Mania, the defining feature of bipolar disorder (BPD), has been the subject of poetry and popular imagination for hundreds of years. Given the fascination with this disorder, it is surprising that there was relatively little psychological research for several decades on the triggers of episodes. In the past decade, though, it has become fairly well established that social factors exert an important influence on the course of BPD (Johnson & Meyer, 2004). Researchers have gradually shifted from believing that biological vulnerability precludes the involvement of social factors in the course of disorder, to recognizing that biological vulnerability might intensify reactions to social difficulties.
In recent years, it has also become abundantly clear that children and adolescents do experience BPD (Kessler, Berglund, Demler, Jin, & Walters, 2005; Lewinsohn, Seeley, Buckley, & Klein, 2002). Researchers have begun to examine the role of life events and psychosocial variables in driving the course of early-onset BPD. Here we consider one of the most well-documented psychosocial effects on adult BPD—life events—and whether parallel findings are likely to emerge in the study of early-onset BPD.
Life Events and BPD
The literature on life events in BPD has been characterized by fairly disparate findings. Much of this disparity, though, can be explained by differences in design and measurement across studies (Johnson, 2005). Before reviewing specific findings, then, we consider methodological issues.
Most researchers studying life events aim to show that stressors cause increases in symptoms. Unfortunately, many of the designs used in this field are not adequate for this task. Consider that mania increases stress levels in many different ways. Because the disorder runs in families, people with BPD may be more likely to encounter high rates of family mental illness and hospitalization. Indeed, a recent study of 1,565 first admissions for BPD suggested that the single life event that was most common in BPD compared to the general population was suicide in a relative: a stressor that is clearly a consequence of family symptoms (Kessing, Agerbo, & Mortensen, 2004). Beyond family symptoms, personal symptoms of disorder, even at subsyndromal levels, are likely to wreak havoc. Residual impairment in social functioning among people with BPD has been documented even after extensive pharmacologic treatment (Fukuda & Etoh, 1994). Similarly, rates of divorce, unemployment, and financial instability are markedly elevated in samples with BPD compared to the general population (Kessing et al., 2004). Although the all too common occurrence of serious stressors in the lives of people with BPD highlights the severity of this disorder, knowing that stress rates are high does little to show that life events are causally related to symptoms. That is, correlational findings are difficult to interpret. Hence, even though researchers have demonstrated that children and adolescents with BPD experience high rates of life stress compared to those with other psychiatric disorders (Tillman et al., 2003), we do not focus on correlational research here. Rather, we focus on studies of how stress influences the course of disorder.
To test whether stress is causally related to symptoms, researchers must use designs that control for the high rates of stress in this population. Two commonly used designs are helpful in this regard: (a) assessments of whether rates of life events are elevated in the period before an episode compared to other periods in the life of a person with BPD, and (b) prospective tests of whether stress predict increases in symptoms.
Beyond design decisions, life events measures are fraught with the potential for error and bias. Solid coverage of the major stressors in a person's life is more difficult than it might seem. Because BPD changes lives so dramatically, people may encounter many types of stressors that are uncommon experiences in the general population. For example, children with BPD may be placed in special classrooms, develop different peer groups, or encounter other atypical forms of stress that are not routinely covered on life event checklists. Consequently, stress checklists, with their coverage of only the most typical life stressors, may miss critical life events. Comparisons of life event questionnaires and interviews illustrate how many life events are missed on standard checklists: in one study, self-report checklists only captured 32% of life events that adolescents described in interviews (Duggal et al., 2000). Thus, life event interviews allow more flexibility to cover idiosyncratic life events.
It is also important for interviews to cover contextual factors that might make an event more or less meaningful for a given person. Yamamoto, Whittaker, and Davis (1998) found that when adolescents rated their own events, their ratings of stress correlated poorly with ratings of the same stressors by professionals. Assessing the context of different life events may allow for more ideographic weighting of event severity.
Interviews can also be helpful as researchers attempt to disentangle another difficult issue highlighted in our discussion of design issues: symptomatic behavior can create stress. For example, a person experiencing psychomotor retardation may have difficulty arriving at the bus stop on time, and a child who is experiencing irritability may create conflicts with parents. Stress generation has been demonstrated in several studies of mood disorders (Adrian & Hammen, 1993) and appears particularly common among adolescents with psychopathology (Sandberg, McGuinness, Hillary, & Rutter, 1998). Adolescents with psychopathology are most likely to report two types of stressors: failure and being misunderstood, both of which could be secondary to symptoms (Liu et al., 2000). Parents report that children with BPD create more life events than do those unaffected by the disorder (Petti et al., 2004). Hence, interviews are important to help decipher whether life events are independent or dependent of mood disorder symptoms.
