Simplified Guide to 21 Common Antidepressants – Mechanisms of Action, Side effects and Indications

Need to know:

• Dose – 25-50 mg nocte
• Metabolised by CYP1A2 – therefore inhibitors like fluvoxamine and ciprofloxacin are contraindications
• Monitor Liver function tests at 3,6,12 and 24 weeks. Discontinue if ALT or AST exceed 3 times normal range.
• We covered a detailed summary of agomelatine previously
• Read about the use of agomelatine in a clinical case of depression

Need to know:

• Effective antidepressant but limited by its tolerability profile.
• Anti-H1 action leads to weight gain; Anticholinergic action leads to dry mouth, constipation, blurred vision and urinary retention; Alpha-1 antagonism leads to orthostatic hypotension and dizziness; Voltage-sensitive sodium channel (VSSC) blockade leads to arrhythmias, coma and seizures in overdose.
• Dose – 50-200 mg nocte
• Effective at low doses 25-50 mg nocte for neuropathic pain.
• Risk of serotonin syndrome when combined with SSRIs or SNRIs.
• Half life- 18-96 hours.

Need to know:

• Blocks Dopamine transporters (DAT’s) in nucleus accumbens and striatum increasing dopamine in these areas which improves ‘positive affect’. Learn more about positive affect in this talk by Prof Malcolm Hopwood
• Dose- 150-450 mg/day
• Available in immediate release (IR) and extended release (XL)
• Metabolised by CYP2B6 into many active metabolites
• Inhibits CYP2D6
• A half life of 21-30 hours
• Reduces seizure threshold
• Common side effects are dry mouth, insomnia and nausea
• Bupropion – Mechanism of Action | Psychopharmacology | Clinical Application
• Naltrexone | Naltrexone – Bupropion Combination – Mechanism of Action, Psychopharmacology and Clinical Application

Need to know:

• SSRI with good and bad enantiomer (R and S)
• R-enantiomer has mild antihistamine properties
• Dose – 20-80 mg /day. (The higher doses are prescribed for OCD)
• Dose-dependent QTc prolongation [Recommended ECG at doses > 40 mg OD].
• Not a potent CYP inhibitor
• A half-life of 24-72 hours.
• SSRIs as a group can be associated with GI bleeding and hyponatraemia in the elderly
• Update on the Mechanism of Action of Selective Serotonin Reuptake Inhibitors (SSRIs)
• Diagnosis and Management of Antidepressant Withdrawal – Understanding the Hyperbolic Curve and SSRI withdrawal

Need to know:

• Tricyclic with selective serotonin reuptake inhibition and noradrenergic activity. It is from a pharmacological perspective best considered as a SNRI. Clomipramine ration of NA/ 5HT∼2:1
• Dose- 25-250 mg/day
• Second line after SSRIs in OCD
• Half-life is 12-26 hours
• Side effects are similar to amitryptiline due to its H1, Alpha1 and VSSC antagonism.

Need to know:

• The active metabolite of Venlafaxine
• Greater Noradrenergic transporter (NAT) inhibition than Serotonin transporter (SERT) inhibition compared to venlafaxine
• Dose – 50-150 mg /day
• Not metabolised by CYP2D6, therefore, no significant variation in serum levels of the active metabolite
• Can reduce vasomotor symptoms in perimenopausal women.
• Can be used in liver dysfunction as not metabolised by the liver
• Venlafaxine (Effexor) and Desvenlafaxine (Pristiq) – Mechanism of Action | Differences | Psychopharmacology | Clinical Application

Need to know:

• Specifically indicated in pain with depression. Can improve diabetic peripheral neuropathic pain, fibromyalgia and chronic musculoskeletal pain
• Milder withdrawal reaction and lower incidence of hypertension as compared to Venlafaxine
• Dose – 60-120 mg /day. Can be administered twice a day
• Half-life is 12 hours
• Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) – Mechanism of Action

Need to know:

• S-enantiomer of citalopram which makes escitalopram the best-tolerated SSRI
• Dose 10-40 mg/day (The higher dose is prescribed in OCD)
• A propensity for QTc prolongation, which is dose-dependent [Recommended ECG at doses > 20 mg OD]
• No significant CYP enzyme interactions
• Psychopharmacology of Selective Serotonin Re-uptake Inhibitors (SSRIs) – Mechanism of Action

Need to know:

• SSRI with 5HT2C antagonism. (More discussion about 5HT2C antagonism in the article on agomelatine)
• 5HT2C antagonism increases prefrontal dopamine which may be activating for some patients; however, may benefit patients with lack of motivation and anhedonia
• Dose – 20-60mg/day
• Inhibits CYP2D6 and CYP3A4. (can increase levels of risperidone, diazepam)
• Long half-life (2-3 days) with its active metabolite having a half-life of 7-14 days
• Update on the Mechanism of Action of Selective Serotonin Reuptake Inhibitors (SSRIs)

Need to know:

• SSRI with sigma(σ)1 binding properties which may contribute to anti-anxiety and antipsychotic properties
• Dose – 100-300 mg /day (The higher doses are used in OCD)
• CYP1A2/CYP2C19/CYP3A4 inhibitor- can increase levels of olanzapine and clozapine (CYP1A2), methadone, benzodiazepines and carbamazepine (CYP3A4)
• Half life – 24-72 hours
• Update on the Mechanism of Action of Selective Serotonin Reuptake Inhibitors (SSRIs)

