Episode 214: Q&A with Dr. Cummings Part 2
By listening to this episode, you can earn 1.25 Psychiatry CME Credits.
Other Places to listen: iTunes, Spotify
Article Authors: Valentina Dannuncio, MD, Joanie Burns, DNP, APRN, PMHNP-BC; David Puder, MD
In this episode, Dr. Puder interviews Dr. Cummings on various questions asked by the audience. If you would like to enter a question for a future episode, you may do so here.
Neither Dr. Puder or Dr. Cummings have any conflicts of interest to report.
We are providing a cleaned up transcript of this episode below, with some additional citations and information.
If You Were Limited To A Choice Of Three Psychiatric Medications…
Dr. Puder:
The first one came from a listener who took this question from, Back From The Abyss, by Dr. Craig Heacock: If you were stuck on a desert island, needing to treat people for the foreseeable future with only three psychiatric medications, which three would you choose? Why?
Dr. Cummings: 1:09
I would probably choose a dopamine antagonist antipsychotic. It's a bit difficult to choose one–something like Risperidone or Haloperidol. I would also choose a mood stabilizer, the most versatile being lithium. Although if I'm on a desert island, my ability to monitor lithium may be limited so I would think about valproic acid, although it's coming up with a lot of issues now in terms of reproductive risk for both men and women. To that point, in the European Union (EU), it's severely restricted (and also in the UK). Essentially, women under 55 can't be prescribed valproic acid unless they are on a permanent form of birth control. But a mood stabilizer would certainly be the second category. And then, I would likely think about an antidepressant. Probably the most likely would be sertraline among the SSRIs because it has the fewest interactions, is fairly well tolerated by most people, and can treat both depression and anxiety disorders.
Valproic Acid And Reproductive Risks
Dr. Puder: 2:26
Nice, okay. So, I am curious. What is the research about valproic acid in men and pregnancy?
Dr. Cummings:
Basically, as people are likely to recall, among its other properties, valproic acid is a histone deacetylase [HDAC] inhibitor, meaning that it blocks the acetylation of the protein that is involved in the winding and unwinding of DNA. As it turns out, one of the side effects of inhibiting the activity of the acetylation of histone is to increase methylation in sperm DNA. First, in animals, they discovered that it was related to neurocognitive and neurobehavioral problems in mice. Just recently, I believe it was Sweden, Finland, and Norway conducted a registry review since they have birth to death registries and found indeed, that there was an increased rate of neuro behavioral disorders in children born to men who were taking valproic acid within three months of their partner becoming pregnant.
“The data showed that around 5 out of 100 children had a neurodevelopmental disorder when born to fathers treated with valproate compared with around 3 out of 100 when born to fathers treated with lamotrigine or levetiracetam” (PRAC 2024).
Dr. Puder:
This is a good education here. Okay.
Dr. Cummings:
The FDA has not moved on any of this data, but given that the European Union (EU) and the UK have, it's very likely the FDA will require restrictions or limitations in the use of valproic acid in the not too distant future. I would think.
Other Desert Island Treatment Considerations…
Dr. Puder: 4:20
I think I would lean more towards lithium, personally. I usually get a pretty decent level at 900-1200 mg. I think I would just look for side effects.
Dr. Cummings:
I mean, you can certainly do it without measuring levels. And, I'm presuming on my desert island, I don't have a lab.
Dr. Puder:
I think I would go more for olanzapine for the antipsychotic. Just because, you know, you get the sleep aid as well as use it for bipolar if you need to. I guess you could use other antipsychotics, too, but it tends to be the one I go to, for someone with bipolar. And I probably agree with you with the sertraline for the antidepressant.
Dr. Cummings:
My hesitation with the olanzapine has to do with, of course, its metabolic side effects. But well, perhaps on a desert island if we don't have a McDonald's, it will be better.
Lithium vs. Valproic Acid
Dr. Puder: 5:23
So, we're on a desert island. We're not eating very much, probably. Okay, so if you had the choice, I guess this goes along with the last question, as well: between Depakote and lithium to treat bipolar, which would you choose? And, is there any reason why you would choose Depakote? Because we have already talked about that mostly you would choose lithium.
