Affective disorders (depression) Flashcards
LO and general points
General points- clinical problem with an underlying basis science
- Introduce and discuss the clinical and neurobiological basis for psychiatric disorders.
- Address current issues about diagnosis and pathophysiology; exemplify this in depression.
Depression (3 lectures)
- Describe the major features of Depression using clinical description.
- Highlight the monoamine hypothesis of depression and “empiriscm”
- Describe classic anti-depressant drugs monoamine modulating drugs.
- Detail the molecular basis for their mode of action
- Describe the re-purposing of ketamine as a novel anti-depression route.
Anxiety 1 lecture (1 slot)
- Introduce pathophysiological state anxiety and list the current classification and complexity of anxiety disorders.
- Highlight the fear pathway as a template to understand anxiety as a brain disease.
- Benzodiazepines and GABA receptors addressing how their wide expression can achieve some selectivity (anxiolytics).
- Discuss confounds to their use.’
- Journal Club
- Discuss the clinical efficacy of antidepressants.
- Is the pharmacotherapy of depression clinically relevant?
- Malignant sadness. The anatomy of depression Lewis Wolpert. Free Press (to read)
- Berton O. and Nesltler, E.J (2006) new approaches to antidepressant drug discover: beyond monoamines. Nat Rev Neuroscience 7 137-151. One of several reviews highlighting limitations of the monoamine hypothesis, mechanisms underlying and novel approaches to treatment of depression (to read)
- Cipriana et. al (2018) (to read)
What is the diagnosis of psychiatric diseases based on and tell me the different types of this?
Largely based on categorisation
- Clinical classification expert view on what you have (inclusion) and don’t have (exclusion)
- Diagnostic statistical manual (DSM currently version 5)
- International classification of disease (ICD currently version 11)
What are the pros and cons of these methods for diagnosing psychiatric diseases?
Pros:
- Has improved diagnosis but lacks pathophysiological definition.
Cons:
- Do not consider symptom overlap in distinct classifications (co-morbidities)- DSM V
- Do not resolve specific disease causation hindering mechanism and drug development.
Categorisations other limitation is that is does not consider the dimensional expression or causes of psychiatric disorder and disease
Why is schizoaffective disorder not as well understood or as well defined as other mental healthy conditions?
Schizoaffective disorder is not as well understood or well defined as other mental health conditions.
This is largely because schizoaffective disorder is a mix of mental health conditions ― including schizophrenic and mood disorder features ― that may run a unique course in each affected person]
Schizoaffective disorder also encompasses depression and anxiety
How do negative symptons of schizoaffective disorder make you feel?
Feel bad about yourself and have adversive (acting against or in a contrary direction) feelings
What is the research domain criteria (RDoC) basic science approach?
- Area of concept you investigate to build an understanding of a complex disorder
- Break down of behavioural domains which add up to contribute how behaviour and dysfunction is expressed in disruptive behaviour
- Positive valence= something that makes you euphoric
- Negative valence= something which makes you sweat or scared for e.g.
- Ability to switch from one system to another would be based on arousal systems
Why is the RDoC a better classification?
- clearer indication of pathology
- help understand and treat
Premise is that the inclusion exclusion criteria has got it wront?
What is the incidence of depression in society?
Major health problem 6% of world and above 20% developed health burden.
Costing £12 billion/year in lost revenue in UK.
Very much a human condition
What is one experiment scientists have done to look at depression in rats?
Put the rats in a glass spherical cylinder to look at their motivation to escape
it was thought that if they stopped trying they had lost motivation and hope and they were able to study this and the different functions in the brain between those motivated and those who weren’t
What does mood reflect?
A change in behavioural state
What is low mood associated with?
Low mood associated with negative thoughts.
Averseness = strong reinforcer to modify behaviour, associated with focus “concentration”.
Thus, impart evolutionary advantage (selected for).
Because depression has such an impact on mood, and creating a low mood, how does this effect focus?
Depression (sustained reflection on negative thoughts) may provide debilitating focus.
A. Pathways that control focus (e.g., prefrontal cortex
B. Modulation of pathways that control focus (5-hydroxytryptamine (serotonin)).
A+B= biological function
D(A+B) = disease; where D (dysfunction)
When diagnosing a psychiatric disorder, like depression, what are some primary indicators that an individual is suffering with this?
Primary indicators
Persistent sadness or low mood
Loss of interests or pleasure
Fatigue or low energy most days most of the time
What is the period of time that the bahaviour must persist in order to be diagnosed with depression?
For at least 2 weeks if present
What are some associated symptoms of depression alonside the primary indicators?
Associated Symptoms alongside the primary indicators
Disturbed sleep
Poor concentration or indecisiveness
Low self-confidence
Poor or increased appetite
Suicidal thoughts or acts.
