Sertraline in Major Depressive Disorder: An Appraisal of Its Importance

The world is facing a significant mental health challenge, especially in Europe. In the last 20 years, the use of antidepressant drugs has skyrocketed globally. Data from the Organisation for Economic Cooperation and Development shows that in 18 European countries, the consumption of antidepressants increased by nearly two and a half times from 2000 to 2020 (OECD, 2023). This surge is emblematic of a broader endeavour in psychiatry, which began with the discovery of certain chemicals' potential to alleviate mental distress. Scientists embarked on a quest to find the elusive "magic bullet"—a medication capable of ameliorating symptoms without unwelcome side effects, a pursuit that continues to shape mental healthcare today. This article delves into the profound influence of a pivotal molecule in this quest: sertraline (Ferguson, 2001).

Major Depressive Disorder - An Overview

Major depressive disorder is universally acknowledged as a significant mental health challenge. MDD is characterised by persistent sadness, anguish, and a loss of interest or pleasure in activities that were once enjoyed. It often leads to cognitive and physical symptoms such as fatigue, changes in appetite or weight, sleep disturbances, feelings of guilt or worthlessness, and difficulty concentrating. These symptoms can be severe and draining, affecting an individual's daily life and relationships. Understanding MDD is crucial as it is not a one-size-fits-all condition (Bains & Abdijadid, 2023; Monroe & Harkness, 2022). Figure 1 presents the classification of mental health problems from the depression spectrum, which MDD is part of.

Traditionally, discussions surrounding depression start by emphasising its dire consequences, underscored by disheartening facts and statistics indicating its profound impact on individuals and society (Furukawa, 2019). While this narrative is emotionally compelling and serves as a strong stimulus for research and action, it does not entirely align with the scientific complexity of MDD. Depression, as a mental health condition, exhibits varying degrees of severity among individuals, even within the same person over time. It is essential to recognise that not every instance of feeling depressed necessarily means a clinically significant mental disorder requiring pharmaceutical intervention. Depression could be understood as a spectrum, and the experiences of patients with depression can manifest differently in terms of intensity, duration, and impact on daily functioning (Monroe et al., 2019).

Figure 1: Classification of depressive disorders (Goodwin & Stein, 2021).

A subset of individuals with depression will deal with recurring episodes throughout their lifetimes, but a larger cohort will remain free of recurrences. Rather than advocating for the dismissal of depression in any form, a nuanced perspective is suggested to be adopted, one that acknowledges the fact of altering degrees of severity along the depression spectrum. This approach not only respects the individuality of depressive experiences but also underscores the importance of tailored interventions. While some may require pharmacological treatment, others may benefit from psychotherapy, lifestyle modifications, or simply time and support. Apart from acknowledging this distinction, it is important to combat the stigma associated with depression (Rottenberg et al., 2018). Encouraging people with depressive symptoms to seek assistance without concern for judgment or societal prejudices is paramount. By nurturing a compassionate and empathetic ambience, doctors can guarantee that individuals, irrespective of their position on the depression spectrum, receive the suitable support and assistance they require. Therefore, it should not be universally regarded as a uniformly severe and lifelong condition that applies universally. Such an oversimplified view may inadvertently deny the diversity within depressive experiences (Hauenstein, 2003).

The far-reaching impact of MDD cannot be underestimated, evidenced by an 18% surge in globally affected individuals between 2005 and 2015 (WHO, 2017). This distressing reality equals a staggering 322 million people—roughly 4% of the world's population (Furukawa et al., 2019). Addressing this monumental challenge necessitates a multifaceted approach to treatment, with medications and psychotherapy forming the base of support. Notably, second-generation antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), emerge as the primary pharmaceutical avenue for navigating the complexities of MDD (Cipriani et al., 2018).

