Patients diagnosed with bipolar disorders (BDs) often experience prolonged latency from illness onset to the start of sustained, long-term prophylaxis (1–4). This may represent a particularly critical period in the natural history of these disorders (5–9). A widely considered hypothesis is that kindling-like phenomena or behavioural sensitization occurs in BD, as reflected in increasingly severe or more rapidly recurring illness episodes over time (5,6). Often cited in support of this concept is evidence that in major affective illnesses the cycle length (that is, the time from the start of an episode to the start of the next) and the intervals of relative wellness between acute episodes may undergo progressive shortening, particularly without treatment (10–12).
The kindling hypothesis of progressive worsening in major affective disorders arises from an animal model of secondarily generalized epilepsy following initially minor and localized, experimentally induced seizures (6,13). This phenomenon is sometimes taken as a nonhomologous model for mood disorders. The model suggests that untreated affective illness may lead to pathophysiological changes in brain tissue of untreated patients. Some neuroradiological and postmortem neuropathological findings have been interpreted as supporting this hypothesis. They include structural changes in brain imaging and postmortem neuropathological changes in the brain tissue of BD patients, as well as suggestions that mood stabilizers may prevent or reverse such changes (7,14–16).
The time between onset of BD illness and the start of prophylactic treatment can be characterized in various ways, such as elapsed time, episode counts, their relation (that is, episodes per time), or other measures of illness intensity. All these measures can be inaccurate when based on incomplete medical records and potentially faulty patient or family recollections about these clinically complex episodic illnesses (17,18). Hospitalization can be a more reliable parameter, but it does not take into account milder episodes. Moreover, neither episode nor hospitalization counts consider subsyndromal illness, which is often a major component of long-term morbidity in BD (19). It is also possible that pathophysiological mechanisms in BD may persist even in the absence of acute episodes or subsyndromal symptoms, suggesting consideration of time rather than illness events. For example, persistent dysregulation of hypothalamo–pituitary–adrenal (HPA) function (20), as well as phase advances in circadian motility rhythms (P Salvatore, personal communication, March, 2003), can persist in BD patients, independent of depression or mania.
Further, it seems plausible to expect that, if BD episodes tend to increase in frequency or become more severe over time, the disorder may also become less treatment-responsive and that earlier prophylaxis may therefore yield superior benefits and clinical outcomes (8,9). However, whether delay of prophylactic treatment in BD leads to inferior treatment response or outcome remains uncertain. To address this question empirically, we reviewed new data from our own studies as well as published reports on the effects of prophylaxis latency on response and outcome in patients with BD and related disorders.
We analyzed new data from our own naturalistic studies carried out in 2 large outpatient clinics for affective disorders in Berlin and Sardinia. Details of the clinical settings, patient characteristics, and diagnostic and clinical assessment methods are detailed elsewhere (2,3). Statistical analyses presented used Statview-5 statistical software (21).
In addition, we retrieved relevant research literature using a Medline-based computerized search from 1966 to April 30, 2003. The search terms were as follows: affective, bipolar, manic-depressive, mood disorder, long-term treatment, maintenance, prophylaxis, duration of illness, delay, latency, lithium, anticonvulsants, antiepileptic drugs, carbamazepine, and valproate. We checked references cited in retrieved papers and recent reviews for further contributions. We included studies if they examined the significance of the time between illness onset and first use of any form of long-term (that is, 6 months or longer) mood-stabilizer treatment in BD or in BD plus other related disorders. We excluded studies if they reported on short-term treatment of acute episodes. We decided against a quality rating of the studies and against using quantitative metaanalytic techniques, since the studies varied highly in methods and outcome parameters.
Within our search period, we identified 11 studies published between 1967 and 2003 (3,8,9,22–29) that provided relevant information (Table 1). They involved 1485 patients, with an average of 135 subjects per study (range 29 to 450). Reported age at illness onset averaged 30.5 years (SD 1.4); latency from onset to start of maintenance treatment averaged 9.58 years (SD 1.32); and prophylaxis or follow-up averaged 5.36 years (SD 3.09) (range 1 to 11 years; means are weighted by number of subjects per study). All studies ascertained the time from illness onset to the start of sustained maintenance therapy retrospectively, and methods of acquiring outcome data during treatment varied. Table 1 summarizes diagnostic and other methods. Several studies (8,9,22,23) included some recurrent unipolar or schizoaffective disorder patients with the BD subjects and did not report each diagnostic group separately (Table 1).
Only 3/11 studies reviewed found a significant association between shorter latency and a better outcome of long-term prophylactic treatment with a mood stabilizer. Two of these studies involved some of the same subjects (8,9), and the third study found the effect only with some outcomes (28). Paradoxically, another study reported that longer latency was associated with better response (25). Most studies (7/11), however, found no relation between longer treatment latency and reduced benefits of long-term treatment (3,22–24,26,27,29).
