Depression may not be caused by the simple deficiency of serotonin in the brain, but rather a complex interplay of various neurotransmitters including serotonin, norepinephrine, glutamate, and histamine at certain brain areas. The above-mentioned novel antidepressants exert their therapeutic benefits by acting on multiple neurotransmitters. The complexity of underlying the neurobiological mechanism should be considered while formulating a plan of care. Major depressive disorder MDD is a major public health concern with significant impairment in psychological, occupational, and social functioning.
The prevalence rates for depression are estimated to be around 3. It is the fourth cause of disability around the world and is estimated to be the second leading cause of disability by [ 1 ]. It affects around million individuals regardless of gender, ethnicity, geographical location, and socioeconomic status, contributing to the overall global burden of disease. Selective serotonin reuptake inhibitors SSRIs are the appropriate first-line options for the treatment of depression along with psychotherapeutic interventions, but many patients either do not respond to different options or intolerant to the undesired effects of medications [ 2 ].
This residual symptoms and functional impairment have a higher risk of relapse into the future episodes of MDD. The debilitating health-related quality of life effects of MDD has an adverse impact on individuals, resulting in academic, interpersonal, social, and occupational impairment. The onset of each new major depressive episode increases the chances of relapse, chronicity, and treatment-resistant depression [ 4 ]. Different ideas have been postulated to understand the reasons for the ineffectiveness of monoamine modulators for the treatment of depression.
The lack of effectiveness can result from poor compliance secondary to the delayed effects of the medications or undesired effects such as sexual dysfunction from the medications. It can be due to the severity of the depressive symptoms in patients struggling with treatment-resistant depression [ 5 ]. The guidelines recommend the selection of a different class of antidepressant with a different mode of action after the failure of antidepressant treatment with SSRIs or selective serotonin-norepinephrine reuptake inhibitor SNRI.
This recommendation is based on the fact that a medication with a different mechanism of action may have a better chance of success than the traditional antidepressants [ 3 ].
This recommendation is based on the heterogeneity of MDD in etiology, underlying the neurobiological mechanism, pathogenesis, course, and prognosis of illness. The serotonin and norepinephrine reuptake inhibitors have different potency of action at their respective receptors, resulting in distinctive clinical effects.
With the distinctive treatment effect, the action of antidepressant medications, for example, SSRIs are restricted due to autoregulatory feedback mechanisms. There are several newer treatment options including desvenlafaxine, vortioxetine, vilazodone, and levomilnacipran with antidepressant actions through different neurochemical actions.
This review article educates the clinicians about the clinical factors including the mechanism of action, pharmacokinetics, clinical efficacy, and safety and tolerability. The authors also provide a summary of evidence-based studies regarding the newer antidepressants. This review articles explored the randomized controlled trials RCTs , open-label trials, and case reports. This article reviews the mechanism of action, pharmacokinetics, clinical efficacy, and safety and tolerability of desvenlafaxine, vortioxetine, vilazodone, and levomilnacipran extended release ER.
The manual search of references and relevant articles for included studies was also performed. Two independent reviewers performed title and abstract screening when available followed by the full-text screening of included articles by selecting case reports, case series, open-label trials, and RCTs.
In the case of disagreement, the consensus was reached by discussion among reviewers or guidance from a senior reviewer SN. The abstract-only articles, conference papers without original data, review articles, theses, posters, book chapters, editorials, letters, commentaries were excluded.
No restrictions on language, country, publication year, age, gender, or ethnicity of patients were applied. After the full-text screening, 41 studies were included in this review articles. It is administered as desvenlafaxine succinate [ 7 ]. Desvenlafaxine causes selective reuptake inhibition at the serotonin 5-HT and norepinephrine NE transporters, resulting in an increased extracellular concentration of 5-HT and NE.
The higher affinity for 5-HT transporters is observed compared to the NE transporters approximately fold with a much weaker affinity for dopamine transporters DATs. However, there are no functional implications on dopamine levels with the concentrations required to inhibit 5-HT and NE transporters for the antidepressant effect.