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are a significant class of drugs in depression management. What sets SSRIs apart from other types of medication is their selectivity for inhibiting the reuptake of serotonin, a neurotransmitter crucial for mood regulation, while sparing other mechanisms. This selectivity offers a distinct advantage over earlier antidepressants by avoiding unwanted anticholinergic and cardiac side effects (Kubanek et al., 2021). Furthermore, SSRIs eliminate the need for dietary and drug-related restrictions characteristic of other first-generation antidepressants. In earlier times, individuals dealing with MDD often had to endure the potential side effects of antidepressant medications as they sought relief from the weight of severe symptoms and profound melancholic states. The potential side effects were, among others, constipation, blurred vision, or even seizures (Ferguson, 2001). The introduction of SSRIs marked a pivotal shift in the equation of risks and benefits. This change enabled healthcare professionals to extend antidepressant treatment to a broader range of MDD patients, those with milder or moderately symptomatic conditions, and even those with subsyndromal manifestations (Hameed et al., 2005).

Figure 2: Schematic diagram showing the mechanism of action of SSRIs (Kaciroti, 2005).

Mechanistically, SSRIs function by obstructing the reuptake process of serotonin molecules, thereby potentiating their presence at synapses within the brain. The augmented availability of serotonin catalyses the amelioration of sentiments of hopelessness, pessimism, and emotional anguish, all of which are commonly encountered in depressive states (Chu & Wadhwa, 2023). The therapeutic action of SSRIs is not reached immediately: their optimal effects necessitate consistent administration over a set time, permitting neurophysiological adaptations conducive to tangible alleviation. Initially, the elevated serotonin levels might be perceived by neurons as locally toxic, leading to stress-related changes in specific cells to adapt to the higher-than-baseline serotonin levels. Consequently, there is a modulation in the activity of distinct neuronal enzymes implicated in serotonin metabolism—some escalate while others diminish. Certain receptors may become desensitised or downregulated, while receptors responsive to serotonin may be synthesised and transported to the cell membrane. These selective gene activation and protein formation processes can take approximately 4–6 weeks, coinciding with the time it takes for an antidepressant to reach its full therapeutic effect. In this view, antidepressants, such as SSRIs, create a new chemical environment in the central nervous system, at first seen as stressful but ultimately favourable (Andrade, 2010).

Moreover, it is noteworthy that many antidepressants, irrespective of their mechanistic pathways, bolster the production and activity of neurotrophic factors within the brain. These factors may reverse MDD-induced brain atrophy, enhance synaptic plasticity, and potentially restore a balance between limbic and cortical activities, ultimately alleviating depression. This capacity to increase gene activity to enhance synaptic levels of neurotrophic proteins often begins with the initial surge of "toxic" serotonin provided, typically through SSRI monotherapy (Williams et al., 2002).

Figure 3: FDA-Approved SSRIs (Staff, 2016).

Intriguingly, the therapeutic effects of SSRIs cannot be explained by mere inhibition of the serotonin transporter, indicating the involvement of additional mechanisms. A contemporary hypothesis proposes that the neuronal stress instigated by SSRIs prompts a recalibration of brain balance, leading to decreased serotonin levels in certain brain regions while elevating them in others (Santarsieri & Schwartz, 2015).

SSRIs have ascended to the pinnacle of popularity due to their relatively mild side effect profiles and broad-spectrum efficacy in addressing the many different manifestations of MDD (Edinoff et al., 2021). Despite being generally well-tolerated, the commonly experienced side effects encompass headaches, sleep difficulties, fatigue, and initial anxiety. Some SSRIs may be associated with different side effects, such as weight gain and sedation, while others might lead to adverse gastrointestinal effects. Certain SSRIs can trigger withdrawal symptoms if abruptly discontinued due to their shorter half-lives. Furthermore, some SSRIs are more likely to interact with other drugs through hepatic enzyme inhibition [Figure 4]. Healthcare providers routinely evaluate these factors when discerning the optimal SSRI for individual patients, as each SSRI is perceived to possess distinct clinical indications, even though current regulatory guidelines regard them as equivalent (Santarsieri & Schwartz, 2015).

Figure 4: Most frequent adverse effects in primary care patients using different types of antidepressants (Sienaert, 2014).

