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Unusual Medication Effects from 2021

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In 2021 we uncovered some paradoxical effects of medications, including meds that can both cause and treat OCD (antipsychotics), depression (benzodiazepines and antidepressants), and cognitive problems (stimulants and anti-dementia medications).

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Published On: 01/03/2022

Duration: 16 minutes, 0 seconds

Referenced Articles: 

Stimulants and Creativity,” The Carlat Psychiatry Report, February 2021

Brexpiprazole Ineffective in Mania,” The Carlat Psychiatry Report, October 2021

The Schizophrenia-OCD Overlap,” The Carlat Psychiatry Report, October 2021

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


Psych meds are rarely as straightforward as their FDA-indications suggest, and today we look at medications that can both cause and treat depression, OCD, and cognitive problems. 

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.

If there’s one thing we learned in 2021, it was that psychiatric medications don’t always behave the way we expect them to.

That’s what stands out as we look back on the 50-odd podcasts of the past year, starting with antidepressants. The name implies that these medications wash away depression much like soap washes away oil and dirt. But the brain is more complex than that, and in our February podcast we detailed 7 situations where depression might actually worsen on antidepressants. Let’s start there, but first a preview of the CME questions for this podcast. 


Which hypnotic has evidence to improve depression and generalized anxiety disorder beyond its sleep benefits?

A. Eszopiclone

B. Melatonin

C. Zolpidem

D. Lemborexant



The first is bipolar depression, where antidepressants are well known to cause mania, but that’s actually rare to see in clinical practice. More likely, you’ll see antidepressants cause mixed states and rapid cycling. When they trigger a mixed state the patient is likely to say that it made their depression worse, because mixed states are a more severe form of depression – with higher levels of anxiety, distress, and suicidality. When they trigger rapid cycling, the patient may not notice at all, because the increase in frequency of depressions is usually gradual, steadily building up over about a year. 

Then there are patients who don’t have full bipolar disorder but have bipolar features – such as depression with mixed features or hypomanias that last less than the official cut-off of 4 days. These patients are also more likely to have worsened mood on antidepressants, but not as likely as those with full bipolar disorder.

KELLIE NEWSOME: But just because a patient’s mood gets worse on an antidepressant, it doesn’t mean they have bipolar disorder. Patients under age 25, those with borderline personality disorder, and those who are sensitive to anxiety or side effects like akathisia. But these are just risk factors for worsening – all of these patients can also improve on antidepressants as well.



KELLIE NEWSOME: Turning to stimulants, you would think that things are more straightforward, but not so fast. In January we looked at how psychiatric medications affect chess playing skills, and in particular a study from 2017 called “Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: A double-blind, randomized controlled trial.” The study randomized 39 competitive chess players to play timed chess against a computer after taking a placebo or 1 of those 3 simulants. To our surprise, the players actually did worse on modafinil and methylphenidate, and the reason is revealing. The stimulants made them over-think their moves too much, and all that second-guessing caused them to run out of time. 

CHRIS AIKEN: In our online issue, we looked at how stimulants affect creativity, and arrived at a similar conclusion. While the research was not definitive, there was a suggestion that stimulants may dampen creative thinking in some patients, so when a patient feels robotic, self-conscious, or lacking in humor and spontaneity on a stimulant you might consider lowering the dose.

We also reported on a study that looked at whether stimulants improve cognition in healthy subjects who don’t have ADHD. That study found they did improve performance on cognitive testing a little, but with a cost. Cognitive performance was actually worse the next day, presumably because people didn’t sleep as well after taking the stimulant. Overall, this research made us question the idea of a “cognitive enhancer.” Most drugs that are touted that way – including stimulants and the anti-dementia medications – seem to help some aspects of cognition while hurting others.



KELLIE NEWSOME: One class of medications that has gone through a major reputation overhaul in the past 2 decades is the antipsychotics, particularly in mood disorders. Before 2000, the general consensus was that these medications treated mania quickly but could cause depression long term. In the years since, so many of these drugs have earned FDA approval in bipolar and unipolar depression that people are starting to look at them as having inherent antidepressant qualities. In October we launched a 3-part series that took a deep dive into this question, and here are a few of the highlights

  1. None of the older “first generation” antipsychotics prevent depression, and some of them may actually cause it.
  2. Among the newer “atypical” antipsychotics, only one of them has robust evidence to prevent depression in bipolar disorder: Quetiapine (Seroquel). One of them – paliperidone (Invega) actually increased the risk of depression over the long term.

