What We Learned in 2020

Table of Contents

A look at the top 10 practice-changing highlights in psychiatry from the 2020 Carlat Report. Tardive dyskinesia, inflammation, lumateperone, top first-line medications, trazodone in depression, Silexan for anxiety, excellent lithium responders, hormones and mood, and ramelteon’s generic debut.

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Each year we hope to bring you clinical updates that can change your practice, and today we’re going to look back at the top 10 from our monthly print edition in 2020.

1. Where to start with tardive dyskinesia

CHRIS AIKEN: If your inbox is like mine, it’s been flooded over the last 3 years with updates about the new VMAT2 inhibitors for tardive dyskinesia (TD): valbenazine (Ingrezza) and deutetrabenazine (Austedo). So we were a bit hesitant to cover this subject – is there really anything new to say? – until we realized something was missing. We couldn’t find any articles that tackled the most basic question we all struggle with: Which one of these should you start with?

We braved an answer in January 2020:  valbenazine (Ingrezza), but only by a narrow margin.

KELLIE NEWSOME: OK both of these have the same mechanism of action, the same side effect profile, and the same cost, So why valbenazine?

CHRIS AIKEN: It’s more practical — Valbenazine is dosed once a day, while deutetrabenazine is dosed twice a day and has to be taken with food. Sounds like a trivial difference, but for patients who are trying to take their meds regularly that’s a big deal.

KELLIE NEWSOME: Yes but what if they are on an antipsychotic that’s dosed twice a day, like ziprasidone, clozapine, quetiapine, or asenapine… then the twice a day deutetrabenazine would fit right into their dosing schedule.

CHRIS AIKEN: Let’s be realistic about schizophrenia. This illness is marked by negative symptoms, and those make patients unable to shower or brush their teeth with anything like a daily frequency. So expecting them to remember to take an antipsychotic twice a day is a bit much. The antipsychotics you mentioned were dosed two or three times a day in their original studies, but all of them – except maybe ziprasidone – have studies showing they be given once a day without loss of efficacy. That’s how I dose them, unless the patient has trouble with side effects that worsen when the blood level peaks, particularly orthostasis.

KELLIE NEWSOME: Any other reason to choose valbenazine?

CHRIS AIKEN: This next one is a bit more tentative, since they’ve never been compared head-to-head, but seemed to have better efficacy in the clinical trials. You’d have to treat 4 patients to see a meaningful response in with valbenazine, compared to 7 patients for deutetrabenazine. Another difference between them is that deutetrabenazine is FDA approved in Huntington’s disease and TD, while valbenazine is only FDA approved in TD. That might look like an advantage, but there was a slight increase in suicidality with deutetrabenazine in the Huntington’s trials, which earned it a black box warning about suicidality in that population. Neither of these drugs seemed to increase suicidality in the tardive dyskinesia studies, but I wouldn’t be surprised if there is a small risk of that which shows up in the post-marketing studies. Both are based on tetrabenazine, an older VMAT2 inhibitor that has been used for TD since the 1970s—and tetrabenazine never caught on because it has a clear risk of causing depression and suicidality.

KELLIE NEWSOME: Unfortunately, for many patients there is one thing is likely to get in the way of using either of them: Cost. Both cost over $70,000 a year. But there are many other ways to treat tardive dyskinesia, and in our January issue we list 8 off-label treatments that are worth considering.

2. Inflammation and Depression

CHRIS AIKEN: This article came out of a conversation I had a while back with Vladimir Maletic. He works with a lot of treatment resistant depression, and I asked if he used genetic testing. He said he rarely ordered it, because the research is not so good for most tests and the results can be misleading. But he did order another test: The C-reactive protein, or CRP, which is a marker of inflammation. Arguably, this marker has better evidence to predict antidepressant response than the famous serotonin transporter gene that’s included on many genetic panels. A high CRP indicated better response to tricyclics and dopaminergics like bupropion and possibly pramipexole, and a lower chance of responding to an SSRI. It’s a pretty common problem – inflammation contributes to about 30% of depression out there, and among treatment resistant cases the rate is closer to 50%.

In our February issue I interviewed Andrew Miller about inflammation and depression. Dr. Miller could have flooded us with cascades of cytokines and interleukins and other inflammatory signals, but he kept it very practical. Read the article and you’ll know how to spot inflammation in depressed patients, how to order and interpret the CRP, and how to choose medications when inflammation is high – including our dosing tips on this dopamine D3 agonist pramipexole.