Sertraline

Sertraline, a member of SSRIs, is a prominent player in depression management. Before initiating sertraline treatment, specific medical tests are typically not necessary, simplifying its administration (Labbate, 2012). To mitigate potential side effects, psychiatrists commonly begin treatment with a subtherapeutic dose of 25 mg for the first week, followed by an increase to 50 mg. Special care is advised for patients with coexisting anxiety, advanced age, or heightened susceptibility to side effects. While some individuals may require doses as high as 300 mg, the maximum recommended dose is 200 mg. It can be taken in the morning, although some patients may experience sedation and may benefit from evening dosing. The key is maintaining a consistent regimen regarding timing, dose, and whether it is taken with or without food (Fredman et al., 2000). Sertraline is commonly recognised by its commercial drug name: Zoloft.

As aforementioned, SSRI drugs are generally well-tolerated. Still, there are some noteworthy considerations regarding their usage [Figure 5]. Sertraline moderately affects certain enzymes in the body that help process other medications. This interaction can vary based on the dose of sertraline. Compared to similar drugs, sertraline's interactions with other medications are usually not as strong (De Vane et al., 2002). The safety profile of sertraline is usually benign, although some individuals may experience common side effects, including diarrhoea and psychomotor agitation. Additionally, adverse effects like drowsiness, headache, or sexual dysfunction, can occur in some patients (He et al., 2004). Notably, sertraline exerts an antiplatelet effect, which may have therapeutic value in specific clinical contexts; it is worth noting that this effect warrants careful monitoring in patients at risk of bleeding. In particular situations, adjustments to antiplatelet therapy may be contemplated (Labos et al., 2011).

Figure 5: Side effects of Zoloft (Schimelpfening, 2023).

Sertraline has the potential to slightly affect the heart rhythm, although this risk is comparatively lower than that associated with other SSRIs (Beach et al., 2014). Additionally, there is a rare but serious condition called serotonin syndrome [Figure 6], which occurs when sertraline is combined with other serotonergic medications, leading to excessive serotonin accumulation within the body. Serotonin syndrome manifests through many symptoms, including myoclonus, muscular rigidity, diaphoresis, tremor, hyperreflexia, agitated delirium, and hyperthermia (Duignan et al., 2020). In the context of paediatric use, sertraline, like many other antidepressants, may elevate the risk of suicidal ideation and behaviour in children, adolescents, and young adults with major depression (Williams et al., 2012). These aspects underscore the importance of careful assessment and risk-benefit analysis when considering sertraline for specific patient populations.

Addressing side effects while using sertraline often requires changes to the treatment plan. These modifications can include decreasing the dose, changing when the medication is taken, or dividing the total daily amount into smaller doses spread throughout the day. Sometimes, low doses of trazodone may be prescribed to manage issues like sexual problems or difficulty sleeping (Stryjer et al., 2009). It is typically recommended to strive for complete relief from depressive symptoms during antidepressant treatment and to continue taking the medication for a maintenance period of at least six months before considering a reduction in dose or discontinuation, naturally in consultation with healthcare providers (Kocsis et al., 2002).

Figure 6: Signs and symptoms of the serotonin syndrome (Francescangeli, 2019).

Comparative Analysis of SSRIs in MDD Treatment

The meta-analysis conducted by Cipriani and colleagues (2018) focused on comparing the efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder. Among the various antidepressants studied, including the widely prescribed sertraline, it was found that all of them performed better than a placebo in relieving depressive symptoms. However, these improvements were generally modest. Regarding sertraline, it exhibited a relatively higher rate of positive responses and fewer individuals discontinuing treatment compared to other options. These results suggest that sertraline is both effective and well-tolerated for treating major depressive disorder in adults. Head-to-head comparisons among these antidepressants exposed variations in their efficacy and dropout patterns, underscoring the necessity for personalised treatment selection.

A study by Sanchez and colleagues (2014) focuses on assessing three SSRIs—escitalopram, paroxetine, and sertraline—in the acute treatment of MDD in adults. As already mentioned, sertraline frequently appears as the preferred initial therapeutic choice. This inclination towards sertraline during the initial stages of therapy can be attributed to its moderate susceptibility to drug interactions and its track record of relatively mild side effects. Nevertheless, the outcomes of this investigation stress the imperative of avoiding a uniform approach when selecting an antidepressant. The study underscores the existence of distinct variations in the efficacy and tolerability profiles among these three SSRIs, with individual responses to these medications exhibiting considerable heterogeneity. For instance, while sertraline is frequently regarded as a sensible initial choice, it is noteworthy to acknowledge that escitalopram exhibits a superior profile compared to paroxetine, which is burdened with a less favourable tolerability record. Paroxetine possesses distinct characteristics, affecting specific enzymes and receptors, which can impact its tolerability (Richelson, 2001).

