Day # 31: SSRI's and SNRI's

Now that we have covered a broad overview of antidepressant medications we can start discussing each drug class separately. Today we are going to cover some of the most commonly prescribed drugs in the world: SSRI's and SNRI's. We will discuss mechanism of action, side effects, and unique characteristics to specific medications within this class.


Today's Content Level: Beginner, Intermediate



INTRODUCTION


SSRIs = Selective Serotonin Reuptake Inhibitors

SNRIs = Serotonin-Norepinephrine Reuptake Inhibitors


SSRIs inhibit presynaptic serotonin pumps that take up serotonin which leads to increased availability of serotonin in synaptic clefts. SNRIs do this for serotonin and norepinephrine.


•Additionally, these medications cause downstream effects to include down-regulation of receptors and increasing brain plasticity. This mechanism has been hypothesized to explain the delay to onset of the antidepressant effect.


•Remember that most antidepressants require a trial of at least 3–4 weeks for any effect with some people requiring as little as 1–2 weeks and some 6–8 weeks for significant improvement.


•Fun fact: Fluoxetine (Prozac) first entered the market in 1986 and is often described as the first SSRI. This is inaccurate. The first SSRI was actually a medication named zimelidine which is now banned for causing Guillain-Barre and other very dangerous effects. Fluvoxamine also entered the market two years prior to fluoxetine, but was not approved for the treatment of depression.


•All antidepressant classes have similar treatment response rates in treating major depression but vary in their mechanism of action, safety, and side effect profiles. SSRIs are the most commonly prescribed antidepressants due to several distinct advantages:

  • Low side effect profile, most of which resolve with time

  • No food restrictions (unlike MAOIs)

  • Much safer in overdose (unlike TCAs and MAOIs)



INDICATIONS


SSRIs and SNRIs are not only used in the treatment of major depressive disorder. They are approved for a variety of conditions.


SSRIs - FDA approved for at least one agent

  • Major Depressive Disorder (MDD). Including geriatric and pediatric.

  • Peripartum and postpartum depression

  • Premenstrual Dysphoric Disorder (PMDD)

  • Generalized Anxiety Disorder (GAD)

  • Panic Disorder (PD)

  • Social Anxiety Disorder (SAD)

  • Obsessive Compulsive Disorder (OCD)

  • Post-Traumatic Stress Disorder (PTSD)

  • Bulimia nervosa

  • Vasomotor symptoms of menopause (paroxetine)

  • Bipolar depression (fluoxetine + olanzapine)


SSRIs - Off-label treatments

  • Premature ejactulation

  • Substance-induced mood disorders

  • Persistent depressive disorder

  • Binge eating disorder

  • Anorexia nervosa

  • Pathological gambling

  • Fibromyalgia


SNRIs- FDA approved for at least one agent

  • Major Depressive Disorder (MDD)

  • Generalized Anxiety Disorder (GAD)

  • Panic Disorder (PD)

  • Social Anxiety Disorder (SAD)

  • Fibromyalgia

  • Diabetic peripheral neuropathy

  • Chronic MSK pain


SNRIs- Off-label treatments

  • Post-Traumatic Stress Disorder (PTSD)

  • Premenstrual Dysphoric Disorder (PMDD)

  • Stress urinary incontinence



SIDE EFFECTS


SSRIs and SNRIs are safer and better tolerated than other classes of antidepressants. Side effects are typically mild and they often go away after using the medication for a few days.


I like to break up these side effects into three categories

  1. Common but typically resolve with time.

  2. Don't typically resolve with time.

  3. Rare or Dangerous.


Common but typically resolves with time

  • Gastrointestinal disturbance: nausea, stomach cramping, loose stools. Most common with sertraline and fluvoxamine. Paroxetine may cause constipation.

  • Headache

  • Insomnia and vivid dreams

  • Decreased appetite, initial weight loss

  • Emotional blunting = "zombie like"

  • Rebound anxiety


Common and doesn't always resolve with time

  • Sexual dysfunction. Can include decreased libido or arousal, anorgasmia in women/men, and delayed ejaculation in men. Sexual dysfunction is the most common side effect with long-term use of the SSRIs, with incidence around 50%. Treatment includes decreasing the dose, adding bupropion (increases DA) or buspirone (antagonism of 5HT via autoreceptor), or use of sildenafil.

  • Restlessness / an akathisia-like state. See prior discussion on akathisia. Much more common in antipsychotics, but antidepressants can rarely lead to akathisia. Highest risk is sertraline.

  • Weight gain? No consistent weight gain in short-term RCTs (4-12 wks), but retrospective cohorts indicate they may cause modest gains of up to 1kg on average after 1 year. 1


Dangerous or rare

  • Slight bleeding risk (with NSAIDs) due to inhibition of platelet binding. Most common with sertraline.

  • Hyponatremia (SIADH)

  • QTc prolongation (controversial). This is likely a drug specific side effect as opposed to side effect of the whole class. Known medications are citalopram, escitalopram, and venlafaxine.

  • Black box warning. In 2004 the FDA issued a black box warning for those ≤24 years old due to a meta-analysis that showed increased risk of suicidal thoughts and behaviors and aggression/hostility in this age group. Patients should be closely monitored in the first 1-2 weeks of treatment.

  • Serotonin syndrome. Serotonin syndrome is a dangerous syndrome that can occur if taking SSRIs/SNRIs in combination with other drugs that increase serotonin (TCAs, MAOIs, Triptans, Tramadol, Linezolid, etc.). Symptoms include confusion, flushing, diaphoresis, tremor, myoclonic jerks, hyperthermia, hypertonicity, rhabdomyolysis, renal failure, death. More on this syndrome in a separate post coming soon.