Beyond the advantages described so far, interviews allow for an extra level of care in controlling for potential participant biases. Adjusting to the onset of a serious mental illness is a very difficult process, and most adolescents and their parents will be motivated to believe that their symptoms were explained by unusual circumstances that are unlikely to recur. Life events provide a particularly reassuring explanation for why an episode started at a given time. Indeed, empirical evidence suggests that in recalling their history, people tend to shift the timing of life events to support the idea that an episode was stress induced (Monroe & Simmons, 1991). Interviewers can combat this tendency by anchoring life event dates to a calendar that displays key holidays, life-style changes, and other dates, a strategy with strong empirical support (Shum, 1998).
Several interview-based measures of life events have been developed for use with child and adolescent populations (Hammen, 1991; Monck & Dobbs, 1985; Sandberg, Rutter, Giles, & Owen, 1993). Such interviews can be tailored to capture developmentally related events, to address difficulties in abstraction and verbalization of complex events, and to weight the relative importance of different types of incidents in an age-appropriate manner. These interviews have established validity in the prediction of major depression among adolescents (Hammen, 1988; Williamson et al., 1998), as well as general psychiatric symptoms (Goodyer, Kolvin, & Gatzanis, 1985; Sandberg et al., 1998).
In this review, then, we will focus on studies of life events that have relied on well-controlled designs (either prospective or considering appropriate time periods as control). We also limit our discussion to studies that included interview-based measures of life events in samples below age 18.
Life events and BPD: Findings within adult samples
Because most psychosocial research has been conducted with adult samples, we briefly highlight the findings in regard to adult BPD before we turn toward findings regarding juvenile BPD. In considering the role of socioenvironmental factors, it is worth noting that two waves of data have emerged. In the first wave, researchers aimed to demonstrate that difficult environments predicted poorer outcomes. Several key findings emerged, indicating that family criticism as well as negative life events predict more symptoms and relapse over time (see Miklowitz & Johnson, 2006, for a review). Indeed, some of these effects appeared to be quite robust; researchers found that negative life events predicted a fourfold increase in the risk of relapse (Ellicott et al., 1990) and a threefold increase in the time to recovery (Johnson & Miller, 1997).
In the second wave, researchers have begun to consider which aspects of symptoms are most influenced by the social environment. Many researchers were able to show that psychosocial variables predicted the course of depression within BPD. For example, studies have now found that expressed emotion and social support predict depression, and that more generally, the socioenvironmental predictors of bipolar depression appear quite similar to those involved in unipolar depression (Cueller, Johnson, & Winters, 2005). Our review will focus on research stemming from this second wave of work, focused on identifying whether life events of different types predict mania and depression.
Given that negative life events robustly predict the course of unipolar depression, it is natural to consider whether negative life events influence the course of bipolar depression. It is worth noting, however, that researchers have also begun to consider other forms of life events that might be important in regard to mania. That is, theory over the past 20 years has pointed toward two systems involved in mania: circadian rhythms and reward pathways (Johnson & Roberts, 1995). Life events related to each of these systems, such as schedule-disrupting life events and life events involving goal attainment, have been studied in relation to mania. In the following sections, we review evidence concerning negative, schedule-disrupting, and goal-attainment life events.
Negative life events
Consistent with the parallels between unipolar and bipolar depression, negative life events are as common before bipolar depression as before unipolar depression, and have been shown to predict the course of depressive symptoms in longitudinal studies (Johnson, 2005). It appears then, the negative life events are important for understanding bipolar depression.
Although negative life events appear important to depression, less research supports their role in triggering mania among adults. At this point, a number of papers have considered the idea that negative life events will precede mania. Among the six available studies that conducted comparisons of rates of life events before episodes compared to after episodes, each study failed to find elevated rates of negative life events before mania (Johnson, 2005). In prospective analyses, no studies that have used careful measurements of life events have found a direct effect of negative life events on the course of mania among adults with bipolar I disorder (Johnson, 2005).
