Antidepressants
Jason Cafer, MD
Slides and handouts – bit.ly/slides2026
Antidepressants – Learning topics
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)
Serotonin reuptake inhibitor (SRI)
SERT
SRI
NRI
Norepinephrine reuptake inhibitor (NRI)
Serotonin and norepinephrine reuptake inhibitor (SNRI)
SERT
SNRI
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
Mirtazapine: noradrenergic and specific serotonergic antidepressants (NaSSA) –
receptor blocker
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
Mirtazapine: noradrenergic and specific serotonergic antidepressants (NaSSA) –
receptor blocker
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
Mirtazapine: noradrenergic and specific serotonergic antidepressants (NaSSA) –
receptor blocker
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
Arbitrarily, they are all ________ and/or _________
Antidepressants
What’s an antidepressant?
Arbitrary category of mostly serotonergic medications
The majority are SRIs
Arbitrarily, they are all serotonergic and/or noradrenergic
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
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
20 out of 47 trials showed superiority over placebo.
?
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
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
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
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
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
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:
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:
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:
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:
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:
depression
Antidepressants for Unipolar Depression
23+ is severe
28+ is very severe
Meta-Analysis Findings:
depression
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
?
moderate
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 (SRIs only)
NNH = 3
Post-SRI sexual dysfunction (PSSD)
arousal disorder
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 (SRIs only)
NNH = 3
Discontinuation symptoms
NNH = 7
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 (SRIs only)
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 (SRIs only)
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 (SRIs only)
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
| Unipolar depression |
Very severe | NNT = 4 |
Severe | NNT = 11 |
Moderate | NNT = 16 |
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
| Unipolar depression | Bipolar depression STEP-BD (7000 patients, 5 yr) |
Very severe | NNT = 4 | NNT = infinity |
Severe | NNT = 11 | NNT = infinity |
Moderate | NNT = 16 | NNT = infinity |
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
| Unipolar depression | Bipolar depression STEP-BD (7000 patients, 5 yr) |
Very severe | NNT = 4 | NNT = infinity |
Severe | NNT = 11 | NNT = infinity |
Moderate | NNT = 16 | NNT = infinity |
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.
23+ is severe
28+ is very severe
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
25–64
(0.64– 0.98)
0.79
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
25–64
(0.64– 0.98)
0.79
Age
<25
≥65
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
25–64
(0.64– 0.98)
0.79
Age
<25
≥65
(0.97– 2.71)
1.62
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
25–64
(0.64– 0.98)
0.79
Age
<25
≥65
(0.97– 2.71)
1.62
(0.18– 0.76)
0.37
(0.18– 0.76)
0.37
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
25–64
(0.64– 0.98)
0.79
Age
<25
≥65
(0.97– 2.71)
1.62
(0.18– 0.76)
0.37
(0.18– 0.76)
0.37
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
25–64
(0.64– 0.98)
0.79
Age
<25
≥65
(0.97– 2.71)
1.62
(0.18– 0.76)
0.37
(0.18– 0.76)
0.37
Antidepressants: FDA Prescribing Info
?
Antidepressants: FDA Prescribing Info
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:
Depression
Are antidepressants much better than placebo?
Yes, for depression that is:
Depression
Are antidepressants much better than placebo?
Yes, for depression that is:
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
Essential to any mental health assessment:
You must exclude a lifetime history of a manic or hypomanic episode.
Serotonin reuptake inhibitor (SRI)
SERT
SRI
NRI
Norepinephrine reuptake inhibitor (NRI)
Serotonin and norepinephrine reuptake inhibitor (SNRI)
SERT
SNRI
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)
SSRIs
Preferred SSRI for (specific indication)
Examples of SSRIs with evidence of superiority over others
SSRIs
Preferred SSRI for (specific indication)
Examples of SSRIs with over others
for bulimia
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
?
↓ anxiety
hallucinations
appetite suppression
decreased dopamine downstream
nausea
intestinal motility
vasoconstriction
?
downstream release of other neurotransmitters
sumatriptan
buspirone
prucalopride
fenfluramine
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
prucalopride
fenfluramine
psilocybin
BLOCKED BY ondansetron
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
prucalopride
fenfluramine
psilocybin
BLOCKED BY ondansetron
BLOCKED BY fluoxetine
Drugs acting on specific serotonin receptor subtypes
?
