Selective Serotonin Reuptake Inhibitors (SSRIs)

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  • For Patients

OVERVIEW OF SSRIs

 

♦ Selective Serotonin Reuptake Inhibitors (SSRIs) are medications used to treat a variety of depressive disorders and anxiety disorders.

 

♦ All SSRIs are potent inhibitors of the serotonin transporter (SERT). Serotonin transporters (SERT) facilitate the removal of serotonin from the synapse by whisking it up into the presynaptic neuron. Serotonin transporters are located at both nerve terminals (i.e., end of neurons) and somatodendritic (i.e., cell body) regions of serotonin neurons 

 

♦ All SSRIs are thought to be equivalent in efficacy for depression but differ in terms of side effects. All SSRIs have sexual side effects. It appears Paroxetine has a higher rate of sexual side effects compared to the others and Sertraline has a lower rate of sexual side effects compared to others.

 

♦ All SSRIs carry a small risk for bleeding (remember that serotonin receptors are found on platelets)

 

♦ All SSRIs have the potential to cause serotonin syndrome (especially when taken in overdose or with monoamine oxidase inhibitors)

 

♦ When switching from an SSRI to a monoamine oxidase inhibitor (MAOI), wait at least 2 weeks after stopping SSRI before starting MAOI (except when switching from fluoxetine to a MAOI which requires at least 5 weeks).

 

♦ All SSRIs typically take 2-6 weeks (sometimes longer) before therapeutic effects are appreciated

 

♦ All SSRIs, with the exception of fluoxetine, may cause a discontinuation syndrome (withdrawal) when stopped abruptly. Paroxetine does not have active metabolites and is likely to cause discontinuation syndrome if stopped abruptly. Fluvoxamine also likely to cause discontinuation syndrome if stopped abruptly. 

 

♦ Many patients complain of inability to feel or a "flat" feeling with inability to laugh, cry, or feel joy while taking SSRIs. This is likely due to serotonin-induced affective blunting. Consider lowering the dose of SSRI or switching to a different medication. 

 

♦ Chronic administration of all SSRIs (most notably fluoxetine and paroxetine), increases their half-life considerably as they inhibit their own metabolism.

 

♦ In general (but not always), higher doses of SSRIs are needed to target OCD and anxiety disorders compared to doses used for depression

 

♦ Women tend to have more favorable responses to SSRIs than men. However, some data suggest SSRIs are less effective in perimenopausal/postmenopausal women (controversial). 

 

♦ Increasing the dose of an SSRI too quickly may cause restlessness, anxiousness, tremors, nausea, vomiting, diarrhea, and irritability.

 

♦ When using SSRIs in individuals with anxiety, generally initiate at a dose lower than the recommended starting dose and increase more slowly to prevent initial side effects, including intolerable anxiety

 

♦ NOTE: Dosing ranges presented below are approximate. Some patients will respond to lower doses and others will require higher doses.

 

For more information about each SSRI, see below. 

 

WHAT ARE SSRIs?

 

♦ Selective Serotonin Reuptake Inhibitors (SSRIs) are a class of medications used to help individuals with depression, anxiety, obsessive compulsive disorder, post traumatic stress disorder, and many other psychiatric disorders. These medications primarily work to enhance serotonin in the brain. Serotonin is a chemical in our brain involved in many important functions including mood regulation, circadian rhythms (sleep), memory, and more. There are very few studies, if any, comparing each medication with the others but we generally consider all SSRIs to be equivalent in terms of their efficacy for depression and anxiety. Clinical experience suggests that not ALL SSRIs are equal in terms of efficacy and side effect profile. 

 

WHAT ARE COMMON SIDE EFFECTS OF SSRIs?

 

Nausea

Indigestion

Headache

Tremulousness

Insomnia 

Emotional "Flattening"

Sexual side effects: Anorgasmia, Delayed Ejaculation, Decreased libido

Bleeding Risk: All SSRIs carry a SMALL RISK for bleeding (remember that serotonin receptors are found on platelets)

Serotonin Syndrome: All SSRIs have the potential to cause serotonin syndrome but this is RARE and only occurs when taken in overdose or with other serotonin medications

 

HOW LONG WILL IT TAKE FOR THESE MEDICATIONS TO BEGIN WORKING?

