Exam revision

Question 1

When and how was lithium first discovered?

Answer 1

Lithium was first discovered in 1948 by John Cade, and he discovered this treatment as he made a prediction regarding the toxicity of urea of people with manic depression while a POW. Tested out urea on guinea pigs with lithium salts and then found that lithium carbonate could successfully treat a manic patient.

Question 2

When was lithium first approved and why did it take so long for approval to be granted?

Answer 2

Lithium was first approved in 1970 for the treatment and control of mania and in 1974 was approved as a prophylactic for bipolar disorder. To this day it is still seen as the gold standard comparative for the treatment of bipolar disorder.
Approval took a long time to be granted as in 1949 the use of lithium was banned following three deaths due to lithium use. Cade’s discovery was published in an obscure Australian journal and so there was resistence from people and companies to believe lithium could be effective.

Question 3

What is bipolar disorder?

Answer 3

Is a mood disorder with symptoms experience by 1-4% of people during their lifetime. There are two types of bipolar disorder: Type 1 is characterised by manic episodes and Type 2 is characterised by hypomania- still disputed whether these are two forms of manic depression or just a spectrum of this disorder; depressive symptoms are more severe in bipolar 2 and manic symptoms are more severe in bipolar 1

Question 4

What are the symptoms seen for a manic episode?

Answer 4

Long periods of feeling high or in an irritable mood, with behaviour changes such as talking quickly, jumping between ideas, restlessness, insomnia, unrealistic beliefs in ones abilities and impulsive behaviour

Question 5

What are the symptoms of a depressive episode?

Answer 5

Long periods of feeling empty, loss of interest in normal activities, tiredness, poor concentration, restlessness, change in eating habits and suicidal thoughts

Question 6

What are the benefits of lithium as a treatment?

Answer 6

• Shown to be an effective treatment for acute mania, bipolar depression, major depression, recurrent depression and aggressiveness
• Large amount of clinical data supporting its efficacy
• Low cost
• Is a prophylactic
• Has anti-suicidal properties (can reduce the risk of suicide by 80%)

Question 7

What are the disadvantages of lithium as a treatment?

Answer 7

• Has a delay onset in acute mania of 6-10 days and a delay onset in depression of 6-8 weeks
• When discontinued as an anti-suidical treatment, there is an increased risk of relapse
• Small therapeutic window; clinical dose is 0.6-1.2 mEq , for mild toxicity the dose is 1.5-2.0 mEq, severe toxicity >2.0mEq- high concentrations can cause death so needs to be monitored

Question 8

How is it thought that lithium has an effect on bipolar disorder?

Answer 8

Thought to be via its actions as a modifier of intracellular second messenger systems; two enzymatic chains have been noted as targets- inositol monophosphatase (IMPase)- key enzyme in the phosphatidylinositol pathway (PI)
- Second enzyme is glycogen synthase kinase 3 (GSK3) which is involved in the Akt pathway

Question 9

Describe the mechanism by which the PI signalling pathway works?

Answer 9

• Phospholipase C is receptor activated and hydrolyses phosphotidylinositol biphosphate (PIP2) to inositol 1,4,5-biposphate (IP3)
• This causes the release of calcium from intracellular stores into the cytoplasm and the release of DAG, which activates protein kinase C

Question 10

How is phosphatidylinositol biphosphate (PIP2) generated?

Answer 10

Either by:
-The biosynthesis of inositol from glucose-6-phosphate by inositol 1, phosphatase (I(1)P) OR
-The recycling of I(1)P from P1 mediated signal transduction
Final hydrolysis of inositol monophosphatase to inositol is catalysed by IMPase

Question 11

What is the effect of IMPase inhibition by lithium?

Answer 11

A decrease in inositol levels
CMP-PA accumulates
IP3 levels decrease

Question 12

What is the evidence that lithium inhibits PI signalling?

Answer 12

Allison and Stewart showed in 1971- inositol concentrations are reduced by 30% in the cerebral cortex
In 1976- showed lithium-treated rats have increased I(1)P concentrations in the the cerebral cortex

Question 13

What are the caveats to the inositol depletion hypothesis?

Answer 13

No evidence that neurochemical deficits in PI signalling are involved in bipolar disorder
No evidence that bipolar disorder is related to the PI signalling pathway
No evidence of the genetics associated with bipolar disorder

Question 14

What was the first drug made by the sussex drug discovery team as a inhibitor of the phosphatidylinositol pathway and what were the problems with this drug?

Answer 14

L-690,300: was seen to be 1,000x more potent than lithium but did not get into cells well- poor cell penetration

Question 15

What was the next drug developed and how was it changed? What were the problems with this drug?

Answer 15

L690,488; was even more potent than L690,300 but very lipophilic and precipitated out when injected in vivo

Question 16

What was found from the crystal structure of IMPase?

Answer 16

Was found to be a homodimer of 30kDa molecular weight with magnesium ions bound to a phosphate- lithium was seen to bind to one of these phosphates in place of magnesium and prevented hydrolysis occurring

1. ) active site is very polar
2. ) inhibitors need to be charged, but when they do they don’t cross the membrane well

Question 17

What have the steps that have been taken now by SSDD to produce a new compound?

Answer 17

Taking a fragment based approach- looking for small fragments which can be built upon to act as inhibitors; can start with small fragments which bind weakly and can then add larger chains on to this
–> Purified the protein, Electrophoresis etc.
–> Crystallography
To try and visualise the protein and try and find suitable fragments