Although the general adult literature has not been supportive of the role of negative life events as a trigger of mania, data among college students has suggested that negative life events (as measured with questionnaires) and negative cognition may interact to trigger mild hypomanic symptoms (Reilly-Harrington, Alloy, Fresco, & Whitehouse, 1999). As there is so little research on these younger populations, this study is worth noting, as it remains possible that the different pattern of findings is due to the younger age of the sample compared to other research.
Schedule-disrupting life events
Theory and clinical observations suggested that sleep disruption might provoke manic symptoms (Wehr, Sack, & Rosenthal, 1987). Naturalistic studies suggest that sleep loss can trigger manic symptoms (Leibenluft, Albert, Rosenthal, & Wehr, 1996). Congruently, experimental studies indicate that more than 10% of patients with bipolar depression develop hypomanic or manic symptoms after induced sleep deprivation (Colombo, Benedetti, Barbini, Campori, & Smeraldi, 1999). Finally, case studies suggest that increasing sleep time may help diminish symptoms of BPD (cf. Wehr et al., 1998). It has also been proposed that more general disruptions in schedules may provoke symptoms of mania (Ehlers, Frank, & Kupfer, 1988).
Based on this literature, researchers have examined whether schedule-disrupting life events are related to manic symptoms. In two retrospective studies, people with BPD reported more schedule-disrupting life events before the onset of manic episodes than before the onset of depressive episodes (Malkoff-Schwartz et al., 1998, 2000). It is worth noting a couple issues for the assessment of schedule-disrupting life events. First, people appear to forget schedule-disrupting life events within a month (Winett, 2001), so researchers probably need to assess sleep disruptions at least weekly. Second, there is a need for prospective studies of whether schedule-disrupting life events predict mania. Third, there is a need for studies comparing sleep-disrupting life events with more general schedule-disrupting life events. Life events that disrupt schedules and those that disrupt sleep, though, are an important topic for further research.
Goal-attainment life events
Theorists suggest that BPD might be tied to dysregulation in the behavioral activation/approach system (cf. Depue, Collins, & Luciana, 1996). This brain-based system has been hypothesized to regulate cognition, affect, and behavior in support of the pursuit of incentives and goals. To facilitate approach behavior, this system has been hypothesized to promote increases in positive affect, attention towards cues of reward, and energy. Certainly, these theoretical outputs of the approach system mirror the symptoms of mania (Depue et al., 1996).
Consistent with this theory, people with BPD and those at risk for the disorder describe themselves as more sensitive to reward, or more likely to experience increases in energy and positive emotions in response to cues reward and incentive (Meyer, Johnson, & Carver, 1999; Meyer, Johnson, & Winters, 2001). People at high risk for the disorder also choose approach-oriented responses to vignettes concerning life situations compared to those at low risk (Meyer et al., 2004). The elevated reward sensitivity appears to be present across manic and euthymic periods among people with BPD (Meyer et al., 2001). Psychophysiological studies also suggest that students at high risk for mania show more pronounced reactions to positive stimuli than do students at low risk (Sutton & Johnson, 2002). Other emotion research suggests a particular sensitivity to positive stimuli compared to negative stimuli (Johnson, Gruber, & Eisner, in press). In sum, a set of studies suggests that BPD is associated with stably high reward responsiveness.
If risk for mania is tied to increased reactivity to incentives, one might expect life events involving goal attainment to predict manic symptoms. This model has been examined using the LEDS goal attainment scale (Leenstra, Ormel, & Giel, 1995), in which goal attainment life events are defined as achieving an interpersonal, occupational, or other goal after a period of personal striving and commitment. In prospective research among people diagnosed with bipolar I disorder, life events involving goal attainment were predictive of increases in manic symptoms, but not depressive symptoms (Johnson et al., 2000). This pattern held even when life events that might have been created by early manic symptoms (e.g., risk-taking behaviors) were excluded from analyses. Hence, early research is supportive of a link between goal attainment life events and mania.
Summary of life events and adult BPD
Research with adults has now established that the social environment is an important predictor of the course of BPD. More specifically, within BPD, negative life events appear to predict increases in depressive symptoms, but not manic symptoms. One study of college students, though, did find that negative life events could predict hypomanic symptoms among cognitively vulnerable students. Manic symptoms have been found to relate to life events involving schedule disruption and those involving goal attainment.
