MAJOR DEPRESSIONNNNNN

Describe the monoamine theory of depression

• first proposed in 1965

• suggests that depression is a functional deficit of monoamine neurotransmitters - noradrenaline and/or 5-Hydroxytryptamine at certain sites of the brain

However, this theory is considered over simplified

Factors influencing depression

Genetics, environment and psychological factors

List treatment goals of depression

Minimise and relieve pyschological and physiological symptoms, improve functional capacity and reduce risk of self harm and suicide.

Challenges of antidepressants 

Time lag between immediate neurochemical effects and clinical benefits - may take 1-3 weeks or up to 1-2 months for patients to see results

Selective serotonin reuptake inhibitors (SSRIs) MOA

Selectively inhibit presynaptic reuptake of 5-HT by binding to the serotonin transporter (SERT), thus increasing the concentration of serotonin in the synaptic cleft, allowing more serotonin to bind to the postsynaptic receptor and enhance neurotransmission.

Selective serotonin reuptake inhibitors (SSRIs) adverse effects and contraindications

Nausea, anorexia, insomnia, loss of libido, and sexual dysfunction.

CITALOPRAM, ESCITALOPRAM, AND FLUOXETINE - can prolong the QT interval, thus increasing risk of cardiac arrhythmias.

Contraindicated with CYP450 enzyme inhibitors, as they can alter concentrations of other drugs

require a 2 week washout period

Serotonin-Noradrenaline reuptake inhibitors (SNRIs) MOA

Inhibit the reuptake of both serotonin and noradrenaline - however, they act in a concentration dependent manner, primarily inhibits serotonin at low doses and noradrenaline at high doses. 

SNRIs inhibit SERT and NET transporters  thereby increasing both neurotransmitters in the synapse

Serotonin-Noradrenaline reuptake inhibitors (SNRIs) adverse effects and interactions

• nausea

• constipation

• dry mouth

• sweating

• cardiovascular issues e.g high blood pressure and tachycardia

• orthostatic hypotension

• hyponatremia

All SNRIs cause serotonin syndrome

Duloxetine is a moderate CYP2D6 inhibitor

Tricyclic antidepressants (TCAs) MOA

Inhibit the reuptake of both serotonin and noradrenaline. They also block cholinergic (muscarinic), histaminergic (H1), and alpha-1 adrenergic receptors

Tricyclic antidepressants (TCAs) adverse effects and overdose safety

Due to a broad receptor blockade adverse effects include, dry mouth, blurred vision, constipation, urinary retention (Anticholinergic effects), sedation (block H1), orthostatic hypotension (a1 adrenergic block) and prolong QT interval and lowr seizure threshold

Monoamine oxidase inhibitors (MAOIs) MOA

MAOIs inhibit monoamine oxidase enzymes (MAO-A and MAO-B) which are responsible for metabolising noradrenaline, dopamine, serotonin within the presynaptic neuron.

MOA-A preferentially metabolises Serotonin, noradrenaline, adrenaline, and dopamine while MAO-B mainly metabolises Dopamine

Describe and provide an example of an irreversible MAOIs

Irreversible MAOIs are non-selective and inhibit both MAO-A and MAO-B for approx 2-3 weeks.

E.g Phenelzine and Tranylcypromine

Describe and provide an example of an reversible MAOIs

Reversible MAOIs are selective to MAO-A

e.g moclobemide

Monoamine oxidase inhibitors (MAOIs) adverse effects

Side effects include hypotension, central stimulation (e.g tremors, excitement, insomnia), increased appetite, weight gain and atropine like effects

Monoamine oxidase inhibitors (MAOIs) interactions

Anything food that is rich in tryamine such as aged cheese or cured meats. the accumulation of tryamine and subsequent release of noradrenaline causes a hypertensive crisis

Moclobemide has a lower risk of this as it is reversible therefore, the body can still metabolise tyramine

MAOIs also interact with serotonergic drugs (Increased risk of serotonin syndrome), sympathomimetic amines, and opioids

Require 2 week washout period

list and describe atypical antidepressants

Mirtazapine - blocks postsynaptic 5-HT receptors, presynaptic alpha 2 adrenergic inhibitory autoreceptors (increasing NA and 5-HT) and histamine H1 receptors

• highly sedating, especially at lower doses, and causes increased appetite and weight gain.

Agomelatine - melatonin MT1 and MT2 receptor agonist and 5-HT2C receptor antagonist. thought to improve the release of dopamine and noradrenaline, and may be useful for patients with depression related insomnia.

• contraindicated with CYP1A2 inhibitors and in liver disease due to hepatotoxicity risk

Minaserin - a TCA acts as an antagonist at H1 histamine, 5-HT2A, 5-HT2c, alpha 1 and alpha 2 adrenergic receptors and is also a noradrenaline reuptake inhibitor.

• causes sedation, may increase seizure risk and rare neutropenia

Reboxetine - highly selective noradrenaline reuptake inhibitor with weak effects on serotonin and dopamine reuptake. - less effective than TCAs

Vortioxetine - new drug that inhibits SERT transporter and has agonist and antagonist effects at several serotonin receptors - increasing serotonin activity

• new so full MOA and side effects are currently unknown

Symptoms of abrupt antidepressant cessation

agitation, insomnia, nausea, vomiting, dizziness, tremors and dyskinesias

Serotonin toxicity/syndrome

caused by excessively high levels of serotonin in the synapses, leading to overstimulation of serotonin receptors - considered a medical emergency.

Can occur when there’s an inadequate washout period, a large or overdose of a single serotonergic agent or more than 1 serotonergic agent being administered concurrently