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Antidepressant augmentation is a common practice, and there are many strategies from which to choose. The 

 recommends a menu approach that encourages patients to collaboratively choose an option that best fits their needs.

 In addition to psychotherapy and lifestyle approaches like aerobic exercise, they recommend augmentation with:

1. Natural treatments: omega-3 fatty acids, L-methylfolate, or light therapy

2. Antipsychotics: aripiprazole, risperidone, or quetiapine

3. Antidepressants: bupropion, imipramine, or mirtazapine

When rapid relief is the priority, an antipsychotic might be the best choice. For favorable tolerability, there is bupropion or a natural therapy, and lithium has strong antisuicide effects, if that is a concern. But what if insomnia is the chief complaint? Mirtazapine is tempting here, but this medication carries a risk of weight gain and did not perform well in several recent, well-designed augmentation trials.

 Instead, a standard hypnotic may be a good option when patients continue to have depression and insomnia on an antidepressant, but not just any hypnotic.

Eszopiclone: The Science Behind Its Potential Effect on Depression

In the early 2000s, a group of sleep researchers set out to investigate whether hypnotics could improve mood in patients with depression and insomnia. The results did not pan out exactly as expected, but they point the way toward a medication with unique potential in depression.

But first, investigators had to overcome a hurdle. At the time, it was thought that hypnotics might cause depression through their sedative effects. That concern was partly put to rest in a 1999 study that tested whether zolpidem could relieve selective serotonin reuptake inhibitor [SSRI]-induced insomnia in patients who had otherwise recovered on the antidepressant. The sleep problems improved with zolpidem and, to the investigators’ relief, the sedating medication did not worsen depression.

Buoyed by this result, the manufacturer of eszopiclone funded a large trial to see if depression might actually improve with their hypnotic. Five hundred and forty-five patients with depression and insomnia were randomized to receive either eszopiclone 3mg or placebo while simultaneously starting a trial of fluoxetine. As expected, the hypnotic improved sleep, but it also improved mood symptoms that were unrelated to sleep. Compared to placebo, those who received eszopiclone experienced a more rapid and complete recovery from depression.

The same group repeated the study with zolpidem ER in a large trial of similar design. Once again, the hypnotic improved sleep, but this time there was no change in mood.

 Replication in China brought the same negative results, and last year zolpidem failed again to lift mood or reduce suicidality when added to an SSRI in a randomized trial of patients with depression, insomnia, and suicidality.

Meanwhile, eszopiclone repeated its success, improving mood and insomnia in 2 additional trials, 1 of which involved peri- and postmenopausal women with insomnia and depressive symptoms.

 Generalized anxiety disorder also improved when eszopiclone was added to an SSRI in a large manufacturer-supported trial that replicated the design of eszopiclone’s pivotal depression trial.

Both the zolpidem and eszopiclone studies involved many of the same investigators, who had pursued this work with the idea that any hypnotic that improved sleep would indirectly improve mood. But to this day eszopiclone remains the only hypnotic with distinct antidepressant effects (ramelteon has mild preventative benefits in bipolar disorder but is not known to treat depression).

 Whether this is a statistical fluke or a true difference is difficult to say, as eszopiclone has not gone head-to-head against other hypnotics in depression. However, eszopiclone does have a unique mechanism of action that might explain its antidepressant effects. To understand that we need to turn to the GABAA receptor.

Compared to the benzodiazepines, the z-hypnotics have more limited effects on GABAA, which is thought to explain why they treat sleep but not anxiety. Specifically, the z-hypnotics are selective for the sleep-inducing GABAA α-1 subunit, while benzodiazepines have additional effects on the α-2 and -3 subunits that are involved in anxiety and depression. But eszopiclone is an exception. It acts at all of the α subunits, and may actually be a little more selective for the anxiolytic α-2 and-3.

 This effect is furthered by eszopiclone’s active metabolite, desmethylzopiclone, which is a selective partial agonist at α-2 and -3 with very little α-1 activity (that is a good thing, as it would otherwise cause a lot of daytime sedation).

 In animal models, desmethylzopiclone reduced anxiety without causing sedation or motor impairment.

 Its effects in humans are not well described, but the trials above give us a hint, and the company that launched eszopiclone has patented this metabolite as a potential anxiolytic.

