Affective disorders (O'Connor) Flashcards
How is psychiatric disease diagnosed?
Largely based on categorization:
- Clinical classification expert view on what you have (inclusion) and
don’t have (exclusion).
Done using clinical guides:
- Diagnostic Statistical Manual (DSM currently version V)
- International Classification of Disease (ICD currently version 11)
Pros:
- Has improved diagnosis but lacks pathophysiological definition.
Cons:
- Do not consider symptom overlap in distinct classifications (co-morbidities).
- Do not resolve specific disease causation hindering mechanism and drug development.
What is the concept of dimensionality in psychiatric disorders and how do they vary across different conditions?
Dimensionality refers to the breadth of circumstances beyond a specific cause
Disorders range from mental retardation (often linked to autism) to bipolar disorder, involving diffuse brain circuit involvement
Cognitive dysfunction is severe in conditions like mental retardation, while bipolar disorder often retains higher cognitive function
Positive symptoms (e.g., euphoria) and negative symptoms (e.g., maladaptive behaviors) vary across disorders
Early-onset disorders (e.g., autism) contrast with conditions emerging later (e.g., bipolar)
Genetic factors are complex, with more severe mutations often associated with early-onset disorders
What is the tension between DSM-5 classification and neuroscience in psychiatric diagnosis?
DSM-5 focuses on classification criteria, often ignoring brain functions
It uses inclusion/exclusion criteria to diagnose disorders.
Neuroscientists suggest breaking disorders into research domains (cognitive, social, arousal, sensory systems)
These domains help investigate conditions in new ways.
Traditional methods, especially expert-based clinical scores, remain more effective
What are research domains in psychiatric disorders, and how do they differ?
Research domains break down disorders into specific components for better study
Depression involves negative valence (low mood), while bipolar includes positive and negative valence
Cognitive systems associated with brain function are disrupted in psychiatric conditions
Social interactions also play a role in these disorders
Arousal systems, like those affected in depression, impact motivation
Sensory responses, often disrupted in autism, form another domain
These domains help compartmentalize disorders and understand their varying contribution
How has modern research advanced the study of psychiatric disorders?
Current research explores brain function at the genetic, molecular, and cellular levels
Different cell types in the brain interact to build circuits controlling physiology and behavior
Neural systems, or circuits, underlie behavior and are key to understanding psychiatric conditions
Research focuses on how these circuits contribute to disorders like depression and autism
Neurodevelopment plays a significant role, especially in early-onset disorders like autism
Environmental interactions with brain systems are also crucial to understanding outcomes in psychiatric conditions.
What are the two approaches to studying psychiatric disorders, and how do they compare?
Psychiatry (via DSM-5) organizes disorders based on clinical criteria
Neuroscience seeks to break disorders into research domains for deeper investigation
Traditional psychiatric methods focus on clinical scores and expert judgment
Neuroscience looks at brain circuits, genes, molecules, and environmental factors
There is still debate on how much neuroscience has improved diagnostic outcomes
Traditional methods are still considered more penetrative and useful at this stage
What is depression?
It is a pathophysiology of mood
Major health problem 6% of world and above 20% developed health burden
Cost of mental health burden is £120 Billion per year based on an LSE report (2022)
Depression Cost are > £15 billion/year in lost revenue in UK based on estimates (2002).
Very much a human condition
Depression is very difficult to model in preclinical models
What are the primary indicators and associated symptoms of depression?
Primary indicators
- Persistent sadness or low mood
- Loss of interests or pleasure
- Fatigue or low energy most days most of the time
Persistence of behaviour
- For at least 2 weeks if present probe.
Associated Symptoms
- 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.
Primary indicators + Persistence + Associated Symptoms = Diagnosis of disease
What are the levels of depression and the requirements for them?
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
Which parts of the brain are responsible for the symptoms of depression?
