changes for learning and memory consolidation
- Importance of optimal sleep for adults: 7-9 hours per night
- Variations based on age, activity level, or other factors
Circadian Rhythms:
- Regulation by light and food intake
- Role in governing biological processes
- Impact on metabolism
Effect of Sleep Problems:
- Disruption due to psychological and social stressors
- Associated with mental disorders (depression, anxiety, etc.)
- Exacerbation of metabolic disorders (diabetes, obesity, heart disease)
- Contributing cause for onset of various disorders
Impact of Sleep Deprivation:
- Depression, anxiety, cognitive impairment, mania, psychosis in extreme cases
- Genetic association with clock genes and mental/metabolic disorders
- Increased risk for metabolic disorders: diabetes, epilepsy, Alzheimer's disease
Mitochondria's Role:
- Synchronized with circadian rhythms
- Energy production decreases at night, increases during the day
- Mitochondrial fission and ATP production controlled by DRP1 protein
- Feedback cycle between mitochondria and circadian clock through DRP1.
Impact of Sleep Deprivation on Mitochondrial Function:
- Impairment in mitochondrial function upon sleep deprival
- Specific impact on hypothalamus, an area regulating metabolism and hormones
- Hormonal imbalances caused by sleep problems (cortisol levels)
- Melatonin's role in mitophagy and cognitive impairment.
Long-Term Effects of Sleep Deprivation:
- Increased risk for Alzheimer's disease due to mitochondrial dysfunction and beta-amyloid accumulation.
Mitochondria's Role in Sleep and Mental Health:
NAD and Circadian Rhythm:
- NAD (nicotinamide adenine dinucleotide) is a metabolic cofactor controlled by circadian clocks
- Affects mitochondrial activity, resulting in more ATP production
- Disrupted circadian rhythm leads to off-balance NAD production and mitochondrial dysfunction
Mitochondria's Role in Sleep Regulation:
- Researchers have found that mitochondria play a direct role in regulating sleep in fruit flies
- Mitochondrial ROS levels linked to neurons that induce sleep
Impact of Mitochondrial Defects on Sleep Patterns:
- Fruit flies with mitochondrial defects exhibit disrupted circadian rhythms and sleep patterns
- Humans with mitochondrial defects often experience sleep-disordered breathing problems
Effect of Light on Mitochondria:
- Different wavelengths of light (red, blue) impact mitochondrial function differently:
- Red light stimulates ATP production
- Blue light inhibits ATP production and increases ROS production
Mitochondria's Role in Brain Function:
- Light exposure affects the brain through several mechanisms:
- SCN detects light, sending circadian signals to mitochondria
- Urocanic acid (UCA) produced from skin cell exposure to light stimulates neurons that make glutamate
- Brain photobiomodulation therapy increases ATP production and stimulates neuroplasticity through mitochondrial actions
Effects of Sleep, Light, and Circadian Rhythms on Symptoms:
- Mood disorders exhibit diurnal variation (fluctuations based on time of day)
- People with dementia can experience sundowning (agitation during night)
- Seasonal affective disorder is linked to reduced sunlight exposure
Treatment Approaches:
- Adequate sleep is crucial for mental and metabolic health
- Identify underlying causes of sleep problems through healthcare professionals' assessment.
Interventions for Treatment:
- Sleep hygiene: improving sleep quality through practices such as consistent bedtime routine, avoiding screens before bed, and creating a dark, quiet sleeping environment
- Cognitive behavioral therapy for insomnia (CBT-I): addressing negative thoughts and behaviors associated with sleep difficulties through therapy sessions
- Sleeping pills: short-term use for unusual stress situations but can impair natural sleep architecture and long-term use may have adverse effects
- Light exposure: correcting imbalances in light exposure during the day or at night, such as bright-light therapy (10,000 lux) to regulate circadian rhythms and improve sleep
- Brain photobiomodulation: an experimental intervention for various conditions including depression, dementia, Parkinson's disease, and trauma brain injury.