Desvenlafaxine also affects hypothalamus which is an important regulator of biological functions like mood, sleep cycle, stress response, sexual behaviors, temperature, and pain sensations [ 8 ]. Desvenlafaxine is available in 50 and mg tablets. It can be taken without meals as food does not appear to have a clinically significant difference. It is metabolized by conjugation and to a minor extent by oxidation through CYP3A4 [ 7 ]. Findling et. The efficacy of desvenlafaxine for MDD has been established in several RCTs and open-label studies among adults [ 9 - 17 ].
It improves the quality of life, as measured by an improvement in mood, social relationships, daily functioning, leisure activities, economic status, and physical mobility [ 13 ]. In patients with liver pathology, it alleviated the symptoms of depression [ 18 - 19 ]. An open-label trial also evaluated the efficacy of desvenlafaxine among children aged years and adolescents aged years. The higher doses were associated with an increased incidence of treatment-emergent side effects [ 20 ].
The treatment-emergent adverse effects AEs are dose-related with desvenlafaxine and are the most common reason to discontinue treatment. Serious AEs were reported in 0. An analysis of AEs reported completed suicide in one, suicidal attempt in three, and suicidal ideations in five patients taking desvenlafaxine.
However, the difference in suicidal behaviors was not statistically significant among desvenlafaxine and placebo groups. The most common AEs are nausea, headache, dizziness, insomnia, and dry mouth. Other side effects included fatigue, hyperhidrosis, tremors, blurred vision, sedation, increased anxiety, mydriasis, dyspepsia, affective lability, muscle spasms, and taste perversion. In patients taking desvenlafaxine, vital signs, laboratory results, and electrocardiogram EKG findings were clinically insignificant.
Small increases in pulse and blood pressures were observed possibly due to noradrenergic effects of desvenlafaxine but they were clinically insignificant. Desvenlafaxine was associated with a lower risk of QTc prolongation compared to placebo. Abrupt discontinuation or dose reduction were associated with dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue, abnormal dreams, and hyperhidrosis.
The discontinuation rates are higher among patients taking it for a longer duration, needing a gradual taper [ 7 ]. In pregnant rats and rabbits, desvenlafaxine causes a decrease in fetal weight with no evidence of teratogenicity. However, there are not adequate studies in pregnant women [ 7 ]. It contains the beta polymorph of vortioxetine hydrobromide and administered as an immediate-release tablet [ 22 ]. Vortioxetine exerts its therapeutic effects through multimodal activity with a modulation of the 5-HT receptors and an inhibition of the 5-HT transporters [ 22 ].
Beside the modulatory effect on the 5-HT receptors and transporter, it also enhances the extracellular concentration of various neurotransmitters such as dopamine, histamine, noradrenaline, and acetylcholine [ 23 ].
The series of inhibitory feedback in response to prolonged SERT blockade decreases the extracellular 5-HT concentration and also attenuates the activation of 5-HT 1A and 5-HT 1B auto-receptors of the serotonergic system. The partial agonist activity of vortioxetine counteracts the 5-HT1B autoreceptor activity and in turn, increases the serotonin synthesis and release.
The full agonist activity of vortioxetine on the 5HT 1A receptor normalizes the serotonin release through the likely mechanism of rapid desensitization of 5HT 1A auto-receptors. The antagonist effect on the 5-HT 3 receptor inhibits the GABA-mediated inhibition of the interneurons, thereby increasing the extracellular serotonin concentration. Similarly, the blockade of 5-HT 7 and 5HT 1D receptors has shown the effect of antidepressants in an animal study.
The 5-HT system has a favorable impact on mood, affect, and cognition. Vortioxetine modulates the essential neurotransmitters which are involved in cognitive regulation such as glutamate, acetylcholine, histamine, dopamine, and noradrenaline [ 24 ]. Vortioxetine is available as 5, 10, and 20 mg tablets. It can be started at 10 mg once daily and the dose can be increased to 20 mg based on the tolerability and clinical response [ 22 ].
