Kellie Newsome, PMH-NP

Blue light is getting blamed for everything from eye strain to cancer lately, but what does it do to our patients with depression and bipolar disorder. A lot, as you will see in this podcast, but it depends on what time of day it is shining.

, the Voice of Psychiatry. With thoughtful insights into the world of mental health, this podcast provides timely clinical commentary and practical cutting-edge pearls for you and your practice. We hope you enjoy.

I am Chris Aiken, the Mood Disorders Section Editor for 

, and I am Kellie Newsome, a psychiatric NP and the cohost of the 

: The biological clock is set by the daily rhythms of light and dark – morning sunrise and evening sunset. And this clock is so integral to bipolar disorder that you could almost rename it 

. Actually, patients prefer that name over bipolar disorder, and it gets to the heart of the problem. Bipolar is tightly linked to the genes that regulate the biological clock, and lithium actually 

 the clock by altering the expression of those genes.1 Many of the behavioral therapies for bipolar disorder, like dark therapy and social rhythm therapy, also work through the biological clock, helping patients to keep it running smoothly by regulating their exposure to light, darkness, and the timing of daily activities.

But bipolar is not the only mental illness that is linked to disrupted circadian rhythms. 

 is as well, though to a lesser extent – for example, rates of circadian rhythm disorders like the phase-delay night owl syndrome are more common in bipolar and unipolar, but they are about 20% less common in unipolar. And research is exploring circadian rhythm therapies in 

But while researching is advancing in the circadian direction, society is moving the other way. Indoor living and nocturnal light are dampening the natural signals that set the biological clock, and there is evidence that this is causing harm in our patients. In this podcast, we will explore those dangers, but first a little background on how light – and in particular blue light – set the biological clock.

 Light suppresses melatonin, but not just any light. It is the color that matters here, and blue light in the 460-480 nm range is particularly good at suppressing melatonin and promoting wakefulness. In the 1990s, a new photoreceptor called melanopsin was discovered that only responds to blue light, and it is this receptor that regulates melatonin production through the suprachiasmatic nucleus, the time-keeper of the biological clock.

What that means is that the body’s internal clock depends on strong shifts in blue-spectrum light at the bookends of the day: morning and night. High levels of evening blue light, and low levels in the morning, disrupt not just circadian rhythms but also the clock genes implicated in bipolar and other psychiatric disorders.

The main source of that blue light are electronic gadgets that were not available 20 years ago. Smart phones, LED screens, and energy-efficient bulbs emit a blue haze of light that is very different from the yellow starlight that we evolved under. This light may look white, like fluorescent bulbs, but white light has a lot of the blue wavelength within it. Distance also matters here. A cell phone close to your face emits about as much blue light as a large screen TV across the living room.

: The problem is not just psychiatric. Blue light is associated with physical health risks including obesity, diabetes, cancer, cardiovascular and neurologic diseases, gastrointestinal ulcers, and adverse reproductive outcomes.

 The American Medical Association released a 

 calling for reductions in nocturnal blue light, and psychiatry is catching on as well. The American Academy of Child and Adolescent Psychiatry updated their 

 in 2018. They no longer recommend night lights for anxious children and instead emphasize elimination of blue-light sources in the bedroom. Child psychiatrists in Canada have even 

: It is the young and old that are most vulnerable to these light changes, as we will see in the research here.

 But they are also the patients who are more likely to sleep with some lights on. So, if your patient needs a light at night – whether because of a childhood phobia or a fall risk – they can purchase amber nightlights that do not emit the blue wavelength.

: Psychiatric patients in general are more sensitive to the circadian disrupting effects of evening blue light, particularly patients with bipolar disorder. Melatonin is delayed, diminished, and more easily suppressed by blue light in these patients.

 Circadian disruptions often trigger new episodes of mania and depression, such as shift work, seasonal changes, and travel across multiple time zones.

: Travel across time zones is only a problem with air travel, because the clock has time to adjust when you travel by land or sea unless you are driving at 300 miles per hour. And on average it only causes problems when patients travel across 2 or more time zones. Mania is more common with west to east travel, and depression more likely when travelling east to west. A simple rhyme can help you remember it – west is depressed – because travelling westbound can trigger depression.

