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). However, using 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 could be efficient, however solely together with temper stabilisers (Goodwin et al., 2016).
Proof means that the chance 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’s some proof that extended remedy with antidepressants could 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 chance of antidepressant-induced mania in folks with bipolar despair.
There isn’t any clear consensus on using antidepressants for bipolar despair, however some proof suggests they could worsen manic signs.
Strategies
Rohde et al.’s (2024) research employed a ‘goal trial emulation’ mannequin (Matthews et al., 2022), whereby they had been in a position to 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 standard RCT are upheld: individuals are recognized, screened based on rigorous standards after which the info is stratified as a proxy for randomisation. Authors assessed mania as psychiatric admission with a main prognosis of a manic or hypomanic episode.
Outcomes
The ultimate research 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 research achieved energy of 90%.
- The totally adjusted fashions which included the complete pattern, confirmed no statistically important associations between antidepressant remedy and mania or hypomania, (hazard charge ratio=1.08, 95% CI=0.72 to 1.61) (a hazard ratio of 1 signifies the dearth of an affiliation).
- Antidepressant remedy was not considerably related to danger of mania or hypomania
- amongst these handled with temper stabilisers (hazard charge ratio=1.16, 95% CI=0.63 to 2.13)
- or people who did not obtain a temper stabiliser (hazard charge ratio=1.16, 95% CI=0.65 to 2.07).
- Secondary analyses indicated that the chance 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 chance of mania.
Conclusions
This was a goal trial emulation which used observational knowledge from Danish well being registers to evaluate the chance of mania in bipolar despair following antidepressant use over a interval of 1 12 months.
Authors concluded: “findings recommend that the chance of antidepressant-induced mania is negligible” and highlighted the necessity for additional analysis. Nonetheless, proof from different research means that extended remedy with antidepressants is linked with elevated danger of manic or hypomanic signs in BD (McGirr et al., 2016; Yatham et al., 2023; Tondo et al., 2010).
Though the research 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 matter is warranted.
Additional long-term RCTs are wanted to attract particular conclusions on the protection 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 research was bigger than any of the earlier antidepressant trials with bipolar despair sufferers.
- Prolonged ‘follow-up’ interval: this research adopted sufferers for a 12 months, except both readmission or demise occurred. This represents one of many longest follow-up intervals for a research of this situation.
Nonetheless, regardless of the varied upsides to their research design, there stay quite a few limitations and disadvantages. In any case, 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 ‘stay’ research.
- Restricted administration of individuals: Rohde et al. had been in a position to assign individuals to situations, however couldn’t prohibit their course of remedy. Greater than 1 / 4 of these initially assigned to the non-antidepressant situation on this trial ultimately began a course of antidepressants.
- Restricted utility of findings: Rohde et al.’s knowledge didn’t facilitate distinctions between bipolar I and II problems. Because of this their research can’t inform as as to whether there’s a distinction in charges of antidepressant-induced [hypo]mania between the 2 sorts.
- Diminished generalisability: the eligibility standards for this research excluded individuals who skilled an episode with out being hospitalised, thereby limiting the research’s relevance to sufferers who’ve been admitted at the very least as soon as.
This trial emulation sought a steadiness between the mixed advantages of RCTs and observational knowledge and their attendant drawbacks.
Implications for observe
The authors clarify how their findings point out that the chance 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 facet impact of remedy. Furthermore, the outcomes of their emulation research help the notion that antidepressants don’t essentially trigger mania.
As knowledge continues to build up on this space, we could ultimately witness a shift in clinicians’ attitudes in the direction of the prescription of antidepressants as remedy for bipolar despair, particularly within the short-term. Nonetheless, present pointers for bipolar dysfunction don’t suggest monotherapy of antidepressants (Goodwin et al 2016). Presently, 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 danger of mania. Rohde et al. recommend that this warning could also be mirrored of their knowledge, with their findings indicating a extra extreme scientific course amongst sufferers that had been not handled with an antidepressant. This cohort, on common, noticed the next 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 in opposition to the notion that antidepressants are essentially at fault for elevated charges of manic episodes, they aren’t conclusive. That is due in no small half to the restrictions of the research described beforehand. To this finish, we imagine that additional analysis is merited to be able to totally perceive whether or not:
- individuals who chorus from taking antidepressants for the whole lot of a future research (together with follow-up) fare higher or worse than these which might be prescribed with antidepressants all through a trial;
- distinctions between bipolar I and II are additional mirrored when it comes to 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 attributable to a bipolar episode.
As soon as these points are addressed, not solely will we all know with better confidence the general impression of antidepressant remedy throughout the context of bipolar dysfunction, however clinicians can be extra knowledgeable as as to whether a given affected person may 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 research 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 Threat 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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