MDD

Question 1

What mood disorders are outlined in the DSM-5?

Answer 1

Bipolar and depressive disorder are split

Question 2

What are mood disorders?

Answer 2

Affective disorders (how you display/report how you feel). Disordered feelings - extreme or inappropriate mood. Can look at mood as having different levels (temperament, which fluctuates).

Question 3

What is dysthymia?

Answer 3

Can dip into more negative affect - milder form of depression, longer duration - 2 years or more

Question 4

What symptoms need to be present to be diagnosed with MDD?

Answer 4

At least one of these: depressed mood, loss of interest/pleasures (anhedonia).
At least three/four of these: weight/appetite change, sleep disturbances, psychomotor agitation/retardation, fatigue/loss of energy, guilty/worthlessness, executive dysfunction (e.g. difficulty memorising), suicidal ideation (16% suicide rate)

Question 5

How long do symptoms need to be there to be diagnosed?

Answer 5

Need to be present for 2 weeks or more consistently to be diagnosed with MDD

Question 6

What is major depressive disorder?

Answer 6

May happen just once, but many people relapse into another episode = a recurrent disorder.

Question 7

What is the prevalence of mood disorders?

Answer 7

MDD has a lifetime prevalence of 6.7%, and a 12-month prevalence of 4.1% - women suffer a lot more than men

Question 8

What is the epidemiology of MDD?

Answer 8

Runs in families. Moderate heritability - 2-3 times more likely to have depression if you have 1st degree relatives with it. Has 37% heritability, whereas bipolar disorder has 85% heritability - much more heritable than MDD. Several genes have been linked to depression.

Question 9

What is the concordance rate of MDD in twins?

Answer 9

Concordance rate is 69% for MZ twins compared to 13% for DZ twins - arguing for genetic basis

Question 10

What is depression most common in?

Answer 10

Most common (heritable) in women than in men - more likely to inherit, but there is not much research on this. More heritable in women then in men (40% vs 30%)

Question 11

What is the genetics of MDD?

Answer 11

Failed to find significant associations - may be strong contribution from various genes, but nothing strong that will stand out. Not a clear cut disorder - some people show opposite symptoms (e.g. where one person can’t sleep another wants to sleep all the time)

Question 12

What did Caspi et al (2003) find?

Answer 12

Longitudinal study, tested why stressful experienced lead to depression in some but not others. Recorded stressful life experiences from ages 3-20. MDD doesn’t just appear - need negative life event along with polymorphism. A functional polymorphism in the promoter region of the serotonin transporter (5-HTT) gene was found to moderate the influence of stressful life events of depression (short vs long)

Question 13

What is the gene-environment interaction (Caspi et al 2003 continued)

Answer 13

Good interaction between genetic allele that they carry and their negative life event. In all measures, those who had inherited short alleles from both parents were more vulnerable to developing MDD if they also experienced lots of negative life events. However, this is an interaction – doesn’t mean someone who inherits short-short is determined to have MDD, it is also determined by life events

Question 14

What is the serotonin transporter susceptibility?

Answer 14

Caspi et al - those with 2 long alleles were more likely to respond to antidepressants than those with 2 short, were more likely to respond to placebo, and has better long-term outcome following treatment. Tryptophan depletion was more likely to induce symptoms of depression in those with one or two short alleles.

Question 15

What is the monoamine hypothesis?

Answer 15

Depressive symptoms caused by insufficient activity of monoaminergic neurons. Monoamine levels low. Monamine agonists should reverse symptoms.

Question 16

What are monoamines?

Answer 16

Dopamine, epinephrine, norepinephrine, (adrenaline and non-adrenaline), and serotonin

Question 17

How do monoamines work?

Answer 17

Influx of calcium is responsible for neurotransmitter release in the synapse, which transports down the synaptic terminal, and releases neurotransmitters in the synapse. Binds to postsynaptic neuron and has some effect on this. Part of this process is reuptake or being broken down by enzyme (e.g. monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT)). These break down the neurotransmitters

Question 18

What is early evidence pointing toward chemical imbalance?

