Sertraline hydrochloride (also sold under brand names Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton, Xydep, Serlain, Concorz) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. In 2006 it was the most prescribed antidepressant on the U.S. retail market with 28,060,000 prescriptions.
History
The history of sertraline goes back to the beginning of 1970s when Pfizer chemist Reinhard Sarges synthesized a norepinephrine reuptake inhibitor tametraline Tametraline's development was soon stopped because of undesired stimulant effects shown in animal trials. Several years later, biochemist Kenneth Koe and chemist Willard Welch generated and tested derivatives of tametraline in vitro for the serotonin reuptake inhibition. Welch then prepared stereoisomers of the most promising candidate, which were tested in vivo by animal behavioral scientist Albert Weissman. The most active (+)-cis-isomer was taken into further development and eventually became sertraline. During the development, the group had to overcome the initial reluctance of Pfizer bureaucracy to pursue sertraline, as Pfizer was considering licensing an antidepressant candidate from another company.
Sertraline was approved by the Food and Drug Administration (FDA) in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committee. The committee achieved a consensus that sertraline is safe and efficient for treatment of the depression. During the discussion, Paul Leber, Director of the FDA Division of the Neuropharmacological Drug Products noted that it was a "tough decision", since the treatment effect on outpatients with depression is "modest to minimal". Other experts emphasized that the drug's effect on inpatients is not different from placebo and criticized poor design of the trials by the drug's manufacturer Pfizer. For example, 40% of the participants dropped out of the trials, significantly decreasing their validity.
Until 2003, sertraline was only approved for use in adults ages 18 and over; that year it was approved by the FDA for use in treating children ages 6 to 17 with extreme obsessive compulsive disorder. In December 2003, the UK Medicines and Healthcare Products Regulatory Agency issued a guidance that SSRIs except fluoxetine are not suitable for the treatment of depression in minors. However, sertraline still can be used for the treatment of OCD in children and adolescents. In February 2005 the FDA, changed the labeling of SSRIs, except fluoxetine, adding a boxed warning pertaining to pediatric suicidality.
The patent for Zoloft brand of sertraline expired in June 2006, and the drug is now available in generic form.
Indications
Approved
Sertraline is prescribed for the treatment of depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder (PD) and social phobia/social anxiety disorder.
Depression
The original clinical trials demonstrated only moderate efficacy of sertraline for depression (see History). Nevertheless, later research firmly established sertraline as one of the drugs of choice for the treatment of depression in outpatients.
Sertraline has a similar effect on core depressive symptoms as the tricyclic antidepressants (TCAs) but like other SSRIs has more tolerable side effects, which often results in a better quality of life.
For example, similar improvement of depression scores was achieved in both sertraline and amitriptyline groups. At the same time, sertraline resulted in a much lower rate of side effects than amitriptyline (49% vs 72% vs 32% for placebo), particularly dry mouth, somnolence, constipation and increased appetite. However, there were more cases of nausea and sexual dysfunction in the sertraline group. Furthermore, sertraline patients showed a greater improvement of the subjective quality of life on such measures as work satisfaction, subjective feeling, perceptions of health and cognitive function.
A large and thorough double-blind study compared sertraline prescribed for chronic (longer than 2 years) depression or depression with dysthymia to the "gold standard" of depression treatment TCA imipramine. Sertraline was equivalent to imipramine for both of these indications during the first 12 weeks of the study and the 16 weeks continuation phase. Only 11% of patients on sertraline suffered severe side effects vs. 24% on imipramine. Constipation, dizziness, tremor, dry mouth, micturition disorder and sweating adverse effects were observed more often with imipramine, and diarrhea and insomnia with sertraline. Sertraline patients also reported significantly better social and physical functioning. Interestingly, the patients who achieved a remission during the trial (30% of the sample) did not differ from the healthy population on the measures of marital, parental, physical and work functioning and were close to normal on social adjustment and other measures of interpersonal functioning.
Sertraline also has efficacy similar to nefazodone and fluoxetine,.
Several clinical trials demonstrated that sertraline used for the treatment of depression in elderly (older than 60) is superior to placebo and comparable to another SSRI fluoxetine, and TCAs amitriptyline, nortriptyline and imipramine. Sertraline had much lower rate of adverse effects than these TCAs, for the exception of nausea, which occurred more frequently with sertraline. In addition, sertraline appeared to be more effective than fluoxetine or nortriptyline in the older than 70 subgroup.
Unapproved, off-label, and investigational
Sertraline can also be used in the treatment of general anxiety disorder, binge eating disorder, and premature ejaculation.
There is also evidence that sertraline may be effective in the treatment of refractory neurocardiogenic syncope in children and adolescents.
A study has shown that sertraline is an effective treatment for impulsive aggressive behavior in personality disordered patients.
It has also been used to treat Tourettes Syndrome.
Side effects
Sertraline can have adverse effects, including: sleep disorder (both insomnia and increased sleep time), asthenia, gastrointestinal complaints, tremors, weight gain, confusion, dizziness, anorgasmia, nausea/vomiting, bruxism, mild depersonalization, and decreased libido. Sertraline, like all of the other SSRI drugs, can increase anxiety and depression symptoms in the first few days/week of use. These side effects generally go away as the body adjusts chemically to the drug. Sertraline can induce mania or hypomania in around 0.5% of patients. It has also been known to cause minor weight loss initially but weight gain over time. It is contraindicated in individuals taking monoamine oxidase inhibitors (MAOIs) or undergoing electroconvulsive therapy. Patients are advised to stop taking MAOIs for at least 14 days before beginning a course of sertraline.
