Bipolar dysfunction presents a novel problem for sufferers and clinicians in medication, because it entails managing two fully totally different shows of the identical sickness, each when it comes to therapy and stopping relapse. Completely different therapy choices are additionally not equally efficient in both treating or stopping episodes of mania or melancholy.
Subsequently, within the first episode of mania in bipolar dysfunction, the query clinicians face shouldn’t be solely “how can I deal with this particular person and get them higher as shortly as potential?”, but additionally the right way to forestall future relapses. Tips similar to NICE (NICE, 2014) and British Affiliation of Psychopharmacology (Goodwin et al 2016) recommend utilizing a second-generation antipsychotic (SGA) as a primary choice and including a temper stabiliser if this isn’t efficient. For sufferers who do reply effectively with SGAs and get well, clinicians and sufferers are confronted with a call concerning long-term therapy for relapse prevention: do I keep on with the present antipsychotic remedy which has led to restoration, or do I change or add a temper stabiliser for relapse prevention?
As SGAs are additionally an choice for relapse prevention, it appears many are selecting to ‘stick’, reasonably than threat a change with new remedy with unknown efficacy and negative effects from a person perspective. As earlier elves have famous, the usage of lithium is declining (Edward & Ahmed 2019) although it stays the only remedy in stopping depressive relapses in bipolar dysfunction (Swiffen 2025).
The latest paper by Szmulewicz et al (2026) used observational information to match the danger of relapse between these on temper stabiliser monotherapy, SGA monotherapy and mixture remedy of a temper stabiliser and SGA.
Strategies
The researchers used information from digital well being data of sufferers handled inside first episode psychosis providers and explicitly emulated a ‘goal trial’, i.e. said how a hypothetical randomised managed trial (RCT) would reply their analysis query.
On this case, the goal trial was assessing whether or not temper stabilisers alone, SGAs alone or a mix of each have been higher at stopping relapse (outlined as hospitalisation or emergency division attendance on account of any psychiatric motive) in sufferers with bipolar dysfunction who had been handled for mania with psychotic signs. Members have been aged over 16 years have been included from a number of first episode psychosis cohorts in North America, Chile and Spain. Sufferers have been included in the event that they hadn’t been taking antipsychotics or temper stabilisers over the earlier 3 months and have been categorised as being began on both SGAs (Olanzapine, Risperidone, Aripiprazole or Quetiapine), temper stabilisers (Lithium or Valproic Acid) or mixture remedy.
The examine adopted members as much as 2 years, or till relapse or loss to observe up. In addition to general relapse they checked out manic/combined relapse, and depressive relapse/suicide-related occasion as secondary outcomes. Over the two-year interval, particular person members might be eligible for a number of “trials” e.g. in the event that they have been on a temper stabiliser, then discontinued for greater than 3 months, after which commenced an antipsychotic.
The examine used each intention-to-treat (based on assigned therapy) and per protocol (based on adherence to therapy) analyses. Sensitivity analyses have been carried out to analyse a spread of various potential situations that would have affected the outcomes.
Outcomes
There have been 371 eligible members with first episode psychotic mania that corresponded to 465 therapy initiations (as some members contributed multiple “trial” in the course of the observe up). There have been 112 temper stabiliser monotherapy initiations (in 79 particular person sufferers), 167 second-generation antipsychotic monotherapy initiations (in 108 particular person sufferers), and 186 mixture remedy initiations (in 184 particular person sufferers).
The median observe up was 19.8 months and throughout the entire cohort 42% had a relapse, 35% have been misplaced to observe up and 4% had a change of prognosis.
After adjusting for baseline variations (together with demographics, baseline severity, substance use dysfunction, earlier episodes or admissions, earlier remedy use) the 2-year threat of relapse was:
- 42.3% for temper stabiliser monotherapy,
- 49.5% for SGA monotherapy and
- 42.2% for mixture remedy.
Head-to-head comparisons of confirmed a threat discount of -7.3% (-15·8 to -1·4) for temper stabilisers in comparison with SGA monotherapy, and -7.4% (-16·0 to -2·1) for mixture remedy in contrast with SGA monotherapy. Basically which means that the danger of relapse was very comparable between temper stabiliser monotherapy and mixture teams, which have been each about 7 share factors decrease than the SGA monotherapy group.
The outcomes have been comparable within the per-protocol evaluation which took into consideration therapy adherence. After adjusting for related confounders, the 2-year threat of relapse was 38·9% for temper stabiliser monotherapy, 46·8% for SGA monotherapy and 38·4% for mixture remedy. Head-to-head comparisons confirmed a -7·9% (-13·9 to 0·5) threat discount for temper stabilisers in comparison with SGA monotherapy, and -8·4% (-15·4 to -0·8) for mixture remedy in contrast with SGA monotherapy. These outcomes have been just like the intention-to-treat evaluation, although the arrogance intervals evaluating temper stabilisers to SGA monotherapy included zero, which suggests a much less important distinction between these teams.
In secondary evaluation the danger of manic or combined relapses was very comparable throughout teams, however the threat of depressive relapse was decrease in both the temper stabiliser monotherapy -5·2% (-11·1 to -0·1) or mixture remedy -7·0% (-12·1 to -1·9) teams in comparison with SGA monotherapy.
Conclusions
Subsequently, relapse charges have been decrease in these receiving temper stabilisers alone or together with antipsychotics, in comparison with SGAs alone. This means that in first episode mania with psychosis, a therapy technique ought to embrace a temper stabiliser to forestall relapse, both alone or together with an SGA.