Conversely, although sertraline is usually well-tolerated, it can interact somewhat with other medications. In light of this, escitalopram, a unique type of antidepressant, seems encouraging due to its effectiveness and tolerability. Furthermore, nonclinical data hints at the possibility that escitalopram might provide superior results, potentially due to its interactions with serotonin receptors (Undurraga & Baldessarini, 2012). In summary, while sertraline is most commonly the initial choice in MDD therapy, selecting an antidepressant should be individualised, factoring in patient-specific characteristics, preferences, and potential contraindications.

Figure 7: First-choice antidepressants for MDD (Osser, 2019).

Contraindications

Like any drug, sertraline comes with several contraindications and precautions that must be carefully considered before prescribing. It should not be administered to patients with a known hypersensitivity to sertraline or its components, as this could lead to adverse reactions (Richelson, 2001). Coadministration of sertraline with certain medications, such as thioridazine or pimozide, is contraindicated due to the risk of potentially dangerous interactions. Patients taking other serotonergic medications should be familiarised with the potential risks of combining these drugs with sertraline. The rationale behind these precautions is linked to the aforementioned serotonin syndrome (Sola et al., 2006). Furthermore, sertraline in solution form contains 12% alcohol, which is an important consideration, especially for patients prescribed disulfiram in order to avoid an alcohol-disulfiram reaction (Singh, 2023).

Ensuring Patient’s Safety

Monitoring patients taking sertraline is crucial to ensure their safety and well-being. Regular assessment should focus on detecting any unusual changes in behaviour, increased anxiety, signs of worsening depression, or thoughts of self-harm, particularly when adjusting the dose of sertraline. Occasionally, sertraline may trigger manic episodes in individuals at risk of bipolar disorder. Therefore, scrutinising manic symptoms is vital, especially if there is a family history of bipolar disorder (Leverich et al., 2006).

As aforesaid, it is necessary to observe for any signs of abnormal bleeding, medication side effects, or withdrawal symptoms that may occur if sertraline is abruptly discontinued. Increased bleeding risk is particularly relevant when sertraline is used alongside aspirin, NSAIDs, warfarin, or other anticoagulants, as it can affect platelet function and potentially lead to bruising, nosebleeds, or bleeding disorders (Andrade et al., 2010). For elderly patients, monitoring should extend to mental status changes and regular appraisals of sodium levels, as sertraline use may pose a risk of developing a syndrome of inappropriate antidiuretic hormone secretion or hyponatremia (Singh, 2023). Although sertraline is generally considered safe for individuals with a history of heart conditions, periodic electrocardiograms are advisable to monitor the QT interval due to its minor effect on QT prolongation (O’Connor et al., 2010). In the case of pregnant or breastfeeding patients, sertraline is considered safe, but therapeutic drug monitoring could be a consideration for added assurance regarding both maternal and infant safety. When prescribing sertraline during the third trimester of pregnancy, a meticulous evaluation of the risk versus benefit is required based on individual patient circumstances (Paulzen et al., 2017). Neonates exposed to sertraline late in the third trimester have been reported to experience complications necessitating prolonged hospitalisation, tube feeding, and respiratory support (Shen et al., 2017).

Figure 8: Treatment algorithm for MDD (Santarsieri & Schwartz, 2015).

