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 Noradrenaline Serotonin Selective Antidepressants (NaSSAs)?
NaSSAs are a class of antidepressants that primarily enhance the levels of noradrenaline and serotonin in the brain.
NaSSAs are often used when SSRIs (Selective serotonin reuptake inhibitors) are not working
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 anti depressant paradox?
Drug administration rapid effect on the levels of Monoamine in the
CNS.
In general consistent with an inhibition of monoamine degradation (MAO) or inhibition of monoamine uptake.
However it takes 2-6 weeks of drug treatment to see an effect on clinical signs of depression.
This paradox predicts a long term change in brain structure function in response to drug treatment.
What is the short term process in the requirement of long term treatment of depression via antidepressants?
Inhibit uptake monoamine (e.g. serotonin) impacts increased signalling
Measured by microdialysis as increased in Raphe nucleus, locus coeruleus and cortex (activates repitoire of receptors)
Locally this can inhibit neuronal firing and release by activating negative autoreceptors (e.g.5HT1A) that Inhibit firing or release.
This means over a short period of time, a downregulation in signalling due to higher activation of inhibition via negative autoreceptors
Therefore, no increase in mood
What is the medium term process in the requirement of long term treatment of depression via antidepressants?
Prolonged treatment/exposure leads to down regulation of auto receptors reduced feedback inhibition, leading to increase neuron firing and chemical transmission
Other noted changes include
- Down regulation b2 postsynaptic receptors
- Down regulation of a2 auto receptors
- Down regulation of 5HT2 receptors.
Overall sense of a homeostatic response of pathways returns to signalling to pre-treatment levels.
What is the long term process in the requirement of long term treatment of depression via antidepressants?
increased neurone firing after autoreceptor downregulation is indicative of an adaptive response after treatment and serotonin has been implicated in longer term and possibly more sustained changes supported by GROWTH FACTOR EXPRESSION (e.g. BDNF).
This is associated with synaptic plasticity neurogenesis and synaptogenesis.
Sustained rewiring of circuits associated with mood.
What is the relationship between the prefrontal cortex and mood regulation?
Depression may involve interactions between focused circuits and an executive center, such as the prefrontal cortex
Prefrontal cortex is critical for controlling mood by regulating brain states
What brain structures interact with the prefrontal cortex, and what neurotransmitters do they regulate?
Dorsal Raphe Nucleus:
- Major serotonin (5HT) center
Locus Coeruleus:
- Controls noradrenaline
Basal Frontal Cortical System:
- Primarily cholinergic (acetylcholine)
Ventral Tegmental Area:
- Important for dopamine
Each neurotransmitter influences mood, alertness, motivation, and reward
What is the reciprocal communication in brain circuits?
Prefrontal cortex communicates with monoamine and other pathways, like the dorsal raphe
These brain centers influence each other reciprocally, essential for complex brain states
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
How does 5HT influence behavior according to the animal motivation experiment?
5HT release is linked to motivation and brain tone modulation
Suggests that drugs targeting 5HT can significantly influence behavior by modulating specific circuits
What key insight does the animal motivation experiment provide about psychiatric disorders?
Disorders like depression involve distributed effects across brain regions
Symptoms emerge from complex interactions across multiple regions and circuits, not isolated areas
What is the clinical need for new approaches to depression treatment?
Antidepressants not taking an affect is recognised as an issue in 20-30% of diagnosis
This could be due to a possible misdiagnosis
There are many reason for non-responders (ranging from non compliance to genetic background)
Not helped by limited insight into mechanisms
Could potentially cause individuals with sustained depression that self harm or suicide
Either due to non-response or long therapeutic potential
What is ketamine and why is it notable in psychiatric treatment?
Fast-acting compound with acute effects
Different mode of action from traditional antidepressants
Known recreationally and in clinical settings
What receptor does ketamine primarily affect, and how?
Acts on the NMDA (N-methyl-D-aspartate) receptor, a key glutamatergic receptor
Blocks the channel within the receptor rather than the agonist binding sites
How common are NMDA receptors in the brain?
Present in about 70% of synapses, crucial for excitatory transmission
How do NMDA receptors function under normal conditions?
Require glutamate binding and a second agonist, glycine, for activation
Allow sodium influx, leading to cell depolarization
This permits controlled calcium influx, impacting metabolic processes
What role does magnesium play in the NMDA receptor?
