From the Editor
After starting lithium in the hospital, his life was transformed. My patient didn’t have another hospitalization, and he went back to excelling at his job and raising his young family.
There are many lithium success stories. But how safe is it for our patients’ kidneys? Though lithium has been used for decades, there is still controversy. We know that lithium can affect the kidneys, but how much renal change is naturally occurring (aging), due to psychiatric illnesses (like bipolar), or the medication itself?
In a new paper just published in The Lancet Psychiatry, Filip Fransson (of King’s College London) and his co-authors attempt to answer these questions with a cross-sectional cohort study drawing on 2,200 people from Sweden. They review kidney function over time for the general population, those with schizoaffective disorder and bipolar, and compare them to those on lithium. They find a significant connection between lithium and renal decline, but only after a decade of use. We consider the paper and its clinical implications.
In the second selection, Dr. Nick Glozier (of The University of Sydney) and his co-authors consider suicide rates during the pandemic in a new research article for the Australian & New Zealand Journal of Psychiatry. They note the dire predictions – of a “suicide epidemic” – that weren’t realized, and consider why, noting several factors, including that the economic downturn was mitigated by government action. Ultimately, though, they write: “suicide is an inherently difficult (stochastic) event to predict.”
Selection 1: “Kidney function in patients with bipolar disorder with and without lithium treatment compared with the general population in northern Sweden: results from the LiSIE and MONICA cohorts”
Filip Fransson, Ursula Werneke, Vesa Harju, et al.
The Lancet Psychiatry, October 2022
Lithium is a first-line maintenance treatment for bipolar disorder. However, one concern is the risk of kidney damage, requiring frequent monitoring of kidney function. More than half of patients discontinue lithium because of adverse effects. Increased creatinine concentrations arising from glomerular dysfunction or polyuria and polydipsia (nephrogenic diabetes insipidus) due to tubular dysfunction account each for 9% of all episodes of lithium discontinuation.
So begins a paper by Fransson et al.
Here’s what they did:
“In this cross-sectional cohort study, we used clinical data from the Lithium–Study into Effects and Side-effects (LiSIE) retrospective cohort study, which included patients with bipolar disorder or schizoaffective disorder whose medical records were reviewed up to Dec 31, 2017, and the WHO Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study, covering a representative sample of the general population in northern Sweden aged 25–74 years. The primary outcome was the age-associated decline of creatinine-based eGFR, assessed using linear regression. We adjusted for sex and grouped for different lengths of lithium exposure (never or <1 year, 1–5 years, >5–10 years, and >10 years). For patients with moderate-to-severe kidney disease we identified the underlying nephropathy in the case records.”
Here’s what they found:
- They drew 785 people from LiSIE and 1549 from MONICA.
- Demographics. Many patients were female (LiSIE: 63%; MONICA 52%) and, on average, middle aged (49.8 years; 51.9 years).
- Illness. “Adjusted for duration of lithium exposure, eGFR declined by 0.57 mL/min/1.73 m2/year… in patients with bipolar disorder or schizoaffective disorder and by 0.57 mL/min/1.73 m2/year… in the reference population.”
- Lithium. Lithium added 0.54 mL/min/1.73 m2 per year of treatment.
- Years of exposure. “After more than 10 years on lithium, decline was significantly steeper than in all other groups including the reference population (p<0·0001).”
A few thoughts:
1. This is an important study.
2. The above summary is too concise to fully explain the nuances and details of this paper.
3. The results in two quick sentences: patients with bipolar or schizoaffective disorder had similar eGFR decline compared to the reference population after adjusting for lithium use; treatment with lithium led to a significantly steeper decline of eGFR but in those who used for more than 10 years.
4. The individual experience varied greatly. They write: “Our findings suggest that the speed of change in GFR varies substantially between individuals. The patient longest exposed to lithium (>41 years) did not develop chronic kidney disease, but one patient had an eGFR of only 15 mL/min/1.73 m2 after 30 years of lithium exposure. In this case, causes other than lithium had been ruled out by kidney biopsy. Hence, probabilities derived from research studies cannot uncritically be applied to individual patients.” (!)
They propose the following model:
5. What are the clinical implications? In an accompanying paper, “Lithium: balancing mental and renal health,” Rebecca Strawbridge and Dr. Allan H. Young (both of King’s College London) provide clinical advice:
“These cautions do not preclude the use of long-term lithium as recommended in guidelines, given its effectiveness and safety for many people, and the ability for renal monitoring to circumvent chronic kidney disease. In cases when lithium discontinuation is indicated, alternative mood stabilisers are available. We advocate regular, careful eGFR monitoring adhering to guidelines, and we recommend large-scale audits and interventions to enhance monitoring.” (!!)
