Neurological Disease- Depression Flashcards
What plays a role in the etiology of depression?
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
What is depression characterised by?
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
Why is depression an issue for public health?
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
When were antidepressants first discovered?
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
What is Iproniazid?
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
What is the mechanism of action of iproniazid?
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
What is imipramine?
Was the first tricylic antidepressant (TCA)
Mechanism of action: inhibition of NT re-uptake into the pre-synaptic cell
What is the one of the hypotheses to explain depression?
Monoamine deficiency hypothesis
What did investigation into the mechanism of action of antidepressant drugs lead to?
A better understanding of the biochemical events underlying depression
Drugs increased NT concentration in the synaptic cleft
What does the monoamine deficiency hypothesis suggest?
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
So how is the hypothesis of monoamine described?
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)
How do antidepressants correct monoamine deficiency?
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
How is the mechanism underlying NT loss explained?
Examples:
- Increased activity/levels of monoamine oxidase
- Loss of function in enzymes that synthesise NTs
- Altered numbers/sensitivities of NT receptors/reuptake transporters
What is reserpine?
Reserpine was a drug used to treat hypertension
Clinical observations demonstrated it induced a syndrome resembling depression
How did knowledge of reserpine relate to depression?
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
What was reserpine used to develop?
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
How is depression treated?
Medication
All act by altering monoaminergic transmission
Since initial discovery the number and diversity of drugs have increased
Psychotherapy
What are the 3 main classes of antidepressants?
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
What was the first MAOI?
Iproniazid was the first MAOI
Led to development of drugs that were more effective at inhibiting MAO activity
What are the safety problems of MAOIs?
Iproniazid withdrawn in 1960s: hepatic toxicity
MAOIs: hypertensive episodes (cheese effect)
Headaches following cheese and red wine consumption
Where are MAO enzymes located in the body?
CNS and PNS
MAO-A associated with depressive disorders
Original MAOIs irreversibly inhibited both isoenzymes
Why are MAO enzymes (A) significant?
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)
What do TCAs do?
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
What are the new antidepressants developed to improve safety?
MAOIs and TCAs antidepressant activity discovered accidentally
Selective Serotonin Reuptake Inhibitors (SSRIs) designed to act at a specific target
Serotonin reuptake transporter
Why are SSRIs an improvement?
Improvements in selectivity of action
SSRIs selectively inhibit the reuptake of serotonin
Increase in serotonin in synaptic cleft
First line of treatment
What is the problem with antidepressants?
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
How long can it take for the clinical effect of antidepressants to be observed?
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
Why is the monoamine hypothesis difficult to validate?
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
What is the initial effect of antidepressants?
Is to increase NT levels
Occurs within hours of administration
Autoreceptors on pre-synaptic cells stimulated and inhibit further NT release
What is autoreceptor sensitivity?
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
What else can increased exposure to NT after treatment cause?
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
What is the reason for the delayed onset of action of antidepressants?
Delayed onset of action until receptor number and activity is returned to normal
Then changes in mood become apparent