  • Seizures (0.2%): very rare


Discontinuation phenomenon: when deciding to stop or change the patients medication it is important to understand the risk for a discontinuation phenomenon if the medication is stopped abruptly. It is not technically described as a "withdrawal" and is not dangerous but it is extremely uncomfortable. Symptoms include headaches, insomnia, dizziness, nausea, and malaise. This can be prevented by tapering off of these medications. The only SSRI/SNRI that does not require a taper is fluoxetine due to its' long half life.


What about SSRIs/SNRIs in pregnancy? SSRIs are better studied in pregnancy and breastfeeding mothers than SNRIs. It is generally accepted that the risks to both baby and mother are greater for untreated depression than the risks associated with SSRI exposure during pregnancy. Studies following children exposed to fluoxetine in utero show no related decreases in IQ, language, or behavioral issues. Fluoxetine appears to be safest during pregnancy and sertraline during breastfeeding, however if the patient is stable on a different medication it is usually best to not switch. The only SSRI that should not be used during pregnancy is paroxetine due to potential teratogenicity. 2


•Another important note. SSRIs and SNRIs have important metabolic interactions with the CYP450 enzymes in the liver which are an important class of enzymes the metabolize the majority medications on the market. It is always a good idea to look up a drug interaction checker when describing any psychotropic medications to a patient on multiple medications. See chart below as an example.



SPECIFIC DRUG CHARACTERISTICS


SSRI’s: Citalopram (Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac), Fluvoxamine (Luvox), Paroxetine (Paxil), Sertraline (Zoloft)


SNRI’s: Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Venlafaxine (Effexor)

**also Milnacipran (Savella) for fibromyalgia and Levomilnacipran (Fetzima) for MDD


Traditionally all unipolar antidepressants were thought to have equivalent efficacy and tolerability on a population level (STAR*D trial). Emerging evidence from network meta-analyses by members of the Cochrane collaboration suggests that sertraline and escitalopram may have a slight edge for adults and fluoxetine for children.



Citalopram (Celexa)

  • Fewest drug–drug interactions.

  • Citalopram and escitalopram have the lowest side effect profile of SSRIs/SNRIs.

  • Dose dependent QTc prolongation. Extends QTc by 10-20ms.


Escitalopram (Lexapro)

  • Levo-enantiomer of citalopram. It has similar efficacy and possibly, even fewer side effects and drug-drug interactions.

  • Citalopram and escitalopram have the lowest side effect profile of SSRIs/SNRIs.

  • Dose dependent QTc prolongation (less than citalopram). Extends QTc by 5-10ms.

  • Sedation not typically expected but varies patient to patient.


Fluoxetine (Prozac)

  • Longest half-life, with active metabolites; therefore, no need to taper (self-tapering due to long half-life ~5 days).

  • Best studied and deemed safe in pregnancy.

  • First-line for use in children and adolescents.

  • Common side effects: more "activating" = insomnia and anxiety, sexual dysfunction.

  • Show to improve motor recovery and depression after stroke (FOCUS and FLAME trials).

  • Can elevate levels of antipsychotics, leading to increased side effects.

  • Also comes in liquid formulation.


Fluvoxamine (Luvox)

  • Currently approved only for use in obsessive-compulsive disorder (OCD).

  • Common side effects: GI upset (nausea in particular).

  • Multiple drug interactions due to CYP inhibition.


Paroxetine (Paxil)

  • Highly protein bound, leading to several drug interactions.

  • Common side effects: anticholinergic effects (e.g., sedation, constipation, weight gain), orthostatic hypotension, and sexual dysfunction.

  • Short half-life leading to withdrawal phenomena if not taken consistently. Worst discontinuation syndrome out of all of the SSRIs.

  • Due to the above reasons it is the least commonly prescribed SSRI in my experience even though it has more FDA approved indications than any other SSRI.


Sertraline (Zoloft)

  • Highest risk for GI disturbances (nausea, diarrhea, abdominal cramps).

  • Very few drug interactions.

  • Typically more sedating and less activation

  • Other common side effects: initial insomnia, sexual dysfunction.

  • Good choice during breastfeeding (low/undetectable levels in breastfed infants).

  • Best choice (well-studied) in the presence of cardiac disease (SAD-HEART trial).


Venlafaxine (Effexor) and Desvenlafaxine (Pristiq)

  • Often used for depression, anxiety disorders, and neuropathic pain.

  • Low drug interaction potential.

  • Side-effect profile similar to SSRIs, with the exception of increased blood pressure (BP) in higher doses. Do not use in patients with untreated or labile BP.

  • Worse discontinuation phenomena than SSRIs. Associated with intense headaches that patients often describe as "brain zaps".

  • New form: desvenlafaxine (pristiq) is the active metabolite of venlafaxine. It is expensive and without known benefit over venlafaxine.


Duloxetine (Cymbalta)

  • Often used for people with depression, neuropathic pain, and in fibromyalgia.

  • Side effects are similar to SSRIs, but more dry mouth and constipation relating to its norepinephrine effects.

  • Hepatotoxicity may be more likely in patients with liver disease or heavy alcohol use.

  • Expensive.



CONCLUSION


Today was a bit of a longer read so I apologize for that. I hope it was helpful for beginner learners as well as for those that have been doing this a little bit longer. Next up will be our review quiz and then we will cover serotonin syndrome and then jump right back into the other antidepressant classes.


Resources for todays post include Stahl’s Essential Psychopharmacology, The Maudsley Prescribing Guidelines in Psychiatry, First aid for the psychiatry clerkship, and Pocket Psychiatry.



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