SSRIs
SSRIs
SSRIs
weak antihistamine
SSRIs
SSRIs
moderate anticholinergic
SSRIs
inhibits nitric oxide synthase
→ erectile dysfunction
SSRIs
SSRIs
Sigma-1 antagonist
SSRIs
Ion channel blocker
Ion channel blocker
Ion channel blocker
SSRIs
SSRIs
SSRIs
QT prolongation
SSRIs
SSRIs
Pure S-enantiomer of citalopram
SSRIs
Racemic mix: 50% R- / 50% S-
R- interferes with efficacy of S-
Pure S-enantiomer of citalopram
SSRIs
Pure S-enantiomer of citalopram
Racemic mix: 50% R- / 50% S-
R- interferes with efficacy of S-
SSRIs
Based on pharmacodynamics (mechanism of action), choose your favorite.
Single-drug fatality in overdose
QT prolongation
These two are ok but inferior to other SSRIs (side effects).
1 in 10,000
Single-drug fatality in overdose
1 in 7,000
1 in 2,500
1 in 10,000
QT prolongation
These two are ok but inferior to other SSRIs (side effects).
Pharmacokinetic interaction visuals
inHibitor
“High and Hurried”
Pharmacokinetic interaction visuals
inHibitor
“High and Hurried”
inDucer
“Down and Delayed”
Pharmacokinetic interaction visuals
inHibitor
“High and Hurried”
inDucer
“Down and Delayed”
sensitive substrate
Pharmacokinetic interaction visuals
inHibitor
substrate
Pharmacokinetic interaction visuals
substrate
inHibitor
Pharmacokinetic interaction visuals
substrate
inHibitor
Pharmacokinetic interaction visuals
substrate
inHibitor
Pharmacokinetic interaction visuals
substrate
inHibitor
Pharmacokinetic interaction visuals
inHibitor
substrate
inHibitor
substrate
Pharmacokinetic interaction visuals
inHibitor
substrate
Pharmacokinetic interaction visuals
“High and Hurried”
Pharmacokinetic interaction visuals
inDucer
substrate
Pharmacokinetic interaction visuals
substrate
inDucer
Pharmacokinetic interaction visuals
substrate
inDucer
Pharmacokinetic interaction visuals
substrate
inDucer
“Down and Delayed”
Pharmacokinetic interaction visuals
inHibitor
“High and Hurried”
Pharmacokinetic interaction visuals
inHibitor
“High and Hurried”
“Down and Delayed”
inDucer
Pharmacokinetic interaction visuals
sensitive substrate
inHibitor
“High and Hurried”
“Down and Delayed”
inDucer
Pharmacokinetic interaction visuals
sensitive substrate
inHibitor
“High and Hurried”
“Down and Delayed”
inDucer
Pharmacokinetic interaction visuals
sensitive substrate
not an inHibitor
not an inDucer
inHibitor
“High and Hurried”
“Down and Delayed”
inDucer
Pharmacokinetic interaction visuals
sensitive substrate
not an inHibitor
not an inDucer
not a sensitive substrate
inHibitor
“High and Hurried”
“Down and Delayed”
inDucer
SSRIs
SSRIs
SSRIs
“Fluffer
inHibitors”
Which of the following drug interactions is expected with fluoxetine (Prozac)?
A) 50–150% increase in amitriptyline
B) 100–200% increase in metoprolol
C) 100% increase in atomoxetine
D) 30% reduction of active form of tamoxifen
Which of the following drug interactions is expected with fluoxetine (Prozac)?
A) 50–150% increase in amitriptyline
B) 100–200% increase in metoprolol
C) 100% increase in atomoxetine
D) 30% reduction of active form of tamoxifen
all ~true
Which of the following drug interactions is expected with fluoxetine (Prozac)?
A) 100–300% increase in amitriptyline
B) 400–500% increase in metoprolol
C) 300% increase in atomoxetine
D) 65–75% reduction of active form of tamoxifen
all true
SSRIs
SSRIs
SSRIs
SSRIs
SSRIs
SSRIs
SSRIs
SSRIs
SSRIs
Considering both pharmacodynamics & pharmacokinetics, choose your favorite.
