CNS: depression, BPD and anxiety disorders (spring) Flashcards
what are the three broad categories of brain function?
Input (perception): The process of handling data transmitted to the CNS from sense organs. e.g. sensory cortex, thalamus and reticular formation.
Processing: Integration of new data and association with existing information (memory), cognition, emotional components. e.g. cortex and limbic system
Output: The consequential output following cognitive function. Can be voluntary or involuntary, such as movement or homeostasis. e.g. Cerebellum, basal ganglia, motor cortex, hypothalamus.
what are the three Anatomical Brain Planes?
Coronal (frontal)
Horizontal (transverse)
Sagittal
what is grey matter and white matter?
Grey matter: the areas dense in neuronal cell bodies (as well as glial cells and neuropil).
White matter: the areas dense in myelinated axonal tracts (with fewer cell bodies)
the cerebral cortex:
which species is the cerebral cortex largest in?
what percentage of neurons in the brain does it contain?
what is the cerebral cortex responsible for?
Evolutionary young area, proportionally larger in humans than other mammals
Contains 90% of total neurons in the brain
Responsible for abstract thought, judgement, memory and interpretation and integration of sensory input.
name the cortical lobes and a briefly state what each is involved in
frontal lobe: higher, executive functions
parietal lobe: integration sensory information
temporal lobe: processing sensory information
occipital lobe: visual processing
The Limbic System
what regions does it include?
what is the Limbic System responsible for?
what are the overall behaviors of the Limbic system determined by?
what does limbic system dysfunction manifest as?
Includes hypothalamus, amygdala, hippocampus, thalamic nuclei, olfactory and other regions
Responsible for the application of emotion (feelings) to cognitive functioning: e.g. fear, love, rage, pleasure etc.
Overall behaviors are largely determined by balance between cortical and limbic functions.
Limbic system dysfunction often manifests as emotional disturbance
describe the roles of the Thalamus, Hypothalamus, Hippocampus and Amygdala
Thalamus acts as pre-processor and relay for sensory information - dysfunction can result in perceptual symptoms e.g. hallucination
Hypothalamus helps coordinate NS with endocrine system (via pituitary) and sympathetic NS (PNS) - fight or flight
Hippocampus is important for learning and memory
Amygdala is involved in fear processing and emotional memories
Basal Ganglia
what are they?
what are they responsible for?
main components of the Basal Ganglia?
what is Basal Ganglia dysfunction associated with?
interconnected nuclei within the cerebrum
Responsible for coordinating voluntary motor activity and for aspects of cognition, learning and memory and emotion.
Main components:
- Striatum (dorsal: putamen & caudate nucleus; ventral: nucleus accumbens & olfactory tubercule)
- Globus pallidus (GPe, GPi)
- Subthalamic nuclei (STN)
- Substantia nigra (SNc, SNr)
Dysfunction is associated with many disorders, including Huntington’s and Parkinson’s disease.
The Brainstem
what are the main components?
what three centres does the brain stem contain?
what is the brain stem responsible for?
which amine neurotransmitters does the brain stem contain?
Main components: midbrain, pons and medulla
Contains visual, auditory and motor centres
Responsible for many involuntary functions:
- Respiration, cardiovascular control, pain sensitivity control
- alertness, consciousness (reticular formation, throughout the brainstem)
Contains the majority of cell bodies for amine neurotransmitters
- dopamine: substantia nigra & ventral tegmental area (midbrain)
- noradrenaline: locus coeruleus (in reticular formation)
- 5-hydroxytryptamine (serotonin): Raphé nuclei (in reticular formation)
- cholinergic neurons in the medial septum
what do ascending and descending pathways in the relay station do?
Ascending pathways carry information to the brain
Descending pathways carry information to the periphery
label the parts of the brain stem
What’s the difference between Psychiatry and Neurology?
cell types that comprise the CNS
Neurons
- Principal signalling units
- Connections and properties underlie higher behavioural functions
- 100,000,000,000 in humans
Glia
- As many glia as neurons
- Oligodendrocytes: make myelin
- Astrocytes: homeostasis, synaptic modulation, blood brain barrier (BBB)
- Microglia: brain’s immune system
- (there are also ependymal cells)
Other relevant non-neural cells
- Endothelial cells, pericytes (BBB)
describe the roles of Astrocytes, Oligodendrocytes, and Microglia
Astrocytes
- Stellate (fibrous and protoplasmic)
- Physical support for neurons
- Neurotransmitter uptake and Ionic homeostasis
- Signalling to neurons
- Release gliotransmitters (response to Ca2+)
- Respond to CNS injury: formation of glial scar, repair
- End feet interact with capillaries: support formation BBB
Oligodendrocytes
- Myelinating cells of the central nervous system
- Each cell myelinates several axons
Microglia
- Macrophage-like cells, cells of the immune system resident in CNS
- Respond to CNS inflammation and injury
- Can engulf (phagocytose) “foreign” bodies
- Contribute to repair, but also to injury
Blood Brain Barrier
what is the Blood Brain Barrier?
how is it formed?
how are different molecules transported?