Among the 3 studies reporting superior outcomes with shorter treatment latency (8,9,28), that of Franchini and coworkers (8) investigated the illness course of 270 BD and recurrent major depression patients. With earlier treatment, they found relatively greater sparing of morbidity (that is, reduced episode frequency during vs before treatment) among quartiles based on treatment latency. This finding was supported in a later report on 61 similar patients (9), 30 of whom were included in the earlier report (8). The association of latency and improvement was not corrected for the correlation found between more severe pretreatment illness and treatment latency. Moreover, episode frequency during treatment appeared not to differ among latency groups (8). The third seemingly positive study evaluated 56 BD I patients for retrospective and current morbidity, without prospective follow- up (28). Hospitalization rate, risk of suicide attempts, and social functioning during the previous year were all less favourable when prophylaxis had been started later. However, the morbidity measures provided include periods before and during long-term treatment, which confounds interpretation of the results.
In addition, Maj and coworkers studied late loss of treatment response and reported that, among 53 lithium-treated BD patients who had been stable for 5 years, 8 had started lithium treatment somewhat later than the others and experienced 2 or more relapses in the following 5 years (24). However, a multivariate analysis disconfirmed this suggestive finding in a small and unusual sample. Moreover, the 8 late-relapsing subjects had other unfavourable outcome predictors, including more subsyndromal affective morbidity and substance abuse during the first 5 years of treatment (22). Also, Garcia-López and colleagues found a weak, nonsignificant correlation between longer treatment latency and a higher relapse rate during a period of prophylaxis and an apparently short time of lithium discontinuation (27). This finding was uncontrolled for pretreatment illness severity. Finally, the single study finding that longer treatment latency predicted a better outcome involved only 29 BD I patients (25). Of these, only 6 were considered nonresponders, leaving the significance of the association between treatment latency and outcome unclear.
Among studies providing data regarding pretreatment illness severity (3,8,9,22–24,29), all show an association between more severe illness and earlier start of prophylaxis (although only for some measures in 1 study ). Our studies (2,3,29–31) quantified such relations and found highly significant correlations with treatment latency (nonparametric Spearman rs, all P < 0.0001): 0.58 for pretreatment hospitalization rate (3), 0.66 for pretreatment episodes yearly (2), and 0.67 for pretreatment percentage of time ill (2,29). However, none of our studies found a relation between treatment latency and response when pretreatment illness severity was controlled for in the statistical analysis (3) or when only morbidity during long-term treatment was considered (2,3,29).
For further analysis, we also pooled data from our studies (2,3,30,31, and unpublished data). These studies involved 750 patients with BD and related disorders (n = 475 BD I, n = 157 BD II, n = 69 recurrent major depressive, and n = 49 schizoaffective). Almost all cases were treated in monotherapy (652 with lithium, 59 with carbamazepine or divalproex, 20 with an antipsychotic, and 19 with an anti- depressant) for a mean of 5.03 years (SD 5.30). By diagnosis, treatment latency ranked as follows: major depression (mean 11.2 years, SD 11.1) = schizoaffective (mean 10.9 years, SD 10.6) = BD II (mean 9.8 years, SD 8.8) > BD I (mean 7.6 years, SD 8.2); F3,746 = 6.28, P = 0.003 overall, with BD I shorter than all others by post hoc testing. Latency averaged 9.2 years (SD 9.0) in women and 7.5 years (SD 8.5) in men; F1,748 = 6.47, P = 0.01. There were strong correlations between greater pretreatment morbidity (that is, episodes yearly, hospitalizations yearly, hospitalized days yearly, or approximate percentage of days ill yearly) and shorter treatment latency (Table 2). This correlation accounted for an apparently greater relative change in morbidity (by all the pretreatment measures just listed) before vs during treatment. Correlations of pretreatment morbidity and its improvement with treatment were strongest among patients with schizoaffective disorder and unipolar depression, less strong among BD I patients, and weakest (nonsignificant) in BD II patients (Table 2). In contrast to changes in morbidity during vs before treatment, there were no robust relations for morbidity during prophylaxis and treatment latency, either overall or for any subgroup (that is, for patients with bipolar, unipolar depressive, and schizoaffective disorders), save for a suggestive bivariate relation for patients with unipolar major depression—a relation that was not sustained in multivariate analysis (not shown).
