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H. Steven Moffic, MD, in this very special episode of the weekly Psychiatry & Society series, interviews a patient, Nancy Dale Alterman. By sharing her story about how ECT treatment improved her life, she hopes to help others and end stigma. 

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. He is an advocate for mental health issues relate to climate instability, burnout, Islamophobia, and anti-Semitism for a better world. He serves on the Editorial Board of

is a patient who has lived in Denver her whole life. She is an artist and is also very involved in nonprofits focusing on the mental health community, and various causes, including animal welfare.

ECT played an important role in this patient's journey to recovery.

Heroic Journey to Recovery: A Patient's Story

“Charlie” is an 18-year-old Caucasian male with recently diagnosed bipolar disorder. He has no significant family psychiatric history. His early growth and development was typical, although he was a colicky baby. In early elementary school, he was demanding and outspoken, with increased energy. At age 10, his parents noticed some mood changes and that he was overly sensitive. Charlie had worsening mood lability at age 13, with periods of irritability and depression. At times, he was active and bossy on the playground—other times, he preferred to isolate inside and read during recess. He had some intermittent sleep difficulties and periodic anger outbursts at home. He also occasionally reported some unusual experiences. At age 16, his symptoms dramatically worsened, and he was hospitalized for a first episode of mania.

There is a recent increased effort to identify at-risk subjects for major psychiatric disorders, including 

 and bipolar disorder, and to predict individuals with prodromal symptoms who will progress to full-threshold disorder.

 First-episode mania (FEM) has been less frequently studied than first-episode psychosis (FEP). Furthermore, studies of FEP do not typically distinguish between affective and non-affective FEP,

 Risk/vulnerability markers include a family history of mood disorders and 

 for bipolar disorder, perinatal complications, worse premorbid adjustment, and increased 

 aimed to identify symptomatic and temporal differences between the prodromal phases of FEM and FEP with onset in young adulthood or adulthood, as well as differences in risk factors and vulnerability markers. The authors performed a retrospective cross-sectional analysis, as part of a larger 2-year study in Spain. Diagnosis was confirmed using a semi-structured interview according to DSM-5 criteria. Inclusion criteria were outpatients aged 18 to 45 and a FEM or FEP in the past 4 years. They excluded subjects with intellectual disability, severe medical conditions (eg, HIV or cancer), alcohol or other substance dependence, or 

Data on clinical features at illness onset, current clinical symptoms and treatments, and medical histories were collected. Data on prodromal symptoms (within 3 years of onset) were obtained retrospectively from patients (and caregivers), including using the semistructured Bipolar Prodrome Symptom Scale-Retrospective. Data on risk factors, including family history of psychiatric disorders, life stressors, childhood trauma, delayed language or psychomotor development, nocturnal enuresis, and difficulties in writing and reading were assessed. Clinical information on mental health services during youth (including diagnoses and medications) were also obtained. Logistic regression models were used to investigate prodromal symptoms as predictors of FEM and FEP. Differences in the duration of prodromal symptoms in FEM and FEP were assessed using Student’s t-test.

The study sample included 108 subjects (n=72 with FEM and n=36 with FEP). There were no sociodemographic differences between subject groups, except worse psychosocial functioning in patients with FEP. Subjects with FEM had a significantly shorter duration of untreated psychosis. There were no significant differences in the number of total prodromal symptoms between FEM and FEP. Social isolation was significantly associated with the prodromal stage of FEP, and increased energy or goal-directed activity with the prodromal stage of FEM. FEP was associated with a longer and more gradual onset and slower deterioration than FEM. The depression symptom “physically slowed down” was most associated with a gradual onset pattern, whereas “increased energy” was most associated with more rapid onset. There were higher rates of obstetric complications and reading/writing difficulties in FEP than FEM. Impaired premorbid adjustment was characteristic of FEP; otherwise, there were no differences in vulnerability factors.

The authors concluded that different clinical symptoms were associated with the prodromal phases of FEP and FEM; FEP was associated with a longer prodrome; reading/writing difficulties differentiated FEP and FEM; and impaired premorbid adjustment was more characteristic of FEP. The main study strength was the use of comprehensive and exhaustive assessments. Study limitations included the relatively small sample size (particularly for FEP) and the potential for recall bias with retrospective assessments.

