Paroxetine

Neurotransmitters mediate communication between adjacent neurons. Paroxetine has an effect on the neurotransmitter serotonin. Source: NIH.

Paroxetine is one of a class of medicines called selective serotonin reuptake inhibitors (SSRIs) that are used to treat depression and other mental illnesses. It works by changing how the brain handles serotonin, a neurotransmitter involved in mood and behavior. Paroxetine offers several important differences from other medicines in the SSRI class and is available in several formulations, all of which are only available by prescription. It is one of the most widely prescribed antidepressant medications in the US. Although it offers tremendous symptomatic relief to many individuals, it is associated with a very difficult withdrawal and carries several important risks.

Other Names

• Paxil IR is the immediate-release form of the paroxetine HCl
• Paxil CR is the controlled-release form of the paroxetine HCl
• Pexeva is the brand name for paroxetine mesylate (Noven Therapeutics LLC).

Outside the US the drug is sold under the following names:

• Seroxat
• Parotin
• Aropax
• Xetanor
• ParoMerck
• Rexetin

Uses

Paroxetine is approved for treatment of major depression, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, post-traumatic stress disorder and social phobia in adults. Paroxetine is also sometimes used to treat chronic headaches, tingling in the hands and feet caused by diabetes, and certain male sexual problems. Paroxetine is also used with other medications to treat bipolar disorder (mood that changes from depressed to abnormally excited). Paroxetine CR is approved for the treatment of major depression, social anxiety disorder, panic disorder and premenstrual dysphoric disorder in adults. This broad range of indications differentiates paroxetine from other marketed SSRIs.

How Paroxetine Is Taken

Paroxetine is available in the following dosage forms:

• Tablet (Immediate Release)
• Tablet, Extended or Controlled Release
• Suspension

Initially, the smallest dose available (10 mg of the immediate-release (IR) form) is taken in the morning. The dose is increased in 10 mg/day increments as necessary at intervals of at least one week. The IR form is available in 10-, 20-, 30-, and 40-mg tablets and in suspension form. The controlled-release (CR) form is available in 12.5-, 25-, and 37.5-mg tablets that show equal or better efficacy than the IR form and are easier for the body to tolerate. ^[1]

How Paroxetine Works

Paroxetine works by helping to restore the balance of a certain neurotransmitter called serotonin, which is a natural substance in the brain that acts as a chemical messenger between nerve cells. Paroxetine elevates the circulating levels of serotonin by preventing it from being taken back up into the cells. In addition to inhibiting serotonin reuptake, paroxetine is also a relatively potent reuptake inhibitor of another neurotransmitter called norepinephrine.

How the Body Affects Paroxetine

Paroxetine is well-absorbed from the gut, whether or not it is taken with food. Paroxetine is metabolized in the liver by an enzyme known as cytochrome P450 2D6. Because of different versions (polymorphisms) in this enzyme that handle paroxetine at different rates, there are maked differences in steady-state blood concentrations of paroxetine at a given dosing level.^[2] This is probably inconsequential, since no consistent relationship between paroxetine levels and clinical response (or adverse outcome) has been found.^[3]

Benefits

Relief of symptoms associated with the mental illnesses listed in "Uses" can be of tremendous benefit. In addition, paroxetine is sometimes used off-label for conditions that are not included in the list of approved indications; several of these are listed in the "Research" section.

Risks

Interactions

Paroxetine may cause harmful interactions with any of the following medicines:

• Clorgyline
• Furazolidone
• Iproniazid
• Isocarboxazid
• Linezolid
• Moclobemide
• Nialamide
• Pargyline
• Phenelzine
• Pimozide
• Procarbazine
• Selegiline
• Thioridazine
• Toloxatone
• Tranylcypromine

Precautions

FDA alerts

• In July 2006 the U.S. Food and Drug Administration (FDA) issued an alert for paroxetine regarding possible life-threatening serotonin syndrome when used with medicines in the triptan class that are sometimes used to treat migraine headaches. Signs and symptoms of serotonin syndrome include restlessness, hallucinations, loss of coordination, rapid heart beat, increased body temperature, fast changes in blood pressure, overactive reflexes, diarrhea, coma, nausea, and vomiting. Serotonin syndrome may be more likely to occur when starting or increasing the dose of an SSRI or a triptan.

• Also in July 2006 the FDA issued an alert for paroxetine (and other SSRIs) regarding a six-fold increased risk for infant persistent pulmonary hypertension (IPPH) in children whose mothers took drugs in this class during pregnancy. Babies born with IPPH have abnormal blood flow through the heart and lungs and do not get enough oxygen to their bodies; the condition can be fatal.

Risk of suicide

• Suicidal thoughts or actions in people taking paroxetine are of concern. These were described in 2005 in a review article^[4] that received much attention in the popular press. Persons taking paroxetine may be more likely to think about killing themselves or actually try to do so, especially during the initial phase of treatment or after an increase in dosage.

Withdrawal

Decreasing the dosage of paroxetine too quickly is associated with withdrawal or discontinuation symptoms. ^[5]

Risk to the fetus

• Recent evidence suggests that paroxetine may be associated with an increased risk of cardiac abnormalities.^[6]
• Babies delivered to mothers taking paroxetine late in pregnancy have developed problems, such as difficulty breathing and feeding.
• Babies delivered to mothers taking paroxetine early in pregnancy are sometimes born with heart problems.

