Affective Disorders

Advanced Seminars in Neuroendocrinology

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SharleenYuan – 4 September

“I SWEAR I’M NOT CRAZY!!”A Very Brief Primer on Affective Disorders and the Affective Spectrum

  1. Affective Disorders = Mood Disorders
  2. Depressive disorders
  3. Bipolar disorders
  4. Substance-Abuse Mood Disorders
  5. ADHD
  6. Attention-Deficit/Hyperactivity Disorder
  7. Anorexia nervosa
  8. Bulimia nervosa
  9. Cataplexy
  10. Dysthymic Disorder
  11. Schizophrenia
  12. Schizoaffective Disorder
  13. Social Phobias
  14. Fibromyalgia
  15. Generalized Anxiety Disorder
  16. Irritable Bowel Syndrome
  17. Migraines
  18. OCD
  19. Obsessive-Compulsive Disorder
  20. Panic Disorder
  21. PTSD
  22. Post-Traumatic Stress Disorder
  23. Premenstrual Dysphoric Disorder
  24. PMS
  25. BPD
  26. Borderline Personality Disorder
  27. Major Depressive Disorder
  28. Low mood – inability to experience pleasure
  29. Multiple episodes
  30. May effect 20% of the population
  31. Co-morbidity is very common
  32. Monoamine Hypothesis
  33. Low available levels of serotonin (5-HT)
  34. Norepinephrine (NE)
  35. Dopamine – reward system
  36. Hypersensitivity to Stress
  37. Schizophrenia
  38. Disturbances in perception, emotion, attention
  39. 3 main categories

1)Positive symptoms – are expressed

  1. Hallucinations: visual, auditory
  2. paranoia

2)Negative systems – behaviors lost

3)Cognitive abnormalities

  1. affect 0.5-1% of the population
  2. expression begins later in life

1)males express schizophrenia at puberty

2)women express schizophrenia at menopause

  1. increased DA in mesolimbic pathway
  2. genetic, environmental
  1. PTSD
  2. Symptoms follow extreme traumatic stressor
  3. Stress –induced changes in the neural systems
  4. 8% of the population

Dave Arendt – 11 September 2009

Evidence of altered cortical and amygdala activation during social decision-making in schizophrenia Baas D, A Aleman, M Vink, N Ramsey, EHF de Haan, RS Kahn 2008

NeuroImage 40: 719-727

  1. 1% chance of developing Schizophrenia
  2. 3 million Americans
  3. 50% are homeless
  4. 1.5 million suicidal
  5. Symptoms of Schizophrenia
  6. Positive – added to normal behavior
  7. Delusions
  8. Paranoia, grandiosity, persecution, thought broadcasting, thought receiving
  9. Hallucinations
  10. Auditory, visual, olfactory, tactile
  11. Disturbance of Thought
  12. Inability to form thought, no goal in conversation
  13. Negative – subtracted from normal behavior
  14. Anhedonia, flattened affect, emotional withdrawal, attention deficits, disorganized speech
  15. Acquisition later in life
  16. Puberty in males
  17. Menopause in women
  18. Genetic and Environmental causes
  19. Identical twins show 50% concordance
  20. Therefore 50% environmental
  21. Some studies suggest 73-90% heritable - ?
  22. Deletions and duplications genes associated with axonal guidance and synaptogenesis
  23. Environmental causes include
  24. Stress
  25. Neural damage
  26. During embryonic development
  27. axonal guidance and synaptogenesis
  28. obstetric complications
  29. maternal infection
  30. epigenetic modulation
  31. Neural components of Schizophrenia
  32. Dopamine (DA)
  33. Dopaminergic drugs have classically used for treatment
  34. D2 antagonists (e.g. haloperidol…)
  35. Typical antipsychotic drug
  36. Suggests hyperdopaminergic state in schizophrenia
  37. Suggests that D2 hyper-stimulation causes positive symptoms
  38. D1 antagonists
  39. Serotonin (5-HT)
  40. 5-HT2A
  41. 5-HT2C
  42. Glutamate – NMDA receptors
  43. GABA
  44. Ranking face “trustworthiness” after viewing during fMRI – resulted in greater variability in those with Schizophrenia
  45. Decreased amygdalar activation with Schizophrenia
  46. Right amygdala has reduced overall activity in those with Schizophrenia
  47. Left amygdalar activity is reduced in those with Schizophrenia when viewing a “Trustworthy” face
  48. Inverse activation pattern of the right insula between those with Schizophrenia and controls
  49. Schizophrenia – low activity for “Trustworthy” faces, high for “untrustworthy” faces
  50. Controls – higher activity for “trustworthy” faces, lower for “untrustworthy” faces
  51. Left medial orbitofrontal cortex (OFC; part of PFC) showed reduced activation in those with Schizophrenia when viewing neutral faces

