Antidepressants

Jason Cafer, MD

Slides and handouts – bit.ly/slides2026

Antidepressants – Learning topics

• Key differences between antidepressant classes and their clinical implications

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• Risk-benefit analysis of antidepressants vs placebo across ages and depression severities

​

• Core mechanisms and interactions of the most-prescribed antidepressants

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• Applied understanding beyond exam preparation

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• Supplemental materials for self-study include MCQs, visuals, and recall aids

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Slides and handouts – bit.ly/slides2026

Antidepressants

What’s an antidepressant?

​

​

Slides and handouts – bit.ly/slides2026

Antidepressants

What’s an antidepressant?

​

Arbitrary category of mostly serotonergic medications

​

​

Slides and handouts – bit.ly/slides2026

Antidepressants

What’s an antidepressant?

​

Arbitrary category of mostly serotonergic medications

​

The majority are serotonin

reuptake inhibitors (SRI)

​

​

Slides and handouts – bit.ly/slides2026

Serotonin (5-hydroxytryptamine)

Serotonin Transporter (SERT)

SERT

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

Serotonin Transporter (SERT)

NRI

Norepinephrine reuptake inhibitor (NRI)

Medications FDA-approved for Depression

SRI as principal mechanism

​

​

SRI but not principal

​

​

​

​

​

​

No significant SRI activity

​

​

​

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

​

SRI but not principal

​

​

​

​

​

​

No significant SRI activity

​

​

​

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

​

SRI but not principal

​

​

​

​

​

​

No significant SRI activity

​

​

​

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

SRI but not principal

​

​

​

​

​

​

No significant SRI activity

​

​

​

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

SRI but not principal

​

​

​

​

​

​

No significant SRI activity

​

​

​

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

​

​

​

​

​

​

No significant SRI activity

​

​

​

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

​

​

​

​

No significant SRI activity

​

​

​

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

​

Trazodone - atypical antidepressant

​

​

No significant SRI activity

​

​

​

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

Trimipramine (Surmontil) - TCA

Trazodone - atypical antidepressant

Nefazodone - atypical antidepressant

​

No significant SRI activity

​

​

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

Trimipramine (Surmontil) - TCA

Trazodone - atypical antidepressant

Nefazodone - atypical antidepressant

​

No significant SRI activity

Bupropion (Wellbutrin) - NDRI

Mirtazapine (Remeron) - atypical antidepressant

​

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

Trimipramine (Surmontil) - TCA

Trazodone - atypical antidepressant

Nefazodone - atypical antidepressant

​

No significant SRI activity

Bupropion (Wellbutrin) - NDRI

Mirtazapine (Remeron) - atypical antidepressant

​

​

Nortriptyline (Pamelor) - TCA

​

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

Trimipramine (Surmontil) - TCA

Trazodone - atypical antidepressant

Nefazodone - atypical antidepressant

​

No significant SRI activity

Bupropion (Wellbutrin) - NDRI

Mirtazapine (Remeron) - atypical antidepressant

Gepirone (Exxua) - atypical antidepressant

Desipramine (Norpramin) - TCA

Nortriptyline (Pamelor) - TCA

Protriptyline (Vivactil) - TCA

Amoxapine - TCA

​

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

Trimipramine (Surmontil) - TCA

Trazodone - atypical antidepressant

Nefazodone - atypical antidepressant

​

No significant SRI activity

Bupropion (Wellbutrin) - NDRI

Mirtazapine (Remeron) - atypical antidepressant

Gepirone (Exxua) - atypical antidepressant

Desipramine (Norpramin) - TCA

Nortriptyline (Pamelor) - TCA

Protriptyline (Vivactil) - TCA

Amoxapine - TCA

Phenelzine (Nardil) - MAOI

Tranylcypromine (Parnate) - MAOI

Selegiline (EMSAM patch) - MAOI

​

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

Trimipramine (Surmontil) - TCA

Trazodone - atypical antidepressant

Nefazodone - atypical antidepressant

​

No significant SRI activity

Bupropion (Wellbutrin) - NDRI

Mirtazapine (Remeron) - atypical antidepressant

Gepirone (Exxua) - atypical antidepressant

Desipramine (Norpramin) - TCA

Nortriptyline (Pamelor) - TCA

Protriptyline (Vivactil) - TCA

Amoxapine - TCA

Phenelzine (Nardil) - MAOI

Tranylcypromine (Parnate) - MAOI

Selegiline (EMSAM patch) - MAOI

​

Approved for depression, not “antidepressant”

Esketamine (Spravato) - NMDA antagonist

Zuranolone (Zurzuvae) - Neuroactive steroid

Medications FDA-approved for Depression

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

Trimipramine (Surmontil) - TCA

Trazodone - atypical antidepressant

Nefazodone - atypical antidepressant

​

No significant SRI activity

Bupropion (Wellbutrin) - NDRI

Mirtazapine (Remeron) - atypical antidepressant

Gepirone (Exxua) - atypical antidepressant

Desipramine (Norpramin) - TCA

Nortriptyline (Pamelor) - TCA

Protriptyline (Vivactil) - TCA

Amoxapine - TCA

Phenelzine (Nardil) - MAOI

Tranylcypromine (Parnate) - MAOI

Selegiline (EMSAM patch) - MAOI

​

Approved for depression, not “antidepressant”