Highly selective, semipermeable membrane acts as a barrier to protect brain from the periphery
Endothelial cells form tight junctions (TJ). Adherens junctions (AJ) stabilise. TJs make the brain inaccessible for polar molecules unless actively transported. Can pose a problem for getting therapeutic compounds into the brain.
crossing the barrier:
- Some large molecules enter CNS by receptor-mediated transcytosis (e.g. insulin) or non-specific adsorptive-mediated transcytosis (e.g. albumin)
- Some molecules have specific transporters (e.g. glucose, amino acids, nucleosides)
- Some water-soluble factors cross by paracellular transport, some lipid-soluble can diffuse
- Efflux transporters actively pump some molecules OUT (e.g. P-glycoprotein)
- Most drugs pass by diffusion: need low MWt and high lipid solubility (also affected by e.g. charge, protein binding…)
give structural features of Neurons
Dendrites
- Basal
- Apical
Cell body
- Nucleus
Axon
- Initial segment
- Hillock
- Myelin Sheath
- Node of Ranvier
Nerve terminals
- Presynaptic terminal
what differences in neurons can you get?
Morphological differences:
- Shapes
- Spines
- Myelinated or unmyelinated
Chemical differences - use different neurotransmitter systems
- Glutamate (50% of neurons)
- GABA (30% of neurons)
- Amines: dopamine or 5-HT (serotonin) or noradrenaline
- Acetylcholine
- Neuropeptides
Physiological differences
- neurotransmitter receptor and ion channel repertoires
how are neuronal signals carried in the body?
what causes the neuronal signal?
The neuronal signal is electrical and Electrical signals in the body are carried by charged ions.
These ions can be positively or negatively charged
- Positive: cations (Na+, Ca2+, K+)
- Negative: anions (Cl-, protein anions)
The neuronal signal is caused by ions moving across the cell membrane of a neuron.
The Cell Membrane
function?
is the cell membrane lipophilic or hydrophilic and what properties does this give?
what is the voltage?
Separates the inside of the cell from the outside environment- Separates intracellular and extracellular solutions that have different ionic concentrations (i.e. concentration gradients)
Cell membrane is lipid-based: high electrical resistance, Intrinsic capacitance properties.
These properties prevent the movement of most substances across the membrane (e.g. water, ions, proteins)
At rest, the inside of the cells is slightly negative compared to the outside (approx -70mV for a neuron, typical cell ranged from -40 to -80 mV)
How are Ions Distributed in the cell?
All ions are present on both sides of the membrane, but at different concentrations which leads to the resting membrane potential of -70mV in the neuron
How do Ions Cross the Membrane?
Neuronal function is a dynamic state
Ion channels:
- Are selective for specific ions (e.g. Na+ channel)
- Allow movement of ions across the membrane down their concentration or electrical gradient (electrochemical)
- Can be open or closed
- Can be opened by: Ligands- specific chemicals (ligand-gated channels), or Changes in the membrane potential/voltage (voltage-gated channel)
describe the movement of Sodium (Na+), Potassium (K+), and Chloride (Cl-) ions into and out of cells.
Sodium (Na+)
- High concentration outside the cell
- Pumped out of the cell in exchange for K+
- Na+ channels are closed at the resting membrane potential (-70mV)
- When channels open, Na+ will enter the neuron along the concentration gradient
- Vm becomes more positive
Potassium (K+)
- High concentration inside the cell
- Pumped into the cell from the outside
- Many K+ channel types are open at rest to fine tune the resting potential
- When voltage gated K+ channels open, K+ flow along the concentration gradient out of the neuron
- Vm becomes more negative
Chloride (Cl-)
- High concentration outside the cell
- Pumped out of the cell by a co-transporter
- Most Cl- channels are ligand gated (e.g. GABA and glycine receptor types)
- When ligand gated Cl- channels open, Cl- flows along the concentration gradient into the neuron
- Vm becomes more negative
what is The Action Potential and what is it responsible for?
what is an action potential reliant upon?
Binary unit of information transfer in the nervous system
Responsible for conveying information intracellularly (within a neuron)
Responsible for initiating electrochemical transmission intercellularly
Reliant upon voltage-activated ion channels
how does a Post-synaptic Potential work?
Dendrites receive signals from other neurons
Open ion channels in the dendrites to produce “graded responses”
Grading dependent upon volume of NT and receptor present
Responses can either be inhibitory or excitatory
compare Excitatory and Inhibitory Responses
Excitatory:
- Excitatory post-synaptic potentials (EPSPs) are due to an influx of Na+/Ca2+ ions.
- Makes inside of cell less negative (depolarisation)
Inhibitory:
- Inhibitory post synaptic potentials (IPSPs) are due to an influx of negative ions (Cl-)
- Makes inside of cell more negative (hyperpolarisation)
what determines whether an action potential (AP) will fire or not?
