Paroxetine : Antidepressant repurposed to treat childhood sarcoma

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A new study has found that a commonly prescribed antidepressant may halt growth of a type of cancer known as childhood sarcoma, at least in mice and laboratory cell experiments.

The findings, from researchers at Karolinska Institutet in Sweden and MD Anderson Cancer Center in Texas, ignite hope of novel treatment strategies against this disease. The study is published in the journal Cancer Research.

“Although this study was done in mice and we do not yet know how translatable the results are to humans, it gives us hope for repurposing common drugs for young cancer patients desperately requiring better treatment options,” says the study’s first author, Caitrín Crudden, a former Ph.D. student in the receptor signaling pathology group at the Department of Oncology-Pathology at Karolinska Institutet.

The study examined commonalities between two large groups of cell surface receptors, the so-called G protein-coupled receptors (GPCRs) and the receptor tyrosine kinases (RTKs).

GPCRs are targeted by more than half of all developed drugs to treat conditions such as allergies, asthma, depression, anxiety and hypertension, but have so far not been widely used to treat cancers.

RTKs, on the other hand, are targeted by drugs against cancers, such as breast and colon cancers, due to their implication in a variety of cellular abnormalities.

One receptor in the RTK family that plays a key role in many cancers, including childhood sarcoma, is the insulin-like growth factor receptor (IGF1R). However, previous attempts to develop anti-cancer drugs against this receptor have failed.

In this study, the researchers scrutinized the IGF1R and found that it shares a signaling module with the GPCRs, meaning it may be possible to affect its function through drugs targeting the GPCRs.

This strategy opens new possibilities of repurposing well-tolerated drugs to silence this tumor-driving receptor and thereby halt cancer growth.

To test their hypothesis, the researchers treated childhood (Ewing) sarcoma cells and mouse models with Paroxetine, an anti-depressant drug that impairs a serotonin reuptake receptor that is part of the GPCR-family.

They found that this drug significantly decreased the number of IGF1R receptors on the malignant cells and thereby suppressed the growth of the tumor. The researchers also uncovered the molecular mechanism behind this cross-targeting.

“We have developed a novel strategy to control the activity of these tumor-driving receptors by striking the GPCRs,” says Leonard Girnita, researcher in the Department of Oncology-Pathology, Karolinska Institutet, and principle investigator of the study.

“To our knowledge this represents a new paradigm for the entire class of cancer-relevant RTKs and could be used as a starting point for the rational design of specific therapeutics in virtually any pathological conditions.

This is especially important considering the huge number of GPCR-targeting medicines already in clinical use and with low toxicity.”

Next, the researchers plan to develop their strategy to selectively cross-target multiple RTKs and to verify their findings in a clinical setting.


Paroxetine is a selective serotonin reuptake inhibitor (SSRI), and, as such, is identified as an antidepressant. It is FDA approved for major depressive disorder (MDD), obsessive-compulsive disorder (OCD), social anxiety disorder (SAD), panic disorder, posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and premenstrual dysphoric disorder (PMDD), vasomotor symptoms associated with menopause.[1]

Paroxetine is not FDA approved for use in children and adolescents less than 18 years of age; however, clinicians do use off-label in this group.

Off-Label Use

  1. Obsessive-compulsive disorder (in children and adolescents)
  2. Social anxiety disorder (in children and adolescents)
  3. Separation anxiety
  4. Dysthymia
  5. Body dysmorphic disorder
  6. Postpartum depression
  7. Premature ejaculation
  8. Malignancy related pruritus unresponsive to standard treatment

Mechanism of Action

As an SSRI class drug, paroxetine’s signature mechanism of action is to block the serotonin reuptake transporter (SERT) and thus increase the concentration of synaptic serotonin. Current theory suggests that the diminished serotonin concentration in the depressed brain induces the upregulation of serotonergic receptors.

By increasing the synaptic serotonin concentration, paroxetine thus induces the downregulation of the previously upregulated serotonin receptors, thus normalizing the receptor concentration. [2] Furthermore, in a radioligand study, paroxetine showed some affinity for muscarinic, adrenergic (alpha and beta), dopaminergic (D2), serotonergic (5-HT2), and histaminergic (H1) receptors.[3] These receptors have also appeared to contribute to its antidepressant effects, as well as its side effect profile.

