1. Overview  Huntington’s Disease Degeneration of caudate nucleus and putamen Uncontrollable movements, jerky limb movements Progressive, cognitive and emotional changes Gene that codes the huntingtin protein (htt) (chromosome 4) No cure Death (10-15 years)   Alzheimer’s Disease   Amyloid Plaque   Neurofibrillary Tangle   APP gene – chromosome 21   Protective value of intellectual activity   Cholingeric agonists (acetylcholinesterase inhibitors)   NMDA receptor antagonist (memantine)   Multiple Sclerosis   Autoimmune disorder, attacks myelin   Interferon β   Glaterimer acetate (copaxone)

2. Schizophrenia and the Affective Disorders Chapter 16

3. Schizophrenia  Description Schizophrenia is a serious mental disorder characterized by disordered thoughts, delusions, hallucinations, and often bizarre behaviors.

4. Schizophrenia “Splitting of psychic functions” “Splitting of psychic functions” Refers to the breakdown of integration of emotion, thought, and action Refers to the breakdown of integration of emotion, thought, and action Affects 1% of the population Affects 1% of the population A diverse disorder – multiple types exist with varied profiles A diverse disorder – multiple types exist with varied profiles Scientific American (2008)

5. Schizophrenia Symptoms Negative and Cognitive symptoms are closely related, may involve dysfunction in similar brain areas Negative and Cognitive symptoms are closely related, may involve dysfunction in similar brain areas Negative and Cognitive symptoms are not specific to schizophrenia Negative and Cognitive symptoms are not specific to schizophrenia See Table 16.1

6. Diagnosis ► The recurrence of only 2 symptoms for one month ► 1 symptom is necessary if the person exhibits delusions that are particularly bizarre or hallucinations that include 1 voice providing a running commentary or 2 voices conversing

7. Schizophrenia ► Biological Basis Classification - according to onset Classification - according to onset ► acute ► chronic – gradual onset, progressive deterioration ► ~ 1/3 of those diagnosed will show progressive deterioration & become chronic schizophrenics

8. Behavioural Genetics Heritability : statistic which gives an estimate of the total variance in a trait that is attributable to genetic variation in a group Heritability: statistic which gives an estimate of the total variance in a trait that is attributable to genetic variation in a group Maximum value of the estimate is 1.0 (which is equivalent to 100%) Maximum value of the estimate is 1.0 (which is equivalent to 100%) Important: Because a trait is heritable, does NOT mean it cannot be altered by the environment Important: Because a trait is heritable, does NOT mean it cannot be altered by the environment Example : Example: Height is a heritable trait Height is a heritable trait Table manners is not Table manners is not

9.  Heritability Schizophrenia is a heritable trait Not likely to be a single gene (dominant or recessive) Several genes or susceptibility hypothesis Schizophrenia: Heritability Schizophrenia.com

10.  Susceptibility hypothesis (genetic propensity, not necessarily expressed) Risk for Sz is 17% in children with a Sz parent but ALSO in children of unaffected MZ parents – risk is being passed on in genes. Lack of expression of Sz in normal MZ co-twins tells us that environment is important to Sz. Schizophrenia: Heritability Fig. 16.1

11. Schizophrenia: Heritability Also linked: paternal age Also linked: paternal age Children of older fathers Children of older fathers Copying error in DNA replication (spermocytes); high amount of replication (divides everyone 16 days after puberty) Copying error in DNA replication (spermocytes); high amount of replication (divides everyone 16 days after puberty) Genes identified: Genes identified: No single gene No single gene DISC1: Disrupted in schizophrenia DISC1: Disrupted in schizophrenia Neuronal migration Neuronal migration Neurogenesis Neurogenesis Function of PSD in excitatory neurons, function of mitochondria Function of PSD in excitatory neurons, function of mitochondria EPIGENETICS: EPIGENETICS: Mechanisms that control the expression of genes (environmental control e.g. toxins) Mechanisms that control the expression of genes (environmental control e.g. toxins)

