Sertraline , sold under the trade name Zoloft , among others, are antidepressants of the selective serotonin reuptake inhibitor class (SSRI). It is primarily used for major depressive disorders, obsessive-compulsive disorder, panic disorder, and social anxiety disorder. Its effectiveness is similar to other antidepressants. Sertraline is taken by mouth.
Common side effects include diarrhea, sexual dysfunction, and sleep problems. Serious side effects include an increased risk of suicide in those younger than 25 years and serotonin syndrome. It is unclear whether the use during pregnancy or breastfeeding is safe. It should not be used in conjunction with MAO inhibitors. Sertraline is believed to work by increasing the effects of serotonin in the brain.
Sertraline was approved for medical use in the United States in 1991 and originally sold by Pfizer. Currently available as a generic drug. In the United States the wholesale cost is around 1.50 USD per month by 2018. By 2013 there are over 41 million prescriptions, making it the most prescribed antidepressant and the second most prescribed psychiatric drug in the United States.
Video Sertraline
Medical use
Sertraline is used for a number of conditions, including major depressive disorder (MDD), obsessive-compulsive disorder (OCD), body dysmorphic disorder (BDD), post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder, and anxiety disorder social (SAD). It has also been used for premature ejaculation and vascular headaches but evidence of its effectiveness in treating these conditions is not strong.
Depression
A 2008 review concluded that 51% of studies from various SSRIs yielded positive results. Sertraline is statistically similar in efficacy to other SSRIs such as paroxetine, citalopram, escitalopram and venlafaxine (SNRI). Evidence suggests that sertraline may be more effective than fluoxetine (Prozac) for some depression subtypes.
The evidence shows no benefit in children with depression.
With depression in dementia, there is no benefit compared to placebo or mirtazapine.
Comparison with other antidepressants
Tricyclic antidepressants (TCAs) as a group are considered to work better than SSRIs for melancholic depression and in hospitalized patients, but not necessarily for more severe depression. In line with this generalization, sertraline is no better than placebo in inpatients (see History) and as effectively as TCA clomipramine for major depression. Comparative efficacy of sertraline and TCA for melancholic depression has not been studied. A 1998 review suggested that, because of its pharmacology, sertraline may be more efficacious than other SSRIs and similar to TCA for the treatment of melancholy depression.
A meta-analysis of 12 new generation antidepressants suggests that sertraline and escitalopram are best in terms of efficacy and acceptance in the acute phase treatment in adults with unipolar MDD. Reboxetine is significantly worse.
Comparative clinical trials show that sertraline has similarities with depression to moclobemide, nefazodone, escitalopram, bupropion, citalopram, fluvoxamine, paroxetine, and mirtazapine. There is low quality evidence that sertraline is more efficacious for the treatment of depression than fluoxetine.
Elderly
Sertraline is used for the treatment of depression in elderly (older than 60) patients superior to placebo and comparable to other SSRI fluoxetine, and TCA amitriptyline, nortriptyline (Pamelor) and imipramine. Sertraline has a much lower rate of side effects than this TCA, with the exception of nausea, which occurs more frequently with sertraline. In addition, sertraline appears to be more effective than fluoxetine or nortriptyline in subgroups aged older than 70. The 2003 sertraline vs placebo trial in elderly patients showed statistically significant (that is, not likely to happen by chance), but a very simple clinical improvement in depression and no improvement in quality of life.
A meta-analysis of SSRIs and SNRIs that looked at partial responses (defined as at least a 50% reduction in depression scores from baseline) found that sertraline, paroxetine and duloxetine were better than placebo. Due to the safety of duloxetine and venlafaxine, the increased dizziness got worse, but not much security data was reported.
Obsessive-compulsive disorder
Sertraline is effective for the treatment of OCD in adults and children. It was better tolerated and, based on the intention to treat the analysis, performed better than the standard clomipramine gold OCD treatment. It is generally accepted that the sertraline dose required for effective OCD treatment is higher than the usual dose for depression. The onset of action is also slower for OCD than for depression.