Administration

Paroxetine is administered orally. The medication should be titrated based on the patient’s symptoms and tolerance to dosage. The drug can be taken with or without food. In addition to regular tablets, it is available in a controlled-release tablet, as well as liquid form. Paroxetine may be administered at any time of the day, depending on toleration.

Metabolism

The steady-state mean values of T1/2 is 21 hours. Paroxetine undergoes metabolism via hepatic CYPP450 2D6. The urine excretes 2%, 62% metabolized over a 10-day post-dosing period, 36% excreted in the feces. Paroxetine inhibits CYP2D6 and, thus, its own metabolism; plasma concentrations can potentially double following dosage increases of 50%. [4]

For Major Depression [1]

Immediate-release formulas

  • Adults: start with 20 mg by mouth (PO) daily and increase by 10 mg weekly with a max of 50 mg per day
  • Geriatric adults: start with 10 mg PO daily and then increase by 10 mg weekly with a max dose of 40 mg per day PO

Controlled-release formulas:

  • Adults: Start with 25 mg PO daily then increase by 12.5 mg weekly with a max of 62.5
  • Geriatrics: Start with 12.5 mg PO once daily then increase to 12.5 if needed weekly

Generalized Anxiety Disorder [1]

Immediate release formulas

  • Adults: 20 mg PO once daily. Titrate the dose by 10 mg per day at weekly intervals if required with a max dose to 60 mg per day
  • Geriatric Adults: 10 mg PO once daily and titrate 10 mg per day at weekly intervals. Usually effective at 20 mg PO daily but can increase up to 40 mg per day

Premenstrual Dysphoric Disorders [1]

Controlled-release tablet

  • Adult Females: 12.5 mg per day PO. Effective doses were between 12.5 to 25 mg per day

Immediate-release formulation

  • Adult females: 5 mg per day to 30 mg per day

Vasomotor Disorder Secondary to Menopause [1]

Controlled release tablets: 12.5 mg PO daily and titrated to 25 mg PO weekly

Obsessive-Compulsive Disorder[1]

Immediate release formulation

  • Adult: 20 mg once daily and increase by 10 mg per day weekly intervals if tolerated. Titrate the dose include 40 mg PO once daily with a max of 60 mg per day
  • Geriatric: 10 mg once daily. If needed increase to 10 mg per day at weekly intervals with a max dose of 40 mg per day
  • Children and adolescents seven years and older: 10 to 50 mg PO; 10 mg per day increase at intervals of a week with a max of 50 mg per day 

Panic Disorder [1]

Immediate-release formulation

  • Adult: 10 mg PO once daily and increase the dose to 10 mg per day at weekly intervals with a target dose of 40 mg per day with a max dose of 60 mg per day
  • Geriatrics: 10 mg PO once daily and increase 10 mg per day at weekly intervals with a target dose of 40 mg per day. Max dose is 40 mg per day
  • Children and adolescents seven years and older: 10 mg PO; Max dose 40 mg per day

Controlled-release tablets

  • Adults: 12.5 mg PO once daily and increase by 12.5 mg at weekly intervals. The effective dose range is 12.5 to 75 mg per day with a max dose of 75 mg per day
  • Geriatrics Adults: 12 mg PO daily and increase by 12.5 mg at weekly intervals. The effective dose is 12.5 to 75 mg per day. The recommended maximum dose is 50 mg per day

Post Traumatic Stress Disorder [1]

Immediate-release formulation

  • Adults: 20 mg PO daily. Effective doses range from 20 to 50 mg per day. With a max dose of 60 mg per day
  • Geriatrics: 10 mg PO once daily and increase by 10 mg per day at a weekly interval. Max dose of 40 mg per day PO

Social Phobias [1]

Immediate release formulation

  • Adult: 20 mg per day PO; Effective dose range is 20 to 60 mg per day; Titrate to 10 mg per day weekly; Max dose of 60 mg per day
  • Geriatric adults: 10 mg PO and titrate by 10 mg per day; Target the dose 20 mg per day with a max dose of 40 mg per day
  • Children and adolescents eight years and older: 10 mg per day and titrate 10 mg per day at a weekly interval; The maximum dose of 50 mg per day PO

Controlled release formulation

  • Adult: 12.5 mg per day PO and titrate at intervals of at least one week and an increase of 12.5 mg per day; Max dose of 37.5 mg per day PO

Renal Impairment: Adults [1]

For patients with renal impairment, the dosage is based on creatinine clearance, as shown below.