Overall contribution of EPSPs and IPSPs
Temporal summation (when two or more PSPs coincide in time). Two EPSPs together have a much greater effect than one alone, IPSPs have the opposite effect
Each neuron can receive thousands of inputs from other neurons, each of which may be inhibitory or excitatory. Gives rise to spatial summation that also determines whether AP fires or not
describe what happens in an Action Potential using glutamate as an example
- Resting neuron membrane potential at -70mV
- Glutamate released from presynapse
- Activates AMPA/kainate receptors, influx of Na+ leading to depolarisation
- Cell depolarises (NMDARs slower and voltage-dependent)
- Resulting depolarisation called an excitatory postsynaptic potential (EPSP)
- Subsequent APs can occur before Vm returns to rest and summate
- If/when summated EPSPs reach the threshold for voltage-gated Na+ channel activation (~-55mV), allowing rapid entry Na+ and an action potential will fire, propagating the signal
- All or nothing
- For inhibitory NT (e.g. GABA), instead get inhibitory PSPs (IPSPs)
summarise an Action Potential
After temporal and spatial summation, if there is a large enough depolarisation at the axon hillock, AP fires
Action potentials are “all or nothing”
APs propagate from dendrite to axon terminals where presynapses are located
Arrival of APs at the presynapse triggers a sequence of events that result in neurotransmitter release into the synaptic cleft where they can act on pre- or post-synaptically located receptors
Which brings us to the chemical synapse
what does electrochemical transmission tranduce?
neurotransmitter is released into the synaptic cleft.
Activates receptor postsynaptic cell
- Ionotropic (fast-acting, channels/pores)
- Metabotropic (slower, prolonged, via 2nd messengers)
Downstream cellular effects
what type of neurotransmitter is glutamate?
what receptors does glutamate act at?
most common excitatory neurotransmitter in the CNS (~50% of neurons)
acts at ionotropic (fast, ion conducting: AMPA, NMDA and Kainate) and metabotropic (slower, G-protein coupled: mGluR) glutamate receptors
what is another name for GABA??
what type of neurotransmitter is it?
which receptors does GABA act at?
g-amino-butyric acid
principal inhibitory neurotransmitter
acts at ionotropic (GABAA) and metabotropic (GABAB) receptors
apart from glutamate and GABA, name neurotransmitters/ receptors
endocannabinoids, adenosine, glycine, acetylcholine, dopamine, noradrenaline, serotonin (5-HT), peptides, hormones etc.
what happens after Ionotropic receptor activation?
Ionotropic receptor activation opens channel to allow influx of specific ions
Glutamate receptors allow + ions (above), GABAA allow in Cl- ions (see later)
Can thus lead to depolarisation (e.g. glutamate) or hyperpolarisation (GABA)
what type of receptors are Metabotropic neurotransmitter receptors and what does this mean?
what determines the downstream effect?
Metabotropic neurotransmitter receptors are G-protein coupled (GPCRs)
7-TM pass receptors
On binding ligand, get dissociation and activation of G-protein signalling
Depending on which type G protein (G𝝰X – where X is: s, i/o, q/11 or 12/13) it is coupled to determines downstream effect (second messenger systems).
give examples of small NTs and large NTs
Small NTs
- Amino acids (e.g. glutamate, GABA, glycine), typically fast-acting
- Monoamines (e.g. dopamine, noradrenaline, serotonin), diffuse effects, synthesised from tyrosine and tryptophan, neurons of brainstem
- Soluble gases (Nitric oxide)
- Acetylcholine
Large NTs: Neuropeptides (e.g. endorphins, substance P, neuropeptide Y)
Ionotropic vs Metabotropic Receptors
Ionotropic: Fast, IPSPs & EPSPs, Ligand-gated ion channels
Metabotropic: Slower, receptor activates intracellular signals, may activate or close ion channels, may increase/decrease gene expression
give examples of Ionotropic and Metabotropic Glutamate Receptors
Ionotropic: AMPAR (fast activation, responsible for most fast excitatory NT in CNS), NMDAR (slower, voltage-dependent block at resting), Kainate R
Metabotropic: mGluR1-8 (Class I: mGluR1 & 5, Gq; Class II: mGluR2&3, Gi/G0; Class III mGluR4-8, Gi/G0)
what types of receptors are GABAAR and GABABR?
what does GABA binding cause at the GABAAR receptor?
what does GABABR stimulate and inhibit?
GABAAR is a ligand-gated ion channel
- Other drugs acting at allosteric sites or within the pore can modulate GABA actions at the receptor (e.g. benzodiazepines)
- GABA binding causes opening of the conducting pore that allows Cl- to pass
- Inhibitory as Cl- flows into the cell causing hyperpolarisation
GABABR is metabotropic, GPCR, Gi/G0-coupled
- stimulates GIRKs (GPCR-coupled Potassium channels) and inhibit VGCC (voltage-gates calcium channels)
name NT receptors and their receptor type
GABA: GABAAR (ionotropic); GABABR (metabotropic, Gi/G0)
Glutamate: NMDAR, AMPAR, KainateR (ionotropic); mGluRs (metabotropic, 1-8)
Dopamine: D1-5 (all metabotropic, D1/5=Gs, D2-4=Gi/G0-coupled)
Serotonin: 5-HTR1-7 and sub-types, metabotropic except 5HT-3 (ligand-gated ion channel)
- 5HT1 & 5, Gi/G0-coupled
- 5HT2, Gq/11-coupled
- 5HT4-7, Gs-coupled
Noradrenaline (norepinephrine): adrenergic receptors (adrenoceptors): a1+2, b1-3 (all metabotropic)
- a1 is Gq-coupled, a2 is Gi-coupled
- b1-3 all Gs-coupled
Acetylcholine: Nicotinic nAChRs (ionotropic); muscarinic mAChRs M1-5 (metabotropic, M1,3,5 are Gq-coupled, M2 & 4 are Gi/o-coupled)
what does Activation of presynaptic Neurotransmitter receptors lead to?