JustinSmith – 18September 2009

Brain-derived neurotrophic factor plasma levels in patients suffering from post-traumatic stress disorder L Dell'Osso, C Carmassi, A Del Debbio, M Catena Dell'Osso, C Bianchi, E da Pozzo, N Origlia, L Domenici, G Massimetti, D Marazziti, A Piccinni 2009 Prog Neuro-Psychopharm Biol Psych 33: 899-902

  1. Post-traumatic Stress Disorder (PTSD) develops in response to a severely traumatic event
  2. Include
  3. Combat
  4. Sexual and/or physical assault and/or abuse
  5. Especially for children
  6. Terrorist attacks
  7. Serious accidents
  8. Car wrecks
  9. Natural disasters
  10. Earthquake, tornado, hurricane, fire, floods
  11. Produces intense fear and/or helplessness
  12. Specific symptoms:
  13. Re-experiencing
  14. nightmares
  15. Flashbacks of the trauma
  16. Intrusive thoughts
  17. Avoidance
  18. Stimulation or context
  19. Hyper-arousal
  20. exaggerated startle response
  21. sleep disturbances
  22. Impaired learning and concentration
  23. Blunted affect – feeling numb
  24. Development and after
  25. Intensity or duration of trauma
  26. Predisposition to stress
  27. Prior stress experiences
  28. Losing someone close to you
  29. Proximity to the traumatic event
  30. Strength of reaction
  31. Loss of control
  32. Help and support after the event
  33. Early stressful experiences potentiate the development of PTSD in response to a traumatic stress
  34. BDNF mRNA in hippocampal CA1 is diminished at 7 days following predator stress
  35. Predator stress = cat odor
  36. Stressed population includes variable responsiveness
  37. EBR = extreme behavioral response, 38.7%of population
  38. PBR = partial behavioral response, 48.4%
  39. MBR = minimal behavioral response, 12.9%
  40. BDNF binds to TrkB receptors
  41. TrkB receptor mRNA in CA1 is increased at 7 days following predator stress
  42. TrkB mRNA increased in EBR animals
  43. And in PBR animals
  44. BDNF mRNA expression in orbitofrontal cortex (OFC) is decreased following footshock and Hycontextual stress in rats with chronic corticosterone (B) exposure
  45. NMDA NR2B and AMPA GluR2/3 and pGluR1 subunits
  46. Prior stressors and chronic B decreases fear extinction
  47. Patients with PTSD have decreased plasma BDNF
  48. Not affected by the number of traumas
  49. Also not affected by time since the trauma
  50. Plasma BDNF is correlated with brain BDNF
  51. Do specific brain regions correlate?
  52. PTSD patients also have decreased hippocampal volume

SharleenYuan – 2 October 2009

Aberrant functional connectivity of dorsolateral prefrontal and cingulate networks in patients with major depression during working memory processingN Vasic, H Walter, F Sambataro, RC Wolf 2009 Psych Med39: 977-987