Considerations in Applying Life Events in Adolescents
Although one might expect that adult findings would simply generalize to the study of adolescents, there are several reasons this is a poor assumption. Some of these have to do with developmental changes in the clinical phenomenology of the disorder. For example, among children and adolescents, BPD is likely to be marked by complex patterns of symptoms (Craney & Geller, 2003; Findling et al., 2001), high rates of comorbidity (Biederman, 1995; Carlson & Youngstrom, 2003; Geller et al., 2001), and a particularly strong influence of family history on onset (Strober et al., 1988; Todd, Neuman, Geller, Fox, & Hickok, 1993). The complexities of this disorder and its expression among younger populations are likely to create hurdles for researchers trying to map psychosocial triggers of symptoms.
Other issues in the study of early-onset BPD, though, have to do with changes in the nature and impact of life stress over time. As children mature and become increasingly autonomous, the importance of events within different domains changes. For example, more so than for adults, stress levels of a child are highly related to the nature of family functioning.
Change in the nature of stressors has been particularly well studied among adolescents. As individuation occurs, family stress has been shown to intensify (Laursen, 1996). Meanwhile, peer relationships take on increased salience in daily activities, and also become more central in determining emotional satisfaction. For girls, the levels of disclosure within these relationships tend to intensify (Rudolph & Hammen, 1999). Although one would expect the increased intimacy of these relationships to offer protection and support, girls seem to experience greater awareness of threats to relationships (Laursen, 1996) and also experience more distress over relationship events as they move into adolescence (Wagner & Compas, 1990). Changes in body composition associated with puberty induce new concerns about weight, coupled with the pressures involved with dating. Taken together, researchers have labeled early adolescence as a period of intense stress, particularly for girls (Ge et al., 1994).
Rudolph and Hammen (1999) have found that adolescents tend to experience more stress generation than younger children do, perhaps related to their increasing autonomy in interpersonal and academic decisions. That is, as youth begin to make increasingly complex decisions, symptoms play a larger role in shaping whether stress is generated. Among adolescents with depression, those with comorbid disorders may generate the highest levels of symptom-related stress (Daley et al., 1997).
As the capacities for abstraction and self-reflection increase, the nature of appraisal processes for stressors evolves. It has been argued that early in life, stress appraisal may be driven by reactions of caretakers and moderated by the proximity of caretakers. By school age, children begin to develop more independent appraisals of stressors and to consider issues of ineffectualness and culpability in the creation of stressors. By mid-adolescence, appraisals of stress are based less on caregiver evaluations and more on self and peer evaluations (Pynoos, Steinberg, & Piacentini, 1999). As stressors become more independently appraised, then, one would expect cognitive biases to become more pronounced in determining the effects of stress. By adolescence, the role of life events is clearly moderated by the cognitions that a child holds about those life events (Turner & Cole, 1994).
The effects of life events on depression during childhood and adolescence
Life stress has been shown repeatedly to influence a broad range of symptoms among children and adolescents, including externalizing symptoms (Rudolph et al., 2000). Stressful life events are the largest factor associated with increased dysphoria among teenagers (Brooks-Gunn & Warren, 1989; Larson & Ham, 1993; Simmons & Blyth, 1987). In particular, loss events (e.g., death) and trauma (e.g., sexual abuse, victimization, and family conflict) have been linked with increased rates of depressive symptoms among adolescents even years after the events occur (Franko et al., 2004).
Several aspects of stress appear to be important to consider in predicting depressive symptoms. Interpersonal stressors appear closely tied to the emergence of depressive symptoms among girls during adolescence (Rudolph & Hammen, 1999; Williamson et al., 1998). Interpersonal stressors that are chronic may be particularly powerful triggers for the genesis of depressive episodes (Williamson et al., 1998).
Beyond understanding the most important forms of stress, a key question is which children will be most vulnerable to the effects of life events. It is well documented that offspring of parents with a mood disorder are at increased risk of developing a mood disorder (Goodman & Gotlib, 1999). A number of studies have focused on understanding stress as a predictor of depression among these offspring. One of the findings from this set of studies is that current depression in the mother seems to amplify the effects of life stress among children (Hammen, Burge, & Adrian, 1991). That is, children who do not have a depressed parent appear relatively resilient to the effects of life stress, but those with a depressed mother appear more affected by the presence of life stress. It also appears that mothers with more negative affect may generate more stress (Ellenbogen & Hodgins, 2004), particularly if negative affect is expressed in their communication style within the family (Hamilton, Jones, & Hammen, 1993).