Activation of these receptors tends to decrease further release of neurotransmitter from the presynaptic cell. (negative feedback)
give examples of affective disorders
define affect and mood
affective disorders (also known as mood disorders) include illnesses with abnormally high or low mood, i.e. mania and depression.
Affective disorders broadly include:
Unipolar depression/major depressive disorder including its variants, bipolar disorder, dysthymia (subthreshold depression), cyclothymia…
Affect: an objective description of a person’s emotional behaviour
Mood: an individual’s prevailing subjective emotional state
What is Depression?
Depressed mood is a normal part of life
Sadness and melancholy are normal responses to many everyday occurrences and will remit spontaneously
Definition of clinical depression relies upon an understanding of what a normal response to a given situation should be
Symptoms can be emotional, behavioural, physical and thought-based
Depressed mood and/or loss pleasure in activities are central to depression
how are genes and environment related to depression?
Family history is common in depression
Genetic and/or environmental components
Temperament/personality
what is each of these neurotransmitters related to?
Noradrenaline (norepinephrine, NA, NE)
Serotonin (5-hydroxytryptamine, 5-HT)
Dopamine
Noradrenaline (norepinephrine, NA, NE): Energy, concentration, memory, fight or flight
Serotonin (5-hydroxytryptamine, 5-HT): Mood, impulse control, cognition, appetite
Dopamine: Reward, pleasure, motivation, alertness, appetite
criteria for Diagnosis of Depression
Two main diagnostic criteria scales are used in diagnosis: DSM-V and ICD-10
Patient must exhibit at least one (DSM-V) or 2* (ICD-10) key symptoms: low mood, loss interest/pleasure, loss of energy (ICD-10 only)
For depression diagnosis DSM-V requires at least 5 out of 9 symptoms whilst ICD-10 requires 4 out of 10 (including the core symptoms) – NICE preference is DSM-V due to evidence base
Symptoms should have been present for at least 2 weeks and be of sufficient severity for most of each day
Not consistent with previous behaviour/personality and not secondary to other treatment
Scales such as Hamilton Depression Rating Scale or the Beck Depression Inventory frequently formalise the diagnosis
Need assess severity of symptoms
But it’s all subjective
what two questions should HCPs ask people who may have depression?
what happens if patients answer yes to either of these?
During the last month, have you often been bothered by feeling down, depressed or hopeless?
During the last month, have you often been bothered by having little interest or pleasure in doing things?
If patients answer yes to either of these, a HCP qualified to perform a mental health assessment for the patient should do so.
- Current ICD-10 or Current DSM-5
- A biopsychosocial assessment (BPA) should also be performed and risk of suicide assessed
- Depression questionnaires can also be used in conjunction (e.g. HADS, BDI-II and PHQ9)
compare diagnosis with ICD-10 and DSV-IV
DSM-IV requires at least 5 out of 9 symptoms
ICD-10 requires 4 out of 10 symptoms
Must include core symptoms:
- 1 of 2 from DSM-IV and
- 2 of 3 from ICD-10
give the ICD-10 and DSV-IV scores for different classes of depression (sub-threshold, mild, moderate, severe, persistent sub-threshold)
Persistent sub-threshold - at least 2 and <5 symptoms for at least 2 years (sometimes referred to as dysthymia)
what are the 3 principle treatment types for depression?
Criteria for determining most appropriate?
what is the most common apptoach?
Three principal divisions:
- Pharmacological
- Psychosocial
- Psychological
Criteria for determining most appropriate:
- Urgency
- Efficacy
- Prior history
- Presence of psychosis
- Contraindications/ADRs
- Cost
A multidisciplinary approach is most commonly used
for the 4 stepped care model give the Focus of Intervention and Nature of Intervention for each step
Examples of Psychological & Psychosocial Treatments for depression
Low intensity psychosocial: typically for persistent sub-threshold or mild to moderate depression
- Individual guided self-help based on CBT
- Computerised CBT (CCBT)
- Group physical activity programmes (sub-threshold or mild)
Group CBT: an alternative to low intensity psychosocial if declined/unsuitable
High intensity psychological: for persistent sub-threshold or mild to moderate depression where low intensity psychosocial has failed (instead of an antidepressant) OR for use in moderate to severe depression (in combination with antidepressant)
- Individual cognitive behavioural therapy (CBT)- can be very successful (e.g. 16-20 sessions over 3-4 months)
- Interpersonal therapy (IPT, e.g. 16-20 sessions over 3-4 months)
- Behavioural couples therapy (e.g. 15-20 sessions over 5-6 months)
which therapies are preferred for sub-threshold and mild depression and why?
Low intensity psychosocial therapies preferred approach for sub-threshold and mild depression as risk-benefit ratio for use of antidepressants is considered poor
which Antidepressants are used for Treating Depression?
