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Neuroscience: From Molecules to Behaviour > Depression > Flashcards

Depression Flashcards

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1
Q

Do anti-depressants work immediately?

A

No. There is usually a 2-3 week lag before you notice any improvements in patients.

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2
Q

What is depression? Why is the definition of depression different to that of schizophrenia?

A

Depression is defined as an affective disorder, unlike schizophrenia which is a psychotic-like disorder.

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3
Q

How are depression symptoms categorised?

A

Emotional

Biological

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4
Q

What are the emotional symptoms of depression?

A
  • Low mood
  • Low self-esteem
  • Loss of motivation
  • Anhedonia
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5
Q

What are the biological symptoms of depression?

A
  • Loss of libido
  • Sleep disturbance
  • Loss of appetite
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6
Q

What is anhedonia?

A

= inability to experience pleasure in/through anything.

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7
Q

Unipolar depression is characterised by the combination of both…

A

…emotional and biological symptoms.

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8
Q

What is another type of depression?

A

Bipolar depression

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9
Q

How does bipolar depression differ from unipolar depression?

A

It differs in terms of an individual experiencing more extreme mood swings. Both types exhibit the classical symptoms of depression, but those with bipolar depression show periods of “manic” depression, whereby the individual goes into a sort of ‘overdrive’ where they have a general increase in psychomotor activation and a more agitated appearance.

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10
Q

Are unipolar and bipolar depression treated in the same way?

A

No. The treatment for both varies, because bipolar has two phases: ‘manic’ and ‘depressive’.

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11
Q

What could the manic phase of bipolar depression be treated by?

A

Lithium, which has many actions, but generally exerts its effects by acting as a membrane stabiliser.

Effective for the manic phase.

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12
Q

Historically, theories of depression have focussed on disorders of ______ and ______.

A

Noradrenaline

Serotonin

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13
Q

What are noradrenaline and serotonin?

A

Monoamine neurotransmitters, important in the CNS. Neurons that utilise these neurotransmitters permeate profusely throughout the brain.

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14
Q

The US name for noradrenaline is ______.

A

Norepinephrine

It’s the same thing!

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15
Q

In terms of noradrenaline, cell bodies are located in the ______. All of the noradrenergic neurons, utilising noradrenaline, project from this region.

A

locus coeruleus

However, nerve fibres from here permeate throughout all regions of the brain, including higher brain centres e.g. cerebral cortex.

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16
Q

What is the locus coeruleus region of the brain involved in?

A

Involved in the individual’s overall level of arousal.

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17
Q

What does low levels of activity in the locus coeruleus lead to?

A

Essentially, if you have low levels of activity in the locus coeruleus, your behaviour points towards things like sleeping, consuming food i.e. laid-back behaviours.

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18
Q

What does high levels of activity in the locus coeruleus lead to?

A

Leads to a more aroused and alert state.

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19
Q

If you record activity in the locus coeruleus in experimental animals, what do you see?

A

Depends on their level of activity:

  • if they’re sleeping in their cages, you see low levels of activity in the locus coeruleus.
  • if they’re active and responsive to external environmental stimuli, you see elevated activity in the locus coeruleus
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20
Q

Where do serotonin cell bodies originate?

A

They originate in an area in the Pons, called the Raphe nucleus. However, the nerve fibres permeate throughout all regions of the brain, including higher brain centres e.g. cerebral cortex.

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21
Q

Historically, why have people focussed on noradrenaline and serotonin as theories for depression?

A

A number of measures have indicated that levels of either one, or both, of these neurotransmitters may be severely decreased in individuals suffering from depression.

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22
Q

What is the problem with the results surrounding noradrenaline and serotonin theories of depression?

A
  1. They are not always reproducible.
  2. Depending on the results you are looking at i.e. whether you’re looking directly at levels of neurotransmitter, or indirectly at metabolites of these neurotransmitters, different answers have been given.
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23
Q

Why do experiments looking at the noradrenaline and serotonin theories of depression use indirect values as measures?

A

Because measuring neurotransmitters in living animal brains is very difficult (especially humans!!)

Instead, scientists look at brain tissue after death (post-mortem), but there are a number of artefacts that can affect the results.

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24
Q

Besides observations of neurotransmitter levels or levels of neurotransmitter metabolites, what other data can support the monoamine (noradrenaline/serotonin) hypothesis of depression?

