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Day # 34: Atypical and Novel Antidepressants

Welcome back to our current theme of depressive disorders. From a pharmacology perspective we have now covered a broad overview of antidepressants, SSRIs/SNRIs, and serotonin syndrome. Today we will cover “atypical” or “novel” antidepressant medications.

Today's Content Level: Intermediate


•As we discussed in days # 30 and 31, SSRIs and SNRIs are typically considered the first-line medication option for depressive and anxiety disorders.

•The “atypical” or “novel” grouping of medications will be discussed today. This is essentially a list of antidepressants that have a “miscellaneous” mechanism of action and don’t fit neatly into the SSRI, SNRI, TCA, or MAOI groups.

•While they are not often considered first-line these medications are still commonly used due to some of the unique affects that will be described under each drug heading.

The medications that will be discussed today include:

  • Bupropion (Wellbutrin)

  • Levomilnacipran (Fetzima)

  • Trazodone (Desyrel)

  • Nefazodone (Serzone)

  • Vilazodone (Viibryd)

  • Mirtazapine (Remeron)

  • Vortioxetine (Trintellix)

  • Ketamine / S-Ketamine



  • Bupropion is a Norepinephrine-Dopamine Reuptake Inhibitor. It inhibits the presynaptic pumps that take up norepinephrine and dopamine. This leads to increased availability of these two neurotransmitters in the synaptic clefts.


  • It was originally approved by the FDA in 1985 (before fluoxetine), however at the time the recommended dose was 400-600mg and was associated with a risk of seizures. The drug was removed for 3 years before being reintroduced with a max dose of 450mg.

Indications -> Used in the following:

  • Major depressive disorder (MDD)

  • MDD with seasonal pattern (seasonal affective disorder)

  • SSRI/SNRI augmentation

  • Sexual side effects: often used to treat the sexual side effects of other antidepressants (decreased libido or arousal, anorgasmia in women/men, and delayed ejaculation in men)

  • Smoking cessation: FDA approved for smoking cessation. Often used in combination with nicotine substitutes.

  • Bipolar depression: not FDA approved however less likely to precipitate mania than other antidepressants as seen in the STEP-BD trial when prescribed atop a mood stabilizer.

  • ADHD: some efficacy in the treatment of adult ADHD as a non-stimulant option. Chemical structure is similar to stimulants such as adderall and ritalin.

  • Cocaine use disorder: reduces cravings during detoxification.

Side Effects

  • Its relation to stimulants gives it a unique side effect profile for an antidepressant.

  • Relative lack of sexual side effects as compared to the SSRIs.

  • Potential benefit for weight loss.

  • Can lower the seizure threshold (risk is 2% with 600mg and 0.1% with 300-450mg).

  • Contraindicated in patients with high risk of seizure (epilepsy, eating disorders, and traumatic brain injuries).

  • Common side effects include headache, insomnia, worsened anxiety/panic, dry mouth, tremor, and nausea.

Random Pearls

  • Available in immediate release IR, sustained release SR, and extended release ER.

  • Commonly used to augment SSRI/SNRI or to reduce sexual side effects.

  • In combination with naltrexone, bupropion showed a 4-5kg greater weight loss than placebo after one year. 1

  • May cause a false positive urine drug screen for amphetamines.

  • Can worsen symptoms of anxiety/panic.

  • Can worsen psychosis/delirium (secondary to dopaminergic activity). There are cases of severe psychosis with use during pregnancy.



  • Levomilnacipran is technically a serotonin-norepinephrine reuptake inhibitor (SNRI). Some authors include it among the other SNRIs and others include it in the atypical category due to its much higher selectivity for the reuptake blockade of norepinephrine than serotonin.

  • It is an enantiomer of milnacipran (savella) which is a medication approved for the treatment of fibromyalgia. Levomilnacipran is approved for the treatment of MDD whereas milnacipran is not.

Indications -> Used in the following:

  • Major depressive disorder (MDD)

  • May also inhibit a site for a beta amyloid precursor protein. This medication may ultimately be considered in the treatment of Alzheimers disease.

Side Effects

  • Hypertension, tachycardia

  • GI symptoms (nausea, abdominal cramps, constipation)

  • Hyperhidrosis

  • Urinary hesitancy or retention

  • Sexual side effects / Erectile dysfunction

Random Pearls

  • It may inhibit the site for a beta amyloid precursor protein. This medication may ultimately be considered in the treatment of Alzheimers disease.


Mechanism-> Trazodone affects multiple neurotransmitter systems. It includes:

  • Strong blockade of serotonin receptors (5-HT2A/C)

  • Mild blockade of serotonin reuptake (increasing levels in the synapse)

  • Alpha 1 antagonist

  • Antihistamine at low doses

Indications-> Used in the following:

  • Insomnia: shown to decrease the number of nightime awakenings. Also shown to improve the perception of sleep quality. However it is not recommended by the American Academy of Sleep Medicine for chronic (primary) insomnia due to no clear evidence of improvement of sleep efficiency. Commonly used in insomnia secondary to depression or anxiety. 2

  • Major depressive disorder: ranks as one of the least effective antidepressants in addition to being the most poorly tolerated. Dosage required to treat depression causes intolerable drowsiness and low blood pressure. 3

  • Agitation/Anxiety PRN

Side Effects

  • Sedation

  • Orthostatic hypotension: caution in the elderly as this is a falls risk!

