Serotonin, Some Migraine, Depressive disorders, Perinatal

Clinical features of major depression

Emotion symptoms

- Depressed mood

- Anhedonia

Vegetative symptoms:

- Significant weight loss or gain/decrease or increase appetite

- Insomnia or hypersomnia

- Psychomotor agitation or retardation

Cognitive symptoms:

- Feeling of worthlessness/excessive or inappropriate guilt

- Inability to concentrate/indecisive

- Recurrent thoughts of death/ suicide

A diagnosis can be made if patient has a depressed mood or anhedonia + 3 other symptoms for 2 weeks

Symptoms may take days-weeks to develop - prodrome can include anxiety and mild depressive symptoms

Children: irritable

major neurotransmitters

- Noradrenaline

- Serotonin (5-HT)

- Dopamine

- GABA

Anhedonia (negative symptom)

inability to experience pleasure or joy

Depressed mood

Feeling of sad or empty, hopeless, tearful, irritable

Neural circuitry that regulates mood

1. Frontal cortex (FC) and hippocampus (HP) involved in cognition

2. Nucleus accumbens (NAc - rewarding) and amygdala (Amy - aversive) involved in emotion

3. Hypothalamus (Hyp) and monoamine brainstem nuclei (DR,LC) involved in vegetative symptoms. E.g. appetite and energy

Catecholamines (monoamine)

- Noradrenaline (NA)

- Adrenaline

- Dopamine (DA)

Characterised by the catechol ring

Indoleamines (monoamine)

- Serotonin (5-HT)

Characterised by the indol ring (middle ring)

Serotoninergic Synapse

Key steps at the synapse:

1. Synthesis of serotonin from L-tryptophan

2. The packaging of serotonin into the vesicles

3. Release of serotonin into the synapse

4. Action of serotonin at its various receptors

5. Reuptake of serotonin via high affinity transporters

6. Degradation of serotonin via degradative enzymes. Occurs in presynaptic neurons and surrounding cells

Serotonin synthesis

L-Tryptophan 1- -> 5-hydroxytryptophan (5-HTP) 2- -> serotonin (5-HT)

Addition of hydroxy group into the 6 membered ring at step 1. Decarboxylation of 5-HTP COOH to give serotonin 5-HT

*Enzyme:

1. Tryptophan hydroxylase (cytoplasm, rate limiting)

2. L-aromatic acid decarboxylase (dopa decarboxylase, cytoplasm)

Serotonin storage

- Active transport into vesicles (1.1M) via VMAT (vesicular monoamine transporter)

- Stored in a way that prevents leakage out of the vesicle into the cytoplasm.

- Active storage

- Often driven by H+ electrochemical gradient across vesicular membrane generated by ATP-dependent H+ pump

Serotonin release

TRADITIONAL SYNAPTIC RELEASE

1. Terminal depolarisation via action potential moving down the neuron

2. Ca2+ channels open and Ca2+ enters

3. Ca2+ entry promotes fusion of vesicles with the cell membrane

4. Exocytosis of monoamine from vesicles into the synaptic space

Serotonin and Noradrenaline (NA) release

Diffusely projecting neurotransmitters:

- Modulatory aerosol: large amount of serotonin can be released from varicosities into extracellular space addition to the traditional synaptic release.

- In this way serotonin can reach a lot more areas along its projection route.

- Concentration gradients in projection areas of varicosities

VARICOSITY RELEASE

- Varicosities: buds that come off axons in projection pathways

- Release large amounts of NA/5-HT into extracellular space - allows activation of receptors on nearby neurons

BASELINE TONE OF RELEASE AND ACTIVITY in target neurons due to spontaneous firing of cells releasing 5-HT

- spontaneous/tonic firing

- continuous, low-level release of serotonin in the absence of specific synaptic activity

- slower tonic firing allows for integration of information over a longer period of time

Specific stimuli can elicit rapid bursts, superimposed on baseline "tone"

- rapid and discrete neuronal firing akin to traditional neurotransmission

Serotonin pathway

Key regions: hypothalamus, hippocampus, and amygdala

- also important: septum, thalamus, cortex,cerebellum

Serotonin receptors

5HT1-4

All serotonin receptors are excitatory except 5-HT 1

When serotonin binds to its receptors, the down stream effect is slower as GPCRs require activation of second messengers and phosphorisation of "stuff".