In sum, life stress robustly predicts juvenile psychiatric symptoms, and particularly depression. Researchers have begun to trace the key dimensions of such stress, but also to understand individual and family differences that may moderate vulnerability to stress. Maternal depression appears to offer a double hit, in that it is tied to greater reactivity to stressors and greater stress exposure for offspring.
Studies of stressors among children and adolescents with BPD
Two teams have examined the influence of life events on the course of juvenile BPD using careful interviews. First, Hillegers and colleagues (2004) used the adolescent version of the Life Events and Difficulties Schedule to examine the influence of life events among 140 offspring of 86 parents with BPD. This study was particularly intriguing in that it examined the onset of disorder. At 5-year follow-up, 38 of the children had developed a mood disorder, only 4 of whom met criteria for BPD according to the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) for school-aged children. The onset of these mood disorders was clearly related to the cumulative number of severe negative life events over a 5-year period: each severe life event increased risk of future onset by approximately 10%. Findings, however, were limited by the 5-year period covered by interviews. Indeed, analyses of the data suggested that participants forgot about 11% of severe events per year, such that about half of the events from 5 years before would have been forgotten.
In subsequent analyses, the authors addressed this difficulty with recall by examining links between severe life events and episodes (either new onsets or recurrences) of mood disorders that occurred within 14 months of interview (Wals et al., 2005). As with previous analyses, life events were clearly tied to mood disorders. On the other hand, more detailed analyses suggested that dependent life events, rather than independent life events predicted episodes of mood disorders. Offspring with a dependent life event during the 14-month follow-up period had 5.4 times the risk of a mood disorder episode. These robust effects for dependent life events indicate the need for great care in dissecting links between life events and symptoms. In more careful analyses controlling for baseline symptoms of anxiety and depression, dependent life events were still associated with more than double the risk of onset. Nonetheless, with the small sample size of the study (only 13 offspring developed a mood episode during the time period), the life event effect was not significant after adding covariates to the model.
Taken together, then, this line of work provides some indication that life events predict onset of disorder and the development of episodes, particularly depressive disorders. Nonetheless, these results also provide a cautionary tale about the difficulties of understanding life stress, in that much of the life stress appears to be the result of emergent symptoms of anxiety and depression. Nonetheless, the simple magnitude of the effects of life stress suggests the need to examine stress in a larger sample of youth at risk for BPD.
In one such study, Kim and colleagues (2006) followed 38 adolescents with BPD who were enrolled in a 9-month family treatment program. Participants met diagnostic criteria for BPD using the K-SADS with parents and children. Life events and chronic stressors were evaluated with the UCLA Life Stress Interview (Hammen, 1991), and the presence of full or subsyndromal symptoms was assessed every 3 months with the K-SADS. Results highlight the need for specificity in defining stressors. For example, the mean severity of life events, either for independent or dependent life events, did not correlate with changes in symptoms over time. On the other hand, adolescents who experienced more chronic stress in family and romantic relationships during the follow-up period also experienced more sustained depressive symptoms over time. Similarly, those youths with chronic stress in peer relationships also experienced more sustained manic symptoms. These findings are consistent with those in the unipolar depression field highlighting the effects of chronic interpersonal stress. Unfortunately, the analyses performed in this study did not provide a specific analysis of whether symptoms increased in the months after a severe life stressor, but rather examined stressors across the follow-up period as a correlate of change in symptom levels.
Beyond examining whether different forms of life stress influenced the course of disorder, each of the studies of life events in juvenile BPD has also considered how age influences life event vulnerability. Post and Weiss (1998) have argued that episodes of BPD become more autonomously triggered over time, such that life events will be less important to later recurrences compared to initial episodes. This idea has not received consistent support in adult populations (see Johnson & Fingerhut, 2006), but studies of children and adolescents allow for a more appropriate test for this model, as they capture earlier phases of the disorder.
