Discussion

This study identified relevant proteomic markers to be largely associated with changes in functional but unexpectedly not cognitive outcomes following cognitive remediation therapy in people with euthymic bipolar disorders. Although an increase in the BDNF during the intervention period was correlated with increased functional benefits in the trial, no protein changes significantly mediated subsequent outcomes to cognitive remediation compared with TAU. Across comparisons, three markers – IL-6, Mip1β and PlGF – demonstrated no significant effects.

Interestingly, lower levels of growth factors (BDNF, bFGF, VEGF-C) and IL-7 as a regulatory cytokine preceded better functional outcomes. Moderation analyses demonstrated that for the BDNF, this association appeared mainly confined to the TAU group. For two other pro-inflammatory cytokines – IL-16 and TNF-β – a moderation effect in the reverse direction was identified, suggesting a magnification of cognitive remediation effects on functioning in people with lower baseline cytokine levels. IL-16 levels reduced during the intervention period similarly between groups. Three other markers showed reductions over time that were significantly more pronounced in TAU versus cognitive remediation participants; indeed, cognitive remediation appeared to mostly attenuate the reductions in protective growth factors – the BDNF, the bFGF and VEGF-C.

Overall, we interpret these findings as broadly indicative of a protective effect of cognitive remediation on declines in some proteins that are broadly associated with poorer cognitive functioning.^{Reference Strawbridge, Carter, Saldarini, Tsapekos and Young12} This appears most pertinent for three neurotrophic growth factors – the BDNF, the bFGF and VEGF-C – for which similar results emerged: cognitive remediation attenuated a reduction in each of these compared to TAU, and lower baseline levels across the sample predicted better functional outcomes, although only for the BDNF did this appear specific to participants not undergoing cognitive remediation therapy. Only for the BDNF also was a reduction over time associated with poorer functional outcomes in the trial. The BDNF was indeed considered a priori the primary candidate marker examined, with the most substantial prior support suggesting a key role in illness-related cognitive impairment and improvement following therapy, mostly in individuals with psychoses, but also in those with bipolar disorders.^{Reference Mora, Portella, Piñol-Ripoll, López, Cuadras and Forcada27} In particular, previous studies have reported increases in the BDNF during clinical trials to be associated with superior cognitive gains after both pharmacological^{Reference Vinogradov, Fisher, Holland, Shelly, Wolkowitz and Mellon22,Reference Wu, Shi, Chen, Chen, Xiu and Zhang23} and non-pharmacological^{Reference Fisher, Mellon, Wolkowitz and Vinogradov24} therapies.^{Reference Penadés, García-Rizo, Bioque, González-Rodríguez, Cabrera and Mezquida25,Reference Penadés Rubio, Catalán, López Vilchez, Arias Sampériz, Gozález-Rodríguez and Galán26} The latter aligns to some extent with our findings, although its profile in the current study is less of a rising BDNF in cognitively treated individuals and more of BDNF reductions in the absence of treatment or benefit. Relevant here is the lack of evidence thus far that cognitive remediation effectiveness is associated with age.^{Reference Tsapekos, Strawbridge, Cella, Wykes and Young6} Moreover, we observed no full mediation and no association with cognition itself, although in this trial cognitive and functional outcomes were closely related. The reason for BDNF reductions in this sample receiving TAU over a 3 month period is unclear; for example, even over several years a lack of significant change in serum BDNF has been reported.^{Reference Wu, Wolkowitz, Reus, Kang, Elnar and Sarwal28,Reference Yee, Lee and Lee29} Conversely, a report of reduced BDNF manifesting over a long period in people who had a depressive illness compared with those without concluded that the BDNF can be considered a state marker of affective illness.^{Reference Ihara, Yoshida, Jones, Hashizume, Suzuki and Ishijima30} However, our population were not experiencing depressive symptoms during the trial and subsyndromal depression severity did not differ between groups or timepoints.^{Reference Strawbridge, Tsapekos, Hodsoll, Mantingh, Yalin and McCrone5}

