Selective Serotonin Reuptake Inhibitors

July 6, 2020 Rima Pharmacology 0

• Selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed class of antidepressants worldwide. They are extensively used because of their better safety and effectiveness profile when compared with other antidepressants.
• The first antidepressants monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) were developed in 1950s. Due to their many serious side effects, a new class of antidepressants called SSRIs was launched in the late 1980s. The first major SSRI marketed is fluoxetine.  It was launched in 1987.
• Some commonly used antidepressants are:
– Paroxetine
– Fluvoxamine
– Sertraline
– Citalopram

Mechanism of action of Selective Serotonin Reuptake Inhibitors 

Figure- Mechanism of action of SSRIs (Source- Chigome et al, 2007) (VMAT- Vesicular Monoamine Transporter, 5- HT (5 hydroxy tryptamine)

• Depression is associated with low level of serotonin in brain (as well as low level of noradrenaline, dopamine and other brain chemicals). Serotonin is a neurotransmitter which have good influence on mood, emotion and sleep. It is also known as ‘feel- good chemical’. After conveying message, serotonin is reabsorbed by nerve cells which is known as ‘reuptake’.
• SSRI bind to serotonin transporter and inhibit reuptake of serotonin by tryptaminergic neurons. This results in availability of more serotonin to transmit message between neurons and help to relieve symptoms of depression. The term selective is used as they mainly affect serotonin, not other neurotransmitters.

Pharmacokinetics of Selective Serotonin Reuptake Inhibitors 

• They are well absorbed after oral administration. Their absorption is not affected by food (except sertraline whose absorption is increased by food). Co-administration with food may be helpful to prevent GI related side effects.
• Most of them have long plasma half-life ranging between 16-36 hours which permit once a day dosing. Metabolism takes place majorly in liver. Their dosage should be reduced in patients with hepatic impairment. Some metabolites are active and have half-life longer than of parent compound.
• Fluoxetine has much longer half-life (about 50 hours) and its active metabolite S-norfluoxetine has long half-life of 10 days. It is available as sustained release preparation which allows once a week dosing.

Therapeutic Uses of Selective Serotonin Reuptake Inhibitors 

• In mild to moderate depression. They help to relieve symptoms like low mood, feeling of worthlessness, restlessness and difficulty in sleeping.
• First pharmacological choice for treating obsessive compulsive disorder in children and adolescents.
• Used in post-traumatic stress disorder.
• Used in bulimia nervosa.
• To treat generalized anxiety disorder and social anxiety disorder.
• In stroke recovery.
• Used off label to treat premature ejaculation, pre-menstrual dysphoric disorder (PMDD) and hot flushes caused by menopause, fibromyalgia, eating disorder and chronic pain management.

Adverse Effects

• Although they are considered to be safer than TCAs and MAOIs, they are not free from side effects. Common side effects include GI disturbance (anorexia, nausea, vomiting, diarrhea), CNS disturbance including headache, transient insomnia, anxiety, agitation and somnolence. Impact on appetite may lead to weight loss or weight gain.
• They can cause sexual problems including sexual dysfunction, decrease in sexual thoughts and desire and anorgasmia (delayed orgasm). Some people especially, children and young adults may have increased suicidal thoughts.

Discontinuation syndrome

  • Sudden stoppage of SSRIs may cause withdrawal symptoms (particularly agents with shorter half-life and inactive metabolites). The signs and symptoms are headache, agitation and irritation, nervousness, sweating, vomiting, tremor and changes in sleep pattern.
  • Fluoxetine has lower risk of causing discontinuation syndrome as it has long half-life and active metabolites.

Drug Interaction

  • SSRIs when used with certain other medications, may produce serotonergic syndrome due to hyperstimulation of 5-HT1A receptors in brain stem. The symptoms of serotonergic syndrome are agitation, insomnia, flushed skin, hypertension, diarrhea, abdominal cramps, shivering and twitching. Drugs which may cause such syndrome when used together or immediately prior to SSRIs are:
    – MAOI
    – Lithium
    – Levodopa
    – Amphetamine
    – Two or more SSRI (especially with fluoxetine)
    – Bromocriptine
    – Pethidine.
  • Fluoxetine and paroxetine inhibit elimination and increase toxicity of drugs like TCAs, alcohol, theophylline, anticonvulsants like phenytoin, antipsychotic drugs like tramadol and methadone and some anti-arrhythmic and beta-adrenergic antagonist drugs.
    • Drugs like painkillers (aspirin, ibuprofen) and anticonvulsants like carbamazepine decrease efficacy of SSRI.
    • Citalopram, escitalopram and sertraline have less potential to cause drug-drug interaction as they are weaker inhibitor of cytochrome P-450 enzymes so, they are preferred in patients who are on multi-drug therapy.

Contraindication

  •  It should not be used in:
    – Manic phase of bipolar depression.
    – Narrow angle glaucoma.
    – Serious kidney, liver or heart problems.
    – In bleeding disorder such as hemophilia.
  •  Should be used cautiously in kids and young adults.
  • SSRIs should not be used together with MAOI and ECT (Electro Convulsive Therapy) while  using in pregnancy and breastfeeding mothers, should be discussed with their physician. The risks and benefits of SSRIs are weighed. The administration of SSRI during pregnancy may increase risk of:

– loss of pregnancy.
– congenital heart disease in baby.
– development of rare condition called persistent pulmonary hypertension in newborn (PPHN) which causes breathing and circulation problems.

Generally, SSRI are not recommended during pregnancy (particularly during first trimester). However, if risks of depression outweigh the potential risk of treatment, SSRI may be prescribed.

Note- FDA requires all antidepressants to carry black box warning, the strictest warning for precautions.

Medical Disclaimer- Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances

Reference

  1. https://www.mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825
  2. https://www.researchgate.net/publication/322031160_Review_of_selective_serotonin_reuptake_inhibitors
  3. Molero Y, Lichtenstein P, Zetterqvist J, Gumpert CH, Fazel S. Selective Serotonin Reuptake Inhibitors and Violent Crime: A Cohort Study. PLOS Medicine. 2015: 1-19.
  4. Kotapati VM, Khan AM, Sara Dar, Begum G, Bachu R,  Adnan  M et al. The Effectiveness of Selective Serotonin Reuptake Inhibitors for Treatment of Obsessive-Compulsive Disorder in Adolescents and Children: A Systematic Review and Meta-Analysis. Front Psychiatry. 2019; 10: 523.
  5. Costagliola C, Parmeggiani F, Semeraro F, Sebastiani A. Selective Serotonin Reuptake Inhibitors: A Review of its Effects on Intraocular Pressure. Curr Neuropharmacol. 2008; 6(4): 293–310.
  6. Pharmacology and pharmacotherapeutics. 24th
  7. Lippincott Illustrated Reviews Pharmacology, 6th edition.