Any mood or anxiety disorder sufferer I’ve ever known has had a keen interest in meds. Makes sense. Though certainly not intended to be a stand-alone remedy, they can have the quickest impact. Last week we began a discussion of the bipolar meds scoop from 2019. Let’s continue, and wrap it up…
Aspirin? Fewer studies, but fewer risks (stroke and bleeding primary). But, hey, how ’bout this? Aspirin improves sexual dysfunction in men using lithium.
We got our series rolling last week featuring the work of psychiatrist Chris Aiken, MD from Psychiatric Times. We’re going to finish by turning to Dr. Aiken’s follow-up article Novel Approaches to Bipolar: What Worked, and What Did Not, in 2019.
Dr. Aiken is the director of the Mood Treatment Center and an instructor in clinical psychiatry at the Wake Forest University School of Medicine. You need to know that Dr. Aiken doesn’t accept honoraria from pharmaceutical companies.
Let’s get busy…
Novel Approaches to Bipolar: What Worked, and What Did Not, in 2019
Dr. Aiken kicks things off by emphasizing that his first article, which we reviewed last week, addressed traditional interventions. The target of this go-round is novel approaches in the treatment of bipolar disorder. Remember, this is within the context of 2019.
N-acetylcysteine: Down, but Not Out
The anti-inflammatory N-acetylcysteine (NAC) is the primary antioxidant in the brain. It’s used to treat acetaminophen overdose, as well as respiratory and lung conditions. NAC has been studied as a treatment for numerous psychiatric disorders, including bipolar.
Well, according to Dr. Aiken NAC was the biggest floparoo of 2019. Seems it failed in three controlled trials of bipolar depression. And that’s a disappointment, given it showed promise in a 2008 trial.
Specifically, NAC ended-up working at month six for patients with subsyndromal depression who weren’t in full depressive episodes. Aiken cites this gem from the 2008 study: those who got better felt worse within four weeks of stopping NAC. Hmmm.
Anti-inflammatories and Mitochondrial Therapies: Mixed Results
Dr. Aiken states NAC is a component of two developing stories in bipolar disorder: inflammation and mitochondrial dysfunction. Both play a role in the generation of bipolar and both are positively impacted by NAC.
But there were other anti-inflammatories put to the test in 2019. Celecoxib (Celebrex) and aspirin showed positive results as augmenting agents in bipolar depression. This underscored results from prior research.
Celecoxib was dosed at a twice daily 200 mg in augmenting escitalopram (Lexapro). Aspirin was dosed at a once daily 1000 mg as a NAC add-on. 81 mg twice daily worked in an earlier trial in the augmentation of minocycline (Minocin).
So much for the good news. The anti-diabetic agent pioglitazone (Actos) may have fared well in a 2015 trial, but crashed in 2019. Atorvastatin (Lipitor), despite having some nice earlier trial results for depression and cognition, failed to repeat in 2019. The 2019 trial focused upon cognitive function in bipolar and unipolar depression. Incidentally, it’s atorvastatin’s anti-inflammatory properties that deliver the psychiatric effects.
Okay, the mitochondrial theory. Eh, it didn’t produce in 2019. In the NAC trials, a cocktail of sixteen nutraceuticals with potential mitochondrial benefits was tested. Though included were compounds with known anti-depressant effects, the cocktail didn’t separate from placebo.
The Take-Away
According to Dr. Aiken, the role of NAC in bipolar disorder treatment has been clipped, but not tossed-out. Fact is, NAC is one of a handful of therapies that can work for subsyndromal depressive symptoms – common particularly in bipolar II.
In animal studies, NAC also protected the kidneys against lithium toxicity. By the way, NAC is safe, low-cost, and well-tolerated.
Aiken reports that celecoxib is one of the better-studied anti-inflammatories for the treatment of bipolar and unipolar depression. Keep in mind, it’s better suited for short-term use, as using it long-term can increase the risk of stroke, heart attack, internal bleeding, and possible kidney toxicity. Still, short-term use needs to be reserved for treatment-resistant cases.
Aspirin? Fewer studies, but fewer risks (stroke and bleeding primary). But, hey, how ’bout this? Aspirin improves sexual dysfunction in men using lithium.
As he did in his first piece, Dr. Aiken has produced and provided a helpful chart…
Let’s Take It Home
I understand how much the development of meds for the mood and anxiety disorders means to anyone reading this. Don’t forget, I’ve been on this merry-go-round for a long time.