Monoamine oxidase inhibitors (MAOIs)- Many dangerous side-effects, rarely used (sub-group called RIMAs safer)
Inhibitors of monoamine uptake- e.g. Selective Serotonin Reuptake Inhibitors (SSRIs) and tricyclics (TCAs)
Modulators of serotonin (5HT) receptors and other NT receptors- e.g. NaSSa, SMS and others
St John’s Wort- Unknown MoA, may be problematic due to effects upon hepatic enzyme activity, OTC but unlicensed and many interactions
name 8 types of pharmacological therapy used to treat depression
- Tricyclic antidepressants (TCAs) and 2nd generation cyclics (consider with TCAs)
- Selective serotonin reuptake inhibitors (SSRIs) – typical first line
- Monoamine oxidase inhibitors (MAOIs)
- SNRIs – Serotonin and noradrenaline reuptake inhibitors
- NaSSa – noradrenergic and specific serotonergic antidepressant (e.g. mirtazapine)
- SARIs – serotonin antagonist and reuptake inhibitor
- SMS – Serotonin modulator and stimulator (e.g. Vortioxetine) inhibits reuptake serotonin (SERT) + modulates many 5HT receptors
- NRI – Noradenaline reuptake inhibitor (e.g. Reboxetine)
what are Significant distinguishing features between drugs typically based on?
Antimuscarinic, anti-adrenergic and antihistaminic activity (adverse effects)
Sedative action (not linked to any single transmitter)
Cardiotoxic and/or convulsant action in overdose
SSRIs
examples?
efficacy?
onset?
side effects?
another indication?
e.g. sertraline, fluoxetine, paroxetine, citalopram, escitalopram
Similar efficacy to TCAs
Slow onset (2-4 weeks)
Fewer side effects, no anticholinergic, lack of toxicity in overdose, less sedating than TCAs
Side effects: Nausea, sexual dysfunction, insomnia, anxiety
Also used for some anxiety disorders
Washout when switching to be considered – discontinuation symptoms
Tricyclics (TCAs)
examples?
moa?
onset?
side effects?
e.g. imipramine, clomipramine, lofepramine,
Relatively non-selective inhibitors of noradrenaline and serotonin (5-HT) reuptake
Slow onset (2-4 weeks)
Side effects: dry mouth, blurred vision, constipation, urinary retention (mAChRs); sedation, drowsiness (histamine H1), weight gain. Greater CV risk
Problem for compliance
Toxicity in overdose
give dosing examples of the following SSRI’s:
- Sertraline for depression/GAD:
- Citalopram for depression:
- Escitalopram for depression/GAD:
- Fluoxetine for major depression:
- Paroxetine for major depression/GAD:
the following SNRI:
- Venlafaxine for major depression/GAD:
the following NaSSa:
- Mirtazapine (major depression):
Sertraline for depression/GAD: 50mg, if required increases 50mg to max 200mg/day with min. week interval
Citalopram for depression: 20mg, if required increase to max 40/day interval 3-4 weeks
Escitalopram for depression/GAD: 10mg then if required increase to max 20/day
Fluoxetine for major depression: 20mg then if required increase up to max 60mg/day with min. 3-4 week interval
Paroxetine for major depression/GAD: 20mg/day (max 50mg)
Venlafaxine for major depression/GAD; 75mg then if required increase to max 375mg/day (MD, in 2 divided doses if immediate-release, once for modified) or 225mg/day (GAD). With interval 2+ weeks
Mirtazapine (major depression): 15-30mg 2-4 weeks, bedtime. Can increase to 45mg/day
what is the moa of:
SSRIs
SNRIs
NaSSa
SSRIs: All potent inhibitors SERT; Sertraline inhibits DAT (less than SERT); (Sigma 1 some agonists, sertraline antagonist)
SNRIs: Potent inhibitors SERT, inhibit NET (duloxetine more than venlafaxine)
NaSSa: Antagonists of 5-HT2A, 5-HT2C, 5-HT3; a2A/B/C; H1 (very potent)
give dosing examples of the following TCAs:
- Clomiprimine (depression):
- Imiprimine (depression):
- the following SARIs: Trazodone for depression (esp. sedating):
an example of an SMS:
an example of an NRI:
an example of an MAOIs/RIMA:
Clomiprimine (depression): 10mg/day then can be increased 30-150mg gradually
Imiprimine (depression): upto 75mg/day (divided doses), can increase 150-200mg gradually [Clomiprimine more sedating, Imiprimine, less sedating]
SARIs: Trazodone for depression (esp. sedating) 150mg, can be increased to 300mg (for anxiety initially 75mg)
SMS: Vortioxetine – newer agent. Can be used when others have failed
NRI: Reboxetine – an alternative 2nd line agent
MAOIs/RIMA: subclass of MAOI, reversible inhibitor MAO-A. Safer, less side effects other MAOIs (e.g. moclobemide)
give the moa for:
TCAs:
SARIs:
SMS:
NRI:
MAOIs/RIMA:
TCAs: Inhibit SERT, NET, antagonists of 5-HT2A, 5-HT2C (& others), H1, H2, a1 adrenergic, mAcR Agonists of Sigma -1 & 2 …
SARIs: (Serotonin antagonist and Reuptake Inhibitor): Potent antagonist of 5-HT2A, a1; weak SRI and inverse agonist H1
SMS: Inhibits SERT and modulates several 5HT receptors
NRI: Inhibits NET.
MAOIs/RIMA: subclass of MAOI, reversible inhibitor MAO-A.
what is Electroconvulsive Therapy (ECT) used for?
Severe psychotic depression
Bipolar disorder with psychotic symptoms
Future Changes/Current Research for depression treatment
Ketamine - NMDAR antagonist but may work via other targets. Rapid action.
