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 higher 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 Mental Elf blog post 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 higher 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 might worsen manic or hypomanic signs in BD (Ghaemi et al., 2021; McGirr et al., 2016; Yatham et al., 2023).
A current goal trial emulation by Rohde et al. 2024, aimed to shed some mild on the danger of antidepressant-induced mania in folks with bipolar despair.
There is no such thing as a clear consensus on the usage of 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 have been capable of leverage information gathered 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 information is compiled and manipulated such that the rules that govern a conventional RCT are upheld: contributors are recognized, screened based on rigorous standards after which the information is stratified as a proxy for randomisation. Authors assessed mania as psychiatric admission with a main analysis 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 have been comparable between the antidepressant and non-antidepressant teams.
Apparently, 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 have been handled with one other sort of antidepressant.
Rohde et al (2024) declare that contemplating the impact dimension of a hazard ratio of 1.77 (primarily based on a meta-analysis by McGirr et al., 2016), their research achieved energy of 90%.
- The totally adjusted fashions which included your 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 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 information 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 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 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:
- Massive pattern dimension: their use of Danish nationwide registers offered them with a last cohort of 979 – this, they be aware, 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 loss of life occurred. This represents one of many longest follow-up durations for a research of this situation.
Nevertheless, regardless of the assorted upsides to their research design, there stay quite a few limitations and downsides. In spite of everything, whereas goal trial emulations search to approximate the scientific rigour of RCTs by making use of their rules to observational information, they’re not an ideal substitute for correctly managed ‘stay’ research.
- Restricted administration of contributors: Rohde et al. have been capable of assign contributors 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 finally began a course of antidepressants.
- Restricted utility of findings: Rohde et al.’s information didn’t facilitate distinctions between bipolar I and II issues. Because of this their research can not inform as as to whether there’s a distinction in charges of antidepressant-induced [hypo]mania between the 2 varieties.
- Lowered generalisability: the eligibility standards for this research excluded contributors who skilled an episode with out being hospitalised, thereby limiting the research’s relevance to sufferers who’ve been admitted a minimum of as soon as.
This trial emulation sought a steadiness between the mixed advantages of RCTs and observational information and their attendant drawbacks.
Implications for apply
The authors clarify how their findings point out that the danger of antidepressants inflicting mania in bipolar dysfunction sufferers is negligible, and that whereas widespread in sufferers handled with antidepressants, manic episodes are probably merely a consequence of the recurrent nature of the dysfunction and never a aspect impact of remedy. Furthermore, the outcomes of their emulation research assist the notion that antidepressants don’t essentially trigger mania.
As information continues to build up on this space, we might finally witness a shift in clinicians’ attitudes in the direction of the prescription of antidepressants as remedy for bipolar despair, particularly within the short-term. Nevertheless, present pointers for bipolar dysfunction don’t suggest monotherapy of antidepressants (Goodwin et al 2016). At the moment, 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 information, with their findings indicating a extra extreme medical course amongst sufferers that have 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 aren’t conclusive. That is due in no small half to the constraints of the research described beforehand. To this finish, we imagine that additional analysis is merited with the intention to totally perceive whether or not:
- contributors who chorus from taking antidepressants for the whole thing 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 by way of their response to antidepressant remedy; and
- the severity of manic signs is, on common, higher amongst these taking antidepressants – no matter whether or not they have been or are hospitalised as a consequence of a bipolar episode.
As soon as these points are addressed, not solely will we all know with higher confidence the general affect of antidepressant remedy inside the context of bipolar dysfunction, however clinicians will likely be extra knowledgeable as as to whether a given affected person might stand to learn from such a course of remedy, primarily based on their distinctive circumstances (e.g., sort 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
Major 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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