CNS: depression, BPD and anxiety disorders (spring)

Question 1

what are the three broad categories of brain function?

Answer 1

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.

Question 2

what are the three Anatomical Brain Planes?

Answer 2

Coronal (frontal)

Horizontal (transverse)

Sagittal

Question 3

what is grey matter and white matter?

Answer 3

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)

Question 4

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?

Answer 4

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.

Question 5

name the cortical lobes and a briefly state what each is involved in

Answer 5

frontal lobe: higher, executive functions

parietal lobe: integration sensory information

temporal lobe: processing sensory information

occipital lobe: visual processing

Question 6

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?

Answer 6

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

Question 7

describe the roles of the Thalamus, Hypothalamus, Hippocampus and Amygdala

Answer 7

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

Question 8

Basal Ganglia

what are they?

what are they responsible for?

main components of the Basal Ganglia?

what is Basal Ganglia dysfunction associated with?

Answer 8

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.

Question 9

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?

Answer 9

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

Question 10

what do ascending and descending pathways in the relay station do?

Answer 10

Ascending pathways carry information to the brain

Descending pathways carry information to the periphery

Question 11

label the parts of the brain stem

Answer 11

Question 12

What’s the difference between Psychiatry and Neurology?

Answer 12

Question 13

cell types that comprise the CNS

Answer 13

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)

Question 14

describe the roles of Astrocytes, Oligodendrocytes, and Microglia

Answer 14

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

Question 15

Blood Brain Barrier

what is the Blood Brain Barrier?

how is it formed?

how are different molecules transported?

Answer 15

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…)

Question 16

give structural features of Neurons

Answer 16

Dendrites

• Basal
• Apical

Cell body

• Nucleus

Axon

• Initial segment
• Hillock
• Myelin Sheath
• Node of Ranvier

Nerve terminals

• Presynaptic terminal

Question 17

what differences in neurons can you get?

Answer 17

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

Question 18

how are neuronal signals carried in the body?

what causes the neuronal signal?

Answer 18

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.

Question 19

The Cell Membrane

function?

is the cell membrane lipophilic or hydrophilic and what properties does this give?

what is the voltage?

Answer 19

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)

Question 20

How are Ions Distributed in the cell?

Answer 20

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

Question 21

How do Ions Cross the Membrane?

Answer 21

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)

Question 22

describe the movement of Sodium (Na+), Potassium (K+), and Chloride (Cl-) ions into and out of cells.

Answer 22

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

Question 23

what is The Action Potential and what is it responsible for?

what is an action potential reliant upon?

Answer 23

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

Question 24

how does a Post-synaptic Potential work?

Answer 24

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

Question 25

compare Excitatory and Inhibitory Responses

Answer 25

**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)

Question 26

what determines whether an action potential (AP) will fire or not?

Answer 26

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

Question 27

describe what happens in an Action Potential using glutamate as an example

Answer 27

1. Resting neuron membrane potential at -70mV 2. Glutamate released from presynapse 3. Activates AMPA/kainate receptors, influx of Na+ leading to depolarisation 4. Cell depolarises (NMDARs slower and voltage-dependent) 5. Resulting depolarisation called an excitatory postsynaptic potential (EPSP) 6. Subsequent APs can occur before Vm returns to rest and summate 7. 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 8. All or nothing 9. For inhibitory NT (e.g. GABA), instead get inhibitory PSPs (IPSPs)

Question 28

summarise an Action Potential

Answer 28

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

Question 29

what does electrochemical transmission tranduce?

Answer 29

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

Question 30

what type of neurotransmitter is glutamate? what receptors does glutamate act at?

Answer 30

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

Question 31

what is another name for GABA?? what type of neurotransmitter is it? which receptors does GABA act at?

Answer 31

g-amino-butyric acid principal inhibitory neurotransmitter acts at ionotropic (GABAA) and metabotropic (GABAB) receptors

Question 32

apart from glutamate and GABA, name neurotransmitters/ receptors

Answer 32

endocannabinoids, adenosine, glycine, acetylcholine, **dopamine**, **noradrenaline**, **serotonin** (5-HT), peptides, hormones etc.

Question 33

what happens after Ionotropic receptor activation?

Answer 33

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)

Question 34

what type of receptors are Metabotropic neurotransmitter receptors and what does this mean? what determines the downstream effect?

Answer 34

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).

Question 35

give examples of small NTs and large NTs

Answer 35

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)

Question 36

Ionotropic vs Metabotropic Receptors

Answer 36

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

Question 37

give examples of Ionotropic and Metabotropic Glutamate Receptors

Answer 37

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)

Question 38

what types of receptors are GABA_AR and GABA_BR? what does GABA binding cause at the GABA_AR receptor? what does GABA_BR stimulate and inhibit?