  • If the CrCL is 30 to 60 ml per minute: No need to change the dosing
  • If CrCl less than 30 ml per minute:
    • Immediate release formulation: 10 mg per day; increase if needed by 10 mg per day increments at an interval of at least a week; maximum dose: 40 mg per day
    • Controlled release formulation: 12.5 mg per day; increase if needed by 12.5 mg per day increments at interval one week; maximum dose: 50 mg per day

Hepatic Impairment Adults [1]

In hepatic impairment, plasma concertation of two times normal can occur.

  • If mild to moderate: no change in dosage.
  • If severe
    • Immediate-release formulations: 10 mg per day and if needed increase by 10 mg per day at intervals of 1 week; maximum dose of 40 mg per day
    • Controlled release formulation: 12.5 mg per day; increase if needed by 12.5 mg per day increments at intervals of 1 week; Maximum dose of 50 mg per day

Adverse Effects

Many of the side effects of paroxetine are dose-dependent. The most common side effects include drowsiness, dry mouth, loss of appetite, sweating, sleep disturbance, and sexual side effects. Clinicians can address sexual side effects medications like sildenafil).

Discontinuation syndrome is more common and more severe with paroxetine than with other SSRIs; this may be due in part to the fact that it inhibits its own metabolism. Withdrawal symptoms from discontinuation include dizziness, lethargy, nausea, vomiting, headache, fever, chills, vivid dreams, electric shock-like-sensation, dyskinesia, anxiety, crying, irritability, and depersonalization.[5]

Other Adverse Effects

  • Psychiatric: Apathy and emotional flattening (indirect decrease of dopamine), hypomania, or mania (1%). In children and adolescents and young adults (18 to 24 years of age) paroxetine increase the risk of suicide
    • Induction of agitation or manic state may be representative of an underlying bipolar condition that requires the addition of a mood stabilizer, lithium, an atypical antipsychotic, and/or the discontinuation of paroxetine
  • Nervous system: Extrapyramidal symptoms, dizziness, headache, tremor
  • Metabolic: hyponatremia (SIADH), weight gain
  • Cardiovascular: Edema, chest pain, palpitations, tachycardia, vasodilation
  • Dermatologic: Alopecia, eczema, photosensitivity, purities
  • Gastrointestinal: Constipation, diarrhea, nausea

Contraindications

There are only a few absolute contraindications for the use of paroxetine. Absolute contraindications include concurrent use of monoamine oxidase inhibitors (MAOIs), thioridazine, and pimozide. Concomitant use of MAOIs and paroxetine can precipitate serotonin syndrome. Concurrent use of thioridazine and paroxetine can induce cardiac arrhythmias; similar effects can occur with pimozide and paroxetine.[6] 

Precautions that should be acknowledged when prescribing paroxetine include concurrent tricyclic antidepressant (TCA) use, concomitant tamoxifen use, and drugs affecting hepatic metabolism. Paroxetine inhibits TCA metabolism, leading to possible TCA toxicity. Tamoxifen is active once metabolized by CYP4502D6; thus, paroxetine essentially inactivates tamoxifen. 

