Anti-Depressants
SSRIs
Fluoxetine, sertraline, citalopram, escitalopram, paroxetine
These are inhibitors of the serotonin transporter (SERT) which prevent reuptake of serotonin (5-HT) from the synaptic cleft, potentiating its action.
They are first-line in the treatment of depression but can take a few weeks to work.
When starting patients on SSRIs, review them after 2 weeks. If young (<30) or at a higher risk of suicide then it is suggested to review them after 1 week, as a side effect can be increased suicidal thoughts in the early phase of treatment.
Side Effects
Gastric irritation – due to 5-HT receptors in gut
Bleeding – due to 5-HT in platelets
Hyponatreamia – due to SIADH
Anxiety and suicidal thoughts (more in young people)
Weight gain
Sexual dysfunction
Headaches
Specific Effects
Citalopram and escitalopram have a high risk of lengthening of the QTc interval
In pregnancy – Paroxetine during pregnancy (<20 weeks) can lead to heart defects
Sertraline (>20 weeks) causes persistent pulmonary hypertension of the Newborn
In breastfeeding, sertraline is the SSRI of choice
In children, fluoxetine is the SSRI of choice and it has the longest half-life
The SSRIs also interact with other drugs which increase 5-HT activity:
NSAIDs – this can lead to risk of bleeding, therefore must be given with a proton-pump inhibitor
Serotonin noradrenaline reuptake inhibitors (SNRIs)
Duloxetine, venlafaxine
These drugs inhibit both serotonin and noradrenaline (NA) reuptake to potentiate 5-HT and NA transmission at the synaptic cleft.
They act as SSRIs at low doses, whereas a higher dose is needed to achieve the noradrenergic effects.
Side Effects
High Na (hypertension, tachycardia)
SSRI side effects
Noradrenaline re-uptake inhibitors (NARIs)
Reboxetine, atomoxetine
These drugs help to boost noradrenergic and dopaminergic activity in the prefrontal cortex but are less effective for depression than the SSRIs and SNRIs.
Side Effects
Insomnia
Postural hypotension
Sweating
5-HT2 antagonists
Trazodone, nefazodone
These can cause substantial drowsiness at low doses so are often used off label to treat insomnia as well as anxiety and depression.
Side Effects
GI disturbances
Priapism (erection for hours)
Tricyclic Antidepressants
Amitriptyline, nortriptyline
These drugs inhibit the NET (NA transporter) and SERT (5-HT reuptake protein) but not the dopamine (DA) transporter.
They have many side effects as they are antagonists of α-adrenoceptors, muscarinic acetylcholine and histamine H1-receptors.
Side Effects
ACh block – memory dysfunction, dry mouth, blurred vision, constipation, urinary retention
H1 effects – weight gain and sedation
Alpha-receptors – postural hypotension giving reflex tachycardia and arrhythmias
Lengthening of the QTc interval
Block Na+ channels in heart/brain – seizure, coma, arrhythmia and delirium in overdose
SIADH – leads to hyponatraemia
MAO-inhibitors
Phenelzine, tranylcypromine, moclobemide
These inhibit the activity of the enzyme monoamine oxidase (MAO-A and MAO-B) which degrades noradrenaline and serotonin, prolonging their action.
There are associated with a high risk of discontinuation syndrome on cessation.
Side Effects
Postural hypotension
In the presence of indirectly acting sympathomimetics (e.g. tyramine in food, amphetamine) they can lead to excessive Na transmission giving arrhythmia and hypertension
Can also cause Serotonin syndrome when given with SSRIs
Atypical Antidepressants
Mirtazapine
This drug inhibits negative feedback α2-receptors on 5-HT neurones, which is thought to lead to enhanced noradrenergic and serotonergic activity in the brain.
It is a strong antagonist of serotonin 5-HT2A and 5-HT3.
It is also a a potent antagonist of histamine H1 receptors, a property that may explain its prominent sedative effects.