Strengths and limitations
This cohort examine which emulated a ‘goal trial’ is a well-designed, vital examine which contributes to our understanding of how remedies might cut back relapse following first episode psychotic mania. The authors acknowledge that the perfect examine to reply this query can be an precise RCT (versus an emulation of 1), however there are sensible difficulties when it comes to the set-up, retention and funding for these. The authors have explicitly outlined the goal trial, used sturdy evaluation to account for quite a lot of potential confounders and sensitivity evaluation of a spread of different situations, which provides additional weight to their findings.
Nonetheless, a problem with all observational research is the danger of uncontrolled confounding when a variable that influences each the publicity and the end result is left unmeasured or unadjusted. Right here there might have been elements that would have affected the selection of therapy and have been linked to the end result, regardless of changes within the evaluation. There was larger baseline severity within the group began on SGA monotherapy, and in addition the next proportion of antidepressants prescribed on this group, although these have been adjusted for within the evaluation. The authors acknowledge different potential unmeasured confounders, similar to persona traits, household historical past, in addition to threat profile which might have affected therapy selections and outcomes. That stated, the examine design evaluating three teams provides some additional weight to their findings, as logically chances are you’ll count on these with better threat of relapse or poor preliminary response to be on mixture remedy, which had comparable outcomes to the temper stabiliser group, however considerably decrease relapse charges than the SGA monotherapy group.
It’s price contemplating that drugs used within the examine have been grouped as ‘temper stabilisers’ or ‘SGAs’ on account of pattern dimension issues. Lithium was essentially the most generally used temper stabiliser and the SGAs used have been Olanzapine, Risperidone, Aripiprazole and Quetiapine, with Olanzapine and Risperidone used most ceaselessly. There may be proof of variations amongst antipsychotics in stopping depressive relapses with Quetiapine exhibiting higher proof in comparison with Risperidone and Aripiprazole (Kishi et al 2021), which might have affected the outcomes.
Lastly, the examine didn’t assess hostile results of medicines or explicitly report discontinuation on account of hostile results. Uncomfortable side effects are a serious consideration within the selection of prescribing long-term remedies for relapse prevention and subsequently make up a substantial a part of the session and decision-making course of in scientific apply.
Implications for apply
This examine demonstrates in an actual world setting that temper stabilisers, both alone or together with SGAs, might cut back relapse charges following first episode psychotic mania in comparison with SGAs alone. Although the examine was not randomised, it was a well-designed cohort examine which emulated a goal trial. Furthermore, together with current proof it provides additional weight to the discovering that temper stabilisers, specifically lithium, are preferable for stopping relapse in sufferers with bipolar dysfunction.
Future research ought to affirm these findings with well-designed randomised research. Ideally totally different temper stabilisers (e.g. lithium and valproate), and totally different SGAs ought to be in comparison with decide if there are variations with particular drugs. Research that study hostile results and discontinuation in a real-world setting would additionally assist clinicians and sufferers of their determination making.
The examine helps so as to add additional proof to reply the scientific query for a lot of sufferers with bipolar dysfunction: when a manic episode has been efficiently handled with antipsychotics, to be able to forestall relapse, ought to I stick or twist? Many sufferers and clinicians seem reluctant to change, which can have led to the declining use of lithium and improve of SGA use in bipolar dysfunction. This can be on account of considerations about negative effects, monitoring necessities, or just uncertainty as to what additional profit can be achieved by switching. Sufferers might usually really feel they’re managing effectively with their preliminary SGA, and subsequently are reluctant to ‘rock the boat’ or change one thing that seems to be working.
Szmulewicz et al’s findings recommend that beginning with a temper stabiliser might provide a greater various, significantly for lowering the danger of depressive relapse, which is commonly essentially the most difficult and disabling temper section of bipolar dysfunction for sufferers. With the ability to present clinicians with this info will hopefully result in a extra knowledgeable dialogue with sufferers about whether or not to ‘stick or twist’.
Assertion of pursuits
Tobias Rowland has no conflicts of curiosity to declare. All intelligence used within the writing of this weblog was strictly non-artificial.
Editor
Simon Bradstreet.
Hyperlinks
Major paper
Alejandro Szmulewicz, Yu-Hsin Liang, Gonzalo Martínez-Alés, Ryan O’Dea, Lorna Thorpe, Sarah Conderino, José Rubio, Kerry Smith, Deepak Sarpal, Covadonga Díaz-Caneja, Celso Arango, Paul Vöhringer, Sophia Aldunate, Ridha Joober, Jai Shah, Ashok Malla, Diane Fredrikson, Lakshmi Yatham, Miguel Hernán, Dost Öngür (on behalf of the BD-CAUSAL Collaboration) (2026). Comparative effectiveness of temper stabiliser monotherapy versus second-generation antipsychotic monotherapy versus mixture remedy for continuation and upkeep therapy after a primary episode of psychotic mania in North America, Chile, and Spain: a goal trial emulation utilizing information from the BD-CAUSAL Collaboration. The Lancet Psychiatry, 13, 861-869
Different references
Goodwin GM., Haddad PM., Ferrier IN. et al (2016). Proof-based tips for treating bipolar dysfunction: Revised third version suggestions from the British Affiliation for Psychopharmacology. Journal of Psychopharmacology 2016, Vol. 30(6) 495 –553.
Kishi, T., Ikuta, T., Matsuda, Y. et al (2021). Temper stabilizers and/or antipsychotics for bipolar dysfunction within the upkeep section: a scientific assessment and community meta-analysis of randomized managed trials. Molecular Psychiatry 26, 4146–4157 (2021).
NICE (2014). Bipolar dysfunction: Evaluation and Administration | Steering | NICE. Nationwide Institute for Well being and Care Excellence.