The psychosis and mania prodromes, coupled with risk and vulnerability markers, may contribute to identification of individuals at increased risk of conversion to fulminant disorders. Together, this information may help identify targeted early treatment strategies based on individual characteristics.

is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

1. Arango C, Díaz-Caneja CM, McGorry PD, et al. 

3. Barajas A, Pelaez T, González O, et al. 

Predictive capacity of prodromal symptoms in first-episode psychosis of recent onset.

4. Fusar-Poli P, Cappucciati M, Rutigliano G, et al. 

Diagnostic stability of ICD/DSM first episode psychosis diagnoses: meta-analysis.

5. Verdolini N, Borras R, Sparacino G, et al. 

Prodromal phase: differences in prodromal symptoms, risk factors and markers of vulnerability in first episode mania versus first episode psychosis with onset in late adolescence or adulthood.

Predicting mania versus psychosis: Researchers performed a retrospective study of prodromal symptoms, risk factors, and vulnerability markers in first-episode mania and psychosis.

Prodromal Mania and Psychosis

Last month we taught you how evening light can worsen mood. Today we teach you how to fix that. 

, "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’m Chris Aiken, the Mood Disorders Section Editor for 

, and I’m Kellie Newsome, a psychiatric NP and the cohost of the 

: Evening light worsens sleep and mood, and 

 we unraveled the biology behind that association. To recap, evening light – particularly the blue wavelength suppresses melatonin, worsening 2 systems that are already fragile in people with mood disorders: sleep and circadian rhythms. In animal studies it even altered the core architecture of the brain – shrinking the dendritic spines that 

But you don’t have to go into the woods and live deliberately to fix this problem. Today, we’ll teach you how to use blue light filters to stabilize the circadian rhythms that regulate mood and sleep, and how to use them in 

: There are 2 well-known photoreceptors in the eye. The rods see black and white, and the cones add color vision. But in the 1990s a new photoreceptor was discovered – melanopsin – which only responds to the blue wavelength of light. This photoreceptor doesn’t help us see, but it does regulate our circadian rhythm. In the past, this system worked well because we didn’t have much blue light in the evening. There were candles, starlight, fireplaces – all yellow light.

: Except once a month when the blue moon was full. And it’s no coincidence the word lunatic arose in the middle ages as a term for mental illness. It was believed that some people went into temporary bouts of insanity that followed the lunar cycle – the moon. Seven hundred years later, 

 linking the full moon to worsening of psychiatric disorders continue to roll in.

: And in today’s world, every night is a full moon, because cell phones, plasma TVs, and energy efficient bulbs emit a lot of blue light. But technology has also come to the rescue in the form of blue light filtering glasses. These are amber colored glasses, and when you wear them they filter out close to 100% of blue light. They’ve gained popularity among sports figures and celebrities, because wearing them at night improves sleep – which then raises cognitive and athletic performance. But most models out there do not filter enough blue light to make a meaningful difference in psychiatric disorders. We recommend the glasses that were used in the clinical research – and there are 2 types. Some studies have used Uvex glasses, eg Uvex Skyper S1933X and Uvex Ultra-spec 2000, which are $10 to 15 dollars on Amazon.

Any pair on that site will work, and these are much better quality for a higher price, around $50.

: I keep a pair of these glasses at my desk for patients to try on. They’re usually surprised to see the world looks quite pleasant through them. They don’t make things dark, but give the world a relaxing, yellow hue. Some patients find them so soothing that I have to warn patients not to wear them during the day, because doing so will flip their circadian rhythm in the wrong direction. When you wear them, your brain will think it’s in pitch darkness, and we only want that effect at night.

: Wearing them has real biological effects. When you put them on, your melatonin starts to rise, the same as it does in a 

 Sometimes patients ask if they can just take melatonin instead, but that doesn’t have the same effect. In a recent randomized controlled trial, taking artificial melatonin did nothing to stabilize mood in bipolar disorder.

 So it’s not enough to have melatonin drizzled on the brain. There are other biological effects involved in pumping out the brain’s indigenous melatonin that are necessary here.

