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Five New Findings in Psychopharmacology

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Bupropion-dextromethorphan combo in depression. Lithium for COVID-19. The top med for nicotine cessation. Mirtazapine in OCD. Mediterranean diet in depression. 

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Published On: 07/04/2022

Duration:  20 minutes, 21 seconds

Referenced Article: Chris Aiken, MD, Kellie Newsome, PMHNP have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.


Science inches forward one study at a time, and every day we scour the research for new additions that change our practice. Today we bring you 5 of them.

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

KELLIE NEWSOME: Last month, Dr. Aiken launched a new feed on LinkedIn and Twitter: The Daily Psych. Everyday, he posts a new study that will inform, and sometimes change, your practice. Because the progress of science never sleeps. To follow, search for Chris Aiken, MD on LinkedIn or follow his twitter handle, @chrisaikenmd.

Today, we’re going to bring you the best studies from the past month.


  1. A new option for treatment resistant depression

AXS-05 is bupropion-dextromethorphan combination that hopes to gain FDA approval for major depression. You probably know of bupropion – Wellbutrin – but we’re guessing that dextromethorphan is not something you typically prescribe. This drug was FDA-approved as cough suppressant in 1958, and it’s still available over the counter in cough medicines like Robitussin and DayQuil. But you may know it through Nuedexta, which is FDA-approved for Pseudobulbar Affect – a neurologic condition that causes uncontrollable laughing and crying.

Dextromethorphan has several properties that suggest it may treat depression. Like ketamine, it increases glutamate by blocking the NMDA receptor. Like an SNRI, it increases  norepinephrine and serotonin through reuptake inhibition. It also has anticonvulsant and neuroprotective effects. A handful of reports support dextromethorphan’s antidepressant effects, but until now all of them have been uncontrolled.

Two randomized, placebo controlled trials found success for this antidepressant combo in major depression. The first trial was a little small – 80 patients – but it has a more meaningful design of the two because it compared bupropion with placebo to bupropion with dextromethorphan. What’s most impressive in this trial is the remission rates. At 6 weeks, there were three times as many remissions with the combo pill than with bupropion alone: 47% vs. 16%.

The second trial is large – 327 patients – but it compared the bupropion-dextromethorphan combo with a pure placebo, and since we already know that bupropion treats depression it wasn’t so surprising to see the treatment arm work. What does stand out in this study is the speed and degree of the effect. While most antidepressant trials separate from placebo at 4 weeks, this one separated at 2 weeks, and the remission rates were on the high side – 40% vs. 17% with placebo. The main draw-back in the study was the high drop-out rate in the dextromethorphan combo group – 24%; for reference, drop-out rates beyond 20% are considered problematic.

While bupropion is often energizing, dextromethorphan can make people drowsy. The main side effects of the combo pill were dizziness, nausea, headache, somnolence, dry mouth, decreased appetite, and anxiety. Other risks to be concerned about with dextromethorphan are addiction, dissociation, and psychosis. None of those problems showed up in these trials, but they are known to occur with dextromethorphan, particularly in high doses above 300mg. In this study, it was dosed at 90 mg/day, with bupropion at 210 mg/day, and both doses were divided twice a day. 

So should we start prescribing dextromethorphan for depression? It is available over the counter, and 7.5 ml twice-a-day will give the same dose as they used in this study, for around $20 a month. I have used it in depression, with mixed results, but I reserve it for highly treatment resistant cases, and both of these studies excluded patients with treatment resistant depression. 

If you do add dextromethorphan, I’ll give you a few warnings

  1. Be careful with SSRIs and SNRIs – it can cause serotonin syndrome
  2. Dextromethorphan has a very short half-life of 2-4 hours, but bupropion actually extends its half-life by blocking its metabolism at CYP2D6. So there’s another reason to stick with bupropion. The prescription version – Nuedexta – achieves a similar effect by pairing dextromethorphan with an inert CYP2D6 inhibitor – quinidine. The quinidine-dextromethorphan combo has also been studied in uncontrolled trials of depression, usually as 10mg of quinidine twice a day with 30-45 mg of dextromethorphan twice a day. If you go this route, both ingredients are available on their own for a much lower price than the branded Nuedexta. 


