The findings of our decision suggest that at the current state of knowledge, lithium continuation should be recommended in most cases even in the presence of long-term adverse renal effects. In some patients, switching to ACs might become an option but only if ACs outperformed lithium regarding relapse prevention. Our decision analysis focused on outcomes at discrete points of time. Modeling of transitional states in between, although theoretically possible, would not have enhanced the accuracy of the model because of the lack of reliable data. Also, this would have made the model less transparent and clinically intuitive, and the ultimate goal of this model was to map the decision process as it takes place in the consulting room every day. At the starting point of maintenance treatment, concerns about relapse and – to a lesser extent – suicide prevention are most important eclipsing any considerations about ESRD in the remote future. After 20 years of treatment, our model indicates that the risk of relapse is still the main driver for the choice of a mood stabilizer even if CKD has occurred. Concerns about ESRD become more significant though. Concerns about suicide risk statistically play a subordinate role, presumably because the risk is much smaller than the risk of relapse. At this point, many patients are referred to a renal specialist. But the remit for such referrals may be unclear if the referring psychiatrist does not include a risk assessment, which can guide the renal specialist in his deliberations on whether to continue lithium or not. Specifically, the referrer should outline the expected consequences of discontinuing lithium and switching to ACs. The BALANCE study suggests that patients may fare better switching to combination therapy rather opting for valproate monotherapy (16
). But this would not remove lithium from the equation. Thus, a nephrologist referral might better concern the management of the associated risks of continued lithium use in patients who have developed CKD such as cardiovascular problems, anemia, and mineral bone disease. Indeed, very little is known about the risk of suicide in patients switching from lithium to ACs at a late stage but it may be lower than previously thought (10
). Patients who have not committed suicide within the first twenty years of BPAD may have a more benign course irrespective of the mood stabilizer chosen. But not all patients treated with lithium develop CKD and not all patients with CKD develop ESRD. Hence, there may be specific risk factors yet to be identified. Intuitively, it would appear that the risk of ESRD might be higher in those patients who continued lithium despite CKD. Clinical intuition would also suggest that lithium discontinuation would halt progression of CKD. However, this has not been shown (34
) and it is now known that some patients have indeed progressed to ESRD despite lithium discontinuation (6
). In our model, we relied on the only long-term population-based study which reported that half of all ESRD patients had progressed to this state despite having stopped lithium (6
). Possibly, there is a ‘point of no return’ where CKD progresses irrespectively, and this threshold may lie between a creatinine clearance of 25 and 40 ml/min (24
Like any statistical model, our decision analysis has some limitations, which may affect its generalizability and validity. In our decision analysis, in line with the BALANCE trial (16
), we have not considered SGAs although they are increasingly used in the treatment for BPAD. Olanzapine and quetiapine have been licensed for the maintenance treatment for BPAD but only fairly recently so and we could not identify sufficient SGA data for inclusion into our decision tree. To our knowledge, there is only one study available exploring the risk of suicide while on olanzapine maintenance treatment (36
) and trials assessing SGAs for maintenance monotherapy are not available at all. Currently, it also appears much more likely that SGAs are used in combination with other mood stabilizers so that the effect in both branches of the tree would have canceled out in any event. At present, it remains unclear whether maintenance treatment with SGAs is really tenable long-term. Physicians may switch to other mood stabilizers once adverse effects such as weight gain and impaired metabolic control emerge and the risk of cerebrovascular events increases (37
). However, as demonstrated in the BALANCE trial (16
), adding a second mood stabilizer to lithium may yield better results than switching to another agent. Again, this trial did not purport to address the risk of adverse effects that may potentiate with the length of treatment.
