Evaluating the risk of mild serotonin syndrome in primary care: a retrospective case series of patients with treatment-resistant depression

Introduction

Serotonin syndrome is an acute state with symptoms of excessive serotonin activity in the central nervous system (CNS) that can range from mild discomforts, like shivering and diarrhoea, to severe manifestations including muscle rigidity, fever, and even seizures that could potentially be life-threatening (1,2). Serotonin syndrome is caused by the administration of a single drug or combination of drugs that enhances the serotonin levels; from among a wide range of prescribed medication and over-the-counter drugs to even herbal supplements (1-3). Some specific combinations have been noted to be very high-risk, such as opioids and serotonergic agents likely to trigger serotonin syndrome. For example, it significantly increases the potential for serotonin syndrome when co-prescribed with antidepressants (4).

This spectrum of causative agents underlies the complexity and potential under-recognition of serotonin syndrome in primary care, more so in its milder forms. Selective serotonin reuptake inhibitors (SSRIs) are considered first-line treatments for depression and anxiety due to their good safety profile and tolerability; however, treatments for treatment-resistant depression are less clearly defined (5).

Primary care practitioners play a crucial role in the early detection and management of serotonin syndrome. The condition may seem to be very subtle, especially if mild, yet it may go unrecognised for proper intervention before it develops (6). The exact prevalence of serotonin syndrome cannot be fully established due to varied clinical presentation and a lack of awareness amongst healthcare providers. Mild cases are harder to diagnose because the symptoms can be nonspecific and easily attributable to other causes. The under-recognition of serotonin syndrome, especially its milder forms, among patients treated for anxiety and depression in primary care continues (1).

A critical part in the differential diagnosis of serotonin syndrome is the consideration of common antidepressant side effects that may overlap with or are recognised symptoms of serotonin syndrome (1-3). Some recognised side effects of SSRIs include agitation, confusion, sweating, gastrointestinal disturbances, and tremors. These overlapping symptoms can make the clinical management of patients complex, and, in turn, it is important for healthcare providers to probe carefully into the temporal relation between the introduction of new serotonergic agents and symptom onset.

This retrospective case series is a reflection on the risk of mild serotonin syndrome in treatment-resistant depression, an especially vulnerable group due to high rates of polypharmacy. We utilised the Hunter Serotonin Toxicity Criteria, whose diagnostic strength is widely accepted in serotonin syndrome, and modified Sternbach criteria for screening mild cases that can be undertaken at a primary care setting (7,8). We also aimed to assess the outcome of various interventions in patients presenting with symptoms suggestive of this condition. We present this article in accordance with the AME Case Series reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-123/rc).

Case presentation

Ethical considerations

This case series was performed under a proper ethical framework for retrospective research and did not require ethical approval. It comprised an analysis of already existing medical records in the absence of clinical contact or a change in patient care. Data collection was safeguarded by stringent privacy standards, protecting full anonymity and confidentiality.

Patients’ data were de-identified in advance during the analysis process to secure personal data. De-identification of the individual patients’ data was done by removing all identifiers linking data to individual patients to guarantee privacy and compliance with data protection regulations. The data were accessed and analysed only by an experienced medical doctor, and there was no external participation in the data collection process, analyses, or interpretation.

All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and in line with the Helsinki Declaration (as revised in 2013). Written informed consents were obtained from the patients for the publication of the case series. A copy of the written consent is available for review by the editorial office of this journal.

Case series

This is a retrospective case series in which we gathered data from a group of primary care patients with treatment-resistant depression who developed the features of mild serotonin syndrome, after the introduction of a second agent of antidepressant. All the patients were discussed with the community mental health team.

The case series included 20 patients (mean age 40.4 years; 55% female) with anxiety and depression of an average duration of 5.3 years. Only patients who were manifesting new-onset symptoms compatible with serotonin syndrome since the introduction of the second serotonergic agent were considered for inclusion. New symptoms that occurred following the addition of this agent but that were not a feature of the baseline presentation minimised the likelihood of misinterpretation of the pre-existing condition.