They also remind us that lithium may be more work than other psychiatric medications, but it may also be better medication for our patients:
“Lithium’s properties are well characterised, and its clinical benefits remarkable for their breadth. As well as being the gold-standard mood stabiliser for patients with bipolar disorder, lithium is effective in unipolar depression, and evidence supports benefits related (but not limited) to suicidality, neuroprotection, and cognition.”
That Comment can be found here:
6. Their last point is a very good one. In a recent BJP paper, for example, Fitzgerald et al. compared lithium to other medications for those with bipolar (n over 33 000), finding use of the medication was linked to fewer suicides, self-harm events, and psychiatric hospitalizations. This paper was considered in a past Reading and can be found here:
Two cheers then for lithium.
7. Like all studies, there are limitations. The authors note several including: “we did not link the two datasets. Therefore, some individuals might be present in both samples.”
The full Lancet Psychiatry paper can be found here:
Selection 2: “What happened to the predicted COVID-19-induced suicide epidemic, and why?”
Nick Glozier, Richard Morris, and Stefanie Schurer
Australian & New Zealand Journal of Psychiatry, 16 October 2022 Online First
In the early 2020, as the COVID-19 pandemic raged across the Northern Hemisphere and threatened the entire world, researchers, advocates and modellers predicted an ensuing suicide epidemic, widely reported in the media. In Australia’s case, the predictions were terrifyingly grim: c. 1000 extra suicide deaths per year for 5 years in a population of 25.7 million. To put this number into context, in Europe, with a population of 735 million in 2009, there were 4884 excess suicide deaths in the year following the Global Financial Crisis.
Despite these high-end predictions, by the end of 2020, there was no such epidemic. After 15 months, the suicide rates in most countries that produced data had remained stubbornly static and in some cases declined.
So begins Glozier et al.
They consider several reasons that the suicide epidemic never happened; three are outlined here:
Governments buffered the economic downturn and provided more health services
“One crucial reason for why the suicide epidemic may not have happened is that governments counterbalanced the economic and mental costs of lockdowns by increasing public expenditure. In some countries, these resulted in sustained incomes and limited job dislocation, as seen in Australia in 2020, where the unemployment rate actually fell in 2020 as foreign workers left the country.”
They note, though, that other countries didn’t follow that pattern: “In other countries, the unemployment rate rocketed, e.g. the United States, with claims going from a few hundred thousand to over 6 million per week and widespread poverty, only partially ameliorated by a one-time direct cash payment of US$1200 per person (+US$500 per child). Yet the United States, like Australia, showed no increase in its suicide rates, although an increase in the ‘deaths of despair’ not seen elsewhere, suggesting little consistency that could help predictions.”
Some countries also expanded mental health services; Australia added .75% to expenditures. Still, they note: “The health service and economic responses differed dramatically between countries where the suicide rates remained constant, suggesting these factors provide little or no consistent rationale.”
People were not as distressed by the pandemic and lockdown as predicted
“Another reason for lower suicide rates than predicted could have been that people were more resilient in their mental health responses to the lockdowns than predicted by the model. Indeed, in some countries, positive changes in mental health were observed during the earlier lockdowns as was found for the United Kingdom. Mental health in the United States recovered within 4 months (i.e. by June 2020). A subsequent meta-analysis of all of the global studies of the mental health pandemic lockdown demonstrated only a very small and transient (effect size of 0.17) increase in the rates of mental ill-health, some of which could also be attributed to other confounders, e.g. fear of the virus, and no reduction in positive psychological functioning.”
They consider the “natural experiment” in Australia where one state, Victoria, was locked down for more than three months whereas other states kept open. “[The] lockdown led only to a small increase in mental ill-health on average, but that mental ill-health effects were observed for mothers of young dependent children.”
Economic downturn may not cause suicide after all
“Another potential cause of the overprediction of suicide may stem from the fact that model assumptions exaggerated not only the spikes in unemployment but also the relationship between economic downturns and suicide.”
They note the unevenness of data historically. “Evidence from the late 1990s South East Asia financial crisis showed variable impacts of recessions on the suicide rate, with increases in Japan and Korea but no change in Taiwan. A recent analysis of Australia’s unemployment–suicide link utilising administrative time series data for 40 years from 1979 to 2017 showed no relationship between unemployment and mortality on average and, if anything, a slightly lower level of suicide deaths during periods of higher unemployment. Although evidence on the unemployment–suicide nexus exists for the United States, no such link is found in Asia-Pacific countries, France and studies of the OECD countries overall have resulted in conflicting results…”
A few thoughts:
1. This is a well-argued paper, impressively drawing on many studies.
2. In terms of the suicide epidemic that never happened, thank goodness. But we should be careful about minimizing the effects of the pandemic for some. Suicide is one metric, but not the only one.
3. This line is worth repeating: “suicide is an inherently difficult (stochastic) event to predict.”
The full ANZJP research article can be found here:
Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.