In our model, we did not consider the risk of diabetes insipidus although this is much more common than ESRD. However, this reflects recommended clinical practice where monitoring for glomerular renal impairment via serum creatinine or estimated glomerular filtration rate (eGFR) is routine but screening for tubular damage is uncommon (38
). If the risk of ESRD was deemed clinically irrelevant, although rare, this would indeed compromise the validity of our model. But it would also imply that regular serum creatinine or eGFR monitoring should be abandoned. Also, ESRD as a long-term adverse effect may become more relevant in future because the first generation of patients who have received lithium maintenance therapy is coming off age (39
). There is obviously a level of uncertainty around the assumptions made in our model. We addressed this by conducting a sensitivity analysis choosing generous ranges for the best and worst case scenarios covering the various estimates obtained from the literature review. For instance, there is still considerable uncertainty about the comparative effectiveness of lithium and ACs in long-term maintenance treatment for BPAD. Meta-analyses have too short a horizon to address this question. However, we based our assumptions about relapse prevention on the most recent trial and register data available (16
). The only detailed long-term cohort study in the area does not include treatment with ACs (11
). Regarding the risk of completed suicide, data were too limited to consider valproate on its own in the model, and the range of the sensitivity analysis covered the existing risk estimates. Some studies such as the DUAG-6 (17
) study, the STEP-BD study (40
), some other cohort studies (41
), and a recent meta-analysis (21
) seem to point toward equivalence between lithium and ACs. Another recent trial of 98 patients with BPAD and past suicide attempts comparing lithium and valproate failed to detect a significant treatment difference regarding further suicide attempts (43
). Thus, if lithium was ultimately to lose its status as therapeutically superior, adverse effects of other mood stabilizers might become more prominent in clinical decision making. Our model identifies this as an area of continued uncertainty and a research priority.
We did not conduct an economic analysis with this model because this would have shifted the focus to the likelihood of recurrences of manic and depressive episodes and the associated treatment costs. Such models already exist (44
) but tend not to factor in the costs of long-term physical adverse effects. Including costs in our model might have come to an inappropriate inverse conclusion because lithium treatment most likely increases life expectancy and renal replacement therapy is extremely costly.
The decision of whether to stop lithium treatment when faced with the risk of ESRD and the prospect of renal replacement therapy remains a huge clinical dilemma. Maintenance treatment for BPAD is a staple of psychiatric practice, yet the evidence on which clinicians and patients can base their treatment choices is extremely limited.
Indeed many patients taking mood stabilizers long-term may not adhere to treatment, and this adversely affect the clinical outcome. About 50% of patients taking lithium seem to discontinue their treatment within the first six months (46
), and others only take lithium intermittently (48
). Regarding ACs, data on adherence to long-term treatment are not available. Failure to adhere is most likely multifactorial. Patient education, prevention of alcohol and substance abuse, and family involvement may improve adherence rates. Equally important in this context is the prevention and containment of side-effects (49
Clearly, lithium is not only associated with renal adverse effects but also with other clinically relevant side- effects. Some notable side-effects such as psoriasis and hyperparathyroidism are less common with a prevalence of approximately 6% each (50
). Other adverse effects such as hypothyroidism are more common. Persistent hypothyroidism may affect approximately 10% of lithium-treated patients but the prevalence may substantially rise in the elderly (48
). Currently, we do not know how such adverse effects may affect the risk of relapse. A recent subanalysis of clinical trial data suggested that such physical adverse events may indeed be relevant to the mental status. Subjects with BPAD treated with lithium who required an intervention for a depressive episode had significantly higher levels of thyroid stimulating hormone (TSH) than those who did not (55
). Neither are ACs side-effect free. Valproate carries a substantial risk of congenital malformations including an increased the risk of cardiac and neural tube defects. The risk is dose dependent and may exceed 20% at exposure to high doses (56
). This limits the use of valproate maintenance treatment in women of childbearing age. Very rarely, valproate is associated with severe hepatotoxicity and pancreatitis but the true prevalence may be underestimated (57
). Lamotrigine is commonly associated with cutaneous reactions; about 10% of exposed patients develop some form of rash. Careful titration to the target dose decreases the risk. As the risk of rash seems dependent on the speed of titration rather than the absolute dose, it is possible to re-expose patients who have developed a rash using a lower speed of titration. However, about 0.1–0.3% of patients treated with lamotrigine develop serious rashes such as Steven Johnson syndrome (59
). Unfortunately, in clinical practice it is not always easy to draw a clear distinction between ‘harmless’ and serious rashes (59
). This uncertainty raises again a clinical dilemma if and when to discontinue or re-challenge in those patients who have responded well to lamotrigine but have developed a rash of ambiguous severity. Ultimately, irrespective of the treatment used, it is always important to find an acceptable trade-off between numbers needed to treat and numbers needed to harm (60
Regarding long-term treatment for BPAD, our decision analysis is a first attempt to quantify the trade-off between effects and risks exploring the gray zone of the ‘reality in between’ (61
). In common with previous findings (62
), our study demonstrates that psychiatrists should not withhold or discontinue effective treatments for fear of somatic adverse effects. At the current state of knowledge, lithium initiation and even continuation in the presence of long-term adverse renal effects should be recommended in most cases. However, each case is different and we hope that our decision analysis provides support to clinicians who have to make difficult clinical decisions every day, particularly for those ‘close-call situations’ where the choice is not intuitively clear.