Dr. Cummings:
I would choose lithium over Depakote or valproic acid if those were the only two mood stabilizers available. Lithium has a broader spectrum of activity. It is very good at treating mania and hypomania. It is moderately good at treating depression, which valproic acid is not especially antidepressant. It also reduces suicide risk and reduces violence risk better than valproic acid does. So in general, I see lithium as being the better mood stabilizer. Its caveats, of course, are that it has a narrow therapeutic index and also has a number of issues related to renal function.
“Using a long follow-up period and what we believe is the largest sample ever reported, we found that rates of suicide-related events were significantly decreased during lithium treatment but not valproate treatment, with a possible difference between them. Since the within-individual analyses drew information exclusively from people who attempted suicide during follow-up, our results demonstrated that the association between lithium and reduced suicide-related events existed even among a high-risk population, which is unlikely to be studied in randomized-controlled trials. Moreover, our suggestive between-drug differences supported evidence of unequal antisuicidal effects for lithium and valproate. Finally, we estimated that, in the absence of potential confounding, more than 10% of suicide-related events could have been prevented if all patients had been treated with lithium during the entire follow-up. (Song et al., 2017).
Lithium And Suicide Risk Reduction
Dr. Puder: 6:40
We've had a couple of questions on this so I’ll jump ahead here.
What is Dr. Cumming’s take on the notion that lithium has less value and effect than previously thought on reducing suicide risk in patients in the treatment of bipolar disorder and MDD? What's the current opinion about lithium's value in this regard? And they're referring to this article, which is Katz 2021 in JAMA, which looked at 519 veterans and they were randomized to lithium or placebo. The mean lithium concentration at three months was 0.54 mEq/L for patients with bipolar disorder, so a lower level than we might treat most bipolar patients. No overall difference in repeated suicide-related events between treatments were found. The hazard ratio was 1.10; 95% CI, 0.77-1.55.
Dr. Cummings:
My comment would be they essentially used a subtherapeutic dose of lithium. And indeed, you know, most studies have found that the optimal range for maintenance treatment with lithium in bipolar illness is in the range of 0.6 to 1.0 mEq/L, with the more severely ill or more frequently cycling patients doing somewhat better at 0.8 to 1.0 mEq/L. So my comment on that would be if you actually give people subtherapeutic amounts of medication, it makes it less likely the medication will work. My other comment would be that there have been subsequent studies with much larger sample sizes. I believe the last one was published by in 2017:
“During follow-up, 10,648 suicide-related events occurred. The incidence rate was significantly decreased by 14% during lithium treatment (hazard ratio 0.86, 95% confidence interval [CI] 0.78-0.95)” (Song et al in 2017).
Studies Involving Veterans
Dr. Puder: 8:57
When you test veterans, sometimes it's harder to get findings than we might find elsewhere. I remember a TMS study (Yesavage et al., 2018) which was not very positive for veterans. Any thoughts on that population in general?
“In this TMS study of 164 participants, there was no significant difference in remission rates among those getting rTMS and those getting sham” (Yesavage et al., 2018).
Dr. Cummings:
One it's, in most cases, heavily skewed toward male patients. So it's not a good representation of the population as a whole. The other comment I would make, I worked in the VA (veteran affairs) for seven years, and a lot of the veteran patient population is fairly complexly ill much of the time. They often have, in addition to bipolar illness or other psychiatric illness, issues with substance abuse, as well as often multiple intercurrent medical conditions.
My main critique of this study would be that it’s a fairly small sample size. Most of the subsequent studies on lithium have had ends in the 1000s, have included both genders and a much more community-based sample, and have used therapeutic doses.
Hydroxyzine and Diphenhydramine
Dr. Puder: 10:15
Is hydroxyzine safer than diphenhydramine in terms of anticholinergic burden?
Dr. Cummings:
Yes. That's one I can give an unequivocal answer. Diphenhydramine was the very first antihistamine to be produced. I believe, in 1946. It is highly anticholinergic. Hydroxyzine was produced in the early 1950s. It was assumed to be anticholinergic because it was another antihistamine. However, subsequent Ki studies (dissociation constant studies) have found that, depending on species, the Ki ranges from 600 to greater than 10,000. Affinity for a receptor is one over the Ki , which means one over 600 to one over greater than 10,000. Essentially, that means the drug has a little affinity for acetylcholine receptors.