Esketamine (Spravato) - NMDA antagonist

Zuranolone (Zurzuvae) - Neuroactive steroid

Auvelity = bupropion + dextromethorphan

Serotonergic

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Trazodone - atypical antidepressant

Nefazodone - atypical antidepressant

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

Trimipramine (Surmontil) - TCA

​

No significant SRI activity

Bupropion (Wellbutrin) - NDRI

Mirtazapine (Remeron) - atypical antidepressant

Gepirone (Exxua) - atypical antidepressant

Desipramine (Norpramin) - TCA

Nortriptyline (Pamelor) - TCA

Protriptyline (Vivactil) - TCA

Amoxapine (Asendin) - TCA

Phenelzine (Nardil) - MAOI

Tranylcypromine (Parnate) - MAOI

Selegiline (EMSAM patch) - MAOI

​

Approved for depression, not “antidepressant”

Esketamine (Spravato) - NMDA antagonist

Zuranolone (Zurzuvae) - Neuroactive steroid

Auvelity = bupropion + dextromethorphan

Serotonergic

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Trazodone - atypical antidepressant

Nefazodone - atypical antidepressant

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

Trimipramine (Surmontil) - TCA

​

No significant SRI activity

Bupropion (Wellbutrin) - NDRI

Mirtazapine (Remeron) - atypical antidepressant

Gepirone (Exxua) - atypical antidepressant

Desipramine (Norpramin) - TCA

Nortriptyline (Pamelor) - TCA

Protriptyline (Vivactil) - TCA

Amoxapine (Asendin) - TCA

Phenelzine (Nardil) - MAOI

Tranylcypromine (Parnate) - MAOI

Selegiline (EMSAM patch) - MAOI

​

Approved for depression, not “antidepressant”

Esketamine (Spravato) - NMDA antagonist

Zuranolone (Zurzuvae) - Neuroactive steroid

Auvelity = bupropion + dextromethorphan

Noradrenergic

Serotonergic

Serotonergic

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Trazodone - atypical antidepressant

Nefazodone - atypical antidepressant

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

Trimipramine (Surmontil) - TCA

​

No significant SRI activity

Bupropion (Wellbutrin) - NDRI

Mirtazapine (Remeron) - atypical antidepressant

Gepirone (Exxua) - atypical antidepressant

Desipramine (Norpramin) - TCA

Nortriptyline (Pamelor) - TCA

Protriptyline (Vivactil) - TCA

Amoxapine (Asendin) - TCA

Phenelzine (Nardil) - MAOI

Tranylcypromine (Parnate) - MAOI

Selegiline (EMSAM patch) - MAOI

​

Approved for depression, not “antidepressant”

Esketamine (Spravato) - NMDA antagonist

Zuranolone (Zurzuvae) - Neuroactive steroid

Auvelity = bupropion + dextromethorphan

Noradrenergic

Serotonergic

Antidepressants

What’s an antidepressant?

​

Arbitrary category of mostly serotonergic medications

​

The majority are SRIs

​

​

Antidepressants

What’s an antidepressant?

​

Arbitrary category of mostly serotonergic medications

​

The majority are SRIs

​

They are all ________ and/or _________

​

​

Antidepressants

What’s an antidepressant?

​

Arbitrary category of mostly serotonergic medications

​

The majority are SRIs

​

They are all serotonergic and/or noradrenergic

​

​

Serotonergic

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Trazodone - atypical antidepressant

Nefazodone - atypical antidepressant

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

Trimipramine (Surmontil) - TCA

​

No significant SRI activity

Bupropion (Wellbutrin) - NDRI

Mirtazapine (Remeron) - atypical antidepressant

Gepirone (Exxua) - atypical antidepressant

Desipramine (Norpramin) - TCA

Nortriptyline (Pamelor) - TCA

Protriptyline (Vivactil) - TCA

Amoxapine (Asendin) - TCA

​

Approved for depression, not “antidepressant”

Esketamine (Spravato) - NMDA antagonist

Zuranolone (Zurzuvae) - Neuroactive steroid

Auvelity = bupropion + dextromethorphan

capable of causing life-threatening serotonin toxicity if combined with MAOI

Serotonergic

SRI as principal mechanism

Citalopram (Celexa) - SSRI

Escitalopram (Lexapro) - SSRI

Fluoxetine (Prozac) - SSRI

*Fluvoxamine (Luvox) - SSRI (OCD)

Paroxetine (Paxil) - SSRI

Sertraline (Zoloft) - SSRI

Venlafaxine (Effexor) - SNRI

Desvenlafaxine (Pristiq) - SNRI

Duloxetine (Cymbalta) - SNRI

Levomilnacipran (Fetzima) - SNRI

*Milnacipran (Savella) - SNRI (fibromyalgia)

