Childhood abuse and individual-level characteristics

The variable that was associated with the earliest AAO was childhood abuse. This aligns with a large body of evidence indicating that maltreatment in childhood is associated with an earlier AAO,^{Reference Agnew-Blais and Danese8} and is more common in individuals with bipolar disorder compared with healthy controls.^{Reference Daruy-Filho, Brietzke, Lafer and Grassi-Oliveira27} As suggested by prior research, the trauma of childhood abuse may expedite the AAO of bipolar disorder.^{Reference Daruy-Filho, Brietzke, Lafer and Grassi-Oliveira27,Reference Geoffroy, Etain, Scott, Henry, Jamain and Leboyer52} For instance, recent research (which has partial sample overlap with the current study) found that the path between childhood abuse and an earlier AAO was selectively explained by individuals’ mood instability.^{Reference Marwaha, Briley, Perry, Rankin, Diflorio and Craddock53} The authors suggest that mood instability – defined as rapid and intense fluctuations in affect – may bring forward illness onset in children who are vulnerable because of abuse, with increased mood instability developing into episodes of mania or depression.^{Reference Broome, Saunders, Harrison and Marwaha54,Reference Berk, Post, Ratheesh, Gliddon, Singh and Vieta55} However, the causal nature of this relationship is yet unclear. It may be that behavioural difficulties and emotional dysfunction resulting from an early bipolar disorder AAO confer greater social and emotional vulnerability, which, in turn, has been identified as a major risk factor for childhood abuse.^{Reference Fleming, Mullen and Bammer56,Reference Sheikh57} Thus, there may be a bi-directional relationship between mood instability and childhood abuse, with increased mood lability reducing an individual's resilience to childhood abuse, and/or vice versa, with childhood abuse increasing the likelihood for mood instability. Prospective longitudinal studies are needed to elucidate the precise nature of the relationship between mood instability, childhood abuse and how it relates to early-onset bipolar disorder.

The mediating effect of mood instability on the relationship between trauma and early-onset bipolar disorder parallels our finding that irritable temperament was associated with an earlier AAO. Irritable temperament has been positively associated with mood instability, borderline symptoms, impulsivity and grandiosity,^{Reference Walsh, Royal, Barrantes-Vidal and Kwapil58} as well as predicting manic symptoms.^{Reference Iasevoli, Valchera, di Giovambattista, Marconi, Rapagnani and de Berardis59} It has been suggested that irritable temperament forms part of a broader bipolar disorder spectrum and represents a prodromal phase of the disorder,^{Reference Duffy, Jones, Goodday and Bentall60} and, as with mood instability, may accelerate the onset of manic or depressive episodes meeting diagnostic criteria. Indeed, the association between high levels of trait irritability and an earlier AAO may be an artifact of the increased likelihood of these individuals manifesting behavioural problems that are brought to the attention of psychiatric services, in turn making it more likely to receive an early (or timely) diagnosis. Indeed, the diagnosis of pre-pubertal bipolar disorder, which is prevalent in North America, requires irritability (not mania) as a core symptom for diagnosis.^{Reference Duffy61,Reference Wozniak62}