Success Story: Kaleb's Case:
- Struggled with ADHD, frustration, and depression since preschool
- Parents tried disciplinary strategies and rewards, then a stimulant medication for ADHD which caused sleep problems
- Insulin resistance: eating sweets to cope with stress and schoolwork, resulting in weight gain around the waist
- Interventions: cutting out sweets during the week and using bright-light therapy every morning while playing video games
- Improvements: tantrums at school stopped, depression and focus improved, straight As in high school even during COVID-19 pandemic.
Contributing Causes: Food, Fasting, and Gut
Diet's Effect on Metabolism and Mitochondria:
- Diet impacts obesity, diabetes, cardiovascular disease, mental health, brain function, appetite, eating behaviors, addiction, loneliness, social isolation, anxiety, depression.
- Neural circuits for appetite and eating behaviors overlap with neural circuits for social isolation and addiction.
Nutrients and Vitamins:
- Three vitamins required for energy metabolism within mitochondria: thiamine, folate, vitamin B12.
- Deficiencies in these vitamins can cause widespread symptoms including mental ones (depression, apathy, etc.).
- Importance of checking for deficiencies in patients with psychiatric and neurological disorders.
Food Quality:
- Food supply has changed dramatically in last fifty years: genetically modified plants, processed foods, artificial ingredients.
- Controversies over which dietary factors are bad for health (fat, carbohydrates, animal-sourced products).
Trans Fatty Acids (TFAs):
- Man-made, processed fats once marketed as healthier alternative to saturated fats.
- Toxic to human health: increased risk of cardiovascular disease, depression, behavioral aggression, irritability, Alzheimer's disease.
- Animal study showed TFAs can affect baby rats' anxiety levels, ROS production, inflammation, and glucocorticoid receptors in hippocampus.
Maternal Diet and its Impact on Children's Health:
- Study demonstrates interconnection between mother's diet during pregnancy and children's anxiety, mitochondrial function, inflammation, and glucocorticoid receptor levels (stress response)
- Trans fats banned in the US since 2018; potential link to higher rates of depression and anxiety among American youth?
Maternal Trauma and Mental Illness:
- Parents can transmit vulnerability to mental illness from their trauma history
- Research suggests that if a mother ate trans fats during pregnancy, it may affect metabolic health
Fiber and Mental Health:
- Fiber is crucial for overall health and aging
- High fiber intake associated with lower rates of depression and cognitive impairment (Mediterranean diet)
- Butyrate, a short-chain fatty acid produced by gut microbes from fiber, plays role in mental health:
- Serves as primary fuel source for mitochondria in gut cells and liver cells
- Directly impacts mitochondrial function, efficiency, and dynamics (fusion/fission)
- Plays a role in sleep regulation through the liver or portal vein
Overeating and Mental Health:
- Junk food can be addictive, leading to high insulin and glucose levels
- High blood glucose levels might impair mitochondrial function in neurons, affecting mood, cognitive processing, memory, attention, sadness, anxiety, and Alzheimer's disease risk.
Mitochondria's Role in Glucose Regulation:
- Mitochondria in the ventromedial nucleus of the hypothalamus (VMH) regulate glucose levels throughout the body by fission and ROS production control. Dysfunctioning mitochondria may cause glucose regulation issues, leading to sadness, anxiety, and increased Alzheimer's disease risk.
Obesity, Metabolism, and Mitochondrial Function:
- Impact of Obesity on Metabolism: Thin individuals feel "stuffed" after overeating, leading to decreased food intake or increased metabolism. Obese people have different responses: metabolic rate may not increase, or metabolism can decrease (metabolic adaptation).
- Mitochondria's Role in Obesity and Mental Health: Both conditions are linked to mitochondrial dysfunction; impaired mitochondria can worsen both obesity and mental disorders.
- Insulin Resistance and Mitochondrial Function: Insulin resistance (IR) affects both body and brain metabolism, leading to increased insulin production and impaired mitochondrial biogenesis. This inhibits the body's response to stress and promotes weight gain.
- Mitochondria and Brain Cells: Dysfunctional mitochondria in brain cells can cause inflammation, leading to obesity even before any significant weight gain. UCP2 protein plays a role in this process by affecting mitochondrial dynamics (movement, fusion, and fission).