In this way, eszopiclone resembles the benzodiazepines, which have been used to treat depression and hasten the response to antidepressants in over 3 dozen controlled trials.

 In most of those trials, their antidepressant effects were independent of their anxiolytic effects, just as eszopiclone treated symptoms of depression that were unrelated to sleep.

Despite this research, benzodiazepines are not used routinely for depression because of their risk of tolerance and abuse. Those risks may also apply to eszopiclone, but the trials above provide some reassurance. In several of them, eszopiclone was replaced with a placebo after 2 months of treatment without any loss of the antidepressant and anxiolytic gains. Nor was there any rebound insomnia and, in some studies, it stabilized sleep patterns in a way that continued after the hypnotic was stopped.

Does all this elevate eszopiclone to the level of antidepressant augmentation? Possibly. It does have more positive results than some the augmentation strategies that are endorsed by evidence-based guidelines.1 But there are 2 caveats. First, eszopiclone was only studied in patients with comorbid insomnia, but this is not a major hurdle as it is the rare patient with depression who does not struggle with sleep (about 15%).

 More significantly, eszopiclone was started in tandem with an antidepressant in these augmentation trials, so we do not know if it could turn things around when added later, after a few antidepressant failures.

When selecting a hypnotic in depression or generalized anxiety disorder, eszopiclone should be on the list. The treatment need not be long-term. Most patients were able to taper off the hypnotic after recovery. To bolster those odds, start out with the expectation of short-term use and guide the patient toward 

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

The psychopharmacology algorithm project at the Harvard South Shore Program: an update on unipolar nonpsychotic depression.

Mirtazapine augmentation: Running low on rocket fuel.

. September 2019. Accessed August 27, 2021.

3. Asnis GM, Chakraburtty A, DuBoff EA, et al. 

Zolpidem for persistent insomnia in SSRI-treated depressed patients.

Efficacy and tolerability of Z-drug adjunction to antidepressant treatment for major depressive disorder: a systematic review and meta-analysis of randomized controlled trials.

5. McCall WV, Benca RM, Rosenquist PB, et al. 

Reducing suicidal ideation through insomnia treatment (rest-it): a randomized clinical trial.

6. McCall WV, Blocker JN, D'Agostino R Jr, et al. 

Treatment of insomnia in depressed insomniacs: effects on health-related quality of life, objective and self-reported sleep, and depression.

7. Joffe H, Petrillo L, Viguera A, et al. 

Eszopiclone improves insomnia and depressive and anxious symptoms in perimenopausal and postmenopausal women with hot flashes: a randomized, double-blinded, placebo-controlled crossover trial.

. Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder.

Melatonin receptor agonists-ramelteon and melatonin-for bipolar disorder: a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials.

. Searching for perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics.

Molecular actions of (S)-desmethylzopiclone (SEP-174559), an anxiolytic metabolite of zopiclone.

12. Carlson JN, Haskew R, Wacker J, et al. 

Sedative and anxiolytic effects of zopiclone's enantiomers and metabolite.

13. Benasi G, Guidi J, Offidani E, et al. 

Benzodiazepines as a monotherapy in depressive disorders: a systematic review.

Wisniewski SR, et al. Insomnia in patients with depression: a STAR*D report.

A hypnotic might be a good option for augmenting depression treatment, but which hypnotic has the best evidence for efficacy? 

An Overlooked Strategy for Antidepressant Augmentation?

One of the biggest stories in psychopharmacology in recent years was not a very promising one. Mirtazapine, which has been used since the 1990s to augment antidepressant treatment, failed to work in the first well-designed studies to test that strategy.

 Now a new analysis offers more specific direction on when mirtazapine augmentation might still be useful in major depressive disorder (MDD).

Interest in mirtazapine augmentation began with a theory. Like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine affects serotonergic and noradrenergic transmission, but it does so through a different mechanism, suggesting a potential synergy with combination therapy. Mirtazapine also has the potential to reduce SSRI side effects, including nausea, insomnia, and sexual dysfunction.

The strategy took off from there, aided by the catchy nickname 

 that Stephen Stahl, MD, PhD, coined for the venlafaxine-mirtazapine combination. But the empiric support for the strategy was always thin, mostly resting on a singular placebo-controlled trial that was significantly hindered by its 26-subject size.

After more than 20 years of clinical use, mirtazapine augmentation was finally tested in 2 high quality trials (large, double-blind, randomized, placebo-controlled), 1 from the United Kingdom (UK) and 1 from China.