: We can add nocturnal blue light and ambient bedroom light to that list of circadian disruptors. Evening use of smartphones delays and reduces melatonin secretion, and impairs sleep and cognition with a medium effect size (0.5), which means the effect should be noticeable to the casual observer.

 A viscous cycle is at play here, as evening-types (night owls) have a greater tendency to use electronics at night, and that use independently shifts circadian rhythms toward the evening type (phase delay).

 The evening chronotype is prominent in adolescents, and being a night owl is a risk factor for bipolar disorder, depression, and substance abuse.

Ambient bedroom light is also a problem, as it passes through the eyelids and suppresses melatonin during sleep. In controlled animal studies, ambient nocturnal light causes depression, impedes learning, and has detrimental effects on the brain. It lowers BDNF and shortens the dendritic spines that are essential for learning and cognition.

The circadian system is also involved in critical periods of brain development, and disruptions of light signals may play a role in the onset of psychiatric illnesses as well as their exacerbation.

 When mice are exposed to nocturnal dim light as infants, they grow up to have more anxiety as adults.

 Human studies have found a strong link between rapid flux of 

A study from Japan illustrates the problem for our patients.15 They followed 863 older adults for several years, carefully measuring how much light they were exposed to in their bedrooms. On follow up, the risk of depression was directly correlated with how much light they were exposed to in their bedrooms. Those who slept in pitch darkness had the lowest risk, but what is interesting is how little light was necessary to accomplish the shift: 5 lux – which is equivalent to a night light – was the cut off. Those who slept with at least 5 lux in their bedroom had double the risk of depression 2 years later.

That study was not controlled, although they attempted to control for confounders that might otherwise explain the association. But buried in the discussion was a sentence that struck me. The authors believed that the health risks of evening light are so well documented in animal and epidemiologic human studies that a controlled trial would be unethical in humans. In other words, we already know too much to learn anymore.

Instead, it is time for action, to educate our patients to follow the natural flow of day and night. That means bright light in the morning, low levels of blue light in the evening, and pitch dark in the bedroom. Those steps are not easy to follow in the modern world, and in a future podcast we will review new technologies that can ease those changes.

, and you can also catch us every Monday on the 

is the Mood Disorders Section Editor for 

 He has written several books on mood disorders, most recently

 with his cohost Kellie Newsome, PMH-NP. The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for

and is also a practicing psychiatric mental health nurse practitioner in Winston Salem, NC, at the Mood Treatment Center. Raised in Tasmania, Australia, Kellie moved to the United States in 1998.

Lithium and bipolar disorder: Impacts from molecular to behavioural circadian rhythms.

2. Charrier A, Olliac B, Roubertoux P, et al. 

Clock genes and altered sleep-wake rhythms: their role in the development of psychiatric disorders.

Suicide attempts in children and adolescents: The place of clock genes and early rhythm dysfunction.

Health consequences of electric lighting practices in the modern world: A report on the National Toxicology Program's workshop on shift work at night, artificial light at night, and circadian disruption.

Disruption of adolescents' circadian clock: The vicious circle of media use, exposure to light at night, sleep loss and risk behaviors.

The bipolarity of light and dark: A review on bipolar disorder and circadian cycles.

Circadian rhythm in bipolar disorder: A review of the literature.

Effects of smartphone use with and without blue light at night in healthy adults: A randomized, double-blind, cross-over, placebo-controlled comparison.

Outdoor light at night (LAN) is correlated with eveningness in adolescents.

10. Kivelä L, Papadopoulos MR, Antypa N. 

11. Bedrosian TA, Vaughn CA, Galan A, et al. 

Nocturnal light exposure impairs affective responses in a wavelength-dependent manner.

Clock genes control cortical critical period timing.

13. Borniger JC, McHenry ZD, Abi Salloum BA, et al. 

Exposure to dim light at night during early development increases adult anxiety-like responses.

Solar insolation in springtime influences age of onset of bipolar I disorder.

Bedroom light exposure at night and the incidence of depressive symptoms: a longitudinal study of the heijo-kyo cohort.

Podcasts

Blue light is associated with a host of physical health maladies, including obesity, diabetes, and cancer. But what does it do to patients with depression or bipolar disorder? 