- Mitochondria and Food Consumption: Mitochondria play a crucial role in the brain's response to high-calorie diets, potentially driving obesity or preventing it. More research is needed on how mitochondrial function affects long-term health outcomes when consuming toxic foods.
Fasting, Starvation, and Eating Disorders:
- Fasting: Going without food for any length of time; changes to metabolism and mitochondria occur during extended fasting periods.
- Impact on Metabolism: Fasting leads to increased metabolic rate and weight loss in some cases. Conversely, starvation can result in decreased metabolic activity and weight gain due to the body's attempt to conserve energy.
- Eating Disorders: Mitochondrial dysfunction is linked to anorexia nervosa and other eating disorders, further emphasizing the connection between mitochondrial function, metabolism, and mental health.
Effects of Fasting on the Human Body and Mind
Benefits of Fasting:
- Prompts body to be frugal
- Encourages autophagy
- Healing potential for cells
- Mitochondria change shape and form long tubular networks
- Spring-cleaning process for cells
- Healthy mitochondria are protected
Consequences of Starvation:
- Lowered metabolism to conserve energy
- Heart rate slows, body temperature declines
- Sluggish, irritable, unmotivated, distractible, obsessed with food
- Depression, anxiety, fatigue, poor concentration, hypomania symptoms
- Malfunctioning cells and organ failure (brain included)
- Mental symptoms: depression, irritability, insomnia, mania, eating disorders, confusion, memory disturbances, hallucinations, delusions
Eating Disorders:
- Starvation can cause mental symptoms
- Societal pressure to lose weight and be thin
- Young women in ballet dancing experience metabolic disturbances
- Impaired feeding behaviors and body image distortion
- Anorexia: mitochondrial impairment in brain, oxidative stress, specific part of mitochondria affected
- Vulnerability to eating disorders due to preexisting mental health issues or rewarding experiences from overeating or undereating.
The Role of Gut-Brain Axis and Microbiome in Mental Health
Impact of Eating Disorders on Mental Health:
- May become a way of life for some, despite causing health problems
- Increases risk of developing mental disorders due to seeking relief from discomforts
Gut-Brain Axis and Microbiome's Role in Health:
- Intestinal tract plays significant role in metabolic and mental health
- Communication between gut and brain occurs through various mechanisms:
- Trillions of bacteria, fungi, and viruses influence weight gain or loss by altering nutrient extraction
- Hormones and neuropeptides produced by cells lining the intestinal tract travel to brain and affect metabolism and brain function
- Gut has an intricate nervous system that communicates directly with the brain via vagus nerve
Role of Gut Microbiome in Mental Disorders:
- Increasing evidence for its role in depression, anxiety, autism, schizophrenia, bipolar disorder, eating disorders, epilepsy, and neurodegenerative disorders
- Gut bacteria produce metabolites, neurotransmitters, and hormones that affect brain function when absorbed into the bloodstream
Interactions between Mitochondria, Gut Microbes, and Signals:
- Gut microbes send signals directly to mitochondria in cells lining the gut and immune cells, changing metabolism and inflammation.
Dietary Interventions as Treatments for Mental Symptoms:
- Addressing nutritional deficiencies or removing dietary allergens/toxins
- Eating a healthy diet, such as Mediterranean diet
- Fasting, intermittent fasting (IF), and fasting-mimicking diets to improve metabolic health by stimulating autophagy and mitophagy
- Improving gut microbiome balance through dietary changes or supplements
- Changing diet to address metabolism and mitochondrial function issues
- Losing weight for those who are obese or gaining weight for underweight individuals.
Caution with Nutraceuticals and Vitamin Supplements:
- Taking excessive vitamins and supplements may cause metabolic problems; balance is key
- A comprehensive discussion of various nutraceuticals and their effects on mitochondrial function is beyond the scope of this book.
