Depression

Question 1

What is depression?

Answer 1

An affective disorder - extreme or inappropriate mood. Depression is called Major Depressive Disorder.

Question 2

How is Major Depressive Disorder diagnosed?

Answer 2

Depressed mood and/or anhedonia (without pleasure) plus 5 or more other from the following list for nearly everyday for 2 weeks: body weight changes, sleep changes, motor retardation or agitation, fatigue or loss of energy, worthlessness or guilt, diminished ability to think or concentrate, recurrent thoughts of death or suicidal thinking.

Question 3

How common is depression?

Answer 3

5% of the population are depressed at any point in time. 30% of the population have had at least 1 episode of depression. 30,000 suicides in the USA per year are due to depression. 3x more likely in women than in men.

Question 4

What is the heritability of depression?

Answer 4

Moderate heritability (37%). 2-3 times more likely to have depression if our relatives are diagnosed with MDD. Concordance rate goes up for MZ twins compared to DZ twins but still a lot of room for environmental factors.

Question 5

What causes depression?

Answer 5

The monoamine hypothesis - depressive symptoms are caused by insufficient activity of monoaminergic neurons. Monoamine agonists should be able to reverse the symptoms. Problem is neurochemicals that are not at their normal level. Types of monoamines - dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and serotonin.

Question 6

What is early evidence pointing towards chemical imbalance?

Answer 6

Lower levels of 5-HT metabolite 5-HIAA in the CSF of depressed individuals (Asbera et al., 1976). Lower levels of dopamine metabolites to noradrenaline metabolites in the CSF of depressed individuals. HOWEVER, findings have been small & inconsistent.

Question 7

What is evidence from Reserpine?

Answer 7

Used to treat blood pressure in the mid-20th century. Caused depression in patients as a side-effect. Reserpine blocks the packaging of monoamines into the vesicles, so when the neurons are activated no neurotransmitter is release, so have low levels of monoamines.

Question 8

What is further evidence in support of the monoamine hypothesis?

Answer 8

All effective antidepressants affect 5HT/NA systems. Mood elevating substances e.g. amphetamines and ecstasy elevate monoamine levels.

Question 9

What are monoamine oxidase inhibitors? (types of antidepressants)

Answer 9

MAO inhibitors e.g. iproniazid or phenelzine - inhibit the breakdown of monoamines in the presynaptic terminal so they increase the level of monoamines taken up into the vesicles. Side effect: increase sympathetic tone & “cheese effect” = cheese products contains tyramine which is normally deactivated by MAO in the level. In the presence of MAO inhibitor tyramine is not broken down = causes an increase in heart rate & blood pressure.

Question 10

What are other antidepressants?

Answer 10

Tricyclic antidepressants - inhibit the reuptake of serotonin and noradrenaline. Most widely prescribed are SSRIs (selective serotonin reuptake inhibitors). SSRIs and SNRIs have fewer side effects than the tricyclic antidepressants.

Question 11

Why has the monoamine hypothesis been described as ‘too simple’?

Answer 11

An acute decrease in serotonergic activity in healthy people has no effect on mood, only those with a history of depression.
Although SSRIs and SNRIs increase the levels of serotonin and noradrenaline very rapidly, the drugs do not relieve the symptoms of depression until they have been taken for several weeks - therefore, something other than a simple increase in monoaminergic activity is responsible for the normalisation of mood.

Question 12

What is the stress hypothesis of depression?

Answer 12

qThere is a shrinkage of the hippocampus in depressed people. The longer people wait before they seek treatment, the more the volume of their hippocampus reduces. In the hypothalamus we have CRF that sends a message to the pituitary gland, to release ACTH into the blood stream, which goes down to the adrenal cortex to release cortisol (HPA axis).

Question 13

What happens with HPA and negative feedback in depressed people?

Answer 13

Amygdala is stimulated (perceiving a threat). If look at depressed people, can trace back onset to a negative effect. This was fed into the HPA axis to release cortisol. Hippocampus has lots of cortisol receptors, and its job is to give a negative feedback to the hypothalamus to stop this alarm system. However, if have chronic activation this results in constant activation of cortisol in the hippocampus, and therefore a lot of neurons begin to die. Because it loses neurons, they don’t give that negative feedback we need for activation to be terminated, leading to a cycle of activation.

Question 14

Do antidepressants result in increased neurogenesis in the hippocampus?

Answer 14

Eventually give rise to neurogenesis in the hippocampus (need this as volume has been reduced). MAO-I, SSRI, and NE reuptake inhibitor all cause an increase in neurogenesis in the hippocampus compared to healthy subjects.

Question 15

What is the neurogenic hypothesis?

Answer 15

Neurotrophins or neurotrophic factors are important for the normal development of a healthy nervous system. Injections of BDNF in the rat brain reduces neuronal death and also protects neurons that have been treated with neural toxins. The levels of BDNF are reduced in people that suffer from depression this seems to be reversed by treatment with antidepressants.

Question 16

Why are some people more susceptible than others in developing depression?

Answer 16

In a prospective-longitudinal study, Caspi et al (2003) tested why stressful experiences lead to depression in some people but not in others. Followed 847 people over a period of more than 20y, starting at age 3, and recorded the occurrence of stressful events in their lives, including abuse during childhood, romantic disasters, bereavements, illnesses, and job crises. A functional polymorphism in the promoter region of the serotonin transporter (5-HTT) gene was found to moderate the influence of stressful life events on depression (short vs long). This epidemiological study provided evidence of a gene-by-environment interaction, in which an individual’s response to environmental insults is moderated by his or her genetic makeup.

Question 17

What is the role of a serotonin transporter?

Answer 17

Rausch et al. (2002): depressed people with two long alleles were more likely to respond to treatment with an antidepressant drug than were those with one or two short alleles. People with two long alleles were even more likely to respond to the placebo. Lee et al. (2004) found that depressed people with two long alleles who were treated with antidepressant drugs had a much better long-term outcome (up to three years) than did people with one or two short alleles. Neumeister et al. (2002) found that tryptophan depletion was more likely to produce symptoms of depression in people with one or two short alleles.

Question 18

How does ketamine act as an antidepressant?

Answer 18

Rapid onset antidepressant effect within a few hours following a single IV dose (Berman et al., 2000). 70% response rate at 24 hours following a single infusion (Zarate et al., 2006). Provides further support for NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression.

Question 19

What is Transcranial Magnetic Stimulation (TMS)?

Answer 19

Gives electrical current to the skull. Inactivates certain areas and can target specific regions, but there are limits on what areas it can affect.

Question 20

What is Electroconvulsive Therapy (ECT)?

Answer 20

Used when not responding to any treatment. About 30% are not responsive to any treatment. Problem is there is memory loss - therefore it is left as a last resort.