CNS Pharmacology

Question 1

What are the positive symptoms of Schizophrenia?

Answer 1

Hallucinations
• Auditory (persecutory, exhortatory)
• Tactile and olfactory
• Visual?
These false perceptions are very real

Delusions
• Paranoid
• Grandiose
     -Thought broadcasting
     -Thought insertion

Dysfunction of logical thought patterns- Knight’s move thinking

Question 2

What are the negative symptoms of Schizophrenia?

Answer 2

• Depression
• Anhedonia
• Self-neglect
• Social withdrawal

Question 3

People with Schizophrenia often have abnormal ways of thinking. Give examples:

Answer 3

They may have trouble organizing their thoughts or making logical connections.

They may feel like the mind is racing from one unrelated thought to another.

Sometimes they experience “thought blocking,” a feeling that thoughts are removed from their head.

Question 4

Is Schizophrenia the same as multiple personality disorder?

Answer 4

No

Question 5

Describe the aeitiology of Schizophrenia

Answer 5

Genetic or environmental

Shows a strong but incomplete genetic tendency

In first relatives the risk is 10%

However in monozygotic twins the probability of the other being affected is only 50%

Morphological characteristics- enlarged cerebral ventricles

Question 6

What are the neurodevelopmental factors which influence predisposition to Schizophrenia?

Answer 6

• Environmental influences in early foetal development have been identified as possible predisposing factors, particularly maternal viral infections
• These studies suggest that the disease is associated with a neurodevelopmental disorder affecting mainly the cerebral cortex
• Brain imaging studies show cortical atrophy in the early course of the disease, which may increase with time and correlate with progression of the disorder.

Question 7

Describe the features of the dopamine hypothesis

Answer 7

• Postulates that schizophenics have altered DA activities in specific areas of the brain that use dopamine as a neurotransmitter.(1) Limbic system (the emotional brain) (2) Frontal lobes (3) Pre-frontal cortex
• Brain lesions of these areas cause psychotic symptoms
• Amphetamines that also stimulate dopamine release can induce psychosis and exacerbate symptoms in schizophrenics
• Serendipitous chlorpromazine! Drug discovery in reverse! A pre-operative tranquiliser and D2 antagonist that alleviates psychosis – positive symptoms only!
• Clinical efficacy correlates with binding affinity for the D2 receptor
• Increased levels of D2 receptors found in the post mortems of schizophrenics (upregulation?)

Question 8

Give examples of first generation antipsychotics

Answer 8

Phenothiazines
• Chlorpromazine
• Thioridazine
• Trifluoperazine

Thioxanthenes
• Flupenthixol

Butyrophenones
•Haloperidol

Question 9

What are the four major pathways that are poignant to pathophysiology and treatment of Schizophrenia?

Answer 9

1. Mesocortical DA system
2. Mesolimbic DA system
3. Tuberoinfundibular system
4. Nigrostriatal system

Question 10

Describe the role of dopamine in Schizophrenia

Answer 10

• Positive symptoms are thought to result from overactivity in the mesolimbic dopaminergic pathway activating D2 receptors
• Negative symptoms may result from a decreased activity in the mesocortical dopaminergic pathway, where D1 receptors predominate

Question 11

What is the aim of the treatment of negative and cognitive symptoms of Schizophrenia?

Answer 11

To increase dopamine neurotransmission

Question 12

What is the aim of the treatment of positive symptoms of Schizophrenia?

Answer 12

To decrease dopamine neurotransmission

Question 13

First generation anti-psychotics (D2 antagonists) are often characterised by debilitating side effects

What are the extrapyramidal side effects?

Answer 13

Tremor
Rigidity
Akinesia
Akathisia
Acute dystonic reactions
Neuroleptic malignant syndrome (fatal in 10%)
Tardive dyskinesia

Question 14

What are acute dystonic reactions?

Answer 14

Spasms of the neck and facial muscles

These sustained muscle contractions cause abnormal postures or repetitive movements - OCULOGYRIC CRISIS

Question 15

Describe the additional binding properties of first generation antipsychotics

Answer 15

Muscarinic receptor block

• Anti-cholinergic side effects
• Dry mouth and eyes
• Blurred vision
• Increased intraocular pressure
• Constipation
• Urinary retention

H1 histamine receptor block

• Sedation
• Anti-emetic

α1-adrenergic receptor block Postural hypotension

Question 16

What were the problems with first generation antipsychotics?

Answer 16

Antagonism of D2 receptors of the mesolimbic pathway is believed to relieve the positive symptoms of schizophrenia, however;

• Systemically administered antipsychotics do not discriminate between D2 receptors in other brain regions
• Unwanted motor effects (D2 blockade in the nigrostriatal pathway)
• Enhanced prolactin secretion (D2 blockade in the tuberoinfundibular pathway)
• Reduced pleasure (D2 blockade in the reward component of the limbic system)
• Perhaps worsen the negative symptoms (D2 blockade in the pre-frontal cortex, though only expressed at a low density and D1 predominate.

In reality, First Generation anti-psychotics were not highly specific for D2 and blockade of D1 also occurs thus exacerbating the negative symptoms)

Question 17

Describe the serotonin hypothesis for Schizophrenia

Answer 17

• Serotonin hypothesis pre-dates the dopamine hypothesis. LSD, a partial agonist at 5-HT2A receptors produces hallucinations
• Current thinking maintains that 5-HT is NOT involved in the pathogenesis of schizophrenia
• However, pharmacological manipulation of 5-HT receptors combined with D2 antagonism may yield drugs with improved therapeutic profiles