A

Various compounds with actions on monoamine neurotransmitters can lead to certain effects in depressed patients, indicating the role of these neurotransmitters.

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25
Q

Historically, the first group of antidepressants found to be of any use are …

A

… the tricyclic antidepressants.

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26
Q

How are tricyclic antidepressants linked to schizophrenia treatment?

A

Tricyclic antidepressants are derived from phenothiazine, which is the same class of compounds from which schizophrenia treatments are derived.

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27
Q

What effect do tricyclic antidepressants have on depressed patients?

A

Generally, it leads to an increased mood in some depressed patients.

Important to note that they do not work in every patient!

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28
Q

How does the effect of tricyclic antidepressants on depressed patients support the monoamine hypothesis of depression?

A

The action of these drugs is to block noradrenaline and 5-HT (serotonin) reuptake. I.e. if the drug is blocking reuptake (into the presynaptic terminal) of noradrenaline/serotonin, and leads to increase in mood, you can infer that increased amounts of noradrenaline/serotonin at the synapse = good mood.

This supports the hypothesis that depleted levels of noradrenaline/serotonin (i.e. the monoamine hypothesis) may be causing depression.

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29
Q

What other classes of drugs support the monoamine hypothesis of depression?

A
  • Monoamine oxidase (MAO) inhibitors
  • Reserpine
  • alpha-Methyltyrosine
  • Methyldopa
  • Electroconvulsive therapy
  • Tryptophan (5-hydroxytryptophan)
  • Tryptophan depletion
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30
Q

How do monoamine oxidase (MAO) inhibitors support the monoamine hypothesis of depression?

A

They increase stores of noradrenaline and 5-HT in presynaptic vesicles, and increase mood.

I.e. more noradrenaline/serotonin = better mood.

31
Q

How does reserpine support the monoamine hypothesis of depression?

Is reserpine used clinically?

A

Conversely to MAO inhibitors, reserpine INHIBITS noradrenaline/serotonin storage in presynaptic vesicles, accompanied by a DECREASED mood in depressed patients.

I.e. less noradrenaline/serotonin = worse mood.

This drug is not used clinically, it is only used experimentally to induce a depressed-like state in model animals.

32
Q

How do a-Methyltyrosine and methyldopa support the monoamine hypothesis of depression?

A

They both inhibit the synthesis of noradrenaline, which seems to lead to a decrease in mood.

Note: a-Methyltyrosine leads to the calming of manic patients!

33
Q

Is it only pharmacotherapy (i.e. drugs) that support the monoamine hypothesis of depression?

A

No. Other forms of therapy can also support it.

One example is electroconvulsive therapy (predates pharmacotherapy), which is thought to increase central nervous system responses to noradrenaline and 5-HT, accompanied by an increase in mood in depressed patients. However, mechanisms of electroconvulsive therapy are still not entirely understood.

I.e. heightened response to monoamines = better mood

34
Q

How does tryptophan (5-hydroxytryptophan) support the monoamine hypothesis of depression?

A

It increases synthesis of 5-HT, and leads to an increased mood in some depressed patients in SOME studies.

35
Q

How does tryptophan depletion support the monoamine hypothesis of depression?

A

It leads to a decrease of brain 5-HT synthesis, and induces relapse in SSRI-treated patients.

I.e. when treated patients have depleted levels of tryptophan, they have a relapse, confirming the important of 5-HT synthesis in depression treatment.

36
Q

How do drugs within the class of tricyclic antidepressants differ, and what does this suggest about depressed patients?

A

Some are more potent at blocking noradrenaline re-uptake, and some are more potent at blocking 5-HT re-uptake.

Some people respond better to one compound than they do to another, suggesting that they may be more than population of depressed patients within the unipolar depression group. I.e. some individuals may be suffering from depression to a reduction in noradrenaline, and some may be suffering through a reduction in serotonin.

Knowledge of this is important for better treatment.

37
Q

Are the causes of depression a little more complex than just the monoamine hypothesis?

A

Yes. There is a lot of evidence suggesting the role of a number of other key players involved in depression.

38
Q

How exactly might low levels of monoamine neurotransmitters be leading to depression?

A

A degree of increased cell death (i.e. neural apoptosis) might lead to depressive symptoms.

39
Q

What causes neural apoptosis?