Yes, I know there weren’t any revelations in the series that would have you crack open the champagne. But given our current knowledge of the brain, and the rest of the body, we have to accept in-by-inch progress. I mean, what choice do we have? And you know what? I’m pleased creative research continues.
In the meantime, look to meds, but don’t forget they aren’t the only game in town. Be sure to research and implement non-med options as indicated.
Oh, before we part company: Do you think your psych med prescriber stays current on research? If you don’t, why not talk about it? Heck, bring articles like this to appointments. Just sayin’…
I f you’re being tormented by a mood or anxiety disorder, you’re likely interested in the happenings on the meds front. Who could blame you?! Often, unipolar depression and anxiety get top billing. But we’re going to take a look at the scoop from 2019 for bipolar disorder meds. Let’s roll…
Compared with other mood stabilizers, those using lithium had 50% fewer suicide attempts, better functioning, and less depression and aggression.
We have lots of information to review, so we need to get right into it. But I have to mention that reference for this piece is an article from Psychiatric Times, Bipolar Disorder: Practice-Changing Trials from 2019.
The piece was written by Chris Aiken, MD. Dr. Aiken is the director of the Mood Treatment Center and an instructor in clinical psychiatry at the Wake Forest University School of Medicine. It’s important to know that Dr. Aiken doesn’t accept honoraria from pharmaceutical companies.
Now, Dr. Aiken has written another article pertaining to the bipolar disorder meds scoop from 2019. I was going to review it here, but it would have made for a very long piece. So stay tuned, I’ll be back with “Part 2” in a handful of days.
Bipolar Disorder: Practice-Changing Trials from 2019
As in the original article, we’re going to do quick highlight summaries. Of note, Dr. Aiken points-out that in addition to official FDA decrees, over a dozen randomized controlled trials on bipolar disorder meds were released in 2019.
Cariprazine in Bipolar I Depression
Cariprazine (Vraylar) has been studied for bipolar depression since 2009. Results have been largely positive for the 1.5 mg daily dose. Interestingly enough, raising the dose to 3 mg daily doesn’t increase efficacy. There was a new trial in 2019 that produced essentially the same findings.
It seems compared to other atypical antipsychotics, cariprazine’s advantage is its tolerability, as well as proven efficacy in relieving both depression and mania.
Atypical Antipsychotic Augmentation Post-Mania
According to an analysis of a 2016 study, when risperidone (Risperdal) was used to augment a mood stabilizer in the treatment of mania it prevented relapses for up to six months. Longer use (up to a year) only resulted in additional weight gain.
Dr. Aiken says this provides a different spin on the maintenance story, because earlier studies stopped the antipsychotic after two to three months. So it wasn’t clear if the med could be safely stopped at a later point. Now we know that discontinuation at six months is feasible – with a slow taper. Dr. Aiken recommends lowering the dose every two weeks, keeping the original mood stabilizer in place.
Lithium & Children
In a trial of children aged seven to twelve, lithium, in contrast to risperidone, kept working to prevent manic episodes after six months.
Separately, lithium performed well in a large study from 2019 that followed youth with bipolar disorder for an average of ten years. Compared with other mood stabilizers, those using lithium had 50% fewer suicide attempts, better functioning, and less depression and aggression.
Carbamazepine/Lithium: Reborn
Carbamazepine (Tegretol) and valproate (Depakote) have been used to augment lithium for years. Thing is, the two were never compared head-to-head until 2019.
The number of study subjects was small, but validity was supplied by a long duration. Pertaining to mania and depression, both anticonvulsants performed similarly. However, carbamazepine was better tolerated in terms of weight gain, fatigue, and sexual dysfunction.
Thyroid Augmentation for Anxiety
Supraphysiologic (greater than normally present in the body) thyroid doesn’t sound like a good idea for someone struggling with anxiety. However, a 2019 study – analyzing a 2014 trial – found it didn’t worsen anxiety, and anxiety symptoms didn’t predict antidepressant effects. So it appears as though levothyroxine (Synthroid) may be helpful for bipolar depression.
TMS Doesn’t Harm Cognition – Might Even Help
Bipolar depression responds to both electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS). But ECT is limited by its cognitive effects. Not only did a 2018 study show that TMS in bipolar disorder didn’t cause cognitive deficits, a 2019 study found that for euthymic bipolar patients, TMS actually improved cognitive measures.
Rivastigmine & Memantine
Dr. Aiken quickly mentions the anti-dementia drugs rivastigmine (Exelon) and memantine (Namenda) for the treatment of bipolar mania. He says the trial results were either not significant or not clinically significant. He’ll pass on both until more data is available.