Mediterranean Diet and Mental Health
Benefits of Mediterranean Diet (MD) for Depression:
- Reduces depression risk: MD adherents less likely to develop depression
- Improves symptoms in some people with major depression
- SMILES trial showed higher remission rate (32% vs. 8%)
Mitochondria's Role:
- Studies on monkeys revealed improved brain mitochondrial function and energy utilization patterns on MD
- Fasting, intermittent fasting (IF), and fasting-mimicking diets also play a role in mental health treatment
- Ketones produced during fat metabolism serve as alternate energy source for cells and signal molecules
Benefits of Intermittent Fasting:
- Improves mood, cognition, and neuron protection from Alzheimer's disease and epilepsy
- Higher levels of GABA activity reduce hyperexcitability in the hippocampus region
- Mitigates oxidative stress, inflammation, improves mitophagy and biogenesis, increases BDNF production
Ketogenic Diet:
- Developed as a fasting alternative to prevent starvation for epilepsy treatment
- 85% success rate in seizure reduction or stoppage (1920s)
- Resurrected in the 1970s for treatment-resistant epilepsy
- Best-studied dietary intervention for its effects on the brain
The Ketogenic Diet and its Impact on Metabolism and Mental Health
Benefits of the Ketogenic Diet:
- Provides alternate fuel source for insulin-resistant brain cells
- Changes neurotransmitter levels
- Regulates calcium channels
- Decreases inflammation
- Improves gut microbiome
- Increases overall metabolic rate
- Reduces insulin resistance
- Induces mitophagy and mitochondrial biogenesis
Long-Term Healing:
- After months or years on the diet, cells have more healthy mitochondria
- Can stop the diet after 2-5 years and remain well
- Effective for severe, treatment-resistant psychotic disorders
Clinical Trials:
- Ongoing trials for bipolar disorder and schizophrenia
- Small Alzheimer's disease trial showed improvement in daily function and quality of life on ketogenic diet
Versions of the Ketogenic Diet:
- Tailored to personal preferences (vegetarian, vegan, carnivore)
- Important to work with healthcare provider for medical supervision
Gut Microbiome and Mental Health:
- Role in mental and metabolic health is in its infancy
- Interventions: avoid antibiotics, diet, probiotics, fecal microbial transplants (experimental)
Dietary Considerations:
- Identify and correct dietary deficiencies
- Avoid allergens and toxic foods
- Change diet to address underlying insulin resistance
- Dietary interventions can still play a role in treatment even if metabolic issues are non-dietary
Success Story: Mildred's Journey
- Abusive childhood leading to PTSD, anxiety, depression, schizophrenia diagnosis at age 17
- Tried various medications with no improvement
- Obese, weighing 330 pounds by age 70
- Encouraged to try ketogenic diet for weight loss at Duke University clinic
- Noticed significant improvements in psychotic symptoms within two weeks
- Lost 150 pounds and remains symptom-free off medication after thirteen years.
Contributing Causes: Drugs and Alcohol
Impact of Drugs and Alcohol on Mental Disorders:
- Drugs and alcohol lead to mental disorders
- People with mental disorders more likely to use drugs and alcohol
- Both substances and predisposition contribute to mental illness
- Brain energy theory offers clarity: drugs converge on metabolism and mitochondria
Drugs and Mitochondria:
- Most drugs stimulate or inhibit cells
- Broad effects throughout the body
- Receptors found on mitochondrial membranes
- Drugs impact mitochondrial function directly
Feedback Loop:
- Different ways to enter feedback loop: social influences, predisposition
- Impaired metabolism and mitochondrial function
- Dependence on substances for feeling normal
- Vicious cycle leading to continued use
Impact of Alcohol:
- Profound effects on metabolism and mitochondria
- Toxic to liver and brain
- Mitochondria play primary role in toxicity
- Alcohol dehydrogenase (ADH) converts alcohol into acetaldehyde
- CYP2E1 enzyme located on mitochondria or endoplasmic reticulum
- Acetate used as fuel source by mitochondria
Impact of Excessive Alcohol Use:
- Enzyme systems back up, leading to increased acetaldehyde levels
- Mitochondrial impairment and destruction from large doses
- Chronic alcohol consumption causes chronic oxidative stress
- Lasting effects on mitochondria: swelling, reduced ATP production, calcium management issues.
