Depression (A*)

Question 1

What is the most common form of depression?

List 4 other types of depression.

Answer 1

• Major depressive disorder (clinical depression) is the most common form of depression.
• DSM-5 names 8 other types of depressive disorder. Examples include:

1 - Manic depression (bipolar disorder).

2 - Dysthymia (persistent depressive disorder).

3 - Postnatal depression.

4 - Seasonal affective disorder.

Question 2

List 10 symptoms of depression.

Answer 2

Symptoms of depression include:

1 - Low mood.

2 - Suicidal ideation.

3 - Low motivation, including anhedonia (the inability to feel pleasure during activities that would otherwise be pleasurable).

4 - Low energy.

5 - Low self-esteem / guilt / worthlessness.

6 - Motor agitation (restlessness).

7 - Social withdrawal.

8 - Reduced ability to concentrate.

9 - Weight change.

10 - Changes to sleeping pattern (hyper- / insomnia)

Question 3

List 3 problems with rating scales used for the diagnosis of depression.

Answer 3

Problems with rating scales used for the diagnosis of depression include:

1 - The scales usually attribute equal importance to each symptom. In reality, this will vary from patient to patient.

2 - Patient error means symptoms are not always accurately reported in the questionnaires.

3 - The scales are not always applicable to animal models, making them difficult to use in research.

• This could be because of difficulties answering specific questions on the scale or because of difficulties replicating depression in the animal, since depression is a multifaceted pathology.

Question 4

What is the monoamine theory of depression?

What is a major unanswered question for this theory?

What evidence is there for it?

Answer 4

• The monoamine theory of depression states that depression is due to hypoactivity at monoaminergic synapses in the brain, specifically involving noradrenaline and 5-HT, and sometimes dopamine (for details on specific role, see card 5).
• A major unanswered question for this theory is whether defects of monoamine transmission are the cause of depression or just a consequence of it.

Evidence for the theory includes:

1 - NA and 5-HT-targeting drugs have some efficacy in treating depression. Examples include:

• Monoamine oxidase inhibitors (MAOIs).
• Tricyclic antidepressants (TCAs).
• Selective serotonin / noradrenaline reuptake inhibitors (SSRIs / SNRIs).

2 - Specific genes linked to 5-HT have also been linked to depression.

See A card 19 for details on dopamine.

Question 5

Give an example of a hormonal change in depression.

What causes this change?

What is the effect of antidepressants on this hormonal change?

Answer 5

• Cortisol is high in depression.
• This is caused by defects in the HPA axis, but the exact cause is unknown.
• The problem is likely with the 5-HT / NA signalling. Under normal conditions:

1 - Cortisol binds to glucocorticoid receptors on the locus coeruleus to increase NA transmission to the hypothalamus. This increases the number of glucocorticoid receptors in the hippocampus.

2 - Cortisol binds to glucocorticoid receptors on the raphe nucleus to increase 5-HT signalling to the hippocampus. This decreases the number of glucocorticoid receptors in the hippocampus.

• Binding of cortisol to glucocorticoid receptors in these sites causes negative feedback on the HPA axis.
• The hippocampus has the highest density of glucocorticoid receptors in the nervous system. When cortisol binds to glucocorticoid receptors on the hippocampus, it inhibits CRH release from the hypothalamus.
• In depression, the number of glucocorticoid receptors in the hippocampus is reduced, meaning the negative feedback potential of the hippocampus in response to high cortisol is decreased.
• Impairment of cortisol negative feedback can be shown with a dexamethasone suppression test and by measuring CRH.
• The abnormal cortisol can be corrected by antidepressants (but see A* card 20).
• Interestingly, over half of patients with Cushing’s disease develop MDD.

Question 6

Is cortisol involved in the pathogenesis of depression or is it just a consequence of other mechanisms causing depression?

How is this known?

Answer 6

• It is thought that cortisol is involved in the pathogenesis of depression.
• This is because CRH administered cerebroventricularly to animals triggers the development depressive symptoms.
• CRH antagonists didn’t work as antidepressants, but it’s not known why.
• See card 10 for details.

Question 7

Why might childhood stress predispose to depression later in life?