Need to know:

• More potent noradrenaline transporter inhibitor (NAT) than SERT inhibitor (Milnacipran SERT:NAT ratio : 1:1) ; Levomilnacipran SERT:NAT (1:2)
• Dosed twice daily due to a short half-life of 6-8 hours
• Dose : 50-100mg BD
• Minimal CYP metabolism
• Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) – Mechanism of Action

Need to know:

• Mirtazapine works through α2 pre-synaptic antagonism and 5HT2A, 5HT2C, 5HT3 and H1 antagonism
• Alpha 2 antagonism increases serotonin and noradrenaline release
• Combined use with SNRIs is termed as California rocket fuel due to its significant NA and DA potentiating properties
• Dose 15-60 mg/day
• Lower doses have a sedating property due to greater antihistamine effects which is also responsible for weight gaining properties.
• It is metabolised primarily in the liver by demethylation and hydroxylation via cytochrome P450 enzymes, CYP1A2, CYP2D6, CYP3A4. One of its major metabolites is desmethylmirtazapine.
• Mirtazapine – Mechanism of Action and Psychopharmacology By Dr. Sanil Rege

Need to know:

• SSRI with muscarinic anticholinergic and noradrenaline transporter (NAT) inhibitory actions
• More calming and sedating than other SSRIs
• Greater discontinuation symptoms contributed by additional anticholinergic withdrawal
• Dose – 20-60 mg/day
• Inhibitor of CYP2D6 and CYP3A4
• Half life -24 hours
• Psychopharmacology of Selective Serotonin Re-uptake Inhibitors (SSRIs) – Mechanism of Action

Need to know:

• Dose – 8-12 mg/day (administered twice a day)
• Metabolised by CYP3A4 (avoid ketoconazole and erythromycin)
• Half life -13 hours
• Common side effects include insomnia, fatigue, nausea, dry mouth and constipation

Need to know:

• SSRI with DAT inhibition and sigma(σ)1 binding properties
  
• DAT inhibition can be beneficial in patients with fatigue, poor concentration and amotivation but can result in activation
• The sigma(σ)1 binding properties contribute to its anxiolytic and antipsychotic properties
• Dose – 50-200 mg/day
• Inhibits CYP2D6 – can increase levels of TCA’s and Risperidone
• Half life-24-72 hours
• Psychopharmacology of Selective Serotonin Re-uptake Inhibitors (SSRIs) – Mechanism of Action

Need to know:

• Nefazodone is not used due to rare liver toxicity
• Trazodone at lower doses (25-150 mg) is used as a hypnotic due to its 5HT2A, α1 and H1 antagonism
• Trazodone acts as an antidepressant at higher doses (150-600mg) due to 5HT2A/C antagonism and SERT inhibition
• Trazodone has biphasic elimination, with a redistribution half-life of about one hour and an elimination half-life of 10-12 hours

Need to know:

• SERT inhibition at lower doses (75-225 mg)
• NAT inhibition at higher doses (> 225 mg)
• XR version is available to reduce discontinuation symptoms
• Dose 75-375mg /day with food
• Metabolised by CYP2D6/3A4. Due to CYP2D6 genetic polymorphisms there can be significant variability in plasma levels of venlafaxine
• Can increase BP at higher doses
• Headache, sexual dysfunction, sweating and gastrointestinal symptoms are common with venlafaxine. Can also cause
  withdrawal agitation
• Venlafaxine (Effexor) and Desvenlafaxine (Pristiq) – Mechanism of Action | Differences | Psychopharmacology | Clinical Application

Need to know:

• Serotonin 5HT1A partial agonist (like buspirone) and reuptake inhibitor
• Results in greater serotonin elevation in the brain
• Dose – 10-40 mg/day
• Metabolised by CYP 3A4
• Half-life is 25 hours
• Highly protein bound, therefore, can displace other medications that are protein bound, e.g. warfarin

Need to know:

• Read about vortioxetine in more detail.
• Dose 10-20mg/day
• Long half-life of 66 hours

In this article, we have focused on the commonly used antidepressants.

Other antidepressants include MAOIs and psychostimulants.

Monoamine Oxidase Inhibitors (MAOI) – Mechanism of Action | Psychopharmacology | Clinical Application

Modafinil and Armodafinil – Mechanism of Action | Psychopharmacology | Clinical Application

Dexamphetamine and Lisdexamfetamine- Mechanism of Action, Side Effects and Dosing

Methylphenidate – Mechanism of Action, Side Effects and Dosing

The common underlying effect for many antidepressants (TCAs, SSRIs, and ketamine) may be linked to the binding of the BDNF receptor (the transmembrane domain of tyrosine kinase receptor 2 (TRKB)) facilitating increased expression and signalling of brain-derived neurotrophic factor (BDNF) which promotes neuronal plasticity and antidepressant responses. [Casarotto et al., 2021]

Besides these anti-inflammatory effects and astrocyte modulation have also been postulated.

Mechanism of Action of Selective Serotonin Reuptake Inhibitors (SSRIs) – The Latest