Major Depressive Disorder is the leading cause of disability in the U.S. for those between the ages 15-44. The disorder affects approximately 14.8 million American adults, which is roughly 6.7 percent of the adult population, every year. In 2011, Sertraline was the second-most prescribed antidepressant on the market, with over 32 million prescriptions written. In this research paper I will discuss the creation, structure, and activity of the antidepressant known as Sertraline Hydrochloride, trade named Zoloft or Lustral.
Sertraline is an antidepressant and belongs to the class of antidepressants known as selective serotonin-reuptake inhibitors, or SSRI’s. Within this class of drugs known as SSRI’s, there are very distinct structural differences, however they all exhibit very similar pharmacological activity. SSRI’s work to block serotonin reuptake and increase serotonin stimulation of somatodendritic 5-HT1A and terminal autoreceptors. Chronic use leads to the desensitization of somatodendritic 5-HT1A and terminal autoreceptors. While they are potent inhibitors of neuronal serotonin reuptake, they have little to no effect on norepinephrine or dopamine reuptake.
Sertraline is used in the treatment of major depressive disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, and social anxiety disorder. The drug was designed to provide users with an overall clinical effect of increased mood and decreased anxiety. Sertraline is available in capsules and film-coated tablets with dosages ranging from 25-200 mg. Sertraline is designed to be taken once daily and may take several weeks of daily use before clinical effect is seen. Side effects of Sertraline include nausea, diarrhea, dyspepsia, dry mouth, somnolence, dizziness, insomnia, tremors, sexual dysfunction (primarily ejaculatory delay in males), headache, and sweating. These symptoms will most generally appear within the first 2 weeks of use.
Background and History
The history of sertraline dates back to the early 1970s, when a Pfizer chemist by the name of Reinhard Sarges invented a series of psychoactive compounds that were based on the structures of two neuroleptics, chloroprothixene and thiothixene. This led to the development of tametraline, a norepinephrine and dopamine reuptake inhibitor. Development of tametraline was ceased due to some undesired stimulant effects. In 1977, a pharmacologist by the name of Kenneth Koe asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Among those they produced were a number of potent norepinephrine and triple reuptake inhibitors as well as a serotonin reuptake inhibitor, which was derived from the, generally inactive, cis-analog. Stereoisomers of this serotonin reuptake inhibitor were then generated and tested in vivo by animal behavioral scientist Albert Weissman. The most potent and selective (+)-isomer was taken and further developed into sertraline.
The FDA approved Sertraline in the US in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committee. The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of major depression. Sertraline entered the Australian market in 1994 and became the most often prescribed antidepressant in 1996. In 2011, sertraline was the second most prescribed antidepressant in the US retail market, with 37,208,000 prescriptions written. Until 2002, 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 aged 6 or older with severe obsessive-compulsive disorder. In 2005, the FDA added a black box warning concerning pediatric suicidal behavior to all antidepressants, including sertraline. In 2007, labeling was again changed to add a warning regarding suicidal behavior in young adults ages 18 to 24. The U.S. patent for Zoloft expired in 2006, and sertraline is now available in generic form.
Sertraline has the chemical formula C17H17Cl2N. It goes by the IUPAC name (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine. Sertraline has an average molecular weight of 306.23 and a monoisotopic molecular weight of 305.07. Sertraline appears as a white, powdery solid at room temperature. Functional groups within a molecule of sertraline include a phenyl group, an aryl halide group, and an amine group.
The experimental water solubility of sertraline is 3.5 mg/L. The drug has a melting point between 243 and 245 degrees Celsius. LogP, or hydrophobicity, of sertraline is measured to be approximately 5.1 and logS is estimated to be -6.3. Sertraline has a pKa of 9.85, making it slightly basic. Within a molecule of sertraline there is one hydrogen bond donor and one hydrogen bond acceptor, and the molecule has an overall physiological charge of 1. There are two rotatable bonds within the molecule. Sertraline has a refractivity of 85.74 and a polarizability of 32.44. The drug contains a polar surface area of 12.03 A2.