  1. 5.4% of Americans have major Depression
  1. Symptoms of Depression – must be
  1. Low mood
  2. Feelings of worthlessness, self hate
  3. Inappropriate guilt
  4. Anhedonia
  5. Inactivity or withdrawal from usual activities
  1. Must be present for more than 2 weeks
  2. Multiple episodes are characteristic of major depression
  3. Hypotheses of Depression
  4. Monoamine hypothesis
  5. 5-HT depletion hypothesis
  6. Neurotrophin hypothesis
  7. BDNF
  1. Left dlPFC shows increased activity with major depression
  2. Some studies show hypoactivity
  3. Studies are not consistent for antidepressant drug use
  4. dlPFC is important for working memory
  5. hyperactivity in dlPFC may be a compensatory mechanism for working memory
  6. with working memory task people with depression perform normally while the task is relatively simple
  7. when the task become more difficult those with depression exhibit a delay in response time
  8. and reduced accuracy
  9. compared with healthy controls
  10. Increased activity of dlPFC associated with the task delay in depressed patients
  11. Anterior Cingulate Cortex (ACC) plays a key role in emotional expressionandaffect regulation
  12. ACC also important for cognitive processing
  13. ACC is activated during low cognitive demand
  14. ACC shows significant activation during depression

Inger Appanaitis – 9 October 2009

Abnormal activity in hypothalamus and amygdala during humour processing in human narcolepsy with cataplexy S Schwartz, A Ponz, R Poryazova, E Werth, P Boesiger, R Khatami, CL Bassetti 2008Brain131: 514–522

  1. Cataplexy
  2. Sudden loss of muscle tone with preserved consciousness
  3. 1:2000 or 0.05% of population afflicted
  4. Respiratory and eye muscles not affected
  5. Similar to REM sleep
  6. Episodes last few – 30 s
  7. Sleep deprivation increases frequency and severity of attack
  8. Severity may be partial or complete
  9. Slackening of jaw – total collapse
  10. Functionally linked but distinct from narcolepsy
  11. Consciousness not preserved
  12. More common 0.02-0.16%
  13. Genetic factors: 5 – 15% inheritance (1st degree relatives)
  14. Damage to hypocretin (HCrt = orexin) system = reduced HCrt
  15. Recurrent intrusions of REM sleep into the transition period between sleep and wakefulness
  16. N1 – N2 – N3 – N2 – REM
  17. Narcolepsy: eliminate much of non-REM (N1 – N3) sleep
  18. Some take naps to manage sleepiness
  19. NC = narcolepsy with cataplexy
  20. Cataplexy is a common (70%) feature of narcolepsy
  21. Hypocretin produced in lateral hypothalamus
  22. 2 hypocretins – HCrt1(orexin A, OrxA) & HCrt2(orexin B, OrxB)
  23. HCrt2is an excitatory neuromodulator
  24. HCrt1 KO – disrupted sleep
  25. HCrt1can reverse the effects of sleep deprivation
  26. HCrt2KO - cataplexy
  27. Normal concentrations of HCrt1 in CSF is 320 pg/ml
  28. Narcoleptic patients often have < 20 pg/ml
  29. Amygdala is strongly activated during REM sleep in humans
  30. Amygdalar neuronal firing during cataplexy in dogs
  31. Involved in emotional information processing
  32. Humor is the 1o stimulus engendering cataplexy
  33. Patients and controls did not different in images judged as humorous
  34. Patients often rated significantly fewer humorous images as funny
  35. Funny images rated as less humorous
  36. Patients with cataplexy humor stimulated activity in R amygdala, insula, R inferior parietal and fusiform complex, and L nucleus accumbens, R inferior frontal cortex and hypothalamus
  37. Humor – dramatic reduction in hypothalamic activity during cataplexy attack
  38. Similar to sleep state
  39. Humor stimulated increased activity in R hypothalamus in controls
  40. R inferior frontal ctx is involved in inhibibiting amygdala and cataplectic response
  41. These regions associated with emotional (including humor) are reward processing
  42. Measured in fMRI

Amanda Henke – 30 October 2009

Decreased brain-derived neurotrophic factor in medicated and drug-free bipolar patientsGS de Oliveira, KM Ceresér, BS Fernandes, M Kauer-Sant’Anna, GR Fries, L Stertz, B Aguiar, B Pfaffenseller, F Kapczinski 2009, J Psychiatric Res43: 1171–1174