Esketamine is S(+) enantiomer of ketamine. Now licenced in UK (2020) intranasal antidepressant (specialist use), treatment-resistant depression
TMS – transcranial magnetic stimulation
Psilocybin (mushrooms) – 5HTR agonist, structurally related to 5HT (5HT2AR)
Increasing dopamine
what is the 4 step Treatment Strategy for depression?
Step 1: Recognition, assessment and monitoring
Step 2: Recognised depression. For persistent sub-threshold or mild to moderate depression:
- Can recommend a low intensity psychosocial intervention (if decline can consider group CBT)
- Usually no antidepressant for sub-threshold or mild symptoms unless specific exceptions
Step 3: Persistent sub-threshold and mild to moderate that fails to respond to initial interventions and for moderate to severe depression:
- Can recommend a high intensity psychological intervention OR antidepressant
- Moderate to severe depression antidepressant AND e.g. CBT or IPT
Step 4: Complex and severe depression:
- Referral to specialist services
- May include psychological and pharmacological therapy
- ECT in certain serious cases
- Often combination treatments
Patient Advice and Care if Prescribed Antidepressants…
what is important to highlight when Initiating therapy?
Follow-up?
Changes?
Switching?
Initiating therapy: Important to highlight
- Full effect takes time (e.g. 2-4 weeks)
- Important to take as prescribed and continue after remission (e.g. 6 months+)
- Potential side effects and interactions
- Risk and nature of discontinuation symptoms with all antidepressants, particularly those with a shorter half-life (e.g. paroxetine and venlafaxine), and how to minimise
- Antidepressants are not addictive
Follow-up: Typically see after 2 weeks of initiation then every 2-4 weeks after for 3 months (may then extend)
Changes: Considered if no improvement, significant side effects, patient preference. If switching, many considerations (wash-out, interactions etc.). Can try alternative SSRI or other class.
Switching: Often can direct switch between SSRI/SNRIs (except fluoxetine). For others may need different protocol such as cross-tapering (e.g. SSRI to mirtazapine) or taper/stop*/switch (e.g. SSRI to moclobemide, *1 week)
Consider co-morbidities and adverse effects profile.
what is bipolar disorder?
repeated episodes of mania (or hypomania) and depression
symptoms of mania
how long does an attack last?
Abnormally elevated mood, unwarranted optimism, exuberance, over-confidence, inflated self-esteem, hyperactivity, excessive libido and little sleep
Increased drive and extrovert behaviour but often socially tactless
Makes compliance problematic
Attack lasts a week or more
how do you classify bipolar disorder and what are the 2 classes?
Classification: ICD-10 (or DSM-IV) criteria used to define
Bipolar I disorder = more severe mania
Bipolar II disorder = hypomania (mania less severe)
according to NICE guidance, BPD is suspected if the individual has had any symptoms of…
(1) Mania; (2) Hypomania (3) Depression and a history of previous episodes of mania or hypomania (4) A mixture of both manic and depressive symptoms.
Mania is suggested by…
Abnormally elevated mood, extreme irritability, and sometimes aggression
Increased energy or activity, restlessness, and decreased need for sleep
Pressure of speech or incomprehensible speech
Flight of ideas or racing thoughts
Distractibility, poor concentration
Increased libido, disinhibition, and sexual indiscretions
Extravagant or impractical plans (for example business investments, spending sprees)
Psychotic symptoms: delusions (usually grandiose) or hallucinations (usually voices)
Diagnosis of a manic episode requires symptoms of mania lasting …
Diagnosis of a manic episode requires symptoms of mania lasting for at least 7 days which usually begin abruptly
Hypomania is suggested by …
symptoms of mania that are not severe enough to cause marked impairment in social or occupational functioning, and the absence of psychotic features.
Diagnosis of a hypomanic episode requires symptoms to last…
for at least 4 days
A mixed episode is suggested by…
Depression is suggested by…
A mixed episode is suggested by a mixture, or rapid alternation (usually within a few hours), of manic/hypomanic and depressive symptoms.
Depression is suggested by feelings of persistent sadness or low mood, loss of interest or pleasure, and low energy.
Detection of bipolar disorder in people presenting with depressive symptoms may be improved by asking about a history of overactive, disinhibited behaviour lasting 4 days or more. what questions would you ask?
‘Do you currently (or have you in the past) experienced mood that is higher than normal, or do you feel much more irritable than usual, and have others noticed?’
‘At the same time, do you have increased energy levels so that you are much more active or do not need as much sleep?’
what are the aims of BPD treatment?
Control manic and depressive attacks
Minimise recurrence and stabilise mood
how do you Control manic attacks?
Prophylaxis for long-term treatment including mood stabilising drugs and psychological interventions (e.g. CBT). Mood stabilisers include:
sedative anti-psychotics (atypicals)
Mood stabilisers include:
- Lithium (common, long-term mood stabiliser but not immediately effective)
- Anticonvulsants, particularly Sodium valproate (can help manage manic phases)
- Other anticonvulsants used such as lamotrigine and carbamazepine
- Some atypical antipsychotics e.g. olanzapine or quetiapine
- Antidepressants not typically used or if used are in combination
- Benzodiazepines may be used short-term for mania
Treatments for Mania and BPD
Lithium (carbonate) for acute mania or bipolar disorder and BPD prophylaxis
Antipsychotics (Atypicals, D2 antagonists and other mechanisms/targets)
Antiepileptic/anticonvulsants MoA not fully understood
Lithium (carbonate) for acute mania or bipolar disorder and BPD prophylaxis
- why does it need careful monitoring?
