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From an update on at-home ketamine therapy to the psychopharmacologic treatment of bipolar depression, here are highlights from the week in Psychiatric Times.

The Week in Review: March 13-17

"Organized medicine and specialty organizations are key pillars of support for individual physicians that provide opportunities to advocate for more funding and resources for the medical system and education."

Organized Psychiatry Provides Strength and Value to Mental Health Professionals

"This is what you shall do: Love the earth and sun and the animals..."

Preface to Leaves of Grass

 is an award-winning psychiatrist who has specialized in the cultural and ethical aspects of psychiatry. A prolific writer and speaker, he received the one-time designation of Hero of Public Psychiatry from the Assembly of the American Psychiatric Association in 2002. To create a better world, he is an advocate for treating mental health issues related to climate instability, burnout, Islamophobia, and anti-Semitism. He serves on the Editorial Board of

We may need the luck of the Irish to avoid future disasters…

Social Psychiatric Predictions About the Future: A Series

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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.

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