Selective Serotonin Reuptake Inhibitors (SSRI)

Indications

  • General Comments
    • Selective serotonin reuptake inhibitors (SSRI) are widely prescribed medications
    • SSRI have a high therapeutic to toxicity ratio and are associated with less toxicity than tricyclic antidepressants (TCA)
  • Anorexia Nervosa
  • Bulimia
  • Depression (see Depression, [[Depression]]): most depressants prescribed in the US are SSRI’s
  • Obsessive-Compulsive Disorder
  • Panic Disorder
  • Social Phobia

Agents

  • Citalopram (Celexa) (see Citalopram, [[Citalopram]])
    • Highly selective presynaptic SSRI: minimal effects on norepinephrine and serotonin reuptake
    • Bicyclic phthalane derivative
    • Terminal half-life: 35 hours
    • The drug is hepatically metabolized, but has less effect on the cytochrome P450 enzyme system than other SSRI
    • Although didesmethylcitalopram is only a minor metabolite (<10%) in human studies, it has been implicated in the cardiac toxicity of citalopram
  • Escitalopram (Lexapro) (see Escitalopram, [[Escitalopram]])
  • Fluoxetine (Prozac) (see Fluoxetine, [[Fluoxetine]])
  • Fluvoxamine (Luvox) (see Fluvoxamine, [[Fluvoxamine]])
  • Paroxetine (Paxil) (see Paroxetine, [[Paroxetine]])
  • Sertraline (Zoloft) (see Sertraline, [[Sertraline]])
  • Vortioxetine (Brintellix) (see Vortioxetine, [[Vortioxetine]])

Pharmacology

  • SSRI are metabolized in the liver by cytochrome P-450 mixed function oxidase microsomal enzymes
  • They are highly bound to plasma proteins and have a large volume of distribution
  • Peak plasma levels: occur in 2-10 hrs
  • Most SSRI have half-lives of approximately 20-24 hrs
    • A notable exception is fluoxetine, and its active metabolite, norfluoxetine, which have half-lives of 2-4 days and 8-9 days, respectively
  • Hence, the addition of serotonergic medications to a patient’s regimen must not occur until 2-3 weeks after discontinuation of an SSRI (some recommend a 5-week “wash-out” period for fluoxetine prior to initiation of an MAO inhibitor)

Serotonin Physiology

  • Serotonin (5-hydroxytryptamine, 5HT) is a central and peripheral nervous system neurotransmitter
    • Serotonin is synthesized from L-tryptophan in the brainstem raphe nucleus and is stored in presynaptic vesicles -> released by neuronal activation
  • Serotonin Metabolism
    • Excess serotonin is taken back up into presynaptic vesicles by active transport or locally metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid
    • Systemic serotonin is metabolized via hepatic mixed function oxidases
      • Inhibition of particular mixed function oxidases by medications or other substances (grapefruit, etc) -> decreased serotonin metabolism -> increased drug effect
  • Serotonin Receceptors: there are 7 distinct 5HT receptors (with further specific subtypes), producing a wide variety of physiologic effects
    • Most central nervous system 5HT receptors are located in the brainstem raphe nuclei
    • The physiologic manifestations of serotonin syndrome are largely due to stimulation of 5HT1a and 5HT2 receptors
  • Serotonergic Projections to Thalamus and Cortex
    • Sleep-Wake Cycles
    • Mood
    • Thermoregulation
    • Appetite
    • Pain Perception
    • Sexual Function
  • Serotonin Projections to Brainstem and Medulla
    • Muscle Tone
  • Precipitants of Excess Serotonergic Activity
    • Large Doses or Combinations of Serotonergic Agents: may occur in overdoses
    • Direct 5HT Receptor Stimulation
      • Buspirone (Buspar)
      • Carbamazepine (Tegretol)
      • Lithium
      • Lysergic Acid Diethylamide (LSD)
      • Mescaline-containing cacti (peyote, etc)
      • Triptans (Sumitriptan, etc)
    • Direct 5HT Release from Stored Vesicles
      • 3,4 methylenedioxymethamphetamine (MDMA, Ecstasy)
      • Amphetamines
      • Cocaine
      • Codeine
      • Dextromethorphan
      • Levodopa
      • MAO Inhibitors: methylene blue, etc
      • Pentazocine (Talwin)
      • Reserpine
    • Increased Availability of 5HT Precursors
      • L-Tryptophan
    • Decreased 5HT Reuptake
      • Amphetamines
      • Carbamazepine (Tegretol)
      • Cocaine
      • Dextromethorphan
      • Hypericum Species (St. John’s Wort)
      • Linezolid
      • Meperidine (Demerol)
      • Methadone
      • Nefazodone
      • Selective Serotinin Reuptake Inhibitors (SSRI)
      • Tramadol (Ultram)
      • Trazodone (Desyrel)
      • Tricyclic Antidepressants (TCA)
      • Venlafaxine (Effexor)
    • Decreased 5HT Degradation
      • Hypericum Species (St. John’s Wort)
      • MAO Inhibitors
    • Other
      • Methylphenidate (Ritalin)
      • Ginseng
      • S-Adenosyl-Methionine

