DEPRESSION :PENCIL2: B+B2 LECTURE 6 - Coggle Diagram
B+B2 LECTURE 6
Major Depressive Disorder (MDD) diagnosed if 5 (or more) if these behaviours are present: DSM-5 Criteria…
Reduced interest in pleasure (Anhedonia)
Significant weight loss
Disturbed sleep (Insomnia / hypersomnia)
Abnormal motor activity (Psychomotor Agitation / Psychomotor Retardation)
Fatigue, tiredness, or loss of energy
Feelings of worthlessness or excessive guilt
Diminished ability to think or concentrate
Recurrent suicidal ideas (with or without a plan)
Each symptom is a complex behavioural pattern
Difficult to accurately diagnose due to subjectivity of diagnostic criteria.
Each involves multiple malfunctioning brain areas.
Depression is (at least) 5 of the above symptoms.
No simple answers
Diagnosis is a judgement call by a Clinician.
There are other types of depression
Manic phases and depressive phases.
William Battie (1703-1776)
First psychiatrist - origin of the word ‘batty’ to describe someone who is mentally ill.
Worked at Bethlehem Hospital in London → term ‘Bedlam’ (shortening)
Argued that mental illness should be studied in the same way as physical illness.
2 million people diagnosed with depression in the UK
Suggested that up to 30% of patients may not respond to drug treatment.
No update on drug treatments since the late 1950s / early 1960s.
SSRIs don't always work...
Drug study of MDD patients
102 subjects split into three 5-HTT different groups: l/l, (long, long), l/S (long, short) and s/s (short, short)
Patients treated with fluvoxamine (SSRI)
MDD measured with HDRS
The scale of the pharmacological problem...
STAR*D, a large scale test of drug efficacy using increasing levels of treatment (2006)
Citalopram (SSRI) for 14 weeks
Different antidepressants + Optional CBT
Different antidepressants + Lithium or Thyroid Hormone
Antidepressants + monoamine oxidase inhibitors or serotonin-norepinephrine reuptake inhibitors (SNRI)
STAR*D Results (2006)
Responded at Level 1 – 47% or all subjects
Remission at Level 1 – 28-33% (Works in a third of people)
Remission at Level 2 – 25% (CBT seemed to work as well as drugs)
Remission at Level 3 - 12-20%
Remission at Level 4 – 7-10%
Withdrawal rates increased at each level
Approx. 70% of all subjects who completed showed remission (got better)
30% have drug-resistant depression.
Some groups showed better response (women, better educated, wealthier)
The Genetics of Depression
MDD is highly heritable (50% chance if parent is diagnosed)
Just because you have a genetic predisposition to develop something doesn’t mean that you will develop it.
Genetics on its own isn’t enough to develop depression - it’s an interaction between genetics and the environment.
MDD is more heritable in women than in men.
women tend to be diagnosed more frequently than men, and male diagnoses tend to be more severe.
We all have at least some of the genes that correlate with MDD.
The extent to which we have genes that cause MDD varies.
There are about 3 billion base pairs in the human genome.
Almost all are identical across all humans.
Single nucleotide polymorphisms, or SNPs (“snips”) result in changes across individuals and groups.
Mapping these SNPs is much easier since the Human Genome Project.
Heritability studied in genome-wide association studies (GWAS)
Can be used to create a ‘roadmap’ of Depression.
Just some of the 44 variants...
Weight and body size (OLFM4 and NEGR1)
Neuron development and brain inflammation (LRFN5)
Over-activation in the fight-flight systems (RBFOX1).
Neurotransmitter systems for dopamine (DRD2)
Calcium signaling (CACNA1E and CACNA2D1)
Glutamate Neurotransmitter(GRIK5 and GRM5)
Presynaptic vesicle trafficking (PCLO)
Brain development (TCF4)
Lesch et al. (1996)
Gene SLC6A4 (commonly known as 5-HTT) regulates the expression of serotonin in the brain.
Individuals carrying one or two copies of the relatively low-expressing short allele (S) of 5-HTT exhibit elevated neuroticism.
Neuroticism is a personality trait involved in the propensity to depression.
Can be used to identify likelihood of developing depression.
Use polygenomic sequencing to compare my own DNA to the roadmap.
Estimate how likely I am to develop depression at some point in my life.
Also interesting to look at what co-varies with depression.
Genes and the Environment
Caspi et al. (2003)
The 5-HTT gene transports serotonin.
Dunedin Multidisciplinary Health and Development Study of 1037 children (52% male)
Three groups on the basis of their 5-HTTLPR genotype; s/s homozygotes, s/l heterozygotes, l/l homozygotes
Then measured the number of stressful life events.