 

♦ All SSRIs typically take 2-6 weeks (sometimes longer) before therapeutic effects are appreciated

 

ARE THESE MEDICATIONS ADDICTIVE?

 

NO, these medications are not addictive. Recall that addiction and dependence are different things. Addiction represents the behavioral changes in someone who begins altering their life to obtain or use something despite the negative consequences that occur when doing so (marital discord, health consequences, job loss, etc). Dependence represents the physiological changes that occur after taking a medication or drug for a long time such that when the medication/drug is stopped there are withdrawal symptoms. If you stop taking a blood pressure medication after taking it for years, your blood pressure will likely “rebound” or increase. Therefore, you are considered dependent on your medication. All SSRIs, with the exception of fluoxetine (Prozac), may cause a mild discontinuation (withdrawal) syndrome if stopped abruptly. However, if tapered appropriately, you are unlikely to experience a discontinuation syndrome

 

HOW LONG DO I HAVE TO BE ON AN ANTIDEPRESSANT?

 

♦ The recommended duration of treatment depends on the severity of your symptoms prior to starting the medication and whether you’ve experienced previous episodes of depression. However, the general recommendation is to take the medication for at least 9-12 months before beginning to taper off the medication.

 

RISK OF MANIA, HYPOMANIA, AND RAPID-CYCLING IN BIPOLAR DISORDER

 

♦ All antidepressants carry a small risk of inducing a manic or hypomanic episode in patients with a preexisting diagnosis of bipolar disorder. All antidepressants carry a small risk of causing “rapid cycling” (>4 mood episodes in a year) in patients with a preexisting diagnosis of bipolar disorder

 

THINGS MAY GET WORSE BEFORE THEY GET BETTER

 

♦ It isn’t uncommon to experience initial side effects such as a small increase in anxiety, tremulousness, nausea, and indigestion for 3-4 days BUT THESE ALMOST ALWAYS GO AWAY with continued use of the medication. The therapeutic effects of these medications are thought to result from the brain slowly adapting to the presence of the medication. This can take 2-6 weeks.

 

FINAL COMMENTS

 

♦ Sometimes people report an “inability to feel” or a “flatness” feeling with inability to laugh, cry, or feel joy while taking SSRIs. This usually resolves with reducing the dose or discontinuing the medication

 

♦ In general (but not always), higher doses of SSRIs and SNRIs are needed to target anxiety disorder symptoms (OCD, PTSD, Generalized Anxiety) compared to doses needed for depression

 

♦ Women tend to have more favorable responses to SSRIs than men. However, some data suggest that perimenopausal/postmenopausal women do not respond as robustly to SSRIs.

 

♦ When using SSRIs in individuals with anxiety, we generally initiate the medication at a dose lower than the recommended starting dose and increase more slowly to prevent initial side effects

ADDITIONAL INFORMATION

 

Half-Life: Fluoxetine 1-6 days; Norfluoxetine (Metabolite) 14-16 days
Starting Dose: 10mg-20mg PO once daily
Target Dosing Range: 20mg-60mg PO daily
BEST Time to dose: Morning
How to Dose:
>>Increase dose by 20mg every 4-6 weeks as tolerated until response.
>>If positive response, continue at that dose for at least 4-6 weeks
>>Use the minimum effective dose
>>Max dose 80mg/day
Pregnancy: Safe
Breastfeeding: SAFE
FDA Indications:
1) Major depressive disorder (age 8 and older)
2) Obsessive-compulsive disorder (age 7 and older)
3) Panic disorder
4) Bulimia
5) Binge eating disorder
6) Premenstrual dysphoric disorder
7) Bipolar depression (as an adjunct with olanzapine also known as Symbyax)
8) Treatment-resistant depression when used in combination with olanzapine

 

ADDITIONAL INFORMATION

 