The lack of relation between treatment latency and treatment response is further illustrated by our analysis of subsamples of extreme latencies. These include the shortest and longest quartiles in our Berlin samples (3,30,31, and unpublished data on unipolar depression patients; Table 3) and less than or equal to 1.5 years vs more than 1.5 years in our Sardinian sub- samples (2,29; Table 3). Even at these extremes of maintenance-therapy delay, the differences in morbidity during treatment in both studies were very small (3.2% and 7.0% of time ill, respectively). Moreover, based on pooled data from all these studies (2,3,29–31, and unpublished), 253 patients with no detected morbidity during maintenance treatment and 112 who were ill 50% or more of the time showed virtually no difference in average treatment latency (8.29 years, SD 9.03 vs 8.57 years, SD 9.22, respectively; nonparametric Mann–Whitney U-test z = 0.16, P = 0.798).
A misleading interpretation of greater changes in morbidity with shorter treatment delay can also be avoided by using multivariate logistic regression methods, with control of pretreatment morbidity. Partial modelling using data for 147 BD I patients treated with lithium or carbamazepine, taken from one of our studies (3), produced a highly significant (but misleading) association between improvement in morbidity (that is, change in days yearly in hospital before-minus-during prophylactic treatment) and treatment latency. However, we found this association only when we excluded pretreatment morbidity (defined as hospitalized days yearly prior to initiation of prophylaxis) from the model, whereas no relation to latency was found when we included pretreatment morbidity. As well, whether we included pretreatment morbidity among the independent factors or not, this modelling found no relation between the stated measure of treatment response and pretreatment episode count, sex, age at the start of treatment, or family history. Similarly, this modelling found no relation between the stated measure of treatment response and whether treatment was with lithium or carbamazepine (Table 4).
Finally, based on pooled data from our studies of 750 patients with BD and related disorders (2,3,29–31, and unpublished), we provide an illustrative figure (Figure 1) to indicate the lack of relation between treatment latency and morbidity during prophylactic treatment, as well as enormous variance in treated morbidity among individual patients (coefficient of variation = SD / mean percentage of time ill = 128%; range 0% to 100%).
Figure 1 Relation of approximate proportion of time ill during long-term
maintenance treatment (% time ill) to treatment latency (averaging 8.58
[SD 8.85] years) among 750 Sardinia (n = 451) (2,27) and Berlin (n = 299)
(3,28,29, unpublished data) patients (n = 461 women, 289 men) diagnosed
with DSM-III-R or DSM-IV bipolar I (diamonds; n = 475), bipolar II (inverted
triangles; n = 157), schizoaffective (squares; n = 49), or major depressive
(circles; n = 69) disorders, treated for an average of 5.03 (SD 5.30) years
with lithium (n = 652), an anticonvulsant (mainly carbamazepine; n = 91),
or an antidepressant (n = 7) alone
Several noteworthy observations emerged from this study. First, the time from onset or first diagnosis of BD and related syndromes to first long-term prophylactic treatment with a mood stabilizer was remarkably long. Delay averaged 9.6 years, and was shortest among BD I patients, especially men. Longer latency to sustained mood-stabilizing treatment among patients with mainly depressive illnesses (that is, unipolar and BD II disorders), and in women, probably reflects more compelling clinical presentations among men displaying mania.
Second, more severe illness before starting prophylaxis was strongly associated with earlier treatment, leading to an apparent association of greater relative improvement following shorter delay. This relation likely reflects clinical decision making, with earlier interventions for more compelling indications. In addition, very prolonged prophylaxis latency probably reflects apparent dilution of finite morbidity in these recurring disorders over many years at risk, producing low estimates of morbidity over time. Of some importance, the strong inverse relation of morbid intensity and treatment latency implies, and produced, greater relative decreases in several measures of morbidity before vs during treatment. However, unless analyses are controlled for pretreatment morbidity (Table 4) or only morbidity during treatment is considered, one can easily be misled into concluding that earlier intervention produces a superior response. The evident error of such an interpretation is illustrated by the lack of correlation between treatment latency and several measures of morbidity during prophylaxis (Figure 1, Tables 2 and 3).
The present findings add further strong support to this conclusion, made earlier with respect to treatment latency specifically (2,3,29–31) and to the number of episodes (and associated latency) before prophylactic treatment (32). We recommend that assessments of the relations between pretreatment morbidity or illness duration and treatment effectiveness either consider only morbidity during treatment or control statistically for the potentially misleading effects of pretreatment morbidity, particularly when changes in morbidity are taken as the measure of treatment effectiveness. We found that studies suggesting that shorter (or longer) treatment latency may predict a better treatment outcome did not control for the relation of pretreatment morbidity to treatment latency (8,9,25,28).