  • Priapism: a sustained penile erection that is a medical emergency. Always discuss this rare but potential risk with your patients so they can seek emergency services immediately if they experience this. Mnemonic: trazaBONE.

  • Headache, nausea

  • Arrhythmia (rare)

  • Does not have the sexual side effects of SSRIs

  • Does not affect rapid eye movement (REM) sleep

Random Pearls

  • Because of orthostatic hypotension in higher doses, trazodone is not frequently used solely as an antidepressant.

  • It is commonly used to treat insomnia often when initiating an SSRI until insomnia improves as the depression resolves.

  • Dosing for sleep: start at 25-50mg per night. Max of 200mg per night.

  • Can be used as a PRN for agitation/anxiety. Most commonly used in elderly patients or those with TBI’s for whom benzodiazepines and antipsychotics are undesirable.

  • Dosing for agitation/anxiety PRN: 12.5-25mg.

  • May increase levels of digoxin and phenytoin.

  • Nefazodone (Serzone) has the same mechanism as trazodone although it is rarely used as it carries a black box warning for rare but serious liver failure.



  • Structurally similar to trazodone.

  • Selective serotonin repute inhibitor and serotonin agonist (5HT1A).

  • It is similar to an SSRI + buspirone.


  • Major depressive disorder (MDD)

Side Effects

  • GI side effects (nausea, abdominal cramps) are most common.

  • May be mild QTC prolongation at doses ≥ 80mg.

  • Less sexual side effects than other SSRIs.

  • Less weight gain than other SSRIs.

Random Pearls

  • Newer medication thus it is more expensive than existing antidepressants.

  • Limited head-to-head data compared to traditional SSRIs.


Mechanism-> Mirtazapine affects serotonin, norepinephrine, and histamine receptors.

  • Blocks central alpha-2 adrenergic receptors.

  • Potent serotonin antagonist (5HT2 and 5HT3)

  • Also blocks histamine receptors (H1).

Indications -> Used in the following:

  • Major depressive disorder - particularly if patient also has insomnia or weight loss. Ranks as one of the most effective antidepressants. Often used for elderly patients with depression, insomnia, and poor appetite. 4

  • Augmentation of other antidepressants.

  • Appetite stimulation (off-label).

  • Secondary insomnia (off-label): insomnia secondary to depression.

Side Effects

  • Sedation. Over half of patients experience somnolence. Worsened by alcohol or other sedatives. (strong histamine affinity)

  • Weight gain, increased appetite, increased cholesterol (strong histamine affinity). Ranks as the worst offender for weight gain amount antidepressants.

  • Less GI symptoms than other antidepressants but still can have symptoms when initiating.

  • Dry mouth

  • Dizziness

  • Constipation

  • Serotonin syndrome (especially in combination with MAOI).

  • Rare: Reduction of absolute neutrophil count (ANC) and agranulocytosis.

  • Case reports of fulminant hepatotoxicity.

  • Minimal sexual side effects compared with placebo and much less than SSRIs.

Random Pearls

  • Higher doses (above 30mg) leads to higher norepinephrine effects and less sedation (less active on histamine receptors at higher doses).

  • Observe for fever, chills, sore throat, etc due to potential for reduction in absolute neutrophil count and agranulocytosis.

  • Used off-label to reduce side effects associated with chemotherapy.


Mechanism -> Vortioxetine has complex direct effects on individual serotonin receptor subtypes. Known effects include:

  • Selective serotonin reuptake inhibition

  • Mixed serotonin antagonism (5HT3) and agonism (5HT1A)


  • Major depressive disorder (MDD)

Side Effects

  • Similar to other SSRIs including GI side effects, dry mouth, constipation, and sexual dysfunction.

Random Pearls

  • May have greater improvements in cognitive dysfunction secondary to depression than other antidepressants.


Mechanism -> Ketamine is a dissociate agent that acts in the following ways:

  • NMDA receptor antagonist

  • Weak agonist of mu and kappa opioid receptors

  • Weak agonist of dopamine (D2) receptors

  • Antidepressant mechanism is hypothesized to be secondary to a glutamate surge and prosynaptogenic activation

Indications -> Used in the following:

  • Ketamine has received a lot of research and media attention recently for its rebranding for the use of treatment resistant depression. It was primary used as an anesthetic but also used as a recreational drug. Current psychiatric uses include the following:

  • Treatment-resistant depression: produces rapid antidepressant response. Even one dose can significantly reduce depression in over half of patients although affect is usually transient. For more sustained treatment infusions or intranasal s-ketamine is given two or three times weekly. The long-term efficacy of ketamine has not been investigated by most studies. 5

  • Suicidal ideation: recent studies show rapid and clinically significant reduction in suicidal ideations compared with placebos. Reduced SI is transient but last for 40 minutes up to 10 days after the infusion. 6

  • Other, less well studied, uses include PTSD, OCD, and chronic neuropathic pain.

Side Effects

  • Nausea

  • Dizziness

  • Dissociative symptoms -> temporary and often diminishes with repeat dosing

  • Tachycardia and hypertension (mild)

  • Risk of bladder toxicity

  • Risk of drug abuse

Random Pearls

  • Routes of administration include IV, IM, and intranasally. It has poor oral absorption.

  • Typically administered in research settings, interventional psychiatry clinics, or private ketamine clinics.


I hope you learned something today. While not considered first-line for depression, these medications add great value to the arsenal of medications used in psychiatry due to their unique mechanism and affects. Next lesson we will tricyclic and tetracyclic antidepressants (TCAs).

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