US Sales Rank, All Antidepressants
#1
#2
#3
SSRIs
#1
#3
#7
#9
#2
#14
NRIs
#4
strong inHibitor
→ do not
prescribe casually!
No serotonin!
❖ No sexual side effects
❖ No withdrawal symptoms
❖ No weight gain
❖ Probably less likely to destabilize
bipolar disorder
➤ although ineffective for bipolar depression
NRIs
#4
wake promotor
ADHD med
ADHD
med
strong inHibitor
→ do not
prescribe casually!
NRIs
#4
wake promotor
ADHD med
ADHD
med
#13
#18
strong inHibitor
→ do not
prescribe casually!
metabolized to
2D6
SNRIs
#6
#8
#11
#17
#12
Pain med
Atypical Antidepressants
#10
#5
#15
#16
only non-reuptake
inhibitor in top 20
→ exclusively a receptor blocker
→ principal mechanism is blocking alpha-2A norepinephrine receptors
Slides and handouts – bit.ly/slides2026
Evidence-based Alternatives to Antidepressants
Light Therapy
Bright light therapy
Dawn simulation
Lifestyle Modifications
Sleep hygiene improvement
Social rhythm therapy
Mediterranean diet
Social connection and support
Stress reduction techniques
Stress management
Mindfulness practices
Yoga
Tai chi
Music Therapy
Art Therapy
Ecotherapy (nature exposure)
Digital Therapeutics
FDA-cleared apps
Social Prescribing
Volunteer work
Group activities
Social skills training
Psychotherapy
Cognitive Behavioral Therapy (CBT)
Interpersonal Therapy (IPT)
Behavioral Activation (BA)
Psychodynamic Therapy
Problem-Solving Therapy
Acceptance and Commitment Therapy
Mindfulness-Based Cognitive Therapy
Exercise
Aerobic exercise (moderate to vigorous)
Resistance training
Regular structured physical activity
Group exercise programs
Brain Stimulation Therapies
Electroconvulsive Therapy (ECT)
for severe/treatment-resistant
Transcranial Magnetic Stimulation (TMS)
Vagus Nerve Stimulation (VNS)
Transcranial Direct Current Stimulation (tDCS)
External Combined Occipital and Trigeminal
Afferent Stimulation (eCOT-AS; ProLivRx)
Medications/Supplements
Lithium
T3 Thyroid hormone
SAM-e
Omega-3 fatty acids (EPA)
Vitamin D
Creatine
Saffron
L-methylfolate
St. John's Wort (drug interactions)
Moderate Evidence
Acupuncture
N-acetylcysteine (NAC)
Curcumin/turmeric
Zinc
Magnesium
L-tryptophan/5-HTP
B-complex vitamins
Inositol
Probiotics
Virtual Reality Therapy
These 4 are not for bipolar (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
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, even 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:
5-HT
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:
5-HT
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:
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:
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:
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:
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:
Twitchiness but not life-threatening serotonin toxicity:
Attenuated effect:
SRI + MDMA
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Transporter (SERT)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Serotonin Releaser – Effect of MDMA (Ecstasy, Molly)
Attenuated effect:
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
SRI activity |
|
|
|
MAOI activity |
Phenelzine (NARDIL) |
Tranylcypromine (PARNATE) |
Isocarboxazid (MARPLAN) |
Selegiline (EMSAM) ≥9 mg/day patch) |
Linezolid |
Methylene blue (IV) |
Metaxalone (SKELAXIN) |
Unexpected life-threatening combos
SRI activity |
Tramadol (ULTRAM) |
Dextromethorphan |
Fentanyl |
MAOI activity |
Phenelzine (NARDIL) |
Tranylcypromine (PARNATE) |
Isocarboxazid (MARPLAN) |
Selegiline (EMSAM) ≥9 mg/day patch) |
Linezolid |
Methylene blue (IV) |
Metaxalone (SKELAXIN) |
MAOI activity |
Phenelzine (NARDIL) |
Tranylcypromine (PARNATE) |
Isocarboxazid (MARPLAN) |
Selegiline (EMSAM) ≥9 mg/day patch) |
Linezolid |
Methylene blue (IV) |
Metaxalone (SKELAXIN) |
Unexpected life-threatening combos
SRI activity |
Tramadol (ULTRAM) |
Dextromethorphan |
Fentanyl |
Tapentadol (NUCYNTA) |
Cyclobenzaprine (FLEXERIL) |