Cognitive behavioral therapy alone is superior to sertraline in adults and children; However, the best results are achieved by using a combination of these treatments.
Panic disorder
The treatment of panic disorder with sertraline results in a decrease in the number of panic attacks and improved quality of life. In four studies of double-blind sertraline proved superior to placebo for the treatment of panic disorder. The response rate is independent of the dose. In addition to reducing the frequency of panic attacks by about 80% (vs. 45% for placebo) and reducing generalized anxiety, sertraline results in improved quality of life in most parameters. Patients rated as improving on sertraline reported better quality of life than those who "improved" on placebo. The authors of the study argued that the increase achieved with sertraline was different and the quality was better than the improvements achieved with placebo. Sertraline is equally effective for both men and women. Although not appropriate, the comparison of sertraline trial results with separate trials of other anti-panic agents (klomipramine, imipramine, clonazepam, alprazolam, fluvoxamine and paroxetine) shows an estimate of the equality of these drugs.
Other anxiety disorders
Sertraline is effective for the treatment of social phobia. Improved scores on the Liebowitz Social Anxiety Scale were found with sertraline but not with placebo. The combination of sertraline and cognitive behavioral therapy has superior response rates when used in children.
There is tentative evidence that sertraline, as well as other antidepressants, may help with generalized anxiety disorder symptoms. Tests are generally short and medical length is associated with side effects.
Premenstrual dysphoric disorder
SSRIs, including sertraline, reduce the symptoms of premenstrual syndrome. Side effects such as nausea are common. Sertraline is effective in relieving the symptoms of premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome. Significant increases were observed in 50-60% of cases treated with sertraline vs 20-30% of cases in placebo. Improvements begin during the first week of treatment, and in addition to mood, irritability, and anxiety, improvement is reflected in better family function, social activity and quality of life in general. Working functions and physical symptoms, such as swelling, bloating and breast tenderness, are less responsive to sertraline. Taking sertraline only during the luteal phase, ie, 12-14 days before menstruation, proven to work as well as ongoing care.
Other indications
Sertraline when taken daily can be beneficial for the treatment of some aspects of premature ejaculation. The disadvantages of SSRIs are that they require ongoing daily care to delay ejaculation significantly, and it is unclear how they affect the psychological pressure of those with a person's condition or control over the time of ejaculation.
The benefits of sertraline in PTSD are not significant according to the National Institute of Clinical Excellence. However, others feel that there are benefits from their use.
Maps Sertraline
Contraindications
Pregnancy and lactation
A study comparing sertraline and its major metabolites, desmethylsertraline, in maternal blood to their concentrations in cord blood at delivery suggests that fetal exposure to sertraline and its metabolites is approximately one-third of maternal exposure. The concentrations of sertraline and desmethylsertraline in breast milk vary widely and, on average, are of the same order of magnitude as their concentration in maternal blood plasma. As a result, more than half of breast-fed infants receive less than 2 mg/day of combination of sertraline and desmethylsertraline, and in many cases these substances are undetectable in their blood. No changes in serotonin uptake by breast-fed infant platelets were found, as measured by serotonin levels of their blood before and after their mothers started sertraline treatment.
Side effects
Compared with other SSRIs, sertraline tends to be associated with higher levels of psychiatric side effects and diarrhea. It tends to be more active (ie, associated with anxiety, agitation, insomnia, etc.) levels higher than other SSRIs, other than fluoxetine.
For more than six months of sertraline therapy for depression, people showed an insignificant weight gain of 0.1%. Similarly, treatment for 30 months with sertraline for OCD resulted in an average weight gain of 1.5% (1 kg). Although the difference was not statistically significant, weight gain was lower for fluoxetine (1%) but higher for citalopram, fluvoxamine and paroxetine (2.5%). Of the sertraline group, 4.5% gained significant weight (defined as more than 7%). These results were better than placebo, where, according to the literature, 3-6% of patients received more than 7% of their initial weight. A large weight gain was observed only among female members of the sertraline group; the significance of these findings is unclear because of their small size. The incidence of diarrhea is higher with sertraline - especially when prescribed at higher doses - compared to other SSRIs.
