Overview Huntington’s Disease Degeneration of caudate nucleus and putamen Uncontrollable movements, jerky limb movements Progressive, cognitive and emotional

OverviewOverview

Huntington’s DiseaseHuntington’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)

SchizophreSchizophrenia and nia and

the the Affective Affective

DisordersDisordersChapter 16Chapter 16

SchizophreniaSchizophrenia

DescriptionDescription Schizophrenia is a serious mental disorder characterized by

disordered thoughts, delusions, hallucinations, and often bizarre behaviors.


““Splitting of psychic Splitting of psychic functions”functions” Refers to the Refers to the

breakdown of breakdown of integration of integration of emotion, thought, and emotion, thought, and actionaction

Affects 1% of the Affects 1% of the populationpopulation

A diverse disorder – A diverse disorder – multiple types exist multiple types exist with varied profileswith varied profiles

Scientific American Scientific American (2008)(2008)

Schizophrenia Schizophrenia SymptomsSymptoms

Negative and Cognitive Negative and Cognitive symptoms are closely symptoms are closely related, may involve related, may involve dysfunction in similar brain dysfunction in similar brain areasareas

Negative and Cognitive Negative and Cognitive symptoms are not specific symptoms are not specific to schizophreniato schizophrenia

See Table 16.1See Table 16.1

DiagnosisDiagnosis

► The recurrence of only 2 symptoms for one The recurrence of only 2 symptoms for one monthmonth

► 1 symptom is necessary if the person 1 symptom is necessary if the person exhibits delusions that are particularly exhibits delusions that are particularly bizarre or hallucinations that include 1 bizarre or hallucinations that include 1 voice providing a running commentary or 2 voice providing a running commentary or 2 voices conversingvoices conversing


► Biological BasisBiological Basis Classification - according to onsetClassification - according to onset

► acuteacute► chronic – gradual onset, progressive chronic – gradual onset, progressive

deteriorationdeterioration

► ~ 1/3 of those diagnosed will show ~ 1/3 of those diagnosed will show progressive deterioration & become progressive deterioration & become chronic schizophrenicschronic schizophrenics

Behavioural GeneticsBehavioural Genetics

HeritabilityHeritability: statistic which gives an : statistic which gives an estimate of the estimate of the total variance in a trait that is attributable to genetic total variance in a trait that is attributable to genetic variation in a groupvariation in a group

Maximum value of the estimate is 1.0 (which is equivalent Maximum value of the estimate is 1.0 (which is equivalent to 100%)to 100%)

Important: Because a trait is heritable, does NOT mean it Important: Because a trait is heritable, does NOT mean it cannot be altered by the environmentcannot be altered by the environment

ExampleExample::

Height is a heritable traitHeight is a heritable trait

Table manners is notTable manners is not

HeritabilityHeritability Schizophrenia is a

heritable trait Not likely to be a

single gene (dominant or recessive)

Several genes or susceptibility hypothesis

Schizophrenia: Schizophrenia: HeritabilityHeritability

Schizophrenia.comSchizophrenia.com

Susceptibility hypothesis (genetic propensity, not necessarily Susceptibility hypothesis (genetic propensity, not necessarily expressed)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: Schizophrenia: HeritabilityHeritability

Fig. 16.1Fig. 16.1

Schizophrenia: Schizophrenia: HeritabilityHeritability Also linked: paternal ageAlso linked: paternal age

Children of older fathersChildren of older fathers Copying error in DNA replication (spermocytes); high Copying error in DNA replication (spermocytes); high

amount of replication (divides everyone 16 days amount of replication (divides everyone 16 days after puberty)after puberty)

Genes identified:Genes identified: No single geneNo single gene DISC1: Disrupted in schizophrenia DISC1: Disrupted in schizophrenia

Neuronal migrationNeuronal migration NeurogenesisNeurogenesis Function of PSD in excitatory neurons, function of Function of PSD in excitatory neurons, function of

mitochondriamitochondria

EPIGENETICS:EPIGENETICS: Mechanisms that control the expression of genes Mechanisms that control the expression of genes

(environmental control e.g. toxins)(environmental control e.g. toxins)

http://www.youtube.com/watch?http://www.youtube.com/watch?v=kp1bZEUgqVIv=kp1bZEUgqVI

Antipsychotic DrugsAntipsychotic Drugs

Much of our understanding of Much of our understanding of schizophrenia is a consequence of the schizophrenia is a consequence of the drugs that are able to treat itdrugs that are able to treat it