Most of 5-HT receptors are modulators, except 5-HT 3

5-HT3: ligand gated ion channels, really fast transmission, mediate function.

5- HT1 Transduction mechanism

Mainly Gi coupled- decrease adenylate cyclase activity to decrease cyclic AMP

5-HT 1 clinically useful drugs

5- HT1A agonist for anxiety: buspirone

5- HT1D agonist for migraine: sumatriptan

5-HT2 Transduction mechanism

Mainly Gq coupled - increase phospholipase C activity to increase IP3/DAG

5-HT 2 clinically useful drugs

5-HT2A,C antagonist for migraine prophylaxis: pizotifen, mianserin

5-HT2A antagonist antagonist for anti psychosis: clozapine

5-HT3 transduction mechanism

Ligand- gated ion channel - conducts Na+

5-HT3 clinically useful drugs

5-HT3 antagonist for antiemesis: ondansetron

5-HT 4 transduction mechanism

Mainly Gs coupled - increase adenylate cyclase activity to increase cyclic AMP

5-HT4 clinically useful drugs

5-HT4 agonist for gastroesophageal reflux: cisapride

5-HT4 agonist for irritable bowel syndrome (IBS): tegasarod

Serotonin Re-Uptake

Active transport into neurons via high affinity Na+- dependent membrane transporter protein (SERT)

Main mechanism for terminating serotonin synaptic action

Serotonin Degradation

5-HT 1- -> 5- hydroxyindole acetaldehyde 2 - -> 5- hydroxyindole acetic acid (5-HIAA)

*enzyme:

1. Monoamine oxidase

2. Aldehyde dehydrogenase

5-HIAA: metabolite measured in urine to understand serotonin turnover

Serotonin effects in the nervous system

Hallucinations (visual/ auditory cortex, brainstem)

Sleep, wakefulness (brainstem, hypothalamus)

Mood and anxiety (limbic system)

Feeding behaviour (hypothalamus)

Regulation of body temperature and blood pressure (hypothalamus)

Control of sensory transmission and nociception (spinal cord, brain stem, cortex)

Centrally mediated GIT function (brainstem)

Clinical roles for drugs acting on 5-HT

Anxiety

Depression

Eating disorders

Pain

Migraine

Nausea, emesis

GI disorders (IBS, reflux)

monoamine theory of depression

- a theory that hypothesise depression is caused by a functional deficit of monoamines at certain sites in the brain (not enough monoamine being released)

- Destroyed by pre-synaptic MAO (DA, NA, 5-HT) & synaptic COMT (NA, DA)

- hypo-noradrenergic and hypo-seretoninergic state leads to receptor hyper-responsiveness -> reinstating homeostasis

Antidepressants increase synaptic levels of NA and 5-HT to normal levels

AND down regulates receptors to normal levels accounts for slow action of drugs

Neuroplasticity/ neurotrophic hypothesis

Suggests that depression may be associated with changes in neuroplasticity and the functioning of neurotrophic factors in the brain

Neurogenesis - formation of new neurons from stem cell precursors in lateral ventricles and dentate gyrus (hippocampus formation)

Key players are BDNF (brain derived neurotrophic factors) and TrkB receptors

- Major role in birth, survival and maturation of neurons

5-HT and NA promote neurogenesis (likely via 5-HT1A, 5-HT2B and alpha 2, beta receptors), possibly mediated by BDNF

Stress and depression associated with

- decreased BDNF and TrKB receptors

- decreased neurogenesis (↓ cell proliferation, survival, and differentiation)

- genetic polymorphism in BDNF which predicts depression chronicity

DRUGS:

- Monoamine reuptake inhibitors

- Monoamine oxidase inhibitors (MAOIS)

(Neuroplasticity/ neurotrophic hypothesis) Stress and depression are associated with:

- Neuronal loss in the hippocampus and prefrontal cortex

Imaging studies of pt show neurodegeneration in these regions

- Decreased BDNF and TrKB receptors

- Decreased neurogenesis

Decreased cell proliferation, survival and differentiation

Depression may be related to a generic polymorphism in BDNF which predicts chronicity

DRUGS:

- Tetracyclic antidepressants

- Multimodal activity drugs: Serotonin reuptake inhibitors and 5-HT1 receptor agonist/partial agonist

antidepressant drug class

- Monoamine reuptake inhibitors

- Monoamine oxidase inhibitors (MAOIS)