During two weeks of healthy volunteer treatment, sertraline slightly improves verbal fluency but does not affect word learning, short-term memory, alertness, flicker flicker time, choice reaction time, memory range, or psychomotor coordination. In spite of the lower subjective appraisal, that is, the feeling that they are doing worse, there is no clinically relevant difference observed in objective cognitive performance in the group of people treated for depression with sertraline for 1.5 years compared with healthy controls. In children and adolescents who take sertraline for six weeks for anxiety disorders, 18 out of 20 memory sizes, attention and alertness remain unchanged. The attention is split up and verbal memory under fault conditions decreases slightly. Due to the many actions taken, it is likely that this change is still by chance. The unique effects of sertraline on dopaminergic neurotransmission may be associated with this effect on cognition and alertness.
Sexual
Like other SSRIs, sertraline is associated with sexual side effects, including sexual arousal and difficulty reaching orgasm. The frequency of sexual side effects depends on whether they are reported by people spontaneously, as in factory trials, or are actively asked by a doctor. While nefazodone, bupropion, and reboxetine did not have a negative effect on sexual function, 67% of men in sertraline had difficulty ejaculating versus 18% before treatment. Sexual arousal disorders, defined as "inadequate lubrication and swelling for women and erectile difficulties in men", occur in 12% of people in sertraline compared with 1% of patients with placebo. Mood enhancement resulting from treatment with sertraline sometimes neutralizes these side effects, so sexual desire and overall satisfaction with sex remain the same as before sertraline treatment. However, under the action of placebo, desire and satisfaction increased slightly.
Some people experience persistent sexual side effects after they stop using SSRIs. This is known as Post-SSRI Sexual Dysfunction (PSSD). Common symptoms in this case include genital anesthesia, erectile dysfunction, anhedonia, decreased libido, premature ejaculation, vaginal lubrication problems, and female nipple discomfort. The level of PSSD is unknown, and no treatment is established.
Suicide
The FDA requires all antidepressants, including sertraline, to carry a box warning stating that antidepressants may increase the risk of suicide in people younger than 25 years. The warning is based on statistical analysis conducted by two independent groups of FDA experts who found a twofold increase in suicidal ideation and behavior in children and adolescents, and 1.5 times increased suicide rates in the 18-24 age group.
The idea of ​​suicide and behavior in clinical trials is rare. For the above analysis, the FDA combines the results of 295 trials of 11 antidepressants for psychiatric indications to obtain statistically significant results. Considered separately, the use of sertraline in adults reduces the likelihood of suicidal behavior with marginal statistical significance of 37% or 50% depending on the statistical techniques employed. The FDA analysis authors note that "given the large number of comparisons made in this review, opportunities are a very plausible explanation for these differences". More complete data submitted later by producer Sertraline Pfizer shows an increase in suicidal behavior. Similarly, the analysis by the UK MHRA found a 50% chance of suicide-related events, not reaching statistical significance, in patients taking sertraline compared with those on placebo.
Concern has been raised that suicide acts among participants in various studies are not reported in published articles that report the study.
Termination syndrome
The antidepressant termination syndrome is a condition that can occur after interruption, dose reduction, or discontinuation of antidepressant drugs, including sertraline. Symptoms may include flu-like symptoms and sleep, sensory, movement, mood, and mind disorders. In most cases, the symptoms are mild, short-lived, and cured without treatment. More severe cases are often treated with temporary drug reintroduction with a slower rate of ovarian reduction.
Overdose
Acute overdose is often manifested by emesis, lethargy, ataxia, tachycardia and seizures. Plasma, serum or blood sertraline and norsertraline concentrations, its main active metabolites, can be measured to confirm the diagnosis of poisoning in hospitalized patients or to assist in the investigation of medicolegal against death. Like most other SSRIs, its overdose toxicity is considered relatively low.