Irritability is not the only trait measure that appears to be predictive of an earlier AAO. Greater endorsement of schizotypal personality traits – including magical thinking, paranoid ideation, ideas of reference and social isolation or anxiety – was also associated with an earlier AAO in our model. As with irritability, it is thought that schizotypy represents a dimensional trait that indexes the genetic liability to bipolar disorder and forms part of the bipolar disorder spectrum.^{Reference Mahon, Perez-Rodriguez, Gunawardane and Burdick63} Although this is the first known study to specifically investigate schizotypal personality traits in relation to bipolar disorder AAO, previous research indicates that schizotypal traits are elevated in those with bipolar disorder and predict future hypomanic episodes.^{Reference Joyce, Luty, McKenzie, Mulder, McIntosh and Carter64,Reference Schürhoff, Laguerre, Szöke, Méary and Leboyer65} There is a growing body of evidence demonstrating that genes (e.g. variants of the catechol-o-methyltransferase gene) may interact with environmental factors, such as childhood abuse, to contribute to elevated levels of schizotypal traits in bipolar disorder.^{Reference Savitz, der van Merwe, Newman, Stein and Ramesar66} Additionally, greater genetic liability for schizophrenia in individuals with bipolar disorder has been associated with increased schizotypy scores.^{Reference Hori, Matsuo, Teraishi, Sasayama, Kawamoto and Kinoshita67} As our findings show a link between increased schizotypal traits and early AAO, this lends support to the idea that earlier- versus later-onset bipolar disorder may differ in genetic aetiology, and highlights the importance of recognising the role of genetic interactions with the psychosocial predictors in our model. Of note, however, schizotypal traits and irritable temperament were partially correlated with other personality traits not included in our final model (e.g. trait neuroticism, cyclothymic temperament, depressive temperament). These correlated, but not included, temperament traits may also be of predictive relevance. As dimensions of personality are known to be traits that cluster, this should be considered when interpreting the impact of personality traits on AAO.^{Reference Iasevoli, Valchera, di Giovambattista, Marconi, Rapagnani and de Berardis59}

Life experiences and familial risk

Pertinent to the discussion of gene-environment interactions, we found that ‘family history of suicide’ was predictive of an earlier AAO, which is in line prior research.^{Reference Post, Altshuler, Kupka, McElroy, Frye and Rowe17,Reference Chen, Kao, Lu, Yang, Liao and Jang68} A family history of suicide confers a stronger familial/genetic loading for suicidality and corresponding psychiatric disorders, which supports the view that genetics contribute to an increased vulnerability for an earlier AAO in bipolar disorder. This is consistent with evidence suggesting that early onset may be a more heritable form of bipolar disorder than late onset, with studies demonstrating differences in transmission patterns and more pronounced familial aggregation in early- compared with late-onset bipolar disorder.^{Reference Etain, Mathieu, Rietschel, Maier, Albus and McKeon10,Reference Geoffroy, Etain, Scott, Henry, Jamain and Leboyer52,Reference Priebe, Degenhardt, Herms, Haenisch, Mattheisen and Nieratschker69} Beyond specific genetic influences, a family history of suicide can convey increased transgenerational risk based on intra-familial behavioural interactions and their associated stressors.^{Reference Post, Altshuler, Kupka, McElroy, Frye and Rowe17,Reference Serretti, Chiesa, Calati, Linotte, Sentissi and Papageorgiou70} This, in turn, influences family environment and reciprocal offspring resilience,^{Reference Miklowitz, Simoneau, Sachs-Ericsson, Warner, Suddath, Mundt, Goldstein, Hahlweg and Fiedler71} hinting that epigenetic mechanisms may be at play in bipolar disorder AAO.^{Reference Agnew-Blais and Danese8,Reference Daruy-Filho, Brietzke, Lafer and Grassi-Oliveira27,Reference Post, Altshuler, Kupka, McElroy, Frye and Rowe29}

Looking beyond childhood abuse and family suicide, our model also suggests that other negative early-life experiences may catalyse disorder onset. Namely, ‘the death of a close family friend or relative in the 6 months before bipolar disorder onset’ correlated with an earlier AAO. Within the psychological framework of the diathesis stress model, it is thought that early negative life events interact with predisposed vulnerability to precipitate disorder onset.^{Reference Brietzke, Mansur, Soczynska, Powell and McIntyre72,Reference Horesh, Apter and Zalsman73} Accordingly, evidence suggests a dose effect of exposure to stressful life events on the AAO of bipolar disorder, with a greater number of early stressors being significantly associated with an earlier AAO.^{Reference Hosang, Korszun, Jones, Jones, McGuffin and Farmer31,Reference Post, Altshuler, Leverich, Nolen, Kupka and Grunze32} In contrast to this, however, we found that that the following life events were associated with a later AAO: birth of a child, major financial crisis and/or death of parent, partner, child or sibling in the 6 months before bipolar disorder onset; as well as seeking work without success for 1 month pre-onset. Yet, the direction of these relationships is unclear. For instance, these are all life events that become more common with increasing age, which therefore confounds the direction of these associations with a later AAO. In support of this, we can see from Fig. 1 that the coefficient variability of these four variables is greater than the others (i.e. ‘flatter’ density plots), which suggests that the relationship between these life events and AAO may be less reliable than the other predictors in our model, and is likely weakened by age being a possible confound. Equally, there were small numbers of participants reporting these negative life events, which could have weakened the strength of their relationship to AAO. This slightly less robust association may also be partially attributed to the finding that the effect of life events on the emergence of bipolar disorder diminishes with age,^{Reference Hillegers, Burger, Wals, Reichart, Verhulst and Nolen74} perhaps because of the development of appropriate coping strategies or the presence of other neutralising life events.

