Clinical Neuroscience of Depression Flashcards
Clinical Neuroscience
major depressive disorder (MDD) is only diagnosed if a patient exhibits 5 (or more) behaviours, what are these behaviours?
- Depressed mood
- Reduced interest in pleasure (Anhedonia)
- Significant weight change
- 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)
what happens with each symptom?
- each symptom has a complex behavioural pattern
- involves multiple malfunctioning brain areas
how does diagnosis of depression happen?
itās a judgment call by a clinician to establish whether someone is depressed
* no blood tests or easy ātests ā for depression
what does DBS stand for?
deep brain stimulation (brain surgery where electrodes are implanted into brain regions and can be turned off and on
what does VNS stand for?
vagus nerve stimulation
what does TMS stand for?
tranmissional magnetic stimulation
when did chlorpromazine, imipramine and iproniazid was introduced?
1953-1960
when was VNS approved?
2005
when was TMS approved?
2008
what is the main pharmacological intervention for depression?
SSRIs developed from an accidental discovery when working on tuberculosis treatments
what is beckās cognitive model of depression?
the idea that depressive symptoms are generated and maintained by a combination of maladaptive cognitions
Beck suggests that individuals with depression are said to be prone toā¦
- selectively attend to negative stimuli (biased attention)
- experience greater awareness/perception for negative stimuli (biased processing)
- ruminate about depressive ideas (biased thought and rumination)
- recall depressive episodes with more frequency (biased memory)
- possess negative internal reps about the self and environment (negative schemas)
what is a cognitive neuroscience model of depression?
the idea that a number of different brain regions are involved in depression which can be mapped to the different cognitive patterns thought to trigger and sustain a depressive episode
a meta-analysis of reduced hippocampal volume in MDD (Videbech and Ravnkilde, 2004)
- found a difference in hippcampal volume between depressed group and control group (reduced hippocampal volume in depressed individuals)
issues with hippocampal studies..
never know if an individualās brain was always like that or it was different before they were diagnosed with depression
what is the neurotrohic hypothesis of depression?
- human post-mortem data shows decreased BDNF in the hippocampus
- this impairs memory encoding and demonstrates neuroplasticity at a very specific anatomical level
- but we donāt know if itās a cause or result of depression
what is depression associated with?
- increased amygdala activity (stronger negative responses, influences memory retrieval)
- decreased activity in right VLPFC and right DLPFC and superior parietal cortex (problems attending to positive stimuli/problems regulating amygdala response)
- atypical fronto-striatal activity (problems with reward processing)
what is the neurochemistry of depression?
- glucorticoids
- brain derived neurotropic factor (BDNF)
- Monoanimes
what is glucocorticoids?
- (mainly cortisol in humans)
- steroid hormone which increases blood sugar, suppresses immune system, increases metabolism
- increased cortisol levels raise performance during stress
what are brain deprived neurotropic factors?
- maintains and supports growth of neurons / synapses
- expressed in many brain areas but especially related to memory formation in the hippocampus
- Relates to the neurotrophic theory of depression (a key character)
what are monoanimes?
neurotransmitters that are released by neurones to send signals to other neurones
* Dopamine
* Serotonin
* Noradrenaline
what is dopamine?
reward and motivation, supports approach and consummatory behaviors
* released from ventral tegmental area (VTA) to forebrain networks
what is serotonin?
āhappinessā molecule but also many complex behaviors (e.g. dominance)
* released from Dorsal Raphe to forebrain networks
what is noradrenaline (also called norepinephrine)?
āfight or flightā molecule that prepares the body for action
* Released to organs all over the body
describe monamine treatmentsā¦
- have to overcome homeostatic feedback mechanisms (2-4 weeks); therefore takes 2-4wks until monoamines begin to work
- many side effects (insomnia, restlessness, aggression, suicidal thoughts, dizziness, nausea, headaches)
- effects can wash-out over time
- should not be a single treatment but as part of a treatment program (i.e. antidepressants and CBT)
- people may say that they feel better immediately after starting drug treatments ā almost definitely a placebo effect, as shouldnāt work for 2-4 weeks.