Answer 18

Lower levels of the 5-HT metabolite 5-HIAA in the cerebrospinal fluid (CSF) of depressed individuals (especially suicidal patients) (Asberg et al. 1976). Lower levels of DA metabolites (e.g. HVA) or NE metabolites (e.g. MOPEG) in the CSF of depressed individuals. However, the changes in these studies have been small and inconsistent. Also, changes in metabolites may not be the best way of measuring subtle changes in neurotransmitter function. Found evidence to support monoamine hypothesis – lower levels of metabolites = lower levels of neurotransmitters = depressed symptoms.

Question 19

What is evidence from reserpine?

Answer 19

Used to treat blood pressure in the mid-20th century. Caused depression in patients as a side effect. Reserpine blocks the packaging on monamines into the vesicles so when the neurons are activated no neurotransmitter is release - supported by the monoamine hypothesis.

Question 20

What is further evidence in support of the monoamine hypothesis?

Answer 20

All effective antidepressants act on 5HT/NE systems. Mood elevating substances e.g. amphetamines and ecstasy elevate monoamine levels.

Question 21

What are monoamine oxidase inhibitors (MAOIs)?

Answer 21

e.g. Iproniazid or phenelzine - inhibit the breakdown of monoamines in the presynaptic terminal, so have more available to be repackaged and released. Increase the proportion of monoamines taken up into the vesicles, and eased symptoms.

Question 22

What are side effects of MAOIs?

Answer 22

Increased sympathetic tone and ‘cheese effect’. Cheese products contain tyramine which is normally deactivated by MAO in the liver. MAOs mean tyramine is not broken down, which leads to an increase in heart rate and blood pressure.

Question 23

When was the discovery of modern antidepressants?

Answer 23

1952: but doctors initially missed the point. Amphetamines were used for depression in the 50s - increased neurotransmitter levels.

Question 24

What are tricyclic antidepressants?

Answer 24

Inhibit the reuptake of 5-HT and NE. Block the reuptake for serotonin and non-adrenaline.

Question 25

What are SSRIs?

Answer 25

In 1980-1990 the Selective Serotonin Reuptake Inhibitors (SSRIs) were synthesized, with fluoxetine (Prozac) being the first one (also Sertaline (Zoloft), Paroxetine (Paxil), citalopram (Celexa), Fluvoxamine (Luvox) etc). Great variability in how effective they are across patients. Also SNRIs – serotonin - norepinephrine reuptake inhibitors. SSRIs and SNRIs have fewer nonspecific actions, and therefore fewer side effects, than the tricyclic antidepressants.

Question 26

Does the monoamine hypothesis paint the whole picture?

Answer 26

An acute decrease in serotonergic activity in healthy people has no effect on mood, only those with a history of depression. Time-course disparity (drugs take weeks to have an effect even though they increase neurotransmitter activity straight away)

Question 27

What is the stress-diathesis hypothesis of depression (neurogenic hypothesis)?

Answer 27

Argues people who are depressed are experiencing stress - in a chronic state of alert, and that involves over-activation of the HPA axis.

Question 28

What is the HPA axis?

Answer 28

Involves hypothalamus, pituitary glands, and adrenal glands (involved in the release of cortisol). In situation where person perceives stress, leads to activation of HPA. Hypothalamus sends a releasing factor to the anterior pituitary, which sends ACTH through the blood to activate the adrenal cortex, which releases cortisol. There is a negative feedback system also to shut this system down, but in MDD there is a problem that occurs in negative feedback that comes from the hypothalamus – it is chronically active. The amygdala is activated, and this leads to release of ACTH and cortisol to handle the threat/stress, and this cortisol circulates, reaches the brain, and is received by the hippocampus. This sends a message to the hypothalamus that allows it to shut down the system. However, in HPA seems to be damage in the hippocampus so this stopping message doesn’t go through. This causes neurons in the hippocampus to die because of chronic activated of cortisol – this is a vicious cycle.

Question 29

Do antidepressants result in increased neurogenesis in the hippocampus?

Answer 29

Chronic treatment of antidepressants (2-4 weeks) - around this time there is neurogenesis in the hippocampus, which is around the time people come out of their depressive episode. Therefore not just the neurotransmitters - support of the neurogenic hypothesis.

Question 30

What did Duman 2002 find about the neurogenic hypothesis?