Depressed Mood (Limbic system/Arousal Centres)
Hopelessness and guilt (Limbic system)
Recurrent thoughts of death and suicide (Amygdala)
Low self esteem (Amygdala)
Irritability (Amygdala/Hypothalamus)
Modified appetite (+/-) (Hypothalamus)
Weight Loss or Gain (Hypothalamus)
Decreased ability to concentrate or think (Hippocampus/Cortex)
Insomnia or hypersomnia (Superchiasmatic nucleus)
Decreased interest in pleasurable stimuli (Nucleus Accumbens/Ventral tegmental area)
What causes depression?
Genetics
Environment
Sex differences
Defined Environment-Genetic interaction
What is the role of stress in depression?
Stress in the environment can lead to changes in brain state, increasing the likelihood of depression.
Not everyone responds the same; some individuals are more prone to low mood and depression.
Changes from stress can lead to brain states meeting the criteria for clinical depression.
How does the brain process stress biologically?
The brain reacts to both acute and chronic stress, triggering a cascade.
Higher-order brain structures recognize stress, signaling to the hypothalamus.
This response initiates changes in brain state associated with stress.
What is the hypothalamus’s role in the stress response?
The hypothalamus is a brain structure controlling metabolic responses.
In stress, it releases corticotropin-releasing factor (CRF).
CRF acts on the pituitary gland, further progressing the stress response.
What is the function of the pituitary gland in stress signaling?
CRF from the hypothalamus stimulates the pituitary gland.
The pituitary releases adrenocorticotropic hormone (ACTH) into the bloodstream.
ACTH targets the adrenal cortex to promote steroid hormone production.
How do steroid hormones impact the body during stress?
Steroid hormones, produced in the adrenal cortex, are lipid-soluble and act slowly.
These hormones can alter tissue metabolism, including brain tissues.
They work over extended periods (hours to days), modifying physiological responses.
Describe the negative feedback loop in the stress pathway.
Glucocorticoids, produced in response to stress, act back on the hypothalamus.
This negative feedback loop helps regulate CRF release, controlling the stress response
Disruption of this feedback loop can lead to pathological stress.
What are the effects of chronic or unregulated stress on the brain?
Prolonged stress elevates corticosteroid levels, harming brain physiology.
High levels of corticosteroids can cause neuron death and synaptic loss.
Stress may also impact key areas like the hippocampus and amygdala, affecting behavior.
How do CRF receptors contribute to stress and depression?
CRF receptors, particularly CRF1 and CRF2, are found in various brain regions.
These receptors play roles in stress response, with CRF1 linked to anxiety and depression responses.
CRF2 receptor involvement is more complex and not fully understood but thought to balance CRF1 effects.
What is the impact of stress on depression and brain sensitivity?
Depression patients often show a blunted stress response, meaning they turn off stress signals less effectively.
This blunted response may contribute to ongoing high-stress hormone levels, worsening depression symptoms.
How do individual differences affect stress responses?
Each person’s reaction to stress varies based on individual brain function and stress sensitivity.
This variability means that similar stressors may not cause depression in everyone.
How might blocking CRF receptors aid in the treatment of depression?
Research suggests blocking CRF receptors could have antidepressant effects.
This treatment approach targets the stress signaling pathway, which is overactive in depression.
Animal models have shown promising results, where CRF receptor blocking helps manage depressive behaviors.
What is the monoamine theory of depression?
In the 1960’s, two serendipitous observations put monoamines (noradrenalin, serotonin, (5-HT), dopamine) at the forefront of depression research
Iproniazid
- Was in trials for TB and patients reported an elevation in mood
Imipramine
- Was in trials as antipsychotic drugs indication to improve mood
Iproniazid mechanism of action
Major target was inhibition of monoamine oxidase
Monoamine oxidase is a mitochondrial enzyme that metabolizes neuroactive form of monoamines
Inhibition increased bio-availability of neuroactive monoamine
This lead to an increase in mood
Imipramine mechanism of action?
It elevates levels of monoamines
Adrenalin >serotonin>dopamine
By blocking reuptake of released transmitter (monoamine) into cells
This results in an increase in mood
Pharmacological Evidence Supporting the Monoamine Hypothesis
Antidepressant Mechanism:
- Drugs that increase monoamine levels (e.g., tryptophan supplements) or enhance monoamine sensitivity have shown antidepressant effects.