- Tetracyclic antidepressants

- Multimodal activity drugs: Serotonin reuptake inhibitors and 5-HT1 receptor agonist/partial agonist

Monoamine reuptake inhibitors

- Tricyclic antidepressants (TCAs)

- Selective serotonin reuptake inhibitors (SSRIs)

- Serotonin and noradrenaline reuptake inhibitors (SNRIs)

- Noradrenaline reuptake inhibitors (NRIs)

TCA examples

Amitriptyline

Clomipramine

Doxepin

Imipramine

Dothiepin

Nortriptyline

Trimipramine

MOA of TCAs

Block the re-uptakeof 5HT & NA into the pre-synaptic terminals

Indication of TCAs

Depression

Urge incontinence (anti-cholinergic effect)

Nocturnal enuresis

Adjunct in pain medications

ADHD

Migraine prophylaxis

AE of TCAs

- Anticholinergic effects- especially in elderly

- Sedation

- Dry mouth

- Blurred vision

- Constipation

- Urinary retention

- Cardiotoxicity

- QT interval prolongation

- Increased heart rate

- Postrual hypotension

- Arrythmia

- Slows cardiac conduction

- Reduced seizure threshold

Less hypotension and ADR in elderly with nortriptyline

TCA counseling points

Efficacy limited by AE

CV screen before use

Anticholinergic (esp elderly), sedation, dry mouth, blurred vision, constipation, urinary retention, cardiotoxicity, QT interval prolongation, increase in heart rate, postural hypotension, arryhthmia, slows cardiac conduction, reduced seizure threshold

- Nortriptyline - less hypotension / ADRs in elderly

TCA withdrawal symptoms

Cholinergic rebound: hypersalivation, runny nose, abdominal cramping, diarrhoea, sleep disturbance

MORE LIKELY: amitriptyline, doxepin

SSRI MOA

Selectively inhibit pre-synaptic 5HT reuptake = ↑ 5HT in synaptic cleft

SSRIs examples

Citalopram

Escitalopram

Fluoxetine

Paroxetine

Sertraline

Fluvoxamine

Dapoxetine

Indication SSRI

Major depression

Anxiety disorders (e.g. OCD)

Bulimia nervosa

Premenstrual dysphoric disorder (severe PMS)

PTSD (paroxetine)

Practice points SSRI

Generally equi-effective for depression

Little difference in efficacy or tolerability within class or between other classes

Limited value in increasing dose beyond recommended dose

Insomnia (except fluvoxamine, paroxetine)

- Fluoxetine: longer t1/2 than others SSRIs -> withdrawal effects unlikely BUT requires a longer washout period before new antidepressant is commenced (14 days)

Suicidal thoughts on initiation

May reduce seizure threshold -> increased risk

May provoke manic episode

Bleeding risk in elderly (>80yrs)

Not approved in children with depression

- increased risk of suicidal ideation

- Fluvoxamine, sertraline: approved for OCD

Potential DDI (SSRI)

CYP1A2 inhibitor: fluvoxamine (strong)

CYP2D6 inhibitor: clomipramine, fluoxetine (strong), paroxetine (strong), sertraline (weak)

CYP3A4 inhibitor: fluvoxamine

AE of SSRI

• Nausea

• Agitation

• Insomnia - take mane

• Drowsiness - fluvoxamine, paroxetine

• Tremor

• Dry mouth

• Diarrhoea

• Dizziness

• Headache

• Sweating

• Asthenia - loss of strength / energy

• Anxiety

• Weight gain / loss

• Sexual dysfunction

• Rhinitis

• Myalgia

• Rash

Serotonin toxicity

Causative drugs: antidepressants, SJW, opioids (fentanyl, pethidine, tramadol, dextromethorphan), lithium, tryptophan. Phentermine, linezolid

Symptoms: increasing severity

• Restlessness

• Diaphoresis / sweating

• Tremor

• Shivering

• Myoclonus - sudden involuntary muscle contraction / jerk of limb

• Confusion

• Convulsions

• Death

SSRI and SNRI withdrawal symptoms

Dizziness, nausea, paraesthesia, anxiety, agitation, tremor, sweating, confusion, electric shock sensations

