From Dr. David Avery

1. From Dr. David Avery

2. Mapping Mental Illness: What Discoveries in Neuroscience Reveal about the Roots of Schizophrenia, Depression, Bipolar Disorder, and Alcoholism.

3. Summary • Mental Illnesses are real illnesses. • Mental Illnesses are strongly determined by environmental and genetic factors and are associated with changes in the brain. • Treatments are effective. • Those with mental illnesses have often been neglected by society. • We should encourage the mentally ill to exercise their free will while we recognize that their free will might be limited by powerful biological and psychological forces. • Recognition of the reality of mental illness and empathy for that suffering can help move us to action in helping the mentally ill.

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5. Mental Illnesses are Real Illnesses • Although public opinion toward mental illness has changed somewhat over the last 50 years, a common attitude in society is that mental illnesses are not “real” illnesses. • Some still say, “They have simply made bad choices” • Empathy sometimes is difficult to muster. • Public policy toward the homeless mentally ill reflects this. • Many are not aware of the power of the forces determining behavior in the mentally ill.

6. Why Skepticism about Mental Illness? • Unlike other medical disorders, like diabetes, no definitive lab tests. • Mental illness involves behavior. • In the absence of knowledge about the environmental and biological factors involved, the behaviors may appear entirely volitional.

7. Outline • History • Definitions of Major Depression, Bipolar Disorder, Schizophrenia • Prevalence • Environmental Factors • Genetic Predisposition • Brain Structure and Function • Treatments • Choice or Illness? • Empathy

8. 1955 1969

9. Major Depressive DisorderFive (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: • 1) depressed mood most of the day • 2) markedly diminished interest or pleasure in all, or almost all, activities • 3) significant weight loss when not dieting or weight gain or decrease or increase in appetite • 4) insomnia or hypersomnia • 5) psychomotor agitation or retardation • 6) fatigue or loss of energy • 7) feelings of worthlessness or excessive or inappropriate guilt • 8) diminished ability to think or concentrate, or indecisiveness • 9) recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

10. Bipolar Disorder: Major Depressive Episode + a Manic or Hypomanic episode Criteria for a manic episodeA distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least one week (or any duration if hospitalization is necessary). During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: • inflated self-esteem or grandiosity, potentially including grandiose delusion • decreased need for sleep (e.g., feels rested after only 3 hours of sleep) or persistent difficulty falling asleep • more talkative than usual or pressure to keep talking • flight of ideas or subjective experience that thoughts are racing • distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli) • increase in goal-directed activity (either socially, at work or school, or sexually or psychomotor agitation • excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

11. Schizophrenia Two or more of the following, each present for much of the time during a one-month period (or less, if symptoms remitted with treatment): • Delusions • Hallucinations • Disorganized speech, which is a manifestation of formal thought disorder • Grossly disorganized behavior (e.g. dressing inappropriately, crying frequently) or catatonic behavior • Negative symptoms: Blunted affect (lack or decline in emotional response), alogia (lack or decline in speech), or avolition (lack or decline in motivation) Duration of at least one symptom for 6 months.

12. Alcohol Dependence DSM-IV Alcohol Dependence (3 criteria for over 1 year) : • Tolerance (increased drinking to achieve same effect) • Alcohol withdrawal signs or symptoms • Drinking more than intended • Unsuccessful attempts to cut down on use • Excessive time related to Alcohol (obtaining, hangover) • Impaired social or work activities due to Alcohol • Use despite physical or psychological consequences

13. One Year Prevalence Rates- What percent have experienced the disorder in the past year? NIMH, 2008

15. Prevalence of Alcohol Dependence

16. Homelessness, Mental Illness, and Alcoholism • 39% report some form of mental health problem, and 20 to 25 percent meet criteria for serious mental illnesses. • 38% report alcohol use problems. • 26% report other drug use problems. • 66% report substance use and/or mental health problems. http://mentalhealth.samhsa.gov/publications/allpubs/homelessness/

17. Mentally ill die 25 years earlier, on average People with serious mentalillness die at age 51, on average, compared with age 76 for Americans overall. Their odds of dying from the following causes, compared with the general population: Cause:Times more likely to die: • Heart disease 3.4 • Diabetes 3.4 • Accidents 3.8 • Respiratory ailments 5 • Pneumonia, influenza 6.6 Source: Joseph Parks, Missouri Department of Mental Health

18. Suicide and Mental Illness More than 90 percent of people who kill themselves have a diagnosable mental disorder, most commonly a depressive disorder or a substance abuse disorder. Cornwell et al, 1995

19. Avery,1977

20. If mental illness is a myth, it a myth associated with increased mortality.

21. A Bio-Psycho-Social Modelof Mental Illness: • Biological Factors • Psychological Factors • Social Factors

22. Bio-Psycho-Social Model of Depression: Examples of Some Biological Factors • Genetic Predisposition • Decreased 5HIAA (metabolite of serotonin) in urine • Increased Cortisol Levels • Short REM Latency • Increased EMG activity • Decreased Sweating • Decreased Salivation • High Nocturnal Temperatures • Etc.