Depressive Effects:
- Drugs that deplete monoamine storage (e.g., reserpine) or inhibit monoamine synthesis (e.g., alpha-methyltyrosine) can lead to mood-lowering effects.
Monoamine Receptor Changes in Depression at Post Mortem
Small but measurable alterations in monoamine receptors, specifically 5HT 2A receptors, have been found in brain tissue from individuals with depression
Genetic Evidence in Monoamine Hypothesis
Potential Genetic Predisposition:
- Certain mutations affecting serotonin synthesis, such as those in serotonergic transporters, are linked to an increased risk of depressive episodes.
What happens when you elevate Monoamines?
Widespread increase in key transmitters across brain regions
Transmitters can potentially act on a broad number of receptors.
Why is selectivity important in developing antidepressants?
Generic compounds often cause significant side effects.
Selective drugs improve efficacy and reduce side effects.
Increased adherence due to fewer adverse effects.
What are the benefits of developing more selective antidepressants?
Improved mood enhancement with fewer side effects.
Potential for once-daily dosing due to slower metabolism.
Enhanced therapeutic outcomes and patient compliance.
How did fluoxetine (Prozac) improve on previous antidepressants?
Higher affinity for serotonin transporters compared to imipramine.
Reduced side effects and longer half-life.
Widely prescribed for depression and anxiety.
What distinguishes the action of selective reuptake inhibitors like fluoxetine?
Binds with high affinity specifically to serotonin transporters.
Minimal binding to dopamine and noradrenaline transporters.
Allows targeted treatment with lower doses.
What is the significance of distinct molecular transporters in neurotransmitter action?
Each neurotransmitter (serotonin, dopamine, noradrenaline) has its own transporter.
Enables the development of selective drugs targeting specific neurotransmitters.
Differences in structure allow for biased targeting in drug design.
What is the mechanism of action for serotonin transporters?
It binds serotonin (5HT) outside the cell and transports it inside.
Utilises a substrate binding site similar to enzymes.
Requires sodium and chloride for transport against the concentration gradient.
How do drugs like fluoxetine inhibit serotonin transport?
Bind to the substrate binding site of the transporter.
Act as classic competitive inhibitors to prevent serotonin uptake.
Slow down or stops translocation of serotonin into the cell
This means that active serotonin remains outside the cell and can act on other receptors - improving mood
How many binding sites are there on serotonin receptors?
In addition to the substrate binding site, there’s an allosteric binding site
What is the structural arrangement of the serotonin transporter?
Contains twelve transmembrane domains.
Substrate binding site formed by the first and sixth transmembrane domains, which is facilitated by an inwards folding, placing the 1st and 6th transmembrane domains together
Two sodium ions are necessary for transport function.
How does the presence of an additional binding site influence the action of antidepressants like citalopram?
The additional site can also be bound by the SSRI (Selective serotonin reuptake inhibitors) and prolong the drug’s occupation of the substrate binding site.
This enhances the drug’s effectiveness by elevating serotonin levels for a longer duration.
What are the three ways that NaSSA’s work?
Selective increase in Noradrenalin by autoreceptor block
Selective increase in Serotonin by heteroreceptor block
Additional blocking or activating on sub-classes of receptor
NaSSAs are often used when SSRIs are not working
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Overview of antidepressant drugs
What is the animal model experiment measuring motivational state?
Rat placed in water as an indirect measure of motivational state (more immobility suggests depressive-like behavior)
Surrounded by a magnetic field, magnet on rat’s foot, measures movement
Optogenetics is used via a light regulating brain circuits through ion channels from algae
Channel is inserted in neurons, activating cells when exposed to specific light wavelengths
Allows precise stimulation of brain regions to study circuit interactions
Virus containing the ion channel injected into prefrontal cortex
Targets neurons, likely glutamatergic, connecting to the dorsal raphe
How does fiber optic stimulation affect the animal’s behavior in the motivation experiment?
