Neurological Disease- Depression

Question 1

What plays a role in the etiology of depression?

Answer 1

Gene(s) responsible not identified
Family history can be used to assess risk

Non-genetic factors also contribute
e.g. trauma, stressful life events, abuse, illness
Psychosocial interventions can be useful in disease prevention

Question 1

What is depression characterised by?

Answer 1

Changes in mood
- Misery, pessimism
- Low self esteem
- Feeling of worthlessness
- Loss of motivation, loss of energy
- Weight or appetite alterations
- Insomnia

Potentially life-threatening
Suicide a considerable risk
Can occur from childhood to late life

Question 2

Why is depression an issue for public health?

Answer 2

Causes morbidity across the entire age spectrum
Affects 1 in 5 people in their lifetime
Can be difficult to diagnose and treat
Socio-economic considerations
Cost of treatment (e.g. medication)
Time off work

Question 3

When were antidepressants first discovered?

Answer 3

Antidepressants were first introduced in the 1950’s
First drugs were not designed to treat depression
e.g.
Serendipitous clinical observations
Iproniazid originally used in treatment of tuberculosis

Question 4

What is Iproniazid?

Answer 4

Anti-depressant activity discovered as patients treated with the drug had changes in their mood
‘Greater vitality’ increase in social activity
Clinicians suggested that the psychostimulant effect of iproniazid could be exploited in other patients
Use of drug in non-tuberculosis patients was initiated

Question 5

What is the mechanism of action of iproniazid?

Answer 5

Iproniazid inhibited the activity of the enzyme monoamine oxidase (MAO)
MAO breaks down neurotransmitters (NTs) in the synaptic cleft
Increases NT concentration
First group of antidepressants termed MAO inhibitors

Question 6

What is imipramine?

Answer 6

Was the first tricylic antidepressant (TCA)
Mechanism of action: inhibition of NT re-uptake into the pre-synaptic cell

Question 7

What is the one of the hypotheses to explain depression?

Answer 7

Monoamine deficiency hypothesis

Question 8

What did investigation into the mechanism of action of antidepressant drugs lead to?

Answer 8

A better understanding of the biochemical events underlying depression
Drugs increased NT concentration in the synaptic cleft

Question 9

What does the monoamine deficiency hypothesis suggest?

Answer 9

Hypoactivity of monoaminergic neurotransmission is central to depression pathogenesis
The symptoms of depression are improved by agents that act by various mechanisms to increase synaptic concentrations of monoamines

Question 10

So how is the hypothesis of monoamine described?

Answer 10

Hypothesised that depression is caused by a deficiency (depletion) in monoamine NTs
5-HT (serotonin)
Noradrenaline
Dopamine
Monoaminergic neurons regulate a broad range of brain functions (e.g. mood)

Question 11

How do antidepressants correct monoamine deficiency?

Answer 11

Anti-depressants increase monoamine NT levels in the synaptic cleft by:
- Inhibiting monoamine NT reuptake
- Inhibiting NT breakdown (monoamine oxidase activity)
Antidepressants correct a chemical balance

Question 11

How is the mechanism underlying NT loss explained?

Answer 11

Examples:
- Increased activity/levels of monoamine oxidase
- Loss of function in enzymes that synthesise NTs
- Altered numbers/sensitivities of NT receptors/reuptake transporters

Question 12

What is reserpine?

Answer 12

Reserpine was a drug used to treat hypertension
Clinical observations demonstrated it induced a syndrome resembling depression

Question 13

How did knowledge of reserpine relate to depression?

Answer 13

Knowledge of mechanism of action of reserpine helped identify events underlying the pathogenesis of depression
Empties nerve terminals of monoamine NTs
Suggests a deficiency in monoamine transmission causes depression

Question 14

What was reserpine used to develop?

Answer 14

Used to develop an animal model of depression
Animal model responded to anti-depressant drugs (i.e symptoms reversed)
Provides more evidence that a deficiency in NTs is important to disease pathogenesis

Question 15

How is depression treated?

Answer 15

Medication
All act by altering monoaminergic transmission
Since initial discovery the number and diversity of drugs have increased
Psychotherapy

Question 16

What are the 3 main classes of antidepressants?

Answer 16

Monoamine oxidase inhibitors (MAOI)- Inhibit NT breakdown in synaptic cleft

Tricyclic antidepressants (TCA)- Inhibitors of NT re-uptake (non-specific)

Selective serotonin re-uptake inhibitors (SSRIs)- Inhibit re-uptake of serotonin by (pre-synaptic) neurons

Question 17

What was the first MAOI?

Answer 17

Iproniazid was the first MAOI
Led to development of drugs that were more effective at inhibiting MAO activity

Question 18

What are the safety problems of MAOIs?

Answer 18

Iproniazid withdrawn in 1960s: hepatic toxicity
MAOIs: hypertensive episodes (cheese effect)
Headaches following cheese and red wine consumption

Question 19

Where are MAO enzymes located in the body?

Answer 19

CNS and PNS
MAO-A associated with depressive disorders
Original MAOIs irreversibly inhibited both isoenzymes

Question 20

Why are MAO enzymes (A) significant?

Answer 20

Selective and reversible inhibition of MAO-A could improve effectiveness of drugs and reduce side effects
e.g. moclobemide
BUT MAOIs had a lower efficacy than TCAs: limited therapeutic use (not first choice drug)

Question 21

What do TCAs do?

Answer 21

Tricyclic antidepressants (TCAs) e.g imipramine, amitryptyline
Inhibit NT re-uptake into pre synaptic terminal
Increase NT concentration in the synaptic cleft
Unwanted side effects

Question 22

What are the new antidepressants developed to improve safety?

Answer 22

MAOIs and TCAs antidepressant activity discovered accidentally
Selective Serotonin Reuptake Inhibitors (SSRIs) designed to act at a specific target
Serotonin reuptake transporter

Question 23

Why are SSRIs an improvement?

Answer 23

Improvements in selectivity of action
SSRIs selectively inhibit the reuptake of serotonin
Increase in serotonin in synaptic cleft
First line of treatment

Question 24

What is the problem with antidepressants?

Answer 24

Antidepressants have a delayed onset of action
Major limitation of all anti-depressant drugs
Speed of onset of drugs is important
Delayed onset can:
Reduce compliance and increase patient risk

Question 25

How long can it take for the clinical effect of antidepressants to be observed?

Answer 25

NT concentrations are increased within hours of treatment commencing
It takes several days to weeks of treatment for the clinical antidepressant effect to be observed

Question 26

Why is the monoamine hypothesis difficult to validate?

Answer 26

If depression is caused by low levels of monoamine NTs, the depression should decrease as the levels of NT increase
However hypothesis of monoamine is difficult to validate due to delayed onset of action
NT receptor hypothesis used to explain this phenomenon

Question 27

What is the initial effect of antidepressants?

Answer 27

Is to increase NT levels
Occurs within hours of administration
Autoreceptors on pre-synaptic cells stimulated and inhibit further NT release

Question 28

What is autoreceptor sensitivity?

Answer 28

Over time the autoreceptors become less sensitive to increased NT concentration
Termed autoreceptor desensitisation
NT release is no longer inhibited
Increase in NT concentration in synaptic cleft

Question 29

What else can increased exposure to NT after treatment cause?

Answer 29

A compensatory decrease in post synaptic receptor number and sensitivity
An increase in concentration of NT causes a desensitsation and downregulation of post-synaptic receptors

Question 30

What is the reason for the delayed onset of action of antidepressants?

Answer 30

Delayed onset of action until receptor number and activity is returned to normal
Then changes in mood become apparent