♦ Fluoxetine’s antagonist actions at 5HT2C receptors enhances dopamine and norepinephrine release in the prefrontal cortex. Olanzapine also has 5HT2C antagonism and may explain the reasoning for combining Fluoxetine with Olanzapine for bipolar depression

 

♦ Fluoxetine is a weak inhibitor of the norepinephrine transporter (NET) at higher doses (>60mg)

 

♦ Fluoxetine can be activating for many individuals and therefore is a good option for those without energy or motivation. Probably NOT be the best option for those with severe anxiety

 

♦ Fluoxetine rarely causes discontinuation symptoms and is often used to treat SSRI discontinuation syndrome because it has an active metabolite with a half life of up to 2 weeks!

 

♦ Fluoxetine is a potent inhibitor of CYP2D6. Therefore, Fluoxetine is not the best choice for those taking Tamoxifen, Codeine, or other medications requiring CYP2D6 for metabolism

 

HALF-LIFE: Sertraline 25hours; N-desmethylsertraline (metabolite) 2-3 days
STARTING DOSE: 25mg-50mg PO once daily
TARGET DOSING RANGE: 50mg-200mg
BEST TIME TO DOSE: Morning
HOW TO DOSE:
>> Initial 25mg PO daily
>> Increase by 25mg every 4-6 weeks as needed to max dose 200mg/day
>> Max dose 200mg daily (some may require up to 300mg/day)
PREGNANCY: SAFE
BREASTFEEDING: SAFE (minimal secretion in breast milk)
FDA INDICATIONS:
1) Major depressive disorder (age 8 and older)
2) Panic Disorder
3) Obsessive Compulsive Disorder
4) Social Anxiety Disorder
5) Post Traumatic Stress Disorder
6) Premenstrual dysphoric disorder

 

ADDITIONAL INFORMATION

 

♦ Sertraline weakly inhibits the dopamine transporter (DAT). Therefore, sertraline may be more activating and have less sexual side effects (likely due to DAT inhibition).

 

♦ Combination of Bupropion (Wellbutrin) and Sertraline (Zoloft) or “Well-Oft” is often prescribed for the additive DAT inhibition

 

♦ Sigma receptors may have role as anxiolytic (anxiety reliever) and antipsychotic

 

♦ Sertraline has Sigma-1 receptor binding properties (may be good for psychotic depression)

 

♦ Sertraline is an inhibitor of CYP2D6 at doses >100-150mg

 

HALF-LIFE: <20 hours (no active metabolites)
STARTING DOSE: 10mg-20mg PO once daily
TARGET DOSING RANGE: 20mg-50mg PO daily
BEST TIME TO DOSE: Evening (at bedtime)
HOW TO DOSE:
>> Initial 10mg-20mg PO once daily
>> Increase dose by 10mg-20mg every 4-6 weeks
>> Max dose 50mg daily
PREGNANCY: AVOID IN PREGNANCY (if possible)
BREASTFEEDING: SAFE
FDA INDICATIONS:
1) Major depressive disorder
2) Panic Disorder
3) Obsessive Compulsive Disorder
4) Social Anxiety Disorder
5) Post Traumatic Stress Disorder
6) Generalized Anxiety Disorder
7) Premenstrual Dysphoric Disorder

 

ADDITIONAL INFORMATION

 

♦ Paroxetine has anticholinergic properties which means it causes sedation and sometimes weight gain

 

♦ Paroxetine is not the best first choice for the elderly or those who are sensitive to side effects

 

♦ Paroxetine is good for anxiety and anxious depression especially when insomnia is present

 

♦ Paroxetine is a weak inhibitor of norepinephrine transporters (NETs) (only relevant at higher doses)

 

♦ Nitric Oxide Synthetase (NOS) inhibition is probably why paroxetine is notorious for sexual dysfunction in men

 

♦ Paroxetine has no active metabolites and a relatively short half life which means it is likely to cause discontinuation syndrome if stopped too quickly

 

♦ Cholinergic rebound may occur if stopped too quickly (diarrhea, sweating, muscle weakness, autonomic changes)

