Offending drugs and conditions

• DM, HIV, cardiovascular diseases, dementia, overactive bladder: patients can feel depressed and embarrassed about their conditions.
• Clonidine, methyldopa, reserpine, BB (esp. propranolol), procainamide: act centrally, or because they are lipophilic (propranolol, procainamide) and can cross blood-brain barrier to act on CNS.
• Anabolic steroids, corticosteroids: steroids often cause mood changes.
• Barbiturates, benzos, narcotics (methadone, etc.), chloral hydrate, ethanol: alcohol, and CNS depressants can lead to (or worsen) depression.
• Isotretinoin, indomethacin, interferon: depression is a rare side effect of these drugs.

 

Serotonergic agents

• Know your list! Increased risk of 5HT syndrome when used in combination.
• SSRI, SNRI, TCA, MAOI, St John's wort, mirtazapine, lithium: mood meds.
• Meperidine, tramadol, cyclobenzaprine, gabapentin, Lyrica: pain.
• ephedrine and analogs (pseudoephedrine), dextromethorphan: stimulants.
• linezolid: the only antibiotic on the list.
• Triptans: 5-HT agonists for migraine; Ergotamine: they are non-selective 5HT agonists also used for migraine due to their vasoconstrictive property.
• Serotonin syndrome:  agitation, high body temperature, sweating, shivering, confusion, mental changes.

 

Pharmacotherapy side effects

• All antidepressants carry a boxed warning for suicidal thoughts in children and young adults, MedGuides are required. (All drugs require MedGuide for a reason, know what reason they are for, e.g: NSAIDs due to vasoconstriction ↑ BP and CV risks).
• SSRI or SNRI: May cause reduced libido and arousal, erectile dysfunction. (5HT is responsible)
• Bupropion: Contraindicated to use in patients suffering from anxiety and seizure.
• Mirtazapine: Strong antihistamine and sedation properties. Useful as an appetite stimulant, can cause weight gain.
• Duloxetine: Useful in patients suffering from depression with fibromyalgia or diabetic neuropathic pain.

 

Selective serotonin reuptake inhibitors (SSRI)

• Drugs: Fluoxetine (Prozac, Sarafem), Paroxetine (Paxil), Fluvoxamine (Luvox), Sertraline (Zoloft), Citalopram (Celexa), Escitalopram (Lexapro).
• MOA: increases levels of serotonin (5-HT). Serotonin regulates mood, sleep, libido, deficiency can cause anxiety and depression.
• Indications: depression, obsessive-compulsive disorder (OCD), and social anxiety disorder (SAD).
• SE: ↓ libido, GI effects, SIADH (impaired ADH -> hyponatremia), headache, restless leg syndrome, ↑ bleeding risk, avoid in patients with cardiovascular disease due to ↑ risk of QT prolongation (only sertraline is recommended in patients with CV disease, QT most notable with citalopram/escitalopram).
• FDA issued a warning for SSRI during pregnancy: persistent pulmonary hypertension of the newborn.
• Fluoxetine: longest half-life, requires a 5-wk wash-out period before initiating an MAOI; Sarafem is for the premenstrual dysphoric disorder (PMDD); fluoxetine + olanzapine = Symbyax in resistant depression.
• Paroxetine: most anticholinergic agent, short half-life; Brisdelle 7.5mg approved for hot flashes related to menopause.
• Fluvoxamine (Luvox): dosing is higher than others (100mg), and has more drug interactions (it is a strong 1A2 inhibitor).
• DI: 2 weeks wash out with MAOIs (5 weeks after switching from fluoxetine to MAOIs).
• ↑ bleeding risk with anticoagulants, antiplatelets, NSAIDs.
• ↓ tamoxifen effectiveness because tamoxifen requires enzyme (2D6) conversion to its most active form. Most SSRI (fluoxetine, fluvoxamine, paroxetine) are enzyme inhibitors 2D6.

 

Serotonin-norepinephrine reuptake inhibitors (SNRI)

• Drugs: Venlafaxine (Effexor), Duloxetine (Cymbalta), Desvenlafaxine (Pristiq), Milnacipran (Savella)
• MOA: increase reuptake of serotonin (5-HT) and Norepinephrine (NE): Norepinephrine is associated with mood and arousal (fight or flight). The suffix is epinephrine, the action is similar to epinephrine, ramp up your body, ↑ BP/HR/pulse, sweating, anxiety (think about stimulant effects).
• SE: ↑ BP/HR/sweating, dizziness, insomnia, restless leg syndrome, ↑ risk of bleeding, ↓ libido, CI in uncontrolled narrow-angle glaucoma (due to elevation on BP).
• Indication: depression, neuralgia (duloxetine), fibromyalgia.
• Desvenlafaxine: mydriasis, increased risk for intraocular pressure (IOP), fecal ghost shell.
• Milnacipran: only used in fibromyalgia.
• DIs: Most are 2D6 inhibitors, require a 2-wks washout period with MAOI.

