Anti-psychotics (Block 4)

Question 1

Dopamine

Answer 1

The monoamine dopamine (DA) is a catecholamine
Its cellular action is principally inhibitory

Question 2

Where is dopamine found?

Answer 2

At high concentrations in the basal ganglia

Question 3

Roles of dopamine

Answer 3

Involved in motor control
Behavioural effects
Endocrine control in the pituitary

Question 4

What receptors does dopamine act through?

Answer 4

Via a number of receptor subunits (D1-D5)
GPCRs

Question 5

Psychosis

Answer 5

A general term to describe loss of touch with reality
Associated with a variety of disorders, but mostly schizophrenia

Question 6

Schizophrenia symptoms characterisation

Answer 6

Characterised by multiple symptoms that are divided into “positive” and “negative”

Question 7

What does a “positive” schizophrenia symptom mean?

Answer 7

A symptom additional to normal behaviours

Question 8

What does a “negative” schizophrenia symptom mean?

Answer 8

Lacking compared to normal behaviours

Question 9

Debilitations of schizophrenia

Answer 9

Despite pharmacological treatments, patients have a reduced life expectancy
Top 10 for disease burden

Question 10

Commonality of schizophrenia

Answer 10

Affects up to 1% of the population (~600,000 people in the UK)

Question 11

Typical age of onset for schizophrenia

Answer 11

Men: 23-28
Women: 28-32
Often has earlier phase of social isolation and withdrawal

Question 12

Schizophrenia - genetic component

Answer 12

There is a significant UNIDENTIFIED genetic component to schizophrenia
There’s a 14% increase in incidence for a dizygotic sibling and a 50% incidence for a monozygotic sibling

Question 13

Schizophrenia genetic hypothesis

Answer 13

The more closely-related to the family member to the person with schizophrenia, the greater their chance of developing the disorder

Question 14

Why is it hard to pinpoint the genetic component of schizophrenia?

Answer 14

It seems to be involved in several genes rather than just one

Question 15

Why is schizophrenia one of the most important psychiatric illnesses to be studied?

Answer 15

It affects young people
It’s often chronic
It’s usually highly disabling
Leads to suicide attempts in 50% of cases, ~10% of which are successful
Clinical phenotype varies greatly
Variability may have a bearing on efficacy of antipsychotic drugs in individual cases

Question 16

“Positive” symptoms of schizophrenia

Answer 16

Hallucinations
Delusions
Thought disorders

Question 17

Hallucinations

Answer 17

Perceptions in the absence of real stimuli
Can be auditory and visual

Question 18

Delusions

Answer 18

Delusions of persecution and loss of control over own thoughts and actions
Nature of delusions determined by social and historical factors

Question 19

Thought disorders

Answer 19

Making speech hard to follow
Problems with “selective attention”

Question 20

“Negative” symptoms of schizophrenia

Answer 20

Loss of empathy
Inappropriate or blunted mood; repetitive activity
Anhedonia
Apathy
Attention impairment

Question 21

Associations of positive schizophrenia symptoms

Answer 21

Acute episodes

Question 22

Associations of negative schizophrenia symptoms

Answer 22

Chronic schizophrenia

Question 23

Early treatment for schizophrenia

Answer 23

Confinement to asylums up until 20th Century
Fist antipsychotic - Chlorpromazine - 1950s
First antidepressant - Imipramine

Question 24

Chlorpromazine

Answer 24

First antipsychotic
Tried on schizophrenic patients in the 1950s as a sedative and found to stop hallucinations
Strong antagonist of D2 dopamine receptors

Question 25

Imipramine

Answer 25

First anti-depressant Actually a failed attempt to make a new antipsychotic, but found to improve mood

Question 26

Schizophrenia - abnormalities of dopaminergic neurotransmission

Answer 26

Original dopamine theory of schizophrenia: more dopamine than usual. Further research: thought that schizophrenic individuals have abnormally high numbers of D2 receptors

Question 27

Schizophrenia - dopamine antagonists

Answer 27

Dopamine antagonists are effective in controlling the positive symptoms of schizophrenia, and in preventing amphetamine-induced behavioural changes

Question 28

Dopamine receptor subtypes implicated in schizophrenia

Answer 28

D2 receptors may be implicated in the positive symptoms -> overactivity in mesolimbic pathway D1 receptors may be implicated in the negative symptoms -> decreased activity on mesocortical pathway

Question 29

Treatment of schizophrenia - "typical"/first-generation antipsychotics

Answer 29

Loosely defined term to describe older antipsychotics; tend to: Cause extra-pyramidal side effects Act against positive but NOT negative symptoms Unselective binding to dopamine receptors

Question 30

Examples of typical/first-generation antipsychotics

Answer 30

Phenothiazines Butyrophenones

Question 31

Extra-pyramidal side effects of typical/first-generation antipsychotics

Answer 31

Cause 2 major kinds of motor disturbance in humans: Acute dystonia and tardive dyskinesia Results directly or indirectly from D2 receptor blockade in the nigrostriatal pathway One of main disadvantages of these drugs

Question 32

Acute dystonia

Answer 32

Involuntary movements, often similar to Parkinson's. Includes: Rigidity Tremor Inability to sit still Slowing of voluntary movements

Question 33

Tardive dyskinesia

Answer 33

Occurs after long-term treatment in 10-20% of patients Causes large involuntary movements Symptoms may worsen with reduced antipsychotic doses

Question 34

Schizophrenia treatment - atypical antipsychotics

Answer 34

More recently developed compounds Fewer extra-pyramidal side effects Efficacy against positive and negative symptoms Different receptor selectivity profile

Question 35

Atypical antipsychotics examples

Answer 35

Dibenzodiazepines - clozapine and risperidone Newer: benzamides and quetiapine

Question 36

Benzamidine example

Answer 36

eg. Amisulpride Selective antagonist at D>2 receptors

Question 37

Quetiapine

Answer 37

Similar binding profile to clozapine, but with lower affinities

Question 38

Effectiveness of schizophrenia treatment

Answer 38

Even with the latest drugs, ~30% of patients don't respond to treatment. Difference between those who respond and those who don't is unknown

Question 39

Clinical potency and correlation with D2 receptor affinity

Answer 39

Correlation exists between the therapeutic dose of an antipsychotic and the drug's affinity for the D2 receptor So a larger dose is required if the drug's affinity for the D2 receptor is relatively weak

Question 40

Schizophrenia - neural imaging

Answer 40

MRI scans reveal structural neuronal deficits Schizophrenia patients have smaller cortices and larger ventricles, particularly in medial temporal lobe and left hemisphere Many changes are NOT progressive, indicating there are developmental changes in addition to possible degeneration

Question 41

Schizophrenia - potential causes

Answer 41

Dopamine theory Glutamate theory Serotoninergic system

Question 42

Dopamine theory - evidence

Answer 42

Compounds that increase dopaminergic signalling activity can induce psychoses There is a correlation between D2 receptor antagonist affinity and clinical antipsychotic efficacy Structural deficits in the brain suggest a loss of control of dopaminergic function

Question 43

Glutamate theory

Answer 43

Dysfunction in glutamatergic neurotransmission has been suggested as a cause based on: The psychotomimetic actions of NMDA receptor channel blockers Reduced glutamate binding in post-mortem studies of schizophrenic people

Question 44

Serotoninergic system

Answer 44

5HT has been proposed to play a role in schizophrenia, with some antipsychotics selectively blocking 5HT>2A receptors LSD also has psychotomimetic properties Serotonin modulates DA actions, so this is not necessarily incompatible with the dopamine theory