1. Schizophrenia and Other Disorders A talk given by Elaine M. Hull at the Lawton Chiles High School, Tallahassee, FL, February 2007

2. A bit of history Hideyo Noguchi, 1911: Syphilis (delusions, grandiosity, impulsivity, altered thought structure) is due to bacterium. Emil Kraeplin, 1919: dementia praecox (paranoia, grandiose delusions, auditory hallucinations, abnormal emotional reg., bizarre thoughts)—partly genetic Eugen Bleuler, 1911: key is dissociative thinking; also delusions, hallucinations, affective disturbance, autism.

6. Genes Genes scattered across all but 8 chromosomes have been implicated Most important: –Neuregulin 1: NMDA, GABA, & Ach receptors –Dysbindin: synaptic plasticity –Catechol-O-methyl transferase: DA metabol. –G72: regulates glutamatergic activity –Others: myelination, glial function Paternal age: more cell divisions in sperm

7. Twin studies Why does one twin become schizophrenic and the other does not? –Lower birth weight –More physiological distress –More submissive, tearful, sensitive –Impaired motor coordination

9. Structural changes in brain Hippocampus, amygdala, parahippocamp. –Smaller in affected twin (static trait) –Disordered hippocampal pyramidal cells Correlation between cell disorder and severity May be due to maternal influenza in 2 nd trimester –Also in entorhinal, cingulate, parahippocampal cortex

13. Structural changes in brain Larger ventricles –Subgroup: inverse correlation between ventricle size and response to drugs

15. Structural changes in brain Increased loss of gray matter in adolescence

17. Structural changes in brain Shrinkage of cerebellar vermis Thicker corpus callosum Frontal lobes –Abnormal neuronal migration in one study –Dendrites have fewer spines –But no major structural abnormalities –Measures of frontal function impaired

18. Functional changes in brain Hypofrontality hypothesis –Discordant twins: low frontal blood flow only in affected twin –Wisconsin card sorting task Schizophrenics can’t shift attn. to other criterion Functional imaging: frontal lobe activity lower at rest, esp. in right hemisphere, does not increase during task. Drug treatment increased activation of frontal lobes

20. Neurochemical changes LSD, mescaline  confusion, delirium, disorientation, visual hallucinations. But schizophrenic hallucinations are mostly auditory Schizophrenics given LSD say it’s different from their symptoms

21. Dopamine hypothesis Amphetamine (very high doses)  paranoia, delusions, auditory hallucination Also exacerbates symptoms of schiz. Effects blocked by DA antagonist chlorpromazine Phenothiazines (incl. chlorprom.) & all other typical neuroleptics block D2 receptors and alleviate (+) symptoms.

23. Atypical neuroleptics Clozapine blocks 5-HT2A receptors > D2 As effective as typical neuroleptics on (+) symptoms, more effective on (-) symptoms Fewer motor side effects (tardive dyskinesia) Actually increase DA release in frontal cortex –L-DOPA can even be beneficial

25. Glutamate hypothesis Problem with DA hypothesis: time course Phencyclidine (PCP): dissociative anesthetic  –Auditory hallucinations –Depersonalization –Delusions –Noncompetitive NMDA antagonist (blocks Ca 2+ channel)

28. Glutamate hypothesis 2 weeks PCP in monkeys  schiz.-like symptoms –Including poor performance on frontal lobe- sensitive task Dose- & time-sensitive Ketamine (NMDA antag)  similar effects So, why not give glutamate agonists to treat schizophrenia?????

29. Glutamate hypothesis Seizures!! (also excitotoxicity) Try mGluR agonists: 8 subtypes of mGluR –Some modulate glutamate release –Others modulate dopamine systems

30. Reconciliation Maybe hypofrontality results in hyper- dopaminergic state in NAc Carr & Sesack, 2000, JNs: –PFC sends Glu axons to VTA DA cells that  PFC Result: positive feedback to PFC –PFC sends Glu axons to VTA GABA cells that  NAc Result: PFC inhibits NAc (probably amygdala, too)

31. Carr & Sesack, 2000, JNs:

32. Laruelle et al., 2003, NYAS

33. Schizophrenia Summary PFC and hippocampus cell density and activity are lower in schizophrenics; neither works well. –Hippocampal neurons are also disorganized. There is normally a positive feedback between PFC and VTA DA neurons that  PFC –Less PFC activity decreases that (+) feedback. There is normally a negative feedback between PFC and NAc. (May inhibit impulses, thoughts) –Less PFC activity decreases that (-) feedback.