Agitation or slowing of movements
Guilt or self-blame.
The Primary indicators + persistence + associated symptoms= diagnosis of disease, tell me how many symptoms are required for each of the following scenarios
- not depressed
- mild depression
- moderate depression
- severe depression
not depressed (fewer than four symptoms)
mild depression (four symptoms)
moderate depression (five to six symptoms)
severe depression (seven or more symptoms, with or without psychotic symptoms)
symptoms should be present for a month or more and every symptom should be present for most of every day.
Biological basis for the multiple dysfunctions in depression
What are some of the diagnostic criteria for depression?
Depressed mood
Irritability
Low self esteem
Modified appetite (+/-)
Hopelessness and guilt
Weight loss or gain
Decreased ability to concentrate or think
Insomnia or hypersomnia
Decreased interest in pleasurable stimuli
Recurrent thoughts of death and suicide
What are some of the associated brain regions with depression and how do some of them link with the diagnostic criteria of depression?
Associated brain region
Limbic system/ arousal centres
Amygdala/ hypothalamus
Amygdala
Hypothalamus
Hippocampus/ cortex
Superchiasmatic nucleus
Nucleus accumbens/ ventral Tegmental area
Amygdala
Stress has been found to be involved in the aetiology (the cause, set of cause, or manner of causation of a disease or condition) and potentially treatment of depression. Tell me stress’ involvement in depression
Also tell me about any neurotransmitters and different compounds involved
- Stress is a prima facta in triggering depression
- Dysregulation of the feedback inhibition elevating corticotrophin releasing hormone (CRH) and glucocorticoids in depressed patients in animal models of depression
- Elevated glucocorticoids kill cells, and cause synapse loss
- Glucocorticoids inhibitory to synaptogenesis and neurogenesis in brain (hippocampus)
- Additionally, CRF1 and CRF2 receptors exist in outside hypothalamic-pituitary axis (e.g., amygdala)
- Changes in CRF receptor levels in post-mortem brains of depressed patients
- Antagonists against CRF receptor have some good indication in treatment of depression
What type of feedback system is stress?
Stress is a negative feedback system
The pituitary gland releases hormones that then cause the adrenal gland to flood the bloodstream with the “stress hormone” cortisol. The cortisol, along with the regular stress response, lowers the production of CRF, thus causing a negative feedback loop in which the mechanism slows down and stops.
Briefly, what is the monoamine theory of depression, name two compounds involved in this theory (don’t explain them as we will do that next)
Monoamine theory of depression
Elevating the levels of the neurotransmitter available for signalling improves mood (as has been blunted due to depression)
1960s two serendipitous observations put monoamines (noradrenaline, serotonin (5-HT), dopamine) at the forefront of depression research
2 compounds: Iproniazid and Imipramine
Tell me about Iproniazid and it’s involvement in the monoamine theory of depression
- A carbohydrazide and a member of the pyridines
- Iproniazid was in trials for TB and patients
- TB patients reported an elevation in mood.
- Major target was inhibition of monoamine oxidase, mitochondrial enzyme
- metabolizes neuroactive form of monoamines.
- Inhibition increased bioavailability of neuroactive monoamine.
- Mitochondrial inhibitor
- Involved in metabolism of biogenic amines
Tell me about the relationship between MAO and Iproniazid
Several antidepressants and mood stabilisers were compared with the effect of well known MAO inhibitors such as Iproniazid
This drug was typically used as an anti-TB drug before it was observed that patients taking it exhibited excitement and euphoria
MAO-B metabolises dopamine and MAO-A metabolises all of the monoamines
Tell me about imipramine and its involvement in the monoamine theory of depression
- Imipramine in trials as antipsychotic drugs indication to improve mood.
- Elevated levels of monoamines
- Adrenalin >serotonin>dopamine
- By blocking reuptake of released
- Transmitter (monoamine) into cells.
- Has some antipsychotic activity
- Some indications of mood improvement
- Tricyclic antidepressant elevate extracellular levels of biogenic monoamines- as levels of monoamines are regulated by reuptake into the cell after release
What do both of the drugs, iproniazid and Imipramine, have in common?
The drugs either increases the bioavailability of active form of transmitter and the other the extracellular levels of transmitter. Both elevate levels in different ways and have mood improvements
When the monoamine hypothesis is considered in a neurobiological context there are elevated synaptic monoamines (noradrenaline, dopamine and serotonin)
Tell me some of the evidence in favour of the monoamine hypothesis
Think about the following…
- What makes something an antidepressant
- What makes something a mood depressor
- What chemical inbalances are there in patients with depression, how can this be measured
- Do genetics have an involvement
- Pharmacological-drugs that increase content (see above) or synthesis (tryptophan-horlicks) or sensitivity to monoamines are antidepressant
- Drug that depletes storage (reserpine) or synthesis (alpha-methyltyrosine) of monoamines act as mood depressors.
