Bipolar dysfunction (BD) is a disabling situation characterised by episodes of mania or hypomania, alternating or co-occurring with despair (American Psychiatric Affiliation, 2013; GBD, 2019).
Analysis means that depressive signs are predominant in BD and will current better burden in comparison with elevated options (Judd et al., 2002; Judd et al., 2003; Miller et al., 2014). Nonetheless, the usage of antidepressants for bipolar despair is debatable, as their security and efficacy stay unsure (McGirr et al., 2016; Pacchiarotti et al., 2013; Sachs et al., 2007).
As highlighted in a Psychological Elf weblog put up by Prof Joseph Hayes, the Nationwide Institute for Well being and Care Excellence (NICE) 2014 pointers for BD (NICE, 2014) point out that fluoxetine could also be preferable to different antidepressants. The British Affiliation for Psychopharmacology 2016 pointers recommend that antidepressants in BD might be efficient, however solely together with temper stabilisers (Goodwin et al., 2016).
Proof means that the danger of mania could also be better for tricyclic antidepressants (TCA), in comparison with selective serotonin reuptake inhibitors (SSRIs) (Goodwin et al., 2016; Tondo et al., 2010). Though findings from randomised managed trials (RCTs) are conflicting, there may be some proof that extended remedy with antidepressants might worsen manic or hypomanic signs in BD (Ghaemi et al., 2021; McGirr et al., 2016; Yatham et al., 2023).
A latest goal trial emulation by Rohde et al. 2024, aimed to shed some gentle on the danger of antidepressant-induced mania in individuals with bipolar despair.
There isn’t any clear consensus on the usage of antidepressants for bipolar despair, however some proof suggests they might worsen manic signs.
Strategies
Rohde et al.’s (2024) examine employed a ‘goal trial emulation’ mannequin (Matthews et al., 2022), whereby they had been capable of leverage knowledge accrued by Danish nationwide registers whereas incorporating core traits of the gold customary in evidence-based drugs: the randomised managed trial (RCT).
In a goal trial emulation, pre-existing observational knowledge is compiled and manipulated such that the ideas that govern a conventional RCT are upheld: individuals are recognized, screened in line with rigorous standards after which the information is stratified as a proxy for randomisation. Authors assessed mania as psychiatric admission with a major analysis of a manic or hypomanic episode.
Outcomes
The ultimate examine cohort consisted of 979 sufferers with bipolar despair, 36.6% (n = 358) of whom acquired remedy with antidepressants. The intercourse and age traits had been comparable between the antidepressant and non-antidepressant teams.
Curiously, of these handled with antidepressants, solely 62.6% used them concurrently with temper stabilisers. Amongst sufferers within the antidepressant group, round 50.5% (n=181) acquired an SSRI, 14.3% (n=51) a TCA and 11.5% (n=41) a serotonin and norepinephrine reuptake inhibitors (SNRIs). The remaining 85 sufferers had been handled with one other kind of antidepressant.
Rohde et al (2024) declare that contemplating the impact measurement of a hazard ratio of 1.77 (based mostly on a meta-analysis by McGirr et al., 2016), their examine achieved energy of 90%.
- The absolutely adjusted fashions which included all the pattern, confirmed no statistically important associations between antidepressant remedy and mania or hypomania, (hazard fee ratio=1.08, 95% CI=0.72 to 1.61) (a hazard ratio of 1 signifies the shortage of an affiliation).
- Antidepressant remedy was not considerably related to threat of mania or hypomania
- amongst these handled with temper stabilisers (hazard fee ratio=1.16, 95% CI=0.63 to 2.13)
- or people who did not obtain a temper stabiliser (hazard fee ratio=1.16, 95% CI=0.65 to 2.07).
- Secondary analyses indicated that the danger of bipolar despair recurrence was not related to antidepressant use (hazard ratio=0.91, 95% CI=0.65 to 1.27).
These findings indicated that remedy with an antidepressant was not considerably related to the danger of mania.
Conclusions
This was a goal trial emulation which used observational knowledge from Danish well being registers to evaluate the danger of mania in bipolar despair following antidepressant use over a interval of 1 12 months.
Authors concluded: “findings recommend that the danger of antidepressant-induced mania is negligible” and highlighted the necessity for additional analysis. Nevertheless, proof from different research means that extended remedy with antidepressants is linked with elevated threat of manic or hypomanic signs in BD (McGirr et al., 2016; Yatham et al., 2023; Tondo et al., 2010).
Though the examine by Rohde and colleagues (2024) improved our understanding of the so-called “temper swap” following remedy with antidepressants in BD, given its methodological limitations and the conflicting findings from the literature, additional analysis on this subject is warranted.
