Lecture 6 the brain Depression the brain and psychedelics Flashcards
Core needs for a diagnosis of depression
Mood change and/or anhedonia
Other key symptoms of depression
weight changes
poor concentration
fatigue
agitation
hyper/insomnia
Evidence that physiological damage to the brain can cause depression, Robinson et al, 1982
103 patients who had suffered a stroke
1/3-2/3 after found to meet the criteria for depression, not explained by clinical symptoms
Those with left hemisphere damage had more depression than right hemisphere
Closer lesion is to frontal lobe increase likelihood of depression
Incidence of depression in people who have brain tumours in their frontal lobes (Wellisch et al, 2002)
Patients with tumours in the frontal lobe were much more likely to have depression compared to those with tumours elsewhere
which lesion of the brain increases likelihood of depression
The dorsolateral prefrontal cortex
Which lesion of the brain reduces likelihood of depression
ventromedial prefrontal cortex
Effect of reduces activity of DLPFC
promotes depression
Effects of increased activity of VMPFC
promotes depression
Brain stimulation techniques: Electroconvulsive therapy
- Involves applying current to the brain of sufficient intensity of induce seizures (anesthetized state)
- Not focal and quite controversial
- ECT argued to be effective in treating severe depression, some disputals
- Can produce cognitive defects
Brain stimulation techniques: Transcranial magnetic stimulation, George et al., 2000
Experimental group: 2 weeks of TMS stimulation to the left Dorsolateral Prefrontal Cortex, switching between high and low intensities
Control group had 2 weeks of ‘Sham’ no electrical stimulation involved
Brain stimulation techniques: Transcranial magnetic stimulation, George et al., 2000 findings
After two weeks of TMS stimulation to the left dorsolateral prefrontal cortex depressive symptoms were reduced
higher up of stimulation the less depressed
Ventromedial prefrontal cortex:Deep brain stimulation
Surgically implanting electrodes into the brain to change activity in a specific region
Ventromedial prefrontal cortex:Deep brain stimulation, Mayberg et al, 2005
Electrodes were implanted into the ventromedial prefrontal cortex: can be effective for some but may only work in the short term
What does deep brain stimulation do to the brain?
At baseline patients with severe depression show hypoactivation in dorsolateral prefrontal cortex and hyperactive ventrolateral prefrontal cortex. DBS reverses this pattern after 6 months of stimulation is underactive compared to controls - reduced activity in ventromedial prefrontal cortex, reducing depression
Why it is needed in depression to turn of the VMPFC
enables concentration and people to turn of their wandering brain from all their thoughts
How to test the effects of drugs on behaviour
compare the effects of a placebo substance and an active substance through a questionnaire and a cognitive test
Clinical evidence: Randomised controlled trial (RCT)
- Active treatment
- Comparator
Randomly allocate to a condition
Assess the outcome
Important method as removed bias from treatment allocation
RCTs in mental health
Active insulin injection, placebo substance found no evidence for difference on psychotic symptoms between the two groups after 6 months
Khan and Brown (2015) RCTs in mental health
Placebo = 40% symptom reduction
waiting list = 10% symptom reduction
Antidepressants = 50% symptom reduction
Both psychotherapy and antidepressants together 60-70% symptom reduction
Lines of evidence for serotonin theory of depression
- Reducing the raw materials needed to make serotonin can induce depression
- Change the way serotonin is recycled at the synapse is a treatment for depression
What serotonin is made from
Tryptophan absorbed through our diets e.g., salmon, beef, milk
What are the effects of changing tryptophan levels in healthy participants (men) Young et al., 1985:
- Gave people a Tryptophan-Free Drink(Depletes 5-Ht - less serotonin levels)
- Balanced Amino Acid Drink (~normal 5-HT) - maintain regular serotonin levels
- Tryptophan-containing drink (Boosts 5-HT) - increases serotonin levels
What are the effects of changing tryptophan levels in healthy participants (men) Young et al., 1985:Findings
depleting 5-HT levels increased depression
What are the effects of changing tryptophan levels in healthy participants (men) Young et al., 1985:Findings, relating to emotional material
They did this with earphones on
Three levels of distractions:
- Low (stats)
- High (Bombings)
- Dysphoric (feelings of hopelessness)The group who has their Tryptophan levels depleted, lower serotonin, had more interference from emotional material.