Complications

• Bleeding problems may be noted if paroxetine is taken with aspirin, NSAIDs (nonsteroidal anti-inflammatory drugs, such as ibuprofen or naproxen), or other drugs that affect bleeding.
• Mania is a possible side effect of paroxetine.
• Sexual problems may be encountered that include impotence (erectile dysfunction), abnormal ejaculation, difficulty reaching orgasm, or decreased libido (sexual desire).
• Other side effects include weakness, dry mouth, constipation, yawning, infection, diarrhea, sweating, dizziness, tremor, nervousness, nausea, difficulty sleeping, decreased appetite, and sleepiness.

History

Discovery

After fluoxetine was introduced in 1988, research efforts by other pharmaceutical companies became focused on discovery and commercialization of other SSRIs. Paroxetine was the third SSRI approved by the FDA for treatment of depression. Paroxetine CR was developed to improve gastrointestinal tolerability, and the drug is also available in suspension form.

Manufacturer

When formulated as the hydrochloride salt (paroxetine HCl), paroxetine is marketed by GlaxoSmithKline as Paxil

Alternatives

Paroxetine shares its mechanism of action with other SSRIs marketed for depression including fluoxetine (Prozac), citalopram (Celexa), sertraline (Zoloft), and others. Paroxetine is approved for use in a wider variety of anxiety disorders than any other antidepressant. Compared to other SSRIs, paroxetine can result in more sedation and constipation.

Research

Several completed clinical trials report on potential new uses for paroxetine, including

• Reducing the incidence and severity of pathological gambling^[7]
• Reducing the risk of blood clots^[8]
• Decreasing the risk of heart attack by decreasing platelet activity^[9]
• The use of paroxetine in the treatment of patients with Fibromyalgia Syndrome ^[10]
• The use of controlled release paroxetine compared to immediate release paroxetine in the treatment of patients with major depression. ^[11]
• The use of paroxetine vs placebo combined with aerobic exerciseor relaxation in the treatment of panic disorder. ^[12]

Clinical Trials

A list of ongoing clinical trials is available here: paroxetine trials.

Interesting Facts

• The brand name "Paxil" has been used in the title of songs by Landspeedrecord! ("The Paxil Song"), Moses McCartney ("Paxil Pusher"), John Danley ("Paxil Eyes"), and Seamus ("A Paxil a Day Keeps the Doctor At Arm's Length"). The artists Stay Down, Snax, Peter Parker, and Instant Death have all recorded songs entitled "Paxil," while the artists Jazzpunkensemblet and Nevera have recorded songs entitled "Seroxat."

• Johnston-Murphy shoe company markets "Paxil" as a plain toe oxford men's shoe.

• In trying to bring favorable connotations to their brand name, marketers at GlaxoSmithKline may have noticed that the first three letters of "Paxil" correspond to the Latin word for "peace."

References

1. ↑ Golden RN, Nemeroff CB, McSorley P, Pitts CD, Dubé EM. Efficacy and tolerability of controlled-release and immediate-release paroxetine in the treatment of depression. J Clin Psychiatry. 2002 Jul;63(7):577-84. [1]
2. ↑ Lane RM. Pharmacokinetic drug interaction potential of selective serotonin reuptake inhibitors. Int Clin Psychopharmacol. 1996 Dec;11 Suppl 5:31-61. [2]
3. ↑ Tasker TC, Kaye CM, Zussman BD, Link CG. Paroxetine plasma levels: lack of correlation with efficacy or adverse events. Acta Psychiatr Scand Suppl. 1989;350:152-5. Citation Only
4. ↑ Aursnes I, Tvete IF, Gaasemyr J, Natvig B. Suicide attempts in clinical trials with paroxetine randomised against placebo. BMC Med. 2005 Aug 22;3:14. Abstract Full Text PDF
5. ↑ Himei A, Okamura T. Discontinuation syndrome associated with paroxetine in depressed patients: a retrospective analysis of factors involved in the occurrence of the syndrome. CNS Drugs. 2006;20(8):665-72. [http:pubmed.gov/16863271 Abstract]
6. ↑ Williams M, Wooltorton E. Paroxetine (Paxil) and congenital malformations. CMAJ. 2005 Nov 22;173(11):1320–1. Abstract
7. ↑ Kim SW, Grant JE, Adson DE, Shin YC, Zaninelli R. A double-blind placebo-controlled study of the efficacy and safety of paroxetine in the treatment of pathological gambling. J Clin Psychiatry. 2002 Jun;63(6):501-7. Abstract
8. ↑ Kotzailias N, Andonovski T, Dukic A, Serebruany VL, Jilma B. Antiplatelet activity during coadministration of the selective serotonin reuptake inhibitor paroxetine and aspirin in male smokers: a randomized, placebo-controlled, double-blind trial. J Clin Pharmacol. 2006 Apr;46(4):468-75. Abstract
9. ↑ Sauer WH, Berlin JA, Kimmel SE. Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation. 2003 Jul 8;108(1):32-6. Abstract
10. ↑ Patkar AA, Masand PS, Krulewicz S et al. A randomized, controlled, trial of controlled release paroxetine in fibromyalgia. Am J Med. 2007 May;120(5):448-54. Abstract
11. ↑ ClinicalTrials.gov. A Local Register Study For Major Depression Of Paroxetine Controlled Release
12. ↑ Clinicaltrials.gov. Paroxetine vs Placebo Combined With Aerobic Exercise or Relaxation in Panic Disorder (Exparox)

External Links

Medline Plus: Paroxetine