  1. Bipolar Disorder
  2. Onset typically between 15-30
  3. Up to 6% of people are bipolar (1.2-1.5% diagnosed) but also 1% of children
  4. Often un-diagnosed for up to 10 years
  5. Damage to the brain
  6. Two types: Bipolar I & II
  7. Diagnosis : must have 3-4 symptoms of mania
  8. The depressive phases are assumed
  9. Depression is 3X more common
  10. Diagnosis depends on length, severity and number of cycles of manic episodes
  11. Mania
  12. Decreased sleep
  13. Decreased appetite
  14. Grandiosity
  15. Distractibility
  16. Engage in excessively in pleasurable yet harmful activities
  17. Spending sprees
  18. Sexual promiscuity
  19. Foolish business ventures
  20. Flight of ideas
  21. Agitation
  22. Depressive Phase Symptoms
  23. Sadness
  24. Hopelessness
  25. Suicidal thoughts or behavior
  26. 10-20% chance of suicide
  27. Anxiety
  28. Guilt
  29. Sleep problems
  30. Appetite problems
  31. Fatigue
  32. Loss of interests in daily activities
  33. Problems concentrating
  34. Irritability
  35. Chronic pain with no known cause
  36. Bipolar patients have increased amygdalar size, activity and dysfunction
  37. Reduce hippocampal volume during adolescence
  38. BDNF
  39. Val66met SNP
  40. Single Nucleotide Polymorphism of valine for methionine at codon 66
  41. disrupts proBDNF-sortilin interaction in Golgi
  42. Reduces BDNF secretion
  43. Increased [BDNF] after treatment with antidepressants, mood stabilizers, atypical antipsychotics
  44. Bipolar patients have lower plasma [BDNF] than healthy humans
  45. Manic and Depressed Bipolar patients have lower plasma [BDNF] than euthymic Bipolar patients
  46. Euthymic = without symptoms: have plasma [BDNF] equivalent to healthy controls
  47. Regardless of drug treatment
  48. Both treated and drug free bipolar patients have lower plasma [BDNF]
  49. But, drug free bipolar patients have lower plasma [BDNF] than those being treated
  50. Plasma [BDNF] are negatively correlated with both severity of mania and severity of depression

Kristi Tschetter – 6 November 2009

Anxiety, mood, and substance use disorders in parents of children with anxiety disordersAA Hughes, JM Furr, ED Sood, AJ Barmish, PC Kendall 2009 Child Psychiatry Human Dev40: 405–419

  1. 5 major types of Anxiety Disorders
  2. Generalized Anxiety Disorder (GAD)
  3. Chronic anxiety – not stimulated by any event
  4. After 6 months
  5. 6.8 million Americans
  6. Twice as many women as men
  7. Obsessive-Compulsive Disorder (OCD)
  8. Recurrent unwanted thoughts/obsessions and/or repetitive behavior
  9. 2.2 million Americans
  10. Gender neutral
  11. 1/3 develop symptoms as children
  12. Panic Disorder (PD)
  13. Unexpected and repeated episodes of intense fear
  14. May include chest pain, heart palpitations
  15. Includes a sense of unreality, fear of impending disaster, and loss of control
  16. Post-Traumatic Stress Disorder (PTSD)
  17. Develop after exposure to a terrifying event
  18. Social Phobia (Social Anxiety Disorder)
  19. Overwhelming anxiety and excessive self-conciousness in everyday social situations
  20. 15 million Americans; gender neutral
  21. Usually begins in childhood/adolescence
  22. Genetically heritable at some rate
  23. Substance Use Disorder (SUD)
  24. Internalizing
  25. Trait
  26. Anxiety
  27. Depression
  28. Withdrawl
  29. Somatic complaints
  30. Externalizing
  31. State
  32. Attention problems
  33. Aggressive behavior
  34. Rule breaking actions
  35. Children of Low-income depressed mothers
  36. Significant association between lower socioeconomic state and higher rates of psychiatric disorders
  37. Higher major depression in families with income below $10,000
  38. Significantly higher lifetime prevalence of any psychiatric disorder
  39. More depressive disorders, separation anxiety disorder
  40. Higher oppositional defiant disorder, , and suicidal ideation
  41. Anxiety in Parents with children that have anxiety disorders
  42. Mothers of children with anxiety disorders also have higher levels of trait and state anxiety
  43. Fathers had higher levels of state anxiety only
  44. Odds: any parental lifetime anxiety disorder were 2.33(fathers)-2.53(mothers)x higher
  45. Mothers and Fathers of Anxious children also had more symptoms of depression
  46. Mothers, not Fathers, had more anxious or depressive self talk
  47. odds of paternal Substance Use Disorder were 2.52x higher in Anxious children
  48. not significant when anxious disorders held constant
  49. fathers were self medicating
  50. Maternal Social Phobia was 2.09x higher in youth with Social Phobia
  51. Obsessive-Compulsive Disorder was 7.61x higher in mothers of youth with OCD
  52. Suggests that environment and behavior strongly influence the development of anxiety disorders in children, along with genetic predisposition