Clomipramine (Anafranil) - TCA

Imipramine (Tofranil) - TCA

Vilazodone (Viibryd) - atypical antidepressant

Vortioxetine (Trintellix) - atypical antidepressant

SRI but not principal

Trazodone - atypical antidepressant

Nefazodone - atypical antidepressant

Amitriptyline (Elavil) - TCA

Doxepin (Silenor) - TCA

Trimipramine (Surmontil) - TCA

​

No significant SRI activity

Bupropion (Wellbutrin) - NDRI

Mirtazapine (Remeron) - atypical antidepressant

Gepirone (Exxua) - atypical antidepressant

Desipramine (Norpramin) - TCA

Nortriptyline (Pamelor) - TCA

Protriptyline (Vivactil) - TCA

Amoxapine (Asendin) - TCA

​

Approved for depression, not “antidepressant”

Esketamine (Spravato) - NMDA antagonist

Zuranolone (Zurzuvae) - Neuroactive steroid

Auvelity = bupropion + dextromethorphan

capable of causing life-threatening serotonin toxicity if combined with MAOI

NOT capable of causing life-threatening serotonin toxicity if combined with MAOI (Gillman)

Serotonin Toxicity - don’t say “serotonin syndrome”

Fever

Dilated pupils

Agitation

Sweating

5-HT

Hyperreflexia

“Twitchy frog”

Serotonin Toxicity - don’t say “serotonin syndrome”

Fever

Dilated pupils

Agitation

Sweating

5-HT

Hyperreflexia

“Twitchy frog”

Onset within 24 hours of medication addition.

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

Hunter criteria for serotonin toxicity:

Potent serotonergic agent plus any of the following:

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

Hunter criteria for serotonin toxicity:

Potent serotonergic agent plus any of the following:

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

Hunter criteria for serotonin toxicity:

Potent serotonergic agent plus any of the following:

For serotonin toxicity to be life-threatening, there must be fever.

​

​

100.4°F

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

For serotonin toxicity to be life-threatening, there must be fever.

​

​

​

?

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

For serotonin toxicity to be life-threatening, there must be fever.

​

​

​

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

For serotonin toxicity to be life-threatening, there must be fever.

​

The only way to achieve life-threatening serotonin toxicity is with a massive increase of serotonin in the synapse, which requires:

​

​

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

For serotonin toxicity to be life-threatening, there must be fever.

​

The only way to achieve life-threatening serotonin toxicity is with a massive increase of serotonin in the synapse, which requires:

​

• MAOI overdose

​

​

​

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

For serotonin toxicity to be life-threatening, there must be fever.

​

The only way to achieve life-threatening serotonin toxicity is with a massive increase of serotonin in the synapse, which requires:

​

• MAOI overdose
• MAOI + SRI

​

​

​

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

For serotonin toxicity to be life-threatening, there must be fever.

​

The only way to achieve life-threatening serotonin toxicity is with a massive increase of serotonin in the synapse, which requires:

​

• MAOI overdose
• MAOI + SRI
• MAOI + MDMA (ecstasy; serotonin releaser)

​

​

​

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

For serotonin toxicity to be life-threatening, there must be fever.

​

The only way to achieve life-threatening serotonin toxicity is with a massive increase of serotonin in the synapse, which requires:

​

• MAOI overdose
• MAOI + SRI
• MAOI + MDMA (ecstasy; serotonin releaser)
• Possibly MDMA overdose

​

​

​

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

For serotonin toxicity to be life-threatening, there must be fever.

​

The only way to achieve life-threatening serotonin toxicity is with a massive increase of serotonin in the synapse, which requires:

​

• MAOI overdose
• MAOI + SRI
• MAOI + MDMA (ecstasy; serotonin releaser)
• Possibly MDMA overdose

​

Twitchiness but not life-threatening serotonin toxicity:

​

​

​

​

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

For serotonin toxicity to be life-threatening, there must be fever.

​

The only way to achieve life-threatening serotonin toxicity is with a massive increase of serotonin in the synapse, which requires:

​

• MAOI overdose
• MAOI + SRI
• MAOI + MDMA (ecstasy; serotonin releaser)
• Possibly MDMA overdose

​

Twitchiness but not life-threatening serotonin toxicity:

• SRI overdose

​

​

​

​

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

For serotonin toxicity to be life-threatening, there must be fever.

​

The only way to achieve life-threatening serotonin toxicity is with a massive increase of serotonin in the synapse, which requires:

​

• MAOI overdose
• MAOI + SRI
• MAOI + MDMA (ecstasy; serotonin releaser)
• Possibly MDMA overdose

​

Twitchiness but not life-threatening serotonin toxicity:

• SRI overdose
• Multiple SRIs

​

​

​

Gillman, P. K. (2011). CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology, 25(3), 429-436.

For serotonin toxicity to be life-threatening, there must be fever.

​

The only way to achieve life-threatening serotonin toxicity is with a massive increase of serotonin in the synapse, which requires:

​

• MAOI overdose
• MAOI + SRI
• MAOI + MDMA (ecstasy; serotonin releaser)
• Possibly MDMA overdose

​

Twitchiness but not life-threatening serotonin toxicity:

• SRI overdose
• Multiple SRIs

​

Attenuated effect:

SRI + MDMA

• SRI interferes with MDMA’s serotonin-releasing mechanism

​

​

Serotonin (5-hydroxytryptamine)

sumatriptan

buspirone

prucalopride

BLOCKED BY ondansetron

Medications that selectively activate serotonin receptors do not contribute to serotonin toxicity.