In vivo, vortioxetine shows a linear, and dose-proportional relationship, i. It has moderate oral bioavailability that is independent of food intake. The study also revealed a significant separation of vortioxetine from placebo over the graph at the higher dose 20 mg suggesting that a higher dose may potentially yield a better outcome. It takes hours to attain maximum plasma concentration after dosing, and with multiple doses, the terminal half-life is approximately hours.
In the liver, the CYP isoforms extensively metabolize the vortioxetine through oxidation and subsequent glucuronic acid conjugation to a pharmacologically inactive carboxylic acid metabolite. However, the increased risk of bleeding is explained by inhibition of serotonin uptake by platelets, an increase in gastric acid secretion, and modulation of the CYP metabolism [ 26 ].
The efficacy of vortioxetine for MDD was established in nine RCTs in adults at a dose range of mg [ 3 , 25 , 27 - 33 ]. The doses of mg were found to be in effective range with a lack of effectiveness with lower doses of 2. The maximum dose of vortioxetine 20 mg exhibits a greater clinical response compared to the lower doses for vortioxetine [ 27 - 30 ].
This dose of 20 mg was also associated with a higher risk of side effects. The improvement in global functioning [ 23 , 25 , 28 - 29 , 31 - 33 ], quality of life [ 28 - 29 , 32 ], and anxiety [ 23 , 25 , 28 - 29 , 31 - 32 , 34 ] was also reported with vortioxetine.
In an open-label trial of 52 weeks, it was effective in relapse prevention of depressive symptoms [ 34 ]. Table 3 provides a summary of the characteristics of these trials including sample size, duration, doses, and age ranges of the participants. Lu:LuA, No. The side effect profile of vortioxetine has an indirect effect on the management of depressive symptoms. Sexual dysfunction is not an uncommon side effect of medication with serotonin reuptake inhibitor and is one of the reasons for treatment discontinuation and noncompliance [ 29 ].
Interestingly, the side effects including abnormal orgasm, ejaculation disorder, decreased libido, erectile dysfunction were reported to be higher with a low dose of vortioxetine 2. The gender has a variable effect on the incidence of AEs in vortioxetine with men at a higher risk compared to women [ 23 ].
In a study of vortioxetine 15 mg, two serious AEs stress fracture and suicidal ideation were reported [ 29 ]. There was no clinically significant relevance to suicidal ideation and behavior as measured by the Columbia Suicide Severity Rating Scale [ 27 , 29 , 33 ]. There was no change in vital signs, laboratory test results, weight, or EKG parameters for participants [ 23 , 25 , 29 - 30 ]. Sudden discontinuation of vortioxetine after two weeks of treatment showed no clinically significant withdrawal effect versus placebo [ 28 - 29 ].
In a pregnant patient, vortioxetine 5 mg was discontinued after one month. Delivery of the healthy baby mg in weight was reported [ 23 ]. It can cause decreased fetal weight and delayed ossification in animal studies [ 22 ]. Vilazodone enhances serotonergic activity by selective inhibition of serotonin reuptake through the blockade of SERT.
This effect is further intensified because of partial agonist activity at 5-HT 1A receptors [ 35 ]. Vilazodone tablets are available in 10,20, and 40 mg strengths.
The recommended dose range is mg once daily. Vilazodone should be titrated, starting with an initial dosage of 10 mg once daily for seven days which can be titrated to 20 mg once daily. The dose can be increased to 40 mg once daily after seven days.
The administration of Vilazodone without food affects the systemic bioavailability and diminished clinical effectiveness due to inadequate drug levels [ 35 ]. Vilazodone has a dose-proportional pharmacokinetic activity mg. It reaches peak concentration in four to five hours after administration and has an elimination half-life of 25 hours.
A sequence of open-label studies conducted by Boepally and colleagues identified the effect of CYP3A4 inhibition or induction on the pharmacokinetics of vilazodone. Together, they have synthesized a large amount of medical literature into a comprehensive, yet understandable, concise, reader-friendly guide that features useful tables pertaining to the efficacy of specific medications and summaries of important clinical pearls of wisdom that are summarized at the end of each chapter into Key Clinical Concepts.
