Chris Aiken, MD

Stimulant medications have long been the mainstay of treatment for attention-deficit/hyperactivity disorder, but psychopharmacology is no longer the only game in town. Join us for a discussion on new nonpharmacological treatment approaches as Dr Chris Aiken, Psychiatric TimesTM Mood Disorders Section Editor and the Director of the Mood Treatment Center, talks with Dr Stephen Faraone, Distinguished Professor and Vice Chair of Research of Psychiatry and Behavioral Sciences at Upstate Medical University.

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Don't fall into the trap of these 3 myths about mania in bipolar disorder...

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

Matcha Sustains Caffeine's Benefits

A study compared matcha, a highly caffeinated green tea, to other sources of caffeine. Which had the greatest cognitive benefits? 

The Cognitive Benefits of Matcha

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 

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.

Articles

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. 