2. 1 David Helfgott plays Rachmaninov Piano Concerto #3 Copenhagen Philharmonic, 1995 RCA Victor-BMG Classics as in the movie “Shine” Born in Melbourne 1947 1962-1970 several schizophrenic episodes 1966-70 Royal College of Music 1970-1980 Hospitalized in Australia 1984- present concert pianist According to the biography by his wife, his present medication consists of: (1) chlorpromazine (Thorazine), a D2 receptor blocker for schizophrenia; and (2) an anticholinergic for tardive dyskenesia.

3. 2 Bi 1 “Drugs and the Brain” Lecture 23 Tuesday, May 16, 2006 Schizophrenia, a cognitive disorder; Depression, a mood disorder

4. 3 Schizophrenia. (Additional resource, Dr. Michael McIntosh’s lecture, #19) : 1. Clinical description (lecture 19, slides 9-10) 2. Genetics (lecture 19, slide 28) 4. Pathophysiology: schizophrenia as a developmental disorder 4. Pathophysiology: Objective measurements and animal models (lecture 19, slides 31, 32, 33, 34, ) 5. No known heterozygote advantage 6. Therapeutic approaches: (also Lecture 19, slides 36, 37) Disclaimer Lectures 23 and 24 deal with psychiatric disease. Henry Lester is not a psychiatrist--not even a physician. Don’t change any medical treatment that you might now be receiving on the basis of these lectures. Don’t give any medical advice based on these lectures or problem set 7.

5. 4 1. Clinical description also Nestler p 389 The range of clinical features shows that schizophrenia affects multiple complex brain systems Negative symptoms: Decreased motivation, diminished emotional expression Cognitive deficits: Impairments in attention, executive function, some types of memory Sensory abnormalities: Gating disturbances Sensorimotor abnormalities: Eye tracking disturbances Motor abnormalities: Posturing, impaired coordination Positive symptoms: Delusions, hallucinations, thought disorder

6. 5 Schizophrenia is polygenic and probably genetically multifactorial Twin data for concordance in schizophrenia vary enormously. In studies published since 1968 (DSM criteria): monozygotic (n = 239) 22% dizygotic (n = 512) 8% (general population1%) 2. Genetics

7. 6 Concordance for Lifetime Risk of Schizophrenia 0%10%20%30%40%50% general population 1st cousins uncles/aunts nephews/nieces grandchildren half siblings parents siblings children fraternal twins identical twins shared DNA 100% 50% (1st-degree relatives) 25% 12.5%

8. 7 Molecular Neuroscience Clinical Neuroscience Human Genome and Associated Data

9. 8 We describe a map of 1.42 million single nucleotide polymorphisms (SNPs) distributed throughout the human genome, providing an average density on available sequence of one SNP every 1.9 kilobases. This high-density SNP map provides a public resource for defining haplotype variation across the genome, and should help to identify biomedically important genes for diagnosis and therapy. The International SNP Working Group (Lander et al)

10. 9 20% 80% 60% 40% 20% 80% 30% 70% Locus A Chomosome 12 no linkage to schizophrenia Locus B Chomosome 8 may be near a gene that helps to cause schizophrenia sequence A1 sequence A2 sequence A1 sequence A2 Controls Schizophrenics sequence B1 sequence B2 sequence B1 sequence B2 Hunting for Genes with SNPs specific place in sequence

11. 10 20% 80% 60% 40% 20% 80% 30% 70% Locus A Chomosome 12 no linkage to schizophrenia Locus B Chomosome 8 may be near a gene that helps to cause schizophrenia sequence A1 sequence A2 sequence A1 sequence A2 Controls Schizophrenics sequence B1 sequence B2 sequence B1 sequence B2 Hunting for Genes with SNPs recombination

12. 11 SNP assays are now done in “high-throughput” modes: hundreds of PCR reactions; results spotted onto chips; mass spectrometry or other method to resolve single-nucleotide differences slides from Lecture 15:

13. 12 Polygenic the disease occurs only if several genotypes are present together Genetically Multifactorial several distinct genes (or sets of genotypes) can independently cause the disease Partially penetrant nongenetic factors may also be required, or the disease could be inherently stochastic Polygenic Genetically Multifactorial Partially Penetrant Three concepts used in describing complex diseases