 

 Tricyclic antidepressants (TCA)

• MOA: inhibit the reuptake of 5HT and possibly NE, highly anticholinergic.
• SE: cardiotoxicity (QT prolongation with overdose, orthostatic hypotension), anticholinergic (constipation, dry/blurred vision, avoid use in BPH and narrow-angle glaucoma), vivid dreams.
• Avoid use in elderly due to risk of fall, if we have to, chose low-dose nortriptyline or desipramine for fewer anticholinergic effects.
• DIs: MAOIs, 2D6 substrate. Notice that almost every class must be avoided using together with MAOIs, simply because they target duplicate NTs.

Tertiary amines

• Amitriptyline (Elavil, Limbitrol), doxepin (Sinequan), clomipramine (Anafranil), imipramine (Tofranil), trimipramine (Surmontil)

Secondary amines

• Desipramine (Norpramin), nortriptyline (Pamelor), protriptyline (Vivactil)

 

Monoamine oxidase inhibitors (MAOIs)

• Drugs: phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), selective MAOIs-B (selegiline (Eldepryl, Zelapar), rasagiline (Azilect)). It is difficult but very important to know their names.
• MOA: Inhibits enzyme monoamine oxidases, prevents the breakdown of catecholamines (5-HT, NE, DA, histamine).
• This is also an “amine”, similar chemical structure to the above TCAs (tertiary and secondary amines), however, it might only be more potent (targets more neurotransmitters compared to TCAs).
• SE: anticholinergic effect, sedation, serotonin syndrome when taken together with other serotonergic agents, sexual dysfunction (effect from 5HT).
• Notorious for drug and food interactions (why? Target so many NTs), avoid tyramine-rich food (cheese, red wine, bacon, etc.).
• MOAI-B inhibitors are selective for dopamine (DA), therefore they have a place in Parkinson’s disease (low in DA) treatment: they help raise DA level, also recall MAOIs’ anticholinergic effects on muscle: relax and smoothen muscle movements.

 

Other antidepressants 

Bupropion (Wellbutrin, Zyban)

• Indication: depression (Wellbutrin), smoking cessation (Zyban).
• MOA: Nicotinic anticholinergic, blocks DA and NE reuptake.
• SE: tends to be more activating (insomnia, anxiety), minimum weight gain (unlike most of the antidepressants), anticholinergic effects (constipation/dry mouth), decreased seizure threshold (caution on patients with a history of seizure, max dose 450mg)
• Less risk of reduced libido compared to SSRIs (it does not target 5HT).

 Mirtazepine (Remeron)

• Indication: depression, insomnia, anorexia.
• SE: Sedation (prominent at a low dose, therefore, treats insomnia), increased appetite/weight gain (prominent therefore treats anorexia), dry mouth.
• At a lower dose, more depressing effects: somnolence, can be used PRN, e.g: 7.5mg HS PRN for insomnia; at higher doses more activating and is used to treat depression, the dose must be taken continuously, NOT prn, e.g: 30mg QD.
• Rarely used for younger patients due to concern of weight gain and appetite-stimulating effect, but a good choice for frail, elderly patients with insomnia and poor appetite.

 Serotonin modulators

• Drugs: Trazodone (Desyrel, Oleptro CR), Nefazodone (Serzone).
• MOA: Inhibit reuptake of serotonin (5HT), has blocking activity on H1 and alpha-1 receptors.
• SE: Orthostatic hypotension (recall alpha receptors' role in BP), sedation (sedative property comes from H1 blocking effect), priapism (5HT is related to libido, maybe that is where priapism come from).
• Similar to mirtazapine, at a lower dose, more depressing effects (somnolence), smaller doses are used to treat insomnia, e.g: 50mg HS PRN for insomnia; at higher doses more activating and it is used to treat depression: doses should be taken continuously, NOT prn, e.g: 300mg QD.
• Nefazodone has an increased risk of hepatotoxicity and is rarely used.

Adjunct therapies

• For resistant depression only, do not initiate antipsychotics unless patients failed multiple antidepressants.
• First-line in depression treatment: Li, lamotrigine, quetiapine; Or olanzapine + SSRI
• Aripiprazole (Ability): augment response to antidepressants.
• Olanzapine/fluoxetine (Symbyax): dosed daily at bedtime.

 

Quiz

Which of the following could potentially contribute to serotonin syndrome?

1. Tramadol
2. Citalopram
3. Imitrex
4. Gabapentin
5. Apresolin

 

A patient with severe anxiety and depression shall avoid which of the following antidepressants? (Select All that applies) 

1. Paroxetine 
2. Fluvoxamine 
3. Duloxetine
4. Mirtazapine
5. Bupropion 

 

Answers

1. Abcd have serotonin activity in the brain. Apresolin (hydralazine) is an antihypertensive medicine.
2. E. Bupropion (Wellbutrin) is an antidepressant of the aminoketone class. It is indicated for the treatment of major depressive disorder (MDD). To minimize the risk of seizure, increase the dose gradually. Due to its CNS stimulating property, it shall be avoided in patients suffering from severe anxiety. In such patients, one can use mirtazapine for its sedative effects.

 

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