Maneeshi Prasad – 13 November 2009

Long-lasting depression-like behavior and epigenetic changes of BDNF gene expression induced by perinatal exposure to methylmercuryOnishchenko, N, N Karpova, F Sabri, E Castren, S Ceccatelli 2008 J Neurochem 106: 1378-1387

  1. Depression
  2. 1 in 6 lifetime; 9.5% in a given year; 18.8 million Americans
  3. Twice as many women (12%) as men (6.6%)
  4. Coexists with chronic pain, arthritis, diabetes, HIV
  5. Also associated with Anxiety Disorders
  6. PTSD, OCD, Panic Disorder, Social Phobia, GAD
  7. Neural Circuitry of Depression
  8. PFC, Cingulate – Cg25, hippocampus, amygdala, VTA, NAc, dRaphe, LC
  9. Depressed patients have reduced hippocampal and PFC
  10. Due to high levels of stress and low levels of BDNF
  11. Neural activity in amygdala and subgenual cingulate cortex is highly increased in individuals with depressive symptoms
  12. Neurotrophic Hypothesis of Depression
  13. Depressed patients have lower hippocampal, PFC, and plasma Brain Derived Neurotrophic Factor (BDNF)
  14. Depressed patients have higher BDNF in Nucleus Accumbens (NAc)
  15. Stress reduces BDNF synthesis and release
  16. Antidepressants stimulate increased BDNF and VEGF synthesis and release
  17. Also stimulate BDNF TrkB receptors
  18. BDNF also stimulates neurogenesis
  19. Antidepressants also stimulate increased neurogenesis
  20. Antidepressant effects can be blocked by inhibiting neurogenesis or BDNF
  21. Methylmercury (meHg) exposure increases depressive behavior in mice
  22. Fluoxetine (Prozac) reduced depressive behavior in meHg treated mice
  23. BDNF mRNA is reduced in dentate gyrus (DG) of meHg treated mice
  24. 12 wks (3 months) and 14 months after meHg treatment
  25. Long-lasting effect
  26. CA1 & CA3 are not effected
  27. No effect on TrkB receptors
  28. BDNF mRNA reduction is reversed by fluoxetine treatment in meHG treated mice
  29. Treatment with meHg yields methylation of histones and DNA
  30. Yields decreased transcription of BDNF and glucocorticoid receptors (GR)
  31. Chronic Defeat Stress & Maternal Separation Stress can result in histone and/or DNA methylation
  32. Trimethylation of H3K27 and deacetylation of H3 histone subunit of the BDNF IV promoter
  33. Histones have 8 subunits, H3 is one
  34. Methylation and deacetylation of IV promoter silences BDNF gene
  35. Fluoxetine increases acetylation
  36. Increasing BDNF transcription – increased BDNF mRNA
  37. Methylation occurred at specific CpG (cytosine phosphate guanine) sites: -109, -66, -35, -24
  38. CpG-66 and CPG-35 upstream of BDNF gene includes the CaRE1 and CRE
  39. Ca++ response element and CREB response element
  40. Long lasting: 14 months
  41. Methylation is reversible via environmental interactions