Answer 7

Childhood stress is thought to predispose to depression later in life because early stress changes the set-point of the HPA stress system through slow epigenetic changes, causing a rise in cortisol (see card 8 for possible mechanism).

Question 8

What causes the change in glucocorticoid receptor expression in the hippocampus in depression?

How can this be targeted to treat depression?

Answer 8

• The hippocampus contains stem cells that normally undergo neurogenesis throughout life. In depression, neurogenesis is decreased, resulting in a decrease in the number of hippocampal dopaminergic neurones that express the glucocorticoid receptors.
• This might be due to changes in the ‘neurotrophic soup’, e.g. brain-derived neurotrophic factor (BDNF), in the extracellular environment.
• Changes in BDNF synthesis could be due to stress, because glucocorticoids inhibit BDNF expression (hence card 7 about child stress causing depression).
• Restoration of the ‘neurotrophic soup’ can be achieved by stimulation of 5-HT2A receptors, which increases BDNF production, causing neurogenesis. This might underpin the delay between taking an antidepressant and seeing a clinical effect, since neurogenesis is slow.

Question 9

List 3 drugs that increase BDNF expression.

Answer 9

Drugs that increase BDNF expression include:

1 - 5-HT agonists.

2 - Ketamine, an NMDA antagonist.

3 - Agonists for mGluR subtypes 2 and 3.

Question 10

List 2 non-pharmacological treatments for depression.

Answer 10

Non-pharmacological treatments for depression include:

1 - Cognitive behavioural therapy.

2 - Electroconvulsive therapy.

Question 11

A* (ish):

List 2 limbic structures that undergo atrophy in depression.

Answer 11

Structures that undergo atrophy in depression:

1 - Hippocampus.

2 - Frontal lobe.

Question 12

Quite big boy A*:

Give an example of a signalling pathway that is an emerging target for treating depression.

How can this be targeted to treat depression?

Answer 12

• Wnt-Fz-GSK3-b-catenin pathway is a potential novel target for treating depression.

1 - The Wnt protein binds to Fz GPCRs.

2 - This causes a cascade of downstream events that lead to activation of Dv1, a member of the dishevelled (Dsh) protein family.

3 - Dv1 inhibits glycogen synthase kinase-3 (GSK3).

• GSK3 can also be inhibited by other phosphorylating agents such as Akt, lithium and S6K.
• Akt can be activated by 5-HT1A receptors.

4 - Inhibition of GSK3 leads to an increase in beta catenin, which is normally degraded by GSK3.

• The increase in beta catenin as a result of Wnt-Fz-GSK3-b-catenin signalling results in an increase in beta catenin-mediated gene transcription.

Role in depression:

• The genes upregulated by beta catenin promote neurogenesis, neuroplasticity and neuroprotection.
• GSK3 promotes amyloid beta production and induces inflammatory responses.

Potential for drug treatment:

1 - GSK3 antagonists have antidepressant effects in mouse models.

2 - Ketamine increases BDNF release, which in turn increases Akt activation. Akt phosphorylates GSK3, causing an antidepressant effect.

3 - Valproic acid increases GSK3 phosphorylation by inhibiting histone deacetylase (HDAC), however the opinions on valproic acid are mixed. Nonetheless, HDAC inhibition is a potential target for antidepressant drugs.

Question 13

Very big boy A*:

Give an example of a glutamate-targeting drug that has antidepressant effects.

What are the advantages of this drug over conventional antidepressants?

Describe the role of NMDA receptors in depression.

List 2 pieces of evidence for this.

How can this be targeted to treat depression?

Answer 13

• Ketamine is a glutamate-targeting drug that has antidepressant effects.
• The effects are rapid, long-lasting and work in treatment-resistant patients.
• Ketamine is thought to cause antidepressant effects by activating the mTOR pathway:

1 - Ketamine metabolites increase extracellular glutamate.

• The mechanism for this is unknown, but it is likely more complicated than just blocking NMDA receptors.

2 - Glutamate binds to AMPA receptors receptors, causing excitation and opening voltage-gated Ca2+ channels.

3 - Excitation results in BDNF release.

4 - BDNF binds to extracellular tropomyosin receptor kinase B (TrkB) receptors, which activates PI3K-Akt and Ras-MAPK signalling pathways.