Chlorpheniramine |
Meperidine (DEMEROL) |
Ziprasidone (GEODON) |
Centanafadine (SIMTRIYO) |
Medication | Concern | Gillman Verdict | Comment |
Lithium | Indirect “serotonergic” | ✅ Safe | No evidence of MAOI interaction |
TCAs (low dose) | Weak SRIs | ⚠️ Exception of clomipramine and imipramine | Most are NRI dominant |
Mirtazapine | Marketed as a noradrenergic and specific serotonergic antidepressants (NaSSA) | ✅ 100% certainly safe | Actually antiserotonergic; demonstrated to treat serotonin toxicity in animal models |
Trazodone (low dose) | Weak SRI | ✅ Safe at <100 mg | Caution at higher doses |
Ondansetron | 5-HT3 antagonist | ✅ Safe | No SRI activity |
Atypical antipsychotics | 5-HT receptor antagonist effects | ⚠️ Exception of ziprasidone | No MAOI/SRI interaction |
Meds Often Avoided but Likely Safe with MAOIs
→ not implicated in dangerous serotonin toxicity
1. Which statement about antidepressant efficacy is correct?
A) SSRIs are more effective for mild/moderate depression
B) Antidepressants prevent suicide across all age ranges
C) SSRIs are evidence-based for bipolar depression
D) The placebo response diminishes with increasing depression severity
2. A 22-year-old presents with depression. Which risk-benefit consideration is most accurate?
A) SSRIs have favorable risk-benefit in young adults
B) Risk of suicidality is decreased in this age group with SSRIs
C) SSRIs show increased suicidality risk vs placebo in this age group
D) Age does not affect SSRI risk-benefit ratio
3. Which medication requires the most caution regarding drug interactions?
A) Sertraline
B) Escitalopram
C) Fluoxetine
D) Mirtazapine
4. Which is correct regarding suicide prevention?
A) All antidepressants have equal efficacy
B) SSRIs are most effective
C) Lithium shows strongest evidence
D) Psychotherapy shows strongest evidence
5. Which antidepressant works through a fundamentally different mechanism?
A) Venlafaxine
B) Fluoxetine
C) Mirtazapine
D) Duloxetine
6. Regarding antidepressant discontinuation syndrome, which is correct?
A) Can be physically dangerous if untreated
B) May occur with all serotonin reuptake inhibitors
C) May occur with any antidepressant class
D) Should not be discussed with patients to avoid declining essential treatment
7. Considering drug-drug interactions, which SSRI is more appropriate for patients taking multiple medications?
A) Paroxetine
B) Escitalopram
C) Fluoxetine
D) Bupropion
8. Which of the following is an effect of fluoxetine (Prozac)?
A) Tripling warfarin levels
B) 400-500% increase in metoprolol levels
C) Doubling cyclosporine levels
D) 50% increase in lithium levels
9. Regarding properties of amitriptyline, which statement is INCORRECT?
A) Large potential for weight gain
B) Strong anticholinergic effects
C) Lethality in overdose
D) More effective in depression than venlafaxine
10. Which of the following medications is potentially inappropriate for older individuals?
A) Mirtazapine
B) Sertraline
C) Amitriptyline
D) Lithium
10. Which of the following medications is potentially inappropriate for older individuals? C is correct
A) Mirtazapine - not an α-1 blocker, not anticholinergic
B) Sertraline - not an α-1 blocker, not anticholinergic (although caution that SRIs may decrease bone mineral density)
C) Amitriptyline - essentially contraindicated in geriatric populations due to anticholinergic (more specifically antimuscarinic) and α-1blocking (syncope risk) effects
D) Lithium - but lower dose than for younger individuals. Underutilized in geriatric population considering benefits of preventing dementia, decreased hip fractures (improved bone mineral density)
Antidepressants and lithium have robust antisuicide effects in older individuals, and larger antisuicide effect than in younger individuals.
Correct answers: 1-D, 2-C, 3-C, 4-C, 5-C, 6-B, 7-B, 8-B, 9-D (venlafaxine may be the most effective non-TCA/MAOI antidepressant), 10-C