These patients were previously treated with a single SSRI antidepressant agent, which included fluoxetine (25%), sertraline (25%), paroxetine (5%), citalopram (20%), and escitalopram (25%). Due to inadequate response, a second antidepressant was introduced, comprising of either a serotonin and norepinephrine reuptake inhibitor (SNRI) (venlafaxine: 35%), a tricyclic antidepressant (TCA) (mirtazapine: 35%), a second SSRI (duloxetine: 20%; or vortioxetine: 5%), or a serotonin receptor antagonists and reuptake inhibitor (SARI) (trazodone: 5%).

Comorbidities were present in 60% of the patients, with chronic pain (30%), hypertension (20%), diabetes type 2 (15%), and thyroid disorders (10%) being the most common. Additionally, 50% of the patients were taking other medications or substances alongside their antidepressant therapy, which included cannabis (20%), amitriptyline (10%), co-codamol (10%), bupropion (5%), tramadol (5%), carbamazepine (5%), and undisclosed herbal supplements (5%). This aspect of polypharmacy and the use of substances not declared to the healthcare provider posed a potential risk for the development of mild serotonin syndrome, underscoring the complexity of managing treatment-resistant depression in primary care (Table 1).

The selection criteria for adding a second antidepressant were based on the patients’ history of inadequate response to their first-line antidepressant treatment. The approach aimed at evaluating the safety of combination therapy in patients with treatment-resistant depression.

In this study, we diagnosed mild serotonin syndrome based on the integration of the Hunter Serotonin Toxicity Criteria with the modified Sternbach criteria in a systematic way that increased both sensitivity and specificity of our diagnostic process. The Hunter Serotonin Toxicity Criteria is one of the most appreciated scales developed for this purpose because of the accuracy in screening out serotonin toxicity, which is then supported by vital clinical indicators like clonus (spontaneous, inducible, or ocular), agitation, diaphoresis, tremor, and hyperreflexia, additional hypertonicity, and hyperthermia in severe forms. All patients were investigated with these criteria applied as a primary diagnostic tool, especially those who clearly showed signs of serotonin toxicity after a second serotonergic agent was introduced.

As we wished to detect even less severe cases of serotonin syndrome—perhaps not truly meeting the very narrow stringency of the Hunter Criteria—using the modified Sternbach criteria. The Sternbach criteria include a wider range of symptoms, such as changes in mental status including confusion and hypomania, myoclonus, hyperreflexia, shivering, and gastrointestinal symptoms, for example, diarrhoea. These criteria are less specific than the Hunter Criteria but are beneficial in capturing cases with more subtle presentations that might be missed otherwise. We used the Sternbach criteria to screen patients who presented with suspected serotonin syndrome; we next selected those with probable serotonin syndrome. We then proceeded to use the Hunter Criteria to confirm the same cases. This dual approach allowed us to survey and diagnose a very broad spectrum of serotonin syndrome severity, thus excluding the possible situation of missing any case—mainly the milder ones—in the setting of primary care.

The patients’ symptoms of agitation, confusion, tachycardia, dilated pupils, myoclonus, diaphoresis, and diarrhoea were essentially suggestive and strongly predictive of mild serotonin syndrome; the same was monitored throughout the study. All the diagnoses were made by experienced primary care clinicians with a special interest in mental health, with full assessment being done in liaison with the local community mental health team.

We were particularly interested in the development of new-onset symptoms that had occurred after the introduction of a second serotonergic agent but were not present at the baseline evaluation. Monitoring was conducted by way of follow-up and self-report. In this way, it reinforced the diagnosis and excluded other possibilities responsible for the symptoms.