Sertraline Therapy Discontinuation

The discontinuation of sertraline therapy can give rise to noteworthy withdrawal symptoms, particularly when the cessation of the medication is abrupt. These withdrawal manifestations encompass a range of physiological and psychological effects, including nausea, excessive sweating, dysphoria, heightened irritability, restlessness, vertigo, sensory disturbances like paresthesia and electric shock sensations, tremors, increased anxiety, confusion, headaches, lethargy, emotional lability, disruptions in sleep patterns, hypomanic episodes, tinnitus, and even, though exceedingly rarely, seizures [Figure 9] (Fava, 2015). In order to moderate the risk of encountering these adverse reactions, it is advisable to adopt a gradual tapering approach for sertraline dosage reduction rather than a sudden discontinuation whenever it is feasible. This approach aligns with the established practices in antidepressant management, aiming to ensure a smoother transition for patients. It is essential to acknowledge that the duration and intensity of withdrawal symptoms can significantly vary among individuals. While some may experience mild and transient symptoms, others may endure more protracted and distressing effects. Hence, psychiatrists should exercise vigilance and closely monitor patients throughout the withdrawal process (Singh, 2023).

Figure 9: The possible effects of sertraline withdrawal (Czinkota, 2023).

Conclusions

The comprehensive analysis of sertraline and its place within the landscape of antidepressant therapy for major depressive disorder spotlights several essential considerations for clinicians. Sertraline is a reasonable initial choice due to its moderate drug interaction profile and relatively benign safety record, making it a well-tolerated option for patients initiating MDD therapy. However, this selection should not be based on a one-size-fits-all approach, as the varying efficacy and tolerability profiles among different antidepressants have been reported by scholars. Nevertheless, individualised treatment decisions remain paramount, with factors such as a patient's health history, age, and specific clinical profile all influencing the choice of antidepressants. Vigilant monitoring is paramount during sertraline therapy, focusing on identifying unusual behavioural changes, signs of worsening illness, or adverse effects. Regular assessments for depression and suicidality, especially during dosage adjustments, are essential for patient safety.

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Visual Sources

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Figure 1: Classification of depressive disorders. Goodwin, G. M., & Stein, D. J. (2021). [Ilustration]. Generalised anxiety disorder and depression: Contemporary treatment approaches. Advances in Therapy, 38(s2), 45–51. https://doi.org/10.1007/s12325-021-01859-8

Figure 2: Schematic diagram showing the mechanism of action of SSRIs. Lattimore, K. A., Donn, S. M., Kaciroti, N., Kemper, A. R., Neal, C. R., Jr, & Vazquez, D. M. (2005). [Illustration]. Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and effects on the fetus and newborn: A meta-analysis. Journal of perinatology : official journal of the California Perinatal Association, 25(9), 595–604. https://doi.org/10.1038/sj.jp.7211352

Figure 3: FDA-Approved SSRIs. (Staff, 2016). [Table]. Uspharmacist. https://www.uspharmacist.com/article/ssris

Figure 4: Most frequent adverse effects in primary care patients using different types of antidepressants. (Sienaert, 2014). [Illustration]. Psychiatric times. https://www.psychiatrictimes.com/view/managing-adverse-effects-antidepressants

Figure 5: Side effects of Zoloft. (Schimelpfening, 2023). [Illustration]. Verywell mind. https://www.verywellmind.com/zoloft-side-effects-1067484

Figure 6: Signs and symptoms of the serotonin syndrome. Francescangeli, J., Karamchandani, K., Powell, M., & Bonavia, A. (2019). [Illustration]. The serotonin syndrome: From molecular mechanisms to clinical practice. International Journal of Molecular Sciences, 20(9), 2288. MDPI AG. Retrieved from http://dx.doi.org/10.3390/ijms20092288

Figure 7: First-choice antidepressants for MDD. (Osser, 2019). [Infographic]. Psychopharmacology Institute. https://psychopharmacologyinstitute.com/section/major-depressive-disorder-algorithm-was-the-antidepressant-trial-adequate-node-4-2534-4770

Figure 8: Treatment algorithm for MDD. Santarsieri, D., & Schwartz, T. L. (2015). [Illustration]. Antidepressant efficacy and side-effect burden: A quick guide for clinicians. Drugs in Context, 4, 1–12. https://doi.org/10.7573/dic.212290

Figure 9: The possible effects of sertraline withdrawal. (Czinkota, 2023). [Illustration]. Verywell mind. https://www.verywellmind.com/sertraline-withdrawal-4771948