14. 13 8p21, site of the latest schizophrenia linkage: the neuregulin-1 gene Little Alberts 5-13 © Garland 1  m

15. 14 Neuregulin-1 is a transmembrane protein Neuregulin-1 is proteolyzed to release a growth factor Cleavage #1 #2

16. 15 Like other growth factors, The released fragment of neuregulin-1 activates specific genes See Angelo Stathopoulos cameo in lecture 20, and future Lecture 26 “Erb”

17. 16 Each new advance in neuroscience has been tried out on schizophrenia. There is no satisfactory explanation yet. In general, modern theories of schizophrenia emphasize abnormal neuronal circuits or pathways, rather than individual neurons that either (a) degenerate or (b) fire too fast or too slow Specific cell types may migrate incorrectly in embryonic development 3. Pathophysiology.

18. 17 “The known activities of neuregulins (NRGs) fit well with current hypotheses regarding the neurobiological basis of schizophrenia. Theory 1. Schizophrenia results from a deficiency of glutamatergic innervation relative to dopaminergic innervation. NRG knockout mice display hyperactivity in behavioral tests similar to hyperactivity observed in mice treated with the psychogenic drug phencyclidine (PCP) or with mutations that impair glutamatergic neurotransmission or enhance dopaminergic neurotransmission. Treatment with clozapine reversed the hyperactivity of these mice, and they had reduced levels of the NMDA type of glutamate receptors. Furthermore, application of soluble NRG1 to cultured neurons stimulates transcription of NMDA receptors. Theory 2. Abnormalities in glial biology contribute to the pathology of schizophrenia. Neuregulins are required for initial differentiation of oligodendrocyte precursors and for their survival. A variant of this idea is that a deficiency of glial growth factors––such as NRG–– predisposes to synaptic destabilization. It is clear that NRG signaling is required for the stabilization of nerve-muscle synapses, and evidence for NRG involvement in astrocyte biology might implicate neuregulins in formation or stabilization of central synapses. Theory 3. Schizophrenia results from abnormalities in brain wiring. Neuregulins regulate migration of neuronal precursors in culture. Theory 4. Schizophrenia results from abnormalities in synaptic plasticity. Neuregulin-1 inhibits induction of long-term potentiation, a form of synaptic plasticity studied as a model for the neurophysiological substrates of learning and memory.”

19. 18 (1) Nourishment and health of the fetus Viral infections during pregnancy, Possibly leading to low-level inflammation (Prof. Paul Patterson, Caltech)? (2) Head injury Nongenetic contributions: the other 50%

20. 19 4. Objective physiological measurements that correlate with schizophrenia Biomarkers are objective, measurable biochemical, genetic, or other biological indicators of a physiological or disease process... complex conditions, such as mental illness, might benefit from constellations of several different biomarkers being used in concert... biomarkers could facilitate definitive diagnosis of mental disorders in individuals, assess the susceptibility of individuals to a particular disorder, indicate changes in the severity of a disorder, and show the response of a disorder to a given treatment... Some disorders appear as a broad spectrum where signs and symptoms vary enormously but yet collectively represent one general disorder (e.g. autism spectrum disorders). In other instances, a particular symptom may appear across a variety of mental disorders (e.g., cognitive impairment) or represent an exaggeration of a dimension seen in healthy individuals (e.g., depressed mood)... Biomarkers could aid clinicians in categorizing particular signs and symptoms so that a spectrum disorder could be broken down into well-defined subcategories, allowing differential analysis or treatment. Biomarkers... could be used in basic research to map the variability of a marker across healthy populations.