Dr. Puder:
So hydroxyzine is a very good antihistamine and not very anticholinergic at all.
Dr. Cummings:
No, not whatsoever, in fact. One of the things I like about hydroxyzine is that it is essentially purely antihistaminergic. If your goal is to block H1 receptors to reduce anxiety or to sedate the person, it's a much cleaner approach than using with receptor affinities that you may not want, like diphenhydramine or, for example, quetiapine.
In prior emails, Dr. Cummings has shared from Orzechowski et al., 2005:
In the in vivo part of the study, hydroxyzine had no effect. This is likely because hydroxyzine is rapidly metabolized to cetirizine in intact animals and humans. That is, a drug which has very low affinity for the acetylcholine receptor is metabolized to a molecule that has no affinity at all.
In humans, hydroxyzine’s affinity for the acetylcholine receptor (1/Ki) has been estimated as 1/800 to 1/6000 nM. Assuming that for some reason metabolism to cetirizine was blocked, doses of hydroxyzine which would have a substantial anticholinergic effect would be on the order of several grams. For demented patients, I would be hesitant to use hydroxyzine due to its potent affinity for H1 receptors and likelihood of inducing idiosyncratic agitation. See the attached table.
Dr. Puder:
What's the top dose you could go up to on hydroxyzine?
Dr. Cummings:
The daily maximum in Europe is set at 100 milligrams. It's set fairly low. It used to be 400 milligrams until they noticed that at higher doses in mice, it can prolong QT interval. There haven't been any human reports of QT prolongation with hydroxyzine. So, in a lot of registries, you'll still see the maximum listed as 400mg. Some systems, like the California Department of State Hospitals, have lowered the daily maximum to 200 milligrams a day. For most people, though, essentially if you don't get good sedation at 25-100 milligrams, you probably need to be looking at alternative sedative agents. There is a huge variation in terms of how sensitive people are to histamine blockade. Some people are extremely sensitive to just 25 mg of hydroxyzine, while others can easily tolerate 100 milligrams without any sedative effect. So it depends a lot on the individual.
Once A Day Lithium Dosing
Dr. Puder: 13:23
Please explain how lithium can be used once a day at bed time for increased renal safety.
Dr.Cummings:
We will start with why you can use it once a day. The tissue half-life of lithium is longer than its plasma half-life. The brain half-life, meaning how long lithium stays in neurons, is 28 hours. Greater than a day, so you really don't need to divide the dosing to have an adequate concentration in the brain. On the other hand, the shorter plasma half-life allows you to give the kidneys a rest between doses. Lithium tends to accumulate in the distal principal cells of the nephron where it interferes with protein kinase C [PKC] and the formation of aquaporin-2 [AQP2] channels. If it accumulates to a high enough degree, it will actually interfere with mitochondrial function and you’ll get essentially nonfunctional nephrons as a result. The more often you dose lithium, the more likely it is that the nephrons will suffer. There is no reason to divide the doses, given the brain half-life.
Dr. Puder:
Excellent answer.
ECT For Catatonia
Dr. Puder: 14:55
This person said they have a patient with chronic catatonia that is really only responsive to ECT. Is this sustainable, long-term treatment and how long/how often can they get this?
Dr. Cummings:
Yes, this is a sustainable long-term treatment. How often they will need ECT will vary depending on their catatonia. Unfortunately, there are some people who are pharmaco-resistant, meaning that their catatonia does not respond to any medication, either benzodiazepine at robust doses, or clozapine, which has also been used to treat catatonia, and they require a ECT. Usually, that's an acute course of two to three times per week until they are stable and then a gradual lengthening of the ECT interval until you find the longest period they can go without the catatonia beginning to reemerge. We have two patients at the hospital where I work, who receive monthly ECT and both have been receiving multiple ECT catatonia. I believe one has been having ECT for five years and the other seven years.
Dr. Puder:
By robust doses of lorazepam, we're talking about 15-18 mg a day.
Dr. Cummings:
I think the largest dose we've given was 24 milligrams a day.
