Dopamine and Schizophrenia

Question 1

Dopamine associated conditions

Answer 1

Schizophrenia; Parkinson’s disease; Reward and Drugs of abuse // Attention deficit hyperactivity disorder (ADHD); Tourette’s Huntington’s disease; Bipolar disorders; Depression

Question 2

Which dopamine associated condition is a form of psychosis?

Answer 2

Schizophrenia

Question 3

Epidemiology of schizophrenia

Answer 3

Affects about 1% of the population worldwide; more common in men (20 to 30% prevalence in homeless men); cost accounts for 2.5% of total health spending in the US; strong genetic predisposition ( polygenic)

Question 4

Being born in which season increases the risk of schizophrenia?

Answer 4

Winter

Question 5

Which viruses increase the risk of schizophrenia?

Answer 5

Influenza and Zika, as they both affect development

Question 6

Degree of relatedness and the risk of schizophrenia

Answer 6

Risk of schizophrenia 48% in a monozygotic twin, 17% in a dizygotic twin, which is about the same for other siblings

Question 7

Positive symptoms of schizophrenia

Answer 7

Delusions (especially paranoid); prominent hallucinations (usually auditory and often self-critical); disordered thoughts; problems processing sensory input

Question 8

Negative symptoms of schizophrenia

Answer 8

Withdrawal; emotionally unresponsive; unusual posture

Question 9

Negative symptoms of schizophrenia and antipsychotics

Answer 9

Pharmacological treatment of negative symptoms is much less effective, suggesting that the negative symptoms of schizophrenia could actually be a different disease

Question 10

Prognosis in schizophrenia

Answer 10

65% suffer for as many years; remission and recovery in 25% in a five year period; 10% experience total incapacity; early detection and diagnosis is important, young patients respond well, recover better, have fewer relapses

Question 11

Underlying causes of schizophrenia

Answer 11

Prominent anatomical abnormalities in the brain; dopamine theory

Question 12

Prominent anatomical abnormalities in brain

Answer 12

Reduced blood flow to globus pallidus (basal ganglia to frontal lobes) Reduced blood flow to frontal lobes during memory tests Cortex of medial temporal lobe is thinner Enlarged lateral and third ventricles and widening of the sulci. Enlarged palladium Reduced hippocampus, amygdala, thalamus, nucleus accumbens.

Question 13

Uncertainty surrounding the anatomical theories of schizophrenia

Answer 13

Unclear whether the abnormalities are due to disease or drugs

Question 14

Which anatomical abnormality is most common in schizophrenia?

Answer 14

Enlarged ventricles and widening sulci

Question 15

Another anatomical feature which is particularly interesting in schizophrenia

Answer 15

Is the frontal lobes

Question 16

Dopamine theory

Answer 16

(Carlsson 1960’s) 1951: chlorpromazine calms agitated patients (‘tranquilizer’) - Laborit 1964: chlorpromazine found to mitigate schizophrenic symptoms 1964-: chlorpromazine and other antipsychotics act as dopamine antagonists

Question 17

Standard antipsychotics used against schizophrenia

Answer 17

chlorpromazine (Thorazine) fluphenazine (Prolixin) haloperidol (Haldol) thiothixene(Navane) trifluoperazine (Stelazine) perphenazine (Trilafon) thioridazine (Mellaril)

Question 18

Which type of antipsychotics are DA blockers?

Answer 18

Standard antipsychotics

Question 19

Atypical antipsychotics used against schizophrenia

Answer 19

risperidone (Risperdal) clozapine (Clozaril) olanzapine (Zyprexa)

Question 20

Which type of antipsychotic are serotonin blockers?

Answer 20

Atypical antipsychotics

Question 21

Principal mechanisms of drug action

Answer 21

Question 22

Which adjective is a technical term to describe the mechanism of action of antipsychotics?