A

Noradrenaline and serotonin will act on their respective receptors and these will lead to varied signal transduction pathways. These pathways can activate a detrimental gene transcription or beneficial gene transcription response.

A detrimental gene transcription response will result in neural apoptosis, whereas a beneficial gene transcription response will decrease the processes of apoptosis that are occurring.

So, by altering levels of noradrenaline or serotonin, you can shift processes towards beneficial gene transcription responses you can prevent neural apoptosis AND promote neurogenesis.

40
Q

Antidepressants are shown to increase ______ irrespective of their mode of action, resulting in…

A

neurogenesis

…an alleviation of depressive symptoms

41
Q

What role does stress play in depression?

A

In response to stress, you get an activation of the hypothalamic-pituitary-adrenal axis, which results in the formation and secretion of the hormone cortisol (seen in depressed patients).

Cortisol has a direct effect upon what leads to depressive symptoms i.e. increased neural apoptosis and decreased neurogenesis.

42
Q

What is another compound found in the brain that might lead to depression?

A

BDNF (brain-derived neurotrophic factors) may activate TrkB receptors that lead to different signal transduction pathways resulting in decreased neurogenesis and increased neural apoptosis OR noradrenaline and serotonin might actually be working VIA BDNF.

43
Q

What is another neurotransmitter possibly involved in depression (also involved in schizophrenia)?

A

Glutamate! It appears that via NMDA receptors, there is an effect upon neural apoptosis. I.e. through NMDA receptors we are potentially IMPROVING depressive symptoms.

44
Q

Tricyclic antidepressants are often the most ______ class of compounds.

A

well-documented

45
Q

How do tricyclic antidepressants become active metabolites?

A

Through demethylation in the liver.

I.e. when you take a tricyclic antidepressant, you will get a long half-life, because the metabolites allow the prolonging of its activity.

46
Q

Some drugs within the class of tricyclic antidepressants might lead to better blocking of re-uptake of noradrenaline/serotonin than others and so…

A

… each individual patient may respond differently to each drug, depending on their specific individual brain biochemistry.

47
Q

What are the problems with usage of tricyclic antidepressants, and what has this led to?

A

Problems:

  • Autonomic side effects related to antimuscarinic activity (e.g. dry mouth, visual disturbance)
  • Can also cause sedation and drowsiness (histaminergic antagonist activity i.e. blocking histamine receptors to some degree)
  • Cardiovascular function can also be affected (tachycardia and arrhythmia)
  • Importantly, they have a low therapeutic index (measure of what is a toxic dose is compared to a therapeutic dose)
48
Q

What have the problems surrounding tricyclic antidepressants led to, in terms of research?

A

It has led to the promotion and research of alternative treatments for depression.

49
Q

What are some examples of tricyclic antidepressants?

A
  • Imipramine
  • Desmethylimipramine
  • Hydroxy-DMI
  • Clomipramine (CMI)
  • Desmethly-CMI
  • Amitriptyline (AMI)
  • Nortrptyline (desmethyl-AMI)
  • Hydroxynortriptyline
50
Q

What is a better group of drugs, compared to the tricyclic antidepressants?

A

Monoamine oxidase (MAO) inhibitors

51
Q

What are the different forms of MAO in the brain?

A

Type A. Preferred substrates of type A are noradrenaline and 5-HT so this is the MAO that we’re particularly interested in blocking.

Type B

52
Q

What are some examples of MAO inhibitors and how do they work?

A
  • Phenelzine (non-selective, irreversible)
  • Tranlcypromine (non-selective, irreversible)
  • Moclobemide (selective, reversible)

Both work by inhibiting monoamine oxidases (MAO).

53
Q

What are side effects of MAO inhibitors?

A

Side effects include sleep disturbance and increased appetite.

54
Q

What is the biggest problem with MAO inhibitors?

A

“Cheese reaction”

This occurs due to what happens to tyramine (dietary AA found in foods like cheese and wine). How tyramine is processed can actually lead to a hypertensive crisis if you are using a MAOi.

Tyramine will initiate an excess release of noradrenaline. Inhibiting MAO type A means that you’re normal mechanism for keeping noradrenaline levels under control is significantly impaired, which means that the effect of tyramine is greatly amplified.