If you want to know more about the biological effects of light and darkness listen to our August 2nd podcast on 

Blue Light, Depression, and Bipolar Disorder

. Now, let’s move on to the clinical research.

: In the 1980s Thomas Wehr, MD, and Norman Rosenthal, MD, made a surprise discovery while working at the National Institute of Mental Health (NIMH). Some patients had worsened depression in the wintertime that improved with light therapy. Their research suggested that circadian rhythms played a strong role in mood disorders, something that was already hinted at by the high rates of insomnia in major depression and the fact that a night without sleep often triggered an episode of mania. So, Wehr turned his attention from morning light to evening darkness. He began with normal subjects and placed them in a pitch-dark room for 14 hours overnight, imitating a dark winter night where the sun goes down at 6 PM and rises at 8 AM. The subjects were a little sleep deprived before the experiment, getting about 7 hours per night, something Wehr thought might be due to the artificial evening light of modern life. After a few weeks in the dark bedroom, their 

 to 8 hours and 15 minutes per night, closer to the recommended amount an adult needs.

: Then in 1994 a man came to the NIMH seeking help for rapid cycling bipolar disorder. Most patients don’t call up the NIMH to get help, so we can imagine this man had a pretty bad case. He was a successful engineer with a hyperthymic temperament, but in his 40s he became depressed and started fluoxetine and nortriptyline. He got better on this combination, but then went into a 4-year bout of rapid cycling moods cycling in and out of depression and hypomania every 1 to 2 months. Mood stabilizers did not help, so he came to the NIMH. Wehr knew that sleep disruption could trigger rapid cycling, and he wondered if his super-dark room could stabilize it. He put the patient through the same protocol he used for sleep, placing him in a pitch dark room for 14 hours each night. With this dark therapy, he improved so rapidly that they eased the schedule from 14 hours of darkness to 10 hours each night (10:00 PM to 8:00 AM). He stayed well with that regimen, and that is how dark therapy was 

: But the treatment didn’t really take off. First, it’s hard to get patients in a pitch-dark room overnight. We’re talking so dark that you can’t see your hands in front of your face. Second, we need more than an intriguing case report to put this into practice. The first problem was resolved in the early 2000s by James Phelps, MD.

Phelps was working in private practice in Oregon when he chanced upon 3 discoveries that would open up new therapeutic doors in bipolar disorder. First, he learned about Wehr’s research on dark therapy. Then he learned about the new photoreceptor, melanopsin, that set the circadian rhythm by responding to blue light. He wondered if dark therapy could be accomplished by blocking only the blue wavelength of light, and that brought him to the third piece of the puzzle: blue light filtering glasses. Other fields of medicine had already raised alarms about the hazards of evening blue light (such as increased risk of cancer and heart disease) and a company was manufacturing these to improve sleep and health. Phelps called this 

 and tried the glasses out on his patients. For some, the glasses did nothing, but about half of his patients reported their sleep was better when they wore the glasses 1 to 2 hours before bed.

He then discovered that welders used the same blue-light filters to protect their eyes at the local welding shop, and this opened the door to more treatments because these factory grade lenses were only $7. Phelps tested them and the fit the bill. 

later ran tests of blue light blockers and also concluded that the Uvex safety lenses he was using were among the strongest filters.

Phelps tested the waters, but the definitive study was a full-scale randomized trial in patients who were hospitalized for mania. In addition to treatment as usual, half wore amber lenses in the evening, and half wore (placebo) gray lenses, until sleeping in a pitch-dark room. The improvements were dramatic over the first week, with a large effect size of 1.9, while the control group barely changed.

You don’t need to be in the hospital to do this therapy. Phelps has had success using it in an outpatient practice, and we have as well. Here’s how you do it.

The original protocol required manic patients to be in either pitch darkness or virtual darkness (that is, with the amber glasses on) for 14 hours, from 6:00 PM to 8:00 AM. It took about a week for the mania to improve, and as it did the protocol was relaxed a bit, from 14 hours per night to 10 hours per night. So instead of putting the glasses on at 6 PM, they’d put them on at 7:00 PM, then 8:00 PM, and for prevention thy would move it to 9 or 10 PM. They don’t wear the glasses while asleep. That’s what the pitch-dark bedroom is for. But they do put them on if they are awake and the lights are on.

