Sertraline (Zoloft): Drug Whys
By Mike McEvoy
Generic Name: Sertraline (multiple manufacturers)
Common Brand Name: Zoloft (Pfizer Labs – U.S.)
Popularity: 22nd most commonly prescribed drug between 2002 – 2007 (U.S.)
Class: Antidepressant, SSRI (selective serotonin reuptake inhibitor)
Treatment Uses – Treatment of major depressive disorder (MDD) in adults, obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and social anxiety disorder. Sertraline has also been used effectively in treatment of aggressive behavior and dysthymia (a depressive disorder of less severity and longer duration than MDD). Sertraline has been helpful in treatment of alcoholism, Alzheimer’s disease, some pain syndromes, low blood pressure associated with hemodialysis, dyspnea associated with COPD, post-stroke emotional lability, and treatment of premature ejaculation. Investigational uses (under study) of sertraline include eating disorders, impulse control disorders, generalized anxiety disorder (GAD), and treatment of mild agitation associated with dementia in nonpsychotic patients. Sertraline has not been helpful in treating schizophrenia or eating disorders.
During 2003, British authorities became sufficiently concerned about increased suicide risks in children and teens being treated with another popular SSRI, paroxetine (brand name Paxil, U.S. manufacturer GlaxoSmithKline), that they warned against pediatric use. The U.S. Food and Drug Administration followed suit, but later admitted increasing skepticism about links between antidepressants and suicide risk in children and teens. Clearly, suicide risk is higher in young adults, and untreated depression is the leading cause of these suicides. Subsequent studies confirmed increased suicide risk with antidepressant use in people under 24 years of age and decreased suicide risk in patients > 65 years old. The greatest suicide risk appears in the first one to two months of treatment and during dose adjustment periods (increases or decreases). In the United States, outpatient dispensing of new or refill antidepressant prescriptions such as sertraline to children, adolescents and young adults must be accompanied by an FDA approved medication guide (see: www.fda.gov/cder/Offices/ODS/medication_guides.htm). Adverse SSRI publicity does not appear to have slowed sales or use.
The FDA has also added a Black Box warning (their highest level advisory) to sertraline, stating, “Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders.” Prescribers are cautioned to consider this risk. The FDA also withdrew their approval of sertraline for major depressive disorder (MDD) in children. Sertraline remains FDA approved for treatment of obsessive-compulsive disorder (OCD) in children > 6 years of age.
Some emergency medical providers may remember struggling to deal with overdoses of a much older antidepressant called tricyclic antidepressants (TCAs). They, with their mental health colleagues, cheered the arrival of SSRIs with their far less lethal overdose profiles.
Dosing and Administration – For treatment of depression, dysthmia, and OCD, the initial oral dosing in adults is 50 milligrams daily, adjusted at one-week intervals up to a maximum of 200 milligrams daily. Dosing for panic disorder, PTSD, and social anxiety disorder is initially 25 milligrams daily, increased to 50 milligrams after one week, and then adjusted weekly up to a maximum of 200 milligrams daily. Use for PMDD depends on the menstrual cycle and has a variety of dosing schemes.
In pediatric patients between 6 and 12 years old, the initial dosing is 25 milligrams daily, increased at intervals of at least one week to a maximum of 200 milligrams daily. For 13 to 17-year-old children, initial dosing of 50 milligrams daily with the same adjustment scheme is recommended. Sertraline is available in an oral concentrated solution requiring dilution immediately before administration with at least 4 ounces of water, ginger ale, lemon/lime soda, lemonade, or orange juice only. The concentrate contains 12 percent alcohol (potentially problematic for patients taking disulfuram for alcohol cessation) and is dispensed with a dry natural rubber dropper (problematic for patients with latex allergies). A slight haze after mixing the concentrate is normal.
Depressed patients who respond to sertraline during the first eight weeks of treatment seem to benefit from at least an additional eight weeks of treatment and may require several months or longer treatment.
Sertraline is typically taken as a single daily dose in the morning, although evening dosing will not alter the drug’s effects and is recommended if somnolence (excessive daytime sleepiness) is observed. Peak serum levels may be increased if taken with food but this does not seem to have any clinical implications.
Lower doses are recommended for elderly patients starting at 25 milligrams daily and adjusted upward by 25 milligram increments every 2-3 weeks as tolerated to a maximum of 200 milligrams daily. Patients with Alzeihmer’s dementia-related depression may require even lower starting doses of 12.5 milligrams daily with titration intervals of 1-2 weeks up to a 200 milligram daily maximum. Patients with liver dysfunction (hepatic insufficiency) should also be given lower or less frequent doses of sertraline. Dosage adjustments are not necessary in patients with kidney disease or renal failure.
In adults, minimal toxicity has been seen with doses of 700 to 2100 milligrams. Of 1,027 sertraline overdoses, there were 72 deaths. Obviously, lesser doses are toxic in children. Signs and symptoms of overdosage include sedation, vomiting, tachycardia, nausea, dizziness, agitation, and tremor. Hemodialysis is not helpful in removing the drug from the body. Treatment should be supportive. Serotinin syndrome can be treated with cyproheptadine dosed in adults at 4 to 8 milligrams orally every one to four hours up to a 32 milligram maximum and 0.25 milligrams per kilogram per day in children divided into 6 hour intervals and not exceeding 12 milligrams total daily.
Pharmacology/Pharmacokinetics/Stability – After oral administration of sertraline, peak concentrations are reached in the bloodstream between 4.5 and 8.4 hours. Taking tablets with food increases peak concentrations and shortens time to reach peak levels, but does not affect drug action. Initial effects on depression take two weeks to appear, and peak response is commonly seen after six weeks of treatment. Sertraline remains in the body for an average of 27 hours following a dose. The liver metabolizes nearly all sertraline. Kidneys excrete 40-45 percent and feces carry most of the remainder.
