KELLIE NEWSOME: We continue with the top 10 research updates of the past year, with a focus on lithium, lumateperone, and a German extract of lavender.

CHRIS AIKEN: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor-in-chief of the Carlat Report. 

KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

 A few years ago we asked Robert Post, Founder of the Bipolar Collaborative Network, what his top treatment was for bipolar disorder. “The 3 L’s,” he replied, “Lithium, lamotrigine, and lurasidone.” Today with have research updates on a different set of L’s: Lithium, Lumateperone, and Lavender.

CHRIS AIKEN: I agree with Dr. Post, but I’d rank lumateperone close to lurasidone in bipolar depression. They are both among the better-tolerated options, and both have similar effect sizes. Lumateperone tends to cause more fatigue and dizziness, while lurasidone causes more akathisia and nausea. They both have evidence as monotherapy in depression with mixed features – including unipolar depression with mixed features – but they both suffer from the same setback. Neither lurasidone nor lumateperone are known to work in mania. But lurasidone has one advantage over lumateperone – it is generic. Our next study concerns lumatperone in unipolar depression, and it has changed how I use this medication.

KELLIE NEWSOME: This was an industry-sponsored randomized placebo-controlled trial where lumateperone was added to an antidepressant in major depression in 485 patients who had failed either 1 or 2 past antidepressant trials. The augmentation strategy worked with a medium effect size (0.6), and the main side effects were fatigue, dry mouth, and tremor. The dose was the same that we use in bipolar depression: 42 mg.

This trial has not yet been published, so we have only rudimentary details. A second trial is anticipated later this year, and if it succeeds in a 2nd trials we anticipate it will earn FDA-approval. For now, lumateperone is only FDA approved in schizophrenia and bipolar depression. 

The bottom line: You can add lumateperone to the list of antipsychotics that augment antidepressants. The target dose is 42 mg at night, but I start it lower, at 10.5 or 21 mg, otherwise too many patients stop it early on because of side effects. Let’s run through the other options for antidepressant augmentation.

First are FDA-approved generic options: aripiprazole 5-15 mg, olanzapine-fluoxetine combo 6-12mg (that’s the olanzapine mg, the fluoxetine part runs 25-50), and quetiapine 150-300mg.

Next, FDA-approved branded options: brexpiprazole 2-3 mg and cariprazine 1.5-3 mg.

Finally, off-label options. These may not be approved, but they have good evidence to work from controlled trials: Risperidone 0.5-3 mg and lumateperone 42mg. We’ll add lurasidone here, 20-60 mg per day, although it only has trials as monotherapy for unipolar mixed features – not as antidepressant augmentation.

Missing from this list are ziprasidone – it has only small trials – and Pimavanserin (Nuplazid) – that antipsychotic had promising small trials but failed this year in large trials of antidepressant augmentation. Also missing are the rest of the antipsychotics which have zero evidence in depression. So Dr. Aiken that’s 7 options. Which is your first line?

CHRIS AIKEN: Aripiprazole.

KELLIE NEWSOME: Why is that? 

CHRIS AIKEN: Aripiprazole, Abilify, stands out for antidepressant augmentation in many ways. It has the largest effect size. It has the most number of trials. It has trials in true treatment-resistance – failing 2 or more antidepressants – whereas most of these were tested after only 1 failure. And it has large trials in the elderly. It’s relatively well tolerated within this poorly tolerated class, and it’s generic.

KELLIE NEWSOME: And what dose do you use?

CHRIS AIKEN: Nearly all my patients are on 5 mg aripiprazole, but I recognize that the dosing goes up to 15 mg and many trials averaged around 7-10 mg. So I may be underdosing, but I tend to get side effects like akathisia or affective flattening if I go too high. I’m also aware that some people use lower doses – 2-5 mg – successfully, and while some trials support that one meta-analysis found that 2 mg was no different from placebo. The bottom line: Aripiprazole has a broad dosing range in depression. Some patients, particularly the elderly, may do well at 2-5 mg. Most need at least 5 mg, and it’s worth trying higher than 5 mg to reach for full recovery, but don’t hang out in the high-dose range unless you are sure it made a difference.

CHRIS AIKEN: Here are some other highlights from the world of industry sponsored antipsychotic trial.

1. Iloperidone (Fanapt) was approved in bipolar mania, although I’ll caution that the effect size for this sedating antipsychotic was small, 0.2. 2. Brexpiprazole (Rexulti) submitted data for approval in PTSD, as an adjunctive treatment to patients who don’t respond to sertraline. 2 out of 3 of the trials were positive, suggesting potential approval by the FDA, at a flexible dose of 1-3 mg/day

And we have two failures to report

1. Cariprazine (Vraylar) failed in the maintenance phase of bipolar, reminding us that antipsychotics in general do not have robust data for prevention in bipolar like lithium does. 

