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 larger burden in comparison with elevated options (Judd et al., 2002; Judd et al., 2003; Miller et al., 2014). Nonetheless, 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 Mental Elf blog post by Prof Joseph Hayes, the Nationwide Institute for Well being and Care Excellence (NICE) 2014 tips for BD (NICE, 2014) point out that fluoxetine could also be preferable to different antidepressants. The British Affiliation for Psychopharmacology 2016 tips counsel that antidepressants in BD could be efficient, however solely together with temper stabilisers (Goodwin et al., 2016).
Proof means that the danger of mania could also be larger 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 therapy with antidepressants could 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 individuals with bipolar despair.
There is no such thing as a clear consensus on using antidepressants for bipolar despair, however some proof suggests they could worsen manic signs.
Strategies
Rohde et al.’s (2024) examine employed a ‘goal trial emulation’ mannequin (Matthews et al., 2022), whereby they had been in a position to leverage information amassed by Danish nationwide registers whereas incorporating core traits of the gold normal 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 standard RCT are upheld: contributors are recognized, screened in keeping with rigorous standards after which the info is stratified as a proxy for randomisation. Authors assessed mania as psychiatric admission with a major prognosis 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 therapy with antidepressants. The intercourse and age traits had 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 had been handled with one other sort of antidepressant.
Rohde et al (2024) declare that contemplating the impact measurement of a hazard ratio of 1.77 (primarily based on a meta-analysis by McGirr et al., 2016), their examine achieved energy of 90%.
- The absolutely adjusted fashions which included the complete pattern, confirmed no statistically vital associations between antidepressant therapy and mania or hypomania, (hazard price ratio=1.08, 95% CI=0.72 to 1.61) (a hazard ratio of 1 signifies the shortage of an affiliation).
- Antidepressant therapy was not considerably related to danger of mania or hypomania
- amongst these handled with temper stabilisers (hazard price ratio=1.16, 95% CI=0.63 to 2.13)
- or people who did not obtain a temper stabiliser (hazard price 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 therapy 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 yr.
Authors concluded: “findings counsel that the danger of antidepressant-induced mania is negligible” and highlighted the necessity for additional analysis. Nonetheless, proof from different research means that extended therapy 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 examine by Rohde and colleagues (2024) improved our understanding of the so-called “temper change” following therapy 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 supplied them with some notable methodological advantages:
- Giant pattern measurement: their use of Danish nationwide registers supplied them with a last cohort of 979 – this, they notice, 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 yr, except both readmission or loss of life occurred. This represents one of many longest follow-up intervals for a examine of this concern.
Nonetheless, regardless of the varied upsides to their examine design, there stay quite a few limitations and downsides. In any case, 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 ‘dwell’ research.
- Restricted administration of contributors: Rohde et al. had been in a position to assign contributors to situations, however couldn’t prohibit their course of therapy. 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. Which means that 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 contributors who skilled an episode with out being hospitalised, thereby limiting the examine’s relevance to sufferers who’ve been admitted not less than 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 frequent in sufferers handled with antidepressants, manic episodes are probably merely a consequence of the recurrent nature of the dysfunction and never a facet impact of therapy. Furthermore, the outcomes of their emulation examine help the notion that antidepressants don’t essentially trigger mania.
As information continues to build up on this space, we could finally witness a shift in clinicians’ attitudes in direction of the prescription of antidepressants as therapy for bipolar despair, particularly within the short-term. Nonetheless, present tips for bipolar dysfunction don’t suggest monotherapy of antidepressants (Goodwin et al 2016). Presently, as famous by Rohde et al., clinicians are significantly 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. counsel that this warning could also be mirrored of their information, 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 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 examine described beforehand. To this finish, we consider that additional analysis is merited with a view to absolutely perceive whether or not:
- contributors who chorus from taking antidepressants for everything of a future examine (together with follow-up) fare higher or worse than these which might be prescribed with antidepressants in the course of a trial;
- distinctions between bipolar I and II are additional mirrored by way of their response to antidepressant therapy; and
- the severity of manic signs is, on common, larger amongst these taking antidepressants – no matter whether or not they have been or are hospitalised on account of a bipolar episode.
As soon as these points are addressed, not solely will we all know with larger confidence the general affect of antidepressant therapy throughout the context of bipolar dysfunction, however clinicians will likely be extra knowledgeable as as to if a given affected person might stand to learn from such a course of therapy, primarily based on their distinctive circumstances (e.g., sort 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
Major 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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