34. Schizophrenia Summary The reason D2 antagonists help (+) symptoms: inhibits mostly NAc & other limbic structures. –Few D2 receptors in PFC. The reason PCP  schizophrenic symptoms: mimics the PFC hypofunction, releases NAc. There may also be anomalies in intracellular messengers. No good biochemical/anatomical explanation for (-) symptoms. –Worse in those with greatest physical damage. –But atypical antipsychotics do help (-) symptoms. (How???)

35. Schizophrenia Summary Possible treatments: –Metabotropic glutamate (mGluR1) agonists Increase glutamate or DA release –Glycine or cycloserine Bind to glycine site on NMDA receptor & enable glutamate’s effects –Neither would  seizures –Not yet tested in humans

36. Unipolar Depression Sad & helpless every day for weeks Loss of interests, energy, appetite Feel worthless Contemplate suicide Difficulty in concentrating Restless agitation Little or no pleasure from eating or sex

37. Unipolar Depression 2 X as often in women as in men ~ 5% of adults in US have “clinically significant” depression A genetic component –60% concordance for monozygotic twins –20% for dizygotic twins –Especially for early-onset & among female relatives –Not a single-gene defect

38. Increased blood flow to frontal lobes and amygdala

39. Increased blood flow also in: Parietal cortex (somatosensory/attention) Posterior temporal cortex (language) Anterior cingulate (emotional processing)

40. Cortisol is often increased in depressed people.

44. Effects of high cortisol levels Increase cell death in hippocampus –Probably due to apoptosis –Brief cortisol exposure increases hippocampal activity  helps remember acute stressor. –Hipp  negative feedback on cortisol levels –Lengthy high levels increase cell death, also decrease neurogenesis –As a result  vicious circle: High cortisol  hipp. neurotoxicity  less (-) feedback  high cortisol.

45. Effects of high cortisol levels Depressed people often have bad memories and difficulty reasoning. SSRIs  increased survival of new neurons in hipp., increased memory and reasoning. Hypothesis: –5-HT &/or NE  cAMP  CREB  BDNF –5-HT 4, - 6, - 7 & β are coupled to G s BDNF in rats also increases cell survival in hippocampus and decreases behavioral measures of animal “depression.”

46. Normal sleep pattern

47. Sleep pattern in depression

48. Early entry into REM

49. Altering sleep patterns sometimes helps depression Most depressed people are phase- advanced in their sleep cycles. Some are helped temporarily by total sleep deprivation for 1 night. Others are helped by going to bed from 5pm to midnight for a week & gradually going back to normal.

50. Electroconvulsive therapy Can help those who don’t respond to drug therapy or are suicidal. Unclear why it works. –Increases D 1 & D 2 receptors in NAc –Decreases postsynaptic β NE receptors

52. Regulation of CREB phosphorylation by antidepressant drugs

53. Summary of Depression Symptoms –Sad & helpless; feel worthless –Loss of interests, energy, appetite –Agitated; Contemplate suicide –Can’t concentrate –Little or no pleasure from eating or sex High cortisol  damage hippocampus –Decrease neg feedback; damage memory

54. Summary of Depression Diurnal rhythms phase advanced Genetic predisposition (not just one gene) Women > men (decreased allopregnanolone?) Treatments –SSRIs, MAOIs, tricyclics SSRIs  BDNF  new neuron survival –ECT –Don’t sleep for 1 night; Go to bed earlier –GC antagonist

55. Seasonal Affective Disorder More prevalent in winter. Not necessarily more prevalent in far north or south. Treated successfully with bright light AM & PM. –Dose response curve for both time & intensity –Suppresses melatonin (probably not critical) –5-HT seasonal rhythm (low in winter) SSRIs can treat SAD

56. Light treatment for SAD

57. Bipolar Disorder Manic phase –Overactivity & wakefulness –Talkativeness –Grandiosity Depressed phase: ~ unipolar depression Men & women: similar incidence Earlier onset than unipolar Genes on chromosomes 4, 11, 12, 16, 21, X –Including gene for BDNF

58. Brain activity in manic vs. depressive episode

59. Bipolar Disorder Bipolar I: full-blown episodes of mania Bipolar II: episodes of hypomania Cycles can be a couple of days to a couple of years. ~1% of people have at least a mild case in their lifetime Enlarged ventricles: decreased brain vol. Larger amygdala than normal