Answer 22

Dirty- wide acting thus have far-reaching side-effects

Question 23

Principal side effects of antipsychotics

Answer 23

movement: controlled by many neurotransmitters but particularly a balance between dopamine and acetylcholine

Question 24

Name the effect on movement that dopamine blocking drugs often have

Answer 24

extrapyramidal effects

Question 25

Acute dystonias (Parkinson-type)

Answer 25

involuntary movements (protruding tongue) quick onset REVERSIBLE

Question 26

Tardive dyskinesia

Answer 26

Disabling involuntary movements; slow onset; IRREVERSIBLE

Question 27

Benefits of antipsychotics that block cholinergic transmission and atypical antipsychotics

Answer 27

Fewer extrapyramidal side effects

Question 28

Problems with the D2R hypothesis

Answer 28

General Problems: Known antipsychotics take several weeks to work; No good mechanism explaining anti-D2R correlation with schizophrenia (knockouts, genetics etc) Positive and Negative Symptoms: D2 antagonists primarily block just +ve symptoms Clozapine - Atypical antipsychotic: Poor D2R antagonist (5HT) and yet still efficacious against +/-ve symptoms

Question 29

Why is D4R interesting in relation to schizophrenia?

Answer 29

Expressed in the meso-cortico/limbic systems: cortex; amygdala; hippocampus; hypothalamus; mesencephalon;

Question 30

D4Rs and Schizophrenia

Answer 30

D4 receptors increased in brains from schizophrenia patients; Cloned/expressed human D4 receptors -> Clozapine 10X higher affinity human D4Rs vs. D2Rs; Potential benefits of targeting D4Rs vs. D2Rs -> Reduced extrapyramidal side-effects (Parkinsonism); Drug companies launched improved D4 antagonists e.g. L745870 which is x103 D4 vs. D2 (Merck)

Question 31

Problems with the D4R hypothesis of schizophrenia

Answer 31

Animal models: Beneficial effects D4 antags occur at doses >> than D4R blockade Patients: Random, double blind trial: no improvement even at 4wks

Question 32

Other systems in schizophrenia

Answer 32

Glutamate transmission: decreased NMDA transmission –> psychosis; e.g. PCP (Angel dust) – psychotogenic – blocks NMDARs; conversely D2R antagonist (haloperidol) blocks PCP effects Other transmitter systems: 5HT – evidence LSD (partial agonist (high doses)); but again ‘selective’ drugs found to act on D2Rs!

Question 33

glutamate and schizophrenia

Answer 33

Brains from schizophrenia patients show reduced NMDAR in forebrain at post-mortem (agrees with effect of PCP)-> thus: NMDA agonists might be beneficial. D-Cycloserine: NMDA agonist (binds to the glycine site of R); used as adjunct in treatment (results mixed). mGluR2/3 agonists also being trialled (decreased Glu release in prefrontal cortex)

Question 34

dopamine hypothesis of. schizophrenia version 3

Answer 34

Imaging studies consistently show increased uptake of L-Dopa and synthesis to DA in presynaptic terminals in striatal DA-neurons. Imaging also shows increased release of DA from these neurons D2-blockers (antipsychotics) also block presynapatic D2 receptors that regulate DA release → promotes increase in DA synthesis Should drug development focus on modulating presynaptic DA synthesis and/or release?

Question 35

The drug deadlock

Answer 35

Drugs developed since 1990 no better than older drugs

Question 36

Early diagnosis

Answer 36

Diagnose predisposition for Schizophrenia before symptoms Approach: Machine learning coupled to functional imaging E.g. fMRI to measure emotional response images then algorithms to compare individual activity with those of library standards

Question 37

Candidate genes in schizophrenia

Answer 37

DISC1 Disrupted in schizophrenia DTNBP1 Dysbindin (dystrobrevin binding protein 1) NRG1 Neuregulin 1 AKT1 Protein Kinase B DAOA D amino acid oxidase activator COMT Catechol-O-methyl transferase RGS4 Regulator of G-protein signalling 4 VMAT2 Vesicular monoamine transporter ARC Cytoskeleton NMDAR glutamate signalling CACNA1C Ca channel