KELLIE NEWSOME: And there’s something else at the end of the interview that really changed my practice. You see, I’ve used the CRP to guide treatment, and it really does work – I’m thinking of patients who had not responded to any antidepressants but had elevated CRPs and got better with a dopaminergic. The patients are very grateful. It changed their lives. But Dr. Miller pointed out a catch – we may just be treating the symptom, not the cause. Inflammation wears down dopamine receptors in the brain, so naturally these patients feel less depressed when given a medicine like bupropion or pramipexole. But that doesn’t change the fact that inflammation is wreaking havoc on the rest of their body – causing vascular disease, diabetes, and hastening the aging process. So it’s not enough to treat their depression. We also need to educate them about the causes of inflammation, and help them make lifestyle changes that address the underlying issue, because we don’t have good medication options that reduce systemic inflammation.

3. Lumateperone (Caplyta): A serotonin 5-HT2A story

KELLIE NEWSOME: 2020 brought the 5-HT2A serotonin receptor into the spotlight with the release of lumateperone (Caplyta), a novel antipsychotic that is distinguished by its low D2 dopamine blockade. Dopamine is not the only route to psychosis. Hallucinogens like LSD cause psychosis by activating the 5HT2A receptor, and antipsychotics like pimavanserin and the new addition lumateperone appears to treat psychosis by blocking this receptor. These medications block the 5HT2A receptor in different ways. Pimavanserin is an inverse agonist – which means it activates the receptor but causes it to act the opposite of the way an agonist would, while lumateperone is an antagonist, which means it blocks the receptor, preventing agonists like LSD from activating it.

CHRIS AIKEN: Perhaps some patients will benefit from this mechanism who don’t respond to dopamine blockers, but so far we have no evidence of that and there’s no suggestion that lumateperone is more effective than any antipsychotics o the market. Where it does stand out is tolerability. Antipsychotics with low dopamine blockade, like clozapine and quetiapine, tend to cause less muscle stiffness and other extrapyramidal side effects like akathisia. Lumateperone holds up that promise, and based on the available data it appears to have a favorable metabolic profiles as well.

The 5-HT2A story deepened when researchers from Mass General released a controlled trial showing that the 5-HT2A inverse agonist pimavanserin (Nuplazid) augmented antidepressants. We covered that in medication in our April issue, and a few months later we came across some unpublished controlled trials suggesting that the other 5-HT2A antagonist – lumateperone – treats bipolar depression. Those trials were presented at the international society for bipolar disorders conference, and we presented them in our August issue.

And – as a reminder that nothing in the brain is straight forward – 5-HT2A took a different turn in the evolving story of psilocybin in depression. This year, the FDA fast-tracked psilocybin for major depression, based in part on an uncontrolled trial from 2016 that found remarkable and sustained antidepressant effects from psilocybin in treatment resistant depression. The twist? Psilocybin is a 5-HT2A agonist, while these other antidepressant therapies are 5-HT2A antagonists. How it is that medications with opposite effects on this mysterious receptor can still treat depression is an unanswered question.

4. The best first-line medications

KELLIE NEWSOME: It’s often said that in psychopharmacology everyone has one and all must have prizes. But David Osser doesn’t think so. His psychopharmacology algorithm project takes the bold move of naming the top meds in each category to start with. For depression, that’s bupropion, escitalopram, and sertraline. For bipolar depression, it’s lamotrigine, lithium, quetiapine, or lurasidone. After our interview, Dr. Osser added Cariprazine – Vraylar – to that list, but he shared with us one reservation about this latest edition. Cariprazine’s efficacy in bipolar depression is about half that of the other atypical antipsychotics, based on its number needed to treat.

For classic, euphoric mania it’s lithium; and for dysphoric mania and mixed states it’s quetiapine. His reasoning is based on efficacy, tolerability, and cost, and for the efficacy question he depends on meta-analysis and real-world comparative studies. We interviewed Dr. Osser in our April edition, along with an update on schizophrenia that gives you a 3 step approach to antipsychotic selection. Dr. Osser’s algorithms are available online at www.psychopharm.mobi, and this fall he released their full details in a new book.

5. You can use trazodone for depression

CHRIS AIKEN: It’s often said that trazodone is a good hypnotic but a terrible antidepressant. But let’s look at the facts:

  • It has a low risk of sexual side effects or weight gain.
  • It improves sleep quality, while SSRIs tend to disrupt sleep a little.
  • It has a unique mechanism of action, which makes it reasonable to try when other options have failed
  • Its efficacy is sound – backed by over two dozen randomized controlled trials and demonstrated in severe depression. It compares favorably when tested head-to-head with other antidepressants.