5 - These pathways activate mTOR, resulting in an increase in S6K.

6 - S6K modulates translation directly and indirectly (via inhibition of GSK3 - see previous card).

• These transcriptional changes promote neurogenesis, neuroplasticity and neuroprotection.

7 - One of the transcriptional changes include upregulation of AMPA receptors. This is a form of positive feedback.

Evidence:

1 - Stimulation of AMPA receptors in vitro has been shown to increase BDNF release and subsequently activate mTOR signaling.

2 - BDNF knockout mice do not show an antidepressant response to ketamine.

Potential for drug treatment:

• Not ketamine itself due to the psychotomimetic and addictive nature of ketamine.

1 - Antagonists for NMDA receptors containing the NR2B subunit have antidepressant effects in humans (Preskorn et al., 2008).

2 - AMPA receptor neuromodulator drugs stimulate synaptogenesis in cultured cells.

3 - mGluR subtypes 2 and 3 regulate presynaptic glutamate release, and therefore influence mTOR signalling. Antagonists of these receptors cause antidepressant effects in mice.

Question 14

A*:

List 5 behaviours characteristic of rat models of depression.

Answer 14

According to Wang et al., 2018, behaviours characteristic of rat models of depression include:

1 - Freezing.

• In models of depression, the rats show longer periods of freezing in response to an adverse stimulus, and longer anticipatory freezing in response to neutral stimuli that are taught to be associated with adverse stimuli.

2 - Behavioural despair.

• In the forced swim test, where a rat is placed in water (and is expected to swim to a solid surface), rats show less effort to escape in models of depression, and instead float until rescued.

3 - Increased anxiety.

• In models of depression, rats spend more time in the closed section of the elevated plus maze (see anxiety deck for more detail on the relationship between anxiety and depression).

4 - Changes in exploratory and locomotor behaviour.

• In model of depression, rats spend more time closer to the perimeter of an open space, and are more reluctant to explore the space so instead remain still.

5 - Anhedonia.

• In models of depression, rats show less interest in high-energy foods (such as sucrose water) which would otherwise be preferred by wild type mice.

Question 15

A*:

What is learned helplessness?

How does this relate to depression in humans?

What is the neurological basis for learned helplessness?

Answer 15

• Learned helplessness model is a common animal model of depression.
• It is the phenomenon in which a person / animal, through repeated exposure to an unavoidable adverse stimulus, is taught to believe that they have no control over the occurrence of the adverse stimulus, and so do not try to escape the adverse stimulus even when given a clear chance.
• The ‘uncontrollable’ stressors that are used to induce learned helplessness induce depressive behaviours in animals.
• In humans, uncontrollable adverse events usually precede depression. This is similar to the conditioning process in learned helplessness.
• Uncontrollable stressors have been shown to reduce the release of NA in the locus coeruleus.
• A decrease in monoamine transmission in learned helplessness (and by extension, depression in general) is thought to decrease BDNF signalling, which in turn causes depression behaviours through decreasing hippocampal dopaminergic neurogenesis (card 8), decreasing Wnt-Fz-GSK3-b-catenin signalling (card 12) and decreasing TrkB receptor activation (card 13).

Question 16

A*:

List 4 antidepressant drug classes.

Give an example of each.

For each drugs class, give an example of an unwanted pharmacological action.

What are the side effects of these unwanted actions?

Answer 16

1 - Tricyclic antidepressants (TCAs) such as amoxapine.

• An unwanted pharmacological action is muscarinic receptor antagonism.
• This results in sympathomimetic side effects, such as tachycardia, constipation, urinary retention and difficulty focussing vision.

2 - Older monoamine oxidase inhibitors (MAOIs) such as phenelzine.

• An unwanted pharmacological action is irreversible MAO inhibition (new MAOIs reversibly block MAO).
• This results in increased risk of hypertension and haemorrhage. Avoid cheese reaction!

3 - Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine.

• An unwanted pharmacological action is direct activation of 5-HT2C receptors, which is located in various limbic structures such as the hippocampus and amygdala. Overexpression of 5-HT2C has been linked to anxiety (Kimura et al., 2009).
• This results in insomnia and anxiety.

4 - Serotonin and noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine.