Dr. Nora Volkow's Research on Addiction and Metabolism:
- Dr. Nora Volkow, director of National Institute on Drug Abuse (NIDA), has studied connections between addiction and metabolism for years
- Chronic alcoholics use less glucose in brain and instead rely on acetate from alcohol as energy source
- Alcoholics develop problem with brain glucose metabolism, leading to energy deprivation when sober
- Ketogenic diet showed promise in improving brain metabolism and reducing withdrawal symptoms among alcoholics
- Participants on ketogenic diet needed less detox medication and had fewer cravings
- Brain scans showed improved brain metabolism and reduced inflammation compared to those on standard American diet
- Pilot study demonstrated potential of dietary intervention for alcohol use disorder treatment
Caution:
- Ketogenic diet can increase blood alcohol levels fivefold in rats, leading to increased intoxication risk for individuals with alcohol use disorder.
Marijuana and Brain Energy Theory:
- Marijuana affects endocannabinoid system, targeting CB1 and CB2 receptors located on cell membranes and mitochondria
- Predominant effect is slowing mitochondrial function in neurons through CB1 receptors
- Impacts memory, social behavior, and synaptic function by affecting mitochondrial movement and energy sources
- Long-term use can cause brain aging and thinner cortical regions due to mitochondrial dysfunction.
Mitochondria's Role in Substance Use:
- Various substances impact metabolism and mitochondria, including tobacco, alcohol, caffeine, supplements, marijuana, and recreational drugs
- Addressing substance use is crucial for improving both metabolic and mental health symptoms.
Chapter 17 - Contributing Causes: Physical Activity
The Benefits of Exercise
- Reduces risk for metabolic disorders (obesity, diabetes, cardiovascular disease)
- Improves mental health and wellbeing
- 43% fewer days of poor mental health for exercisers
- Any type of exercise is better than none
- Optimal "dose": 45 minutes, 3-5 times per week
Correlation vs. Causation
- Correlational studies do not prove causation
- Exercise and good health may be related due to reverse causation (healthy people can exercise)
Exercise and Cognitive Decline
- Study found that exercise doesn't prevent cognitive decline
- After controlling for socioeconomic factors, menopause, diabetes, and hypertension, exercise made no difference
- Exercise may still be beneficial due to its impact on mitochondria in the brain
Exercise as a Treatment for Mental Disorders
- Mixed results from studies on exercise as a treatment for depression
- Some show benefits, others don't
- World Health Organization states that exercise improves mood, slows cognitive decline, and delays disease onset in people with depression, schizophrenia, and dementia
Factors Affecting Exercise Effectiveness
- Insulin resistance may block the benefits of exercise (study found significant differences in energy metabolism, oxidative stress, inflammation, tissue repair, and growth factor responses)
- Other lifestyle factors and medications can also impair mitochondrial function, interfering with the beneficial effects of exercise.
Effects of Metformin on Mitochondrial Function during Exercise
- Study: older adults, 12 weeks of aerobic training, metformin vs placebo
- Both groups had reduction in fat mass, glucose, insulin levels
- However, metformin group had no change in whole-body insulin sensitivity
- No improvements in muscle mitochondrial function (study: "Metformin Inhibits Mitochondrial Adaptations to Aerobic Exercise Training in Older Adults")
- Metformin inhibits mitochondrial adaptations during exercise training for older adults
Medication Impact on Exercise and Mitochondria
- Diabetes medications, including metformin: can cause weight gain and insulin resistance over time
- Psychiatric medications (antipsychotics): known to cause serious metabolic disturbances and mitochondrial dysfunction
- People taking these medications may not get full benefits from exercise
Mitochondria's Role in Exercise Benefits for Brain Disorders
- Mitochondria play a role in translating exercise into beneficial effects on the brain
- Neuron development depends upon mitochondrial function (studies: "Mitochondria and Stem Cells")
- Impaired mitochondrial health may prevent full benefits of exercise for mental illness patients
Exercise's Role in Metabolic Capacity Improvement
- Maintaining current abilities: leisurely walk around the block
- Improving metabolic capacity: pushing oneself to increase strength, flexibility, etc. (studies: "Exercise and Metabolism")
- Increased mitochondrial number and improved health in muscle and brain cells
Challenges with Exercise for Metabolically Compromised Individuals
- Risk of injury and heart attacks
- Difficulty following through due to lack of energy and motivation (studies: "Exercising Your Way Out of Depression")
Exercise as a Treatment Summary
- Yes, everyone should exercise, but it may be more challenging for those with chronic mental disorders
- Identify and address factors impairing mitochondrial function for full benefits (studies: "Mitochondrial Dysfunction in Mental Disorders")
- Exercise can improve metabolic capacity, prevent or alleviate mental and metabolic disorders.