21. 20 1. Electroencephalograms 2. Eye pursuit 4. Objective physiological measurements that correlate with schizophrenia

22. 21 Sensory gating anomaly measured electrophysiologically: (a) Observed in schizophrenics (~90%) but in only 8% of the general population (b) Autosomal dominant transmission, even in healthy relatives of schizophrenics (c) This trait has been mapped to the vicinity of a gene on chromosome 15. The gene is a nicotinic acetylcholine receptor.  A, abnormal ratio N, normal ratio schizophrenic

23. 22 Dopamine D2 blockers are the classical “antipsychotic” drugs. See Nestler Figure 17-11, p 402 And Problem Set 7 All dopamine receptors are GPCRs. 5.Therapeutic approaches

24. 23 Again, we highlight neurons that make dopamine; here, note their postsynaptic targets in the frontal cortex Nestler Figure 8-6 from several previous lectures

25. 24 Dyskinesia results from prolonged use of typical antischizophrenic drugs. Dyskinesia has some symptoms like Huntington’s Disease Nestler Figure 8-6 from lectures 22 and 24 GABA-producing “medium spiny” neurons die in HD

26. 25 Current Treatment of Schizophrenia Drug class“Classical” antipsychotics“Atypical” antipsychotics Receptor actions High affinity dopamine D2 antagonists Low affinity D2, high affinity serotonin-2A antagonists Symptomatic effects Reduce positive symptoms; little effect on negative / cognitive symptoms Reduce broad range of symptoms Side effects Frequent extrapyramidal side effects and tardive dyskinesia Blood abnormalities, weight gain, glucose intolerance, CostOff patent$$$

27. 26 from Lecture 13 System-level Action Dopamine “Pleasure” system Noradrenaline “Readiness” system “Perception- Association” system “Decreased neuronal activity” morphine-heroin tetrahydrocannabinol nicotine cocaine amphetamine ethanol ? LSD caffeine phencyclidine

28. 27 Endogenous ligand morphine- heroin agonistendorphins (peptides) THCagonistanandamide nicotineagonistacetylcholine cocaineantagonistdopamine amphetamineantagonist noradrenaline, serotonin, dopamine ethanolagonist?G protein? LSDagonistserotonin caffeineinhibitorcyclic AMP (intracellular) phencyclidineantagonistglutamate from Lecture 13

29. 28 Primary TargetDetails (dates: ) morphine-heroin GPCR (G protein-coupled receptor) (Gi)  -opioid receptor 1985-1993 THCGPCR (Gi)cannabinoid receptor 1988 nicotineagonist-activated channel  4 nicotinic acetylcholine receptor 1905-1995 cocaine cell membrane neurotransmitter transporter dopamine transporter 1980-1991 amphetamine vesicular / cell membrane neurotransmitter transporter vesicular monoamine transporter 1990 - 1995 ethanol? K channel ? G protein-gated inward rectifier GIRK1/2 1993 - 1999 LSDGPCR (Gq)5-HT2a receptor 1985-1990 caffeineenzyme cyclic AMP phosphodiesterase 1965 phencyclidineligand-activated channelNMDA glutamate receptor from Lecture 13

30. 29 Most antipsychotic drugs take at least 2 weeks to exert their effects on the symptoms of schizophrenia. Therefore these drugs teach us too little about the cause(s) of schizophrenia. What happens during those 2 weeks? We don’t know. Presumably the nervous system responds to the initial effect of the drug by readjusting synapses, gene activation, and other processes.

31. 30 “Happy families are all alike. Each unhappy family has its own story.” First sentence of Anna Karenina, Tolstoy, 1873

32. 31 Major Depressive Disorder: a Mood Disorder 1. Clinical description (McIntosh lecture #19, slides 11, 15, 16, 18) 2. Genetics (lecture 19, slide 29, 30 3. Possible causes (lecture 19, slide 67, 68 – 74) 4. Heterozygote advantage? 5. Therapeutic approaches

33. 32 From DSM-IV Summary description of a Major Depressive Episode : The essential feature of a Major Depressive Episode is a period of at least 2 weeks during which there is either depressed mood or the loss of interest or pleasure in nearly all activities. In children, adolescents, and some adults, the mood may be irritable rather than sad. The individual must also experience at least four additional symptoms drawn from a list that includes: changes in appetite or weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts. To count toward a Major Depressive Episode, a symptom must either be newly present or must have clearly worsened. The symptoms must persist for most of the day, nearly every day, for at least 2 consecutive weeks. The episode must be accompanied by clinically significant distress or impairment in social, occupational, or other important areas of functioning.

