Article: Paroxetine

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Paroxetine
Systematic (IUPAC) name
(3S-trans)-3-((1,3-Benzodioxol-5-yloxy)methyl)-
4-(4-fluorophenyl)-piperidine
Identifiers
CAS number 61869-08-7
ATC code N06AB05
PubChem 43815
DrugBank APRD00364
Chemical data
Formula C19H20NFO3 
Mol. weight 374.8
Pharmacokinetic data
Bioavailability complete absorption from GI, but extensive first-pass-metabolization in the liver; max concentration 4.9 (with meals) to 6.4 hours (fasting)
Metabolism extensive, probable hepatic
Half life 24 hours (range 3-65 hours)
Excretion 66% urine, 37% bile
Therapeutic considerations
Pregnancy cat.

D(US)

Legal status

â„ž Prescription only

Routes Oral


Paroxetine or paroxetine hydrochloride is a selective serotonin reuptake inhibitor (SSRI) antidepressant. It was released in 1992 by the pharmaceutical company GlaxoSmithKline and has since become one of the most prescribed antidepressants on the market due to its efficacy in treating depression as well as a spectrum of anxiety disorders ranging from panic attacks to phobias.

Paroxetine has been linked to suicidal ideation and attempts, particularly in children and young adults. It also has a demonstrated withdrawal syndrome, in which some users experience dizziness, electric shock-like sensations, and gastro-intestinal upset.

Trade Names

Paroxetine is marketed under the tradenames Paxil in the United States, Canada and Brazil; Seroxat in Austria, Greece, Poland, Portugal, the UK and China; Aropax in Australia, New Zealand, South Africa and Brazil; Pondera in Brazil; Deroxat in Switzerland and France; Paroxat in Germany, and Cebrilin in Latin America

Indications

Approved

Paroxetine is primarily used to treat the symptoms of depression. It can also be used to treat obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), panic disorder, generalized anxiety disorder (GAD), [1], social phobia/social anxiety disorder, [2] and premenstrual dysphoric disorder (PMDD)[3].

It was the first (and as of 2002, the only) antidepressant formally approved in the United States for the treatment of social anxiety disorder, causing it to be sometimes referred to (although inaccurately) as an anti-shyness drug.

Unapproved/Off-label/Investigational

Paroxetine can also be used in the treatment of premature ejaculation[4], chronic headache[5] and bipolar disorder[6].

Paroxetine has been found to significantly reduce the symptoms of diabetic neuropathy[7].

There is also evidence that paroxetine may be effective in the treatment of compulsive gambling[8] and hot flashes[9].

Pharmacology

Paroxetine the most potent selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI). This activity of the drug on brain neurons is thought to be responsible for its antidepressant effects.

Paroxetine is a phenylpiperidine derivative which is chemically unrelated to the tricyclic or tetracyclic antidepressants. In receptor binding studies, paroxetine did not exhibit significant affinity for the adrenergic (α1, α2, β), dopaminergic, serotonergic (5HT1, 5HT2), or histamine receptors of rat brain membrane. A weak affinity for the muscarinic acetylcholine and noradrenaline receptors was evident. The predominant metabolites of paroxetine are essentially inactive as 5-HT reuptake inhibitors.

Paroxetine Controlled Release (CR)

Paroxetine controlled release contains a Geomatrixâ„¢ tablet that controls the absorption of the drug. Clinical studies show that controlled release tablet provides effective symptom relief with a lower number of patients stopping their treatment due to side effects [10].

However, Paxil CR was released after the patent expired for the original Paxil, which was seen as a ploy by GSK only to increase earnings, as the FDA indicated that the half-life for the original Paxil was ideal for once-daily dosing, and that a CR version was not needed. In addition, the Paxil CR version is slightly less effective than the original and generic paroxetine, which is why the CR version is approved for fewer anxiety disorders.

Chemistry

Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 120° to 138°C and a solubility of 5.4 mg/mL in water.

Adverse effects

8019-45px-emblem-important-svg-paroxetine.png The neutrality and factual accuracy of this section are disputed.
Please see the relevant discussion on the talk page.

Concerns are growing about the side effects of paroxetine.

Recent studies have suggested that a small percentage of adolescents taking the drug are prone to becoming suicidal in the early stages of treatment.[citation needed] In May, 2006 a clinical analysis of trial data showed an increased frequency of suicide in young adults. Some psychologists believe that this is due to the way the drug begins to work in many patients.[citation needed] The first effect most patients notice is a decrease in the lethargy they experienced during their depression. This effect happens before the depression itself improves, so children may end up with enough "energy" and motivation to act on suicidal tendencies they may have already had.[citation needed]

Many adolescents who are prescribed paroxetine are suicidal to begin with. However most studies have compared suicide rates in patients using paroxetine against a control group of depressed individuals not being treated with paroxetine; the paroxetine group was reported to be twice as likely to commit suicide.[citation needed]

In June 2004, New York attorney general Eliot Spitzer began civil proceedings against GlaxoSmithKline over allegations that the company had suppressed five internal studies between 1998 and 2002 on the effects of the drug on both children and adults. The studies suggested that, in children, the drug had effects ranging from that of a placebo to inducing suicidal tendencies in its users. The company responded shortly later by making the results of the studies publicly available.