This text is a must-have reference for psychiatrists and other practicing clinicians, residents-in-training, psychiatric nurses, social workers, and researchers. Download PDF. Haddad and Anderson, in particular, highlight the need for information regarding discontinuation symptoms to be discussed with the patient before they even begin treatment [ Haddad and Anderson, ].
Patient reassurance that side effects will be short-lived and self-limiting [ Zarowitz, ] and do not indicate dependence on the drug [ Ogle and Akkerman, ] is also of vital importance. Three of the articles [ Ogle and Akkerman, ; Tint et al. In addition, Himei and Okamura found that those patients who had experienced adverse symptoms during the early phases of treatment were more likely to suffer from a discontinuation syndrome upon withdrawal and therefore should be monitored closely during discontinuation [ Himei and Okamura, ].
Warner and colleagues emphasize that a gradual dose reduction cannot guarantee to obviate a discontinuation syndrome so that some patients may still prefer to discontinue treatment abruptly in order to curtail the period in which these symptoms are experienced [ Warner et al. Montgomery and colleagues also add that younger patients are more likely to withdraw treatment abruptly and should be educated about the possible side effects [ Montgomery et al.
Of the articles reviewed, the consensus panel recommendations [ Schatzberg et al. They review management strategies formulated by a previous panel which met in [ Schatzberg et al.
In this panel, four specific guidelines were proposed for SSRI discontinuation: reassuring the patient; reintroducing the drug and tapering at a slower rate for severe cases; all drugs with the possible exception of fluoxetine should be slowly tapered to reduce the incidence of a discontinuation syndrome; and initially prescribing or switching to drugs with a longer half-life such as fluoxetine. The panel mostly reiterated this advice but added some clinically significant points such as close monitoring of patient during and after discontinuation with clinicians available for reassurance or questions during this period.
They also add the importance patient education of the syndrome as well as the education of any caregivers involved. Another set of guidelines covers all of the treatment of depression [ Cleare et al.
In the section on stopping antidepressant treatment pp. Despite a plethora of research detailing the existence and manifestation of a discontinuation syndrome following antidepressant withdrawal, the comprehensive literature review identified only 18 articles which provided explicit guidelines on how best to discontinue antidepressant medication in order to avoid unpleasant side effects. Many of the reviewed articles also comment on the lack of guidance available, with McHugh and Krishnadas highlighting the lack of controlled data as to the effectiveness of tapering, the duration by which this should occur or the lowest dose recommended prior to treatment termination [ McHugh and Krishnadas, ].
Likewise, Warner and colleagues [ Warner et al. As well as there being a lack of guidance in general, the available literature comes with its own limitations, putting into question whether or not the advice available is even reliable. For instance, of the articles reviewed in the current study only five are clinical studies [ Tint et al.
This presents a real concern in that the guidance which is available rests upon a weak evidence base from clinical trials.
Similarly, all five studies rely upon self-report measures such as the DESS to measure discontinuation symptoms. The DESS, or discontinuation-emergent signs and symptoms questionnaire, is a item clinician-rated or patient-completed checklist developed by Rosenbaum and colleagues in to assess the number of adverse side effects reported in the literature [ Rosenbaum et al. According to Lader, the DESS is lengthy, which restricts its use in some research and clinical settings but it remains the scale recognized by most regulatory agencies [ Lader, ].
Self-report measures often possess validity problems as information may be wrongly remembered or biased. Similar to the controlled trials reviewed, the case series [ Cromarty et al. The majority of the identified literature were reviews and although these can be useful in collating the available information and providing guidance based upon cumulative findings, reviews are unable to provide any empirical evidence for such recommendations or add any further findings to what is already known.
Consequently, it is not only the general lack of guidance but also the quality of the data available that causes concern. Although there are few studies available, the guidance they provide does possess substantial face validity. From the available literature there is a general consensus that the best method is to taper the drug slowly in order to avoid discontinuation symptoms.