Answer 38

GABA_AR 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 GABA_BR is metabotropic, GPCR, Gi/G0-coupled * stimulates GIRKs (GPCR-coupled Potassium channels) and inhibit VGCC (voltage-gates calcium channels)

Question 39

name NT receptors and their receptor type

Answer 39

**GABA**: GAB_AAR (ionotropic); GABA_BR (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)

Question 40

what does Activation of presynaptic Neurotransmitter receptors lead to?

Answer 40

Activation of these receptors tends to decrease further release of neurotransmitter from the presynaptic cell. (negative feedback)

Question 41

give examples of affective disorders define affect and mood

Answer 41

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

Question 42

What is Depression?

Answer 42

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

Question 43

how are genes and environment related to depression?

Answer 43

Family history is common in depression Genetic and/or environmental components Temperament/personality

Question 44

what is each of these neurotransmitters related to? Noradrenaline (norepinephrine, NA, NE) Serotonin (5-hydroxytryptamine, 5-HT) Dopamine

Answer 44

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**

Question 45

criteria for Diagnosis of Depression

Answer 45

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

Question 46

what two questions should HCPs ask people who may have depression? what happens if patients answer yes to either of these?

Answer 46

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)

Question 47

compare diagnosis with ICD-10 and DSV-IV

Answer 47

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

Question 48

give the ICD-10 and DSV-IV scores for different classes of depression (sub-threshold, mild, moderate, severe, persistent sub-threshold)

Answer 48

Persistent sub-threshold - at least 2 and \<5 symptoms for at least 2 years (sometimes referred to as dysthymia)

Question 49

what are the 3 principle treatment types for depression? Criteria for determining most appropriate? what is the most common apptoach?

Answer 49

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

Question 50

for the 4 stepped care model give the Focus of Intervention and Nature of Intervention for each step

Answer 50

Question 51

Examples of Psychological & Psychosocial Treatments for depression

Answer 51

**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)

Question 52

which therapies are preferred for sub-threshold and mild depression and why?

Answer 52

Low intensity psychosocial therapies preferred approach for sub-threshold and mild depression as risk-benefit ratio for use of antidepressants is considered poor

Question 53

which Antidepressants are used for Treating Depression?

Answer 53

**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

Question 54

name 8 types of pharmacological therapy used to treat depression

Answer 54

* 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)

Question 55

what are Significant distinguishing features between drugs typically based on?

Answer 55

Antimuscarinic, anti-adrenergic and antihistaminic activity (adverse effects) Sedative action (not linked to any single transmitter) Cardiotoxic and/or convulsant action in overdose

Question 56

SSRIs examples? efficacy? onset? side effects? another indication?

Answer 56

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

Question 57

Tricyclics (TCAs) examples? moa? onset? side effects?

Answer 57

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

Question 58

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):

Answer 58

Sertraline for depression/GAD: 5**0mg, 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: 1**0mg 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​**

Question 59

what is the moa of: SSRIs SNRIs NaSSa

Answer 59

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)

Question 60

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:

Answer 60

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)

Question 61

give the moa for: TCAs: SARIs: SMS: NRI: MAOIs/RIMA:

Answer 61

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.

Question 62

what is Electroconvulsive Therapy (ECT) used for?

Answer 62

Severe psychotic depression Bipolar disorder with psychotic symptoms

Question 63

Future Changes/Current Research for depression treatment

Answer 63

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

Question 64

what is the 4 step Treatment Strategy for depression?

Answer 64

**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

Question 65

**Patient Advice and Care if Prescribed Antidepressants...** what is important to highlight when Initiating therapy? Follow-up? Changes? Switching?

Answer 65

**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.

Question 66

what is bipolar disorder?

Answer 66

repeated episodes of mania (or hypomania) and depression

Question 67

symptoms of mania how long does an attack last?

Answer 67

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

Question 68

how do you classify bipolar disorder and what are the 2 classes?

Answer 68

Classification: ICD-10 (or DSM-IV) criteria used to define Bipolar I disorder = more severe mania Bipolar II disorder = hypomania (mania less severe)

Question 69

according to NICE guidance, BPD is suspected if the individual has had any symptoms of...

Answer 69

(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.

Question 70

Mania is suggested by...

Answer 70

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)

Question 71

Diagnosis of a manic episode requires symptoms of mania lasting ...

Answer 71

Diagnosis of a manic episode requires symptoms of mania lasting for at least 7 days which usually begin abruptly

Question 72

Hypomania is suggested by ...

Answer 72

symptoms of mania that are not severe enough to cause marked impairment in social or occupational functioning, and the absence of psychotic features.

Question 73

Diagnosis of a hypomanic episode requires symptoms to last...

Answer 73

for at least 4 days

Question 74

A mixed episode is suggested by... Depression is suggested by...