However, it also blocks the 5-HT receptors in other pathways leading to the side effects of insomnia and sexual dysfunction.
Side Effects
Increased appetite
Weight gain
Sedation
Agomelatine
This enhances melatonin MT1 and MT2 receptors and also blocks 5-HT2C receptors.
It has been shown to resynchronize circadian rhythms in animal models.
It is also thought to boost DA and NA in pre-frontal cortex which gives it antidepressant effect.
Side Effects
Sedation (taken at night)
Elevated liver enzymes
Mood Stabilizers
Lithium
This is a drug that i thought to influence multiple neurotransmitter systems.
It inhibits phospholipid recycling, decreasing activity of messengers DAG and IP3.
It comes in many preparations (carbonate/citrate) with different bio availabilities.
It is used as a first line line maintenance treatment in bipolar disorder.
It has a very narrow therapeutic range is excreted by the kidneys.
Side Effects
GI – nausea and vomiting
Fine tremor
Idiopathic intracranial hypertension
ECG – causes T wave flattening/inversion
Slows activity on EEG
Raised WCC (leucocytosis)
Weight Gain
Lithium also affects many hormonal systems giving endocrine side effects:
ADH – leads to nephrogenic diabetes insipidus + nephrotoxicity
Thyroid – Causes thyroid enlargement and potential hypothyroidism
PTH – Hyperparathyroidism increasing calcium levels
Not used in first trimester of pregnancy due to possible Ebstein’s foetal anomaly (faulty tricuspid valve)
Monitoring and Toxicity
Monitoring:
Due to narrow therapeutic index, lithium levels initially checked weekly then every 3 months
Thyroid and Renal function checked every 6 months
Toxicity:
This occurs at concentrations >1.5mM, due to dehydrations, renal failure or nephrotoxic drugs
These factors cause a decrease in renal function which leads to lithium accumulating in the body
Gives motor signs (coarse tremor and hyperreflexia) and neurological signs (confusion, seizures)
Management:
Haemodialysis in severe toxicity
Complications
The antidepressants are associated with 2 important complications:
Discontinuation Syndrome
This occurs when antidepressant drugs are stopped suddenly and not gradually
The underlying mechanism is unclear, but can affect up to half of patients who stop their medication suddenly
To prevent this, it is suggested that people stay on SSRIs for 6 months after remission from their symptoms and the dose should be gradually reduced over a 4-week period.
Causes
Stopping SSRIs, SNRIs, TCAs and MAO-inhibitors
Risk factors
People who have taken medicines for more than a month + medicines with short half-life
Symptoms
Flu-like symptoms – nausea, vomiting, diarrhoea, headaches, sweating
Sleep disturbances – insomnia, nightmares, constant sleepiness
Sensory and movement disturbances – imbalance, tremors, vertigo, dizziness
“Brain zaps” or shock sensation that starts in the head and moves quickly through the entire body
Mood disturbances – Anxiety, dysphoria
Management
Consider restarting anti-depressant and then weaning off slowly
Switching to anti-depressant with longest half-life (e.g. Fluoxetine)
Serotonin Syndrome
This occurs when there is excessive 5-HT transmission which gives CNS hyperstimulation
It leads to excess autonomic and neuromuscular excitation with an altered mental state
Causes
MAO-inhibitors, SSRIs, ecstasy and amphetamines
Symptoms
Have a fast onset within a matter of hours
Cognitive effects – Headache, agitation, hypomania, mental confusion, hallucinations, coma
Autonomic effects – Shivering, sweating, hyperthermia, vasoconstriction, tachycardia, nausea, diarrhoea.
Somatic effects – Myoclonus (muscle twitching), hyperreflexia (manifested by clonus), tremor.
Management
Supportive management with IV fluids + benzodiazepine
If severe – 5-HT antagonists e.g. Cyproheptadine, Olanzapine
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