Main findings
A comprehensive review of the current literature was completed to investigate whether the effectiveness of treatment of bipolar disorder varies depending on the illness stage. In summary, the literature suggests that treatment earlier in the course of illness is more effective than in the later stages of bipolar disorder. Whilst being based on a small number of studies, this finding is seen for both psychological and pharmacological therapies and the effect is apparent in a range of functional, symptomatic, recurrence, and relapse outcome measures. When confounders were controlled, this effect was attenuated and rendered non-significant in two studies.
Limitations of the literature
There were several methodological limitations to the literature that frames our findings. We wished to answer the question of whether treatment is more effective earlier in illness course. A suitable methodologically robust study design would be to sample treatment naïve individuals with a first episode and multiple previous episodes of illness and compare treatment effectiveness between the groups. We did not identify any studies using this methodology.
A related point is that many of the identified studies included those with multiple episodes who had already received treatment within the previous episodes. A proportion of these patients may have been “treatment resistant”, defined as having received two consecutive medications without recovery (Gitlin
2006). That group may have by definition, been less likely to respond to treatment in comparison to those with first episode and this could bias results in favour of treatment effectiveness earlier in illness course. In the main, it is unknown what proportion of the populations in these studies could be categorised as treatment resistant. However, in one study, approximately 50 % of the sample had previously found the treatment either ineffective or were intolerant to it (Bowden et al.
1994; Swann et al.
1999).
Studies from which relevant data could be extracted showed substantial variations in study design, sampling frames, analytic strategies, and outcomes measured. In addition, whilst nine studies used episode number as the category for comparison, one study reported length of illness (e.g., less than 10 years). Because of this heterogeneity in the literature, we did not statistically combine results in a meta-analysis, as in our judgement, this not feasible or considered potentially meaningful. Instead, we completed a narrative synthesis as the most methodologically sound way to understand the underlying patterns in the literature given the limitations described above. This type of synthesis enabled a richer understanding of the extant literature.
There may have been clinical and socio-demographic differences between the first and multiple episode groups, which could have had independent effects on outcome (Berk et al.
2011; Tohen et al.
2010) whether these were measured or not. Confounders, such as age, have been controlled for in some analyses and significant differences remain between the groups (Franchini et al.
1999; Rosa et al.
2012). In other studies, despite striking absolute differences in outcome (e.g., employment) between the first and multiple admission groups, admission number did not remain significant after controlling for other factors (Jiang
1999). Variable adjustment for confounding and disparate analytic strategies (due to the nature of studies included) means that caution is needed in direct comparisons between studies.
How first episode was classified frequently relied on a first admission to hospital with four studies using the first admission as a proxy for first episode. This is important given that prior to clinical diagnosis, patients have often experienced the previous affective symptoms (Martin et al.
2013) and duration of untreated illness can be lengthy (Berk et al.
2007; Murru et al.
2015). This is the case even after presentation to mental health services (Patel et al.
2015). There is a danger then in reviewing the literature that first episode status is conflated with the first admission or first contact with medical services, when, in fact, this is not the case. This potential variation between studies means that caution should be exercised in conclusions, regarding episode number and treatment effectiveness. It is also difficult to make direct comparison between the bulks of studies that investigate the impact of episode number on treatment effectiveness with a study that details length of illness (Franchini et al.
1999) as the variable analysed.
There were only five studies that compared people with first episode bipolar (with four relying on the first admission for this categorisation) and those with further episodes. Therefore, the current available literature (which included two meta-analyses) is weighted towards the comparisons of people who have already experienced a number of episodes with those having experienced more.
Finally, there may be a treatment confounding effect apparent in our results. For example, patients with the first episode bipolar disorder or in the early stages may have received more robust care than patients in comparison groups given the high priority now given globally to first episode mental disorders. This, of course, is less likely to be an issue for older studies.