  1. Lithium treats COVID

Shortly after the pandemic began, we interviewed Janusz Rybakowski about lithium, and in that interview he suggested that lithium might treat COVID. Lithium has pro-immune effects – it raises the white blood count and regulates B and T lymphocytes, but that’s not why he made this suggestion. Dr. Rybakowski conducted trials in the early 1980’s showing that lithium treated herpes simplex, and it did this by directly destroying the virus, not through pro-immune effects. Since then, lithium has shown antiviral activity against a dozen viruses, including HIV and several coronavirus variants.    

The new trial is the first to show benefits with lithium in a controlled trial of a clinical population with COVID-19. The patients were significantly ill – all required hospitalization for COVID. It was a small trial of 30 patients, and half were given lithium in addition to the hospitals usual therapy for COVID – dexamethasone. After 7-10 days of treatment, all outcomes were significantly better in the lithium group – shorter hospital stay, fewer ICU admissions, and lower levels of inflammatory markers. 30 days later they followed up to look for long-COVID symptoms, which were also attenuated in the lithium group. 40% of the lithium-treated patients had long-COVID neurologic symptoms, compared to 73% of the control patients.

The dose of lithium was similar to what we use in mood disorders, with a target blood level of 0.6-1.2. That is the same blood level used to treat herpes virus. 

This is good news for psychiatric patients on lithium, and promising results for the rest of us. While lithium has risks, it’s unlikely to cause much problem with the short-term 7-10 day treatment used in this study. But if your patient is already taking lithium and develops COVID, watch out for toxicity. Lithium levels can go high when patients are dehydrated, have fever, or take NSAIDs to control viral symptoms.


  1. Varenicline shines for nicotine cessation in depression

A few years ago a friend of mine started varenicline (Chantix) with his primary care doctor for nicotine cessation, and the doctor did something I had never heard of before. He called my friend every day to check for suicidal ideation. Back then, varenicline had a warning about suicidal ideation, and my friend had a distant history of depression, and these two facts had the doctor spooked.

That warning probably caused a whole generation of physicians to shy away from varenicline in psychiatric patients, which is a shame because psychiatric patients are much more likely to smoke and have a much harder time quitting, and that warning is no longer relevant – the FDA removed the black box in 2016 after two studies – totaling 18,000 patients – showed no risk of major psychiatric side effects – including suicidality – with varenicline.

One of those studies was the EAGLES trial, and a new analysis of that data suggests that varenicline is not only safe in depression, it may also be the first-line choice for depressed patients who smoke. 

The analysis looked at 6,653 patients from the EAGLES trial, comparing outcomes for those with depression – 40% of the group – vs. the other 60% who did not have depression. The trial compared 3 nicotine therapies: Varenicline, bupropion, nicotine-patch, and placebo. All of these were used in conjunction with nicotine counseling.

The bottom line: Varenicline outperformed bupropion and nicotine-patch, and those later two were about equal to each other. Varenicline was the clear winner in both depressed and non-depressed patients, after 3 months of use and again after 6 months. Just how much better? Varenicline was 65% more effective than bupropion or nicotine replacement therapy. Put another way, patients were twice as likely to quit with bupropion or nicotine replacement therapy, but they were 3.5 times more likely to quit with varenicline.

And it was safe – varenicline did not lead to psychiatric problems and was just as safe in the depressed patients as it was in the non-depressed patients.

Nicotine cessation is a delicate matter. You need to talk about it with patients, but you don’t want to make them uncomfortable by pushing them too hard to quit. If my patient is not interested in quitting, I’ll still ask about their use, and I’ll remind them that I’m available to help if they ever change their mind. 

