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