Sertraline has been detected in breast milk and in nursing infants, while long-term effects on the children are unclear, limited studies suggest no evidence of adverse effects. Reproductive studies of sertraline in mice and rabbits have shown no harm to fetuses. One human population-based study found no increased risk of fetal malformations, but infants whose mothers took sertraline were more likely to require treatment in a neonatal intensive care unit. Use of any SSRI, including sertraline, after 20 weeks of gestation has been associated with an increased risk of persistent pulmonary hypertension in newborns.
The most recent study conducted in 2007 found no significant association between use of SSRIs in early pregnancy and birth defects. Sertraline is generally well tolerated in pregnancy and does not appear to pose an unusually high risk to the developing fetus. The dangers of failing to treat major depression are significant and must be weighed against potential for harm to the developing fetus. Sertraline should only be used in pregnancies where the potential benefits justify risks.
Sertraline’s mechanism of action in the body may be due to a selective inhibitory effect on presynaptic reuptake of serotonin. It has a weak effect on neuronal uptake of norepinephrine and dopamine. Translated, this means that SSRIs work when brain levels of the neurotransmitter serotonin (known also as 5-hydroxytryptamine or 5-HT) are lacking. SSRIs cause remaining serotonin to stay available longer, making it more effective. In time, natural serotonin levels should rise, allowing the SSRI dose to be reduced and withdrawn.
Sertraline tablets vary in size, shape and color by manufacturer. Oral concentrate solution is clear, colorless, with a menthol smell. Both tablets and liquid should be stored at room temperature of 77 F with excursions to between 59-86 F permitted.
Cautions and Warnings – Aside from the increased suicide risk in young patients, sertraline's most significant warning pertains to use with monoamine oxidase inhibitors (MAOIs). Once a widely prescribed antidepressant, MAOIs are now uncommon, and reserved for patients who don’t respond to newer (and safer) agents. Use of sertraline in patients taking or who have taken an MAOI within the past 14 days can lead to a fatal serotonin syndrome. This syndrome resembles malignant hyperthermia with its rigidity, extremely high fevers, and a constellation of other physical effects resulting from excessive levels of serotonin in the brain.
A minimum of two weeks separation between use of sertraline and MAOIs is imperative. Abruptly stopping sertraline can result in another constellation of distressing symptoms including abnormal movements and sensations. Dosing should be tapered gradually when discontinuing therapy. Caution is recommended when using sertraline in patients with known seizure disorders. Finally, suicide risk is a concern in any depressed patient (not only the young); initiating treatment does not instantly diminish suicide risk. Caution is important with any high-risk patient until remission of depression occurs. Families and significant others should be advised to closely observe patients for clinical worsening, suicidality, or unusual changes in behavior. Prescriptions should be written for the smallest quantity of medication needed for good patient care with the thought in mind of minimizing danger from an overdose. With long-term therapy, periodic monitoring of heart rate, blood pressure, liver function, and blood counts is advised.
Important Side Effects and Interactions – Side effects of newsworthy drugs like SSRIs are difficult to filter. Manufacturers report every effect they become aware of, and the media tends to hype on sensational rather than common side effects. Percentage wise, considering all users of sertraline, the most common side effect reported (by 20- 25 percent of patients) is nausea that gradually decreases and often resolves over three weeks of therapy. Next most common, reported by 14 percent of patients, is delayed ejaculation. Close behind, reported by more than 10 percent of patients are dry mouth, diarrhea, dizziness, headache, trouble sleeping and sleepiness. Less frequent are palpitations, nervousness, rash, loss of sex drive, GI upset, urinary difficulties, tremors, and visual disturbances. While weight gain is commonly ascribed to SSRI therapy, studies show this tends to be limited to a 2-pound gain when it occurs. Similar numbers of patients loose weight with SSRI therapy, typically limited to 1 or 2 pounds.
Rare cases of bleeding from platelet function impairment with sertraline have been reported and seem more common in the pediatric population. Extrapyramidal reactions (EPR), although rare, can occur with SSRIs and tend to happen in the first few days to first month of treatment
One hundred and forty-three drugs and drug classes are reported to interact with sertraline. Of these, the most significant involves MAOI interactions already discussed. The majority of other interactions reported pertain to increased or decreased concentrations of anti-seizure drugs and sertraline when used in combination, as well as changes in sertraline levels when other drugs metabolized by the liver are started or discontinued. There is clear evidence that use of non-steroidal anti-inflammatory agents (NSAIDs) while taking sertraline result in an increased risk of bleeding.
Acetaminophen is a reasonable NSAID alternative for fever and pain. The manufacturer recommends that depressed patients avoid alcohol while taking sertraline although studies did not show any adverse effects of alcohol consumption in healthy subjects taking sertraline. Of course, consumption of alcohol is not wise for any depressed patient. One small study showed that grapefruit juice increased sertraline blood concentrations resulting in greater side effects. While a larger study is needed to confirm this, patients taking sertraline would be smart to avoid grapefruit juice.
Average Costs – U.S.
• 25 mg tablet/50 mg tablet (generic)
Patient cost: $ 1.13 each for all strengths*
Large Hospital cost: $0.12 and 0.08
*(Wal Mart® and Target don’t include sertraline in their $4/month programs but Walgreens does carry the 25 mg tablets in their $1/week, 90 day supply program)
Note: costs promote tablet cutting (ie: a single 50 mg tablet = two 25 mg doses)
1. MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed March, 2009).
2. Albany Medical Center Pharmacy, Albany, New York.