MORE LIKELY: paroxetine

LEAST LIKELY: fluoxetine

SNRI: venlafaxine more likely

SNRI examples

Venlafaxine

Desvenlafaxine

Duloxetine

MOA of SNRIs and TCAs

block reuptake of serotonin and norepinephrine - TCAs are non-selective and block the reuptake of various neurotransmitters, while SNRIs are more selective and primarily target serotonin and norepinephrine

Indication of SNRI

Major depression

Extra indication:

- Venlafaxine: Generalised anxiety disorder, Panic disorder, Social phobia

- Duloxetine: Generalised anxiety disorder, Painful diabetic peripheral neuropathy

AE of SNRI

nausea

dry mouth

constipation

yawning

sweating

dizziness

increased BP (infrequent with duloxetine)

weakness

sexual dysfunction (eg impotence), decreased libido, somnolence (sleepy), insomnia (no sleepy)

headache

blurred vision

tremor

decreased appetite

rash

Practice points for SNRI

- Taper dose over at least 4 weeks in order to minimise risk of withdrawal effects; these are more common with venlafaxine

- Increased suicidal thoughts and behaviour can occur soon after starting antidepressants, particularly in young people; monitor patients frequently and carefully early in treatment

whenever practical, and especially after completing a course of treatment

- check BP before starting treatment, and then check regularly, particularly if using desvenlafaxine or venlafaxine

- consider checking sodium concentration at baseline, and then soon after starting treatment, especially if at risk for hyponatraemia, eg elderly

Tetracyclic Antidepressants examples

Mirtazapine

MOA

- Blocks post-synaptic 5HT2/3 receptors

- Blocks pre-synaptic a2- adrenergic autoreceptors -> enhances NA

- Withdrawal (rare/not observed in others): anxiety, headache, dizziness, nausea

Mianserin

MOA of MAOIs

Inhibit MA breakdown = ↑ NA, DA, 5HT

1) NON-SELECTIVE: irreversibly inhibit MAO‑A and MAO‑B, increasing synaptic conc of Ad, NA, DA, 5HT

- Phenelzine, Tranylcypromine

- binds covalently to MAO-A and MAO-B

- Strong bonds that last a long time, and hard to break due to non-selectivity and irreversible covalent bond.

- Increase risk of toxicity if there's other amine from diet that cant be broken down

2) SELECTIVE: Moclobemide competitively and reversibly inhibits MAO; relatively selective for MAO‑A. increasing synaptic conc of NA, DA, 5HT

- Moclobemide; binds reversibly and selectively to MAO-A

Indication MAOIs

Third-line(AMH):

Major depression (third line)

Some anxiety disorders, including phobic disorders and panic disorder (seek specialist advice)

Second-line (Tim Chen): depression, anxiety disorders (panic disorder, phobias)

Snowflake things for MAOIs

Avoid food containing tyramine while taking MAOIs and 2 weeks after stopping --> hypertensive crisis -- MAO break down tyramine; tyrmaine build-up =. hypertensive crisis; fatal increase in BP; severe headache, palpitations, chest pain

- Mature, aged cheese or out of date cheese

- Fermented, matured or aged meat product: salami

- Protein extracts

- Yeast extracts: vegemite

- Soy bean extracts: tofu, miso

Food containing amides:

- Broad beans (oh no i love broad beans)

- Sauerkraut

- Pickled herring

- Some alcoholic drink

Withdrawal symptoms of MAOIs

Nausea and vomiting

Nightmares

Panic

Restlessness

Hallucinations

Tranylcypromine: delirium, especially if pt is dependent

Multimodal action

Vortioxetine

Vilazodone

Vortioxetine

MOA

- Inhibits 5-HT re-uptake, 5HT-3 antagonist, 5-HT1A re-uptake - antidepressant & anxiolytic

Limited safety and efficacy data especially in elderly

Limited information about use in hepatic and renal impairment

Counsel on dizziness, effects on driving and skilled tasks, esp when starting/changing dose

May be ceased abruptly without tapering

Agomelatine (Valdoxan)

MOA

- Melatonin receptor agonist (MT1, MT2) and 5HT2c receptor antagonist

Similar efficacy to other antidepressants - consider when others not tolerated or failed

Suicidal thoughts and behaviour on initiation

LFTs - baseline, 6, 12 and 24 weeks - cease if aminotransferases >3x ULN

Limited abuse potential or withdrawal effects

CYP1A2 substrate

- Inhibitors: fluvoxamine, ciprofloxacin

- Inducers: omeprazole, smoking (so increases agomelatine metabolism)