- monitoring requirements?
- toxic conc?
- what does a Sustained release formulation help with?
- how long does it take to have an effect?
- side effecs? how would you reduce these?
- interactions?
- moa?
- very narrow therapeutic window
- Blood monitoring – typically 0.6-0.8mmol/L (may have therapeutic effect at 0.4 or may need up to 1.0. MONITOR thyroid and kidney function (and check CVS, renal and thyroid before commencing)
- Toxic at >1.5mmol/L but can have toxicity at lower (therapeutic) doses
- Sustained release formulations help avoid high peak plasma concentrations
- Takes 2-3 weeks to have effect
- Many side effects can include renal, endocrine, cardiac, neurological – reduced by lowering dose
- Drug interactions can affect levels (NSAID, diuretics, ACE inhibitors)
- MoA not fully understood, may include neuroprotection, modulation of neurotransmission, inhibition of GSK-3B or reduction of Inositol
what do Antipsychotics do?
examples?
Can give control of mania and some help to prevent relapse/mood stabiliser
Commonly atypicals such as olanzapine, quetiapine, risperidone (haloperidol is first generation/typical)
what do Antiepileptic/anticonvulsants do?
examples and side effects?
- Typically Na+ channel blockers that decrease AP firing (also putative action on other NT signalling)
- Valproate – mania and prophylaxis of bipolar disorder (possible effects at voltage-gated sodium channels, GABA signalling, and others)
- Carbamazepine – prophylaxis of bipolar patients unresponsive to lithium, may be used for mania
- Lamotrigine – prophylaxis of bipolar disorder (and depression, not mania)
- Significant cognitive side effects
what is initial mania treatment?
what if this is ineffective?
treatment for depression in this period?
what happens after resolution of the acute episode?
usually in secondary care: atypical antipsychotics such as olanzapine, quetiapine, risperidone [or (typical) haloperidol]
If ineffective a second may be tried before adding lithium or sodium valproate (if lithium is unsuitable)
If patient was already taking antidepressants usually tapered and discontinued.
For depression in this period treatment options include e.g. Quetiapine alone, or Fluoxetine + olanzapine, or Olanzapine alone, or Lamotrigine alone
Four weeks after resolution of acute episode establish long-term plan. Can include staying on current mania treatment or e.g. lithium (common) to prevent relapse with/without second agent. Specific psychological therapy may also be offered. If stable, a patient treated in secondary care may continue management in primary care (usually after at least 12 months)
What is anxiety?
“prolonged or exaggerated response to a real or imagined threat, which interferes with normal life and cannot be attributed to any known neurological or organic dysfunction”
what are the Two opposing views of causes of anxiety?
Psychiatrists: conflict between primitive urges and socialised/civilised behaviours
Biologists: biochemical dysfunction (e.g. monoamine neurotransmitters)
Anxiety serves a useful function in day to day life. It becomes aberrant when…
a threat is real but the response is disproportionate
the threat is imagined
List Anxiety mediators
serotonin, noradrenaline, dopamine and GABA in CNS. Also PNS involvement
symptoms of anxiety
Anxiety, worry, despondency, sadness, somatic symptoms (PNS), sleep disturbance
Symptoms can be e.g. behavioural, physiological, cognitive or affective
Clinical features of anxiety
Psychiatric
- Feelings of apprehension, tension, fear, panic or terror, being ‘on edge’
- Hyper-arousal excitability, labile mood, outbursts of hostility, insomnia
- Circling thoughts, inability to concentrate, easily distracted, lapses of memory
Somatic
- Cardiovascular: palpitations, bradycardia or tachycardia; elevated blood pressure; flushing or pallor
- Respiratory: rapid shallow breathing (hyperventilation) or breathlessness (dyspnoea)
- Gastrointestinal: diarrhoea, dyspepsia, dysphagia, churning stomach
- Musculoskeletal: agitation, restlessness, tremor, muscle tension
- Metabolic: elevated blood glucose and glucocorticoids
- Miscellaneous: excessive sweating, urge to defecate or urinate
- Insomnia
types of Generalised anxiety disorder (GAD)
Social phobia
Specific phobias
Obsessive compulsive disorder (OCD)
Panic disorder (PD)
Post traumatic stress disorder (PTSD)
Treatment aims for anxiety
Treatment aims to:
- Discover cause and address/remove it
- Assess the severity of the anxiety response
- Relieve distress
- Institute long-term measures to avoid same/related recurrence
- Institute long-term measures in cases of chronic anxiety
Psychological Treatments for anxiety
- Before looking at pharmacological interventions, consider psychotherapy as the principal means by which anxiety can be treated.
Counselling
Cognitive behavioural therapy (CBT)
Exposure therapy
Mindfulness and relaxation training
Pharmacological treatment for Acute Anxiety
Benzodiazepines (e.g. lorazepam, alprazolam, diazepam)
SSRIs first line for many anxiety disorders e.g. fluoxetine, escitalopram, paroxetine, sertraline, also SNRI (venlafaxine, duloxetine)
Pregabalin (also for epilepsy)
Tricyclic antidepressants e.g. Clomipramine – obsessions, phobias
Buspirone (hydrochloride)
Beta blockers e.g. propranolol
Benzodiazepines for anxiety
moa?
fast or slow acting?
what effect do they have on the body?
adverse effetcs?