And the pitch darkness really does matter. Even light as dim as a nightlight on can interfere with melatonin secretion. In a large epidemiologic study of older adults, sleeping with a night light on doubled the risk of depression over 2 years compared to a pitch-dark bedroom.

But how do they get their bedroom pitch dark in this electric light world? 

, electrical tape over LEDs, towels or draft snakes under doors, or sleeping in the basement. If there is still stray light, patients can also sleep with a good eye mask.

: One problem we run into is patients who feel they can’t sleep without the TV on. Usually the reason is depressive rumination. These patients rely on the TV to distract them from their negative, ruminating thoughts. If that’s the case, we recommend ambient music or boring audiobooks instead. Another problem is patients who are afraid of the dark, such as those with PTSD. Here we have a technological solution. They can use amber colored nightlights that don’t emit any blue light. They are available for around $12.

: One modification we don’t recommend is to rely on blue-light filters on laptops and cell phones. Most devices have a setting that turns down the blue in the evening, and no doubt this is certainly a good thing and we’d recommend it in conjunction with dark therapy, but it doesn’t filter 100% and it isn’t going to take care of the background lights. You can find this feature in your smart phone’s settings, or if you’re using a laptop try downloading f.lux (spell it out) for windows or Candlelight by Oliver Denman for Mac.

But what if your patient can’t put the glasses on at 6 PM? Remember the 14-hour protocol was used for hospitalized mania, and they loosened it up as the patient got better. In practice, you might use dark therapy for hypomania, mild mixed states or as an intervention for early signs of mania. In those cases, putting the glasses on 2 hours before bed might be enough.

: It’s also important to set up expectations. Tell your patient that dark therapy is going to help stabilize their mood, but it may not help them fall asleep. Here’s an interesting pearl from that controlled trial. The patients who got better with the dark therapy didn’t actually sleep more. They slept a little less than the placebo group, but their sleep did get more regular. It went from sleeping and waking at random times to a more steady, stable circadian pattern.

 A lot of times patients will give up on dark therapy because they think it is supposed to help them sleep.

: Dark therapy improves mania, but what does it do to sleep? We found 3 randomized controlled trials that tested them out in insomnia, and they had a large effect, helping patients stay asleep longer, fall asleep earlier, and deepening sleep quality.

 One of them used the blue light blockers as an adjunct to CBT-insomnia, where half the patients had the behavioral therapy with placebo glasses and half used the blue-light blockers. Not only did sleep improve with the blockers, but so did anxiety and depression.10 Another study looked at performance on cognitive tests after wearing the glasses, and that got better as well, probably because the patients were sleeping better.

 In the sleep studies, patients put the glasses on 1.5 to 2 hours before bedtime.

Blue light blockers have been used successfully in jet lag, and they tend to help night owls fall asleep earlier.

: I wear them myself and I can attest to that. I’m more patient and have better attention, a little quicker on my feet, the next day if I wore them before bed.

: Blue light blockers have a big effect in mania and rapid cycling, and for sleep they deepen sleep quality and turn night owls into morning people. But can they help depression? We know from animal studies and epidemiologic studies that blue light causes depression, but when it comes to clinical studies using blue light blockers to treat depression the results are mixed. In that CBT-insomnia study, they did improve depressive symptoms, but those patients had clinical insomnia, not clinical depression.

 Beyond that, we have only 2 controlled trials, 1 positive, 1 negative. The positive one was small (n = 27) and centered on postpartum depression, where nocturnal awakening is the norm. Women who used blue-light blockers and low-blue light bulbs had greater improvements than those who used placebo glasses and bulbs.

 The negative study was also small (n = 20) and included depressed patients with insomnia. The investigators suspected that the glasses might not have worked because the patients found them uncomfortable and did not wear them as much as they should.

: When worn at night, blue light filters have beneficial, biological effects, but can they have side effects? Nothing major showed up in the studies. Possibly headaches, and there are reports of depression in some patients. This usually improves by putting the glasses on later, say, 7 PM or 8 PM instead of 6 PM. Although you can see pretty clearly through the glasses, color vision is distorted so we don’t recommend them while driving.