 Both tested mirtazapine augmentation after unsuccessful treatment with an SSRI or SNRI, and in both mirtazapine worked no better than placebo. These were followed by a third study in which 112 patients who had not recovered on venlafaxine were randomized to either switch to imipramine or augment with mirtazapine. Unfortunately for mirtazapine, the imipramine switch was nearly twice as effective as mirtazapine augmentation.

Those 3 negative trials caused mirtazapine to slide down a few rungs on the augmentation algorithm. But a small signal in the UK trial inspired the investigators to give the data a second look. The study, dubbed the MIR trial, was the largest of the 3 negative trials, and involved 480 primary care patients whose depression did not respond to 6 weeks of an SSRI or SNRI. Although mirtazapine failed to make a difference on the primary outcome of depression, it did improve anxiety on secondary measures.

The investigators reanalyzed the data to see if patients with high levels of anxiety had a more favorable response to mirtazapine augmentation. After stratifying the sample by baseline anxiety level (mild, moderate, or severe on the GAD-7), they found that patients with severe anxiety made significant gains with mirtazapine, while those with no anxiety at baseline did not improve at all with the medication. Those gains included both depressive and anxious symptoms. Patients with moderate anxiety had gains between the 2 extremes.

To test whether anxiety was just a marker for illness severity, they stratified the sample by overall severity of depression. That analysis turned up negative, suggesting that it was the anxious symptoms themselves, and not the overall severity, that was driving the change.

The findings were significant, but are they clinically meaningful? They appear to be, at least in the severe anxiety group where the Generalized Anxiety Disorder-7 scale dropped 2.8 points (out of a max of 21) points and the Beck Depression Inventory II fell 2.8 (max of 63).

Mirtazapine is not the most effective augmentation strategy in depression, but it is worth considering in depressed patients with high anxiety.

1. Rifkin-Zybutz R, MacNeill S, Davies SJ, et al. Does anxiety moderate the effectiveness of mirtazapine in patients with treatment-resistant depression? A secondary analysis of the MIR trial. 

2. Kessler DS, MacNeill SJ, Tallon D, et al. Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR). 

3. Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. 

4. Blier P, Ward HE, Tremblay P, et al. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. 

5. Xiao L, Zhu X, Gillespie A, et al. Effectiveness of mirtazapine as add-on to paroxetine 

 paroxetine or mirtazapine monotherapy in patients with major depressive disorder with early non-response to paroxetine: a two-phase, multicentre, randomized, double-blind clinical trial. 

6. Navarro V, Boulahfa I, Obach A, et al. Switching to imipramine versus add-on mirtazapine in venlafaxine-resistant major depression: a 10-week randomized open study. 

After a string of disappointing results, mirtazapine gets another look in a recent study. 

When to Use Mirtazapine Augmentation

 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

, and you can also catch us every Monday on the 

is the Mood Disorders Section Editor for Psychiatric Times

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. 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

The last week of June 2021 was a momentous one.

After the cancellation of last year’s residency graduation, I was tasked with planning an event to celebrate both the 2020 graduates and those advancing in July. I had never planned an event like this before, especially during a global pandemic. I had no idea how much preparation and effort it would take—the room, food, decorations, tables, chairs, etc. To say it was a little daunting is an understatement.

And while I successfully planned for all the minutiae needed for the event, my wife pointed out a small detail that I had been avoiding as I finally neared the big day: I needed a haircut

The last time I had gone to my friendly local barber, it had been pretty awkward. The shop was full of frustrated, angry workers strained from closures and boasting that they had no intention of following any COVID-19 guidelines. I kept quiet and tried to be polite but was eventually asked what I did for a living. After sharing that I worked in leadership at a local hospital, the demeanor changed. Suddenly the man cutting my hair began to smile almost apologetically, gently touching my shoulder as I paid him and left.

This time, I did not know what to expect. Do I wear a mask? Do I try a new shop? Do I skip it altogether? The earlier experience was making me apprehensive. After talking to my wife, I decided I would go to the same barber. Entering the shop without a mask felt almost alien to me, and I must admit, it was slightly unsettling to sit with 15 or so others waiting on cuts.