Interactions
Sertraline is a moderate inhibitor of CYP2D6 and CYP2B6 in vitro . Thus, in human trials it causes increased levels of CYP2D6 substrate such as metoprolol, dextromethorphan, desipramine, imipramine and nortriptyline, as well as haloperidol substrate CYP3A4/CYP2D6. This effect is dose dependent. In a placebo-controlled study, simultaneous administration of sertraline and methadone led to a 40% increase in the last blood level, mainly metabolized by CYP2B6. Sertraline is often used in combination with stimulant drugs for the treatment of co-morbid depression and/or anxiety in ADHD. Amphetamine metabolism inhibits the CYP2D6 enzyme, but it has not been known to interfere with Sertraline metabolism.
Sertraline has a slight inhibitory effect on the metabolism of diazepam, tolbutamide and warfarin, which is a CYP2C9 or CYP2C19 substrate; this effect is not considered clinically relevant. As expected from in vitro data, sertraline did not alter the human metabolism of the CYP3A4 erythromycin substrate, alprazolam, carbamazepine, clonazepam, and terfenadine; it does not affect the metabolism of the CYP1A2 clozapine substrate.
Sertraline has no effect on the action of digoxin and atenolol, which is not metabolized in the liver. Case reports show that taking sertraline with phenytoin or zolpidem can induce sertraline metabolism and decrease its efficacy, and that taking sertraline with lamotrigine may increase blood lamotrigine levels, possibly by inhibition of glucuronidation.
Clinical reports show that the interaction between sertraline and MAOIs isocarboxazid and tranylcypromine may cause serotonin syndrome. In a placebo-controlled study in which sertraline was administered with lithium, 35% of the subjects experienced tremor, while no one took a placebo.
According to the label, sertraline is contraindicated in individuals taking monoamine oxidase inhibitors or antipsychotic pimozides (Orap). Sertraline concentrate contains alcohol, and is therefore contraindicated with disulfiram (Antabuse). Prescribed information recommends that the treatment of elderly and patients with impaired liver "should be approached with caution." Because of the slower sertraline elimination in this group, their exposure to sertraline may be as high as three times the average exposure for the same dose.
Pharmacology
Action mechanism
Sertraline acts as a potent inhibitor of serotonin reuptake (SRI), with affinity (K i ) for serotonin transporter (SERT) of 0.29 nM and IC value 50 of 2, 8 mM, according to several studies. It is highly selective in inhibition of serotonin reuptake. By inhibiting serotonin reuptake, sertraline increases serotonin extracellular levels and thereby increases serotonergic neurotransmission in the brain. This is an action that is considered responsible for the antidepressant, anxiolytic, and antiobsessional effects of sertraline.
Sertraline has no significant affinity for norepinephrine (NET) transporters or serotonin, dopamine, adrenergic, histamine, or acetylcholine receptors. On the other hand, it does show a high affinity for dopamine transporter (DAT) and sigma? 1 receptor (but not? 2 receptor). However, the affinity for these sites is about 100-fold or lower than for SERT.
Inhibition of dopamine reuptake
Sertraline is an SSRI, but, uniquely among most antidepressants, it shows a relatively high (nanomolar) affinity for DAT in addition to the SERT. Thus, it has been suggested that it may clinically inhibit reuptake of dopamine, especially at high doses. For this reason, sertraline is sometimes described as a serotonin-dopamine reuptake inhibitor (SDRI). This is relevant because dopamine is thought to be involved in the pathophysiology of depression, and an increase in dopaminergic neurotransmission by sertraline in addition to serotonin may have an added benefit to depression.
Tatsumi et al. (1997) found that the value of K i of sertraline in the SERT, DAT and NET of humans was 0.29, 25, and 420Ã, nM, respectively. Sertraline selectivity for SERT over DAT is 86-fold. In many cases, of the various antidepressants assessed in this study, sertraline showed the highest affinity of all for DAT, even higher than the norepinephrine-dopamine reuptake inhibitor (NDRI) numeral (K i = 56Ã, nM ) and bupropion (K i = 520Ã, nM). Sertraline also has similarities to DAT as methylphenidate NDRI (K i = 24Ã, nM). Tametraline (CP-24, 441), a very close sertraline analogue and a sertraline-based compound, is a non-marketed NDRI.