At present, the most recent antidepressant guidelines advise this method and recommend a minimum period of a 4-week taper following long-term treatment, preferably over months for a planned withdrawal of antidepressant medication [ Cleare et al.
However, as highlighted, some debate remains as to the optimum taper schedule implemented. McHugh and Krishnadas add that individuals vary in their propensity to experience discontinuation symptoms and there should be no time pressure on the tapering period when an antidepressant is being terminated altogether [ McHugh and Krishnadas, ]. Despite this, the question of methods of discontinuation will remain an ongoing issue with the release of novel agents for the treatment of depression and information for both practitioner and patient alike needs to be made available.
Currently a number of websites such as WebMD and Harvard Health offer advice to patients considering or presently undergoing drug withdrawal. But information is general and at times contradictory: for example, the duration that a drug should be tapered and the proportion of people likely to experience the syndrome vary between websites. According to Haw and Stubbs, of the patient information leaflets available on antidepressants, not all contain a warning or explanation of the symptoms of the discontinuation syndrome or why it is best not to withdraw these medications abruptly and without the supervision of a medical professional [ Haw and Stubbs, ].
This information should be available and adequate, as noted by van Geffen and colleagues, patients feel less distress from the symptoms they experience when they have been made aware of them and their self-limiting nature [ van Geffen et al. As mentioned previously, specific guidance also needs to be made available for cases in which there is particular concern such as pregnancy and treatment of the elderly. Of the articles reviewed, only one discusses discontinuation in people over the age of 65 years [ Zarowitz, ].
Nor do any of the articles reviewed provide advice as to discontinuation methods in expectant mothers despite the extensive literature which details the concerns that this poses for both mother and child.
One study found some tentative evidence for a dose effect for antidepressants and the risk of neonatal discontinuation symptoms [ Galbally et al. For instance, it may be advisable in certain cases to maintain antidepressant treatment at low doses for those older patients who would find discontinuation particularly troublesome, whilst mothers who chose to continue treatment during pregnancy may choose to refrain from breastfeeding as this along with exposure in utero increases the frequency of discontinuation syndrome seen in infants [ Hale et al.
It may also be beneficial to seek alternative treatments for depression in such cases or even for those patients experiencing mild forms of the disorder before considering medication due to the issues it can create during discontinuation.
For instance, psychotherapy may be effective either alone or as a combined treatment option along with medication [ Coryell, ]. Zarowitz notes, however, that patients over the age of 70 years are less likely to experience a recurrence of depression with pharmacotherapy than with regular psychotherapy sessions [ Zarowitz, ].
Along with providing guidelines and advice, certain measures should be taken in order to avoid or prevent discontinuation symptoms. Most importantly, the selection of patients and choice of antidepressant could reduce the numbers of people experiencing the syndrome. Many of the reviewed studies suggest that fluoxetine requires no taper and is associated with relatively few symptoms on discontinuation. Likewise newer agents such as agomelatine, have been reported to have no associated discontinuation syndrome and therefore patients may benefit from treatment or even switching to these drugs upon withdrawal [ Montgomery et al.
Smeraldi and Delmonte warn, however, that when switching from fluvoxamine to agomelatine the inhibition of CYP 1A2 and 2C9 by fluvoxamine can increase agomelatine levels if prescribed simultaneously [ Smeraldi and Delmonte, ]: a 3-day washout period is preferable to avoid this.
McAllister-Williams and colleagues also warn that the first drug would need to be withdrawn gradually to avoid symptoms recurring but that this can take place once agomelatine treatment has begun, in cases other than with fluvoxamine [ McAllister-Williams et al.
Tapering can also be facilitated by liquid formulations for precision in very gradual dose reductions, whilst tapering strips are now available for some antidepressants, including paroxetine, in which each strip contains a slightly lower dose on each consecutive day [ Groot, ].