Outcome

In this case series, 20 patients had mild symptoms of serotonin syndrome: agitation, confusion, tachycardia, diaphoresis, mydriasis, tremor, and diarrhoea. Most interestingly, other patients were detected who consumed combinations of serotonergic agents and opioids; such a combination of drugs is known to be associated with an increased risk of the serotonin syndrome (4).

Symptoms occurred 1 to 4 weeks after introduction of the second antidepressant, with duration before presentation to the primary care physician ranging from 2 to 11 weeks. This would suggest that there is a knowledge or recognition gap of the early symptoms of serotonin syndrome in patients and, to some extent, primary care.

Interventions varied from discontinuation (45%) or dose reduction of the second antidepressant (25%) to medication adjustment (30%). Medication adjustment involved changes to either the first-line antidepressant, other concurrent medications, or both. Additionally, patient education on drug interactions and the avoidance of herbal supplements or illicit drugs was provided. The outcomes were favourable across the board, with symptoms resolving within a range of 7 to 21 days, highlighting the effectiveness of tailored interventions in managing mild serotonin syndrome in a primary care context.

The majority of cases resolved within 2 weeks of intervention. Specifically, Of the patients, 7 (35%) experienced symptom resolution within 1 week, 5 (25%) by 10 days, another 5 (25%) by 2 weeks, and the remaining 3 (15%) after more than 2 weeks, resulting in full symptom resolution by the end of the observation period. All patients had a resolution of symptoms within 3 weeks, with the median time of symptom resolution being 10 days. This variability underscores the importance of early detection and tailored intervention to mitigate the risks associated with serotonin syndrome, even in its milder forms (Table 2).

The interventions focused on discontinuation or dose reduction of serotonergic medications as a primary approach, applied in 70% of the cases. This included patients P01, P02, P03, P04, P05, P06, P08, P10, P11, P13, P14, P16, P17, and P19. Education on medication risks and the importance of monotherapy or avoiding certain substances was also a common component of the intervention strategy, indicating a multifaceted approach to managing mild serotonin syndrome.

Analysis of cases involving additional substances

In this cohort, 10 out of the 20 patients (50%) were using additional substances known to influence serotonin levels alongside their prescribed antidepressants. These substances included cannabis, opioids such as tramadol, amitriptyline, and other serotonergic agents like bupropion and carbamazepine.

Patients who were on these additional substances exhibited a broader range of symptoms and higher severity scores compared to those who were not using additional serotonergic agents. Specifically, 70% of these patients reported severe agitation and confusion, compared to 40% in the rest of the cohort. The duration of symptoms before resolution was also longer in this subgroup, with a median duration of 14 days, compared to 10 days in patients who were not using additional substances.

Patients with a serotonin syndrome required much more aggressive management: an astonishing number needed total withdrawal of multiple agents or large dose reductions. This, in fact, underlines the greater complexity of the management of the serotonin syndrome in patients exposed to several serotonergic substances.

Overall, our evidence suggests that, with appropriate management, patients who present with mild serotonin syndrome can expect a good prognosis, with the resolution of symptoms within 3 weeks in all cases. This series further underscores the importance of general practitioner (GP)’s awareness and responsiveness to the signs of serotonin syndrome even in its less severe manifestations.

Discussion

This case series demonstrates the importance of carefully monitoring symptoms suggestive of serotonin syndrome, particularly in a population with such high rates of polypharmacy and comorbid conditions that might increase risk associated with the use of multiple serotonergic agents.

Our analysis reveals a significant association between the introduction of a second serotonergic medication and the emergence of symptoms indicative of mild serotonin syndrome. However, it is important to note that we did not evaluate how many patients on two serotonergic agents did not develop symptoms. Future research may need to be directed toward the incidence of serotonin syndrome in the community, the percentage of patients on multiple serotonergic agents but without any trouble, and other potential risk factors.