Dr. Aiken created and included the following chart in his article. Great reference material…
So There You Have It
If you’re doing all you can to manage bipolar disorder, I’m thinking you found what we reviewed relevant and helpful. Knowledge always is, not to mention all-out powerful.
As I said, look for Part 2 of this series in several days. It includes even more valuable information from Dr. Aiken.
Don’t know about you, but those cupcakes look pretty good to me. Thing is, knockin’ a few down when we’re feeling anxious or low may be leveling. But it could be a set-up for a go with depression. Looking for some holiday cheer? Keep up the search…
‘We also know that inflammatory hormones can directly push the brain into a state of severe depression. So, an inflamed brain is typically a depressed brain. And added sugars have a pro-inflammatory effect on the body and brain.’
Would you agree that managing life-interrupting depression and anxiety isn’t a one-hit wonder? I’m telling you, if any of us are putting our money on just one intervention, we’re in for a rude awakening.
Come on, you know as well as I that managing what ails us takes a combo approach. Never forget, the sum is greater than its individual parts. And a constellation of symptoms always calls for a constellation of interventions.
So, what say we talk about the impact of added sugar on depression? I’m thinking you’ll find this interesting and helpful…
Brand New Research
A team of clinical psychologists at the University of Kansas, led by Dr. Stephen Ilardi, have published some pretty cool research in the journal, Medical Hypotheses. By the way, Dr. Ilardi is the author of The Depression Cure.
So here’s the gist of the study results: consuming added sugars can trigger metabolic, inflammatory, and neurobiological processes linked with depression.
The team goes on to submit that on top of winter’s dwindling sunlight, and corresponding changes in sleep patterns, high sugar consumption may well result in a “perfect storm” for the generation of plummeting mental health.
That ought to get our attention, right?
On Come the Sweets
According to Dr. Ilardi…
For many people, reduced sunlight exposure during the winter will throw off circadian rhythms, disrupting healthy sleep and pushing 5-10% of the population into a full-blown episode of clinical depression.
He goes on to say…
One common characteristic of winter-onset depression is craving sugar. So, we’ve got up to 30% of the population suffering from at least some symptoms of winter-onset depression, causing them to crave carbs – and now they’re constantly confronted with holiday sweets.
Of course, we partake. And so begins a seemingly never-ending cycle.
Perhaps a Martini?
Just like consuming sweets
So what fuels this madness? Well, according to Ilardi consuming sweets is like taking a drug – say, having a cocktail.
As most of us know, there’s the “bang” mood-elevating effect. However, in high doses sweets can also have a paradoxical and destructive longer-term consequence of tanking mood. And on come reduced well-being, spiking inflammation, and weight gain.
Ilardi says it may be spot-on to consider added sugar, at sufficiently high levels, flat-out psychologically and physically harmful. Yes, no different than consuming too much liquor.
He acknowledges the evidence suggesting having one alcoholic drink a day is safe, and could have a beneficial effect for some people. But he points-out that alcohol is pure calories, pure energy, non-nutritive, and very toxic at high doses. And so it is for sugars, which when it comes to depression should largely be avoided.
Inflammation of the Brain?
The study team found that inflammation is the most important physiological effect of dietary sugar related to depression. Overall mental health, for that matter.
Absorb this from Dr. Ilardi…
A large subset of people with depression have high levels of systemic inflammation. When we think about inflammatory disease we think about things like diabetes and rheumatoid arthritis – diseases with a high level of systemic inflammation.
We don’t normally think about depression being in that category, but it turns out that it really is – not for everyone who’s depressed, but for about half.
We also know that inflammatory hormones can directly push the brain into a state of severe depression. So, an inflamed brain is typically a depressed brain. And added sugars have a pro-inflammatory effect on the body and brain.
Wow!
The Microbiome
As if what we’ve reviewed isn’t jarring enough, the team takes into account the impact of sugar on the microbiome – as a contributor to depression.
The good doctor points-out that our bodies host over 10 trillion microbes, many of them knowing how to hack into the brain. Ilardi says the symbiotic microbial species (beneficial microbes) hack-in to enhance our well-being. It’s a win-win. We thrive, they thrive (the definition of symbiosis).
But then there are species that can be considered opportunistic – parasitic. Many of these microbes thrive on added sugars, and they can produce chemicals that push the brain into a state of anxiety, stress, and depression. Oh, they’re highly inflammatory.
For the record, Ilardi recommends a minimally processed diet rich in plant-based foods and omega-3 fatty acids for optimal psychological benefit.
