How to assess med response when the patient reports is a poor guide: long-term mood stabilizers, sleep meds, and rapid cycling.

Publication Date: 11/04/2024

Duration: 18 minutes, 12 seconds

KELLIE NEWSOME: We rely on patients to tell us how their meds are working, but sometimes patient report is a poor guide. Today, we step into that difficult terrain with maintenance mood stabilizers, rapid cycling, and sleep meds.

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. 

CHRIS AIKEN: 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.

CHRIS AIKEN: We’re launching a new series on psychopharm secrets. Unlike our usual series, these episodes won’t be back to back. We’ll release them as the secrets come, and we invite you to share your own secrets with us: write to caiken@thecarlatreport.com. We hope to bring you uncommon tips that you won’t find elsewhere, and today’s episode focuses on stuff you won’t even learn by asking your patients.

KELLIE NEWSOME: Psychopharmacology would be easy if you could just try a bunch of meds and ask patients which one they liked best. But if that was all there was to it, we’d be out of a job. Patients are very good at telling us what feels better after a few hours or a few days. It’s the long-term effects they are less clear on.

CHRIS AIKEN: And that brings us to our first secret. Patients may not tell you that lithium has helped when it has. Lithium does have acute effects and benefits in mania and depression, but most of its benefits build up over the long term. Patients function better; they have fewer hospitalizations, less violence, suicide, and legal problems when they take lithium long-term, as well as fewer episodes of mania and depression in bipolar. Compared to other mood stabilizers, people live longer on lithium, and not just because of its anti-suicide effects. They have lower rates of cancer, neurologic, cardiac, and viral illnesses. 

This is true for lithium in both bipolar and unipolar. In unipolar depression, lithium prevented re-hospitalization more than antidepressants did, and lithium, in combination with nortriptyline, has the best evidence to prevent depression after ECT. As a preventive med, lithium may make this stuff go away, but patients aren’t going to notice the absence, and they may tell you that lithium did nothing. The only way to detect this is with a mood chart, where you may see a gradual improvement in mood in the years they were on lithium. They may not recover all the way, but you might see about a 60% overall reduction in their depression rating in the years that they were on lithium. 

KELLIE NEWSOME: I’d add lamotrigine to that list as well. Patients tend to like this mood stabilizer because it has very few side effects, but they sometimes miss its benefits. Lamotrigine is only FDA-approved for prevention of new episodes, mania, and depression, and it does a much better job of reducing depression, cutting their frequency in half. So if your patient with bipolar II disorder has depression 2 times a year, they’ll likely have it once a year on lamotrigine. The problem is that when that depression hits, they may think lamotrigine is not working and ask to come off it. I wouldn’t do that unless I had good reason to suspect from before-and-after mood charts that the medicine did nothing to prevent new episodes.

CHRIS AIKEN:  Our next secret concerns sleep medicines. Your patient is not likely to tell you that their sleep med is not making a meaningful difference. There’s a paradox with sleep medicines. They are very popular with patients, but they don’t work much better than a placebo, and most of them don’t make a difference on the big-ticket items, like sleep quality, next-day functioning, and overall mortality. Exactly the things that sleep is supposed to help us with.

Sleep meds mainly help with falling asleep – initiation insomnia – and even there, the benefits are meager. On average, they help patients fall asleep about 30 minutes faster, but a placebo is responsible for 20 of those 30 minutes, so the true benefit of the hypnotic is only about 10 minutes faster in falling asleep. Outside of that, they do nothing to improve sleep quality, and when we measure next-day cognition, most of them have mixed results – helping a little here and hurting a little there – averaging out to nothing.

KELLIE NEWSOME: The strange thing is, when you suggest tapering off a sleep medicine, most patients are very fearful. They’ll say, I won’t be able to sleep, and I won’t be able to function at work.

CHRIS AIKEN: This disparity between subjective and objective accounts of sleep has baffled sleep researchers for years. My best guess is that patients do feel a benefit with sleep medicines, but it’s not the benefit they were designed to bring. These sleep meds are mostly amnestic agents, so it means patients forget how bad they slept, and they are rewarding agents, which is a kind of benefit that’s hard to put in words other than, when you have that reward, you don’twant to give it up.

