Britain’s 650,000 people with bipolar disorder should take lithium to help control their condition, despite its reputation for dulling the senses, a significant new study has found.
Researchers claim that although the drug does carry some health risks, its overall effectiveness, especially its ability to reduce self-harm and suicide, mean it should be much more widely used.
The findings are contained in the first study comparing the side-effects of the four main mood-stabilising drugs the NHS prescribes. They have prompted calls for a rethink about attitudes towards lithium, given that only an estimated 10% of those with bipolar disorder use it, mainly because patients fear it will cause loss of personality, weight gain and other problems.
The lead author behind the research told the Guardian that widespread “lithium stigma” among patients is leading to them receiving the wrong treatment and ending up admitted to hospital unnecessarily because their condition is not as well controlled as it could be.
“Lithium is a drug with a bad reputation. It is seen by patients, and some psychiatrists, as a dangerous drug. People rightly have suspicions about it. Patients say that the downsides include emotional numbing – feeling that you aren’t connected with your feelings – as well as tremors,” said Dr Joseph Hayes, a psychiatrist at University College London.
But lithium’s reputation is largely misplaced and based on the experiences of patients from the 1960s to the 1980s who were given too large a dose of the drug, he added. The new research, published in the medical journal PLOS Medicine, found that the side-effects of the mood-stabilising alternatives used by most patients are either the same as or worse than lithium, Hayes said.
The paper, co-written by Hayes and four colleagues from UCL and Oxford University, concluded that: “Lithium remains an important treatment for individuals with bipolar disorder.” It accepts that “there is clear evidence that its use is associated with a number of adverse events.”
However, it adds: “These risks need to be offset with the potentially superior effectiveness and anti-suicidal benefits of the drug compared to other treatment options.”
The researchers studied a nationally representative sample of 6,671 patients across the UK who were treated for bipolar disorder between 1995 and 2013. Of those, 2,148 had taken lithium, 1,670 had used valproate, 1,477 had been on olanzapine and 1,376 had taken quetiapine. They experienced side-effects including chronic kidney disease, thyroid disease, weight gain and high blood pressure.
The researchers’ analysis bore out one of the two main criticisms of lithium, but found the other to be baseless. They found that patients on lithium had a higher risk of suffering kidney function problems and developing hypothyroidism or hyperthyroidism and also hypercalcemia. However, none of the drugs caused more severe kidney problems.
Meanwhile, lithium patients were less likely to put on weight than patients on the other drugs. While 15%-20% of those on the three other drugs were more likely to gain more than 15% of their body weight, just 10% of those on lithium put on the same amount of extra pounds. Those on olanzapine added the most weight and experienced high blood pressure as a result.
Separate research has shown that patients on the other three medications are 40% more likely to harm themselves than those on lithium. Bipolar disorder carries one of the highest rates of suicide of any mental illness, alongside schizophrenia and alcohol and drug addiction.
The very limited use of lithium is despite the National Institute for Health and Care Excellence (Nice) advising in 2014 that it should be the standard treatment for bipolar disorder, which is also known as manic depression and is characterised by manic highs and bouts of depression. That superseded its previous view, outlined in 2006, that any of the four drugs were useful first lines of treatment for the condition, which affects about one in 100 people.
“Lithium stigma, which includes some people in the psychiatric community, leads to people using drugs that are less effective . To me as a doctor that’s a big worry because my main aim is to help people to be well and if you aren’t doing that with the best available evidence then you are failing patients,” said Hayes.
“I think that many patients are missing out quite commonly on the best available treatment. That means that people end up in hospital more often than they need to and end up achieving less in their lives than they could do if they were on lithium. The high suicide rate with bipolar disorder should encourage greater use of lithium. There should be more sensible use of it.”
Stephen Buckley, head of information at the charity Mind, said: “We welcome research which adds to our understanding of treatments and medications for people experiencing mental health problems, including bipolar disorder. But as with all areas of mental health there is still more research to be done.