CHRIS AIKEN: The atypical antipsychotics don’t have anything like a class effect in depression, but what about in mania? They may not always work as expected there either. We discovered that only half of them have evidence to treat mania – and those are the same ones that are FDA approved in bipolar mania: aripiprazole (Abilify), asenapine (Saphris), cariprazine (Vraylar), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon). And we can’t assume that the others work but simply haven’t been put through the test. This year, brexpiprazole (Rexulti) failed to treat mania in several large trials, and paliperidone (Invega) – which we just mentioned had a tendency to bring on more depression in bipolar patients – also failed to work consistently in its bipolar mania trials.

KELLIE NEWSOME: So antipsychotics definitely do not have a class effect in depression, and it’s starting to look like they don’t have a class effect in mania either. Another place where we found paradoxical effects with antipsychotics is in OCD, where they can both cause and treat the symptoms. On the one hand, there are half a dozen controlled trials where antipsychotics treated OCD – usually as augmentation of SSRIs, but sometimes on their own, as in a study from 2021 where quetiapine treated OCD in euthymic bipolar patients at a dose of 325mg per day. But on the other hand, antipsychotics can also cause OCD symptoms, particularly clozapine where it’s estimated that 1 in 10 patients develop OCD on the drug.

CHRIS AIKEN: Finally, two of the podcasts that changed the way I think about psychiatric drugs came in the spring of 2021 – on April 5th and April 28th. There we looked at dozens of controlled trials that investigated whether benzodiazepines or z-hypnotics can treat depression. We concluded that the benzos may have antidepressant effects beyond their effects in anxiety – particularly alprazolam (Xanax) – and that one z-hypnotic in particular can effectively augment other treatments in major depression and generalized anxiety disorder. That z-hypnotic is eszopiclone (Lunesta). The reason, we speculated, is that eszopiclone is metabolized into desmethylzopiclone, a non-sedating compound with benzodiazepine-like effects that may reduce anxiety – and depression – during the day. 

That suggests we might prefer eszopiclone for sleep in patients with anxiety and depression, but we might also be concerned about withdrawal problems with long term use. Some of the studies did withdraw the hypnotic without any rebound anxiety or depression, but they did so after a brief trial.

These podcasts helped me pick up on a withdrawal phenomenon in my own practice. I saw a woman who had been on high-dose alprazolam (Xanax) for panic disorder for many years. High doses of alprazolam are sometimes necessary in panic disorder – look closely at the PDR and you’ll find the drug is approved up to 10 mg/day for panic, and typical doses are in the 2-5 mg/day range. But she had not had panic in years and wanted to reduce her dose, which we did. My main concern was a rebound in anxiety, but that’s not what happened. As her daily dose neared the 2mg range, she called with severe depression. It wasn’t typical for her to get depressed, and there was no other explanation for the sudden episode, so we raised the alprazolam backup and her depression resolved.

KELLIE NEWSOME: Paradoxical drug effects are not the only thing we learned in 2021. We also found out that topiramate works in PTSD; that ketamine is not the only glutamatergic drug that can lift treatment resistant depression; that most of the commonly used genetic tests do little to guide psychiatric treatment, but that one test – for the p-glycoprotein gene – can make a meaningful difference in antidepressant dosing, and another set of tests can open up new avenues for Autism. We learned that melatonin might have a synergistic effect with buspirone to treat depression, and we mourned the loss of two of our pioneering colleagues – Hagop Akiskal and Aaron Beck.

CHRIS AIKEN: We also brought some new names to the podcast family. In the first half of the year we launched a separate podcast stream that you can share with your patients – the Pocket Psychiatrist – that teaches behavioral skills for depression, insomnia, and cognition. We welcomed a new journal to the Carlat family – the Hospital Psychiatry Report – edited by Victoria Hendrick from UCLA medical school. 

And now for the word of the day…. Note bloat

KELLIE NEWSOME: Note bloat is when EMR’s contain too many pages of nonessential information, much of it cut-and-pasted, and too much of it inaccurate. It contributes to burn out among professionals, and it’s a safety problem for patients – often the key details of their history are buried in the gibberish. Some blame EMRs and some blame the federal government, which created a reimbursement system in 1995 which ensures that clinicians get paid by the word. Well we have good news – the feds have owned up to their mistake and created new guidelines that will trim these unseemly notes. But it’s up to us to put that into practice, and next week we’ll show you how.

If you’ve noticed a different sound to the podcast that is the work of Zach Davis, who took over as our new audio editor last month. Along with Jeff Ives, Zach has helped us add CME credits to the podcast this year, and you can start earning them by clicking on the link in your podcast notes.

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