KELLIE NEWSOME: Now, that’s true for the benzodiazepines and the z-hypnotics, and I recall one study in mice where the animals found zolpidem even more rewarding than a benzo – but what about the other sleep medicines?

CHRIS AIKEN: Ramelteon – rozerem, the melatonin agonist – is not a controlled substance and has no rewarding qualities. In some studies, ramelteon worked better the longer patients took it, and I’ll emphasize that to patients because they are often rightly concerned that they’ll get dependent on a sleep med. If we look at the raw numbers, ramelteon is slightly less effective than the z-hypnotics at helping people fall asleep, but it has a small benefit in sleep quality and total sleep time, which is unique for it and meaningful for your long-term functioning and health. Overall, ramelteon looks about the same, even on subjective measures of sleep, as the more popular z-hypnotics. But patients just don’t like it as much, and my guess is that its lack of amnestic and rewarding qualities may explain why. I mean, people are not sleeping well on Ambien (Zolpidem). They are not sleeping well on ramelteon either – both of these are fairly weak agents, but at least on Ambien, they forget how bad they slept.

KELLIE NEWSOME: That's a good point, but what about the new ones, the orexin antagonists: Suvorexant (Belsomra), lemborexant (Dayvigo), and the newest Daridorexant (Quviviq)?

CHRIS AIKEN: Those three are controlled substances, just like the z-hypnotics. In animal studies, those orexin antagonists are not particularly rewarding, and they even make animals less likely to use alcohol, opioids, marijuana, and cocaine, which is very promising and something we can’t say for the benzos, which tend to make opioids and cocaine more rewarding. But there is good reason to make these orexin antagonists controlled, which the FDA did. Recreational sedative users rate them with the same liking as they do zolpidem, reminding us that animal studies are not always the bottom line. But in my experience, patients actually don’t like them as much, maybe they don’t feel knocked out on them – or maybe their biggest selling point is also their downfall. The industry brags that these meds promote sleep without the cognitive side effects of the others – in other words, they don’t impair memory or attention. But that means patients are alert and aware after taking them – aware of their ruminative thoughts, aware of how difficult sleep is even with a sleep med – and well, you get where I’m going here.

KELLIE NEWSOME: What I tell patients when starting them is to pay more attention to how they function the next day and worry less about how quickly they fall asleep on them. The orexin antagonists do improve sleep quality, and with that, there are also improvements in next-day cognition – something we don’t see with other sleep meds.

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

1. What is the minimum frequency of episodes in rapid cycling bipolar?

A. Once a month

B. Six times a year

C. Four times a year

D. Twice a year

CHRIS AIKEN: Here is another one patients won’t tell you about… they won't tell you if they are having rapid cycling. Patients do tell me if they are having affective instability, also called lability, or what is known colloquially as mood swings. Affective instability is when emotions shift rapidly over minutes or hours, and while it can be a sign of bipolar disorder, it is even more indicative of borderline personality disorder. But, affective instability is not rapid cycling. By comparison, rapid cycling is not very rapid. Rapid cycling just means at least four mood episodes in a year, and although it is a phenomenon that occurs in bipolar disorder, those four mood episodes do not have to include mania; they could all be depression, and often they are, or if there are manias you don't hear about them, the patient forgets them and doesn'tcome in. I have never heard a patient complain of rapid cycling– instead, they seem to live in the moment, as though each mood episode is its own problem, triggered by an understandable stress. I mean, if you look at three months of your life, you are likely to see a big stress and think thats what caused the episode. The patients don’t see the bigger picture, the pattern of what is going on, and the frequency of these episodes.

KELLIE NEWSOME: This can be a particular problem when an antidepressant is causing rapid cycling. This is how it plays out. You start venlafaxine for depression, not knowing they have bipolar. The antidepressant quickly flips them into hypomania, and then they stabilize, which to the patient, feels like a great recovery. Two months later, they are depressed again, but the med worked so well they call you up and ask if they can raise it, which you do, turning it up from 75 mg to 150mg. By this time, they are rapid cycling, but no one knows it yet, so they naturally cycle out of the episode, and when they do, they think it’s because they raised the med. Then they get depressed again, but this time it happens faster, after just 1 month instead of 2 months. Usually, the patient doesn’t notice the pattern. Instead, they look for something that is going wrong in their life – inevitably, something is – and blame the depression on that. The solution? Raise the med again, this time to 300mg. The next time you get a call, it may be from the patient’s wife, who will tell you that she is walking on eggshells because he is so irritable and agitated – his mood is changing so rapidly she never knows which version of her husband she’s going to meet. He is up and down, manic, depressed. The cycles have gotten so rapid that they are overlapping – causing an anxious, agitated, dysphoric mixed state.