Substance use

The presence of stressful life events has also been associated with alcohol use,^{Reference Paulino, Pombo, Ismail, Figueira and Lesch75} which was identified as a significant predictor in our model. Our model suggests that alcohol use correlates with a slightly later AAO. Previous research has found mixed results, with some studies demonstrating that premorbid alcohol use is significantly associated with an earlier AAO,^{Reference Holtzman, Miller, Hooshmand, Wang, Chang and Hill18,Reference Lin, McInnis, Potash, Willour, MacKinnon and DePaulo21,Reference Azorin, Bellivier, Kaladjian, Adida, Belzeaux and Fakra76} whereas others have found an association with a later AAO.^{Reference Lagerberg, Sundet, Aminoff, Berg, Ringen and Andreassen20,Reference Strakowski, DelBello, Fleck, Adler, Anthenelli and Keck77} Similar to the age-dependent life events we discuss above, the relationship between alcohol use and an early bipolar disorder onset may be confounded by age restrictions on purchasing and accessing alcohol. Equally, however, it may be that increases in alcohol use masks the true AAO of bipolar disorder, with it being unclear if mood and behavioural disturbances are a consequence of incipient bipolar disorder or directly related to heavy alcohol use.^{Reference Berk, Post, Ratheesh, Gliddon, Singh and Vieta55} Thus, individuals may not recognise their first incidence of impairment as specifically related to bipolar disorder, artificially inflating their reported AAO. Early prodromal symptoms, such as sleep disturbances and anxiety symptoms may be attributed to alcohol use rather than recognised as part of the clinical trajectory of early-stage bipolar disorder.^{Reference Stein and Friedmann78} Indeed, anxiety symptoms have been found to be both a cause and a consequence of heavy alcohol use, as well as a clinical precursor in bipolar disorder.^{Reference Duffy79–Reference Kushner, Abrams and Borchardt81} This highlights that the relationship between alcohol consumption and bipolar disorder AAO is likely non-linear, and so our findings must be interpreted with caution.

Despite previously mixed findings regarding the relationship between AAO and alcohol use, our finding that alcohol use was associated with a later AAO and cannabis use was associated with an earlier AAO, directly corroborates previous research that controlled for age as a potential confound.^{Reference Lagerberg, Sundet, Aminoff, Berg, Ringen and Andreassen20} Furthermore, evidence from systematic reviews and meta-analyses points toward a significant association between cannabis use and an earlier AAO in bipolar disorder,^{Reference Sideli, Quigley, la Cascia and Murray82–Reference Bally, Zullino and Aubry84} with results suggesting that cannabis use may trigger the onset of mania.^{Reference Bally, Zullino and Aubry84–Reference Aas, Etain, Bellivier, Henry, Lagerberg and Ringen86} The mechanism behind this effect is unclear, but it has been hypothesised that the principal ingredients in cannabis (tetrahydrocannabinol and cannabidiol) affect mood via their interaction with the endocannabinoid, dopamine and serotonin neurotransmitter systems.^{Reference Gibbs, Winsper, Marwaha, Gilbert, Broome and Singh87,Reference Chadwick, Miller and Hurd88} In contrast, alcohol use is thought to increase the risk for depressive rather than manic symptoms.^{Reference Sideli, Quigley, la Cascia and Murray82,Reference Baethge, Hennen, Khalsa, Salvatore, Tohen and Baldessarini89} This may help explain why increased alcohol use was not associated with an earlier AAO, as the presence of a manic episode is needed before a clinical diagnosis of bipolar disorder can be made.