Magnesium ion blocks the ion channel within the NMDA receptor under resting conditions
Depolarization removes magnesium, allowing ion flow
Receptor activity depends on both membrane depolarization and agonist presence
How does ketamine block NMDA receptor activity?
Binds near the magnesium site within the channel, blocking ion flow without interfering with glutamate binding
Acts as a channel blocker rather than an agonist or antagonist
How was ketamine compared to midazolam for its antidepressed affects?
In a clinical trial
Midazolam is a sedative benzodiazepine
Patients were recruited and then flushed of existing medication and assigned to either treatment
Given a baseline rating of depression using MADRS
They were then infused with drug and then assessed after 1 day for antidepressant activity
There was some follow up based on time that patients remained responders
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)
What is ketamine’s potential as an antidepressant?
Originally known as a horse tranquilliser and recreational drug, ketamine in low doses has shown promise as a fast-acting antidepressant.
Its effects are acute, setting it apart from traditional antidepressants, which often take weeks to become effective.
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 influence neuroplasticity and neurotrophic factors?
Ketamine’s antidepressant effects seem related to changes in neuroplasticity.
It interacts with NMDA receptors and increases Brain-Derived Neurotrophic Factor (BDNF), which is critical for brain structure, memory, and learning.
What role does BDNF play in ketamine’s mechanism?
Ketamine activity requires the acute induction of BDNF protein that depends on translational (protein synthesis) but not transcriptional (new gene expression) control.
Ketamine’s effects rely on BDNF:
- Experiments show that ketamine’s motivational boost disappears in BDNF knockout mice.
This dependency highlights BDNF as essential to ketamine’s antidepressant action
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 ion enters when the NMDA receptor opens, and why is it significant?
Calcium ions enter the NMDA receptor, acting as potent metabolic regulators.
Calcium increases activity of certain kinases, which can phosphorylate and downregulate protein translation.
How does ketamine’s NMDA receptor blockade impact calcium and kinase activity?
Ketamine blocks NMDA channels, reducing calcium entry.
With less calcium, kinase activity drops, leading to disinhibition of protein translation rather than its usual suppression.
How can NMDA receptor blocking lead to an “upstate” in brain circuits?
Depression is linked to reduced activity in certain brain circuits, like those related to motivation.
Blocking NMDA on inhibitory neurons selectively reduces inhibition, thus making the circuit more excitable (or “upstate”).
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.
Why might ketamine’s effect on NMDA receptors have antidepressant potential?
By selectively inhibiting NMDA receptors on inhibitory neurons, ketamine increases excitability in brain circuits.
This shift in brain state may reduce depression symptoms, showing ketamine’s therapeutic potential even with a single dose.
What is ketamines real world potential?
Fast tracked for FDA approval in the USA.
Nasal formulation being developed based on esketamaine (S-isomer which has increased potency).
Delayed prescription in the UK.
What are some cautionary notes being examined for ketamine?
Study of long term physical impacts (kidney).
Long term impacts in terms of psychological impact (reflect on Benzodiazepine in 70’ and 80’s)
Long term efficacy in terms of its therapeutic potential.
Route for “novel” approaches to rising and intractable problem (HNK model suggests a new mode of action).
Large overview of anti-depressant therapies
Differences between anxiety and depression overview
What biological responses are associated with anxiety and how do they manifest in fear situations?
The fear pathway triggers hyperarousal and vigilance, resulting in physiological responses such as increased heart rate, heightened metabolism, and activation of the fight response
This response is a survival instinct, preparing the body to flee from danger
How do past experiences shape the fear response and influence anxiety?
Fearful experiences lead to plastic changes in brain pathways, teaching individuals to avoid dangerous situations
However, in anxiety disorders, these fear responses are triggered in safe environments, causing hypervigilance and a misinterpretation of non-threatening situations
What symptoms and cognitive effects can anxiety have during stressful events like exams?
Anxiety can lead to physical symptoms such as increased heart rate, decreased salivation, upset stomach, and hypervigilance, resulting in an inability to focus
This heightened state of awareness can distract individuals from the task at hand, like taking an exam, and create a debilitating impact on normal functioning
What is the relationship between anxiety, plasticity, and cognitive functioning?