12. http://www.youtube.com/watch?v=kp1bZEUgqVI http://www.youtube.com/watch?v=kp1bZEUgqVI

13. Antipsychotic Drugs Much of our understanding of schizophrenia is a consequence of the drugs that are able to treat it Much of our understanding of schizophrenia is a consequence of the drugs that are able to treat it Chlorpromazine Chlorpromazine Henri Laborit: drug reduced anxiety and shock Developed to treat neuroses and psychoses (not always effective) Calms many agitated schizophrenics Calms many agitated schizophrenics Block DA receptors Block DA receptors

14. Dopamine Theory of Schizophrenia 1960 – link between dopamine and Parkinson’s disease established 1960 – link between dopamine and Parkinson’s disease established Antipsychotic drug side effects suggests role for dopamine – drugs work by decreasing dopamine levels; positive symptoms of schizophrenia are associated with dopamine overactivity Antipsychotic drug side effects suggests role for dopamine – drugs work by decreasing dopamine levels; positive symptoms of schizophrenia are associated with dopamine overactivity Reserpine depletes brain of dopamine and other monoamines by making vesicles leaky Reserpine depletes brain of dopamine and other monoamines by making vesicles leaky Amphetamine, cocaine and L-dopa are dopamine agonists and produce psychosis Amphetamine, cocaine and L-dopa are dopamine agonists and produce psychosis

15. PROJECTIONS Mesolimbic Dopamine VTA-amygdala Drugs that agonize DA release (cocaine, etc.) can also cause positive symptoms of schizophrenia Major CNS dopaminergic systems include: Nigrostriatal System (role in movement) Mesolimbic System (role in reinforcement/reward) Mesocortical System (role in short-term memory, planning, and problem solving) DOPAMINE & POSITIVE SYMPTOMS POSITIVE SYMPTOMS

16. Dopamine Theory of Schizophrenia Laruelle et al (1996) Laruelle et al (1996) Intravenous injection of amphetamine in control and patients with schizophrenia Intravenous injection of amphetamine in control and patients with schizophrenia Amphetamine caused more release of DA in striatum of schizophrenics Amphetamine caused more release of DA in striatum of schizophrenics See Figure 16.2 DA Release

17. Dopamine Theory of Schizophrenia Greater amount of DA release was also correlated with positive symptoms Greater amount of DA release was also correlated with positive symptoms See Figure 16.2 See Figure 16.2

18. Dopamine Receptors

19. Potency of Binding to DA Rs Results Snyder & colleagues demonstrated: ► Potency of a particular drug in binding to DA Rs in vitro was positively correlated with its clinical effectiveness

21. DA Receptors D1-Like D1 & D5 D2-Like D2, D3, D4 All DA receptors are metabotropic This division is based on whether or not receptor activation stimulates formation of the 2 nd messenger, cyclic AMP. Activation of D1-like Rs stimulates cAMP Activation of D2-like Rs inhibits cAMP

22. Anti-Schizophrenic Drugs 2 Classes Phenothiazines Butyrophenones Chlorpromazine Binds to D1 & D2 Receptors Binds to D1 & D2 Receptors Haloperidol (Haldol) Haloperidol (Haldol) Spiroperidol Bind to D2 Receptors only Bind to D2 Receptors only

23. Revised DA Theory of Schizophrenia ► Schizophrenia is caused by hyperactivity at D2 Rs, rather than DA Rs in general ► Based on 2 findings: Selective binding of butyrophenones to D2 Rs Selective binding of butyrophenones to D2 Rs Butyrophenones greater potency in the clinic Butyrophenones greater potency in the clinic

24. Brain Imaging ► Measure DA Rs in brains of recently diagnosed schizophrenics not previously exposed to neuroleptics Radioactive ligand of the D2 R was injected iv & its concentration measured in the corpus striatum Radioactive ligand of the D2 R was injected iv & its concentration measured in the corpus striatum Two Results Two Results ► Brains of schizophrenics have an abnormally high # of D2 Rs ► Higher level of occupancy of those Rs by DA ► Suggest both pre & postsynaptic abnormalities Too much release & too many receptors (modest) Too much release & too many receptors (modest)