Early life stress events (occurring between the ages of 5 and 21)
s/s homozygotes + stress = greater chance of MDD
If you have the s/s homozygote but don’t suffer from early life stress, you have no greater chance of developing depression than somebody with the l/l or s/l homozygote.
The 5-HTT s/s homozygous allele variant is not enough to cause MDD.
A combination of the 5-HTTS s/s variant and multiple early life stress events will increase chances of MDD diagnosis.
MDD is a result of nature and nurture interacting together.
Genetics changes brain structure
Voxel based morphometry (VBM) used to measure gray matter volume of 5-HTT gene.
Carriers of the short-allele (s/s) variant show reduced volume in amygdala and perigenual cingulate.
Connectivity between amygdala and cingulate impaired in 5-HTT group when viewing fearful stimuli.
Summary of main findings
Double dissociation of task (emotion vs cognitive) and brain area (DLPFC vs Amygdala) in MDD compared to controls
DLPFC is hypoactive in MDD
Amygdala is hyperactive in MDD
Having the s/s variant of the 5HTT gene reduces the size of your amygdala and the perigenual cingulate
Reduced serotonin in the brain means the emotional brain circuit is smaller in people predisposed to neuroticism
The Neurochemistry of Depression
Glutocorticoids (mainly Cortisol in humans)
Brain derived Neurotrophic factor (BDNF)
Monoamines (Dopamine, Serotonin, Noradrenaline, Norepinephrine)
Glutocorticoids - Cortisol
A steroid hormone, increases blood sugar, suppresses the immune system, and increases metabolism.
Increased cortisol raises performance during stress.
Brain Derived Neurotrophic Factor (BDNF)
Relates to the Neurotrophic theory of Depression
Maintains and supports growth of neurons / synapses
Expressed in many brain areas but especially related to memory formation in the hippocampus
Monoamines are neurotransmitters, they are released by neurons to send signals to other neurons.
Reward and motivation, supports approach and consummatory behaviours.
Released from Ventral tegmental area (VTA) to forebrain networks
“Happiness” molecule but also many complex behaviours (e.g. dominance)
Released from Dorsal Raphe to forebrain networks
Noradrenaline (also called Norepinephrine)
“Fight or flight” molecule that prepares the body for action
Released to organs all over the body
Discovered in the 1950s, but not really any better understood today
Have to overcome homeostatic feedback mechanisms (2-4 weeks)
Many different side effects (insomnia, restlessness, aggression, suicidal thoughts, dizziness, nausea, headaches)
STAR*D demonstrated prescription is not precise (28/33% at level 1)
Effects can wash-out over time
Should not a single treatment but as part of a treatment program
The Monoamine Theory of MDD
In the healthy brain, monoamine neurotransmitters (yellow) are released and bind to receptors on the postsynaptic neuron. Transmission is terminated by reuptake of the transmitter.
In depression, the decreased concentration of monoamine at synaptic sites produces a mood disorder.
Blockade of the reuptake sites (grey) increases the concentration of monoamine neurotransmitters available at receptor sites and restores mood.
The CoBalT study (Wiles et al., 2013, Lancet)
Tested efficacy of CBT
Usual care (n=235) OR usual care + CBT (n=234)
Monitored over 12 months. Success defined as a 50% reduction in BDI after 6 months
: Improvement seen in 95 participants (46%) in intervention group versus 46 (22%) in usual care (p<0·001).
The Frontal-striatal Pathway
Frontal Cortex is a part of the cognitive control network.
Nucleus Accumbens is part of the reward network.
Amygdala is part of the emotion network.
Ventral Tegmental Area (VTA) links the brain and the brain stem.
Dorsal raef (close to the nucleus accumbens) = where serotonin is released
fMRI Study of Cognitive/ Emotion Processing
Consistently see hypoactive frontal cortices in people with depression (less neural / BOLD activity)
In contrast, we see hyperactive amygdalas in patients with depression in comparison to controls.
30 MDD / 28 controls
Participants judged personal relevance of positive / neutral and negative words
Participants performed a digit sorting task.
MDD subjects show greater activity for negative more than neutral words in bilateral amygdala.
MDD subjects show greater activity for negative words in bilateral amygdala than controls.
MDD subjects show lower activity for digit tasks in DLPFC than controls.
-MDD subjects show lower activity for 5 digit than 3 and 4 digit tasks in the amygdala.
5-HTT Polymorphism impairs the emotional brain network - 's' carriers
Pulvinar has increased volume in s carriers
Medial prefrontal cortex has altered functional coupling with the amygdala in s carriers
Uncinate fasciculus has reduced microstructural integrity in s carriers
Amygdala has increased activity in s carriers
Increased in s carriers...
HPA axis reactivity
Attentional bias to threat
Emotion-induced retrograde amnesia
Aversion to financial risk