“Different people will find that different treatments help with managing their mental health problems. This may be medication, talking therapies, or a mixture of both.”
Finally, Scientists Think They Know How Lithium Treats Bipolar Disorder
Almost 50 years after lithium was first approved to treat patients in the US, scientists think they’ve finally identified the molecular mechanism behind its effectiveness in treating the symptoms of bipolar disorder.
This is a huge deal. One of the biggest hold-ups in pursuit of safer and more effective bipolar medications has been not understanding the treatments we already have.
“The only way that you can make a therapy better is to understand how it was working to begin with,” says lead researcher Evan Snyder from the Sanford Burnham Prebys Medical Discovery Institute.
Bipolar disorder affects approximately 5.7 million adults in the US alone, and is the sixth leading cause of disability in the world. The incapacitating condition causes extreme mood swings between emotional highs (mania) and devastating lows (depression), which can prevent them from living their regular lives.
And to make matters worse, the available treatments are relatively primitive and unreliable.
Lithium only works in approximately one-third of patients. But even if the drug does work, it comes with a raft of side effects, including nausea, muscle tremors, emotional numbing, weight gain, and birth defects.
After a lengthy process of trial and error, the two-thirds of patients who don’t respond are left to search for other options such as antipsychotics, antidepressants, and even electric shock therapy.
The good news is that, if this research is verified and we do finally know lithium’s molecular target, researchers will be able to start screening for gentler and more effective drugs that do the same thing.
It also opens up new possibilities for better ways to test for the condition and predict who will respond to the drug.
As Snyder explains:
“Lithium has been used to treat bipolar disorder for generations, but up until now, our lack of knowledge about why the therapy does or does not work for a particular patient led to unnecessary dosing and delayed finding an effective treatment. Further, its side effects are intolerable for many patients, limiting its use and creating an urgent need for more targeted drugs with minimal risks.
Importantly, our findings open a clear path to finding safe and effective new drugs. Equally as important, it helped give us insight into what type of mechanisms cause psychiatric problems such as these.”
To figure out how lithium was affecting the brain, the researchers mapped it response pathway using human induced pluripotent stem cells (hiPS) – regular cells taken from bipolar patients that either did or didn’t respond to lithium, and were then reprogrammed to behave like stem cells.
They found that a protein called CRMP2 was inactive in the bipolar patients’ cells – a protein that’s associated with nerve cell communication.
But when lithium was added to hiPS cells generated from lithium-responsive patients, it rectified, and CRMP2 activity was returned to normal.
This suggests that the mechanism behind bipolar disorder isn’t necessarily always genetic, as many researchers had previously assumed, but instead is an issue with how the CRMP2 protein is regulated in the cell.
That’s good news, because it indicates that it could be possible to fix the problem with the right medication.
“We realised that studying the lithium response could be used as a ‘molecular can-opener’ to unravel the molecular pathway of this complex disorder, that turns out not to be caused by a defect in a gene, but rather by the post-translational regulation (phosphorylation) of the product of a gene – in this case, CRMP2, an intracellular protein that regulates neural networks,” says Snyder.
“This ‘molecular can-opener’ approach – using a drug known to have a useful action without exactly knowing why – allowed us to examine and understand an underlying pathogenesis of bipolar disorder.”
The team verified their findings using brain specimens from deceased patients with bipolar disorder, showing that they also had neurons with less active than usual CRMP2. They also showed the same mechanism worked in animal models and in cultured live neurons. They also mapped the upstream and downstream effects of the target, creating a map of what they call the “lithium response pathway”.
For now, this is only one study, and the molecular pathway needs to be verified by independent teams before we rewrite the textbooks. It’s also probable that there are many underlying causes of the complex condition, so it’s unlikely that this one mechanism will be the answer to every case of bipolar.
But any knowledge that can help us take better care of the millions of people around the world living with mental health issues is a big step in the right direction.