Paroxetine is not recommended for use during pregnancy or if breastfeeding. Based on epidemiological studies, infants exposed to paroxetine during the first trimester had an increased risk for cardiovascular malformations.[6]

Monitoring

Patients initiated on paroxetine should receive close observation, initially, and monitored for worsening clinical symptoms, behavior changes (mania, social function, anxiety), or suicidal ideations. Labs should include serum sodium concentration to rule out SIADH.[7] 

Vital signs should be monitored for signs of serotonergic hyperactivity. Serotonin syndrome precipitates via the manifestation of changes in mental status, autonomic instability, gastrointestinal symptoms, hyperreflexia, and myoclonus. Serotonin syndrome is treated by discontinuing any of the offending agents. If symptoms continue to escalate, the clinician can administer cyproheptadine.[8]

Toxicity

Though it is rarely lethal in overdose by itself, patients can develop somnolence, nausea, tremor, heart rhythm disturbances, confusion, vomiting, dizziness, and mydriasis. During toxicity, a patient’s airway, oxygenation, and ventilation require evaluation first. The treatment for overdose includes symptomatic supportive treatment. There is no specific treatment for paroxetine toxicity.[9]

Enhancing Healthcare Team Outcomes

Interprofessional teamwork can impact a patient’s outcome positively. The increase in communication between the various department such as pharmacy and psychiatry can overall benefit the patient.[10] 

Each department acknowledges what the patients’ needs and implement the plan. The pharmacist can provide the dosing for the patient and monitor toxicity levels and consult with the prescriber for changes. Each patient is unique; some may require a different dosage because of renal of hepatic dysfunction.

This approach allows the patient to have a correct dosage based on their co-morbid conditions. Nursing should be alert to signs of adverse drug events, improvement in status, or the need for further evaluation, and report such to the clinician. The psychiatrist can also monitor the patient clinically for improvement, or if needed, make changes in the medication. This interprofessional paradigm can improve patient outcomes through enhanced treatment strategies and information sharing. [Level 5]

References

  • 1.Germann D, Ma G, Han F, Tikhomirova A. Paroxetine hydrochloride. Profiles Drug Subst Excip Relat Methodol. 2013;38:367-406. [PubMed]
  • 2.Amidfar M, Kim YK. Recent Developments on Future Antidepressant-related Serotonin Receptors. Curr Pharm Des. 2018;24(22):2541-2548. [PubMed]
  • 3.van Harten J. Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacokinet. 1993 Mar;24(3):203-20. [PubMed]
  • 4.Uttamsingh V, Gallegos R, Liu JF, Harbeson SL, Bridson GW, Cheng C, Wells DS, Graham PB, Zelle R, Tung R. Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetine. J Pharmacol Exp Ther. 2015 Jul;354(1):43-54. [PubMed]
  • 5.Bahar MA, Wang Y, Bos JHJ, Wilffert B, Hak E. Discontinuation and dose adjustment of metoprolol after metoprolol-paroxetine/fluoxetine co-prescription in Dutch elderly. Pharmacoepidemiol Drug Saf. 2018 Jun;27(6):621-629. [PMC free article] [PubMed]
  • 6.Hieronymus F, Lisinski A, Nilsson S, Eriksson E. Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression. Mol Psychiatry. 2018 Aug;23(8):1731-1736. [PubMed]
  • 7.Magalhães P, Alves G, Llerena A, Falcão A. Therapeutic Drug Monitoring of Fluoxetine, Norfluoxetine and Paroxetine: A New Tool Based on Microextraction by Packed Sorbent Coupled to Liquid Chromatography. J Anal Toxicol. 2017 Sep 01;41(7):631-638. [PubMed]
  • 8.Fitzgerald KT, Bronstein AC. Selective serotonin reuptake inhibitor exposure. Top Companion Anim Med. 2013 Feb;28(1):13-7. [PubMed]
  • 9.Calisto V, Ferreira CI, Oliveira JA, Otero M, Esteves VI. Adsorptive removal of pharmaceuticals from water by commercial and waste-based carbons. J Environ Manage. 2015 Apr 01;152:83-90. [PubMed]
  • 10.Pontefract SK, Coleman JJ, Vallance HK, Hirsch CA, Shah S, Marriott JF, Redwood S. The impact of computerised physician order entry and clinical decision support on pharmacist-physician communication in the hospital setting: A qualitative study. PLoS One. 2018;13(11):e0207450. [PMC free article] [PubMed]

More information: Crudden et al., Inhibition of G protein-coupled receptor kinase 2 promotes unbiased downregulation of IGF-1 receptor and restrains malignant cell growth. Cancer Research (2020). DOI: 10.1158/0008-5472.CAN-20-1662

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