Mechanism of Action
As stated before, sertraline is a selective serotonin-reuptake inhibitor. The exact mechanism of action, however, is not fully known. The drug appears to selectively inhibit the reuptake of serotonin at the presynaptic membrane, which results in an increased synaptic concentration of serotonin within the central nervous system. This is thought to be what leads to the functional changes associated with enhanced serotonergic neurotransmission. Therapeutic doses between 50-200 mg taken daily for four weeks resulted in 80-90% inhibition of serotonin transporter in striatum, as measured by a positron emission tomography. Sertraline has little to no effect on norepinephrine or dopamine reuptake and does not antagonize α- or β-adrenergic, dopamine D2 or histamine H1 receptors.
Absorption and Distribution
Sertraline is absorbed slowly once ingested, with maximal concentration in plasma occurring roughly 4-6 hours after ingestion. The drug has a bioavailability of 44%. The volume distribution of sertraline is about 20 L/kg with n oral clearance of 96 L/h. When administered with food, Cmax is 25% greater, Tmax is decreased, and AUC is slightly increased. A steady state is achieved after taking the drug for roughly one week. In the blood, the drug is 98.5% bound to serum proteins, mainly albumin and alpha acid glycoprotein.
Sertraline undergoes extensive first-pass metabolism in the liver. The initial principal pathway of metabolism for sertraline is N-demethylation catalyzed by CYP2B6 with CYP 2C19, CYP3A4, and CYP2D6 contributing to a lesser extent. This produces the major metabolite of sertraline, desmethylsertraline, which is about fifty times weaker as a serotonin transport inhibitor. Sertraline and its metabolite, desmethylsertraline, both undergo hydroxylation, oxidative deamination, and glucuronidation as they are metabolized. Deamination occurs via CYP3A4 and CYP2C19. It has also been stated that sertraline can be deaminated in vitro by monoamine oxidases, however this metabolic pathway has not yet been studied in vivo.
Sertraline has a half-life of 25-26 hours. Its major metabolite, desmethylsertraline, has a half-life of 62-104 hours. The mode of excretion for sertraline and its metabolites is renal. Since sertraline is extensively metabolized, excretion of the unchanged drug is a minor route of elimination. After 9 days, about 44% of single administered oral dose in recovered in urine and about 44% is recovered in feces.
The LD50 of sertraline in rats was found to be about 1327 mg/kg. Symptoms of toxicity include alopecia, decreased libido, diarrhea, ejaculatory disorder, fatigue, insomnia, somnolence, and serotonin syndrome.
There are numerous other drugs that should not be used while taking sertraline. Drugs to avoid include those that may cause bleeding or bruising, such as blood thinners and NSAID’s. MAOI’s should also be avoided as they may cause a serious and sometimes fatal reaction. The use of other drugs that increase serotonin levels, such as other SSRI’s or SNRI’s, should be avoided as they increase the risk of what is called serotonin syndrome. Sertraline may also produce adverse effects when taken with the following: carbamazepine, carvedilol, cilostazol, clozapine, fosphenytoin, Isocarboxazid, metoprolol, propafenone, propranolol, tolterodine, and tramadol. A number of monoamine oxidase inhibitors, such as isocarboxazid, also produce adverse effects.
The synthesis of sertraline is pictured in the following 10-step procedure beginning with 3,4-dichlorobenzoyl chloride.
Because the exact structure of SERT is unknown, bonding between sertraline and SERT itself is not completely understood. The leucine transporter, LeuT, is thought to be similar in structure to SERT and can therefore be used to study the interaction. The picture below depicts the structure of the drug-binding site in the LeuT–sertraline complex.
In conclusion, sertraline is a powerful antidepressant that works to block the reuptake of serotonin. It was approved by the FDA in 1991 and has since taken off as a top selling antidepressant. The drug is highly hydrophobic but only violates Lipinski’s Rule of Five in its LogP, which is 5.1, therefore making it considered orally active. Sertraline is slowly absorbed, highly metabolized, and almost completely excreted. All in all, sertraline appears to be a wonderful drug with few side effects and a high level of benefit.
(3) http://www.nlm.nih.gov/medlineplus/druginfo/meds/a697048.html (4)