Chapter 18: Love, Adversity, and Purpose in Life
Importance of Biological and Environmental Factors for Metabolic and Mental Health:
- Both biological factors (discussed previously) and environmental factors play significant roles
- Environmental factors include food, shelter, temperature, light, infections, allergens, lifestyle choices, people, experiences, love, and purpose in life
Use It or Lose It:
- Applies to more than just muscles: also relates to the brain
- Use leads to growth and resilience; non-use results in atrophy or shrinking
- Body adapts and adjusts metabolic resources based on usage
Brain Development:
- Needs appropriate learning experiences from humans for proper skill acquisition
- Social skills essential for human survival
- Brain undergoes "developmental windows" during which it learns and adapts
Impact of Neglect and Abuse:
- Can lead to various diagnostic categories including autism, learning disorders, mental retardation, PTSD, anxiety disorders, impulse control disorders, mood disorders, personality disorders, and psychotic disorders
- Brain energy problem due to reduced glucose metabolism in some cases
- Developmental windows can close, leading to potential loss of normal brain development
Screen Time and ADHD:
- Children exposed to excessive screen time more likely to develop ADHD
- Two explanations:
- Environment is driving the diagnosis (children learn constant stimulation as norm)
- Biology is the problem (inadequate metabolic activity in specific brain regions)
- Correcting metabolic issues may be necessary for solving the problem.
Strengthening Brain Regions:
- Neurons grow, adapt, and form new connections when used
- Metabolism and mitochondria adapt to needs
- Stress response requires energy and resources, diverting from other cells
- Chronic stress can result in maintenance problems in cells leading to mental and metabolic disorders
Mitochondria's Role in Stress Response:
- Influence all aspects of the stress response
- Production and regulation of hormones and neurotransmitters
- Nervous system responses
- Inflammation
- Epigenetic changes
- Dysfunctioning mitochondria can affect overall health
- Study: direct relationship between everyday stress and mitochondrial function in humans
Impact of Stress on Mitochondria:
- Impairment in mitochondrial function under stress
- Can lead to malfunctioning cells, exacerbating symptoms of mental and metabolic disorders
Stressful Life Events:
- Holmes-Rahe Stress Inventory: common life events and their impact on health
- Death of a spouse or close family member
- Divorce
- Personal injury
- Getting fired
- Retirement
- Reasons for stress: loss, purpose in life, etc.
Purpose in Life:
- Humans are driven to have a sense of purpose
- Hardwired into our brains
- Multifaceted: relationships, self-care, job/purpose
- Dr. Viktor Frankl's observations from concentration camp prisoners
- Those with a sense of purpose had hope and were less depressed
- Logotherapy: psychotherapy based on meaning and purpose in life
- Strong correlation between low sense of purpose and metabolic/mental health issues, early death.
Benefits of a Strong Sense of Purpose:
- Lower cortisol and inflammation levels (studies show health benefits)
- Reduced all-cause mortality and cardiovascular events (meta-analysis)
Spirituality and Religious Beliefs:
- Positive impact on mental health: reduced depression risk
- Brain differences found in those with high importance placed on religion/spirituality
- Decreased rates of cardiovascular disease and all-cause mortality (systematic review)
Addressing Love, Adversity, and Purpose with Treatment:
General Rule for Human Health:
- Maintain full lives: close relationships, meaningful roles, adherence to responsibilities/obligations, adequate resources
Societal Factors Affecting Health:
- War, trauma, poverty, malnutrition, neglect, racism, homophobia, misogyny, ACEs (address efforts to address these issues)
Benefits of Psychotherapy:
- Resolve conflicts: reduce stress impact on metabolism
- Offer skills and strategies for coping with symptoms: improve overall metabolic function
- Change behaviors: enhance sleep quality and address maladaptive responses (trauma, substance use disorders)
- Provide new learning to overcome beliefs, behaviors, and responses that are not adaptive or helpful
- "Exercise" underused brain circuits: strengthen development in underdeveloped regions.