The next move for the team is to start screening existing drugs to see if they can find any molecules that target this same pathway, but with fewer side effects or more success than lithium.
Snyder explains in the video above that if they successfully identify a candidate drug that’s already being used, they could get it into clinical trials within one to two years.
The research has been published in the Proceedings of the National Academy of Sciences.
Lithium For Bipolar Disorder – Pros And Cons Unclear
The most effective long-term treatment for bipolar disorder is lithium. It offers protection against depression and mania and reduces the risk of suicide and short-term mortality. However, according to a study in The Lancet ,safety concerns have made the use of lithium controversial.
The authors examined about 400 articles to research the possible adverse effects of lithium and found abnormalities in the thyroid and parathyroid in about 25% of patients who receive lithium therapy, compared with 3% and 0.1% in the general population. They also observed that lithium causes weight gain and has the potential to slightly reduce the kidney’s ability to concentrate urine.
They highlight that evidence of lithium treatment being associated with congenital abnormalities in pregnancy is still uncertain, and there is very little proof that links lithium to skin problems or hair loss.
The authors recommend that patients should discuss the risks of adverse events with their physicians before starting lithium treatment, and also suggest having a serum calcium test to baseline blood tests due to the high risk of hyperparathyroidism. They also state that the effects of lithium in pregnancy are uncertain and need more evidence, and therefore newly recommend explaining the uncertainty about risk of congenital malformations to women of childbearing age contemplating lithium treatment, instead of considering lithium as a contraindication, saying:
“Women who would like to conceive or have become pregnant while receiving lithium should be advised that the increased risk of congenital malformations is uncertain; patient and clinician should discuss the balance of risks between harm to the baby and maternal mood instability before making a decision to stop lithium therapy.”
They continue saying that more research is also required to clarify the link between lithium, calcium, and the kidneys and suggest that those currently undergoing lithium therapy should have 12-monthly or sooner repeat tests of renal, parathyroid, and thyroid function. The tests should be conducted even more frequently, should an abnormal result be found or the patient has a family history of endocrine disease.
They also recommend to immediately repeat blood tests in patients with changes in mood state, for instance mania and suggest to routinely record any events of adverse effects, including skin and hair disorders, so that these can be added to the existing body of evidence.
The authors highlight that overdosing of lithium is dangerous, and so is taking lithium under circumstances affecting sodium or blood volume depletion. They point out that this occurs in the majority of patients who experience lithium toxicity when they are ill with diarrhea, vomiting, heart failure, renal failure, at times of surgery, or secondary to a drug interaction, for example with non-steroidal anti-inflammatory drugs and angiotensin-converting-enzyme inhibitors.
“Evidence has confirmed the important therapeutic benefits of lithium relative to some of the alternative drugs that have replaced it, which might lead to wider use of lithium. Clinical practice guidelines have long recommended lithium as a first-line long-term treatment for bipolar disorder but its use has decreased, partly because of safety concerns…This review provides a comprehensive synthesis of the evidence of harm that should inform clinical decisions and draw attention to key questions in urgent need of further clarification.”
Australian doctors Dr Gin S Malhi at the University of Sydney, NSW and Dr Michael Berk at the University of Melbourne, VIC, declare in a linked comment:
“In the context of efficacy data that have upgraded the ranking of lithium, and in conjunction with new data that recalibrate the safety risks of alternative drugs, this study provides timely clarification of the toxicity associated with lithium therapy and, on balance, reaffirms its role as a treatment of choice for bipolar disorder.”
Written by Petra Rattue
Low-Dose Lithium: A Different, Important Tool
Suppose your patient with bipolar II disorder is better on lamotrigine—but not better enough. She’s already underway with a psychotherapist whom you know is using bipolar-specific psychotherapy techniques (eg, the new bipolar-specific cognitive behavioral therapy for insomnia, CBT-IB—from you, perhaps!) What are her augmentation options? One of them is clearly lithium, though common reviews of its side effects (eg, a recent CME here in Psychiatric Times) can be daunting.