Zoloft has long been seen as the best option for breastfeeding mothers who wish to continue breastfeeding and be able to take their antidepressants. Despite its apparent safety and effectiveness during the breastfeeding period, recent studies and consumer complaints have seen a need to alter Zoloft's labeling regarding use during the third trimester of pregnancy. Though there are no teratogenic effects associated with Zoloft, there is reason to be concerned about its effects on infants who were exposed to sertraline during the third trimester in utero. It seems that Zoloft use in late pregnancy significantly increases the potential need for hospitalization and breathing assistance in the newborn period and has also been shown to cause an increased risk of neonatal death. In light of this increased risk it is still being used due to the greater potential risk of a seriously depressed mother to herself and her fetus. Like all other medications, Zoloft's use must be decided only after carefully weighing out all potential risks and benefits.
Although SSRI anti-depressants may cause problems in newborn babies whose mothers took Zoloft during pregnancy, the ceasing of Zoloft consumption during pregnancy may cause a relapse of depression.
According to the manufacturer's website, "if depression is left untreated, the risk of childhood suicide increases about 12 times, according to federal figures".
Sertraline and other SSRIs have been shown to cause sexual side effects called Post SSRI Sexual Dysfunction in both males and females taking them. Sometimes, these may last months, years, or indefinitely after the drug has been withdrawn.
Suicidality
According to mentalhealth.com, Zoloft is not currently recommended or advised for use in individuals under the age of 18. After these changes, multiple incidences and at least one medical study showed an increased suicide risk in seniors who were taking Zoloft. In response to these findings, the FDA released a public health warning. This warning indicates that anyone currently using Zoloft for any reason has a greater chance of exhibiting suicidal thoughts or behaviors regardless of age. This warning is questionable, however, due to the types of illnesses Zoloft is used to treat, it is impossible to determine if these tendencies are a side effect of the drug or the illness the drug is meant to treat, though some have found links to increased suicide rates especially among individuals with bipolar disorder.
Discontinuation syndrome
Main article: SSRI discontinuation syndrome
Sertraline, along with other SSRIs, has been associated with a "cessation syndrome." This syndrome has both somatic and psychological elements, although SSRIs fall short of being classified as addictive. This non-addictive classification stems from the fact persons given the drug will not seek it out in ever-increasing quantities. Although sertraline is defined as non-habit forming, the existence of SSRI discontinuation syndrome often necessitates a gradual tapering of one's prescribed dose when seeking to stop SSRI therapy. The prescription insert for Zoloft describes the potential side effects SSRI discontinuation as follows:
"During marketing of Zoloft and other SSRIs and SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms."
Formulations
Sertraline is manufactured by Pfizer and sold as Zoloft in the United States as small green 25 mg tablets, blue 50 mg tablets, and yellow 100 mg tablets (Generic 100 mg sertraline tablets are also yellow), each of which is scored to allow easy halving.
In the UK, the brand name is Lustral and is available in white 50 mg or 100 mg scored tablets, according to the British National Formulary (BNF). Elsewhere in the EU the brand name is Zoloft, available in white 50 mg or 100 mg scored tablets. In Australia, only the 50 mg and 100 mg strengths are available, both as white tablets.
Sertraline is an odorless, white, sparingly soluble crystalline solid. The minimum effective dose is usually 50 mg per day (it can be still effective at 25 mg or 37.5 mg), but lower doses may be used in the initial weeks of treatment to acclimatize the patient's body, especially the liver, to the drug and to minimize the severity of any side effects. Patients who do not experience relief of symptoms at 50 mg a day may have their dose increased, up to 200 mg a day.
Precautions
Liver impairment can affect the elimination of this drug from the body. If someone with liver impairment is treated with sertraline, lower or less frequent dosage should be used.
Patients should limit their alcohol intake while on sertraline (or any antidepressant). Because the liver is doubly taxed with processing both substances (in addition to any other drugs the patient may be taking), alcohol remains in the bloodstream longer, so the effects of alcohol may be more strongly and quickly felt by people taking sertraline or other antidepressants. Heavy alcohol consumption while on any SSRI can damage liver cells much quicker than those off of the drugs.
According to a 1999 study, grapefruit juice might interfere with the metabolisation of sertraline, increasing its concentration in the blood.
People 80 years or older should be started on 25 mg initial dose.
Mechanism of action
Sertraline is primarily a serotonin reuptake inhibitor. It is also a dopamine reuptake inhibitor, but this effect is relatively weak compared to its serotonin reuptake inhibition. As mainly an SSRI, Sertraline blocks the reuptake of serotonin and in effect, keep the neurotransmitters longer on the synapse. This allows more time for the receptors to recognize the serotonin and send the nerve impulse.
Controversy
The brand-name form of sertraline, Zoloft, was widely advertised to consumers as "correcting a chemical imbalance", a claim not found in the FDA-approved product labeling. Hundreds of millions of dollars were spent promoting Zoloft this way while it was still on-patent. Some have argued that this advertising may lead consumers to believe that they must take Zoloft to recover when in fact they may benefit from other non-medical treatments such as psychotherapy or exercise.
In the case of Hawkins v The Commonwealth (an Australian court case from the state of New South Wales), Zoloft was described as an important factor in David Hawkins' murder (through strangling) of his wife. Hawkins had been depressed, was prescribed 50 mg of Zoloft a day and on his first day of treatment took 250 mgs. He claimed on the night of the murder that he couldn't sleep, was agitated and claimed he had hallucinations during the attack on his wife. As a result of this case Zoloft received a large amount of negative publicity, with questions being raised about its impact on behaviour.
In 2004, a Los Angeles nurse sued Pfizer as a private attorney general "on behalf of all California residents who have been misled about Zoloft", claiming the company covered up side effects.
A well-publicized essay published in the December 2005 issue of open access journal PLoS Medicine claimed the direct-to-consumer advertising for Zoloft has been very misleading and could well violate FDA regulations.
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