- Measuring major metabolites in the CSF or urine equivocal. Levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxy indoleacetic acid is elevated in the manic phase of bipolar but are much more varied in CSF plasma, urine of unipolar depressed patients.
- Measurable but not major alterations in several monoamine receptors in particular 5HT 2A in the post-mortem tissue of patients.
- Some genetic mutations associated with deficient serotonin synthesis predispose to depressive episodes (e.g., Serotonergic transporters). (less clear nowadays as evidence is not strong enough)
What area of the brain produces each of the monoamines and what happens when these are elevated?
The monoamines: Serotonin, dopamine, noradrenaline
Widespread increase in key transmitters across brain regions
Dorsal raphe is the central area or serotonin projection
Substantia nigra and VTA project dopamine. Only really projects to the frontal lobe
The Locus Coeruleus projects noradrenaline. This has a wide projection to other areas of the brain
Where can transmitters act when it comes to monoamines, why is this the case?
Transmitters can potentially act on a broad number of receptors
Splice variants in serotonin receptors increase the diversity from the set 7
The above shows all the receptors (do not need to know off by heart)
Shows signalling cascades that each NT can tap into is varied
What is modifying the potency at sites responsible for?
Provide examples…
The increase in transmitter levels
How does the NT serotonin and the drug Fluoxitine interact?
Fluoxetine is one of a group of antidepressants called selective serotonin reuptake inhibitors, or SSRIs. These medicines are thought to work by increasing the levels of a mood-enhancing chemical called serotonin in the brain.
- Secondary transporters Co-transport Na+ and Cl- into cell with the substrate.
- Substrate binds within in Transmembrane domains (TM).
- Uptake inhibitors occupy substrate binding site and prevent translocation of monoamine into cytoplasm.
- Some evidence for more than one SSRI binding site (e.g., citalopram)
- Serotonin and fluoxitine compete for the binding site that serotonin occupies (competitive inhibition)
- Substrate binding with TM domain
- Prevent monoamine being translocated and its retained outside longer
Tell me about the group of antidepressants; SSRIs (selective serotonin reuptake inhibitors) and their binding
What makes up the binding site and what helps with the strength of the binding site?
- Membrane transporter that binds serotonin and changes confirmation to allow reuptake
- Inhibitors occupy binding site to increase the levels of monoamine
- Some of the SSRIs, in addition to competitive binding site, have an allosteric modulation of the transporter
- Image show structural components that come together to make the binding site. Made of the 12 TM domains. Helices 1 and helices 6 create a large proportion of binding site
- There are intra- and extracellular loops associated with transporter. Extracellular loop 4 supports the binding site. Allows the release and capture of drug and monoamine
- Additional effect is stabilising conformation of transport (between allosteric and extracellular 4 loop?)
- Makes the elevation in the synapse more pronounced
Tell me about noradrenaline serotonin selective antidepressant
Not specific, but selective to noradrenaline and serotonin levels
2 important classes shown in the images
Two different kinds of NaSSA drug
Implicate biogenic amines via 3-fold shown on the next section
Does this in three ways: auto receptor block, heteroreceptor block and receptor subtype block…
Tell me about the Noradrenaline serotonin selective antidepressants (NaSSA) and the different ways in which they function
Noradrenaline serotonin selective antidepressants (NaSSA)
- Selective increase in Noradrenalin by autoreceptor block
- Selective increase in Serotonin by heteroreceptor block
- Additional blocking or activating on sub-classes of receptor
Black arrow over the top of receptors shows where the drug is blocking
Associated with NA release is auto receptors. Self-regulation, -ve feedback, auto receptors
Give some examples of the antidepressants, their mechanism of action and some potential side effect risks/ notes
Why are there so many different types of antidepressants?
(NaSSA) noradrenergic and specific serotonergic antidepressant
2 important principles: First is: Different classes of drugs (mechanisms of action above), different drugs have distinct clinical efficacies (who develop drug profiles based on known mechanisms), second is: different side effects, why different classes of drugs are used
SSRIs are not without problematic side effects
What are considered the steps from drug treatment to full efficacy?
When an antidepressant is taken, what is the long term effects of this drug in the brain structure/ function?