Answer 30

Neurotrophins/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. Chronic stress in animals decreases the levels of BDNF and increases cell death. The levels of BDNF are reduced in people that suffer from depression this seems to be reversed by treatment with antidepressants. Increases of BDNF levels in those taking antidepressants.

Question 31

What do imaging studies tell us?

Answer 31

Reduced volume of the hippocampus in depression - the more you suffer without treatment, the more neurons are going to die off/hippocampus will shrink. Can be reversed when take antidepressants. Increased activation in the sACC in people who suffer from depression which is reversed following successful treatment. This area seems to contribute to anhedonia symptom – not motivated.

Question 32

What are treatments for depression?

Answer 32

Pharmacotherapy (effective antidepressants are available), psychology, stimulation methods: ECT, TMS, DBS - more invasive.

Question 33

What is electroconvulsive therapy?

Answer 33

ECT gives artificial seizures to the brain, seems to improve symptoms for a short while. Only use if its the last option - if people try all different sorts of antidepressants and nothing works. Problem is it has negative side effects, e.g. memory loss.

Question 34

How many people are treatment-resistant patients?

Answer 34

STAR*D by NIMH: only 27% of depressed patients achieve remission within 12 weeks, 33% did not achieve remission despite trying 4 different antidepressants. Average time to reach remission for those responsive was 7 weeks. Therefore, there is a need for novel drugs.

Question 35

Is ketamine a novel antidepressant?

Answer 35

Used as an aesthetic drug in the lab and as an illegal stimulant. Effect of ketamine is rapid - takes a few hours/day to take effect. George Crane noticed it improved mood in 1959. Ketamine showed a 70% response rate at 24 hours following a single infusion - IV treatment (Carate et al., 2006)

Question 36

What are the effects of IV ketamine in patients with major depression?

Answer 36

Analog of euphoria - makes people euphoric, but only lasts a short while. Can see psychosis in the first few hours that it takes effect. Murrough et al. (2013) - first day after infusion they respond well, and were still better 7 days later.

Question 37

Are the effects of ketamine positive in being used as an antidepressant?

Answer 37

Antidepressant effects emerge by 2-4 hours. By 24 hours - substantial improvement in depressive symptoms in 50-80% of patients. All symptoms improve, including suicidal ideation. Benefits after a single infusion may last from 1-2 days to more than 2 weeks. Appears effective in treatment-resistant patients, even in those who did not respond to ECT.

Question 38

Is ketamine safe?

Answer 38

Several issues for concern: psychosis, abrupt rebound, bipolar disorder, IV infusion, don’t know if it has an effect in combo with other drugs, risk of dependability/abuse. Side effects of repeated use: neurotoxicity, interaction with opioids and DA, cognitive effects on memory, learning and executive functions (concentration etc.).

Question 39

What are recent insights on the genetics of MDD?

Answer 39

Gene expression microarray studies of cerebral cortices of 5 major psychiatric disorders: ASD, SCZ, BD, MDD, AAD (Gandal et al 2018). One locus was identified which was not observed in other disorders = CD2 was found to be specifically upregulated in MDD. Associated with inflammation and dysregulation of the HPA axis (hormone activity pathways) – more support for neurogenic hypothesis.

Question 40

What is the association between sleep and MDD?

Answer 40

Kraeplin - abnormal patterns in sleep and mental health are linked, offering a chance for early diagnosis. 80-90% of individuals with MDD experience sleep disturbances - may predispose people for mood disturbances especially insomnia. Circadian clock is very important.

Question 41

What is gut microbiota?

Answer 41

Bacteria that exists in our gut may have something to do with HPA axis functioning. Bacteria changes based on our diet. Human Microbiome Project (HMP) – NIH. 10 times the number of human cells and 150 times as many genes as our genome. Evidence points to a bidirectional relationship.

Question 42

What is the microbiota-gut-brain axis?

Answer 42

The brain sends info about the gut – if have a lot of stress and high cortisol release, this is communicated into the gut which may loosen the lining, so maybe the bacteria that exists within the gut may leak, which can increase inflammatory response (which leads to a state of alert). Microbiota also release neurotransmitters which can play a role.