Added sugars? Likely anything above 25 grams daily may cause problems.
All Set
Those cupcakes, right? Heck, all of the sweets that tempt throughout the holiday season. I know it’s hard, but if depression is a problem we have to turn away.
Go figure. The very thing that makes us feel better only makes us worse. Hmmm.
Never fails, right? There are certain things we know we need to do to lessen the impact of our mood or anxiety disorder. But it’s those very things we often don’t do well. And to be brutally honest, at times it’s nobody’s fault but our own. Case in point, my crummy sleep…
‘Deep sleep had restored the brain’s prefrontal mechanism that regulates our emotions, lowering emotional and physiological reactivity and preventing the escalation of anxiety.’
Sleep isn’t my forte. It isn’t insomnia. No, it’s more about getting mentally and physically settled enough to fall asleep. It’s as though I resist it – with intention. And once I finally conk-out, there’ll be numerous awakenings throughout the night.
Sufficient deep sleep is definitely not happening. Furthermore, I know my lousy sleep hygiene is the primary contributor.
Can you relate?
I’ve known for some time I need to work on it. And now I come upon this research…
“Deep Sleep Can Rewire the Anxious Brain”
Groundbreaking sleep and anxiety research was detailed in a Berkeley News article entitled “Stressed to the max? Deep sleep can rewire the anxious brain.”
The piece reviews the work of a University of California Berkeley research team, led by study senior author Matthew Walker and lead author Eti Ben Simon. The findings were just published in the journal Nature Human Behaviour.
In summary, from Dr. Walker…
We have identified a new function of deep sleep, one that decreases anxiety overnight by reorganizing connections in the brain. Deep sleep seems to be a natural anxiolytic (anxiety inhibitor), so long as we get it each and every night.
According to the study, a sleepless night can trigger as much as a 30% increase in levels of anxiety. Of course, a good night’s sleep serves to emotionally stabilize us.
See why the research kicked my tushie?
The Study Skinny
In a series of experiments using functional MRI, polysomnography, and more, the research team scanned the brains of 18 young adults as they viewed emotionally stirring video clips after a full night’s sleep. The scanning was repeated after a sleepless night. Levels of anxiety were then measured using the State-Trait Anxiety Inventory.
The brain scans following the sleepless nights showed a shutdown of the medial prefrontal cortex, known for helping with anxiety management. Also, the brain’s deeper emotional centers were overactive.
According to Dr. Walker…
Without sleep, it’s almost as if the brain is too heavy on the emotional accelerator pedal, without enough brake.
After a full night’s sleep, measurements showed anxiety levels had declined significantly. This was particularly true for the participants who experienced more slow-wave non-rapid eye movement (NREM) sleep.
From Dr. Simon…
Deep sleep had restored the brain’s prefrontal mechanism that regulates our emotions, lowering emotional and physiological reactivity and preventing the escalation of anxiety.
The Work Went On
Beyond the original 18 participants, the team replicated the results in another 30.
The work was then taken beyond the lab to an online study tracking the sleep and anxiety levels of 280 participants over four consecutive days. The results showed the amount and quality of sleep from one night to the next predicted how anxious the participants would feel the next day.
Dr. Simon nicely summarizes the study results…
People with anxiety disorders routinely report having disturbed sleep, but rarely is sleep improvement considered as a clinical recommendation for lowering anxiety.
Our study not only establishes a causal connection between sleep and anxiety, but it identifies the kind of deep NREM sleep we need to calm the overanxious brain.
The study heavily emphasized NREM sleep. So what is it? Here’s some great information on the entire sleep cycle. And here’s much more on deep sleep. As always, how are we going to address something if we don’t know what it is?
That’s That
Come on, you know as well as I do that rising above mood and anxiety disorders requires a customized combo approach. Maybe it’s a little bit meds, some therapy, daily exercise, watching that diet, and optimizing deep sleep. Right?
Hey, I understand we can’t expect ourselves to do all those things well. But I also understand we have way more management over our performance than we might like to think.
Yep, I cause myself to suck at sleep. And it looks as though I’d better get my act together…
Significant and lasting relief: It’s the holy grail for anyone suffering from a mood or anxiety disorder. We want it yesterday, but that mysterious three-pound mass in our skulls says, “No!” Sure, the development of meds and other interventions is important. However, as slow as it may seem, the ultimate answers will come from cutting-edge research. Like this…
‘These brain imaging findings provide a science-based explanation as to why patients with mood and anxiety disorders seem to be locked in to negative mood states…’
You can’t get rid of an illness, fire, storm, bad guy – whatever – if you don’t know where it is, as well as the how’s and why’s of its traditional behavior. Oh, you can come up with mitigating somethings like traditional antidepressants. But that isn’t going to cut it for significant and lasting relief.