25. Side-Effects of Long-Term Anti- Schizophrenic Drugs Similarly to long-term use of Parkinson’s drug treatments, there can be side-effects with long-term use of anti-psychotic drugs. Similarly to long-term use of Parkinson’s drug treatments, there can be side-effects with long-term use of anti-psychotic drugs. Tardive Dyskinesia Tardive Dyskinesia Tardus – slow Tardus – slow Dyskinesia- faulty movement Dyskinesia- faulty movement Late-developing Late-developing TD: unable to stop moving TD: unable to stop moving Supersensitivity: possible that DA receptors become hypersensitive if they are blocked for long periods of time Supersensitivity: possible that DA receptors become hypersensitive if they are blocked for long periods of time D 2 receptors in caudate and putamen D 2 receptors in caudate and putamen

26. Problems with the D 2 Theory Schizophrenia associated with brain damage Schizophrenia associated with brain damage Little damage to dopamine circuitry Little damage to dopamine circuitry Damage not explained by dopamine theory Damage not explained by dopamine theory It takes several weeks of neuroleptic therapy to alleviate schizophrenic symptoms It takes several weeks of neuroleptic therapy to alleviate schizophrenic symptoms Conventional neuroleptics (D 2 blockers) mainly effective for positive symptoms Conventional neuroleptics (D 2 blockers) mainly effective for positive symptoms Negative and cognitive symptoms might be caused by brain damage Negative and cognitive symptoms might be caused by brain damage May be best to think of schizophrenia as multiple disorders with multiple causes May be best to think of schizophrenia as multiple disorders with multiple causes

27. Schizophrenia as a Neurological Disorder Predisposing factors (genetic, environmental, or both) give rise to: Predisposing factors (genetic, environmental, or both) give rise to: 1. Abnormalities in both DA transmission and PFC 2. Abnormalities in DA transmission that cause abnormalities in PFC 3. Abnormalities in PFC cause abnormalities in DA transmission

28. Schizophrenia: Brain Abnormalities Evidence of brain damage Evidence of brain damage Negative and cognitive symptoms Negative and cognitive symptoms Loss of brain tissue Loss of brain tissue Lateral ventricles more than twice as large in schizophrenic patients than control subjects Lateral ventricles more than twice as large in schizophrenic patients than control subjects

29. Possible Causes of Brain Abnormalities Epidemiological Studies Epidemiological Studies Season of birth Season of birth Viral epidemics Viral epidemics Population density Population density Prenatal malnutrition Prenatal malnutrition Maternal stress Maternal stress

30. Possible Causes of Brain Abnormalities Season of birth (seasonality) Season of birth (seasonality) Late winter and early spring (northern hemisphere) Late winter and early spring (northern hemisphere) Reverse in southern hemisphere Reverse in southern hemisphere Possible link: viruses Possible link: viruses Effect seen in cities, not in countryside Effect seen in cities, not in countryside See Figure 16.5

31. Possible Causes of Brain Abnormalities Vitamin D deficiency Vitamin D deficiency Dealberto (2007) Dealberto (2007) Northern Europe: 3-fold increase in schizophrenia in immigrants (equatorial regions) Northern Europe: 3-fold increase in schizophrenia in immigrants (equatorial regions) Thiamine deficiency Thiamine deficiency Two-fold increase in incidence of schizophrenia in offspring of women pregnant during severe food shortage in WWII (Germany and Netherlands) Two-fold increase in incidence of schizophrenia in offspring of women pregnant during severe food shortage in WWII (Germany and Netherlands) Maternal/paternal substance abuse – smoking Maternal/paternal substance abuse – smoking Complications during childbirth Complications during childbirth Mother: Diabetes of mother, bleeding, preclampsia (high blood pressure, protein in urine) Mother: Diabetes of mother, bleeding, preclampsia (high blood pressure, protein in urine) Other: oxygen or blood flow deprivation Other: oxygen or blood flow deprivation