Products: tab, 25 mg (orange), 28, Valdoxan (SE)

How do monoamine reuptake inhibitors works? (SSRI, SNRI,NRI)

Presynaptic:

Block presynaptic NA and/or 5-HT transporters

Postsynaptic:

Increase levels of NA & 5-HT in the synapse

At therapeutic doses they bind with higher affinity (strength of binding) to histamine, 5-HT, muscarinic acetylcholine receptors, and alpha- adrenoceptors -> side effects

- particularly TCAs

How Do Tetracyclic Antidepressants Work?

block alpha- adrenoreceptors and antagonise 5-HT2 & 5-HT3 receptors -> increase NA & 5-HT release -> preferred action on 5-HT1

*The alpha 2 adrenoceptor prevent the release of noradrenaline when they are binded (negative feedback loop). The blockage of these action increase the release of NA and 5-HT

How do Multimodal Action Antidepressants Work?

block presynaptic 5-HT transporters = increase 5-HT release PLUS agonise (vortioxetine) or partially agonise (vilazodone) 5-HT1A receptors

Long Term Effects of Antidepressants

Down-regulation of postsynaptic NA (b- adrenoceptors) and/or 5-HT receptors

- reduction in receptor binding sites

- reduction in agonist response

Increase activity/sensitivity of post synaptic 5-HT1 receptors in hippocampus (except MAOIs )

Decrease activity/sensitivity of presynaptic alpha 2 adrenoceptors and/or 5-HT1 receptors (inhibitory receptors which control NA and 5-HT release)

- Facilitate monoamine release into synapse

Antidepressants & Monoamine theory

Net effect of chronic treatment is an enhancement of monoaminergic function

- optimise monoamine levels and restore optimal receptor sensitivity

- boosting serotonin levels and reducing receptor concentrations -> no longer hyperresponsive

Slow adaptive changes correspond to the time-course of therapeutic effect

- beta 2 adrenoceptors downregulated

- 5-HT2 receptors downregulated

- alpha 2 adrenoceptors downregulated

Antidepressants & Neuroplasticity/Neurotrophic Hypothesis

Antidepressants enhance BDNF signalling, TrKB receptors and neurogenesis

- BDNF stimulates gene transcription of SERT and tryptophan hydroxylase in raphe nuclei

- 5-HT receptor activation stimulates BDNF expression

- by increasing 5-HT synthesis, release and cell function, antidepressants may work to restore network function - -> mood

5-HT and noradrenaline promote neurogenesis

- 5-HT1A and 5-HT2B stimulation

- b-adrenoceptor stimulation

- a2-adrenoceptor blockade

Neurogenic inflammation theory of migraine

1) Activation of nociceptors (triggers for this: changes in blood flow or chemical imbalances in the brain etc)

2) Neuropeptides released: substance P and CGRP)T

3) Substance P and CGRP have vasodilatory effects = increased blood flow to the area, including brain's blood vessels.

4) Neuropeptide release also triggers inflammatory response in surrounding tissues -- inflammation can affect the blood vessels, nerves etc

The combination of vasodilation, inflammation, and irritation of nerves contributes to migraine

Common inflammatory mediators: Substance P, CGRP, 5HT, prostaglandins, bradykinins

[abnormalities in] trigemino-cerobrovasclar system:

- trigeminal nerves/ganglia

- major vessels for regulating cerebral blood flow

- smaller vessels in meninges

understanding: migraine can be triggered by a lot of things. Migraine involves sensitisation of not normally nociceptive (pain) stimuli and also have lower threshold of pain.

Role of 5-HT in migraine

Sharp increase in urinary 5-HIAA during attack

Platelet concentration of 5-HT falls

Migraine sufferers show perturbation of 5-HT metabolism and transmission

5-HT1B and 5-HT2 receptors found on intracranial blood vessels

- 5-HT1B => vasoconstriction

- 5-HT2 => indirect vasodilation

Trigeminal ganglion & nucleus are rich in 5-HT1B/1D/1F receptors

Drugs used to treat migraines (Acute attack)

NSAIDs

Ergotamines ("no one uses them anymore", skip)

Triptans

TCAs

nociceptive fibres

nociceptive receptors response to extreme stimuli of pain. inflammatory mediators: 5-HT, prostagladin, bradykinin CGRP, substance P