In March 2005, the United States Food and Drug Administration ordered the seizure of millions of tablets of Paxil after 3 years of GlaxoSmithKline's unresolved manufacturing problems. These problems involved Paxil CR, a time-release version of the drug. Some capsules were found to break in two, potentially resulting in the user taking only the active element of the drug without the time-release portion, or vice versa.

In September 2005 the Therapeutic Goods Administration (TGA) of Australia issued a warning about the potential for increased birth defects in the babies of pregnant women taking the anti-depressant paroxetine. Early results from GlaxoSmithKline suggested an association between taking the drug in the first three months of pregnancy and birth defects. The risk of cardiovascular defects may double from 1 to 2 percent in babies of women taking paroxetine. A Dutch study suggested a 60 per cent increase in defects. The TGA urged women not to suddenly stop taking the SSRI as withdrawal may cause harmful side effects. In December 2005, the United States Food and Drug Administration issued a similar public health advisory [1]. In this report, the FDA decided to change paroxetine from pregnancy category C to D, indicating a higher degree of caution is warranted when using paroxetine in pregnant women.

General side effects

General side effects are mostly present during the first 1-4 weeks while the body adapts to the drug. Almost all SSRIs are known to cause either one or more of these symptoms:

  • nausea
  • drowsiness
  • headache
  • changes in weight and appetite
  • changes in sexual behaviour
  • increased feelings of depression and anxiety (initially)
  • dry mouth
  • constipation
  • diarrhea
  • rash
  • restlessness or akathisia
  • itch
  • sodium depletion
  • changes in urination
  • sweating

Individuals experiencing any of the following symptoms should contact their doctor immediately:

  • Jaw, neck, and back muscle spasms
  • Fever, chills, sore throat, or flu-like symptoms
  • Yellowing of the skin or eyes
  • Black, tarry stools (this can indicate upper GI bleeding)

Despite these side effects, Paroxetine is effective and generally well-tolerated in adults. Paroxetine is a useful tool in treating major depression, particularly in adults who have not responded to other therapies.

Addictive potential and withdrawal symptoms

8020-20px-circle-question-paroxetine.png The factual accuracy of this section is disputed.

Addictive potential

The manufacturers claim it is impossible to become addicted to paroxetine. Others disagree, and report dependence. This has more to do with the precise meaning of the word "addictive" than the properties of paroxetine: the medical community generally considers that withdrawal symptoms are not enough to regard a drug as addictive—it has to leave the user needing more and more in order to gain the same desired effect. There seems to be some confusion on whether paroxetine and other SSRIs are addictive. They are not addictive in the classic sense as the user does not crave more of the drug. However, there is little or no doubt that many patients suffer withdrawal symptoms when stopping the drug and tolerance may develop over time[citation needed]. Withdrawal symptoms can include sensations of electric shocks in the brain, intense headaches, unusual dizzy feeling, gastro-intestinal upset and a host of other symptoms. Withdrawal symptoms usually disappear when another dose of the medication is taken.

Withdrawal symptoms

Citing data from the World Health Organization, "Paxil has the highest incidence rate of withdrawal adverse experiences of any antidepressant drug in the world". There are personal and anecdotal accounts of withdrawal symptoms from paroxetine. See, for example, [2], [3] and [4]. This is referred to as 'discontinuation syndrome' or withdrawal syndrome and refers to problems which result upon immediate discontinuation of the drug.

Initially, the response of drug regulators (based eg on a report by Price et al, 1995) were that withdrawal symptoms (or 'discontinuation reactions' as SKB/GSK insisted) were generally mild and short-lived, an opinion that has been replaced by mounting concern. Now, it seems about a third of users have problems stopping paroxetine, and the symptoms are strikingly similar ('electric shock' paraesthesia, dizziness, flu-like symptoms, auditory hallucinations, etc). It is clear that what is under discussion is not psychological dependence.

Withdrawal symptom severity varies from individual to individual and can last from months to years. The most common and successful technique for protection against a difficult withdrawal experience is to lower dosage levels gradually over time. Symptoms arising from a dose change often don't fully appear for several weeks. Since paroxetine has a much shorter half life than other SSRIs like Prozac, people have occasionally sought to buffer their withdrawal plan with a liquid form of Prozac. In liquid form, dose diminishments of 1m.g. are easy to achieve.

Suicidal ideation is a frequently reported experience in those withdrawing from SSRIs like paroxetine. Never seek to withdraw from paroxetine or any other SSRI without supervision.

Lawsuits

Many lawsuits filed against GlaxoSmithKline have been settled out of court. Confidential agreements exist that prevent the public from hearing plantiffs who were injured by harmful effects of Paxil. Court clauses extend to the Internet, saying that attorneys and plantiffs, "will not maintain and instead discontinue any website references to Paxil discontinuation or withdrawal".[citation needed] Previously sealed documents and internal company memos suppressed with protective orders, show that Glaxo knew about problems with Paxil before it received FDA approval, but continued to sell the drug for over a decade without warning customers.[citation needed]

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