Blue Light, Depression, and Bipolar Disorder

 Lamotrigine was launched for bipolar disorder in 2003, but it was a quiet launch, and since then a few myths have gathered around it as if to fill that vacuum. Today, we will address 4 of them.

, the voice of psychiatry. With thoughtful insights into the world of mental health, this podcast provides timely clinical commentary and practical cutting-edge pearls for you and your practice. We hope you enjoy it.

 On June 20, 2003, the world had its eyes on the United States’ invasion of Iraq. Some of us were following Martha Stewart’s indictment for insider trading, and quite a few were lining up at bookstores to be the first to buy the 5th installment in the Harry Potter series. But Russell Katz, MD, was busy at his desk on this day at the US Food and Drug Administration (FDA) headquarters, writing a letter to GlaxoSmithKline announcing the approval of their anticonvulsant lamotrigine in bipolar disorder. But the approval was not a slam-dunk. GlaxoSmithKline had submitted 12 trials, and only 2 of them were positive. Lamotrigine did not work in acute mania; it did not work in acute bipolar depression; and it did not work in rapid cycling.

But bipolar disorder (BD) is a chronic condition, and that is where the medication succeeded: in the maintenance phase.

The 2 positive studies looked at lamotrigine in the long term, over 1 and a half years. There, lamotrigine helped patients stay well about twice as long as a placebo.

 Katz knew that long-term studies like this were expensive and hard to come by, but for patients who have to stay on a mood stabilizer year after year it is this kind of data that matters most. So he gave it an indication for delaying new episodes of depression, hypomania, and mania in BD.

 And that is how lamotrigine was launched. But there are a lot of loose threads in that story that have tangled into myths, and today we are going to unravel 4 of them so you can use lamotrigine more effectively in practice.

 But first a warning. Lamotrigine is not a panacea. It works in BD, but it does not treat non-bipolar depression. There the studies are mixed: half positive, half negative. It has positive controlled trials in obsessive compulsive disorder, borderline personality disorder, and depersonalization disorder, but those studies are few and small.

 So do not start prescribing lamotrigine to every moody individual you see, because this medicine has one big risk that makes those uncharted adventures unwise: the potentially fatal rash of Stevens Johnson Syndrome.

That rash is part of the reason that lamotrigine had such a soft launch. Early on, the manufacturer decided not to market lamotrigine to primary care practices, and to minimize direct to consumer advertising. The decision may have hurt their quarterly profits, but it helped them stay in the market. You see, lamotrigine was nearly yanked off the market after its launch in epilepsy 10 years earlier. Back then, doctors were starting the drug at 100mg a day, which lead to an alarming rise in potentially fatal Stevens Johnson rashes. The medication only survived when the company was able to show that it could lower this risk through the slow titrations that we use today. Now that risk is around 1 in 3000.

GlaxoSmithKline was concerned that if they overhyped the drug, then clinicians with little experience in BD would prescribe it to every moody patient they saw, and if they overlooked the DSM in that way they might also overlook the titration instructions, causing a second flare of serious rashes that would cause the FDA to pull the plug again.

 And now let us get into those myths. There are 4 of them.

Myth #2: Lamotrigine does not treat acute episodes of bipolar depression

Myth #3: Lamotrigine is a weak mood stabilizer

Myth #4: It is a good idea to stop lamotrigine when a patient relapses, because it is probably not working

 This one is kind of true. Lamotrigine failed in the acute mania trials, and nothing that we have learned about this drug in the 25 years since suggests that it has any role in acute mania. But lamotrigine does help prevent mania, although it is better at preventing bipolar depression than it is at preventing mania. What that means in practice is that you should not rely on it as the sole maintenance medication in patients with a history of severe mania, but it may be used as monotherapy in bipolar II disorder, where the depressions are more common and the manic symptoms brief and mild.

In fact, many bipolar experts see good results in cyclothymic patients, who cycle frequently between mild depression, hypomania, and mixed states. That observation only supported by open-label studies, but hey – there are zero controlled medication trials in cyclothymic disorder so that is as good as it gets.