60. Treatments for Bipolar Disorder Lithium (for Bipolar I) –Discovered by accident (JF Cade, uric acid) –Not clear why it works (can be toxic) –Usually given during manic phase  prevents subsequent depression and mania –Li + alters Na + transport & “inhibits recycling of membranes involved in second-messenger systems”  reduces responsiveness to transmitters

61. Treatments for Bipolar Disorder Valproic acid (Depakote, Depakene) or carbamazepine (anticonvulsants) –Usually effective only in Bipolar II –Increase GABA activity, block synthesis of arachidonic acid (produced during brain inflammation) Patients don’t like to lose the euphoria and creativity of the manic phase.

62. Summary of Bipolar Disorder Genes on several chromosomes (incl. BDNF) Bipolar I vs. Bipolar II Men & women similar incidence Enlarged ventricles, large amygdala Treatments –Bipolar I: lithium –Bipolar II: Anticonvulsants  GABA activity, decrease arachidonic acid

63. Anxiety Disorders Panic disorder –Can be induced by lactate or CO2 in PD sufferers (only occasionally in normal people) –Increased activity in parahippocampal gyrus, –Decreased activity in anterior temporal cortex & amygdala (seems odd!) –May have 3, rather than 2, repeats of a section on chromosome 15 Also have joint laxity (bend too far)

64. Anxiety Disorders Treatments for panic disorder –Benzodiazepines (e.g., Valium) Increase frequency of Cl - channel openings in response to GABA Have little or no effect alone: safer than barbiturates Allopregnanolone = endogenous agonist at benzodiazepine binding site. –Buspirone (Buspar): 5-HT 1a agonist (G I/O ) –SSRIs: fluoxetine (Prozac), paroxetine (Paxil)

65. Benzodiazepine receptors in brain

66. PTSD

67. Monozygotic > dizogotic concordance –Genetics  1/3 of variance NMDA mechanisms in amygdala –May mediate both the conditioning and the extinction NMDA antagonists in amygdala prevent extinction Hippocampus and PFC also lose effectiveness in extinction

68. PTSD

69. Not due to high levels of glucocorticoids: –Usually PTSD sufferers have LOWER than normal cortisol levels, despite high CRH Maybe it’s the high CRH that  symptoms Or maybe it’s increased responsiveness to CRH or cortisol Individual differences in responsiveness to trauma Sometimes treated with β NE antagonists (propranolol) or protein synthesis inhibitors soon after the trauma or during recall of the trauma

70. OCD

72. Increased metabolism in orbitofrontal cortex, cingulate, and caudate nuclei. Decreased REM latency (~ to depression) At least 2 gene polymorphisms: –For BDNF, 5-HT 2A receptor Treatment: SSRIs

73. Cingulotomy to treat OCD

74. Tourette’s Syndrome

75. Tourette’s syndrome In many ways opposite Parkinson’s disease Treated with dopamine antagonists Monozygotic concordance: 53-77%; dizygotic concordance: 8-23% Witty Ticcy Ray (by Oliver Sacks): “We Touretters…are forced into levity by our Tourette’s and forced into gravity when we take Haldol….You have a natural balance: we must make the best of an artificial balance.”

78. Summary of Mood Disorders Depression symptoms: –Sad & helpless every day for weeks –Loss of interests, energy, appetite –Feel worthless –Contemplate suicide –Difficulty in concentrating –Restless agitation –Little or no pleasure from eating or sex

79. Summary of Mood Disorders Genetic component: 60 vs 20% concordance for identical vs fraternal twins High activity in PFC and amygdala –PFC inhibits NAc—and therefore pleasure and behavioral activation –Amygdala  anxiety High cortisol levels may contribute to depression –Kills hippocampal cells, impairs memory Alteration of sleep cycles sometimes helps SSRIs for unipolar depression –ECT for severe cases that don’t respond to SSRIs Lithium for bipolar disorder –Or drugs that increase GABA effect for milder cases

80. Summary of Mood Disorders There is a genetic component for all. High cortisol levels may contribute to depression –Kills hippocampal cells, impairs memory Alteration of sleep cycles sometimes helps SSRIs for unipolar depression –ECT for severe cases that don’t respond to SSRIs Lithium for bipolar disorder –Or drugs that increase GABA effect for milder cases Anxiety: benzodiazepines, buspirone, SSRIs