It is sobering to realize that nearly a decade may elapse before prophylactic treatment is started in disorders characterized by multiple recurrences with high rates of morbidity, comorbidity, disability, and premature mortality, especially given the availability of effective treatments (33; Table 1). The observed average prophylaxis latency of 9.3 years (Table 1) may actually be even longer, since illness onset is often dated from first diagnosis rather than first symptomatic presentation, and the studies considered here did not address effects of intervention in the very first months of symptoms. Moreover, many cases of BD II are misdiagnosed and potentially mistreated as cases of recurrent non-BD major depression, and cases starting in childhood or adolescence may be difficult to recognize as BD (34). An indication of this diagnostic problem is that the mean onset age in the studies we reviewed was 31 years, whereas a review of early-onset BD suggested a median onset age of about 20 years (35). Egeland and coworkers found high reliability for most of the onset-age criteria for BD encountered in this study, but these researchers also found that initial symptoms typically precede first diagnosis or treatment by substantial periods of time (35). The inclusion of some studies using broadly defined subtypes of manic-depressive illness further contributes to the relatively older onset age reported here: it is well known that non-BD depressive illnesses have an older average onset age (10,31).
In addition to a lack of support for the proposition that early intervention in BD and related disorders leads to superior prophylaxis efficacy, the present analysis also gives reason to remain skeptical about the widely accepted view that BD may tend to have a progressive course, especially without treatment (8,9,10,36). Several studies have not supported this finding, and it is vulnerable to a common but evidently underappreciated sampling artifact that can yield over- representation of patients with faster average cycling times as the episode count rises (37,38).
Finally, for comparison with proposed effects of kindling in BD (36), we searched for studies of the effects of delayed anticonvulsant treatment in epileptic patients. We found 4 such studies (39–42). These reports involved 1121 epilepsy patients, almost all of whom had generalized tonic-clonic attacks, some with secondary generalization from more limited initial ictal events. Latency to anticonvulsant treatment averaged 7.7 years (SD 1.7), and sustained treatment lasted 1.7 years (SD 1.2). In all 4 studies identified, there was no relation between treatment latency and effectiveness of anticonvulsant therapy (39–42).
In conclusion, the studies we considered are subject to the limitations of naturalistic clinical investigations. No study randomly assigned patients to early vs late treatment, nor would such studies be considered ethically feasible. Despite their limitations, the findings of this study offer little support for the concept that an hypothesized progressive worsening tendency in BD also implies that earlier intervention regularly yields superior treatment effectiveness. This provocative conclusion is scientifically interesting as well as clinically optimistic. However, it would be irresponsible not to reemphasize an obvious clinical point: to limit the often devastating and potentially lethal impact of these highly prevalent and treatment-responsive disorders, early diagnosis and inter- vention for BD and other forms of recurrent major affective disorders are greatly to be preferred and vigorously pursued.
The authors are grateful to Edward Bromfield, MD, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts, for expert advice concerning treatment of epilepsy.
Funding and Support
This study was supported by the Max Kade Foundation (Dr Baethge), the Bruce J Anderson Foundation and the McLean Private Donors Psychopharmacology and Bipolar Disorder Research Fund (Dr Baldessarini), and the Stanley Research Institute and the National Association for Research on Schizophrenia and Affective Disorders (NARSAD) (Dr Tondo).
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Manuscript received and accepted May 2003.
1. Research fellow, Consolidated Department of Psychiatry, Harvard Medical School, the Bipolar and Psychotic Disorders Program, McLean Division of Massachusetts General Hospital, Belmont, Massachusetts.
2. Associate Researcher, Consolidated Department of Psychiatry, Harvard Medical School, the Bipolar and Psychotic Disorders Program, McLean Division of Massachusetts General Hospital, Belmont, Massachusetts; Associate Professor of Psychiatry, Department of Psychology, University of Cagliari, Italy; Attending Psychiatrist, Lucio Bini-Stanley Institute Center for Psychiatric Research, Cagliari, Italy.
3. Resident, Department of Psychiatry, UCLA Medical Center, Los Angeles, California.
4. Attending psychiatrist, Department of Psychiatry, Technische Universität Dresden, Dresden, Germany.
5. Associate Professor of Psychiatry and Head, Department of Psychiatry and Psychotherapy, Charité, Humboldt-University of Berlin, Berlin, Germany.
6. Assistant Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts; Associate Director, Perinatal and Reproductive Psychiatry Program, Massachusetts General Hospital, Boston, Massachusetts.
7. Professor of Psychiatry, Consolidated Department of Psychiatry, Harvard Medical School, the Bipolar and Psychotic Disorders Program, McLean Division of Massachusetts General Hospital, Belmont, Massachusetts.
Address for correspondence: Dr C Baethge, Mailman Research Center/McLean Hospital, 115 Mill Street, Belmont, MA 02478-9106
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