I have learned that my experiences in the barbershop were in no way unique, and many of our patients and staff are dealing with similar situations on a daily basis. It is time to embrace the fact that reentry anxiety is affecting more individuals than ever before. This kind of anxiety is frequently seen in the severely isolated, the hypervigilant, and those confined to only certain places over 

 Doesn’t that describe almost all of us? Lockdowns and social isolation may have been necessary, but they are not something our brains are used to, nor can we easily flip a switch back to normal.

The data is there. According to the American Psychological Association, Americans are now experiencing the highest levels of stress since April 2020, with 

 reporting feeling at least one emotion associated with prolonged stress in the past 2 weeks (anxiety 47%, sadness 44%, and anger 39%).

 One study found that 13% of individuals screened positive for posttraumatic stress disorder, despite COVID-19 not fitting Criterion A. Thirteen percent felt they had difficulty with lockdown, 11% feared difficulty obtaining supplies, 10% had significant difficulty self-isolating, and 22% had 

And now I needed to plan a graduation for 2 cohorts of graduates, doubling the event’s normal prepandemic attendance. Graduation is supposed to be a time of celebration and togetherness, but as I am sitting here uneasy about just getting a haircut, I am wondering if it is really a good idea to do this event. This is supposed to be fun; why am I not looking forward to this?

We are supposed to be excited. We are supposed to feel good about doing more things. But reentry anxiety will not allow us to simply enjoy it.

Cognitively, it makes perfect sense: fear of contagion, feelings that the world has changed. I have even heard people joking that their social skills have atrophied, or they no longer know how to dress for various occasions.

What can we do about this? Like most solutions in the field, we need to understand the risk factors for those more likely to struggle with reentry. Look for patients with a history of mental illness, as well as those likely to have been stressed or dealing with trauma over the last year: front-line workers; people of color; parents; and children, teens, and young adults displaced from school.

The mechanism of action is a hard one, described by 

 When individuals repeatedly end a honeymoon phase only to be met with a new crisis, they then must recover from said crisis and adjust to the new situation. The hardest part is that individuals tend to suffer from these crises repeatedly, 

Although many consider reentry anxiety an anxiety disorder, it is really more of an adjustment disorder—especially when it is short term and related to a pandemic that forced us all to adjust. That being said, ruling out other causes for anxiety should be considered if symptoms persist.

But what do we do for these patients with this unique adjustment disorder? One of the first steps is diagnosis. The 

DSM’s description of adjustment disorder

 can guide providers in understanding the clinical symptoms and how to diagnose them appropriately.

Personally, my first step is the same as for all patients with anxiety—to help them give themselves permission to feel anxious. We get anxious—if we did not, we would fail to study for exams or forget to look both ways before crossing a street. Anxiety helps us make good choices in our day-to-day lives, as well as during rapidly changing times. It is important to permit feeling anxiety and to remind ourselves that everyone will deal with this differently. Comparing your feelings and coping skills to others is not productive. Just because certain individuals take longer to readjust, or their feelings are more intense, does not mean anything has gone wrong.

Of course, if patients’ symptoms persist or become disabling, it is important to offer help. Here are a few options that I recommend as appropriate:

. Cognitive behavioral therapy is the gold standard for anxiety disorders, and exposure therapy will likely help a lot. With the variety of options in obtaining it nowadays, it is easier to fit therapy into a busy schedule.

. Some research suggests that mindfulness practices can actually mimic exposure therapy by helping patients feel and desensitize troubling emotions and physical sensations.

. Gradual exposure to more challenging situations will likely begin to extinguish these symptoms. In addition, strong social support through family and friends is always beneficial.

. From a pharmacologic standpoint, I would hold off in mild cases. But for patients with disabling symptoms, a selective serotonin reuptake inhibitor might help them push through while undergoing therapy.

Looking back to my recent trip to the barbershop, I think it is important to acknowledge that many of us have experienced some trauma during this pandemic. There is no single method for getting back to normal. Equally important is that we seek to understand and embrace these feelings of trauma. Start with small outings at first, but start soon. Start with a haircut before you host a large party. Learn from my mistakes. Graduation was fun, but hosting over 100 guests indoors was indeed overwhelming.