Myth #2: Lamotrigine Does Treat Acute Episodes of Bipolar Depression

 Among the 12 trials on Katz’s desk, 5 of them are good candidates for the most disappointing trials in the history of psychiatry. These were the 5 controlled trials in acute bipolar depression, all funded by the manufacturer, and all of them failed. The trials were never published, but most psychiatrists knew about them when lamotrigine was released, and it gave some of us the impression that lamotrigine was a weak mood stabilizer that barely got approved for an indication that was not at the top of the list for doctors or patients.

But we have since learned that lamotrigine does treat acute depression, it just takes a little longer than faster options like the atypical antipsychotics. The problem is that the early studies only lasted 7 weeks, and lamotrigine requires a slow titration that takes 4 to 6 weeks to reach a therapeutic level. Later, lamotrigine did prove efficacious for acute bipolar depression in 2 independently funded randomized placebo-controlled trials.

 Wait a minute. You are saying the industry sponsored trials were all negative but the independent ones were positive? That is a first.

 Yes, and the difference is that the independently sponsored trials gave lamotrigine a little more time. They lasted 8 to 12 weeks instead of 7 weeks. Also, lamotrigine was used as augmentation in these trials – in 1 it augmented lithium and the other quetiapine – but I think lamotrigine can work as monotherapy in acute depression and the real difference here was the timespan.

 One reason we think it works as monotherapy is that John Geddes, MD, FRCPsych, Joseph Calabrese, MD, and Guy Goodwin, DPhil, reanalyzed the original 5 negative trials in an independently funded meta-analysis.

 They found that there was a positive signal in the original studies, but they were too small to detect it. When combined together, totaling 1072 participants, lamotrigine had a small effect, bringing about a meaningful response in 1 out of 11 participants. But hey, cariprazine got FDA approval in bipolar depression with the same number needed to treat, and lamotrigine’s efficacy only starts to build at that 7-week mark. If you use lamotrigine for acute depression, you will probably need to wait about a month and a half to see an effect, and, judging from the longer trials, those benefits are likely to keep building over the next 1 to 4 months.

A common strategy then is to start lamotrigine with a faster-acting agent like an atypical antipsychotic, and then slowly taper off the antipsychotic as lamotrigine starts to kick in. This gives you the best of both worlds: lamotrigine has excellent tolerability over the long term, with a low risk of weight gain, fatigue, cognitive problems, sexual dysfunction, or any of the long-term medical problems that show up in the warnings for antipsychotics.

 One risk we do not think about enough is stroke. Stroke is the #1 cause of death in bipolar disorder, and lamotrigine and lithium are the only mood stabilizers that do not increase the risk of stroke; all the others have some marks against them there.

 I am going to get on a soap box for a minute here and argue that bipolar is not a mental disorder. It’s a physical disorder, and not just because the brain is a physical organ. Heart disease starts 10 to 15 years earlier in individuals with BD, and you can even detect cardiovascular changes in teens with bipolar. Lifestyle may play a part, but I think about all that adrenaline pumping through the veins during mania and mixed states. This is a whole-body illness, and we ought to be thinking about long-term morbidity and mortality when choosing a mood stabilizer, not just relieving acute symptoms.

 is often criticized for promoting biological psychiatry through its black-box, symptom check-list approach. But to me, it is not biological enough. You could read the whole book and walk away with little sense that these mental illnesses are wrecking havoc on the heart, the gastrointestinal tract, the immunologic and neuroendocrine systems. You would never get that sense from reading Harrison’s textbook of internal medicine.

Myth #3: Lamotrigine Is a Weak Mood Stabilizer

 Yes, and that segues back to another myth about lamotrigine, which is that treatments that are slow to act are not strong ones. This is not how chronic diseases are approached in other medical specialties, which naturally take a long-term, disease-modifying view. You will never see a diabetes study that looks at change on a symptom check-list over 4 weeks. Or take hypertension. Clonidine lowers blood pressure right away, but most physicians prefer a thiazide for hypertension because it lowers the long-term risks of morbidity and mortality.

Individuals with bipolar disorder die 10 years earlier on average, and not from suicide. Kellie, can you read the top causes of death in bipolar disorder

Chronic obstructive pulmonary disease (COPD)

 Right, so if you can find a mood stabilizer that reduces those risks, or at least does not increase them, that is golden. Lamotrigine is neutral on all of them, and 

 most of them. Specifically, lithium lowers the risk of heart disease, 

 But we are getting a bit ahead of ourselves here. I mean, long-term medical risks are important when considering a mood stabilizer, but we also want something that prevents the episodes. Here we have an interesting finding from studies that have compared lithium and lamotrigine.