Though a much slower go, this will…
Our Featured Research
Led by University of British Columbia psychiatry professor Dr. Sophia Frangou, a top-notch research team just had its work published in the journal JAMA Psychiatry.
What’s it all about? Well, let’s start with the words of Dr. Frangou from a university news release…
These brain imaging findings provide a science-based explanation as to why patients with mood and anxiety disorders seem to be ‘locked in’ to negative mood states. They also corroborate the patients’ experience of being unable to stop and switch away from negative thoughts and feelings.
Specifically addressed by those brain imaging findings are major depressive disorder, bipolar disorder, posttraumatic stress disorder, and assorted anxiety disorders.
By the way, did you know that up to 90% of those with an anxiety disorder also meet criteria for a mood disorder? And while we’re at it, as many as 70% of those with a mood disorder will meet criteria for an anxiety disorder in their lifetime.
How the Study Went Down
Okay, let’s roll up our sleeves…
Dr. Frangou and team put together what’s known as a meta-analysis. Simply, it’s a statistical analysis that combines the results of multiple studies.
For their work, the team analyzed in excess of 9,000 brain scans (functional MRI, like our featured image) from 226 previously published studies that compared the brain activity of “healthy” (their word, not mine) adults to those who’d been diagnosed with the disorders mentioned above.
The study is believed to be the largest ever analysis of functional MRI brain scans of mood and anxiety disorder sufferers.
The Revealing and Hopeful Findings
As we get into the bottom-line of the study, how ’bout a little art? Visuals always help me learn. And I’ll tell you a little secret. I use the anatomy involved in whatever ails me for visualization purposes. That’s right, in this case I’ll focus upon, say, the amygdala, visualizing it functioning as it should to allow me to feel better. Have you ever done that?
Now, I find all of the anatomy marked on the images interesting, but they aren’t all included in the study results.
Okay, the team found that subjects showed abnormally low activity (hypoactivation) in the inferior (lower surface) prefrontal and parietal cortex, the insula, and the putamen (left of the thalamus in the top image). All are key players in our emotional and cognitive control brain circuitry. They’re responsible for stopping ongoing mental activities and transitioning to new ones.
The team also discovered abnormally high activity (hyperactivation) in the anterior cingulate cortex (ACC in the top image), left amygdala, and the thalamus. These three areas work together to process emotional thoughts and, ultimately, feelings.
For my money, these are incredibly revealing and hopeful findings,
So What!?
Maybe it would be a good idea to toss some relevance and perspective at what we’ve just reviewed.
From the study…
In mood disorders, posttraumatic stress disorder, and anxiety disorders. the most consistent transdiagnostic abnormalities in task-related brain activity converge in regions that are primarily associated with inhibitory control and salience processing.
Now, follow me here. The team flat-out says that the major challenges for anyone struggling with a mood or anxiety disorder are inhibitory control and salience processing.
You may know what they are, but let’s make sure…
Inhibitory control: An executive function that allows us to inhibit our impulses and natural responses to stimuli (internal and external). It’s about selecting the most appropriate behavior to complete our goals. Self-control is a significant aspect.
Salience processing: The cognitive process that predisposes us to focus upon items that are more prominent or emotionally striking (to us), while ignoring items that seem unremarkable. The difference is always significant to us, but often irrelevant by objective standards.
As a lifelong mood and anxiety disorder guy, inhibitory control and salience processing hit me straight between the eyes.
You?
Let’s Head Home
I guess you can tell, this study excites me. And that’s because it not only identifies the major thought and feeling dynamics that trouble mood and anxiety disorder sufferers, it connects them to brain anatomy.
And that’s what’s going to generate efficacious meds and other interventions. Heck, primary in my mind is the general heading of brain stimulation. Can you see what the study can do for targeting?
Yes, the holy grail: significant and lasting relief. It doesn’t come quickly or easily. But I deeply believe it, indeed, will happen.
fMRI image: Neurology Advisor, Basal Ganglia and Limbic System image: HowStuffWorks, Lobes image: McGraw-Hill
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Dr. Aiken states NAC is a component of two developing stories in bipolar disorder: inflammation and mitochondrial dysfunction. Both play a role in the generation of bipolar and both are positively impacted by NAC.
In a series of experiments using 