- Monoamine treatment by itself unlikely to help long term ā should be used as part of a programme, e.g. CBT
but what if monoamine treatments donāt work? The scale of the pharmacological problems. STAR*D, a large scale test of drug efficacy using increased levels of treatment (2006). Procedure:
Level 1: Citalopram (SSRI) for 14 weeks (if people didnāt respond to this, theyād be moved to level 2 and so on)
Level 2: Different anti-depressants (SSRI) + Optional CBT
Level 3: Different anti-depressants + Lithium or Thyroid Hormone
Level 4: Anti-depressants + monoamine oxidase inhibitors or serotonin-norepinephrine reuptake inhibitors (SNRI)
but what if monoamine treatments donāt work? The scale of the pharmacological problems. STAR*D, a large scale test of drug efficacy using increased levels of treatment (2006). Results:
Responded at Level 1 ā 47% or all subjects
Remission at Level 1 ā 28-33%
Remission at Level 2 ā 25% (CBT seemed to work as well as drugs)
Remission at Level 3 - 12-20%
Remission at Level 4 ā 7-10%
but what if monoamine treatments donāt work? The scale of the pharmacological problems. STAR*D, a large scale test of drug efficacy using increased levels of treatment (2006). what are the two variable outcomes?
reduction: responding to medication, yet still have depression
remission: depression symptoms drop so much, they are you are no longer considered to have depression
but what if monoamine treatments donāt work? The scale of the pharmacological problems. STAR*D, a large scale test of drug efficacy using increased levels of treatment (2006). what happened with withdrawal and remission?
- withdrawal rates increased at each level (side effects get worse as each level increases)
- approx. 70% of all subjects who completed showed remission (this means 30% have drug resistant depression; this is why we need other treatments like CBT and brain stimulation)
- some groups showed better response (women, better educated, wealthier)
The CoBAIT study (Wiles et al., 2013) tested efficacy of CBT for two groups of participants. Usual care (n=235) OR usual care and CBT [intervention group] (n=234). Patients were monitored over 12 months and success was defined as a 50% reduction in BDI after 6 months. What did they find?
improvement seen in 95 participants (46%) in intervention group versus 46 (22%) in usual care (p<0Ā·001).
what is the genetic likelihood of major depressive disorder?
- highly heritable (50% chance if parents are diagnosed)
- more in women than men
- we ALL have at least some genes correlating (thereās not one depressive gene but to what extent the gene causes depression varies)
what is polygenomic sequencing?
- about 3 billion base pairs in the human genome
- almost all identical across all humans
- single nucleotide polymorphisms, or SNPs (pronounced āsnipsā) result in changes across individuals and groups (bits in our genome that results in differences between us)
- 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 genetic āroadmapā of depression
what are some of the āhot spotsā genetic locations for major depressive disorder?
- 44 variants argued to map onto 19 genetic pathways to depression (Wray et al, 2018)
- 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)
what is a āroadmapā and why is it useful?
can be used to identify an individuals likelihood of developing depression
what is polygenic risk scores?
polygenomic sequences is used to compare an individualās DNA to the road map and estimate how likely one is to develop depression at some point in their life
* interesting to see what co-varies with depression
Gene SLC6A4 (commonly known as 5-HTT) regulates the expression and transportation of serotonin in the brain, yet has two versions of the gene, a short (s) version and a long (l) version, creating three variant groups: s/s, s/l and l/l. Describe the procedureā¦
- dunedin Multidisciplinary Health and Development Study of 1037 children
- three groups on the basis of their 5-HTTLPR genotype; s/s homozygotes, s/l heterozygotes and l/l homozygotes
- then measured number of stressful life eventsā¦
Gene SLC6A4 (commonly known as 5-HTT) regulates the expression and transportation of serotonin in the brain, yet has two versions of the gene, a short (s) version and a long (l) version, creating three variant groups: s/s, s/l and l/l. Describe the findings..
- found that those with s/s genes who have had a higher amount of stressful life events, the higher amount of self-reported depression symptoms, suicide ideation, reports of depression, major depression episodes
- when there is no maltreatment, groups the same but when thereās severe maltreatment, those with s/s genes, have a 0.6 chance of a major depressive episode while those with l/l only had 0.3 (s/l are in the middle with about 0.45)
- just being in the s/s group in itself is okay, itās the combination with negative events where you might begin to see depression
Gene SLC6A4 (commonly known as 5-HTT) regulates the expression and transportation of serotonin in the brain, yet has two versions of the gene, a short (s) version and a long (l) version, creating three variant groups: s/s, s/l and l/l. Describe the conclusions..
- the 5HTT s/s homozygote allele variant is not enough to cause MDD
- a combination of the 5HTT s/s variant and multiple early life stress events will increase chances of MDD diagnosis
- the risk of MDD is thus an output of both oneās genetic predisposition and oneās environment
Genetics impact brain structure..