34. 33 (click on the text to read the entire excerpt in Word)

35. 34 Leading Causes of Disability in Advanced Economies, 1990 Total (millions)*% Total All Causes46.8 1 Major Depression6.714.3 2 Alcohol use4.59.6 3 Osteoarthritis2.75.8 4 Dementia2.45.1 5 Schizophrenia2.24.7 6 Bipolar disorder1.73.6 7 Cerebrovascular1.63.3 8 Diabetes1.53.2 9 Obsessive-Compulsive Disorder1.53.1 10 Drug use1.43.0 *Years lived with a disability Murray and Lopez, The Global Burden of Disease, 1996

36. 35 Major depressive disorder is by far the most common major psychiatric disease. The lifetime risk for Major depressive disorder in community samples has varied from 10% to 25% for women and from 5% to 12% for men. Major depressive disorder may begin at any age, with an average age at onset in the mid-20s. Approximately 50%-60% of individuals with major depressive disorder, single episode, can be expected to have a second episode. Individuals who have had two episodes have a 70% chance of having a third, and individuals who have had three episodes have a 90% chance of having a fourth. Prevalence

37. 36 Major depressive disorder is 1.5-3 times more common among first-degree biological relatives of persons with this disorder than among the general population. Major depressive disorder is so heterogeneous that very few scientists have tried gene scanning approaches like the approaches that succeeded for cystic fibrosis, Huntington’s disease, and (perhaps) schizophrenia. “Candidate gene” approaches are being pursued. There is evidence for an increased risk of alcohol dependence in adult first-degree biological relatives, and there may be an increased incidence of attention- deficit/hyperactivity disorder in the children of adults with this disorder. 2. Genetics

38. 37 4. Possible causes

39. 38 Multiple transmitter systems are affected in major depressive disorder, suggesting a fundamental cellular defect. Serotonergic system Noradrenaline system Dopamine system Acetylcholine system Glutamate system Steroid-based hormonal systems (the hypothalamic-pituitary- adrenal axis) Nestler 13-3

40. 39 useful arguments questionable arguments based on therapies Manji et al

41. 40 5. Therapeutic Approaches to Major Depression “The tailored subtype-specific ligand” 1.Cloning: isolate the genes for all human receptors for a given drug. 2.Neurobiology: select the appropriate receptor 3.Express each subtype 4.Identify ligands that bind specifically to the target subtype. We now know that there are > 18 genes for serotonin receptors. Most of them are GPCR’s, (but at least 2 are ligand-activated channels). But there is only a single serotonin transporter, and it’s present at all known serotonin synapses. And yet,...

42. 41 from Lecture 11: Summary: Prozac doesn’t change personality; it enables the true personality to function

43. 42 Neurons that make serotonin raphe nuclei from Lecture 13:

44. 43 How might SSRIs work? Perhaps one serotonin receptor is much more able to change levels    kinase P P...other proteins bind to the phosphates... Activated GPCRs are sometimes phosphorylated and endocytosed. This terminates signalling. P P But continual signalling can activate genes During activation, the G protein leaves...... revealing phosphorylation sites... (not a synaptic vesicle)... triggering endocytosis. Lecture 14

45. 44 DSM-IV: “The presence in a depressed patient of a positive family history of bipolar disorder or acute psychosis probably increases the chances that the patient's own depressive disorder is a manifestation of bipolar rather than unipolar disorder and that antidepressant therapy may incite a switch into mania.” The present discussion about the wisdom of prescribing SSRI’s to teenagers

46. 45 depression irritability obsessive-compulsive disorder (OCD) social phobia premenstrual syndrome eating disorders Recent uses for SSRI’s

47. 46 Nonpharmacological Treatments for Depression (in conjunction with antidepressants, or after antidepressants have failed) Psychotherapy - Cognitive behavioral therapy - Interpersonal therapy - Psychodynamic therapy Electroconvulsive therapy Goal = reduce symptoms of depression and return patient to full, active life

48. 47 Public Service Announcements: “Real Men, Real Depression” See also http://menanddepression.nimh.nih.gov/

49. 48 Bi 1 “Drugs and the Brain” End of Lecture 23