Brain Health Restoration: Psychotherapy and Stress Reduction
Psychotherapy:
- Offers relationship with compassionate human being
- Improves mental health outcomes through altered metaphysical beliefs
- Psychedelic therapy as emerging treatment, but not recommended alone
Stress Reduction:
- Eliminate or reduce stressful environmental factors
- Find a new job, change school/workload, seek accommodations
- Manage stress response when safe to do so
- Meditation, prayer, chanting, yoga, Pilates, tai chi, qigong, mindfulness, breathing techniques
Relaxation Response:
- Stress reduction technique
- Improves mental and metabolic health
- Enhances gene expression related to energy metabolism, mitochondrial function, insulin secretion, and telomere maintenance.
- Upregulates mitochondrial ATP synthase and insulin genes
- Promotes mitochondrial resiliency.
Rehabilitation Programs for Chronic Mental Disorders
Importance of Skills Training:
- Many people with chronic mental disorders lack essential skills to thrive independently
- Skills like managing a daily schedule, making friends, holding a job, and finding purpose are crucial
- Restoring metabolic health in the brain won't automatically teach these skills
Role of Rehabilitation Programs:
- Offer education, job training, and basic life skills to individuals with chronic mental disorders
- Aim to help people live as productive members of society
- Need to restore brain function first before effective rehabilitation can occur
Challenges in Current Rehabilitation Programs:
- Lack of focus on restoring brain function prior to skill development
- People trying to perform tasks with impaired brains may experience failure
- Compassion and human connection are essential for the recovery process
Success Story: Sarah's Journey
- Diagnosed with ADHD, learning disability, anxiety, depression, low self-esteem, and panic attacks
- Struggled academically despite medication and had few friends
- Family history of mental illness
- Tried various medications without significant improvement
- Experienced migraines and stomach pain
- Found solace in Pilates classes, leading to exercise regularity and improved mood/anxiety symptoms
- Became an instructor, discovering passion for helping others and making new friends
- Dropped out of college to focus on exercise as a career
- Continues to thrive with minimal medication usage
Key Takeaways:
- Environment, experiences, relationships, roles in society play significant roles in mental/metabolic health
- Psychotherapy can aid metabolic treatment, including diet, exposure to light, and job training for individuals with chronic mental disorders.
Why Do Current Treatments Work?
Evidence-Based Treatments for Mental Disorders:
- Talking (psychotherapy)
- Chemicals (medications)
- Electricity (ECT)
- Magnetic fields (TMS)
- Brain surgery
Explanation of Treatment Effectiveness:
- Impact metabolism and mitochondria
- Changes in neurotransmitter levels, hormones, and neuroplasticity
ECT and TMS:
- Deliver energy directly to the brain
- Stimulate mitochondria and promote mitochondrial biogenesis
- Improve neurotransmitter and hormonal imbalances
- Increase neuroplasticity
Brain Surgery and Electrical Stimulators:
- Cut off overactive brain regions (e.g., epilepsy)
- Stimulate underactive brain regions (e.g., pacemakers for heart)
- Suppress overactive brain regions with fast-paced stimulation (e.g., vagus nerve stimulation)
Treatment Options:
- ECT, TMS, VNS, and/or brain surgery as last resort or emergency treatment
- Brain energy theory offers numerous other treatment options before these are needed
Metabolic Treatment Plan: Developing Your Personalized Approach
Identifying Problems
- Metabolism issues often stem from environmental factors, not genetic defects
- Multifactorial causes require comprehensive diagnosis and treatment
- Diet
- Exercise
- Stress
- Light
- Sleep
- Hormones
- Inflammation
- Relationships
- Love
- Meaning/purpose in life
- Even inherited epigenetic factors can be changed
Treatment Approach
- Personalized medicine recognizes unique treatment plans
- Seek professional help for serious mental disorders
- Dangerous symptoms: hallucinations, delusions, suicidal thoughts/behaviors, self-injury, aggression, substance abuse, eating disorders
- Multifaceted approach required
- Identify offending factors and address them
- Use interventions to improve mitochondrial function or increase supply of mitochondria
- Normal, healthy mitochondria can often fix problems on their own
Implementation Strategy
- Start with one treatment
- Gradually add additional treatments as improvement occurs and energy increases
- Recognize that success requires time and effort.