 Lithium offers better prevention against the manic side, while lamotrigine works better against the depressive side, so combining the 2 makes sense. And one study did that – the LamLit trial – and confirmed that there are indeed additional benefits to combining the 2.

 And that is the long-term perspective that we need to take when choosing a mood stabilizer. This does not come naturally in psychiatry. If you work in a hospital, insurance is pressuring you to get the patient better quickly, so lamotrigine is not going to be your go-to agent. And if you work in an outpatient office, ask yourself: When was the last time a patient came in saying “I’d like a medication to prevent bipolar disorder”? In psychiatry, we treat suffering, and our patients want something that will work quickly.

Myth #4: It Is a Good Idea to Stop Lamotrigine When a Patient Relapses, Because It Is Probably not Working

 In the maintenance trials, lamotrigine delayed the time to a new episode by 197 days, about half a year, vs 86 days or 3 months for placebo. So it is about twice as effective as placebo, but it does not provide 100% protection (no mood stabilizer does). In practice, here is what I tell patients when starting it:

Lamotrigine’s going to have a slow build because you have to raise it slowly to prevent a serious rash. That means you’re going to feel better gradually over the next 1 to 2 months, but on the other hand you are not likely to have many side effects or medicated feelings. And that is a good thing because you are likely to need something long term to prevent mood problems, and this one does not have any major long-term risks. But keep in mind it is not going to prevent all mood episodes, but it will cut the rate of those episodes in half. So instead of having depression, say, every year, it may be every 2 years. But no medication does everything, and there is a lot you can do to raise those odds of success.

Then I talk about behavioral strategies for bipolar and depression. If you are interested in that, we have a separate podcast for patients that teaches these strategies. Search for 

 A common mistake is to stop lamotrigine when an episode returns, which is a bit like stopping blood pressure and cholesterol medications because a patient had a heart attack. Lamotrigine’s most robust effects are in prevention, and prevention is difficult to measure in psychiatry. You would need a before-and-after mood chart to confirm that the medication is lowering the frequency of episodes as it promises to do. Even then the work is difficult because so many other factors can make mood better or worse. What I look for is improvement in the first 3 to 6 months after starting lamotrigine. If a patient stops it, I watch for worsening over the next 3 to 6 months. And I also listen for something that I have heard a lot of patients say on this medication, particularly those with the frequent ups and downs of cyclothymic disorder.

 They say they still feel the same about whatever problems they were having in life, but the feelings are less overwhelming. They see things in perspective better. And that matches up with what we see in neuroimaging studies of lamotrigine. The 

 is less reactive to emotionally disturbing images, there is a rise in brain-strengthening 

 in the amygdala and frontal lobes. Overall, there are volumetric changes in 

, which react to emotional events, and the frontal lobes, which temper those emotions and help individuals see things in perspective.

 That sounds like something we could all use.

Hold it there! This medication is not for everyone, and those imaging studies were done in individuals with bipolar disorder.

 Always on your soapbox. We will be back with more practical updates on

is the Mood Disorders Section Editor for Psychiatric Times

1. Goodwin GM, Bowden CL, Calabrese JR, et al. 

A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder.

Rechallenge with lamotrigine after a rash: a prospective case series and review of the literature.

4. Manning JS, Haykal RF, Connor PD, et al. 

Sustained remission with lamotrigine augmentation or monotherapy in female resistant depressives with mixed cyclothymic-dysthymic temperament.

5. Goldberg JF, Bowden CL, Calabrese JR. 

Six-month prospective life charting of mood symptoms with lamotrigine monotherapy versus placebo in rapid cycling bipolar disorder.

6. van der Loos ML, Mulder PG, Hartong EG, et al. 

Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial.

7. Geddes JR, Gardiner A, Rendell J, et al. 

Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial.

Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials.

Mood stabilisers and risk of stroke in bipolar disorder.

A deep dive into the history, side effects, and efficacy of a controversial drug. 