• An unwanted pharmacological action is H1 receptor antagonism.
• This results in sedative effects.

Question 17

A*:

What is the potential role of dopamine in the pathophysiology of depression?

Answer 17

• The mesolimbic pathway is associated with reward.
• Hypoactivity of the mesolimbic system may therefore explain the anhedonia seen in depression.
• It has been demonstrated in learned helplessness models of depression that dopamine synthesis and release are decreased in mesolimbic structures.
• This could be attributable to a decrease in expression of Kv7.4 channels, which potentiates dopaminergic transmission in the mesolimbic pathway. This is described in more detail in A* card 29 of the dopamine lecture.
• Nonetheless, most studies of depression focus on the hippocampus and prefrontal areas.

Question 18

A*:

List 8 problems with antidepressant drugs.

Answer 18

Problems with antidepressant drugs include:

1 - Diverse side effects.

2 - Long time course of drug vs clinical effect, probably due to neuroadaptation.

3 - Although not addictive, there is potential for abuse.

4 - Patients develop tolerance against antidepressants, requiring the dose to be increased.

5 - A significant proportion of patients undergo relapse following cessation of treatment.

• NICE recommend to continue treatment after symptoms subside, but many drugs do not protect against relapse after a prolonged period of time - e.g. Reimherr et al. (1998) found that fluoxetine does not protect against relapse after 14 months.

6 - Prognosis for depressive disorders following cessation of treatment is unaffected by the duration of treatment.

7 - Long-term effects such as sexual problems and weight gain.

8 - Paradoxical depressant effects of antidepressants, e.g. the SSRI fluvoxamine, which has recently been shown in some studies to cause a worsening of depressive symptoms after 6 weeks of treatment (Cusin et al., 2007).

Question 19

A*:

List 2 possibilities, other than tolerance, that might explain the reduction in efficacy of antidepressant drugs with time.

Describe a possible mechanism underlying tolerance with serotonergic antidepressant drugs.

Answer 19

Possibilities, other than tolerance, that might explain the reduction in efficacy of antidepressant drugs with time:

1 - A decrease in placebo effect.

2 - Drug-induced changes in pathology.

Mechanisms for tolerance in serotonergic antidepressants:

• In depression, there is thought to be an imbalance in the effects of 5-HT. Broadly, in limbic structures, underexpression of 5-HT1 receptors and overexpression of 5-HT2 receptors is thought to contribute to the pathophysiology of depression and anxiety, causing hyperexcitability of limbic structures such as the amygdala and stress pathways (see card 23 in anxiety deck).
• Serotonergic antidepressants (e.g. SSRIs and SNRIs) have been shown to induce long-term effects on serotonergic transmission. For example, enhanced 5-HT1 receptor activation can lead to downregulation of 5-HT2 receptors. This can lead to further changes in serotonergic neurones such as (1) morphological changes, (2) changes in signal transduction and (3) expressional changes that have effects on intracellular signalling cascades.
• The imbalance in 5-HT1/5-HT2 activity, and these downstream effects, increase activity of the HPA axis, worsening depressive symptoms (Fava and Offidani, 2011).

Question 20

A*:

Describe the cholinergic-adrenergic hypothesis of mood disorders.

On which research was this hypothesis founded?

Answer 20

• The cholinergic-adrenergic hypothesis of mood disorders (Janowsky et al., 1972) states that:
• Overactive adrenergic neurotransmission from sympathetic neurones and underactive cholinergic neurotransmission from parasympathetic neurones is responsible for the manic symptoms of mood disorders.
• Underactive adrenergic neurotransmission from sympathetic neurones and overactive cholinergic neurotransmission for parasympathetic neurones is responsible for the depressive symptoms of mood disorders.
• This hypothesis was founded on two pieces of research:

1 - Increases in arousal mediated by adrenergic transmission is inhibited by cholinergic transmission.

2 - Chronic administration of cholinesterase inhibitors reduced manic symptoms in patients suffering from mania, and induced depressive symptoms in healthy patients.

*In short, high ACh = depression, high NA = mania.

Question 21

A*:

What might underlie the physiological changes described in the cholinergic-adrenergic hypothesis of mood disorders?

Give an example of a potential drug based on the cholinergic hypothesis of mood disorders.

