Antibiomania: An update

Abstract

Background

Antibiomania, whereby an antibiotic induces a manic/hypomanic episode in those with or without a pre-existing bipolar condition, is a little-known phenomenon, diagnostically elusive, may be more prevalent than recognised and thus warrants the current overview.

Method

Representative studies and clinical observations are noted.

Results

Several mechanistic issues are considered but with a weighting to the antibiotic causing gut dysbiosis and so activating gut-brain axis pathways that may induce manic/hypomanic episodes.

Conclusion

Future studies should seek to determine the prevalence of antibiomania and whether differing antibiotics effect differential risks, while clinicians identifying such a potential linkage in a patient who has developed a first episode or recurrence of a manic/hypomanic episode should consider nuanced pre-emptive and management strategies in such instances.

It is well recognized that certain drugs and medications can trigger manic/hypomanic episodes – with DSM-5 listing two exemplar drugs of abuse (i.e. cocaine and amphetamine) as well as four exemplar medications (i.e. steroids, L-dopa, antidepressants and stimulants). The potential contribution of antibiotics as having triggering propensities may have been underestimated as antibiotic use is common, thus the capacity of patients and managing psychiatrists to recognise a causal sequence is low.

The first author has assessed several individuals who have experienced the onset of an initial manic episode late in life (including some with no family history of a bipolar condition) and who have been unable to nominate any precipitating stressor other than exposure to antibiotics shortly prior to their episode – but with no causal process speculated by them. A more common sequence (but again rare) is for some patients who have an established bipolar disorder noting that some of their episodes appear to follow antibiotic exposure. ¹ Such reporting may capture a valid phenomenon or reflect the post hoc ergo propter hoc phenomenon in play. Intrigued by the possibility that a causal process may be operative, a literature review was undertaken into what has been described as ‘antibiomania’ and with representative findings outlined.

Psychiatric effects of antibiotics such as penicillin have been reported as early as 1948 ² and resulted in the introduction of Hoigne’s syndrome, characterised by a number of physical symptoms but including psychosis. The term ‘antibiomania’ was later introduced by Abouesh et al. ³ who identified and reviewed 21 literature case reports, as well as 82 cases from World Health Organization (WHO) reports and an unspecified number from the US Food and Drug Administration (FDA).

In overviewing representative literature, we first consider three illustrative case reports. Honzak et al. ⁴ described antibiomania in a 55-year-old woman who developed a severe manic episode after two 500 mg doses of clarithyromycin. AlShakori et al. ⁵ reported on a 74-year-old woman with established bipolar disorder and who experienced a manic episode after several antibiotics (principally metronidazole) were prescribed to treat a perforated gallbladder. Following discontinuation of those antibiotics she showed ‘complete resolution of manic symptoms’. Meszaros et al. ⁶ described the occurrence of a brief manic episode in a 50-year-old man with no psychiatric history shortly after receiving amoxicillin-clavulanic acid and (later) clarithromycin for pneumonia. When the latter was ceased his manic episode ameliorated twelve hours later but when the amoxicillin-clavulanic acid antibiotic was reintroduced his psychiatric symptoms reemerged only to resolve again 1 week after that drug was ceased. Moving beyond case reports, Yolken et al. ⁷ undertook a formal quantitative retrospective study. Their sample included 234 patients hospitalised for acute mania and 555 controls, with the rate of antimicrobial prescriptions (defined as ‘exposure within 3 days of ascertainment’) being higher in those with mania (7.7% vs 1.3%) and which they described as quantifying a ‘substantially increased rate’. Lastly, Lambrichts et al. ⁸ undertook a systematic review of manic/hypomanic episodes being diagnosed in close temporal relationship with an antibiotic being prescribed. They identified 47 cases involving 12 differing anti-bacterial agents – with antitubercular agents, macrolides and quinolones being the most over-represented.

Mechanistic issues have generally been considered broadly^9–11 and include the possibility that infection in and of itself might be an aetiological factor in some instance, ¹² but with distinct consistency in implicating antibiotics as causing gut dysbiosis and, in turn, a manic/hypomanic episode. Gut dysbiosis can reflect (i) loss of beneficial bacteria, (ii) overgrowth of potentially pathological bacteria and (iii) loss of overall bacterial diversity.