To date, the findings on age are relatively mixed. Hillegers and colleagues (2004) tested several different models of the relationship between age, life events, and symptoms. The model that appeared to best fit the data suggested that life events become less influential to the course of disorder over time, but no tests were provided to compare the statistical fit of the different models. In contrast to these findings, Kim, Miklowitz, Biuckians, and Mullen (2006) did not find interactions between the role of independent life events and age in relation to the course of disorder.
Two other analyses have been published concerning the role of dependent life events. Kim and colleagues (2006) found a significant interaction of dependent life events and age. Dependent events were more closely related to symptoms among younger children compared to older children. It is difficult to determine whether this means that symptoms were more likely to contribute to stress generation among younger adolescents, or that dependent life events created more distress and symptoms among the younger adolescents compared to the older adolescents. If it turns out that dependent life events are provoking symptoms, then the findings will be fairly consistent with the Hillegers et al.'s (2004) findings in suggesting that the role of life events could decrease over time. If so, studying life events early in the course of disorder should be a top priority.
Beyond age, Wals and colleagues (2005) examined whether life events appear to operate differentially for those experiencing a first episode versus a recurrence. That is, analyses were provided to examine the influence of dependent life events (within a 14-month period) as a predictor of outcome for those with a first episode (n = 8) compared to those with a recurrent episode (n = 5). Life events were a significant predictor of first episodes. It is not surprising, given the sample size of five, that dependent life events were unrelated to outcome among those with a recurrent episode. Nonetheless, these findings are somewhat consistent with the importance of studying life events earlier in the course of disorder. Although somewhat mixed, these preliminary findings highlight the importance of continuing to examine the effects of age and recurrence as moderators of life stress effects in future studies among both adolescents and adults.
Conclusions
Although there are only two teams that have conducted interview-based longitudinal studies on the role of life events in BPD among children and adolescents, the available studies are methodologically and conceptually strong. Findings suggest that life stress can play a statistically significant role in the onset of mood disorder symptoms among children at risk for mood disorders by virtue of family history. It also appears that among adolescents who are already affected by the disorder, chronic interpersonal stress is correlated with ongoing symptoms.
Nonetheless, the more sophisticated analyses of these studies demonstrate that these effects must be viewed through a transactional lens. That is, the Kim et al. (2006) study suggests that much of the influential stress is from family and peer conflicts and, as such, one must wonder whether it is secondary to familial and individual psychopathology. The Hillegers et al. (2004) study reveals that a major portion of the life stressors could be attributed to the role of emergent symptoms among children. Thus, parental and child psychopathology may form the first part of the sequence, with life events unfolding as a consequence of symptoms. As life events unfold, they may predict an earlier onset and more severe course of disorder. It is important to note, though, that there is considerable variability in whether the chain plays out in this way. One important clinical strategy, then, might be to try to limit the stressors that unfold among children at risk, particularly among those with high levels of parental stress or early signs of disorder. One way to do this might be to provide interventions to bolster interpersonal and problem-solving skills. Even with such attempts to reduce stress, though, most people are going to experience major stressors at some point in their life: friends move, companies go through layoffs, and people die. Given this, interventions to help people cope with the emotional aftermath of stressors are likely to be just as important as stress prevention interventions.
Findings to date, though, indicate a role for negative life stressors as a predictor of depressive maintenance and onset. The Kim et al. (2006) study found that peer stress levels were correlated with sustained manic symptoms, but the Hillegers et al. (2004) study only included four participants with mania. Due to the paucity of studies and analyses available to date, there is little known about whether manic symptoms actually increase after negative life events. As noted above, there is little evidence in prospective studies of adults that mania does increase after negative life events, but findings of one study indicated an effect of negative life events on hypomanic symptoms among college students (Reilly-Harrington et al., 1999). Despite some ambiguity, it is possible that negative life events are more influential for mania symptoms among younger samples than among older samples.
Research with adults has found that life stressors involving goal attainment (Johnson et al., 2000) and schedule disruption (Malkoff-Schwartz et al., 1998, 2000) predict mania. These other forms of life events have not been investigated in early-onset populations. One goal of future research, then, will be to examine different forms of life events among youth with BPD.
Although few studies are available, the findings of early studies suggest that negative life events are tied to the course of adolescent BPD. The effects of such life events, however, appear to be fairly entangled with emergent symptoms as well as family difficulties. Isolating the role of life events from other genetic influences then will require highly sophisticated research designs.