Above indicative of an adaptive response after treatment and serotonin (monoamine signalling) has been implicated in long term and possible more sustained changes involved neurogenesis and synaptogenesis
Sustained rewiring of circuits associated with mood
Progenitor cells can turn into neurons if treated in the right ways
In depressed state lose synaptic connectivity as seen in the image
An excitation of a serotonin mechanism that acts in depression
A paper by Warden et al. showed the following…
Excitation of a discrete subset of prefrontal cortical projection neurons regulates (executes) a motivated state (anti-depressant), Warden et al., (2012) Nature 492. 428-32
What evidence did this paper provide?
image: Magnetic on foot and magnetic coil on end so rather than watching the rat they can measure the movement via the magnets and the response it produces
Channel rhodopsin which makes the ion channel sensitive. Take the channel rhodopsin gene and force cell body to make ion channel in membrane
Distal regions are away from each other and can be discretely stimulated
Can see if shining light on specific region of the brain effects the movement of the rodent
Glutamatergic onto 5-HT pathway –> elevated 5-HT shows an antidepressant effect. Importance of interconnectivity
Ketamine has dose dependent impacts on behaviours producing distinct behavioural states. Explain, using doses some of the different effects they can have
What neurotransmitter is used in the NMDA receptor and how does ketamine interfere with this process?
Antagonist/ blocker of glutamatergic transmission
Excitatory NT= glutamate
Glutamate is released form nerve terminal and depolarises cells via acting on post-synaptic nerve terminals. Depolarisation due to release of Na+ ions and Ca2+?
NMDA: requires 2 agonist (glycine and glutamate) before it can open, depolarise membrane to remove Mg2+, selectivity for Na+ and Ca2+?
Ketamine is a non-competitive inhibitor of NMDA receptor
What are some other NMDA antagonists apart from ketamine?
Phencyclidine (PCP)
Dizocilpine ((+)MK-801)
How did researchers compare ketamine (0.5mg/kg) with midazolam (tranquilizing drug) (0.045 mg/kg) a sedative benzodiazepine?
What did the results show?
- Recruited; flushed of existing medication and assigned to either treatment
- Given a baseline rating of depression
- Infused with drug and then assessed after 1 day for antidepressant activity
- Some follow up based on time that patients remained responders
- This was a double-blind study
Results showed…
- Antidepressant effect with 50% reduction of the MADRS. Supported self-reporting scores.
- Hints at longer term effect based on relapse below 50% reduction (note fall out).
- Adverse effects (e.g., dizziness nausea for both groups and 15% reported dissociative symptoms for ketamine only).
Whats an interesting biological explanation of ketamine activity?
use the following as explanations: Ketamine, CPP and MK-801
- Ketamine treated animals have a reduction in the tine they are immobile
- CPP no effect, or only short term
- MK-801 don’t have the effect
- Supports ketamine’s antidepressant activity
- Thought to be inducing a plasticity…
What did BDNF KO animals show about ketamines activity?
- Link between presence of BDNF and ketamine antidepressant mode of action
- Gene transcription in presence of ketamine didn’t change however, protein expression went up
- Pre-existing mRNA when ketamine is present, shows its intervention in protein translation and leading to more BDNF being made
Protein translation is a multistep process with control points. What are the 3 main steps to this?
Initiation
Elongation
Termination
Tell me the circuit level explanation of how NMDA receptors and glutamate work in pathways that control excitation and the excitation of inhibition
Still a change in state of the circuit but mediated by a selective targeting of the inhibitory component that drives the system.
PV neurons are inhibitory which communicate with pyramidal neurons which are excitatory
PV negative regulates excitatory pathway
Ketamine selectively chooses to inhibit synapses that activates inhibitory neuron. Therefore, activate glutamatergic synapse, so levels of inhibition that pyramidal neuron sees is reduced, pyramidal output of firing is greater
Gamma waves (most active and alert when gamma waves are high. This is a mechanism in which this can happen)
Disquiet with NMDA receptor explanation
Zanos et al., NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature 533(7604): 481–486.
What happens when you take in ketamine?
R enantiomer less potent than the S enantiomer at NMDA receptors
R enantiomer and associated metabolites (i.e., 2R,6R hydroxynorketamine (HNK) enhanced
anti-depressant activity in animal models (e.g., forced swim test).
HNK has no efficacy as an NMDA channel blocker (cf Ketamine).
HNK has a circuit level effect by increasing gamma rhythms measured by EEG.
Evidence for HNK activating EEF2 kinase.
Evidence for HNK leading to an enhanced AMPA receptor mediated glutamate transmission.
WHAT ELSE MIGHT YOU LIKE TO KNOW.
What happens when NMDA receptor activated plasticity?
Tell me the changes that occur when SSRI/ NaSSA antidepressant induced plasticity
Tell me the changed when ketamine NMDA receptor block= antidepressant induced plasticity
Summary of the slow increase in anti-depression armoury
