Selective Serotonin Reuptake Inhibitors (SSRIs)

Contents

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 the medication to work?

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

Are SSRIs 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 take these medications?

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

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

It might get worse before it gets 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.

Additional 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

Antidepressants Table

Selective Serotonin Reuptake Inhibitors (SSRIs)Initial Dose (Range), mgComments
Fluoxetine (Prozac)20 (20-60)Activating. Long half-life. 2D6 Inhibitor.
Paroxetine (Paxil)20 (20-60)Anticholinergic. Sedating. 2D6 Inhibitor. Sexual side effects. D/C syndrome. Pregnancy risk.
Sertraline (Zoloft)50 (50-200)Activating. Dopaminergic. 2D6 Inhibitor at higher doses. GI side effects common early in tx.
Citalopram (Celexa)20 (20-60)Few interactions. QT prolongation (>40mg/day).
Escitalopram (Lexapro)10 (10-20)Few interactions. QT prolongation.
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
Duloxetine (Cymbalta)30 (30-60)Short half life with risk of d/c symptoms. FDA approved for Diabetic neuropathy and Fibromyalgia. Morning dosing. Rarely sedating. May increase BP.
Venlafaxine XR (Effexor XR)37.5 (75-300)Nausea common. May increase BP. Once daily dosing with XR minimizes side effects (i.e., nausea). Reduce dose in renal insufficiency. May help with chronic pain.
Desvenlafaxine (Pristiq)50 (50-100)Active metabolite of venlafaxine. More noradrenergic activity than venlafaxine. Better choice for those with renal and hepatic insufficiency. May help with chronic pain. Short half-life with risk of d/c symptoms.
Atypical Antidepressants
Bupropion (Wellbutrin)100 (100-400)Noradrenergic and Dopaminergic. Minimal sexual side effects. May increase BP. Avoid in those with eating disorders or seizure hx. 2D6 inhibitor.
SR (BID dosing)150 (150-450)
XL (QAM dosing)
Trazodone (Desyrel)25 (25-400)Sedating. Commonly used for insomnia. May increase time in slow wave sleep. No anticholinergic properties. Histamine/α1 at low doses. Minimal sexual side effects. Warn about priapism. May be better for anxiety than depression.
Mirtazapine (Remeron)7.5 (7.5-45)Noradrenergic and serotonergic properties. Has actions at 5HT3 and therefore helps with nausea. Minimal sexual side effects. Sedation and weight gain common. Sedation usually limited to 7.5mg-15mg.

A Closer Look…

 

Fluoxetine (Prozac)

 

Half-Life: 1-16 days
Starting Dose: 10mg-20mg PO once daily
Target Dosing Range: 20mg-60mg PO daily
BEST Time to dose: Morning
Typical Dosing: Start 10mg to 20mg every morning and increase dose by 10mg-20mg every 4-6 weeks as tolerated. 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 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 withdrawal symptoms when stopped because it has an active metabolite with a half life of up to 2 weeks!
  • Fluoxetine is not the best choice if also taking Tamoxifen or Codeine
  • 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

 

Sertraline (Zoloft)

 

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
TYPICAL DOSING: 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 may be more activating and have less sexual side effects than other SSRIs
  • 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

 

Paroxetine (Paxil)

 

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)
TYPICAL DOSING: Initial 10mg-20mg at bedtime. Increase dose by 10mg-20mg every 4-6 weeks. Max dose 50mg per day
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 can be sedating and is usually dosed at night
  • Paroxetine may cause constipation, urinary retention, blurred vision, and weight gain
  • Paroxetine is not the best choice for the elderly or those who are sensitive to side effects
  • Paroxetine is good for anxious-type depression especially when insomnia is present
  • Paroxetine is notorious for causing sexual dysfunction in men
  • Paroxetine has no active metabolites and a relatively short half life which means it is likely to cause withdrawal symptoms if stopped too quickly
  • Paroxetine is not a good choice if also taking tamoxifen or codeine
  • 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)

 

Fluvoxamine (Luvox)

 

HALF-LIFE: 15 hours
STARTING DOSE: 50mg-100mg PO daily
TARGET DOSING RANGE: 100mg-200mg daily
BEST TIME TO DOSE: Any
TYPICAL DOSING: 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

 

Citalopram (Celexa)

 

HALF-LIFE: 35 hours
STARTING DOSE: 10mg-20mg PO once daily
TARGET DOSING RANGE: 20mg-40mg PO daily
BEST TIME TO DOSE: Morning
TYPICAL DOSING: 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

 

Escitalopram (Lexapro)

 

HALF-LIFE: 32 hours
STARTING DOSE: 5mg-10mg PO once daily
TARGET DOSING RANGE: 20mg-40mg PO daily
BEST TIME TO DOSE: Anytime 
TYPICAL DOSING: Initial 5-10mg PO daily. Increase dose by 10mg every 4-6 weeks. Max dose 40mg per day
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 Action of SSRIs

References

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