So why is trazodone so often overlooked? The reason is fatigue, but there’s a way around that. Most studies dosed trazodone twice a day, but it worked just as well – and caused a lot less fatigue – when given entirely at night. Our May issue has other dosing secrets on trazodone, such as how to titrate it to prevent metabolites from shooting up that can get in the way of its therapeutic effects.

6. What to do when you run out of medication options

KELLIE NEWSOME: When is enough enough? Dr. Joe Goldberg attempted an answer in our June interview, at least when it comes to rolling out another antidepressant in treatment resistant depression. Here’s his answer:

“I don’t think I would ever say “enough is enough,” but there is a point at which the probability of medicines having a big effect becomes very, very low. In depression, that point is pretty black-and white in my mind: 5 trials.” At that point, Dr. Goldberg will move toward ECT, ketamine, or high-dose MAOIs, or…. Harkening back to our inflammation interview… the D3 dopamine agonist pramipexole.

But the heart of this interview is where Dr. Goldberg shares his psychological approach to working with people with chronic depression who do not respond to medications. We paired that with an interview with Dr. Lois Choi-Kain on borderline personality disorder, another area where there are real limitations to what medications can accomplish. Dr. Choi-Kain presented a practice psychotherapeutic approach to borderline personality disorder that can be adapted into the medication visit. It centers on helping them work toward realistic life goals, particularly those that provide them with a structured role in work, society, or community.

7. Silexan for anxiety

CHRIS AIKEN: In 2015 Robert Post shared some research on a medication for generalized anxiety disorder that had twice the effect size of SSRIs. The medication, Silexan, is a patented extract of the lavender plant that is available as a prescription in several European countries, but after some sleuthing I was able to track down an over-the-counter product in the U.S. that is made by the same German pharmaceutical firm Schwabe Pharmaceuticals that produces the prescription product.

Generalized anxiety disorder is not very responsive to medications overall, so I’ve had a lot of opportunities to try Silexan in patients who did not respond to conventional therapies. My count is 502 patients, and my close colleagues who used it add another 3,400. The responses have bene pretty good, consistent with what is reported in the research studies, and the extract is well tolerated. The thing that struck me most was seeing patients who’ve been on benzodiazepines for years, and after a month on Silexan they’ve lowered their dose or are not taking them at all for the first time.

KELLIE NEWSOME: Although derived from a plant, Silexan’s pharmacologic properties are more in line with conventional medications than with most natural therapies. But then again, valproic acid and buproprion were both derived from plants.

Like pregabalin, Silexan inhibits calcium channels; like the benzos, it has GABA-ergic effects but it lacks their addictive and rewarding qualities; like ketamine, Silexan is an NMDA antagonist; and like buspirone and vortioxetine, it is a serotonin-1A agonist.

8. Signs of a lithium responder

KELLIE NEWSOME: Dr. Osser gave lithium top billing as a medication for bipolar mania, but only for a certain type – the classic, euphoric, textbook case of mania. That got us wondering what other signs might predict that someone will be a good lithium responder. For that we turned to Dr. Janusz Rybakowski, whose research has helped identify the characteristics of an excellent lithium responder. Those are:

• Clear-cut mood episodes, with full remission between them. So there’s a clear difference between the normal self, the depression, and the mania.

• Relative lack of mixed states and rapid cycling. This doesn’t mean that people with mixed states and rapid cycling won’t respond to lithium, it’s just that they are less likely to get a full recovery on it.

• Few past episodes or hospitalizations.

• Depressive episodes that follow manic episodes, as if following the law of “what goes up must come down”

• Relative absence of psychiatric comorbidity, substance abuse, childhood trauma, and psychotic features. Generally, excellent lithium responders have few psychiatric comorbidities, although one study by Dr. Rybakowski found that comorbid panic disorder predicted lithium response.

• A family history of bipolar disorder and/or lithium response

• Hyperthymic traits (extroverted, natural leader, high energy, short sleeper)

Dr. Rybakowski estimates that 30% of bipolar patients are excellent lithium responders, and starting them on lithium early in the course can help them stay well for years.

CHRIS AIKEN: Dr. Rybakowski was one of the pioneers who discovered lithium’s antiviral properties in the early 1980’s, and he is now part of an international team that’s investigating lithium’s potential role against the coronavirus. But he shared a warning: Viral infections are a common trigger of lithium toxicity. Read more in our August issue, which also also features a 3-stage classification system for diagnosing neuropsychiatric complications of COVID infection.