​

Serotonin toxicity results from excessive actual serotonin in the synapse.

​

​

Unexpected life-threatening combos

Unexpected life-threatening combos

Unexpected life-threatening combos

Unexpected life-threatening combos

Antidepressants for Unipolar Depression

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Clinically significant improvement

= 3 points on HAM-D

Depression

Are antidepressants much better than placebo?

​

Depression

Are antidepressants much better than placebo?

​

Depends on what you’re treating

​

Unipolar Major Depression?

​

​

Depression

Are antidepressants much better than placebo?

​

Depends on what you’re treating

​

Unipolar Major Depression?

Dependent on severity and age

​

​

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

Antidepressants for Unipolar Depression

Meta-Analysis of Data Submitted to FDA for Approved Antidepressants

All (47) clinical trials submitted to the FDA for approval of new-generation antidepressants 1987 – 1999

​

​

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

Antidepressants for Unipolar Depression

Meta-Analysis of Data Submitted to FDA for Approved Antidepressants

All (47) clinical trials submitted to the FDA for approval of new-generation antidepressants 1987 – 1999

​

The antidepressants were

• Fluoxetine (Prozac) - SSRI
• Paroxetine (Paxil) - SSRI
• Citalopram (Celexa) - SSRI
• Sertraline (Zoloft) - SSRI
• Venlafaxine (Effexor) - SNRI
• Nefazodone - atypical

​

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

Antidepressants for Unipolar Depression

Meta-Analysis of Data Submitted to FDA for Approved Antidepressants

All (47) clinical trials submitted to the FDA for approval of new-generation antidepressants 1987 – 1999

​

The antidepressants were

• Fluoxetine (Prozac) - SSRI
• Paroxetine (Paxil) - SSRI
• Citalopram (Celexa) - SSRI
• Sertraline (Zoloft) - SSRI
• Venlafaxine (Effexor) - SNRI
• Nefazodone - atypical

​

20 out of 47 trials showed superiority over placebo.

​

​

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

Meta-Analysis of Data Submitted to FDA for Approved Antidepressants

All (47) clinical trials submitted to the FDA for approval of new-generation antidepressants 1987 – 1999

​

The antidepressants were

• Fluoxetine (Prozac) - SSRI
• Paroxetine (Paxil) - SSRI
• Citalopram (Celexa) - SSRI
• Sertraline (Zoloft) - SSRI
• Venlafaxine (Effexor) - SNRI
• Nefazodone - atypical

​

Graphed not according to trial but by initial severity of depression.

​

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

Meta-Analysis of Data Submitted to FDA for Approved Antidepressants

All (47) clinical trials submitted to the FDA for approval of new-generation antidepressants 1987 – 1999

​

The antidepressants were

• Fluoxetine (Prozac) - SSRI
• Paroxetine (Paxil) - SSRI
• Citalopram (Celexa) - SSRI
• Sertraline (Zoloft) - SSRI
• Venlafaxine (Effexor) - SNRI
• Nefazodone - atypical

​

Graphed not according to trial but by initial severity of depression.

Antidepressants for Unipolar Depression

23+ is severe

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

All (47) clinical trials submitted to the FDA for approval of new-generation antidepressants 1987 – 1999

​

The antidepressants were

• Fluoxetine (Prozac) - SSRI
• Paroxetine (Paxil) - SSRI
• Citalopram (Celexa) - SSRI
• Sertraline (Zoloft) - SSRI
• Venlafaxine (Effexor) - SNRI
• Nefazodone - atypical

​

Graphed not according to trial but by initial severity of depression.

Antidepressants for Unipolar Depression

23+ is severe

28+ is very severe

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

All (47) clinical trials submitted to the FDA for approval of new-generation antidepressants 1987 – 1999

​

The antidepressants were

• Fluoxetine (Prozac) - SSRI
• Paroxetine (Paxil) - SSRI
• Citalopram (Celexa) - SSRI
• Sertraline (Zoloft) - SSRI
• Venlafaxine (Effexor) - SNRI
• Nefazodone - atypical

​

Graphed not according to trial but by initial severity of depression.

Antidepressants for Unipolar Depression

23+ is severe

28+ is very severe

Clinically significant improvement

= 3 points on HAM-D

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

Antidepressants for Unipolar Depression

23+ is severe

28+ is very severe

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

Antidepressants for Unipolar Depression

3 points

on HAM-D

23+ is severe

28+ is very severe

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

Antidepressants for Unipolar Depression

3 points

on HAM-D

23+ is severe

28+ is very severe

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

All groups improved to a clinically significant extent except for 4 placebo groups

Antidepressants for Unipolar Depression

23+ is severe

28+ is very severe

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

moderate

depression

Antidepressants for moderate depression did not separate from placebo

Antidepressants for Unipolar Depression

3 points

on HAM-D

23+ is severe

28+ is very severe

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

Antidepressants for Unipolar Depression

3 points

on HAM-D

23+ is severe

28+ is very severe

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

Antidepressants for Unipolar Depression

3 points

on HAM-D

23+ is severe

28+ is very severe

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

Clinically significant improvement

= 3 points on HAM-D

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Clinically significant improvement

= 3 points on HAM-D

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Clinically significant improvement

= 3 points on HAM-D

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Meta-Analysis Findings:

​

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Meta-Analysis Findings:

​

• Placebo effect for depression is robust

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Meta-Analysis Findings:

​

• Placebo effect for depression is robust ➤ but less so for more severe

depression

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Meta-Analysis Findings:

​

• Placebo effect for depression is robust ➤ but less so for more severe

depression

​

• Other than for very severe depression..