CHRIS AIKEN: That whole process can take 6-12 months to play out after starting the antidepressant, and as things gradually get worse, no one is going to blame the antidepressant, not you and not the patient. To figure it out, you need to be in touch with overarching patterns, but most of us have as much trouble picking up on that as the patients do. Personally, I can’t pick up on rapid cycling unless I am looking at a 12-month mood pattern in a mood chart, but there is one sign that might tip you off that it's happening. Do you have patients who come in every month, and half the time theyare better and half the time they are worse? It seems random, and yes, they always have stressors going on, so it can seem like they are just overly sensitive to stress. But when they are doing well, they also have stressors going on they just don'ttell you about it because they are not as bothered. So when I see that kind of visit pattern in a patient, I am going to lay down my hands and say, I can't help you unless you complete a mood chart outside of the session so I can follow what is going on; if it does indeed turn out to be rapid cycling. The solution is to start a mood stabilizer and slowly taper off the antidepressant. I would start the mood stabilizer first. If you taper it off too quickly, they may have withdrawal symptoms – anxiety and dysphoria – and those symptoms are going to look very close to the problem you are trying to address. Also, stabilize sleep and circadian rhythm, get them up in the morning with light, and have them with total darkness at night. You can apply dark therapy. I have a website that describes how to do it, chrisaikenmd.com/darktherapy, and get them off recreational drugs, which, just like antidepressants, can trigger rapid cycling.

Rapid cycling is slow to recover – so tell the patient it is essential to keep a mood chart, that they are going to get better and worse during treatment, but that what we hope is the bad swings will be less intense, less prolonged, and less frequent over time. I have found that patients don’t like to chart their mood daily, so I have them do it weekly and keep a weekly chart for them at https://chrisaikenmd.com/moodchartweekly. 

With the best treatment, it going to take at least 3 to 6 months to see signs of improvement, and often longer. Some studies suggest that rapid cycling is just a phase of the illness that comes on for reasons we don't understand and lasts several years; when it does come on, eventually, people come out of it, although it is difficult to get them out any faster than that two to three year period that rapid cycling tens to last for.

KELLIE NEWSOME: Mood charting is one way to pick up on long-term medication effects, and if the patient doesn’tchart their mood, I’ll at least have them rate their symptoms at the visit so we can follow those patterns. What else can we do?

CHRIS AIKEN: Assessing medication response is a big part of our job, and I only know four ways to do it:

The first is the patient report. We started out the podcast with that, and we said it is not always that helpful, but it is very important. Just ask the patient if they think the med is helpful, and when you do that, try to ask about objective functional changes on the med, not just how they feel. Like, were they able to stay out of the hospital, stay sober, or keep their job while on it?

Second is rating scales – these are often self-report, like number one, but they are numeric, and they are not as prone to forgetting. It’s amazing how often patients will rate improvement on the self-rated rating scale, but at the same time, tell me that the med is doing nothing. 

The third wheel is input from relatives – if you don’t talk to the relatives, at least ask the patient What have others noticed about you on the medication? Would your wife say if she was here?

And the fourth wheel in this car is your own impression – a lot of that has to do with the mental status. Are they moving briskly where once they were slowed? Does their face react? Do they smile? Can they talk easily about a wide range ofsubjects, or do they always steer toward the negative?

Think about those four wheels of the car as you make your assessment. Rarely do they all line up the same way, but that is what makes this work interesting.

KELLIE NEWSOME: Got your own psychopharm secrets you would like to share? Write to caiken@thecarlatreport.com. Our new issue is out with updates on tapering psych meds, antipsychotics in depression, and updates on Vyvanse, lithium, treatment-resistant depression, and schizophrenia. Get $30 off your first-year subscription with the promo code PODCAST. Your support helps us stay free of influence from the pharmaceutical industry and bring you unbiased information you can trust.