But hold on a minute: most of lithium’s risks are dose-related, particularly the toxicity concerns. Low-dose lithium (eg, a blood level of ≤ 0.7 mEq/L) is far less daunting. Even an inadvertent addition of an antihypertensive or NSAID is unlikely to push a patient from a level of 0.7 to beyond 1.1, although caution is still warranted.
Likewise, lithium’s renal risks—easily avoided with standard monitoring as long as one is prepared to move on to another agent if creatinine levels are rising—are even lower with low-dose lithium. The side effects that make people want to stop treatment (tremor, frequent urination, nocturia) are also much less frequent.
In general, the only significant problems with low-dose lithium are tolerability and thyroid issues. About 1 person in 10 to 15 gets dull, flat, and “blah” (the “lithium made me a zombie” effect, overrepresented in online testimonials). I explain to my patients in advance that if this happens, we’ll give up on it. This adverse effect does not diminish with time and generally persists even if the dose is reduced. Then there’s weight gain: is it dose-related? To my knowledge, this has not been established. I nurture some hope this is so.
That leaves the thyroid issue. Thyroid-stimulating hormone (TSH) levels must be monitored even with low-dose lithium. In women, induction of hypothyroidism is extremely common—and almost predictable in women with a family history of thyroid problems. The latter may be an uncovering of an autoimmune disorder. If your patient has a high-normal TSH value before lithium (eg, 2.5 mIU/L or above, and certainly above 3 mIU/L), she is at even higher risk for lithium-induced hypothyroidism.1
So monitor closely, and even more closely in those at greater risk: for example, every 6 weeks until a trend (up, or flat) is established. Once you have established that the TSH level is not rising, the probability of later hypothyroidism due to lithium is much diminished and you can back off to getting a TSH level with your 6- to 12-month check of creatinine.2
If you do become pregnant on lithium, don’t stop it, call your doc’ or NP. She/he may have you stop, but depending on the timing of your pregnancy discovery, there may be several options. Don’t just stop it and then sit back to watch what happens! that could be riskier to your developing child than continuing lithium.
How do I start?
As I’ve gotten older, my suggested starting dose has gotten lower and lower! Here are some ideas to discuss with your prescriber, who very likely will suggest going faster than this…
The smallest pill is 150 mg. If your symptoms are not extreme, you can take a little longer to move your dose up. In my experience, it’s much better to go slowly: better chances of having lithium work, without side effects!
Start with one tablet at bedtime. Increase by one tablet at bedtime every four days until:
a) your “target symptoms” improve: continue that dose or
b) side effects you cannot tolerate: decrease by one tablet and continue or
c) you reach 600 mg per day/night.
You may split the dose (one in the morning, two in the evening), to decrease minor side effects.
When you have been taking the same dose for more than 4 days, you are ready for a blood test that will show your lithium level. Ask your doctor for instructions on going to the lab. We always check your level before your morning dose (“trough level”) so that we can compare one result with another accurately. Carry your morning dose with you and swallow it after your blood is drawn. It is ok to have breakfast before your lab test.
Does lithium interact with other medications?
Lithium itself does not cause major interaction problems. Other medications may change how the kidney is getting rid of lithium and lead to increased levels. Most blood pressure medications and nearly all “non-steroidal anti-inflammatories” like ibuprofen and naproxen (Motrin, Advil) have strong effects on lithium levels; careful lab testing is usually required with these combinations.
Is this addictive?
There is no “addiction”: if you stop, there is no “craving. However, there is good evidence that stopping lithium suddenly can cause a rapid return of symptoms. It is important to taper slowly off lithium, taking at least several weeks to do so, unless there are reasons to go faster. Stopping over several months is much wiser.
More lithium pages
- lithium could prevent Alzheimer’s?
- lithium risks
- lithium history
- lithium levels go down when manic? sometimes, yesl
- lithium orotate