​

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Meta-Analysis Findings:

​

• Placebo effect for depression is robust ➤ but less so for more severe

depression

​

• Other than for very severe depression, benefit of antidepressant compared to placebo falls below accepted criteria for clinical significance.

​

​

Antidepressants for Unipolar Depression

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLOS Medicine 5(2): e45. https://doi.org/10.1371/journal.pmed.0050045

Cipriani, A., et al. (2010). "Antidepressants versus placebo in depressive disorders: a systematic review and meta-analysis." The Lancet, 376(9758), 635-643.

​

​

​

​

​

23+ is severe

28+ is very severe

Meta-Analysis Findings:

​

• Placebo effect for depression is robust ➤ but less so for more severe

depression

​

• Other than for very severe depression, benefit of antidepressant compared to placebo falls below accepted criteria for clinical significance.

​

• Kirsch et al conclusion: “There is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective”.

​

Antidepressants for Unipolar Depression

23+ is severe

28+ is very severe

Meta-Analysis Findings:

​

• Placebo effect for depression is robust ➤ but less so for more severe

depression

​

• Other than for very severe depression, benefit of antidepressant compared to placebo falls below accepted criteria for clinical significance.

​

• Kirsch et al conclusion: “There is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective”.

​

SRIs are effective for anxiety disorders, OCD, bulimia, etc

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

?

very

severe

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug

Would have improved with placebo

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug

Would have improved with placebo

Would have improved with no intervention

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug

Would have improved with placebo

Would have improved with no intervention

Did not improve

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

?

severe

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug

Would have improved with placebo

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug

Would have improved with placebo

Would have improved with no intervention

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug

Would have improved with placebo

Would have improved with no intervention

Did not improve

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT =

​

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

?

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

~75% of people get better in this example

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

~75% of people get better in this example

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug

Would have improved with placebo

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

~75% of people get better in this example

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug

Would have improved with placebo

Would have improved with no intervention

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

~75% of people get better in this example

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug

Would have improved with placebo

Would have improved with no intervention

Did not improve

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

~75% of people get better in this example

​

Mild depression NNT =

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug

Would have improved with placebo

Would have improved with no intervention

Mood worse due to drug?

Did not improve

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT = ?

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

?

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT = not tested

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT = ?

~68% of people get better in this example

​

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

​

​

​

​

​

Antidepressants for Unipolar Depression

Improved because of active drug?

Mood worse due to drug?

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT = ?

​

​

​

​

​

​

​

​

Antidepressants for Unipolar Depression

Number needed to harm (NNH)

SRIs

​

Sexual dysfunction (SRIs only)

NNH = 3

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., et al. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

Henssler, J., Schmidt, Y., Schmidt, U., et al. (2024). Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis. The Lancet Psychiatry.

Wu et al. (2012). "Use of antidepressants and risk of fractures: a meta-analysis of observational studies." Osteoporosis International.

​

​

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT = ?

​

​

​

​

​

​

​

​

Antidepressants for Unipolar Depression

Number needed to harm (NNH)

SRIs

​

Sexual dysfunction

NNH = 3

​

Post-SRI sexual dysfunction (PSSD)

• Also called persistent genital

arousal disorder

• Potentially irreversible
• epigenetic? neuroplasticity?
• Formally recognized by regulatory agencies in Europe and Canada
• NNH 100–1,000

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., et al. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

Henssler, J., Schmidt, Y., Schmidt, U., et al. (2024). Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis. The Lancet Psychiatry.

Wu et al. (2012). "Use of antidepressants and risk of fractures: a meta-analysis of observational studies." Osteoporosis International.

​

​

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT = ?

​

​

​

​

​

​

​

​

Antidepressants for Unipolar Depression

Number needed to harm (NNH)

SRIs

​

Sexual dysfunction

NNH = 3

​

Discontinuation symptoms

NNH = 7

• Brain zaps/electric sensations
• Dizziness/vertigo
• Nausea
• Anxiety/agitation
• Sleep disturbances
• Paresthesias (tingling/numbness)
• Flu-like symptoms (fatigue, aches)

​

Typically start within 24-72 hours of missed dose

​

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., et al. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

Henssler, J., Schmidt, Y., Schmidt, U., et al. (2024). Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis. The Lancet Psychiatry.

Wu et al. (2012). "Use of antidepressants and risk of fractures: a meta-analysis of observational studies." Osteoporosis International.

​

​

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT = ?