 

♦ Paroxetine is a potent inhibitor of CYP2D6 and should be used with caution with medications requiring CYP2D6 for metabolism (e.g., tamoxifen, codeine)

 

HALF-LIFE: 15 hours
STARTING DOSE: 50mg-100mg PO daily
TARGET DOSING RANGE: 100mg-200mg daily
BEST TIME TO DOSE: Any
HOW TO DOSE:
>> Initial 50mg-100mg PO once daily
>> Doses over 100mg/day of immediate release require BID dosing
>> Increase dose by 50mg/day every 1-2 weeks as tolerated
>> Max dose 200mg/day (some patient require doses up to 300mg/day)
PREGNANCY: AVOID, if possible (not enough data)
BREASTFEEDING: AVOID, if possible (not enough data)
FDA INDICATIONS:
1) Obsessive Compulsive Disorder
2) Social Anxiety Disorder

 

ADDITIONAL INFORMATION

 

♦ Fluvoxamine was never approved for depression

 

♦ Fluvoxamine was approved for Obsessive Compulsive Disorder and Social Anxiety Disorder

 

♦ Fluvoxamine’s actions at Sigma receptors may explain its role as an anxiolytic (anxiety reliever) and antipsychotic. Therefore, Fluvoxamine may be good for psychotic depression

 

♦ Fluvoxamine is an inhibitor of CYP1A2 and CYP3A4

 

HALF-LIFE: 35 hours
STARTING DOSE: 10mg-20mg PO once daily
TARGET DOSING RANGE: 20mg-40mg PO daily
BEST TIME TO DOSE: Morning
HOW TO DOSE:
>> Initial 10mg-20mg PO once daily
>> Increase dose by 10mg every 4-6 weeks to max dose 40mg daily
>> Max dose 40mg/day (some may require up to 80mg/day)
PREGNANCY: SAFE
BREASTFEEDING: SAFE
FDA INDICATIONS:
1) Major depressive disorder

 

ADDITIONAL INFORMATION

 

♦ Citalopram (Celexa) is a racemic (50-50) mixture of R and S enantiomers

 

R-enantiomer may interfere with SERT inhibition

 

R-enantiomer was thought to be “counter therapeutic” and therefore S-enantiomer was isolated (controversial)

 

Citalopram is well tolerated by most people, including elderly individuals 

 

Risk of QTc prolongation (dose dependent >40mg/day)

 

Citalopram is a weak inhibitor of CYP2D6

HALF-LIFE: 32 hours
STARTING DOSE: 5mg-10mg PO once daily
TARGET DOSING RANGE: 20mg-40mg PO daily
BEST TIME TO DOSE: Anytime 
HOW TO DOSE: 
>> Initial 5-10mg PO daily
>> Increase dose by 10mg every 4-6 weeks 
>> Max dose 40mg
PREGNANCY: SAFE
BREASTFEEDING: SAFE
FDA INDICATIONS:
1) Major depressive disorder 
2) Generalized Anxiety Disorder

 

ADDITIONAL INFORMATION

 

♦ Escitalopram (Lexapro) is the S-enantiomer of R,S-Citalopram (Celexa) 

 

Escitalopram is considered a “Pure SSRI” with minimal side effects

 

Almost no drug –drug interactions

 

Some evidence of QT prolongation at higher doses (>20mg) but this is controversial 

Mechanism of SSRIs:

References:

  1. Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
  2. Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
  3. Puzantian, T., & Carlat, D. J. (2016). Medication fact book: for psychiatric practice. Newburyport, MA: Carlat Publishing, LLC.
  4. J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in the medically ill(pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
  5. Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
  6. Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  7. Stahl, S. M. (2014). Stahl’s essential psychopharmacology: Prescriber’s guide (5th ed.). New York, NY, US: Cambridge University Press.
  8. Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
  9. Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.

(Note: the diagrams were created by me, but the theories behind them were taken from numerous textbooks and articles. For more information, I recommend Dr. Stephen Stahl’s Textbook “Stahl’s Essential Psychopharmacology” 4th edition).

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