- voxel brain 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
what does genetic variation mean for medical treatments of depression?
- drug study of 102 MDD patients treated with fluvoxamine (SSRI) split into three 5-HTT groups: l/l, (long, long), l/S (long, short) and s/s (short, short). MDD measured with Hamilton depression rating scale (HDRS) found that genetics interact not just with the environment but also treatment
- s/s have less effect on fluvoxamine alone than it has on other gene types
- genetics interact not just with the environment but also treatment
what are the basis of brain regions in depression?
- DLPFC is hypoactive in MDD: problems with top-down regulation
- Amygdala is hyperactive in MDD: problems with processing negative stimuli
- Disrupted reward processing and biased memory processes
what variant of 5HTT gene has the largest increase of depression?
s/s variant interacts with negative life events to increase your risk of depression (genetics + environment interact to increase your depression)
* s/s variant of the 5HTT is linked to differences in the brain regions associated with depression and may affect treatment
how do monoamine neurotransmitters work in a healthy brain?
monoamine neurotransmitters are released into the synaptic cleft and bind to receptors on the post-synaptic cleft/neurone. Transmission is terminated by re-uptake of transmitter
* signal for presynaptic cell to stop releasing neurotransmitters is they start to hang around in the synaptic cleft
how do monoamine neurotranmitters in depression work?
There is decreased concentration of monoamine at synaptic sites.
* they get released in synaptic cleft and there just isnāt enough and therefore not enough signals
* the way that SSRIs work, they block re-uptake sites (serotonin released, SSRIs plugs that sit in re-uptake site) meaning presynaptic cell keeps putting serontonin into the presynaptic cleft because itās not getting the signal to stop sending it (so not getting stuff reuptaken)
* therefore, blockage of the re-uptake sites increases the concentration of monoamine neurotransmitters available at receptor sites and restores mood
what is biased attention in depression?
- amygdala important for recognition and generation of emotion
- In healthy controls, attention is generally biased towards positive stimuli - individuals with depression instead show an attentional bias for negative stimuli
- Problems allocated attention could contribute to dysphoria (low mood in depression - more negative input because your attend is more towards negative bias)
- Brain regions associated with attention includeā¦
* Parts of the parietal cortex
Prefrontal cortex (PFC), including the VLPFC (ventral lateral pre-frontal cortex) and DLPFC [dorsal lateral pre-frontal cortex) (these areas are particularly important for attentional disengagement
Siegle et al 2007 used fMRI with unmedicated depression patients and healthy controls during two tasks: a digit sorting task (cognitive) and a personal relevance rating of words task (emotional) finding thatā¦
- patients with depression showed increased amygdala activity for negative words, and decreased DLPFC across the board for all tasks
- so a negative emotional response is strongerā¦ and less well regulated by top down-brain areas involved in attention allocation - if the amygdala is creating emotion and DLPFC is there to regulate emotions, so amygdala has a lot more emotional experience but your ability to control/down regulate that emotional response is reduced)
what is biased processing in depression?
- Reward processing affected in depression
- Reward in the brain supported by a fronto-striatal network, neural pathways that connect frontal lobe regions with the basal ganglia (striatum)
- Nucleus accumbens (NAcc ) is part of the reward network ā it is a major input to the striatum (basal ganglia)
- Disruption in this network has been argued to be the basis for anhedonia that we see in depression (loss of pleasure/reward)ā¦
Heller et al (2009) examined brain responses during emotion regulation paradigm via fMRI. Participants instructed to enhance or suppress emotional response to positive or negative images, or simply to attend
- The depression sample failed to sustain Nacc (Nucleus Accumbens activation) activation when amplifying/sustain an emotional response (positive feeling) - perhaps rewatch
- Deficits in sustaining activity in the NAcc were specific to positive emotion
- Patients who fail to sustain NAcc activity report less intense positive emotion (feeling more depressed)
- Difficulties sustaining NAcc activation reflect reduced prefrontal connectivity
what biased memory in depression? what is evidence for a memory effect and what is evidence for an encoding effect? Increased awareness for negative stimuli influences likelihood that negative information will be encoded and later recalledā¦
- activity in the amygdala facilitates the encoding and retrieval of emotional stimuli in healthy individuals by modulating brain regions associated with memory
- biased memory in depression is associated with amygdala hyperactivity, which is positively correlated with activity in the hippocampus, caudate and putamen