​

​

​

​

​

​

​

​

Antidepressants for Unipolar Depression

Number needed to harm (NNH)

SRIs

​

Sexual dysfunction

NNH = 3

​

Discontinuation symptoms

NNH = 7

​

Suicidal thoughts and behaviors

NNH = 50–200 (children, young adults)

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., et al. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

Henssler, J., Schmidt, Y., Schmidt, U., et al. (2024). Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis. The Lancet Psychiatry.

Wu et al. (2012). "Use of antidepressants and risk of fractures: a meta-analysis of observational studies." Osteoporosis International.

​

​

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT = ?

​

​

​

​

​

​

​

​

Antidepressants for Unipolar Depression

Number needed to harm (NNH)

SRIs

​

Sexual dysfunction

NNH = 3

​

Discontinuation symptoms

NNH = 7

​

Suicidal thoughts and behaviors

NNH = 50–200 (children, young adults)

​

GI bleeding

NNH = 200–500

​

​

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., et al. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

Henssler, J., Schmidt, Y., Schmidt, U., et al. (2024). Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis. The Lancet Psychiatry.

Wu et al. (2012). "Use of antidepressants and risk of fractures: a meta-analysis of observational studies." Osteoporosis International.

​

​

Number needed to treat (NNT)

To obtain one response that is not a placebo response

​

Very severe depression NNT = 4

​

Severe depression NNT = 11

​

Moderate depression NNT = 16

​

Mild depression NNT = ?

​

​

​

​

​

​

​

​

Antidepressants for Unipolar Depression

Number needed to harm (NNH)

SRIs

​

Sexual dysfunction

NNH = 3

​

Discontinuation symptoms

NNH = 7

​

Suicidal thoughts and behaviors

NNH = 50–200 (children, young adults)

​

GI bleeding

NNH = 200–500

​

Hip fracture

NNH = 200–500 (older adults)

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., et al. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama, 303(1), 47-53.

Henssler, J., Schmidt, Y., Schmidt, U., et al. (2024). Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis. The Lancet Psychiatry.

Wu et al. (2012). "Use of antidepressants and risk of fractures: a meta-analysis of observational studies." Osteoporosis International.

​

​

Number needed to treat (NNT)

​

​

​

​

​

​

Antidepressants for Depression

El-Mallakh, R. S., Vöhringer, P. A., Ostacher, M. M., Baldassano, C. F., Holtzman, N. S., Whitham, E. A., ... & Ghaemi, S. N. (2015). Antidepressants worsen rapid-cycling course in bipolar depression: a STEP-BD randomized clinical trial. Journal of Affective Disorders, 184, 318-321.

Number needed to treat (NNT)

​

​

​

​

​

​

Antidepressants for Depression

El-Mallakh, R. S., Vöhringer, P. A., Ostacher, M. M., Baldassano, C. F., Holtzman, N. S., Whitham, E. A., ... & Ghaemi, S. N. (2015). Antidepressants worsen rapid-cycling course in bipolar depression: a STEP-BD randomized clinical trial. Journal of Affective Disorders, 184, 318-321.

?

?

?

Number needed to treat (NNT)

​

​

​

​

​

​

Antidepressants for Depression

El-Mallakh, R. S., Vöhringer, P. A., Ostacher, M. M., Baldassano, C. F., Holtzman, N. S., Whitham, E. A., ... & Ghaemi, S. N. (2015). Antidepressants worsen rapid-cycling course in bipolar depression: a STEP-BD randomized clinical trial. Journal of Affective Disorders, 184, 318-321.

Rapid

Mood

Screener

​

88% sensitive

80% specific

for Bipolar I

“YES” to 4 of 6 items

Antidepressants for Bipolar Depression

Conceptual, not actual data

23+ is severe

28+ is very severe

Antidepressants for Bipolar Depression

Conceptual, not actual data

23+ is severe

28+ is very severe

Antidepressants for Bipolar Depression

Conceptual, not actual data

23+ is severe

28+ is very severe

Antidepressants for Bipolar Depression

Conceptual, not actual data

23+ is severe

28+ is very severe

Clinically significant improvement

= 3 points on HAM-D

Antidepressants for Bipolar Depression

Conceptual, not actual data

23+ is severe

28+ is very severe

Clinically significant improvement

= 3 points on HAM-D

Worse than placebo*

​

​

*exception of fluoxetine combined with olanzapine (Symbyax)

Office-based psychiatric visits for treatment of bipolar disorder:

​

~18% prescribed lithium

​

~57% antidepressant

​

~18% antidepressant monotherapy

​

Antidepressants for Bipolar Disorder

Rhee, T. G., Olfson, M., Nierenberg, A. A., & Wilkinson, S. T. (2020). 20-year trends in the pharmacologic treatment of bipolar disorder by psychiatrists in outpatient care settings. American Journal of Psychiatry, 177(8), 706-715.

​

​

Clinically

significant

improvement

Antidepressants for Bipolar Disorder

But I’ve seen antidepressants work for my bipolar patients.

Antidepressants for Bipolar Disorder

But I’ve seen antidepressants work for my bipolar patients.

It is nearly impossible for you or your patient to really know whether the active drug is helping, due to:

​

❖ large placebo

effect in depression

​

❖ natural course of an

episodic illness

Depression

Are antidepressants much better than placebo?

​

Depression

Are antidepressants much better than placebo?