9. When should you consider hormonal therapies for depression?

KELLIE NEWSOME: When I treat women with depression, they often ask about whether their hormones are contributing to their mood problems. From young women who’ve started birth control pills, to women with premenstrual dysphoria, to women in the peri-partum or peri-menopausal years, it’s hard to ignore the relevance that hormones play. But what exactly is that role, and what do we do about it? In our October issue, Ruta Nonacs from Massachusetts General Hospital’s Perinatal and Reproductive Psychiatry Clinical Research Program shed some light on this confusing area.

Here’s what we learned. Peri-menopausal changes do increase the risk of depression, and hormone replacement therapy – HRT – can make antidepressants work better, but the studies are small and the risks are significant. Women can limit those risks by limiting the time they spend on HRT to 5 years. HRT is generally avoided for depression in the post-menopausal phase, but can be used 2nd or 3rd line for depression that occurs as menopause is developing. The exact doses for the HRT are in our October issue, along with a list of birth control pills that have the highest and lowest chance of disrupting mood.

10. Generic spotlight on ramelteon

CHRIS AIKEN: We all get flooded with educational materials when a new medication is launched. At the Carlat Report we take a different tactic. We put a spotlight on meds when they enter the generic market. And 2020’s unsung entry was ramelteon, formerly known as Rozerem. This sleep medicine was rarely used when it was on patent because few insurers would pay for it and a lot of physicians had the impression that this melatonin agonist wasn’t a very strong hypnotic.

In our November-December issue we published a full review of ramelteon, and here are highlights. Yes, ramelteon is not very potent, but neither are any of the other sleep medications on the market. What makes ramelteon stand out is that it is not addictive, is not a controlled substance, and does not cause altered mental states along the lines of sleep walking, sleep eating, and – God forbid – sleep driving. That makes ramelteon a good first line choice for people with a history of addiction and the elderly, where it is one of few hypnotics that are not discouraged by the Beers list of risky medications in the elderly.

This review also opened up an unanswered question that some of our readers have written us about. Most sleep medications are woefully inadequate in their efficacy, improving on placebo by only about 10 minutes in terms of how much they hasten the time it takes to fall asleep, and doing little to improve on the quality or duration of that sleep. So why do patients ask for them, and keeping requesting nightly hypnotics even after testing their meek benefits on their own? Well, like I said, that’s an unanswered question. But it’s worth noting that most sleep medications have other effects that are unrelated to their therapeutic use. They lower anxiety. They dampen racing, ruminative thoughts. And, they are rewarding. Ramelteon is like sleep medicine that’s been stripped bare of all those tangential effects, so your patients may have a little trouble adjusting to it if you’re switching from a benzo or a z-hypnotic. But it’s not without tangential benefits – in the article we identified two psychiatric conditions where ramelteon may have therapeutic effects beyond its hypnotic benefits.

KELLIE NEWSOME: And since ramelteon is a lot safer in the elderly, we recommend trying it in older adults who need to wean off other hypnotics due to falls or other problems. But what about in children? We’re not going there yet, but the manufacturer Takeda did despite a lack of any evidence in younger patients. In 2006 they released an ad showing children getting onto a school bus and sitting in class with the voiceover “Rozerem would like to remind you that it’s back to school season. Ask your doctor today if Rozerem is right for you.” The FDA promptly pulled the ad from circulation.

KELLIE NEWSOME: The other big generic launch in 2020 was pregabalin (Lyrica), which has decent evidence in generalized anxiety disorder, social anxiety disorder, and alcohol use disorders. Generics are usually not available as soon as the patent expires… everything from legal battles to manufacturing problems can delay their release. Once released, insurers start to cover it a bit more and the price goes down a little, but it takes about a year for the cost to really fall because the FDA grants exclusivity to the first generic manufacturer to produce it.

So what’s on our radar for 2021? We hope to see generic equivalents of the smoking cessation aid varenicline (Chantix) and the sublingual antipsychotic asenapine (Saphris). We’ve often wondered why insurers don’t cover Chantix, while they willingly cough up the 170 billion a year – or 9% of the health care budget – that’s due to nicotine-related illnesses. Maybe this turn to generic will convince them that parity isn’t just the law; it also makes economic sense.

Immediate memory

And now for the word of the day…. Immediate memory.

Immediate memory is a type of short-term memory that’s usually measured by the digit span, where you ask a patient to repeat a list of random digits. Few people can remember more than 12 random items, and the average is 7 – which is why phone numbers are 7 digits long.

Information that’s stored in immediate memory is short-lived, fading after a few minutes unless it’s rehearsed. The brain selective transfers relevant information into long-term memory, and most of that pruning takes place during sleep.

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