A single dose of 50 to 200 mg of sertraline has been found to produce a peak plasma concentration of 20 to 55 ng/mL (65-180 m), while chronic treatment with 200 mg/day of sertraline, the recommended maximum dose, has been found to produce maximal plasma levels of 118 to 166 ng/mL (385-542 m). However, sertraline is highly protein bound in plasma, with a 98.5% bound fraction. Therefore, only 1.5% are free and theoretically bioactive. Based on this percentage, the free sertraline concentration would be 2.49 ng/mL (8.13 mM) at most, which is only about one-third of the K i value of Tatsumi et al. found with sertraline in DAT. A very high dose of sertraline of 400 mg/day has been found to produce a peak plasma concentration of about 250 ng/mL (816 nM). This can be estimated to yield a free concentration of 3.75 ng/mL (12.2 m), which is still only about half of K i of sertraline for DAT.
Thus, it seems unlikely that sertraline will produce much inhibition of dopamine reuptake even at clinically used doses well beyond the maximum recommended clinical dose. This corresponds to an 86-fold selectivity for SERT over DAT according to Tatsumi et al. and hence the fact that almost 100 times higher levels of sertraline would be needed to also inhibit the reuptake of dopamine. Appropriate, while sertraline has a very low abuse potential and may even dislike clinical doses, sertraline abuse case reports describe effects such as dopaminergic such as euphoria, mental overactivity, and hallucinations only at doses of 56 times the normal maximum and 224 times the normal minimum. For this reason, the significant inhibition of dopamine reuptake by sertraline in controversial clinical doses, and the work by sertraline from DAT is considered by many clinically irrelevant experts.
Sigma receptor antagonism
Sertraline has a relatively high affinity (nanomolar) for sigma recipes? 1 . On the contrary, it has a low affinity (micromolar) and is not significant for receptors? 2 . Acting as a receptor antagonist? 1 , and able to reverse? 1 receptor-dependent action fluvoxamine, strong receptor agonist, in vitro . However, the sertraline affinity for receptor 1 is more than 100 times lower than for SERT. Although there may be a role for receptor " 1 in sertraline pharmacology, the significance of these receptors in their actions is unclear and may be questioned.
Sertraline is associated with a significantly higher incidence of diarrhea compared with other SSRIs, especially at higher doses. Agonis of? 1 receptors such as igmesine have been found to inhibit intestinal secretions and bacterial-induced bacterial secretions in animal studies, and igmesin show early evidence of efficacy for the treatment of diarrhea in small clinical trials. Sertraline is the only SSRI that acts as an antagonist of the 1 receptor, so this action can be theoretically responsible for higher incidence of diarrhea.
Increased neurosteroidogenesis
Sertraline has been found to directly act on the enzyme 3-hydroxysteroid dehydrogenase (3? -HSD) and modulate its activity, thus increasing the conversion of 5? -dihydroprogesterone to allopregnanolone neurosteroid and thus increase the production of allopregnanolone in the brain. The same applies to certain other SSRIs including fluoxetine and paroxetine. However, subsequent research failed to reproduce these findings, and SSRI direct interaction with 3? -HSD is controversial. However, other studies have found that, at least in the case of fluoxetine and its active metabolite norfluoxetine, it normalizes low allopregnanolone levels in socially isolated rats and in low doses that are inactive on serotonin reuptake (10- to 50-fold lower, special). On the basis of these results, SSRIs such as fluoxetine and norfluoxetine are described as selective steroidogenic steroidogenic stimulants ( SBSSs ).