​

Depends on what you’re treating...

​

​

​

​

​

Depression

Are antidepressants much better than placebo?

​

Depends on what you’re treating...

​

for severe depression?

​

​

​

​

Depression

Are antidepressants much better than placebo?

​

Depends on what you’re treating...

​

for very severe depression

​

​

​

Depression

Are antidepressants much better than placebo?

​

Depends on what you’re treating...

​

for very severe depression, yes.

​

​

​

​

Depression

Are antidepressants much better than placebo?

​

Depends on what you’re treating...

​

for very severe unipolar depression, yes.

​

​

​

​

Depression

Are antidepressants much better than placebo?

​

Depends on what you’re treating...

​

for very severe unipolar depression in older individuals, yes.

​

​

​

​

Antidepressants for Unipolar Depression

Under age 25

?

Antidepressants for Unipolar Depression

Under age 25

Antidepressants for Unipolar Depression

Under age 25

Antidepressants worsen the course of depressive illness for some patients.

Adolescent Suicides

→ increased suicides after FDA warning

Adolescent Suicides

Antidepressants for Unipolar Depression

​

Stone, M., Laughren, T., Jones, M. L., Levenson, M., Holland, P. C., Hughes, A., ... & Rochester, G. (2009). Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Bmj, 339.

Suicidality (ideation or worse) with antidepressant relative to placebo

​

0 1 2

Odds ratio

(95% CI)

Age

Antidepressants for Unipolar Depression

​

Stone, M., Laughren, T., Jones, M. L., Levenson, M., Holland, P. C., Hughes, A., ... & Rochester, G. (2009). Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Bmj, 339.

Suicidality (ideation or worse) with antidepressant relative to placebo

​

0 1 2

Odds ratio

(95% CI)

Age

Antidepressants for Unipolar Depression

​

Stone, M., Laughren, T., Jones, M. L., Levenson, M., Holland, P. C., Hughes, A., ... & Rochester, G. (2009). Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Bmj, 339.

Suicidality (ideation or worse) with antidepressant relative to placebo

​

0 1 2

Odds ratio

(95% CI)

Age

same as placebo

Antidepressants for Unipolar Depression

​

Stone, M., Laughren, T., Jones, M. L., Levenson, M., Holland, P. C., Hughes, A., ... & Rochester, G. (2009). Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Bmj, 339.

Suicidality (ideation or worse) with antidepressant relative to placebo

​

0 1 2

Odds ratio

(95% CI)

Age

half placebo

same as placebo

Antidepressants for Unipolar Depression

for Depression

Stone, M., Laughren, T., Jones, M. L., Levenson, M., Holland, P. C., Hughes, A., ... & Rochester, G. (2009). Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Bmj, 339.

Suicidality (ideation or worse) with antidepressant relative to placebo

​

0 1 2

Odds ratio

(95% CI)

Age

half placebo

double placebo

same as placebo

Antidepressants for Unipolar Depression

​

Stone, M., Laughren, T., Jones, M. L., Levenson, M., Holland, P. C., Hughes, A., ... & Rochester, G. (2009). Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Bmj, 339.

Suicidality (ideation or worse) with antidepressant relative to placebo

​

0 1 2

Odds ratio

(95% CI)

Age

placebo

Antidepressants for Unipolar Depression

​

Stone, M., Laughren, T., Jones, M. L., Levenson, M., Holland, P. C., Hughes, A., ... & Rochester, G. (2009). Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Bmj, 339.

Suicidality (ideation or worse) with antidepressant relative to placebo

​

0 1 2

Odds ratio

(95% CI)

Age

0.83

(0.69– 1.00)

placebo

antidepressants

Antidepressants for Unipolar Depression

​

Stone, M., Laughren, T., Jones, M. L., Levenson, M., Holland, P. C., Hughes, A., ... & Rochester, G. (2009). Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Bmj, 339.

Suicidality (ideation or worse) with antidepressant relative to placebo

​

0 1 2

Odds ratio

(95% CI)

Age

placebo

Age

Antidepressants for Unipolar Depression

​

Stone, M., Laughren, T., Jones, M. L., Levenson, M., Holland, P. C., Hughes, A., ... & Rochester, G. (2009). Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Bmj, 339.

Suicidality (ideation or worse) with antidepressant relative to placebo

​

0 1 2

Odds ratio

(95% CI)

Age

Age

Antidepressants for Unipolar Depression

​

Stone, M., Laughren, T., Jones, M. L., Levenson, M., Holland, P. C., Hughes, A., ... & Rochester, G. (2009). Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Bmj, 339.

Suicidality (ideation or worse) with antidepressant relative to placebo

​

0 1 2

Odds ratio

(95% CI)

Age

Age

Antidepressants for Unipolar Depression

​

Stone, M., Laughren, T., Jones, M. L., Levenson, M., Holland, P. C., Hughes, A., ... & Rochester, G. (2009). Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Bmj, 339.

Suicidality (ideation or worse) with antidepressant relative to placebo

​

0 1 2

Odds ratio

(95% CI)

Age

Age

Antidepressants for Unipolar Depression

​

Stone, M., Laughren, T., Jones, M. L., Levenson, M., Holland, P. C., Hughes, A., ... & Rochester, G. (2009). Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Bmj, 339.