Give an example of a limitation of this drug, and a solution for how this can be resolved.

Answer 21

• Hypercholinergic transmission in depression is thought to be caused by reduced expression of M2 receptors.
• M2 receptors are inhibitory autoreceptors, therefore reduced M2 receptor activity leads to an increase in cholinergic transmission.
• Hyoscine is a nonselective muscarinic antagonist that causes an antidepressant effect by inhibiting facilitatory postsynaptic cholinergic transmission (Furey and Drevets, 2006).
• The limitation of directly stimulating / antagonising the orthosteric site of muscarinic receptors is that receptor internalisation, desensitisation and downregulation will occur with drug exposure. This would require an increasing dose over time (Jeon et al., 2015).
• This could be overcome by developing specific negative allosteric modulators for M2 receptors.

Question 22

A*:

List 8 risk factors for depression.

Answer 22

Risk factors for depression:

1 - Female gender.

2 - History of anxiety disorders.

3 - History of eating disorders.

4 - Family history of depression.

5 - History of drug / alcohol abuse.

6 - Life stressors, especially in childhood.

7 - Age, e.g. during adolescence and menopause.

8 - Ethnicity.

Question 23

A*:

What is the difference between major depressive disorder (MDD), manic depression (bipolar disorder) and dysthymia (persistent depressive disorder)?

How do these disorders differ from grief?

Answer 23

According to DSM-5:

• Major depressive disorder is the presence of at least 5 of the symptoms mentioned in card 2 every day for at least 2 weeks
• Dysthymia (persistent depressive disorder) is a chronic mood disorder that is characterised by a persistent depressive state that lasts for at least 2 years. Patients with dysthymia may occasionally experience brief intervals of normal mood. The symptoms of dysthymia are less severe than MDD, but it is important to note that a diagnosis of dysthymia can coexist with MDD if a patient fulfils the criteria for MDD after 2 years.
• As of DSM3 in 1980, manic depression is known as ‘bipolar disorder’. As of DSM5 in 2013, bipolar disorder is considered separately to depressive disorders. It differs from depressive disorders in that it is characterised by periods of euphoria or overactivity known as manic episodes (or the less severe hypomanic episodes), and major depressive episodes. In depression, the symptoms are not episodic and there are no periods of mania.
• Importantly, major depressive episodes differ from grief in a number of ways:

1 - Grief tends to affect mood in a pulsatile fashion over a number of weeks, rather than being persistent.

2 - Grief decreases in intensity over time.

3 - Grief can be triggered by prompts relating to the adverse event.

4 - Grief does not involve anhedonia - pleasure can still be derived from enjoyable activities.

5 - Grief is not accompanied by low self esteem, worthlessness or self-criticism.

Question 24

A*:

What is the prevalence of major depressive disorder, and manic depression?

Answer 24

• Globally, depressive disorders are the 4th most common cause of disability (World Health Organisation, 2012).

Major depressive disorder:

• The lifetime prevalence of MDD in the UK is 16.2% in the UK (Mian et al., 2014).
• There is a gender difference in MDD prevalence. In the UK, the lifetime prevalence for MDD is approximately 2 times greater in females compared to males.
• There is also an ethnic difference in MDD prevalence. In the UK, MDD is 1.5-2 times more prevalent in Black Caribbean and South Asian females compared to white British females (Williams, 2015).

Manic depression:

• The lifetime prevalence of bipolar disorder in the UK is 1.4% (NICE, 2015).
• No major sex differences exist for bipolar disorder, and data regarding the contribution of ethnicity is unclear (Rowland and Marwaha, 2018).

Question 25

A*:

What is the bundle damage theory?

How does it affect our understanding of the pathophysiology of depression?

Answer 25

• The bundle damage theory states that ‘although synaptic levels of monoamines are normal in chronic monoamine-related disease states, these levels are inadequate in compensating for postsynaptic damage to structures conducting electricity’.
• The monoamine hypothesis of depression states that hypoactivity of monoaminergic neurones is the cause of depression. The bundle damage theory would imply that release of monoamines is actually normal in depression - it is the processes downstream of monoamine signalling that are dysfunctional.
• This would explain the limited efficacy of antidepressant drugs that increase synaptic release of monoamines.