Chlorpromazine Chlorpromazine Henri Laborit: drug reduced anxiety and

shockDeveloped to treat neuroses and psychoses

(not always effective) Calms many agitated schizophrenics Calms many agitated schizophrenics Block DA receptorsBlock DA receptors

Dopamine Theory of Dopamine Theory of SchizophreniaSchizophrenia

1960 – link between dopamine and 1960 – link between dopamine and Parkinson’s disease establishedParkinson’s disease established

Antipsychotic drug side effects Antipsychotic drug side effects suggests role for dopamine – drugs suggests role for dopamine – drugs work by decreasing dopamine levels; work by decreasing dopamine levels; positive symptoms of schizophrenia are positive symptoms of schizophrenia are associated with dopamine overactivityassociated with dopamine overactivity Reserpine depletes brain of dopamine and other Reserpine depletes brain of dopamine and other

monoamines by making vesicles leakymonoamines by making vesicles leaky Amphetamine, cocaine and L-dopa are Amphetamine, cocaine and L-dopa are

dopamine agonists and produce psychosisdopamine agonists and produce psychosis

PROJECTIONSPROJECTIONS

Mesolimbic DopamineMesolimbic Dopamine VTA-amygdalaVTA-amygdala Drugs that agonize DA Drugs that agonize DA

release (cocaine, etc.) release (cocaine, etc.) can also cause positive can also cause positive symptoms of symptoms of schizophreniaschizophrenia

Major CNS dopaminergic Major CNS dopaminergic systems include:systems include: Nigrostriatal System Nigrostriatal System

(role in movement)(role in movement)

Mesolimbic System (role Mesolimbic System (role in reinforcement/reward)in reinforcement/reward)

Mesocortical System Mesocortical System (role in short-term (role in short-term memory, planning, and memory, planning, and problem solving)problem solving)

DOPAMINE & DOPAMINE & POSITIVE POSITIVE

SYMPTOMSSYMPTOMS

POSITIVE SYMPTOMSPOSITIVE SYMPTOMS


Laruelle et al (1996)Laruelle et al (1996)

Intravenous Intravenous injection of injection of amphetamine in amphetamine in control and patients control and patients with schizophreniawith schizophrenia

Amphetamine Amphetamine caused more release caused more release of DA in striatum of of DA in striatum of schizophrenicsschizophrenics

See Figure 16.2See Figure 16.2

DA

Rel

ease


Greater amount of Greater amount of DA release was DA release was also correlated also correlated with positive with positive symptomssymptoms


Dopamine ReceptorsDopamine Receptors

Potency of Binding to DA RsPotency of Binding to DA Rs

ResultsResults

Snyder & colleagues Snyder & colleagues demonstrated:demonstrated:

► Potency of a particular drug in binding to Potency of a particular drug in binding to DA Rs DA Rs in vitroin vitro was positively correlated with was positively correlated with its clinical effectivenessits clinical effectiveness

DA Receptors

D1-Like D2-Like

D1 & D5 D2, D3, D4

•All DA receptors are metabotropic •This division is based on whether or not receptor activation stimulates formation of the 2nd messenger, cyclic AMP.

• Activation of D1-like Rs stimulates cAMP• Activation of D2-like Rs inhibits cAMP

Anti-Schizophrenic DrugsAnti-Schizophrenic Drugs

2 Classes 2 Classes

PhenothiazinesPhenothiazines ButyrophenonesButyrophenones

ChlorpromazineChlorpromazine

Binds to D1 & D2 Receptors

Binds to D1 & D2 Receptors

Haloperidol (Haldol)

Haloperidol (Haldol)

SpiroperidolSpiroperidol

Bind to D2 Receptors only

Bind to D2 Receptors only

Revised DA Theory of Revised DA Theory of SchizophreniaSchizophrenia

►Schizophrenia is caused by Schizophrenia is caused by hyperactivity at hyperactivity at D2 RsD2 Rs, rather , rather than DA Rs in generalthan DA Rs in general

► Based on 2 findings:Based on 2 findings: Selective binding of butyrophenones to D2 Selective binding of butyrophenones to D2

RsRs Butyrophenones greater potency in the Butyrophenones greater potency in the

clinicclinic

Brain ImagingBrain Imaging

►Measure DA Rs in brains of recently Measure DA Rs in brains of recently diagnosed schizophrenics not diagnosed schizophrenics not previously exposed to neuroleptics previously exposed to neuroleptics Radioactive ligand of the D2 R was injected Radioactive ligand of the D2 R was injected

iv & its concentration measured in the iv & its concentration measured in the corpus striatumcorpus striatum