The variabilities in the duration of symptoms before presentation and interventions needed, mainly medication withdrawal or dosage reduction, support the need for caution in the approach and management of cases with treatment-resistant depression. This is especially important in situations with polypharmacy, where drug-to-drug interactions play a crucial role in the development of serotonin syndrome. Montastruc et al. (9) also reported that such interactions, more particularly with serotoninergic reuptake inhibitors, urge judicious pharmacovigilance in clinical practice. Besides, the importance to monitor with caution the drugs falling into this category is added by a comparative study on pharmacovigilance by Elli et al. (10), since they can produce serious adverse drug reactions even including serotonin syndrome.

The resolution of symptoms in all the cases with treatment strategies individualised for each patient brings out more sharply the value of early detection and the implementation of prompt, informed therapeutic strategies. This series also highlights the problems faced by primary care in making a correct diagnosis and handling cases of mild serotonin syndrome due to its non-specific symptomatology and underreporting by patients of the usage of non-prescribed substances. There is a clear need for continued education of patients and healthcare providers regarding the risks of polypharmacy and the importance of frank discussions about all substances being used.

This is consistent with the fact that a number of other studies suggest that early detection and intervention provide the key to better management of serotonin syndrome. The study by Di Salvo et al. (6) further supports the need for standardised criteria in diagnosing serotonin syndrome, which may help standardise some variables and serve as a reference to real-world clinical practice in the definition of our methodology and current best practices.

For instance, Foong et al. pointed out that the clinical presentation of serotonin syndrome was an intricate process, and that it was important for primary care physicians to play a key role in the diagnosis and management of the condition (1). Further, Mikkelsen et al. pointed out that one had to appreciate the fact that symptoms of serotonin syndrome were heterogeneous and that cases have been recorded with mild and severe afflictions, which is consistent with what we noticed in practice, because nonspecific symptomatology could be difficult for early recognition (2).

Our findings are also consistent with those by Ruiz de Villa et al. (3) and further supported by the studies of Montastruc et al. (9) and Elli et al. (10), which report cases of serotonin syndrome precipitated by polypharmacy, indicating a serious contribution of drug interactions to serotonin toxicity. These findings may suggest the need for clinical practice to be more vigilant, especially regarding prescription with combinations that are related to an increase in the risk of serotonin syndrome, such as opioids with serotonergic agents (4). Further, Bennabi et al. highlighted the need for well-elaborated clinical guidelines in treatment-resistant depression, an entity that will often include the use of two or even more antidepressants to reach and sustain a response; hence, it is necessary to remain vigilant in the context of side effects—here, serotonin syndrome (5).

Although our study provides valuable insight into managing such a complex entity in the primary care setting, it also points toward the direction of greater concern for large prospective studies to fine-tune the understanding of risk factors, presentation, and strategies for managing mild serotonin syndrome. Such research is pivotal in developing guidelines that are more holistic in improving patient safety and the effectiveness of treatment given within primary care when treating treatment-resistant depression. Prospective studies in the future should measure the prevalence of serotonin syndrome in patients using several serotonergic medications and assess the efficacy of the different intervention strategies.

Furthermore, awareness should be raised among health care providers about the propensity to serotonin toxicity when two or more serotonergic agents are being prescribed. According to Wang et al., prophylactic measures such as patient education combined with cautious and patient medication use management are significant in minimising the likelihood of the syndrome (11). In the same way, it affirms our recommendation that continuous education on the risk associated with polypharmacy in addition to the need for effective communication regarding all substances taken is provided to the implicated health care provider and patients.

Conclusions

Our study highlights the importance of primary care physicians in the early detection and management of serotonin syndrome and further calls for research to fine-tune the understanding on risk factors, diagnostic improvements, and comprehensive management guidelines.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the AME Case Series reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-123/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-123/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-123/coif). W.J. serves as an unpaid editorial board member of AME Case Reports from July 2024 to June 2026. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and in line with the Helsinki Declaration (as revised in 2013). Written informed consents were obtained from the patients for the publication of the case series. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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