Metabolic Treatment Plans
Effects on Metabolism:
- Interventions can have four types of effects:
- Initiation: Abruptly shifts metabolism, can be helpful or harmful initially
- Adaptation: Body adapts to the intervention, lessening its initial effects
- Maintenance: Metabolism becomes fully adapted to the intervention, stability is achieved
- Withdrawal: Intervention is reduced or stopped, metabolism rebounding too high or low
Designing a Comprehensive Treatment Plan:
- For those with serious mental disorders and impaired brain function:
- Work with a clinician to develop a comprehensive treatment plan
- Identify contributing causes leading to severe metabolic impairment or safety threats (e.g., substance use, abuse, eating disorders, lack of sleep)
- Address these causes first before implementing other treatments
- Choose one or more treatments and give them at least three months to work
- If a treatment doesn't help after three months, consider stopping it
- If a treatment helps but doesn't resolve all symptoms, add another treatment
- Continue adding/trying treatments until desired results are achieved, goals may change over time.
Inpatient and Residential Treatment Programs:
- For those with severe mental disorders or safety concerns:
- Develop inpatient and residential metabolic treatment programs
- Provide customized treatment plans and support from professionals and peers
- Environments where participants can improve their mental and metabolic health together.
Beth's Success Story:
Background:
- Began psychiatric treatment at age 9 for ADHD
- Diagnosed with various disorders: chronic depression, panic disorder, borderline personality disorder, premenstrual dysphoric disorder, and ADHD
- Prescribed multiple medications with limited success
- Frequent hospitalizations
Struggles:
- Impulsive behavior
- Lack of friends
- Low self-esteem
- Chronic depression
- Suicidal thoughts
- Self-harm
- Worsening symptoms despite medication use
Interventions:
- Dialectical Behavior Therapy (DBT) to manage emotions and impulses
- Gradual tapering off medications due to dangerous side effects
- Exercise as a recovery tool
Milestones:
- Finished college
- Became an accomplished athlete
- Found love, job, and self-respect
Outcome:
- Improved mental health and energy levels
- No longer needed psychiatric treatment or medications
- Full recovery from various disorders
Key Insights:
- Medications may contribute to problems for some individuals
- Importance of exercise and healthy lifestyle in recovery.
A New Day for Mental and Metabolic Health
Brain Energy Theory:
- Offers a new model of mental health
- About metabolism and mitochondria, impacting various aspects of human health, aging, and longevity
- Cuts across diagnostic categories and addresses many disorders
- Applies to "mental" illness and related metabolic disorders (e.g., obesity, diabetes, cardiovascular disease, Alzheimer's, epilepsy, chronic pain)
- Offers hope for preventing illnesses and extending healthy, productive life
Theory of Brain Energy:
- Connects the dots to provide a clearer picture of mental illness
- Integrates biological, psychological, and social theories
- Sees mental disorders as metabolic disorders of the brain
- Requires restoring brain energy through normalizing metabolism and mitochondrial function
Potential Applications:
- More effectively applying existing treatments
- Developing new treatment options (e.g., therapeutics, diagnostics, understanding impacts of medications, toxins, etc.)
- Need for multidisciplinary healthcare teams
- Advocacy and self-help initiatives
- Ensuring opportunities for all people to live meaningful lives
Call to Action:
- Grassroots movement to drive changes in understanding and treating mental illness
- Educating and informing the public will take time and effort
- Let's end the suffering and not waste another day