2. Pimavanserin (Nuplazid) sought approval for negative symptoms of schizophrenia, but ultimately its trials there were not successful. This novel antipsychotic also failed in its attempts to augment antidepressants in major depression in large trials, despite showing initial promise there in a small trial.

The bottom line: Consider lumateperone for antidepressant augmentation, and brexpiprazole for to augment SSRIs in PTSD. And don’t assume that antipsychotics are ideal for preventing bipolar disorder. The long term outcomes are much better with lithium.

Esketamine vs Quetiapine in Treatment-Resistant Depression (TRD)

KELLIE NEWSOME: Our next study is a big one, and we probably should have included it in last week’s rundown of treatment-resistant depression. In that episode, we highlighted new trials where TMS surpassed antipsychotic augmentation in TRD. This next study looks at how esketamine compares to antipsychotic augmentation – specifically quetiapine XR. On the surface, it tells us that esketamine is more effective, but there’s some big caveats there.

CHRIS AIKEN: This was a large trial, sponsored by the maker of esketamine (brand name Spravato) and nicknamed ESKAPE-TRD. It enrolled 676 adults who had true treatment-resistance. They had failed 2-6 antidepressants from different classes. The study went on for 8 months, and esketamine was continued for the entire duration, though tapered down to dosing every 1 to 2 weeks. Quetiapine was dosed at the usual 150-300mg.

 At the end of the 8 months, all outcomes favored esketamine, with greater response (76% vs 56%), remission (27% vs 18%), and sustained remission (27% vs. 14%). However, although statistically significant these differences were not that big – just a 2-point difference on the MADRS favoring esketamine, which is arguably not clinically meaningful.

 A few other aspects of this trial may have favored esketamine

1. The esketamine patients had more contact with their providers than the quetiapine

2. The trial was not blinded – only the raters were blinded, and we have studies showing that patient expectations about receiving ketamines greatly inflate their responses, such as when the blind is broken in randomized trials.

Those two problems – provider contact and blinding – apply to the TMS trials as well. The next two problems are unique to this study.

First, they allowed patients in who had already tried low-dose quetiapine, 50 mg, which likely biased the sample toward non-responders of that low-dose. Second, there were twice as many dropouts in the quetiapine group, and these dropouts were counted as poor responders, again stacking the odds against the antipsychotic.

The bottom line: Esketamine may be stronger than quetiapine, but the difference is not big and it isn’t fully proven. However, both of these treatments have serious problems. Quetiapine has more tolerability problems than most psych meds, and esketamine is expensive and its benefits are only proven in the short-term. Quetiapine has decent long-term data for prevention of bipolar depression – and while we hope that translates to unipolar depression, it doesn’t have much data there.

KELLIE NEWSOME: Let’s pause for a preview of the CME quiz for this episode. Earn CME through the link in the show notes.

1. Which mood stabilizer has the lowest rates of sedation and weight gain?

A. Lithium

B. Lamotrigine

C. Valproate

D. Lurasidone

Silexan in Depression

KELLIE NEWSOME: Our next update concerns a medication that is off-label and over the counter in the US, but available by prescription in Europe where it has regulatory approval for generalized anxiety disorder. It’s a proprietary extract of the lavender plant called Silexan, and we’ve highlighted it in the Carlat report before because it has an unusually large effect size in generalized anxiety, 0.8, compared to the small 0.3 effect we see with SSRIs. It also beat paroxetine and equaled lorazepam in head to head trials of anxiety. But until now all the research on this drug has been in anxiety, with possible secondary benefits for insomnia. Our 2024 update is the first trial we’re aware of to test Silexan in major depression.

CHRIS AIKEN: This was a large, industry-sponsored, randomized, placebo-controlled trial of 498 patients with mild to moderate depression. They were divided into 3 groups which received either silexan, sertraline, or placebo for 2 months. The doses here were small, 50 mg for sertraline and 80 mg for silexan, which is important because the 160 mg dose of silexan actually worked better in studies of anxiety.

In the end, both active drugs fared equally well, with a number needed to treat of 9 for Silexan and 8 for sertraline. They showed similar trends on secondary outcomes, although only Silexan brought functional improvements on a disability scale.

Silexan was well tolerated – I’ve used this med in hundreds of patients and the only common side effect I’ve encountered is lavender flavored burping. The cost for this 80 mg dose is $15 per month. You can find it on amazon through the product CalmAid, which licenses the same proprietary formula made by Schwab pharmaceuticals. I have links to the product and how to use it on my website chrisaikenmd.com/supplements.

I think of silexan as a med because it has distinct pharmacologic effects, primarily serotonergic, glutamatergic, and even some effects on the benzodiazepine GABA receptor although it had no rewarding properties in studies of healthy volunteers. 

Although silexan was used as monotherapy in this trial, it can be added to antidepressants and has no known drug interactions. The chemical does bear a resemblance to estrogen, and there has been controversy about whether it can cause estrogenizing effects in teenage boys, like breast enlargement. So far that controversy appears theoretical – there is no clinical evidence of a problem – and lavender oil is routinely used for anxiety on breast cancer units.