Triptans

sumatriptans, zolmitriptan, rizatriptan, eletriptan, naratriptan

sumatriptan cant cross BBB

MOA: 5-HT1B/1D/1F agonist

5- HT1 are inhibitory -> inhibition of further inflammation by:

- inhibit trigeminal nerve transmission peripherally (ganglia) and centrally (trigeminal nucleus caudalis)

- inhibit release of vasoactive peptides from meningeal blood vessels

-stimulate 5-HT1B receptors -> vasoconstriction

tricyclic antidepressants

5-HT and NA transport inhibitors -> decrease 5-HT and NA conc -> inhibition of spinothalamic neurons

neurogenic inlammation theory of migraine

1. c-fibres (nociceptive fibres) -> release Calcitonin gene-related peptide (CGRP) in response to stimuli -> intrcranial blood vessles contrict

however, CGRP is a vessle dilator -> tries to dilate blood vessles again -> risk of plasma protein leakage

at the same time, mast cell degranulation -> secretes 5-HT, bradykinin, histamine, prostagladins

--> both contributes to 'inflammatory soup'

---> leads to neurogenic inflammation and peripheral sensitisation -> lowers threshold to pain respone

----> back to 1.

side note: during a migraine, the release threshold of CGRP to non-nociceptive stimuli is lowered

Triptans inhibitory effects

1. inhibiting the release of neuropeptides (e.g CGRP, SP,NO) from trigeminal ganglia

2. inhibiting activation of trigeminal ganglia

3. inhibiting transmission from trigeminal ganglia

4. inhibiting transmission to the trigeminal nucleus caudalis

Contributing factors to depressive disorders

Family history

Biochemical factors (brain chemistry)

Illness

Personality style

Ageing

Long-term pressures (abusive relationships, bullying, work stress)

Stressful or traumatic events

Diagnostic Criteria for Major Depressive Disorder

DSM-V: ≥5 symptoms during the same 2-week period (at least 1 is depressed mood or loss of interest/pleasure) (NOT INCLUDING symptoms attributable to another condition):

- Depressed mood

- Diminished interest or pleasure

- Significant weight loss

- Insomnia or hypersomnia

- Psychomotor agitation or retardation

- Fatigue or loss of energy

- Feelings of worthlessness or excessive or inappropriate guilt

- Diminished ability to think or concentrate, or indecisiveness

International Classification of Diseases (ICD)-101:

- Mild: ≥4 symptoms

- Mod: 6-7 symptoms

- Severe: ≥8 symptoms

Treatment for depressive disorders

Biopsychosocial and Lifestyle Model

BIOLOGICAL - antidepressants, antipsychotics, mood stabilisers, electroconvulsive therapy, transcranial magnetic stimulation

o 1st line: SSRIs - better tolerated than TCAs and MAOIs

o 2nd line: SNRIS - less well tolerated than SSRIs but better tolerated than TCAs

PSYCHOSOCIAL - CBT, interpersonal therapy, mindfulness, acceptance

SOCIAL - family/friends psychoeducation, support/community groups, caregivers, employment, housing

LIFESTYLE - exercise, diet, sleep, alcohol/smoking/drug cessation, managing substance abuse

Drug choice based on clinical profile (depressive disorders)

Anxiety - SSRIs, SNRIs

Cognitive difficulties - Duloxetine, Vortioxetine

Sleep disturbance - Agomelatine, Mirtazapine

Fatigue - Bupropion

Pain - Duloxetine, TCAs

Melancholia - TCAs

Atypical (increased sleep/appetite) - MAOIs

Psychotic symptoms - antipsychotic meds in addition to antidepressant

Changeover Category A

fluoxetine, vortioxetine

Drug/metabolite with long t1/2

- No gradual withdrawal needed, withdrawal symptoms unlikely

- Wait at least 24 days (fluoxetine up to 5 wks) before starting next antidepressant

- Severe depression: consider hospitalisation during washout/changeover

Changeover Cat B

(TCAs, SSRIs (except fluoxetine), mianserin, mirtazapine)

t1/2 = 24-48h

- Withdraw gradually, withdrawal symptoms (rarely for mianserin)

- Reduce by 25% per day

- Wait 2-4 days before starting next antidepressant

- Severe depression: consider hospitalisation during washout/changeover

Changeover Cat C

(agomelatine, moclobemide, reboxetine, SNRIs)