Suicidality (ideation or worse) with antidepressant relative to placebo

​

0 1 2

Odds ratio

(95% CI)

Age

Age

Antidepressants for Unipolar Depression

​

Stone, M., Laughren, T., Jones, M. L., Levenson, M., Holland, P. C., Hughes, A., ... & Rochester, G. (2009). Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Bmj, 339.

Suicidality (ideation or worse) with antidepressant relative to placebo

​

0 1 2

Odds ratio

(95% CI)

Age

Age

Adolescent Suicides

Suicides increased after the boxed warning.

​

Because doctors stopped prescribing antidepressants?

Adolescent Suicides

Youth depression

treatment visits

Adolescent Suicides

Youth depression

treatment visits

mood improved

due to placebo

mood improved due

to antidepressant

​

mood would have

improved with no

intervention

mood did not

improve

​

mood possibly worse due to antidepressant?

​

Depression

Are antidepressants much better than placebo?

Yes, for depression that is:

​

​

Depression

Are antidepressants much better than placebo?

Yes, for depression that is:

• Very severe

​

​

Depression

Are antidepressants much better than placebo?

Yes, for depression that is:

• Very severe
• Unipolar
• not in individuals with history of mania or hypomania

​

Depression

Are antidepressants much better than placebo?

Yes, for depression that is:

• Very severe
• Unipolar
• not in individuals with history of mania or hypomania
• Older individuals

​

Psychiatric interview

Essential to any mental health assessment:

You must exclude a lifetime history of a manic or hypomanic episode.

Psychiatric interview

My bipolar screening question:

​

Have you, or anyone in your family, been suspected of being bipolar?

​

Have you ever had an elevated mood? (I can explain what that is)

​

Has there ever been a time, lasting several days where you were

• not your usual self,
• in an intense way
• maybe “high on life”
• or extremely irritable
• maybe having lots of big ideas
• maybe talking more than usual
• not needing to sleep as much
• or possibly feeling invincible?

Essential to any mental health assessment:

You must exclude a lifetime history of a manic or hypomanic episode.

NRI

Norepinephrine reuptake inhibitor (NRI)

SSRIs

Which will be your preferred SSRI to prescribe?

SSRIs

SSRIs

SSRIs

SSRIs

SSRIs

SSRIs

SSRIs

Very subtle differences in mechanism of action.

​

None is significantly more effective than others for most of the evidence-based indications of SSRIs.

Preferred SSRI for (specific indication)

​

• Stronger evidence base compared to other SSRIs usually relates to quantity/quality of trials rather than demonstrated superior efficacy

​

• Examples of stronger evidence of efficacy vs placebo (without proven superiority) to other SSRIs:

​

• Adolescent depression – fluoxetine (approved 8+)
• OCD – sertraline, fluoxetine, fluvoxamine
• Panic disorder – sertraline, paroxetine
• PMDD – sertraline, paroxetine, fluoxetine
• Binge eating disorder – fluoxetine & sertraline

SSRIs

Preferred SSRI for (specific indication)

​

Examples of SSRIs with evidence of superiority over others

​

• Established but unlikely to be clinically meaningful:
• Major depressive d/o – escitalopram (efficacy and tolerability)
• PTSD – sertraline (efficacy)
• Social anxiety – paroxetine (efficacy)

SSRIs

Preferred SSRI for (specific indication)

​

Examples of SSRIs with over others

​

• Evidence of superiority – unlikely to be clinically meaningful:
• Major depressive d/o – escitalopram (efficacy and tolerability)
• PTSD – sertraline (efficacy)
• Social anxiety – paroxetine (efficacy)

​

• Possibly meaningful evidence of superiority
• Bulimia nervosa – fluoxetine (efficacy)
• Only FDA-approved medication

for bulimia

• Effect size 0.4-0.5 (NNT = 4)

SSRIs

↓ anxiety

​

hallucinations

appetite suppression

decreased dopamine downstream

nausea

intestinal motility

?

vasoconstriction

?

downstream release of other neurotransmitters

Drugs acting on specific serotonin receptor subtypes

↓ anxiety

​

hallucinations

appetite suppression

decreased dopamine downstream

nausea

intestinal motility

vasoconstriction

?

downstream release of other neurotransmitters

buspirone

Drugs acting on specific serotonin receptor subtypes

?

↓ anxiety

​

hallucinations

appetite suppression

decreased dopamine downstream

nausea

intestinal motility

vasoconstriction

?

downstream release of other neurotransmitters

sumatriptan

buspirone

Drugs acting on specific serotonin receptor subtypes

?

↓ anxiety

​

hallucinations

appetite suppression

decreased dopamine downstream

nausea

intestinal motility

vasoconstriction

?

downstream release of other neurotransmitters

sumatriptan

buspirone

psilocybin

Drugs acting on specific serotonin receptor subtypes

?

↓ anxiety

​

hallucinations

appetite suppression

decreased dopamine downstream

nausea

intestinal motility

vasoconstriction

?

downstream release of other neurotransmitters

sumatriptan

buspirone

fenfluramine

psilocybin

Drugs acting on specific serotonin receptor subtypes