It would be also possible to consider a treatment effect modification effect by an unmeasured factor or factors. For instance, we could speculate that after the intervention period, participants in the TAU group experienced more subjective stress during the subsequent cognitive assessments and, although this may not have strongly affected their cognitive performance, it may have affected BDNF levels at the post-intervention timepoint. Although some previous studies have reported acute stress to reduce the BDNF,^{Reference Sharma, Graham, Rohde and Ceballos31} findings have also been reported in the opposite direction.^{Reference Hermann, Schaller, Lay, Bloch, Albus and Petrowski32} Presence versus absence of the BDNF Val66Met polymorphism (rs6265) can clearly modify changes in the BDNF protein,^{Reference Sharma, Graham, Rohde and Ceballos31} and we were not able to measure this, although we note our similar findings between the BDNF and other similar neurotrophins. Nevertheless, the other markers examined can also be influenced by stress and all of these proteins are well-known to fluctuate according to numerous factors.^{Reference Strawbridge, Carter, Saldarini, Tsapekos and Young12} Even for variables that were measured, we acknowledge that in the current study, potentially confounding factors were not substantively assessed. This was partly attributed to limited associations in our previous study (e.g. no association with BMI or subsyndromal symptoms). However, it was also partly because of the small sample size and exploratory nature of the study, and these will need further consideration in the future.

Increased stress in response to assessments at follow-up is one potential speculative reason outlined above why we may have observed greater proteomic changes overall in participants allocated to the TAU group. It may be of note that functional impairment (FAST) scores reduced by an average of approximately 5 points in the cognitive remediation group between weeks 0 and 25, while there was an average 2 point increase in the TAU group: whether a factor associated with allocation to TAU could explain both a (small) decline in functioning and a decline in neurotrophins will require a more substantial investigation. An unmeasured factor here may also explain the predictive effect of a higher BDNF before poorer functional outcome in TAU-randomised participants, which is as yet unexplained.

In total, a panel of 32 proteins were assayed from the CRiB study, but only nine were examined in this small exploratory study. These nine were selected because of their previous associations with cognitive functioning in a baseline analysis.^{Reference Strawbridge, Carter, Saldarini, Tsapekos and Young12} Mip1β and IL-6 only showed a tentative relationship with cognition in the previous examination, and did not emerge as significant in the present study. Conversely, IL-7 and VEGF-C were strongly and consistently positively associated in the previous analysis and demonstrated similar findings to the BDNF in the current examination. Another neurotrophin – the PlGF – was also consistently associated with impairment previously but did not appear to be associated with cognitive remediation outcomes in this study.

The absence of significant associations with cognitive outcomes was somewhat unexpected. Both of the outcomes that we assessed comprise multiple domains, but this is particularly relevant for cognition. Our cognitive outcome measure was a composite score of several cognitive tests,^{Reference Strawbridge, Tsapekos, Hodsoll, Mantingh, Yalin and McCrone5} which may have masked domain-specific associations. Many studies have compared biomarkers with specific cognitive domains and also reported associations that appear inconsistent between studies.^{Reference Barbosa, Ferreira, Rocha, Mol, da Mata Chiaccjio Leite and Bauer33,Reference Chakrabarty, Torres, Bond and Yatham34} It may be that comparisons with individual cognitive tests measured in this study would have yielded clearer findings, although this was not the case in our BDNF domain-specific mediation model that we tested. The frequent association between biomarkers and functional outcomes is somewhat surprising, given that these markers were considered candidate markers of outcomes to a therapy that principally focuses time on cognitive training. It is perhaps notable, though, that the functional outcome assessed (FAST) contains as one of its six domains ‘cognitive functioning’ (in addition to autonomy, occupational, financial, leisure and interpersonal relationships).^{Reference Rosa, Sánchez-Moreno, Martínez-Aran, Salamero, Torrent and Reinares19}