Admittedly, a week later, I am more comfortable going outside of my bubble; however, I still feel more comfortable wearing a mask at the grocery store. We must all take steps that make us feel personally safe, but we should also push ourselves to get back to our lives.

is chair of Behavioral Health at Arrowhead Regional Medical Center. He also serves as medical director for the Behavioral Health Department at Arrowhead Regional Medical Center. In addition to San Bernardino, Dr. Seigler has practiced clinically in Riverside and across the West Coast as a Vituity

telepsychiatrist since 2017. He received his medical degree from the UCLA David Geffen School of Medicine and completed his postgraduate training at the UCLA/San Fernando Valley residency program. He has a passion for patients’ rights and returning stabilized patients back into the community from long-term placements and conservatorship.

1. Hyde J, Bolton R, Kim B, et al. "I've just never done that:" The influence of transitional anxiety on post-incarceration reentry and reintegration experiences among veterans. 

2. American Psychological Association. Post-inauguration stress survey: More than 8 in 10 Americans (84%) report feeling emotions associated with stress in the last two weeks. January 2021. Accessed July 27, 2021. https://www.apa.org/images/sia-january-emotions-infographic_tcm7-283972.jpg

3. Bridgland VME, Moeck EK, Green DM, et al. Why the COVID-19 pandemic is a traumatic stressor. 

4. Gullahorn JT, Gullahorn JE. An extension of the U-curve hypothesis. 

5. Purtill J. Anxious about going back to normal? It's called 'reverse culture shock'. Australian Broadcasting Company. May 7, 2020. Accessed July 20, 2021. 

6. Substance Abuse and Mental Health Services Administration. Impact of the DSM-IV to DSM-5 Changes on the National Survey on Drug Use and Health. Substance Abuse and Mental Health Services Administration (US); 2016.

Why does the prospect of getting back to normal after the pandemic disturb some patients? And what can be done to overcome these fears?   

Reentry Anxiety

Alzheimer disease (AD) remains one of the most dreaded diagnoses a patient can get. The US Food and Drug Administration (FDA) raised hopes when it approved aducanumab, which promised to be the first disease-modifying drug for AD. But the approval immediately proved controversial. Three FDA board members 

 its patient label, and in mid-July, major hospitals announced that they would not administer the 

, Helen Lavretsky, MD, MS clarifies the issues in the aducanumab debate and offers guidance for clinicians whose patients may ask about it. Going beyond pharmacology, she points out that other treatment options, including mind-body interventions and diet changes, have been shown to slow AD’s progression.

Advice for talking to patients and caregivers about aducanumab and other novel pharmacological options

Mind-body and lifestyle interventions for AD

AD prevention programs, including nutrition, exercise, and stress reduction

Taking care of caregivers, including psychiatrists and other medical professionals

is a professor in-residence in the Department of Psychiatry at the University of California, Los Angeles. Her work on geriatric depression and integrative mental health using mind-body interventions has received national attention, and she has won numerous grants supporting that work. A distinguished fellow of the American Psychiatric Association and a fellow of the American College of Neuropsychopharmacology, she is also on the board of 

Although the new drug aducanumab has grabbed all the headlines, the future of Alzheimer treatment may be just as much about public health campaigns as it is about psychopharmacology. In this episode of Psych Pearls, we find out why.   

What Will the Future of Alzheimer Disease Treatment Look Like? 

Have you run out of ideas for your outpatient with resistant bipolar depression? You might consider the results of 

 about the use of bright fluorescent light.

There have been a fair number of previous studies on light therapy for bipolar disorder. Some studies with this modality of treatment, when compared with likely inactive controls, have not shown efficacy for patients whose disease does not have a seasonal component. Other reports suggested a high rate of switching to mania in patients with bipolar disorder when they received early morning light (the usual timing for light treatment targeting nonbipolar depression). Fortunately, 2 studies showed good results for chronotherapy; in these studies, patients were kept up all night and then administered 

A rare robust finding from a study on bipolar depression. 

Psychopharmacology

An Overlooked Strategy for Antidepressant Augmentation?

When to Use Mirtazapine Augmentation

Four Myths About Lamotrigine

Reentry Anxiety

What Will the Future of Alzheimer Disease Treatment Look Like?

Shining a Spotlight on Bright Light for Acute Bipolar Depression

From Classic and Critical to Integrative Psychiatry: Dan J. Stein, MD, PhD, DPhil

How to Listen to Patients Who Cannot Talk

War—What Is It Good For? Perhaps Modern Psychopharmacology

New Hope for PTSD Treatment?