Positive allosteric modulators of GABA binding to GABAA receptor
Fast-acting relief of severe anxiety (panic disorder, acute stress)
Sedative and hypnotic, reduce muscle tone and coordination
Adverse effects
- Toxicity in overdose (reverse by flumazenil, competitive antagonist)
- Drowsiness, amnesia, confusion, impaired coordination, tolerance and dependence
- (Restrict use)
pregabalin for anxiety
moa?
indications?
inhibition at auxillary a2d subunit of voltage-gated calcium channels, VGCC).
GAD, also for epilepsy
Tricyclic antidepressants for anxiety
give an example and what is it used to treat?
common side effects?
Clomipramine – obsessions, phobias
Common side effects (often muscarinic): dry mouth, dry nose, blurry vision, lowered gastrointestinal motility or constipation, urinary retention
Buspirone for anxiety
moa?
slow or fast onset?
indication?
side effects?
5-HT1A receptor partial agonist
Slow onset of action but no withdrawal effects
Generalised anxiety disorder (e.g. if antidepressants fail), short-term, acute anxiety
Side effects: nausea, dizziness, headache, restlessness
beta blockers for anxiety
how do they help and what are they useful for?
Treats somatic symptoms. Useful for anxiety disorder with strong somatic symptoms e.g. social phobias, panic disorder
Generalised Anxiety Disorder (GAD): diagnosis
The DSM-V diagnostic criteria include:
- At least 6 months of excessive, difficult to control worry about everyday issues, that is disproportionate to any inherent risk, and causes distress, or impairment.
- The worry is not confined to features of another mental disorder, or as a result of substance abuse, or a general medical condition.
- The person experiences at least 3 of the following symptoms most of the time: restlessness/nervousness, being easily fatigued, poor concentration, irritability, muscle tension, or sleep disturbance.
The ICD-10 diagnostic criteria include:
- Anxiety which is generalised and persistent but not restricted to, or even strongly predominating in, any particular environmental circumstances.
- Variable dominant symptoms including persistent nervousness, trembling, muscle tension, sweating, lightheadedness, palpitations, dizziness, and epigastric discomfort.
- Expression of fears such as that the person or a relative will shortly become ill or have an accident.
GAD-7 questionnaire tool
- Scores of 5, 10, and 15 are taken as cut-off points for mild, moderate, and severe anxiety respectively.
what questions are asked in the GAD-7 questionnaire tool to assess severity of anxiety?
The person is asked ‘over the last 2 weeks, how often have you been bothered by any of the following problems?:
- Feeling afraid, as if something awful might happen.
- Becoming easily annoyed or irritable.
- Being so restless that it is hard to sit still.
- Trouble relaxing.
- Worrying too much about different things.
- Not being able to stop or control worrying.
- Feeling nervous, anxious, or on edge.
describe each step in the Stepped Care ladder for GAD
STEP 1: All known and suspected presentations of GAD. Identification and assessment; education about GAD and treatment options; active monitoring
STEP 2: Diagnosed GAD that has not improved after education and active monitoring in primary care (for those without marked functional impairment – based on assessment of severity). Low-intensity psychological interventions: individual non-facilitated self-help, individual guided self-help and psychoeducational groups
STEP 3: GAD with an inadequate response to step 2 interventions or marked functional impairment. Choice of a high-intensity psychological intervention (CBT/applied relaxation) or a drug treatment (typically SSRI sertraline) – see next slide
STEP 4: Complex treatment-refractory GAD and very marked functional impairment, such as self-neglect or a high risk of self-harm. Highly specialist treatment, such as complex drug and/or psychological treatment regimens; input from multi-agency teams, crisis services, day hospitals or inpatient care
Drug Treatment For GAD
Can be treated effectively with CBT or other psychological interventions
If drug therapy used, first line drug: SSRI e.g. sertraline (cost-effective, less interactions and risks than some other SSRIS, but not licensed for this indication so needs consent), escitalopram, paroxetine. 12 weeks then assess, possibly 6-12 months+
SNRIs also recommended alternatives e.g. duloxetine, venlafaxine
Pregabalin an option if SSRI/SNRIs not tolerated
Benzodiazepines only if necessary (typically not in primary care except in crisis)
- Fast-acting, short-term relief
- 2-4 weeks
- e.g. Alprazolam, Lorazepam, Oxazepam, Diazepam
Buspirone, short-term use only
give examples of Patient considerations when using pharmacotherapy, including follow-up and changes
- Expected effects of drug prescribed (e.g. SSRI)
- Gradual development of anxiolytic effect (1 week +)
- Risk activation from SSRI/SNRIs (anxiety, agitation, insomnia)
- Important to take as prescribed and continue after remission (1yr+) to avoid relapse
- Potential side effects of drug, interactions and withdrawal
- Risk suicidal ideation
- Monitoring
Follow-up: within 1 week, then every 2-4 weeks (3 months) then 3-monthly
Changes: Considered if no improvement, significant side effects, patient preference. If switching, many considerations (wash-out, interactions etc.) Note: If patient chose high-intensity psychological intervention but fails to improve, can offer drug therapy and vice versa. Can add non-pharmacological intervention if only partial improvement with drug therapy