Strengths and limitations

This is the only known study that models a wide range of psychosocial markers of AAO in a large, well-characterised sample of participants with bipolar disorder. We use a novel machine-learning approach not previously employed when investigating bipolar disorder AAO, employing bootstrapping, k-fold cross-validation and a held-out validation set to ensure model robustness and reduce overfitting. Our model showed good calibration, indicating that we can be confident in its predictive validity.

There are, however, several methodological limitations that must be considered. Relating to model validation, we did not have an independent sample for external validation. Although we used a held-out test set, this was a subsample of our original data-set and therefore subject to the same limitations as the data used for model building. The most notable of these limitations is the cross-sectional retrospective nature of the study, and the cohort's limited generalisability. As the analyses are not based on prospective data, we cannot be sure of the direction of causality in our model, and it is unclear whether our predictors should be conceptualised as causal risks factors or as risk markers, i.e. a factor that is associated with an outcome but is not necessarily its cause.^{Reference Feinleib90} Although, as with many psychiatric illnesses, it is likely that the relationships are bidirectional and symbiotic. Retrospective studies are also subject to recall bias, which undermines the reliability of self-reported AAO. This was mitigated by referring to medical case notes rather than relying solely on self-report. Yet, it has been suggested that people with bipolar disorder may be more likely to recall depressive compared with manic episodes, or even fail to recognise hypomanic episodes pre-diagnosis as pathological.^{Reference da Silva R, Mograbi, Silveira, Nunes, Novis and Landeira-Fernandez91,Reference Gazalle, Frey, Hallal, Andreazza, Cunha and Santin92} This introduces biases into individuals’ recall of their bipolar AAO. Additionally, as the sample was skewed toward a younger age at study entry (average age of 46 years), late-onset bipolar disorder may have been underreported, thus weakening the reliability of our model. Moreover, a bipolar disorder diagnosis in older age may be masked or missed in favour of more prevalent later-life disorders with psychiatric symptoms (e.g. frontotemporal dementia), further obscuring the true rate of late-onset bipolar disorder. Therefore, as a gold standard, future research investigating bipolar disorder AAO should aim to employ prospective longitudinal methodologies.

Furthermore, the included personality trait predictors had partial correlation with other personality variables not chosen in our final model. Thus, schizotypal personality traits and irritable temperament may not be the most valuable personality predictors per se, but rather represent the predictive importance of a clustering of other personality variables, such as high trait neuroticism and cyclothymic, depressive and anxious temperaments. Additionally, there are other theoretically driven potential psychosocial predictors that would have been interesting to include in our modelling. This includes information on pre-onset smoking and suicide attempts, as well as sleep and circadian rhythms, mood lability and premorbid anxiety, which are known to be important in the manifestation and prodromal stages of bipolar disorder.^{Reference Duffy93,Reference Ritter, Höfler, Wittchen, Lieb, Bauer and Pfennig94} Additionally, given the likely role of gene×environment interactions, including genetic data in future analyses would help to elucidate aetiological mechanisms.

In conclusion, our study sheds light on the importance of several psychosocial markers for bipolar disorder AAO. Identifying these predictors provides is a further step toward understanding key processes in the aetiology of this heterogeneous psychiatric disorder. Our findings suggest that bipolar disorder AAO is likely catalysed via an interplay of genetic susceptibility, individual-level personality traits and exposure to negative life events and trauma in childhood. The identified predictor variables can be used to stratify individuals already at high-risk for bipolar disorder (e.g. offspring of parents with bipolar disorder) into likely AAO groups. Defining these AAO subgroups can help guide treatment provision and streamline approaches to early intervention. Future research should aim to externally validate our model in prospective, phenotypically detailed cohorts.