32. Evidence for Abnormal Brain Development Home movies from families with schizophrenic child Home movies from families with schizophrenic child Compared to normal siblings, schizophrenic child displayed more negative affect and more abnormal movements Compared to normal siblings, schizophrenic child displayed more negative affect and more abnormal movements 265 Danish children (11-13 years) were videotaped eating lunch 265 Danish children (11-13 years) were videotaped eating lunch Children who later developed schizophrenia displayed less sociability and deficient psychomotor functioning Children who later developed schizophrenia displayed less sociability and deficient psychomotor functioning Hypothesis – although schizophrenia is not seen in childhood, the early brain development of children who become schizophrenic is not normal Hypothesis – although schizophrenia is not seen in childhood, the early brain development of children who become schizophrenic is not normal

33. Age of Onset Symptoms rarely begin before late adolescence or early adulthood Symptoms rarely begin before late adolescence or early adulthood Progression: Progression: Negative symptoms  cognitive symptoms  positive symptoms Negative symptoms  cognitive symptoms  positive symptoms See Figure 16.8 See Figure 16.8

34. Abnormal Brain Development Brain damage is sudden (during young adulthood) Brain damage is sudden (during young adulthood) Thompson et al. (2001) Thompson et al. (2001) Adolescence with early onset schizophrenia Adolescence with early onset schizophrenia MRI MRI Normals: Normals: Loss of 0.5-1.0% Loss of 0.5-1.0% Schizophrenic patients: Schizophrenic patients: 2-3% 2-3% See Figure 16.9 See Figure 16.9 Loss: Loss: Parietal to temporal lobe Parietal to temporal lobe Somatosensory and motor Somatosensory and motor Prefrontal cortex Prefrontal cortex

35. Abnormal Brain Development Hypofrontality and Negative and Cognitive Symptoms Hypofrontality and Negative and Cognitive Symptoms Decreased activity of the prefrontal cortex (dlPFC); believed to be responsible for the negative symptoms of schizophrenia. Decreased activity of the prefrontal cortex (dlPFC); believed to be responsible for the negative symptoms of schizophrenia. Above fig: Task required increased concentration and attention Above fig: Task required increased concentration and attention Possibly caused by decreased DA activity in prefrontal regions Possibly caused by decreased DA activity in prefrontal regions See Figure 16.10 See Figure 16.10

36. NMDA, Dopamine and Hypofrontality PCP and ketamine can cause positive, negative and cognitive- like symptoms PCP and ketamine can cause positive, negative and cognitive- like symptoms NMDA receptor antagonists; decrease DA and metabolic activity in frontal cortex NMDA receptor antagonists; decrease DA and metabolic activity in frontal cortex

37. Role of D2 Receptors in Development of Schizophrenia Abnormalities in the striatal DA system may be the cause of schizophrenia Abnormalities in the striatal DA system may be the cause of schizophrenia Virus inserted into striatum that increased D2 recpetors Virus inserted into striatum that increased D2 recpetors Caused the development of behavioral deficits characteristic of schizophrenia Caused the development of behavioral deficits characteristic of schizophrenia Abnormal activity of dlPFC Abnormal activity of dlPFC

38. Treatment with Partial DA Receptor Agonists Atypical drugs are able to reduce ALL symptoms Atypical drugs are able to reduce ALL symptoms Increase DA activity in PFC Increase DA activity in PFC Reduce DA activity in the NA Reduce DA activity in the NA Aripoprazole: Atypical Aripoprazole: Atypical Partial DA agonist Partial DA agonist High affinity for receptor but less than ligand High affinity for receptor but less than ligand Can act like an antagonist Can act like an antagonist Nucleus accumbens Nucleus accumbens Can act like an agonist Can act like an agonist Prefrontal cortex Prefrontal cortex

39. http://www.youtube.com/watch?v=USxHsSWCaJA http://www.youtube.com/watch?v=USxHsSWCaJA