We examined the frequency and concomitant circumstances of the occurrence of severe edema among 462,661 psychiatric inpatients treated with psychotropic drugs between 1993 and 2016. We defined edema as a severe ADR if it lasted more than 1 week and affected legs, arms, face, or multiple body parts, and in any case in which diuretics were used to treat edema. Under these well-defined criteria, we determined an incidence of psychotropic drug-induced edema of 0.50‰. This result differs from the data reported in registration studies, which indicate a higher incidence. However, these studies also include non-severe presentations of edema such as mild ankle edema, resulting in a more generous definition of ADR (European Medicines Agency 2004, 2008, 2010, 2014, 2022).

We did not identify an increased risk of drug-induced edema for any of the psychotropic drug groups, suggesting that it is individual drugs, rather than drug groups, that carry a significant risk of severe edema.

Within our study, mirtazapine was the psychotropic drug implicated in the highest number of edema cases. Mirtazapine-induced edema has mainly been described in case reports (Sullivan (2001); Anttila and Leinonen (2001); Lahdelma and Bruin (1998)). Peripheral edema has been listed as an ADR with a reported incidence of of 2.4% (Food and Drug Administration 1997), while some authors suggest an incidence of about 1% (Lahdelma and Bruin (1998); Anttila and Leinonen (2001)). Both of these incidences are significantly higher than the incidence we found (i.e., 0.60‰). Although the pharmacodynamic properties of mirtazapine have been extensively studied (Fawcett and Barkin 1998), it is not fully understood how they contribute to edema. As mirtazapine does not block 5-HT2 receptors, although discussed as a fundamental pathophysiologic cause, this mechanism does not adequately explain mirtazapine’s propensity to induce edema (Ng et al. 2003). Additionally, mirtazapine has a comparatively low affinity for H1-receptors and muscarinic acetylcholine receptors, which are also associated with drug-induced edema (Ng et al. 2003). Consequently, further studies are needed to elucidate the underlying pathomechanism.

The present study indicated that pregabalin carries a particularly high risk of causing severe edema (0.15%). However, this incidence is considerably lower than the findings of other research groups. Edema has been found to occur in 5.6–8.6% of patients treated with pregabalin [Toth (2014); Freynhagen et al. (2015); European Medicines Agency (2004)]. Baldwin and colleagues (2015) analyzed 13 clinical trials evaluating the efficacy and safety of pregabalin in generalized anxiety disorder and reported that the treatment with pregabalin therapy was discontinued by patients in 0.5% of cases due to peripheral edema. However, the overall incidence of pregabalin-induced edema was low (less than 3%). Elderly patients (Freynhagen et al. 2015) and females (Largeau et al. 2022) appear to be more susceptible to pregabalin-induced edema.

A study considering cases of edema under gabapentinoids reported to the French Pharmacovigilance Center suggests a mechanism of action similar to that of CCBs. Both drugs have a strong affinity for the alpha-1 subunit of voltage-dependent calcium channels resulting in a decreased myogenic tone and causing concentration-dependent vasodilation (Largeau et al. 2022). It remains unclear, whether the edema-causing properties of pregabalin are dose-dependent. While Calandre and colleagues (2016) report a dose–reponse relationship for edema, the 28 studies examined in the meta-analysis of Zaccara and colleagues (2011) did not suggest a dose-dependent effect. However, it must be mentioned that the results of the aforementioned studies encompass patients receiving pregabalin for various indications, including psychiatric and non-psychiatric conditions (except for Baldwin and colleagues 2015), such as neuropathic pain, fibromyalgia, and epilepsy. This diversity in patient populations may limit direct comparability of results. In our study, we did not observe a clear dose–response relationship. In fact, among the group of edema cases, the median dosages were lower than in the total monitored group.

Our study revealed that women were four times more likely to develop psychotropic drug-induced edema than men. The higher risk of edema in women has been previously reported in association with other drugs, such as CCBs (Semel et al. 2010). Several factors may contribute to this gender difference, including heightened body awareness in women (Messerli (2002); de la Sierra (2009)). Furthermore, venous insufficiency and associated venous stasis are more common in women than in men (Lohr and Bush 2013), which can favor the development of edema (Largeau et al. 2021).

Older age is associated with an increased risk of edema due to changes in lymphatic contractility, decreased pump efficiency, and a higher risk of microvascular disease and hyperpermeability (Largeau et al. 2021). Greil and colleagues investigated the incidence of ADRs under psychopharmacotherapy in relation to age. They compared psychotropic drug use and the occurrence of ADRs in hospitalized patients in Switzerland younger than 60 to those older than 60 years and found that psychotropic drug-induced edema was more common in older patients (Greil et al. 2013). Similar trends have been observed with other drug classes, such as CCBs (Fogari et al. 2000) and gabapentinoids (Semel et al. 2010). The result of the present study only partially confirm the relationship between higher age and drug-induced edema. While the incidence of psychotropic drug-induced edema is lowest in those younger than 30 years, it is higher in those 30–60 years of age than in those older than 60 years. However, Greil and colleagues did not find an age relationship for allergic skin reactions as ADR (Greil et al. 2013). Since an allergic genesis of edema has also been postulated (Chen and Chou 2004) and the exact mechanisms of drug-induced edema are not fully understood, this aspect should also be considered.