Associations between antibiotics and gut dysbiosis has long been recognized in relation to the bacterium Clostridoides difficile (C. diff). C. difficile infection (CDI) commonly follows the use of antibiotics which, by their killing of beneficial bacteria, allow C. diff to colonise and multiply, with the subsequent gut inflammation (pseudomembranous colitis) being deadly for many – but also showing a distinct response to faecal microbiota transplantation or FMT. ¹ Multiple antibiotics such as clindamycin, ciprofloxacin, amoxicillin, clarithromycin, cefprozil, imipenem and colistin have been reported as impactful to the microbiome. ¹³

The human gut microbiome is a dynamic collection of bacteria, viruses, fungi, archaea and other microbes which contribute to the gut microbiota (an ecosystem maintaining a symbiotic relationship with their host). Ramirez et al. ¹⁰ noted that early exposure to antibiotics in childhood can lead to a number of gastrointestinal, immunological and neurocognitive conditions. A systematic review of antibiotic-induced changes in the human gut microbiota for the most commonly prescribed antibiotics in the UK was reported by Elvers et al. ¹⁴ and quantified 31 articles identifying antibiotics as causing rapid and lower levels of bacterial diversity and changes in relative abundances.

The gut has its own (enteric) nervous system involving a web of sensory and motor neurons that lie throughout the length of the gastrointestinal tract and this has been termed the ‘second brain’. It is a bidirectional system communicating in a bottom-up manner (‘the gut-brain axis’) or a ‘top-down manner (the ‘brain-gut axis’). Bottom-up signalling occurs via gut microbes, whereby microbes generate multiple chemicals that are sent to the ‘main brain’ via the vagus nerve, sympathetic and parasympathetic nerves and humoral pathways (involving hormones, cytokines and neuropeptides).

Ortega et al. ¹⁵ considered disruption in the gut-brain axis as contributing to the pathogenesis of bipolar disorder. They noted that gut microbiota composition is different in those with a bipolar disorder, reflected by reduced microbial diversity and differing relative abundance of bacterial phyla or taxa. Further, that those with a bipolar disorder have a higher level of intestinal epithelium disruption, so accounting for the greater incidence of irritable bowel and celiac disease in those with the condition. Gut dysbiosis leads to dysfunction in mucosal barrier function and a greater risk of proinflammatory states via upregulation of inflammatory cytokines, with Hamdani and colleagues ¹⁶ detailing how inflammatory cytokines can cross the blood brain barrier. The gut microbiota is a producer and modulator of several neurotransmitters including dopamine, norepinephrine, serotonin and gamma butyric acid (GABA) and thus gut dysbiosis may impact these neurotransmitters so as to initiate mood changes (including manic/hypomanic episodes) via the gut-brain axis. Importantly, Ortega et al. ¹⁴ noted that tetracyclic antibiotics (especially minocycline) have been shown as beneficial in managing bipolar depression. While not formally supported in systemic reviews, their observation suggests that the risk of antibiomania could vary considerably in relation to differing classes of antibiotics.

A high fat, low fibre Western-style diet is recognised as contributing to microbiome dysbiosis. Kennedy et al. ¹⁷ noted that a western diet can impair microbiome resilience to antibiotic treatments. Their study compared mice receiving either a low fat, high fibre diet (RC or regular chow) or a western diet (WD) for 4 weeks and then given a triple antibiotic cocktail. Resilience of the gut microbiome was more severely compromised by mice receiving the WD while only the RC-receiving mice underwent a rapid recovery. While they concluded that specific dietary interventions are ‘at a minimum’ an essential prerequisite for effective FMT, their literature review and study raise the possibility that, while gut dysbiosis may predispose to antibiomania, any such predisposition may have been generated by poor diet.

We suggest that antibiomania has been minimally researched and commonly risks being identified due to links between antibiotic exposure and a manic/hypomanic episode not being recognised by patients and thus going unreported to their managing clinician.

Future research studies should assess large samples of manic/hypomanic patients and determine the rate of any antibiotic exposure prior to the episode – including the antibiotic type to establish whether differing antibiotic types confer differential risks. For those so reporting, investigations should determine whether such episodes occurred in those (i) who had never previously experienced a manic/hypomanic episode, (ii) who had an established bipolar disorder but with it being quiescent (reflecting medication or other treatment modalities) or (iii) those who had a manic/hypomanic episode that was consistent with such episodes in preceding months. Findings would allow prevalence estimates to be derived, differential risks effected by differing antibiotic types quantified, and both the degree to which antibiotics might induce manic/hypomanic episodes in those who had never experienced such states as well as acting as episode triggers in those with an established bipolar disorder. Further research might establish whether those experiencing such a phenomenon had risk factors in play – especially gut dysbiosis and a western diet – and how such risks might be identified (clinically and/or by specific investigations).

Awareness of the phenomenon should encourage clinicians to include inquiring into any antibiotic exposure in those experiencing a new manic/hypomanic episode and, if identified, making the patient aware of a possible causal sequence and the possible need to avoid certain antibiotic types in the future.