Reasons why lowering serotonin levels can induce depression
you have less defences against negative information
Serotonin is a shield from negative information
Tryptophan depletion can induce depressive relapse: Delgado et al, 1990
14/21 patients experienced depressive relapse after taking the tryptophan depleting mixture.
Change the way serotonin is recycled at the synapses is a treatment for depression:
- Neuronal communication is chemical, so stopping presynaptic activity is not going to stop communication. You need to stop post-synaptic chemical interactions.
- Serotonin reuptake transporter (SERT) sucking up all the serotonin
- Selective Serotonin Reuptake inhibitors (SSRI) stop this, therefore increase the amount of serotonin the the synapse
Effectiveness of SSRIs
- Strongest evidence for treating moderate depression
- Responding often defined as a 50% reduction in score of clinical rating tool
- Meta analysis of 56 trials (7374 (Melander et al, 2008) found a 16% different in response rates (Drugs = 48% responder; Placebo = 32%; Number needed to Treat (NNT) = 7)
Criticisms of the ‘chemical’ imbalance theory of depression
Argues it’s overly simplistic
Reductionists
Reduces depression down to just chemical imbalances
Modern day use of psychedelics
Hofman discovery of LSD in 1940’s
Francis Crick discovered DNA supposedly whilst under LSD
Steve Jobs, used LSD to boost creativity
What are psychedelics
soul revealing compounds
cause a radical shift in how you understand yourself and allegedly the universe
Classical psychedelics
LSD, Magic Mushrooms
Non-classical psychedelics
ecstasy, ketamine
Effect of the setting of having a psychedelic drug
where you consume a psychoactive substance can modulate it’s effects e.g., having caffeine in a coffee shop vs a library
Effecting of the set when consuming a psychedelic drug
your mental state prior to consuming this substance can also modulate the effect of drugs, e.g., having a coffee while being relaxed vs whilst being stressed
How do we find out what psychedelics do at the molecular levels in the brain?
Psychedelics, such as psilocybin (Magic Mushrooms), are Serotonin (aka 5-HT)
5-HT2A agonists
Psychedelics mimic the effects of serotonin, somewhat selectively at 5-HT2A receptors
Agonist definition
a substance that binds to a receptor resulting in activation
How do we find out what psychedelics do at the molecular levels in the brain? Measuring
Cannot use FMRIs - to measure serotonin levels in human brains
- But we can pair a specific biomolecule with a radioactive isotope
PET scans to measure effect of drugs on the brain
Participants are injected with a radioactive compound that binds to a specific biological component (e.g., D1 receptors)they function as serotonin 5-HT1A agonists
Level of occupancy of receptors is related to the “psychedelic” experience
The psychedelic experience people have is related to the 5-HT2A receptor binding
Can psilocybin help with treatment resistant depression? Carhart-Harris et al ., 2016
Psilocybin led to significant reductions in depressive symptomology, lasts for 3 months
Can we show that psilocybin is better than antidepressants? Carhart-Harris et al., 2016
Appropriate placebos given in each arm
Anti depressant = - citalopram (10-20mg) daily for 6 weeks
- Psilocybin magic mushroom) two doses of 25 mg 3 weeks apart
Can we show that psilocybin is better than antidepressants? Carhart-Harris et al., 2016, results
Psilocybin reduced depressive symptom more than escitalopram (antidepressant)
What effects does psilocybin have on the brain?
Leads to decreases in activation (BOLD signal) in the brain of healthy volunteers, in the ventromedial prefrontal cortex. Decreasing activity here is associated with treatment response.
Psilocybin increased the connectivity (’talk’) between the subgenual cingulate and posterior cingulate cortex
Functional segregation
One brain region supports one psychological function
Functional integration: Psilocybin
Lots of brain regions work together to support one psychological function - Psilocybin promotes interactions between different brain regions (less modularity)
Psilocybin reduced brain modularity - more talk between regions: Daws et al., 2022
The more psilocybin increased ‘talk’ between different brain areas the greater the symptomatic improvement
Whereas, Citalopram (SSRI) did not consistently change communication between different brain regions
No relation between brain modularity changes and symptom reduction
