major depressive disorder

Diagnosis of MDD is made up of 5+ of what behaviours

• depressive mood

• Reduced interest in please (anhedonia)

• Sig weight change

• Disturbed sleep (insomnia/hypersomnia)

• Abnormal motor activity (psychomotor agitation)

• Fatigue

• Feelings of worthlessness

• Diminished ability to think or concentrate

• Recurrent suicidal thoughts (with or without pain)

History of different treatments of depression

1. TCA - tricyclic antidepressants

2. MAOI - monoamine oxidase inhibitors

3. SSRI - selective serotonin reuptake inhibitor

4. ECT - electroconvulsive therapy

5. DBS - deep brain stimulation

6. TMS - transcranial magnetic stimulation

What is used when depression is resistant

Brain stimulation

What is becks cognitive model of depression

Where depressive symptoms are gained and maintained by combinations of maladaptive conditions

Individuals with depression are prone to:?

• biased attention

• Biased processing

• Biased thought/ rumination

• Negative schemas

• Biased memory

What can brain regions involved in depression be mapped to ?

Mapped to the cognitive distortions thought to trigger and sustain depressive episodes

What is the amygdala part of and important for

Part of limbic system

• important for recognition and generation of emotion and emotional processing

What is a healthy control when looking as biased attention in depression

Attention is generally biased towards positive stimuli

Brain regions associated with attention

• parts of parietal cortex

• Prefrontal cortex, including VLPFC and DLPFC

Increased emotional response to negative stimuli study

Siegle et al- fMRI with unmediated depression patients and healthy controls during 2 tasks

1. Digit sorting

2. Personal relevance ratings of words

• Patients with depression showed increased amygdala activity for negative words and decreased DLPFC for both tasks

• Negative emotional response is stronger, and less well regulated by top-down brain areas involved in attention allocation

Reward in the brain is supported by ?

A fronto-striatal network, neural pathways that connect frontal lobe regions with the basal ganglia

Nucleus accumbens is part of what ? And is a major input to where

Part of reward network and is a major input to the striatum (basal ganglia)

Disruption to the reward network has been argued to be the basis for what

Anhedonia

Studs on altered brain responses during emotional regulation

Heller et al → examined brain responses during emotion regulation paradigm

pps enhanced or suppress emotion response to pos or neg images or simply to attend

• depression patients failed to sustain NAcc activation when amplifying

• Deficits specific to positive emotion

• Those who failed to sustain NAcc activity reported less intense positive emotion

• Difficulties sustaining NAcc activation reflect reduced prefrontal connectivity

Increased awareness for negative stimuli increases the likelihood of what

That negative information will be encoded and later recalled

What did Payne et al find about emotional memory bias

That it emerges over time and sleel and suggest biased memory is not just about attention

What does emotional formation involve

The interaction between the amygdala and the hippocampus

Study on increased amygdala activity leading to negative bias in memory

Hamilton and gotlib

Examined neural correlates of emotional memory in depression

pps viewed neg, pos, and neutral images → memory tested 1 week later

• depressive pps showed better memory for negative images - associated with increased amygdala activity during coding

• Pps showed heightened connectivity between the amygdala and the hippocampus

What does human post mortem data show

Decreased BDNF in hippocampus

What is BDNF responsible for

Promoting brain health through neural growth

What are the neuro chemicals implicated in depression

1. Cortisol

2. Brain derived neurotropic factor (BDNF)

3. Monoamines

   • dopamine

   • Serotonin

   • Noradrenaline

What is cortisol and what does it do

A steroid hormone that increases blood sugar, suppresses immune system, increases metabolism

• increased cortisol raises performance during stress

What is BDNF and where is it expressed

Maintains and supports growth of neurons/synapses

• expressed in many brain areas but especially related to memory formation in the hippocampus

What is a monoamine

Neurotransmitters, released by neurons to send signals to other neurons

What are the 3 monoamines and what are they for

1. Dopamine - reward and motivation

2. Serotonin- happiness molecule

3. Noradrenaline - fight or flight molecule

What do monoamines as treatment mean you have to overcome

Homeostatic feedback mechanisms

• 2-4 weeks

Takes time to kick in

What are many different side effects of monoamine treatment

• insomnia

• Restlessness

• Aggression

• Suicidal thoughts

• Dizziness

What effect has been seen overtime with monoamine treatments

Drug decline over time

What happens when neurotransmitters cross from the pre to post synaptic in a healthy brain

neurotransmitters pushed out of presynaptic neuron , across the synaptic cleft then bind to the receptors of post synaptic side

Once transmission is completed reuptake occurs with the left over serotonin

What is happening to cause not enough serotonin to be taken into the post synaptic neuron

• far less serotonin to begin with

• Reuptake occurs before transmission is finished

How do SSRIs work

Stop the reuptake of serotonin

• don’t increase the amount of serotonin in the brain

What is STAR*D , it’s levels and result

A large scale test of drug efficacy using increasing levels of treatments

Level 1: Citalopram - 14 weeks

level2: antidepressants and optional CBT

Level 3: antidepressants+ lithium or thyroid hormone

Level 4: antidepressants and monoamine oxidase inhibitors or serotonin-neropinephrine reuptake inhibitors

Results :

• 70% of all pps who completed treatment showed remission

• withdrawal rates increased at each level - side effects got stronger

• Some groups showed better responses ( women, better educated )

Study on the efficiency of CBT

Cobalt Et al

• Usual care or usual care+ CBT

• Monitored over 12 months - success defined as 50% reduction in becks depression inventory

Result

• improvement seen in 95 pps(46%) in intervention group versus 46 (22%) in usual care

How heritable is MDD

50% chance is parents are diagnosed

Who Is MDD more heritable in

Woman

How many base pairs are there in human genome

3mil

What result in changes across individuals and groups in polygenetic sequencing

Single nucleotide polymorphisms

Study on the genetic locations for MDD

Wray et al - 44 variants argued to map onto 19 genetic pathways to depression

• weight and body size ( OLFM4 and NEGR1)

• Neuron development and brain inflammation (LRFN5)

• Over activation in flight or flight systems (R FOX1)

• Neurotransmitters systems for dopamine (DRD2)

• Calcium signalling (CACNA1E and CACNA2D1)

• Glutamate neurotransmitters (GRIK5 and GRM5)

• Presynaptic vesicle trafficking( PCLO)

• Brain development (TCF4)

What were the polygenetic risk scores found by Wray

• identify likelihood of developing depression

• Count up risk genes

What is SLC6A4 know as and what does it do

5-HTT

regulates the expression and transportation of serotonin in the brain

What are the versions of the 5-HTT genes

S/s

L/l

S/l

What did caspi et al find when studying genes and the environment

Dunedin multidisciplinary health and development study of 1037 children

Groups on the basis of their 5-HTT

• s/s homozygous

• S/l heterozygous

• L/l homozygous

measures no. Of stressful life events children were exposed to

• found having l/l makes you more resilient even when maltreatment is experienced

• S/s having experienced maltreatment as child increases likelihood of depression

What increases the likelihood of a MDD diagnosis

Having the 5-HTT s/s variant and also early stressful life events

What was pezawas et al study on how genetics impact brain structure

Voxel brain morphometry (VBM) used to measure grey matter volume of 5-HTT gene

• carriers of s/s variant show reduced volume in amygdala and perigenual cingulate

• Connectivity impaired between amygdala and cingulate when viewing fearful stimuli

What was the study on genetic variation with treatment

Smeraldi et al - drug study of MDD patients

102 patients split according to 5-HTT varient

Treated with fluvoxamine

MDD measured HDRS ( Hamilton depression rating scale )