There are known risks of suicidal ideation with selective serotonin reuptake inhibitors (SSRIs), and the risks of some non-psychotropic drugs, as a result of their complex pharmacokinetics, are becoming increasingly clear. This article examines fluoroquinolones and the risk of the serious adverse effect of suicidal ideation in patients taking them.
Fluoroquinolones include levofloxacin (Levaquin), ciprofloxacin (Cipro), ciprofloxacin extended-release tablets, moxifloxacin (Avelox), ofloxacin, gemifloxacin (Factive) and delafloxacin (Baxdela). There are also over 60 generic versions of these medications.
Suicide-related hospital admissions
A study published late last year in the British Medical Journal (Wang et al, 2022) evaluated the association between the initiation of fluoroquinolones and admissions to hospitals or emergency departments due to onset of suicidal ideation. The study concluded that an association was not apparent between fluoroquinolones and increased risk of hospital admissions or emergency department visits due to suicidal ideation when compared with such admissions for patients taking trimethoprim-sulfamethoxazole or azithromycin.
However, the study did not confirm that there is no risk in suicidal ideation in general. Many people who experience suicidal thoughts might not act on them and might never visit a doctor for this. The study only looked at data for hospital admissions and the results are therefore not generalisable to all individuals taking fluoroquinolones.
The authors noted that there are other known risks associated with these drugs, as they cause gastrointestinal, dermatological, cardiovascular, and nervous system side effects, which are well established and non-disputed (Wang et al, 2022). The researchers emphasised that a range of mental health side effects have been reported while using this type of anti-infective agent, with attempted or completed suicides being reported following initiation of fluoroquinolones, with such incidents being reported in people with no previous psychiatric history (Wang et al, 2022). It is for this reason that the FDA advised that all fluoroquinolones be labelled with a boxed warning containing the risks of adverse events, including that of suicidal thoughts.
Wang et al (2022) explored the potential mechanisms that may cause central nervous system events, including suicidality. The researchers noted that fluoroquinolones have a very similar structure to g-aminobutyric acid (GABA) agonists, and therefore the drugs may bind to brain GABA receptors, leading to neurotoxicity. Fluoroquinolones may also stimulate the excitatory N-methyl-d-aspartate (NMDA) and adenosine receptors, which the authors highlight could manifest in observable CNS symptoms. Fluoroquinolones may also cause a reduction in serotonin levels, oxidative stress and lowered antioxidant levels, as well as alterations of various microRNAs—all of which may cause neuropsychiatric adverse effects (Wang et al, 2022).
In the same analysis, Wang et al then evaluated the risk of hospital admission and emergency department visits for suicidal behaviours in a large cohort of people. Despite the lack of a significant association in their particular analysis, these results conflict with other studies, which did find a significant association between suicidal thoughts/risk and fluoroquinolone initiation (e.g. Labay-Kamara et al, 2012; Behera et al, 2014).
The study by Wang et al (2022) is limited by its use of administrative claims data, which lacks information about patient characteristics, such as socioeconomic status and lifestyle factors, which may affect the risk of suicidality, if they differ between drug groups. The primary outcome definition was also based on hospital admissions and emergency department visits with billed ICD-9 codes; thus, the observed absolute risks may underestimate the true incidence of suicidality in antibiotic users.
Quinolone-related suicidal behaviour
In 2016, Samyde et al (2016) confirmed the risk of suicidality while taking fluoroquinolones after investigating risk by analysing the World Health Organization's (WHO) global Individual Case Safety Report (ICSR) database – a global adverse drug reactions database called VigiBase. Disproportionality analyses were carried out to investigate the association between reports of suicidal behaviour and exposure to quinolones, compared to other antibiotics.
The researchers examined the database from December 1970 to January 2015, and identified 992 097 antibiotic-related adverse reactions. Of these, 608 were quinolone-related suicidal behaviours, with a worrying confirmation that 97 cases of these were completed suicides. There was also an increased reporting of suicidal behaviour when compared with the use of other antibiotics. The candidate mechanisms for quinolone-induced suicidal behaviours include GABAA antagonism, activation of NMDA receptors, decreased serotonin levels, oxidative stress, and altered microRNA expressions (Samyde et al, 2016).
The team reported that there was a strong safety signal that indicated an increased risk of suicidal behaviours linked to quinolone use. The plausible psychopharmacological mechanisms may underlie such an association, the researchers reported. Therefore, with the mechanisms being entirely plausible, it is very concerning and quite valid that the suggestion linking suicide to quinolone use is true and much more a problem than anyone could have realised.
New safety labelling
In 2016, the FDA made enhanced warnings for disabling and potentially permanent side effects involving the tendons, muscles, joints, nerves and the central nervous system. Due to the risk of such serious side effects outweighing the benefits for patients with acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis and uncomplicated urinary tract infections, the FDA concluded that fluoroquinolones should be reserved for use in patients with these conditions who have no alternative treatment options.
More recently, after a review of medical literature and advice warning of increased risk to the mental health of people taking this type of anti-infective agent, the FDA released an update in 2018 regarding adverse reactions to fluoroquinolones. In particular, it noted the risks to mental health, as well as to hypoglycaemia. New safety labeling changes were advised in order to strengthen warnings about mental health risks and serious blood sugar disturbances, with the aim of ensuring consistent warnings across labelling for all oral or injectable forms of the drug group.
The changes to labelling ensured that mental health side effects are listed separately from other central nervous system. The FDA (2018) included the following mental health side effects in the labeling:
- Disturbances in attention
- Dsorientation
- Agitation
- Nervousness
- Memory impairment
- Delirium.
Since the initial warnings, similar warnings have been made by the UK government including by the Medicines Healthcare products Regulatory Agency (MHRA) (2019), which covered physical and psychiatric symptoms. They highlighted the importance of stopping the medication as soon as any known serious side effects occur. In addition to psychiatric effects, other serious effects reported include conditions such as tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and impaired hearing, vision, taste, and smell. Most commonly, musculoskeletal effects included tendonitis and tendon rupture and the most common nervous system effect reported was paraesthesia (MHRA, 2019).
Conclusion
The research, in combination with FDA warnings, appear to indicate a link between suicidal ideation (as well as suicide) and fluoroquinolone use. There are also plausible reasons for why the study by Wang et al (2022) may not have fully reflected true risk that is generalisable to the rest of the population, given that it was based on administrative data from hospital wards and emergency departments only. As the FDA (2018) suggests, the use of such antibiotics should perhaps be avoided unless there is no alternative, for patients with bacterial sinusitis due to the risks outweighing the benefits.
In any case of an adverse event, it is important to discontinue the medication and seek an alternative as appropriate, liaising with the primary care physician in charge of that patient. The government's Yellow Card reporting site at https://yellowcard.mhra.gov.uk/ facilitates detailing of any adverse effects noted from a particular medication.
It is important that, where a patient presents with suicidal ideation or intent, they are believed, listened to, protected from harm and helped as much as possible, following the necessary procedures to keep them safe (National Institute for Health and Care Excellence (NICE), 2020).