: We have links to recommended brands of blue-light blockers in the text to this podcast. We hope to see you again on 

, 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.

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

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

2. Henriksen TE, Skrede S, Fasmer OB, et al. 

Blue-blocking glasses as additive treatment for mania: a randomized placebo-controlled trial.

Lunar cycle and psychiatric hospital admissions for schizophrenia: new findings from Henan province, China.

4. Kayumov L, Casper RF, Hawa RJ, et al. 

Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work.

5. Quested DJ, Gibson JC, Sharpley AL, et al. Melatonin In Acute Mania Investigation (MIAMI-UK). 

A randomized controlled trial of add-on melatonin in bipolar disorder.

6. Barbato G, Barker C, Bender C, et al. 

Extended sleep in humans in 14 hour nights (LD 10:14): relationship between REM density and spontaneous awakening.

7. Wehr TA, Turner EH, Shimada JM, et al. 

Treatment of rapidly cycling bipolar patient by using extended bed rest and darkness to stabilize the timing and duration of sleep.

Dark therapy for bipolar disorder using amber lenses for blue light blockade.

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

10. Janků K, Šmotek M, Fárková E, Kopřivová J. 

Block the light and sleep well: Evening blue light filtration as a part of cognitive behavioral therapy for insomnia

11. Zimmerman ME, Kim MB, Hale C, et al. 

Neuropsychological function response to nocturnal blue light blockage in individuals with symptoms of insomnia: A pilot randomized controlled study.

12. Shechter A, Kim EW, St-Onge MP, Westwood AJ. 

Blocking nocturnal blue light for insomnia: A randomized controlled trial.

13. Bennett S, Alpert M, Kubulins V, et al. 

Use of modified spectacles and light bulbs to block blue light at night may prevent postpartum depression.

14. Esaki Y, Kitajima T, Takeuchi I, et al. 

Effect of blue-blocking glasses in major depressive disorder with sleep onset insomnia: A randomized, double-blind, placebo-controlled study.

How to regulate circadian rhythms and regulate mood using dark therapy. 

Blue Light Blockers: A Behavior Therapy for Mania

 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.

I am Chris Aiken, the Mood Disorders Section Editor for 

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

 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

A manic episode is a psychiatric condition characterized by the presence of elevated, expansive, or irritable mood; grandiosity; increased goal-directed activity; risk-taking behaviors; pressured speech; decreased need for sleep; racing thoughts; and distractibility. Most commonly, manic episodes occur because of an underlying primary bipolar disorder. However, manic episodes can occur as a result of multiple other causes, including general medical conditions, substance abuse, and medication side effects. One medication that has been hypothesized to precipitate manic episodes is the chemotherapy agent methotrexate.

Methotrexate is used in the treatment of multiple forms of 

 through folate antagonism; it is also used to treat multiple autoimmune conditions.

 Although there is very limited literature describing an association between methotrexate and the occurrence of manic episodes, there have been reported cases of manic episodes in patients with stable bipolar disorder following the administration of methotrexate.

 To date, however, there have been no reported cases of manic episodes precipitated by methotrexate in patients without an existing diagnosis of bipolar disorder.

This case report demonstrates the acute onset of mania in a patient with no history of 

, which putatively was precipitated by the use of intrathecal methotrexate in the treatment of acute lymphoblastic leukemia.

“Charlie” is an adolescent patient with a prior psychiatric history of attention-deficit/hyperactivity disorder (ADHD) and a medical history of acute lymphocytic leukemia (ALL). He had no prior history of affective or psychotic disorders. Family history was significant for depression in a maternal aunt, but there was no family history of bipolar disorder or psychosis. After the patient was diagnosed with high-risk ALL, he was started on induction chemotherapy. He completed a course of prednisone treatment and received a second dose of intrathecal methotrexate (IT MTX) a few days prior to presentation.

At that time, Charlie presented to the hospital with several days history of altered mental status in the form of irritability, elevated mood, poor sleep, pressured speech, grandiosity, 

Upon admission, computed tomography (CT) head without contrast, magnetic resonance imaging (MRI) brain with and without contrast, magnetic resonance angiography (MRA) head without contrast, and magnetic resonance venography (MRV) head with and without contrast were all unremarkable. Awake electroencephalogram (EEG) was normal. Labs including anti- hyroperoxidase (TPO), thyroid peroxidase antibody, paraneoplastic antibody panel, autoimmune encephalopathy panel, and N-methyl-D-aspartate (NMDA) receptor antibody (CSF and serum) were negative. Ammonia, ceruloplasmin, Vitamin B12, TSH, and T4 were normal.