Anxiety responses involve a constant surveillance of the environment and misinterpretation of cues, indicating a cognitive component in the fear pathway
When fear responses are inappropriately activated, it can lead to neural plasticity that rearranges brain pathways
Overcoming anxiety often requires addressing these maladaptive changes to restore appropriate responses to safe situations
How does a Panic Attack present?
Palpitations, pounding heart, sweating trembling, breathless, feeling of choking chest discomfort abdominal distress, dizzy
or faint, feelings of unreality or detached from oneself, fear of losing control or going crazy, paresthesias (numbness or tingling sensations), chills or hot flushes
These bouts should peak at 10 minutes.
How does agoraphobia present?
Symptoms same as panic attack when placed in an environment where escape is difficult, embarrassing or can not be made without support
Classified if not better explained by other conditions
How does panic disorder present?
4% Prevelance
Recurrent panic attacks, 10 minute peak
Or remain anxious about them recurring for up to month after an attack
May be associated with Agoraphobia
Not due to drug abuse
Are not better explained by co-morbid conditions.
What is specific phobia?
Excessive fear to a specific cue often recognized by sufferer
Not the case for children
Anticipation of cue or avoidance of it interferes with normal life routine
Not explained by other conditions
How does social phobia present?
10% Prevelance
Anxious state induced by social situation, many criteria as for specific phobia
In children they must exhibit otherwise normal ability for social interaction in familiar setting
If aligned with another disorder this can not underlie social phobia.
How does Obsessive Compulsive Disorder present?
Recurrent obsessive thoughts or images intrusive and inappropriate to time or place
Try to neutralize intrusion by distracting routines
Patients recognize the obsessive nature
Compulsions respective behaviours (e.g. hand washing) or inappropriate/excessive behaviours designed to reduce distress
Time consuming routines 1 hour a day Interfering with social or working relations
Not due confounding condition
Define if patient has poor or good insight into their condition
How does Post-Traumatic Stress Disorder (PTSD) present?
7-8% Prevelance
Experienced traumatic or near death experience in which intense fear response ensued
Intrusive recurring memory, dreams or sense of event. Intense response to internal or external cues associated with event
Physiological response by event cues. Persistent avoidance of cue
Diminished expectations quality of life (e.g. career, family etc)
Irritability, insomnia, hyper vigilant difficulty concentrating. Impact on social function and symptoms persist for greater than 1 month
1-3 months (ACUTE);
>6 months (Chronic)
Appears 6 months post traumas (Delayed Onset)
How does acute stress disorder present?
Cause and ensuing outcomes similar to PTSD
Shorter term classified lasting between 2 days and 4 weeks and
occurs within 4 weeks of trauma
Individual shows dissociative behaviour during or following trauma, amnesia, depersonalization
No substance abuse or other underlying cause.
How does generalised anxiety disorder present?
5% Prevelance
Anxiety or worry for more days than not for 6 months
Uncontrolled worry is associated with restlessness, fatigue,
lack of concentration, blank mind, irritability, muscle tension, sleep disturbances
Anxiety can not be specified but brings about disruption of normal life
Is not part of an associated syndrome.
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.
What behavioural responses are used to measure fear in conditioned rodents?
Key indicators include freezing behaviour and piloerection (raised fur).
These responses can be triggered by either the environment or auditory cues, indicating learned associations and changes in neural circuits.
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
How do corticosteroids influence the fear pathway?
Corticosteroids, released during stress, modulate the activity of the amygdala and hippocampus
They can enhance or dampen fear responses by affecting synaptic plasticity in these regions, impacting how fear memories are formed and retrieved
Chronic exposure to corticosteroids can lead to heightened anxiety responses due to persistent activation of the fear circuitry
What are the routes to anxiety pharmacotherapeutic treatment of anxiety disorders?
The current preferred treatment route prioritizes an order of treatments:
1. SSRI. Selective serotonin reuptake inhibitors (increase 5HT levels)
2. Tricyclic antidepressant drugs (increase 5HT and Noradrenalin levels)
3. Benzodiazepines (Potentiate GABA mediated inhibition in CNS and periphery)
4. Anticonvulsant drugs (Stabilize nerve activity, e.g. valporate)
5. Monoamine Oxidase inhibitors (elevate 5-HT levels) not favoured.