Two ResultsTwo Results► Brains of schizophrenics have an Brains of schizophrenics have an

abnormally high # of D2 Rsabnormally high # of D2 Rs► Higher level of occupancy of those Rs by Higher level of occupancy of those Rs by

DADA

►Suggest both pre & postsynaptic Suggest both pre & postsynaptic abnormalitiesabnormalitiesToo much release & too many Too much release & too many

receptors (modest) receptors (modest)

Side-Effects of Long-Term Side-Effects of Long-Term Anti-Schizophrenic DrugsAnti-Schizophrenic Drugs

Similarly to long-term use of Parkinson’s drug Similarly to long-term use of Parkinson’s drug treatments, there can be side-effects with long-term treatments, there can be side-effects with long-term use of anti-psychotic drugs.use of anti-psychotic drugs.

Tardive DyskinesiaTardive Dyskinesia TardusTardus – slow – slow DyskinesiaDyskinesia- faulty movement- faulty movement Late-developingLate-developing

TD: unable to stop movingTD: unable to stop moving SupersensitivitySupersensitivity: possible that DA receptors become : possible that DA receptors become

hypersensitive if they are blocked for long periods of hypersensitive if they are blocked for long periods of timetime

DD22 receptors in caudate and putamen receptors in caudate and putamen

Problems with the DProblems with the D22 TheoryTheory

Schizophrenia associated with brain Schizophrenia associated with brain damagedamage Little damage to dopamine circuitryLittle damage to dopamine circuitry Damage not explained by dopamine theoryDamage not explained by dopamine theory

It takes several weeks of neuroleptic It takes several weeks of neuroleptic therapy to alleviate schizophrenic therapy to alleviate schizophrenic symptomssymptoms

Conventional neuroleptics (DConventional neuroleptics (D2 2 blockers) blockers) mainly effective for positive symptomsmainly effective for positive symptoms

Negative and cognitive symptoms might Negative and cognitive symptoms might be caused by brain damagebe caused by brain damage

May be best to think of schizophrenia as May be best to think of schizophrenia as multiple disorders with multiple causesmultiple disorders with multiple causes

Schizophrenia as a Schizophrenia as a Neurological DisorderNeurological Disorder

Predisposing factors (genetic, Predisposing factors (genetic, environmental, or both) give rise to:environmental, or both) give rise to:

1.1. Abnormalities in both DA transmission and Abnormalities in both DA transmission and PFC PFC

2.2. Abnormalities in DA transmission that cause Abnormalities in DA transmission that cause abnormalities in PFCabnormalities in PFC

3.3. Abnormalities in PFC cause abnormalities in Abnormalities in PFC cause abnormalities in DA transmission DA transmission

Schizophrenia: Brain Schizophrenia: Brain AbnormalitiesAbnormalities

Evidence of Evidence of brain damagebrain damage Negative and Negative and

cognitive cognitive symptomssymptoms

Loss of brain Loss of brain tissuetissue Lateral Lateral

ventricles ventricles more than more than twice as twice as large in large in schizophrenischizophrenic patients c patients than control than control subjectssubjects

Possible Causes of Brain Possible Causes of Brain AbnormalitiesAbnormalities

Epidemiological StudiesEpidemiological Studies Season of birthSeason of birth Viral epidemicsViral epidemics Population densityPopulation density Prenatal malnutritionPrenatal malnutrition Maternal stressMaternal stress


Season of birth (seasonality)Season of birth (seasonality) Late winter and early spring (northern Late winter and early spring (northern

hemisphere)hemisphere) Reverse in southern hemisphereReverse in southern hemisphere Possible link: virusesPossible link: viruses Effect seen in cities, not in countrysideEffect seen in cities, not in countryside



Vitamin D deficiencyVitamin D deficiency Dealberto (2007)Dealberto (2007) Northern Europe: 3-fold increase in schizophrenia in Northern Europe: 3-fold increase in schizophrenia in

immigrants (equatorial regions)immigrants (equatorial regions)

Thiamine deficiencyThiamine deficiency Two-fold increase in incidence of schizophrenia in Two-fold increase in incidence of schizophrenia in

offspring of women pregnant during severe food offspring of women pregnant during severe food shortage in WWII (Germany and Netherlands)shortage in WWII (Germany and Netherlands)

Maternal/paternal substance abuse – smokingMaternal/paternal substance abuse – smoking