After being evaluated by the psychiatric consult liaison (C-L) team, Charlie was started on olanzapine, which was titrated to 10 mg BID for treatment of acute manic and psychotic symptoms. During the following days, Charlie remained disorganized and delusional, so olanzapine was changed to haloperidol 1 mg BID. The next few days he was reported to be doing marginally better, with improved 

 and less pressured speech, though remained somewhat disorganized and delusional.

On day 9 of admission, Charlie received third IT MTX treatment. On the following day, he was very restless, making bizarre hand movements, pacing around the room, with pressured speech and tangential thoughts, and remained hyper-religious with delusions of grandeur. Following reassessment by the C-L team, he was started on sodium valproate and quetiapine in addition to haloperidol 1 mg BID. Total daily doses of sodium valproate and quetiapine were gradually titrated up to 1250 mg and 350 mg, respectively. Charlie could not tolerate further increases in quetiapine beyond 350 mg daily due to excessive sedation, and haloperidol was discontinued due to prolonged QTc. Lorazepam 1 mg TID was added for management of agitation and irritability.

During the following days, Charlie’s sleep started to improve with periods of lucid thoughts. He gradually became much calmer and redirectable, although remained occasionally delusional. As his mental status started to improve, quetiapine was decreased to 300 mg daily and lorazepam was decreased to 0.5 mg in the evening. Sodium valproate was continued at 1250 mg daily.

On day 16, Charlie received a fourth scheduled IT MTX treatment, with deterioration of mental status by the following day. He was noted to have more disorganized speech and delusional thoughts. Quetiapine was gradually titrated to 700 mg daily while sodium valproate was kept at 1250 mg daily.

Charlie showed marked improvement in mental status over the next few days of treatment, with less pressured speech and less disorganization. He continued to have tangential and racing thoughts but with much less intensity. Following stabilization, Charlie was discharged to home on a medication regimen that consisted of sodium valproate 1250 mg daily, quetiapine 700 mg daily, and lorazepam 0.5 mg TID.

After discharge, Charlie was followed by the psychiatric C-L team during outpatient visits to the Hem/Onc clinic. Five days after discharge, his thought process and behavior were noted to be much more organized. He continued to have some delusional thinking but was able to interact and engage in daily activities. Due to complaints of tiredness and increased sleep during the daytime, quetiapine was decreased to 500 mg daily and lorazepam was discontinued. Sodium valproate was continued at 1250 mg daily.

Twelve days following discharge, Charlie received fifth and last IT MTX treatment as scheduled. Six days after that, he was readmitted with acute manic and psychotic symptoms similar to the first admission. Following evaluation by psychiatry, Charlie was continued on sodium valproate 1250 mg daily, and quetiapine was increased to 600 mg daily. Due to elevated valproic acid (113.4 ug/mL, ref range 50-100 mcg/mL) and ammonia (97 umol/ L, ref range 11-32 umol/ L) levels, sodium valproate was subsequently decreased to 750 mg daily. During the following days, his behavior and mental status started to improve. After 6 days of hospitalization, the patient was discharged home on quetiapine 600 mg daily and sodium valproate 750 mg daily.

Seven days later, the patient presented at the outpatient clinic with markedly improved mental status and overall functioning. Sodium valproate 750 mg daily and quetiapine 500 mg daily were continued.

Given that Charlie presented with 4 episodes of severe manic symptoms with psychotic features after administration of intrathecal MTX, a causal association was assumed between the intrathecal MTX and development of these symptoms. After significant discussions between psychiatry and hem/onc, the decision was made to switch ALL treatment from IT MTX to intrathecal cytarabine/hydrocortisone (IT ARAC/HCZ) with oral MTX.

As a result, Charlie continued to present psychiatrically stable with no acute affective or 

A case report and literature review of intrathecal methotrexate-induced mania.

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