Medial Prefrontal Cortex Stimulation:
- Diffuse, with no behavioral effect
Dorsal Raphe Terminal Stimulation:
- Increases motivation (more movement when light is on, decreases when off)
What does the animal motivation experiment reveal about circuit interactions?
Stimulation of the prefrontal cortex activates neurotransmitter release onto dorsal raphe
Dorsal raphe activation releases 5HT, modulating brain tone and mimicking motivational responses
Highlights importance of circuit-specific stimulation to produce behavioral effects
What did the ketamine comparison clinical trial show?
Ketamine has an antidepressant effect with 50% reduction of the MADRS. Supported self reporting scores
It hinted at longer term effect based on relapse below 50% reduction (note fall out)
Adverse effects common in both groups (e.g. dizziness nausea for both groups and 15% reported dissociative symptoms for ketamine only)
How has ketamine’s antidepressant effect been studied in animal models?
Studies using tests like the forced swim test (for motivational behaviour) found that ketamine-treated animals had higher mobility scores (linked to motivation) lasting up to a week post-infusion.
This behaviour suggests sustained antidepressant effects, likely due to ketamine’s NMDA receptor channel-blocking action rather than blocking agonist binding sites.
How does ketamine impact protein translation without changing gene expression?
Ketamine does not increase BDNF through gene expression but by boosting the translation of existing BDNF mRNA.
Confirmed or reinforced by experiments showing that translation inhibitors (anisomycin) but not transcriptional inhibitors prevent ketamine effects.
This mechanism shows that ketamine has a selective effect on protein translation, providing a novel view of how antidepressants might work independently of gene expression.
What is the role of inhibitory and excitatory neurons in the NMDA receptor model of ketamine action?
In simple circuits, pyramidal neurons (excitatory) stimulate inhibitory neurons that release GABA to balance activity.
Ketamine blocks NMDA receptors on inhibitory neurons more effectively, weakening inhibition and allowing the excitatory neurons to stay in an upstate.
Large overview of anti-depressant therapies
Differences between anxiety and depression overview
What is fear conditioning, and how does it illustrate neural plasticity?
Fear conditioning is an animal model used to study fear circuits.
It demonstrates neural plasticity by showing how rodents learn to associate specific cues (either environmental or auditory) with aversive stimuli (like an electrical shock), leading to measurable fear responses.
What are the two types of fear conditioning, and how do they differ?
Unsignalled (contextual) conditioning:
- The rodent associates a specific environment (e.g., a cage with a blue floor) with a shock, leading to fear responses (like freezing) when placed in that environment even without a shock.
Signalled (cued) conditioning:
- The rodent learns to associate a sound (e.g., a bell) with a shock, resulting in fear responses triggered by the sound alone, regardless of the environment.
How does fear conditioning provide evidence for neural plasticity in fear responses?
Fear conditioning shows that rodents can learn to associate neutral cues (like environments or sounds) with aversive stimuli (shocks).
This demonstrates neural plasticity, as the brain adapts to form new connections, allowing the same fear circuit to be activated by different sensory inputs based on past experiences.
What is the “core fear centre” in the brain, and what role does it play?
The amygdala acts as the core fear centre, integrating sensory inputs from various brain regions to generate an emotional fear response (e.g., freezing, piloerection)
It receives inputs from the:
- Hypothalamus (regulates autonomic functions)
- Hippocampus (spatial memory)
- Olfactory lobe (smell)
Outputs from the amygdala influence the orbital cortex (emotional memory) and autonomic nervous system, triggering physical fear responses
How does the fear pathway demonstrate neural modulation?
The fear pathway can be both positively and negatively modulated:
- Positive modulation strengthens fear responses.
- Negative modulation dampens or prevents the emotional response, potentially reducing anxiety
This modulation allows for adaptive responses to different environmental cues, indicating plasticity in how fear is processed
How do the hippocampus and cortex interact with the amygdala in fear processing?
The hippocampus helps the brain learn and recognize spatial contexts linked to fear (e.g., a specific environment)
The prefrontal cortex and cingulate gyrus contribute to executive control over emotional responses, regulating how fear is expressed and managed