Excess amounts of noradrenaline leads to significant stimulation of the autonomic nervous system (sympathetic branch) and this leads to a constriction of resistance vessels in the vasculature = high blood pressure (i.e. hypertensive crisis).

55
Q

How can you reverse the cheese reaction that is caused by MAOi?

A

By using the reversible MAOi called moclobemide, because its effects can be reversed.

56
Q

What does SNRIs stand for?

A

Serotonin/noradrenaline re-uptake inhibitors.

57
Q

What are some examples of SNRIs?

A
  • Venlafaxine
  • Desvenlafaxine
  • Duloxetine
58
Q

When are SNRIs used?

A

When patients are unresponsive to other antidepressants.

59
Q

How are SNRIs similar to tricyclic antidepressants? And how are they better?

A

Similar mode of action (i.e. blocking of monoamine neurotransmitter uptake) BUT with fewer side effects.

60
Q

What are some noradrenaline-specific drugs used to treat depression?

A

Noradrenaline re-uptake inhibitors, such as buproprion and reboxetine.

61
Q

What are some compounds that have ALTERNATIVE mechanisms of action in modulation monoamine levels?

A

Monoamine receptor antagonists have varying receptor affinities and work by binding to monoamine receptors. E.g. bind to a2-adrenoreceptors (mirtazapine, mianserin) and 5HT2A receptors (trazodone) to block negative feedback (controlling monoamine release) = essentially leading to an increase in noradrenaline/serotonin release!

62
Q

What do SSRIs stand for?

A

Selective serotonin re-uptake inhibitors

63
Q

What are the most commonly prescribed antidepressants?

A

SSRIs

64
Q

SSRIs are effective antidepressants with negligible effects on …

A

… noradrenergic, histaminergic or cholinergic systems

65
Q

SSRIs have a lower chance of ______

A

overdose

66
Q

In which class of drugs do active metabolites not contribute to pharmacological activity?

And what is the one exception?

A

SSRIs

Except for fluoxetine

67
Q

Which two SSRIs should not be used with TCAs and why?

A

Fluoxetine and paroxetine

Because they inhibit CYP2D6

68
Q

How do different SSRIs vary?

A

Some are NA-selective, some are 5-HT-selective and some are non-selective

69
Q

What are problems associated with SSRIs?

A
  • Dependence (up to 60%)
  • Sexual dysfunction
  • Serotonin syndrome (i.e. changes to body temperature regulation)
  • Suicidal behaviour (read book Prozac Nation by Elizabeth Wurtzel)
  • Lag period before therapeutic effects are observed
70
Q

In terms of serotonin, what is the reason for the delay in therapeutic effect with SSRIs?

A

Studies suggest:

  • Initially, increased 5-HT concentration has a negative feedback effect mediated by stimulation of presynaptic 5-HT1B and somatodendritic 5-HT1A receptors
  • Over the next 2-4 weeks continued stimulation of these receptors results in their desensitisation = negative feedback effect is reduced
71
Q

How have scientists tried to address this time lag of therapeutic effects of SSRIs?

A

Animal studies

Series of microdialysis experiments were conducted, which investigated the effects of:

  • chronic SSRIs on 5-HT levels
  • acute SSRIs on 5-HT levels
  • acute SSRIs combined with 5-HT1A and 5-HT1B receptor antagonist of 5-HT levels

Found that:
- Acute SSRIs combined with blockade of 5-HT receptors resulted in a larger increase in 5-HT levels than that caused by SSRIs alone

Concluded that:
- 5-HT autoreceptors play a significant role in retraining the elevation of 5-HT caused by acute SSRIs

72
Q

Is increased neurogenesis a common relevant effect of antidepressant action?

A

Lots of evidence pointing to this. So this may be the way forward clinically.

73
Q

What are some experimental compounds for the treatment of depression?

A
  • Ketamine
  • Tianeptine
  • Electroconvulsive therapy (ECT)
  • Galanin
74
Q

Why does tianeptine complicate the theories underlying the causes of depression?

How is this similar to schizophrenia?

A

Because… unlike the monoamine hypothesis of depression, tianeptine works by depleting levels of serotonin in certain brain regions (and leading to improved symptoms!)

Similar to schizophrenia because treating this isn’t always about elevating levels of dopamine. Sometimes, decreasing levels of dopamine in SOME brain regions leads to therapeutic effects.

Neuroscience: From Molecules to Behaviour (5 decks)

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