The study was sponsored by the Medical University of Vienna.

The bottom line: Silexan is one of our most effective options for generalized anxiety, and this new study tells us it is useful for depressive symptoms as well, but why would you choose Silexan when we have so many other options available? One is if the patient prefers a natural treatment. Second is when you’re looking for a novel mechanism of action because the usual monoamines – dopamine, norepinephrine, and serotonin – have not worked. Silexan does work through serotonin – but through serotonin-1A receptors, which is very different from the route of SSRIs. It also affects glutamate (like ketamine) and the gaba receptor, although unlike the benzos it is not addictive and has no rewarding qualities.

KELLIE NEWSOME: Our next update challenges a common assumption about lithium, suggesting that the popular mood stabilizer does not cause weight gain. This was a well designed metaanalysis using the PRISMA guidelines of 9 trials involving over two thousand patients with bipolar disorder. These were long and short term studies, lasting 2 to 12 months. They looked at weight gain 3 different ways, by comparing before and after on lithium, comparing lithium to placebo, and comparing lithium to other meds in head-to-head trials. Here’s how it turned out, basically there was no statistically detectable weight gain. None at all.

Surprised? Well maybe it was underpowered, so let’s look at the trends. There was a non-significant trend toward weight LOSS in the before and after lithium analysis, a non-significant trend toward weight GAIN in the lithium vs placebo analysis, and there was a significant weight LOSS with lithium when it was compared to other meds, which packed on 3 and a half pounds more than lithium did.

Still don’t believe it? They topped it off with a systematic review of more trials, 20 in all, as that allowed them to include studies that didn’t perfectly fit into the meta-analysis. The results were the same – no weight gain with lithium. Specifically, lithium caused no weight gain in 5 out of 6 placebo controlled trials, and less weight gain than other meds in except for lamotrigine and venlafaxine.    

Still doubting? Well, we can point out a limitation in the data. When we compared the short term – less than 3 months – and long term trials – they averaged out the same, that is, no weight gain for either. But the SPREAD in the data was much wider for the long term trials, which suggests that results varied a lot by patient over the long term. However, that spread went both ways – with possible weight loss and weight gain. 

CHRIS AIKEN: This is not the first meta-analysis to show this – I recall one 10 years ago that found weight loss on lithium compared to placebo in short term trials. But what if these studies are missing rare cases – outliers who experience a lot of weight gain. The next paper, from 2023, looked at that. It’s a German paper, which is important because German physicians do a very good job at reporting rare adverse outcomes. That’s why it is from Germany that we get the best estimates of Stevens Johnson syndrome on lamotrigine – around 1 in 3,000 to 1 in 6,000. 

The authors looked at reports of severe weight gain – more than 10% of body weight – on mood stabilizers and antipsychotics in bipolar. Among the 527 cases, lamotrigine had the lowest rates of problematic weight gain. Lithium was slightly higher than lamotrigine, but it wasn’t a significant difference. The ones that did have a significantly higher rate of severe weight gain were olanzapine (12 fold higher), quetiapine (3 fold higher), and valproate (2 fold higher).

Here’s what I’d do in practice. Tell patients that weight gain is possible on any medication, but that lithium is among the few with the lowest rates – both in the short term and the long term. But there are two ways lithium can cause weight gain, and both are controllable. First, lithium can lower thyroid – if you take it for life that risk is 15% - and low thyroid can cause weight gain, but we’re going to watch for that and treat it if needed. In fact, lithium tends to work better – with better depression prevention – if the TSH is kept around 2.4. Second, lithium can make you thirsty, so drink lots of water. Avoid caloric beverages and avoid diet drinks – they cause weight gain indirectly, even though they may have zero calroies.

Among the mood stabilizers, lithium has the just about the lowest risk of weight gain and sedation – two side effects that patients care about. Just about, but not quite – it’s beaten out in those categories by Dr. Post’s other favorite “L”: lamotrigine.

KELLIE NEWSOME: Our final lithium update for the year concerns a new branded formulation of lithium – LiProSal – which the FDA greenlighted to launch trials in bipolar disorder, major depression, PTSD, and dementia from Alzamend. Phase II trials are underway in Alzheimer’s and expected to begin in the psychiatric conditions next year. 

LiProSal hopes to reduce lithium’s side effects by allowing more of the mineral to pass into the CNS so that less circulates in the body. It does this by pairing lithium with the amino acid proline and salicylate (that’s Aspirin).

KELLIE NEWSOME: You can find the slides for this podcast summarizing all of the top 10 studies at chrisaikenmd.com/speakerrequest. Join us next week where we’ll introduce a new med combo for alcohol use disorder, antipsychotic dosage in schizophrenia, and two new tips for using stimulants in ADHD.

The Carlat CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of one quarter (.25) AMA PRA Category 1 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.