Effectiveness of treatments in multiple domains
Psychological or pharmacological treatments at an earlier stage of bipolar disorder are more effective that in the later stages. This is apparent in multiple domains covering outcomes of importance to both clinicians and patients. The literature spans greater effectiveness on relapse, remission, recovery rates, comorbidity, symptomatic and syndromal outcome, global psychosocial functioning, and vocational and residential functioning. The fact that the same trend is seen with different treatment modalities, as well as a variety of outcomes adds validity and potency to our findings.
Timing
The evidence base in the first episode psychosis suggests that using a stage-specific approach to treatment in first episode of illness is more effective than not (Marshall et al.
2011). The underlying tenet of this approach was supported by the current literature review. However, a number of studies, including the two meta-analyses, suggest even after a first episode, less episode number is associated with greater treatment effectiveness. This finding was independent of treatment studied (Lithium, Olanzapine, Divalproex, CBT, psychoeducation) or study design (Berk et al.
2011; Colom et al.
2010; Scott et al.
2007; Swann et al.
1999).
The pivotal point at which earlier treatment was more effective ranged from 5 to 12 episodes. Given the differences between studies and the limitations of the literature, it is difficult to be sure that a pivotal episode number exists between this range after which effectiveness changes or whether this is simply a function of how data were categorised and analysed. Further research is necessary to definitively answer this question.
The early treatment would seem important, but our findings suggest an early phase effect as opposed to a solely first episode effect. A possible interpretation is that for some people, it takes a number of episodes to achieve medication optimisation and adequate adherence and to be able to engage fully in therapy. Whilst the early intervention services for bipolar disorder and their evaluation are in their infancy (Marwaha et al.
2016), evidence from an RCT sampling people early in illness course does suggest that specialised and systematic treatment is more clinically and cost-effective than the standard outpatient care (Kessing et al.
2013). The findings of this review would support an extension of this approach.
Why does treatment earlier in illness course improve outcomes?
The clinical staging approach for bipolar disorder suggests a model, in which there is a progression from “at risk” symptoms to the first presentation, to multiple episodes right through to refractory illness (Kapczinski et al.
2009). Movement through the stages can be due to a combination of genetic vulnerability, life stresses, and substance misuse, and each stage may be linked to abnormalities in biomarkers, such as TNF-alpha, BDNF, and 3-nytrotyrosine (Kauer-Sant’Anna et al.
2009). Advancing illness stage is associated with neuroprogression evidenced by the changes in the brain structure (especially in the fronto-limbic system) (Berk et al.
2011; Mwangi et al.
2016). Alongside these biological changes, there is evidence for a progressively smaller inter-episode period, as episode number increases. Whilst the earlier episodes may need to be triggered, the illness progresses episodes can begin to emerge spontaneously. This has been conceptualized into a stress sensitization-kindling model of bipolar disorder, in which repeated abnormal brain activity reduces the threshold for repeat events increasing the risk of relapse (Post
2007).
These factors are very likely to form part of the explanation for our findings that treatment early in illness course is more effective than in later episodes in terms of both clinical and symptomatic outcomes. This review suggests that the progression to later stages of illness is associated with treatments becoming less effective and these chimes with the requirement for more complex treatment regimes for many people who have well-established bipolar disorder (Post et al.
2010). The greater effectiveness in improving functional outcomes in the early course may be particularly linked to the initial appearance and worsening of cognitive impairments with time, a factor which is known to independently predict vocational functioning in bipolar disorder (Gilbert et al.
2013; Torres et al.
2011). Our findings also paradoxically highlight the scale of the therapeutic challenge to assist people in later stages of the illness, in which there appears to be some level of treatment resistance.
To conclude, this literature review found substantial evidence that both pharmacological and psychological treatments for bipolar disorder are more effective in the earlier stages of illness. The effect, which is demonstrable at the first episode, is also apparent in the early phases of treatment. The findings provide some evidence for the clinical and policy rationale of an early intervention approach in bipolar disorder to improve patient outcomes.