Four Myths About Lamotrigine

I have an unhealthy fear of certain medications. Tricyclics, MAOIs, and lithium. All of these have a reputation for adverse effects that is – perhaps – unearned. In practice, I’m constantly surprised by how well-tolerated they turn out to be. In the case of lithium, that surprise has been confirmed both in medical research and patient surveys. When it comes to the side effects that matter most to patients – sedation,

 ­­– lithium’s tolerability ranks right behind lamotrigine if we look at the clinical research. For example, the 

 is only 1 in 16 to 1 in 27 on lithium, compared to 1 in 5 for many other mood stabilizers.

But let’s look beyond the clinical research. A few years ago a Google company called CureTogether posted 

 asking people with bipolar disorder what they found most helpful in their recovery. Over 3000 responded, and only 2 medications made their top 10 list: Lamotrigine and lithium. The rest of the top 10 were behavioral tools.

Most of the lithium’s adverse effects are manageable, and in this podcast we’ll show you how to do it. To start with, titrate lithium slowly. Lithium’s main benefits are in long-term prevention, so there’s usually no reason to rush it (unless you are trying to help a manic patient stay out of the hospital). Start with 300 mg at night and raise it by 300 mg every 5-7 days. Cut those numbers in half if the patient is frail, elderly, or is taking a medication like a thiazide diuretic that can raise lithium.

The main reason people stop lithium in the early phase is nausea. A slow release version will reduce that risk, as will taking the lithium after a meal or with a glass of milk. Most other adverse effects improve with slow release as well – it cuts their overall rate by about 50% - except one: diarrhea. 4 Patients with diarrhea on lithium due better with instant release lithium that gets in and out of their system faster.

Common remedies for nausea (eg, ondansetron, promethazine, ginger capsules) or diarrhea (eg, loperamide, milk of magnesia) are safe to take with lithium.

Another way to improve side effects is to lower the dose. For most patients, the optimal blood level for long-term prevention is 0.6, or somewhere in the range of 0.4-0.8. The same blood level is ideal for treating depression – whether bipolar depression or unipolar. The only place where you’ll need a high dose is in acute mania, where serum levels of 0.8-1.2 are usually necessary.

 need the same blood levels as adults, but the elderly are different. Aim for a serum level that’s 30% below the usual in patients over age 60, and then further personalize that dose based on their response.

 The blood-brain barrier becomes more permeable as we age, so more lithium gets into the older brain at lower serum levels. Conservative dosing in the elderly has another benefit: These patients are much more sensitive to lithium’s side effects, particularly imbalance and tremor.

Tremor is one of the most common side effects with lithium, and it is very sensitive to the dose. The first step is to lower caffeine and – if possible – other tremor-promoting medications like bupropion (Wellbutrin) or atypical antipsychotics. Beta-blockers help lithium tremor, and although propranolol is the most commonly used, there is research supporting other beta blockers like atenolol, metoprolol, and nadolol for lithium tremor.

 The average dose of propranolol is around 120 mg/day. Usually we start with instant release propranolol and then change to the extended release after figuring out how much they need.

You may read that beta-blockers interact with lithium, and this is true, but the interaction is minor. They usually raise its levels by about 20%.

Another option with dual-benefits for lithium tremor is nimodipine. This calcium-channel blocker has good research for essential tremor, and is used third-line for mania and mania and rapid cycling.

 It’s well tolerated, and a typical target dose is 120mg a day. If your patient doesn’t want to add another medication in and prefers natural remedies, there’s high-dose vitamin B6. In doses from 900-1200 mg/day vitamin B6 improved lithium-related tremor, and it may reduce adverse effects on antipsychotics as well. B6 has open-label data for akathisia and tardive dyskinesia.

 Although natural, high-dose B6 is not risk free and can rarely cause neuropathy which usually resolves with discontinuation of the vitamin. It is hard to find B6 in a dose that high, so I keep a list of products on my 

Weight gain is a side effect on most patient’s minds when considering lithium, but the risk of significant weight gain is much lower than most patients expect. I start with some reassuring data: In a large meta-analysis, patients actually lost weight on lithium during the acute phase of treatment.

 Over the long-term, however, weight gain is possible. About 1 in 3 patients will gain 4-10 lbs on lithium, and most of that weight gain occurs in the first few years of treatment.