The occurrence of drug-induced edema is not necessarily limited to one trigger, but may be favored by a combination of concomitant conditions. The fact that diseases, such as diabetes, chronic venous insufficiency, or obesity, have a negative influence on the development of edema has already been shown [Ely et al. (2006); Wu et al. (2017)]. Within our study, almost half of the patients with drug-induced edema also suffered from at least one of these conditions, with obesity and arterial hypertension playing a particularly significant role. While hypertension was reported in 26 cases and congestive heart failure in four patients with severe edema, prescriptions of antihypertensive drugs were recorded in 40 cases in our study. The difference in these numbers may, in part, be attributed to the possible underreporting of comorbidities. In addition, certain classes of drugs, such as beta-blockers, have indications beyond hypertension and congestive heart failure, such as migraine prophylaxis and glaucoma treatment (Fumagalli et al. 2020). In hypertension, both the disease itself and its progression to congestive heart failure, as well as the treatment with drugs, such as CCBs, beta-blockers, or alpha-agonists, are associated with peripheral edema [Domenic (2003); Besharat et al. (2021)].

On the other hand, the use of ACE inhibitors, an ARB with CCB therapy, or thiazides appears to reduce the incidence of edema [Messerli (2002); Weir et al. (2001)]. However, the fact that discontinuation of imputed psychotropic drugs led to symptom relief in most cases supports the presumption that edema was primarily related to the use of psychotropic drugs rather than the antihypertensive drugs.

Among antidiabetic drugs, insulin and thiazolidinediones are known to cause edema (Sunder et al. 2003). In our study, these drugs played only a negligible role, as thiazolidinediones were not used at all and insulin was used in only one case. Metformin, however, was used in seven patients with drug-induced edema. Interestingly, metformin may reduce the risk of edema by decreasing capillary permeability (Valensi et al. 1995). In general, it is important to consider comorbidities and preexisting drug regimes when edema occurs during treatment with psychotropic drugs as these factors can contribute to the complexity of the condition and its management.

The favorable outcome observed in the majority of the severe edema cases in our study, with symptoms fully resolving in over 80% of cases, suggests that appropriate treatment measures, such as dose reduction or discontinuation of the triggering drug or the use of a diuretic, are effective treatment options. At the end of the observation period, symptoms remained unchanged in only three cases. Due to the multifactorial nature of edema, a precise medical history, clinical examination, and, if necessary, further diagnostic workup, should be performed (Trayes et al. 2013). In the treatment of drug-induced edema, it is recommended to discontinue or reduce the dose of the implicated drugs if possible [Trayes et al. (2013); Tamam et al. (2002)], as it was done in most of the cases in the present study. However, because dose-dependent effects are not consistently described for all drugs (e.g., pregabalin) [Calandre et al. (2016); Zaccara et al. (2011)], the efficacy of this measure in improving edema must be evaluated in each case.

The use of diuretics in the treatment of drug-induced edema can be effective in reducing fluid retention, but it’s essential to consider additional adverse effects associated with diuretic therapy. Read and colleagues investigated such a prescribing cascade in patients with gabapentinoid-induced edema in a cohort study and pointed out relevant diuretic-associated adverse effects, such as orthostasis, falls, urinary incontinence, and electrolyte imbalances (Read et al. 2021). This underscores the importance of a personalized and cautious approach to treatment, especially in older patients, who may already be at higher risk for developing edema as well as ADRs in general (Charlesworth et al. 2015) and are also more likely to be treated with diuretics (Read et al. 2021).

AMSP is a standardized pharmacovigilance program with structured methods of data reporting. The extensive 23-year observation period during which nearly half a million inpatients were monitored offers a unique opportunity to identify rare ADRs in a real-life setting. Due to the inpatient setting, AMSP gathers data on actual drug utilization and not only the prescription of psychotropic drugs as is often the case in outpatient-based studies. However, several limitations of the AMSP program must also be considered. As is common with pharmacovigilance programs, ADRs are often underreported. This may especially be the case for conditions such as edema, which might not always be recognized as drug-related. While AMSP has standardized methods for data reporting, variations in how different monitors assess and document ADRs across different hospitals can introduce inconsistencies in the data. Not all ADRs may come to the attention of drug monitors, and the precise documentation of ADRs may be time-consuming. Furthermore, AMSP only assesses severe ADRs in inpatients and therefore does not include ADRs occurring after discharge unless the patient is (re-)admitted due to the ADR. The identification of the specific drugs responsible for the ADR can be complicated by polypharmacy and underlying comorbidities. It can be challenging to determine whether an ADR is solely caused by a single drug or if it is the result of drug–drug or drug–disease interactions. Additionally, undisclosed or unrecognized comorbidities may also have contributed to the development of edema.

Psychotropic drug-induced edema may severely impact a patient’s overall well-being and therefore could reduce adherence to treatment or necessitate the use of additional drugs to manage the condition. Our study revealed that when considering individual drugs, pregabalin had the highest incidence of edema. Several factors, such as sex, comorbidities, age, and somatic medication, may increase the risk of edema, highlighting the importance of considering these factors when treating patients with psychotropic drugs. While most cases of drug-induced edema showed favorable outcomes and could be managed with therapeutic interventions, such as dose reduction and drug discontinuation, more severe cases may require a comprehensive diagnostic workup and treatment. Fortunately, appropriate therapeutic interventions can substantially alleviate the symptoms.