Complications during childbirthComplications during childbirth Mother: Diabetes of mother, bleeding, preclampsia Mother: Diabetes of mother, bleeding, preclampsia

(high blood pressure, protein in urine)(high blood pressure, protein in urine) Other: oxygen or blood flow deprivationOther: oxygen or blood flow deprivation

Evidence for Abnormal Evidence for Abnormal Brain DevelopmentBrain Development

Home movies from families with schizophrenic Home movies from families with schizophrenic childchild Compared to normal siblings, schizophrenic child Compared to normal siblings, schizophrenic child

displayed more negative affect and more abnormal displayed more negative affect and more abnormal movementsmovements

265 Danish children (11-13 years) were videotaped 265 Danish children (11-13 years) were videotaped eating luncheating lunch Children who later developed schizophrenia displayed Children who later developed schizophrenia displayed

less sociability and deficient psychomotor functioningless sociability and deficient psychomotor functioning

Hypothesis – although schizophrenia is not seen in Hypothesis – although schizophrenia is not seen in childhood, the early brain development of children childhood, the early brain development of children who become schizophrenic is not normalwho become schizophrenic is not normal

Age of OnsetAge of Onset

Symptoms rarely begin before late adolescence or Symptoms rarely begin before late adolescence or early adulthoodearly adulthood

Progression:Progression: Negative symptoms Negative symptoms cognitive symptoms cognitive symptoms positive positive

symptoms symptoms


Abnormal Brain Abnormal Brain DevelopmentDevelopment

Brain damage is sudden Brain damage is sudden (during young adulthood)(during young adulthood)

Thompson et al. (2001)Thompson et al. (2001) Adolescence with early Adolescence with early

onset schizophreniaonset schizophrenia MRIMRI

Normals:Normals: Loss of 0.5-1.0%Loss of 0.5-1.0%

Schizophrenic patients:Schizophrenic patients: 2-3%2-3%

See Figure 16.9See Figure 16.9 Loss:Loss:

Parietal to temporal lobeParietal to temporal lobe

Somatosensory and motorSomatosensory and motor

Prefrontal cortexPrefrontal cortex

Abnormal Brain Abnormal Brain DevelopmentDevelopment

Hypofrontality and Negative and Cognitive Symptoms Hypofrontality and Negative and Cognitive Symptoms Decreased activity of the prefrontal cortex (dlPFC); believed to Decreased activity of the prefrontal cortex (dlPFC); believed to

be responsible for the be responsible for the negative negative symptoms of schizophrenia.symptoms of schizophrenia. Above fig: Task required increased concentration and attentionAbove fig: Task required increased concentration and attention Possibly caused by Possibly caused by decreaseddecreased DA activity in prefrontal regions DA activity in prefrontal regions


NMDA , NMDA , Dopamine and Dopamine and HypofrontalityHypofrontality

PCP and ketamine can PCP and ketamine can cause positive, negative cause positive, negative and cognitive-like and cognitive-like symptomssymptoms NMDA receptor NMDA receptor

antagonistsantagonists; decrease DA ; decrease DA and metabolic activity in and metabolic activity in frontal cortex frontal cortex

Role of D2 Receptors in Role of D2 Receptors in Development of Development of SchizophreniaSchizophrenia

Abnormalities in the striatal DA system may Abnormalities in the striatal DA system may be the cause of schizophreniabe the cause of schizophrenia

Virus inserted into striatum that increased Virus inserted into striatum that increased D2 recpetorsD2 recpetors Caused the development of behavioral deficits Caused the development of behavioral deficits

characteristic of schizophreniacharacteristic of schizophrenia Abnormal activity of dlPFCAbnormal activity of dlPFC

Treatment with Partial DA Treatment with Partial DA Receptor AgonistsReceptor Agonists

Atypical drugs are able to Atypical drugs are able to reduce ALL symptomsreduce ALL symptoms Increase DA activity in Increase DA activity in

PFCPFC Reduce DA activity in the Reduce DA activity in the

NANA

AripoprazoleAripoprazole: Atypical: Atypical Partial Partial DA agonistDA agonist

High affinity for receptor High affinity for receptor but less than ligandbut less than ligand

Can act like an antagonistCan act like an antagonist Nucleus accumbensNucleus accumbens

Can act like an agonistCan act like an agonist Prefrontal cortexPrefrontal cortex

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

Documents

Overview Huntington’s Disease Degeneration of caudate nucleus and putamen Uncontrollable movements, jerky limb movements Progressive, cognitive and emotional