- SNRIs: withdraw gradually

- agomelatine, moclobemide, reboxetine: withdrawal sx not reported or rare

- Wait for 1-2 days before starting next antidepressant (agomelatine can be started immediately if switching from an SSRI or SNRI)

Mood Disorders

Depressive Disorder: higher risk, onset mid 20s, 2F:1M

Bipolar Disorder: lower risk, onset late 20s, 1F:1M, highest suicide risk

Antidepressant Meds Considerations

50% respond to first antidepressant

Onset: 1-2 weeks; statistically significant from placebo at 2-4 weeks

Antidepressant Meds Counselling/Prescribing Guidelines

Discuss drug choice + non-pharm + outcomes

• Single dose prescribed with titration if necessary

• Effective, not addictive, doesn't lose efficacy over time, no long-term AE

Describe likely AE and that they usually decrease with time - unexpected AE may limit adherence - If side effects are intolerable; alternatives

For single episode - treat for 6-9mths after recovery

• multiple episodes may require many years treatment

Withdraw gradually - inform patient of risks + discontinuation syndrome sx

Risk of recurrence is high and increases with each episode

Advise that

• mood may not improve immediately

• not all respond to first drug chosen, and there are other treatment options

• missing doses may reduce effectiveness

• drugs should be tapered gradually because of possible 'rebound' symptoms

• Regular follow-up and monitoring in early stages of treatment (even by phone, or by a practice nurse) may improve compliance

ST JOHN'S WORT - HYPERICUM PERFORATUM

INDICATION: Acute treatment of Major Depressive Disorder in adults

EFFICACY:

May be more effective than placebo in mild-mod major depression

Superior to placebo, as effective as AD, fewer SE than AD BUT not all preparations equal

Further info required about efficacy, safety, and use of standardised products

Discourage SJW use with antidepressants - interactions + risk of serotonin syndrome

Major depressive disorder (MDD) with peripartum onset

Occurs during pregnancy or 4 weeks following delivery (up to 12 months postpartum)

"Baby blues": not perinatal depression

- Mood swings, teariness, overwhelmed and/or anxious

- Starts hours/3-5 days after delivery and lasts a few hours/days

- 50-80% of postpartum women

- CAUSE: Labour + hormonal changes + physical changes = stress.

- Self-limiting

- No treatment needed

Prevalence of perinatal mental illness

10-20% of women

Antenatal (before birth): 10-15.6% Postnatal (after birth): 13-19.8%

Perinatal depression: 12%

More common in developing countries, less prevalent in high-income countries

Perinatal mental illness risk factors

<25, smokers

low-income household

English speakers

overweight/obese

emergency C-Section

- antenatal anxiety

- Major/ negative life events

- Current/ previous exposure to abuse and violence

- Lack of social/partner support

- Unplanned/ unwanted pregnancy

Treatment of perinatal mental illness

Reasoning: decrease risk of relapse of mental illness, suicide, alcohol/tobacco/ other drug use, negative impact on relationships (parental, partner)

1st line: psychological therapy

SSRI use: must be adjunction with psychological therapy

- Escitalopram, sertraline, paroxetine

- Avoid paroxetine (miscarriage, cardiac malformation), fluoxetine (avoid during BF due to long t/12 and high breastmilk conc)

If pt take AD during pregnancy and delivery healthy baby, do not change to a lower breast milk conc AD

Lithium use in pregnancy

Lithium: may ↑ risk of congenital heart defects, neonatal neurotoxicity, hypothyroidism

Avoid in pregnancy, especially 1st trimester

Continuing lithium may be the best option as poorly controlled bipolar disorder may compromise maternal health and carbamazepine, valproate and lamotrigine are not suitable alternatives during pregnancy:

- Use lowest dose possible

- Dose adjustments may be needed -> ↑ Lithium CL as pregnancy progresses

- CL reverts to normal after birth -> give pre-conception dose

- More frequent monitoring e.g. monthly, then weekly, within 24h postpartum

- Pay attention to hydration, salt intake

CONSIDERATIONS FOR POSTPARTUM PSYCHOSIS AND BIPOLAR DISORDER

- Psychiatrist treatment in a specialised centre

- Antipsychotics usually used

- Lithium and/or ECT may be required - Li should not be used while BF

- Valproate - teratogenic risk; do not use if pregnant/ childbearing age