Answer 74

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.

Question 75

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?

Answer 75

'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?’

Question 76

what are the aims of BPD treatment?

Answer 76

Control manic and depressive attacks Minimise recurrence and stabilise mood

Question 77

how do you Control manic attacks? ## Footnote Prophylaxis for long-term treatment including mood stabilising drugs and psychological interventions (e.g. CBT). Mood stabilisers include:

Answer 77

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

Question 78

Treatments for Mania and BPD

Answer 78

**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

Question 79

_Lithium (carbonate) for acute mania or bipolar disorder and BPD prophylaxis_ 1. why does it need careful monitoring? 2. monitoring requirements? 3. toxic conc? 4. what does a Sustained release formulation help with? 5. how long does it take to have an effect? 6. side effecs? how would you reduce these? 7. interactions? 8. moa?

Answer 79

1. very narrow therapeutic window 2. 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) 3. Toxic at \>1.5mmol/L but can have toxicity at lower (therapeutic) doses 4. Sustained release formulations help avoid high peak plasma concentrations 5. Takes 2-3 weeks to have effect 6. Many side effects can include renal, endocrine, cardiac, neurological – reduced by lowering dose 7. Drug interactions can affect levels (NSAID, diuretics, ACE inhibitors) 8. MoA not fully understood, may include neuroprotection, modulation of neurotransmission, inhibition of GSK-3B or reduction of Inositol

Question 80

what do Antipsychotics do? examples?

Answer 80

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)

Question 81

what do Antiepileptic/anticonvulsants do? examples and side effects?

Answer 81

* 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

Question 82

what is initial mania treatment? what if this is ineffective? treatment for depression in this period? what happens after resolution of the acute episode?

Answer 82

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)

Question 83

What is anxiety?

Answer 83

“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”

Question 84

what are the Two opposing views of causes of anxiety?

Answer 84

Psychiatrists: conflict between primitive urges and socialised/civilised behaviours Biologists: biochemical dysfunction (e.g. monoamine neurotransmitters)

Question 85

Anxiety serves a useful function in day to day life. It becomes aberrant when...

Answer 85

a threat is real but the response is disproportionate the threat is imagined

Question 86

List Anxiety mediators

Answer 86

serotonin, noradrenaline, dopamine and GABA in CNS. Also PNS involvement

Question 87

symptoms of anxiety

Answer 87

Anxiety, worry, despondency, sadness, somatic symptoms (PNS), sleep disturbance Symptoms can be e.g. behavioural, physiological, cognitive or affective

Question 88

Clinical features of anxiety

Answer 88

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

Question 89

types of Generalised anxiety disorder (GAD)

Answer 89

Social phobia Specific phobias Obsessive compulsive disorder (OCD) Panic disorder (PD) Post traumatic stress disorder (PTSD)

Question 90

Treatment aims for anxiety

Answer 90

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

Question 91

Psychological Treatments for anxiety

Answer 91

* 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

Question 92

Pharmacological treatment for Acute Anxiety

Answer 92

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

Question 93

_Benzodiazepines for anxiety_ moa? fast or slow acting? what effect do they have on the body? adverse effetcs?

Answer 93

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)

Question 94

pregabalin for anxiety moa? indications?

Answer 94

inhibition at auxillary a2d subunit of voltage-gated calcium channels, VGCC). GAD, also for epilepsy

Question 95

Tricyclic antidepressants for anxiety give an example and what is it used to treat? common side effects?

Answer 95

Clomipramine – obsessions, phobias Common side effects (often muscarinic): dry mouth, dry nose, blurry vision, lowered gastrointestinal motility or constipation, urinary retention

Question 96

Buspirone for anxiety moa? slow or fast onset? indication? side effects?

Answer 96

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

Question 97

beta blockers for anxiety how do they help and what are they useful for?

Answer 97

Treats somatic symptoms. Useful for anxiety disorder with strong somatic symptoms e.g. social phobias, panic disorder

Question 98

Generalised Anxiety Disorder (GAD): diagnosis

Answer 98

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.

Question 99

what questions are asked in the GAD-7 questionnaire tool to assess severity of anxiety?

Answer 99

The person is asked 'over the last 2 weeks, how often have you been bothered by any of the following problems?: * 1. Feeling afraid, as if something awful might happen. * 2. Becoming easily annoyed or irritable. * 3. Being so restless that it is hard to sit still. * 4. Trouble relaxing. * 5. Worrying too much about different things. * 6. Not being able to stop or control worrying. * 7. Feeling nervous, anxious, or on edge.

Question 100

describe each step in the Stepped Care ladder for GAD

Answer 100

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

Question 101

Drug Treatment For GAD

Answer 101

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

Question 102

give examples of Patient considerations when using pharmacotherapy, including follow-up and changes

Answer 102

* 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