But the most important part of this education is to let your patient know that there is something they can do about it. Lithium will make them thirsty, so if they stick with water and avoid caloric beverages they can lower that risk – and that includes avoiding diet soft drinks which actually cause weight gain through indirect metabolic effects even though they have no calories of their own. 

Another way to reduce weight gain is to optimize thyroid function on lithium. Beyond that, any reasonable approaches for weight loss can be used, such as diet, exercise, or medications like topiramate 50-100 mg/day.

Like most psychiatric medications, lithium can cause sexual dysfunction. We know of one evidence-based remedy for this: Aspirin, at least for men. In a randomized, double-blind trial of men with sexual dysfunction on lithium aspirin 240 mg/day improved the problem.

Phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil) can also be used.

Now we get to the most serious risk with lithium: Renal insufficiency. Here is what I tell patients. As you age, the kidneys tend to slow down, and lithium can make them slow down even more in some patients who take it long term. We will monitor the kidneys and may need to lower or stop it if we see this happening, because if we don’t catch it it could – very rarely – go on to kidney failure.

There are at least 3 ways to protect against renal problems on lithium.

First, give the entire dose at night. This strategy improved renal function in a few long term comparison studies.

Next, avoid toxic levels. High levels of lithium can kill kidney cells, and that may be why one large study found a direct correlation between number of toxic episodes on lithium and renal problems. It also looked like the kidneys were spared in that study if the lithium levels were kept at or below 0.8.

Watch out for extreme polyuria and polydipsia. These are signs of nephrogenic diabetes insipidus, which is both an adverse effect on lithium and a risk factor for renal insufficiency. A laboratory test will reveal elevated sodium in the blood and very dilute urine; check for urine osmolality, urine sodium, basic metabolic panel. Nephrogenic diabetes insipidus is a risk factor for future renal insufficiency, and there is some evidence that treating the syndrome can reduce that risk by preventing fibrotic changes in the kidneys, such as with amiloride.

If the serum creatinine starts to rise, lower the lithium to the lowest effective dose and check it more often. Consult a nephrologist if the serum creatinine rises to 1.5 mg/dl.

Another medical risk with lithium is hypothyroidism. This is usually treatable with a thyroid supplement, and you don’t need to stop lithium because the thyroid function goes down. If you do come off lithium, the hypothyroidism usually resolves – but not always – so you can gingerly try to come off the thyroid medication while checking levels. 

Hypothyroidism may be worth addressing on lithium even when it is subclinical. A controlled study from the Mayo Clinic found that patients prescribed lithium were less likely to relapse into depression if their TSH was close to 2.4 microIU/ml.

Lithium has several dermatologic risks. It can cause acne and psoriasis, and some patients report thinner, brittle hair on it although overt hair loss is rare.

Any standard treatments for acne can be used with lithium,10 but one to consider is minocycline. This antibiotic has neuroprotective and antiinflammatory effects, and it may treat depression, according to a handful of small-to-medium size controlled trials in bipolar and unipolar depression (the dose of minocycline for depression is 200 mg/day;

 lower doses are used for acne, eg, 1 mg/kg/day).

 along with their antibiotic to avoid problems in the gut microbiome. Probiotics also have a growing evidence base in depression, anxiety, and bipolar, and there’s some evidence that probiotics help acne. Psoriasis – those scaly, dry patches of skin that worsen in the winter and tend to show up on the elbows, knees, palms, face, or back - is a relative contraindication with lithium. For this I will refer to a dermatologist, but I may suggest 2 CAM treatments that can help bipolar and psoriasis. In a few small trials, psoriasis improved with 

 – both of which are fairly risk free and have small studies in bipolar depression.

Although lithium is a first-line treatment that ranks high on the list of patient’s favorites, it has fallen out of general use, particularly in the United States.

 When drugs meet that fate, they are often reserved for the most refractory patients, such as patients with severe mania who require high doses, which doesn’t help lithium’s reputation. Adverse effects should not stand in the way of its usage – when they are managed carefully and I have found that surprisingly tolerable.

But still, about 1 in 10 patients don’t tolerate it and have to stop the medication.