23. Bio-Psycho-Social Model of Depression: Examples of Some Psychological Factors • Loss of Parent • Childhood Abuse • Low Self Esteem • Guilt, Self-reproach • Pessimistic World View • Etc.

24. Interaction between Genetic Predisposition (e.g.,Serotonin Transporter Polymorphisms) and Stressful Life Events (Caspi, 2003)

25. Social Connectedness Fosters Happiness DDB Needham Life Style Survey Archive, 1975-98 (From”Bowling Alone”, Putnam, 2000)

26. Environmental Influences may be Psychological or Biological Schizophrenia associated with significantly greater probability of: • Medically complicated births. • Viral infection during pregnancy • Viral infection during childhood.

27. Major Depressive Disorder with a Seasonal Pattern (Winter Depression, Seasonal Affective Disorder,SAD) • Hypersomnia (excessive sleep) or difficulty awakening in the morning. • Increased food intake, especially carbohydrate craving • Increased weight • Low mood • Increased irritability • Low energy • Low interest

28. Winter Depression • Greater prevalence at higher latitudes • Associated with abnormalities of the timing of the body clocks. The rhythms of temperature, cortisol, melatonin, and thyroid stimulating hormone are phase delayed. • Effective treatment with bright light treatment • Effective response is associated with normalization of the timing of body clocks.

29. H H H O C C N C CH3 CH30 H H N H Circadian Rhythms and the Suprachiasmatic Nucleus (SCN) Melatonin(N-acetyl-5methoxytryptamine) SCN MEL Adapted from Brzezinski A. N Engl J Med. 1997;336:186-195.

30. We Are Grounded in Nature • Our body clocks respond to light in a very similar way to other animals. • We respond to the changing photoperiod (time from sunrise to sunset) just as many other mammals do. • Winter depression can be viewed as a “Hibernation Response”.

31. Bipolar Disorder and Circadian Rhythms • Bipolar disorder is associated with abnormal timing (desynchronization) of circadian rhythms • A regular light-dark cycle and regular sleep-wake cycle may be helpful in stabilizing the mood swings of bipolar disorder.

32. Treatment of Rapid Cycling Bipolar Patient Using Extended Bed Rest and Darkness

33. Treatment of Rapid Cycling Bipolar Patient Using Extended Bed Rest and Darkness

34. Light-Dark PrinciplesTo Stabilize Body Clocks, Sleep, and Mood • Increase Daytime Light Exposure • Decrease Evening and Nighttime Light Exposure • Create a Regular Sleep-Wake Cycle and Light-Dark Cycle • Find the Optimal Duration of Darkness and Sleep: Avoid Sleep Deprivation. Avoid Excessive Sleep. • “Dark Therapy” : • Dim Lights 2 hours before desired time of sleep onset • Do not turn on lights if one wakes up in the middle of the night.

35. Genetic Studies

36. Twin Studies Can Estimate the Role of Genetic Factors • Identical (Monozygotic) twins have the same genes whereas fraternal (Dizygotic) twins share about 50% of their genes. • If one of the twins has a disorder and the other twin also has the disorder, they are Concordant • If one of the twins has a disorder and the other twin does not have the disorder, they are Discordant. • If the Concordance rate is significantly higher in Monozygotic compared to Dizygotic twins, then heritability is probably present.

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38. Schizophrenia and Genetics • Schizophrenia is not a single illness; there are many subtypes of schizophrenia. • Multiple rare genes are associated with schizophrenia. • Genes associated with schizophrenia are commonly involved in the development of the nervous system. • Many are associated with spontaneous mutations of the genes, that is, not inherited from parents. Walsh et al, 2008

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41. If mental illness is a myth, it is a myth associated with strong genetic predispositions.

42. Imaging Studies of the Brain

44. Major Neurotransmitters • Amino acids: glutamate, aspartate, serine, gaba-aminobutyric acid (GABA), glycine • Monoamines: dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine (adrenaline), histamine, serotonin (5-HT), melatonin • Others: acetylcholine (ACh), adenosine, anandamide, nitric oxide, endorphins, etc

47. Areas Involved in Emotional Regulation Figure 1. Key structures in the circuitry underlying emotion regulation. (A) Orbital prefrontal cortex in green and the ventromedial prefrontal cortex in red. (B) Dorsolateral prefrontal cortex. (C) Amygdala. (D) Anterior cingulate cortex. Each of these interconnected structures plays a role in different aspects of emotion regulation, and abnormalities in one or more of these regions and/or in the interconnections among them are associated with failures of emotion regulation and also increased propensity for impulsive aggression and violence. [From Davidson, Science, 2000]

48. Importance of Prefrontal Cortex:Phineas Gage --1848

49. Major Depression: Critical Change Necessary for Response: ↓ Subcallosal Cingulate (SCC25) Activity Sad Memory Tryp Deplete Increased SCC25 activity seen with induced depressed mood Cg25 activity Mayberg Talbot Decreased SCC25 activity seen with diverse successful treatments (Other changes seen, but more treatment specific) SSRI SNRI Placebo Cg25 Cg25 Cg25 Mayberg Mayberg Kennedy ECT rTMS Nobler George

50. The brain is not exempt from abnormal functioning and structural change. • Just as the heart may have an arrhythmia, the brain can become desynchronized.