Pharmacokinetics
Sertraline is absorbed slowly when taken orally, reaching a maximum concentration in plasma 4 to 6 hours after consumption. In the blood, it is 98.5% bound to a plasma protein. According to the study in vitro studies, sertraline is metabolized by several isoforms of cytochrome 450: CYP2D6, CYP2C9, CYP2B6, CYP2C19 and CYP3A4. It seems unlikely that the inhibition of a single isoform can cause a significant clinical change in sertraline pharmacokinetics. No difference in sertraline pharmacokinetics was observed between people with high and low CYP2D6 activity; however, poor CYP2C19 metabolism has a sertraline level 1.5 times higher than normal metabolism. In vitro data also showed that inhibition of CYP2B6 should have a greater effect than CYP2C19 inhibition, while the contribution of CYP2C9 and CYP3A4 to sertraline metabolism would be small. This conclusion has not been verified in human studies. Sertraline can be devolved in vitro by monoamine oxidase; However, this metabolic pathway has not been studied in vivo . Sertraline main metabolite, desmethylsertraline, is about 50 times weaker as serotonin-transporting inhibitors than sertraline and its clinical effects are negligible.
Non-amine metabolism may also contribute to the antidepressant effects of this drug. Sertraline dideamination was O-2098, a compound that has been found to inhibit the dopamine reuptake transporter protein irrespective of the lack of nitrogen atoms.
Its main active metabolite is norsertraline ( N -desmethylsertraline) which is significantly less biologically active than its parent compounds.
History
The history of sertraline dates back to the early 1970s, when Pfizer chemist Reinhard Sarges discovered a new set of psychoactive compounds based on neuroleptic chlorrothixene structures. Further work on these compounds causes lometraline and then to tametraline, norepinephrine and weaker dopamine reuptake inhibitors. The development of tametraline was immediately discontinued due to the adverse stimulative effects observed in animals. A few years later, in 1977, pharmacologist Kenneth Koe, after comparing the structural features of various reuptake inhibitors, became interested in the tametraline series. He asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Welch produces a number of powerful norepinephrine reuptake inhibitors, but to the surprise of scientists, one representative of the generally inactive cis-analog is the serotonin reuptake inhibitor. Welch then prepared a stereoisomer of this compound, which was tested in vivo by animal behavior scientist Albert Weissman. The most powerful and selective isomer () - is incorporated into further development and is finally termed sertraline. Weissman and Koe recall that the group was not formed to produce SSRI type antidepressants - in the sense that their investigation was not "strongly driven by purpose", and the discovery of sertraline molecules was accidental. According to Welch, they work off the mainstream at Pfizer, and even "do not have a formal project team". The group should overcome early bureaucratic reluctance to pursue the development of sertraline, as Pfizer is considering licensing antidepressant candidates from other companies.
Sertraline was approved by the US Food and Drug Administration (FDA) in 1991 on the recommendation of the Psychopharmacological Drug Advisory Committee; it was already available in the UK the year before. The FDA Committee reached a consensus that sertraline is safe and effective for the treatment of MDD.
Sertraline entered the Australian market in 1994 and became the most commonly prescribed antidepressant in 1996 (data 2004). It was measured as one of the top ten drugs ranked according to cost to the Australian government in 1998 and 2000-01, at a cost of $ 45 million and $ 87 million in subsidies. Sertraline is less popular in the UK (Data 2003) and Canada (data 2006) - in both countries it is the fifth (among drugs marketed for MDD treatment, or antidepressants), based on the number of prescriptions.
Until 2002, sertraline was only approved for use in adults over 18 years of age; that year, it was approved by the FDA for use in treating children age 6 or older with severe OCD. In 2003, the British Drug and Healthcare Regulatory Body issued guidance that, in addition to fluoxetine (Prozac), SSRIs are not suitable for the treatment of depression in patients under 18 years of age. However, sertraline can still be used in the UK for treatment. OCD in children and adolescents. In 2005, the FDA added a box warning about pediatric suicidal behavior for all antidepressants, including sertraline. In 2007, the label was again changed to add a warning about suicidal behavior in young adults aged 18 to 24 years.
Society and culture
General availability
The US patent for Zoloft ended in 2006, and sertraline is now available in generic form and marketed under many brand names worldwide.
References
External links
- List of international brand names for sertraline
- US. National Library of Medicine: Drug Information Portal - Sertraline
Source of the article : Wikipedia
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