Abby Suelflow 20 November 2009

Association between obsessive–compulsive disorder and a variable number of tandem repeats polymorphism in intron 2 of the serotonin transporter geneE Baca-Garcia, C Vaquero-Lorenzo, M Diaz-Hernandez, B Rodriguez-Salgado, H Dolengevich-Segal, M Arrojo-Romero, C Botillo-Martin, A Ceverino, J FernandezPiqueras, MM Perez-Rodriguez, J Saiz-Ruiz 2007, Prog Neuro-Psychopharm Biol Psychiatry31: 416–420

  1. Obsessive-Compulsive Disorder (OCD) consists of unreasonable thoughts and fears (obsessions) that lead to repetitive behaviors (compulsions)
  2. Diagnosis: meet 3 criteria
  3. Have obsessions or compulsions
  4. Obsessions must meet these specific criteria:
  5. Recurrent and persistent thoughts, impulses or images
  6. disturbing and cause distress
  7. Not simply excessive worries about real life problems
  8. You try to ignore or suppress these thoughts, images or impulses
  9. You know that these are a product of your own mind
  10. Compulsions must these specific criteria:
  11. Repetitive behavior that you feel driven to perform
  12. i.e. hand washing, repetitive mental acts (counting silently)
  13. These behaviors or mental acts are meant to prevent or reduce distress about unrealistic obsessions
  14. realize that your obsessions and compulsions are excessive or unreasonable
  15. Obsessions and compulsions significantly interfere with your daily routine
  16. Remarkably diverse symptoms
  17. OCD-PANDAS
  18. Often begins during early childhood
  19. Mean = 9 years before diagnosis
  20. Avg of 17 years prior to useful treatment
  21. Males and females may have different symptoms
  22. Suicidal (1%)
  23. Alcohol/substance abuse
  24. Anxiety disorders
  25. Higher rates of GAD, SAD, panic, and agoraphobia in 1st degree relatives with OCD
  26. Depression
  27. Eating disorders
  28. Inability to attend work/school
  29. Poor quality of life
  30. Troubled relationships
  31. 3.3 million (2-5 million)
  32. OCPD (obsessive-compulsive personality disorder
  33. Excessive perfectionism
  34. Preoccupation with details, rules, lists
  35. Often forgetting the major point of the activity
  36. Patients believe that the behavior improves the quality of life
  37. Genetic links with OCD
  38. 12% prevalence of OCD in 1st degree relatives, 2% in relatives of normal controls
  39. In children OCD heritable with genetic influences 45-65%
  40. But only 27-47% in adults
  41. Environmental influences include
  42. Abuse
  43. Changes in living situation
  44. Illness
  45. Death of a loved one
  46. Relationship concerns
  47. Labor complications, edema during pregnancy, excessive consumption of caffeine/alcohol by mother, and maternal smoking
  48. COMT(Catechol-O-methyltransferase)
  49. Val158met polymorphism
  50. 3-4 fold reduction in enzyme activity
  51. Microdeletions of 22q11 region
  52. MAOA
  53. Treatment: MAO inhibitors
  54. Dopamine
  55. Glutamate (Glu)
  56. Elevated Glu in CSF, Obitofrontal-PFC, striatum
  57. Decreased in anterior cingulated
  58. Transporter gene (SLC1A1) encodes protein called EAAC1
  59. Serotonin (5-HT)
  60. 5-HTT serotonin transporter
  61. 5-HTTLPR promoter polymorphism: 44 bp insertion (L allele) or deletion (S allele)
  62. 5-HTT variant: Ile425Val-linked to treatment-resistant OCD, anorexia nervosa, Asperger’s
  63. Polymorphism in intron 2 of 5-HTT gene with a variable number of tandem repeats (VNTR)
  64. Allele 12
  65. 17 bp VNTR, some people have 9, 10 or 12 copies of the VNTR
  66. 12/12 = 12 copies from mother & 12 from father
  67. 95.9% of OCD patients have an increased number of variable tandem repeats (12 from mother and or father) in allele 12 of intron 2 of the 5-HTT gene
  68. Compared to 86.2-86.5% in other Psychiatric patients and healthy controls

Kristen Ray 20 November 2009