Schizophrenia and Other Disorders

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 2nd 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 Ca2+ 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-HT4, -6, -7 & β are coupled to Gs • 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 D1 & D2 receptors in NAc • Decreases postsynaptic βNE receptors