Additional long-term RCTs are wanted to attract particular conclusions on the security of antidepressants for bipolar.
Strengths and limitations
Rohde et al.’s implementation of a goal trial emulation mannequin offered them with some notable methodological advantages:
- Giant pattern measurement: their use of Danish nationwide registers offered them with a remaining cohort of 979 – this, they observe, meant their examine was bigger than any of the earlier antidepressant trials with bipolar despair sufferers.
- Prolonged ‘follow-up’ interval: this examine adopted sufferers for a 12 months, except both readmission or dying occurred. This represents one of many longest follow-up intervals for a examine of this concern.
Nevertheless, regardless of the assorted upsides to their examine design, there stay quite a few limitations and disadvantages. In spite of everything, whereas goal trial emulations search to approximate the scientific rigour of RCTs by making use of their ideas to observational knowledge, they’re not an ideal substitute for correctly managed ‘dwell’ research.
- Restricted administration of individuals: Rohde et al. had been capable of assign individuals to situations, however couldn’t limit their course of remedy. Greater than 1 / 4 of these initially assigned to the non-antidepressant situation on this trial finally began a course of antidepressants.
- Restricted utility of findings: Rohde et al.’s knowledge didn’t facilitate distinctions between bipolar I and II issues. Which means their examine can not inform as as to if there’s a distinction in charges of antidepressant-induced [hypo]mania between the 2 varieties.
- Decreased generalisability: the eligibility standards for this examine excluded individuals who skilled an episode with out being hospitalised, thereby limiting the examine’s relevance to sufferers who’ve been admitted a minimum of as soon as.
This trial emulation sought a stability between the mixed advantages of RCTs and observational knowledge and their attendant drawbacks.
Implications for follow
The authors clarify how their findings point out that the danger of antidepressants inflicting mania in bipolar dysfunction sufferers is negligible, and that whereas frequent in sufferers handled with antidepressants, manic episodes are doubtlessly merely a consequence of the recurrent nature of the dysfunction and never a aspect impact of remedy. Furthermore, the outcomes of their emulation examine assist the notion that antidepressants don’t essentially trigger mania.
As knowledge continues to build up on this space, we might finally witness a shift in clinicians’ attitudes in direction of the prescription of antidepressants as remedy for bipolar despair, particularly within the short-term. Nevertheless, present pointers for bipolar dysfunction don’t advocate monotherapy of antidepressants (Goodwin et al 2016). At present, as famous by Rohde et al., clinicians are notably cautious when contemplating prescribing antidepressants for sufferers with bipolar dysfunction, given the prevailing view that there’s an elevated threat of mania. Rohde et al. recommend that this warning could also be mirrored of their knowledge, with their findings indicating a extra extreme medical course amongst sufferers that had been not handled with an antidepressant. This cohort, on common, noticed a better variety of hospital admissions, outpatient contacts and episodes of mania than these of their antidepressant-using counterparts.
Whereas the findings of Rohde et al. do serve to bolster a rising physique of proof towards the notion that antidepressants are essentially at fault for elevated charges of manic episodes, they don’t seem to be conclusive. That is due in no small half to the restrictions of the examine described beforehand. To this finish, we imagine that additional analysis is merited so as to absolutely perceive whether or not:
- individuals who chorus from taking antidepressants for the whole thing of a future examine (together with follow-up) fare higher or worse than these which might be prescribed with antidepressants during a trial;
- distinctions between bipolar I and II are additional mirrored by way of their response to antidepressant remedy; and
- the severity of manic signs is, on common, better amongst these taking antidepressants – no matter whether or not they have been or are hospitalised as a result of a bipolar episode.
As soon as these points are addressed, not solely will we all know with better confidence the general affect of antidepressant remedy throughout the context of bipolar dysfunction, however clinicians will likely be extra knowledgeable as as to if a given affected person might stand to profit from such a course of remedy, based mostly on their distinctive circumstances (e.g., kind of bipolar dysfunction and up to date symptom severity).
This examine provides to our understanding of the results of antidepressants for bipolar, however extra proof is required.
Assertion of pursuits
Paul Leeks declares no conflicts of curiosity. Michail Kalfas has acquired honoraria from Neurocentrx Pharma.
Hyperlinks
Main paper
Rohde C, Østergaard SD, Jefsen OH. (2024). A Nationwide Goal Trial Emulation Assessing the Danger of Antidepressant-Induced Mania Amongst Sufferers With Bipolar Despair. The American Journal of Psychiatry 181(7) 630–638. https://doi.org/10.1176/appi.ajp.20230477
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