Varenicline was briefly taken off the market last year due to contamination of the Pfizer product with nitrosamines, a carcinogen that has contaminated many batches of medications in recent years. But is available once again, and now in generic form. Check out our May 2022 issue for more information on using it.


  1. Mirtazapine in OCD

Mirtazapine is controversial in OCD. On the one hand, it is a serotonin 5HT3 antagonist, and other antagonists at this site like the anti-nausea meds ondansetron and granisetron have successfully treated OCD in controlled trials. On the other hand, some have speculated that mirtazapine may cause OCD by blocking another serotonin receptor: 5-HT2. This is the first randomized controlled trial of mirtazapine in OCD, and tested in patients who had failed to respond to a good dose of sertraline – 250mg/day.

Mirtazapine was added to sertraline in this small trial of 61 patients, where half received the treatment and the other half got placebo. After 12 weeks, the YBOCS OCD scores were significantly lower in the mirtazapine group – 11 vs. 19. Mirtazapine was fairly well tolerated, although 2 patients dropped out due to drowsiness, and indeed drop-outs and small size were the main weaknesses in this study, where 24% of the patients did not complete the trial.  

Bottom line – mirtazapine is worth trying in patients who don’t respond to an SSRI, but we’ll keep an open mind for rare events like worsening of OCD on it. 


  1. The Mediterranean Diet Wins Again

In May of 2019 we interviewed Felice Jacka on her groundbreaking SMILES trial, the first randomized controlled trial to show an antidepressant effect with the Mediterranean diet. Dr. Jacka believed the diet would work, but she was surprised by the magnitude of the benefit. Compared to supportive psychotherapy, the diet had a large effect size of 1.2, much larger than the effect size with antidepressants, which is around 0.4. That seemed like a fluke, but a second trial in major depression found an even larger effect – 2.4, and a third randomized controlled trial trial confirmed that the diet worked in people with depressive symptoms who didn’t have the full DSM disorder.

Now we have a fourth trial in clinical depression, and again the Mediterranean diet comes out with a large effect: 1.5. This study used a very similar design to the original SMILES trial. It was about the same size – 72 patients – and compared dietary counseling with a supportive psychotherapy called “befriending” therapy where the therapist offers empathy and support but no real direction. The diet was the same, but the patients were different – this new trial focused on young men with depression. And the new trial used only 3 sessions of dietary counseling, a much trimmed down version when compared to the 12 sessions in the SMILES trial.

The Bottom line – after 4 trials with large effect sizes, we need to start paying attention to what our patients are eating and guide them toward the Mediterranean approach. Check out our May 2019 issue with Felice Jacka, or our November 2021 issue with Drew Ramsey. 

I also have a handout I give to patients on my website at That describes the diet used in the trials, and to simplify it I divide the foods into 3 categories:

  1. Foods to eat more of – vegetables, fruits, nuts, beans, whole grains, fish, and extra-virgin olive oil. I’ll tell patients “replace all your breads and carbs with 100% whole grains, and all your oils and butters with extra virgin olive oil…. You can cook at up to 400 degrees with extra virgin, it actually is less likely to create dangerous polarized compounds at high heats than other oils.
  2. Then foods to eat in moderation – dairy, eggs, chicken/poultry, and lean red meat
  3. Finally, foods to avoid entirely or limit to no more than 3 servings a week – processed foods, fast foods, fried foods, sugary foods, sodas, and deli meats.

KELLIE NEWSOME: Those are our top 5 findings from the past month, but you can scroll through Dr. Aiken’s daily posts to find more. There you will find a link to a new test for dementia that patients can take at home, light therapy for PTSD, levetiracetam (Keppra) in schizophrenia, reviews of the best medications for panic disorder and for rapid cycling bipolar disorder, newly discovered anxiolytic properties of disulfiram, a comparison of cognitive effects of antidepressants, and, on a serious note, a controlled trial that tells us which type of jokes have the greatest benefit in depression. Find him on LinkedIn as Chris Aiken, MD or twitter handle, @chrisaikenmd.

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