About 1 in 3 patients with bipolar disorder respond very well to lithium – and these tend to be the patients with classic, “textbook case” bipolar – with euphoric manias that are cleanly separated from depressions, and low rates of rapid cycling, mixed states, and major psychiatric comorbidities. These need not be patients with bipolar I though – patients with bipolar II can have classic hypomanias, and in one study lithium worked better for bipolar II than bipolar I.

When lithium works well, its benefits tend to last. It is among the top medications that prevent hospitalization.

 Its preventative effects have outshined other mood stabilizers, like valproate, in head-to-head trials, and it has added benefits that are relevant to bipolar disorder. Lithium prevents suicide, dementia, and some new evidence suggests it may lower the stroke risk and aid cardiac remodeling after a heart attack – that’s good news if it holds up, because stroke is the #1 cause of death in bipolar disorder, and cardiovascular disease tends to start 20 years earlier in patients with bipolar disorder than it does in the general population.

I hope you will join us again for more practical updates on PsychPearls, and you can also catch us every Monday on the 

is the Mood Disorders Section Editor for 

 He has written several books on mood disorders, most recently 

 with his cohost Kellie Newsome, PMH-NP. The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for 

 and is also a practicing Psychiatric Mental Health Nurse Practitioner in Winston Salem, NC, at the Mood Treatment Center. Raised in Tasmania, Australia, Kellie moved to the United States in 1998.

Clinical relevance of treatments for acute bipolar disorder: balancing therapeutic and adverse effects.

Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium.

Effects of lithium on cognitive performance: a meta-analysis.

4. Girardi P, Brugnoli R, Manfredi G, et al. 

Lithium in bipolar disorder: optimizing therapy using prolonged-release formulations.

5. Severus WE, Kleindienst N, Seemüller F. 

What is the optimal serum lithium level in the long-term treatment of bipolar disorder--a review?

Lithium in late-life mania: a systematic review.

Lithium tremor revisited: pathophysiology and treatment.

Lithium side effects and toxicity: prevalence and management strategies.

9. AprahamIan I, TeIxeIra de SouSa R, da CoSTa L et al

. Lithium safety and tolerability in mood disorders: a critical review.

10. Murru A, Popovic D, Pacchiarotti I, et al. 

Management of adverse effects of mood stabilizers.

11. Kalita-DE Croft P, Bedford JJ, Leader JP, et al. 

Amiloride modifies the progression of lithium-induced renal interstitial fibrosis.

12. Frye MA, Yatham L, Ketter TA, et al. 

Depressive relapse during lithium treatment associated with increased serum thyroid-stimulating hormone: results from two placebo-controlled bipolar I maintenance studies.

13. Rosenblat JD, Kakar R, Berk M, et al. 

Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis.

14. Zaenglein AL, Pathy AL, Schlosser BJ, et al. 

Guidelines of care for the management of acne vulgaris.

Lithium-associated psoriasis and omega-3 fatty acids.

Treatment of bipolar disorder in a lifetime perspective: is lithium still the best choice?

The new news about lithium: An underutilized treatment in the United States.

Suicidal behavior in mood disorders: response to pharmacological treatment.

 Pharmacological treatment and risk of psychiatric hospital admission in bipolar disorder.

Although lithium is a first-line treatment that ranks high on the list of patient’s favorites, it has fallen out of general use, particularly in the United States. When lithium works well, its benefits tend to last. It is among the top medications that prevent hospitalization. More in this podcast.

Dosing Tips for Lithium: How to Improve Tolerability

Chris Aiken, MD, and Kellie Newsome, PMH-NP, discuss how to dose quetiapine for the treatment of bipolar disorder.

Dr Aikenis the Mood Disorders Section Editor for Psychiatric Times, the Editor in Chief of 

Chris Aiken, MD, and Kellie Newsome, PMH-NP, discuss best practices for dosing quetiapine for the treatment of bipolar disorder.

Kellie Newsome, PMH-NP

Articles

Blue Light, Depression, and Bipolar Disorder

Four Myths About Lamotrigine

Dosing Tips for Lithium: How to Improve Tolerability

Dosing Tips for Bipolar Disorder: Quetiapine

Dosing Tips: Lithium for Bipolar Disorder

Mood Stabilizers for Bipolar Disorder