Another potential method of avoiding unnecessary discomfort during discontinuation may come from the use of specialist nurses that have been trained in antidepressant discontinuation. This strategy has been trialled previously for benzodiazepine withdrawal, with one study in particular reporting that, after a period of one year, two thirds of patients had successfully ceased taking the medication [ Lopez-Peig et al.
Finally, treatment should also be kept as short as possible with the aim of complete discontinuation.
The current study reviews the literature available on the best methods of discontinuation for antidepressant medication. The study focuses upon the newer second-generation antidepressants due to the proportion and severity of the associated discontinuation syndrome. The review stresses the lack of guidance currently available to both practitioners and patients, particularly the lack of controlled data to inform this guidance.
On the whole, more adequate guidelines for tapering and discontinuation need to be made freely available, with particular attention given to topics such as discontinuation in pregnancy and old age.
Also, appropriate methods for specific agents, especially those such as paroxetine which are reportedly more likely to present with severe symptoms, are needed to reduce the current clinical difficulties. The present study is limited in that as a review it cannot add any new information and wider searching of databases may identify research which might have been unknowingly omitted from this review. Conflict of interest statement: The authors declare that there is no conflict of interest. National Center for Biotechnology Information , U.
Journal List Ther Adv Psychopharmacol v. Ther Adv Psychopharmacol. Emma Wilson and Malcolm Lader. Author information Copyright and License information Disclaimer. Email: moc. This article has been cited by other articles in PMC. Abstract Strong evidence supports the existence of a discontinuation syndrome following the withdrawal of antidepressant medication, particularly second-generation antidepressants.
Keywords: antidepressant medication, discontinuation syndrome, gradual dose tapering. Introduction Depressive disorders are currently estimated to affect million people worldwide with approximately 1 in 20 people reporting an episode of depression each year [ Marcus et al.
Results The electronic search identified 18 peer-reviewed publications containing guidelines for antidepressant discontinuation. Table 1. Peer-reviewed publications identified through database search. No significant difference reported in symptoms experienced by those undergoing longer or shorter taper schedules.
Authors suggests drug half-life more important than taper duration Randomized controlled trial: Montgomery et al.
Discontinuation symptoms measured using DESS. Study found no discontinuation syndrome associated with agomelatine and suggest this drug may be useful in the treatment of patients who have experienced adverse symptoms withdrawing from other antidepressant medication. Study demonstrated occurrence of discontinuation syndrome with paroxetine. Analysis: Baldwin et al.
This study primarily investigates the differences between discontinuation syndromes and whether duration of treatment impacts upon occurrence. It was found that duration of treatment was not associated with any increase in the incidence of symptoms occurring.
Although the data does not suggest any effect of tapering within the doses used, the authors note that following abrupt withdrawal in the SAD group there were more incidences of some symptoms e. Analysis: Himei and Okamura [] A retrospective analysis investigating the clinical records of outpatients diagnosed with major depression from two centres in West Japan. All patients had been treated with paroxetine during the previous 5 years and were divided into groups based on the experience of a discontinuation syndrome.
Of patients, 41 experienced a discontinuation syndrome. Study found that those patients who abruptly withdrew treatment or who had experienced adverse effects during early phase of treatment were more likely to experience discontinuation symptoms. The authors recommend tapering gradually and monitoring those patients with prior adverse reactions to medication. Observational cohort study: van Geffen et al. Significantly more adverse effects as a result of discontinuation were reported by those patients who withdrew medication abruptly.
Authors recommend tapering to avoid unpleasant symptoms Case series Cromarty et al. All patients had previously attempted withdrawal. Daily self-monitoring diaries were used to measure target variables. Authors state that it can be argued that CBT intervention has a beneficial effect, particularly in reducing patient anxieties about discontinuing medication.
Consensus panel recommendations Schatzberg et al. Panel recommends gradual dose tapering and potentially switching to longer-acting drugs such as fluoxetine alongside close patient monitoring and education about syndrome. Reviews Ogle and Akkerman [] Systematic literature review. Authors note that they identified no single or complete guideline for antidepressant discontinuation.
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