Adverse Effects

Gastrointestinal Adverse Effects

Increased Risk of Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])

  • Epidemiology
  • Physiology: possibly related to their effects on platelet serotonin

Pulmonary Adverse Effects

Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])

  • Epidemiology: no clear association with the development of adult pulmonary hypertension
    • Maternal use may result in persistent pulmonary hypertension of the neonate
    • Use of SSRI’s is associated with worse prognosis in those with established pulmonary hypertension

Toxicologic Adverse Effects

SSRI Intoxication/Serotonin Syndrome (see Serotonin Syndrome, [[Serotonin Syndrome]])

  • Epidemiology
    • Data from the 2009 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (AAPCC-NPDS) showed 2.4 million total toxic drug exposures in 2009
    • Antidepressants (SSRIs, TCAs, and atypicals) accounted for 102,792 exposures and 260 deaths and were the sixth most common class of drug associated with fatalities
    • Seven fatalities were related to ingestion of SSRI alone
    • Of 260 total antidepressant-related fatalities, SSRI were involved in 42 deaths, mostly in combination with other medications or illicit substances
    • Atypical antidepressants such as venlafaxine (Effexor) and bupropion (Wellbutrin) were involved in a significant number of fatalities, often in combination with alcohol or other prescription medications
    • Incidence of reported SSRI ingestions is higher in women than in men
    • Incidence of death from antidepressant ingestions is higher in men than in women
    • Incidence of SSRI toxicity is highest in persons aged 19-39 years, the age group with the greatest overall number of intentional ingestions
    • Side effects from SSRI are not age-specific, but they may occur more in elderly persons who are more likely to be taking several serotonergic agents or other medications that alter mixed function oxidase CYP metabolism
    • Serotonin toxicity is most likely to develop following the initiation of a new serotonergic medication or the increase in dosage of a previously prescribed SSRI
    • Symptom onset from SSRI toxicity presents within 2-8 hours after acute ingestion, or it may occur over several days if SS develops from initiation of a new therapy or addition of a second serotonergic agent

References

  • Citalopram in the treatment of depression and other potential uses in psychiatry. Pharmacotherapy. 1999;19:675-689.
  • QTc interval prolongation associated with citalopram overdose: a case report and literature review. Clin Neuropharmacol. 2001;24:158-162.
  • Citalopram overdose–review of cases treated in Swedish hospitals. J Toxicol Clin Toxicol. 1997;35:237-240.
  • Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004;42:277-285.
  • Cardiotoxicity and late onset seizures with citalopram overdose. J Emerg Med. 2003;25:163-166.
  • Speculations on difference between tricyclic and selective serotonin reuptake inhibitor antidepressants on their cardiac effects. Is there any? Curr Med Chem. 1999;6:469-480.
  • Mechanism of reversal of toxic effects of amitriptyline on cardiac Purkinje fibers by sodium bicarbonate. J Pharmacol Exp Ther. 1984;231:387-394.
  • Reversal of citalopram-induced junctional bradycardia with intravenous sodium bicarbonate. Pharmacotherapy. 2005;25:119-12