Most used lorazepam 1–4 mg per day, with some using up to 16 mg per day. Some sources recommend a maximum dose of 24 mg and there are cases of such doses being helpful (Taylor et al., 2021; Weder et al., 2008). In contrast, patients with chronic catatonia, especially in the context of schizophrenia, show a less strong response to lorazepam and are more likely to receive ECT (Pelzer et al., 2018; Rasmussen et al., 2016; Ungvari et al., 1999) (Rogers et al., 2023, p. 327-369).
Dr. Puder:
Do you ever see ECT being stretched out longer than one month? Could you stretch it out to two months or three months?
Dr. Cummings:
We have. There aren't enough of these patients to know very well. I think, basically, you stretch the interval as long as you can and it becomes fairly obvious when you have stretched it too long. If you go from four weeks to five weeks and things are fine, good. Then you go to six weeks. But at some point you'll run into a time period where the catatonia begins to reemerge before the next ECT treatment. Essentially, it's a case of finding the best interval for each individual.
Multiple Providers Adjusting Medications
Dr. Puder: 17:22
An anonymous person asks, “Another doctor increased a patient's Xanax [alprazolam], when their provider—you, their psychiatrist—was trying to cut it down over months. What would you do?”
Dr. Cummings:
This is a current, recurring problem. Sometimes known as the “too many cooks in the kitchen problem.” I think the best you can do is collaborate with your colleague about how you're attempting to reduce the use of alprazolam (Xanax), go over the reasons why, and see if you can enlist their aid in letting you be the manager for the alprazolam. Most of the time people are cooperative, particularly if you approach them in a friendly, respectful manner. There's never a guarantee, of course, but the best initial approach is to try to work with your colleagues so you can avoid the “too many cooks” problem.
The Dark Triad: Machiavellianism, Psychopathy, and Narcissism
Dr. Puder:
What are subtle signs of the dark triad? Dark triad being Machiavellianism, psychopathy, and narcissism.
Dr. Cummings:
Basically, this is really a question about the psychopath. How can you tell if somebody is headed down a psychopathic pathway? Most of the studies in children and adolescents show early evidence of indifference to the welfare of others and a tendency toward meeting the diagnostic criteria for conduct disorder. If those are occurring, certainly then an investigation of that person's psychological structure deserves further attention. All the way back to collectively, he noted that many of the prisoners he interviewed who were psychopaths had histories, dating back to childhood, suggesting they were headed in that direction. One of his most important findings was that 75% of those who were psychopathic in adolescence went on to become adult criminals, but 25% did not. So there is such a thing as a prosocial psychopath. What we've never figured out since then, however, is how to tilt the balance in the direction of making it more likely that people with the biological underpinning of psychopathy will become productive members of society rather than criminals.
Dr. Puder:
If you were to teach a child how to identify someone who is dark triad, how would you teach that child?
Dr. Cummings:
I’d probably have a discussion with a child and ask them to consider questions like, “Does this person seem indifferent to others, meaning indifferent to the needs or cares of others? Do they ignore rules? Are they always breaking the rules? They don't care what happens to other people?” Those are often, I think, the earliest signs of somebody who's headed down the psychopathic pathway.
Dr. Puder:
Knowing all you know about forensic psychopathology (and those of you listening for the first time, Dr. Cummings is someone who works at a forensic hospital and has seen many violent sexual predators), how would you help parents to teach their kids to not be groomed by a predator? Is there anything you would teach the parents to do, so as to make it more difficult for the child to be groomed?
Dr. Cummings:
The most important element in preventing grooming is to be sure there is an open communication channel between the child and the parents. Groomers are typically only successful when they can isolate the child from the parents. So teaching the child to look out for phrases like, “Why don't we talk but don't tell your parents about this?” That's been one of the unfortunate features of the internet, as it has made it easier for some groomers to get children involved in the conversation online and move them further and further down the pathway of being groomed while not telling their parents. So good, open communication with the parents is vital to prevent that.
Dr. Puder:
Did you hear about the Boy Scouts sex abuse settlement? The number of survivors seemed egregious.
Dr. Cummings:
Yes, I heard about the settlement and the number of survivors who had been abused ran into the 1000s, I believe.
Dr. Puder:
…with more than 12,000 survivors in the case. I would say, to answer this myself, “Who are you, as the parent, being groomed by to trust with your child? Because usually there's a grooming of the parent, as well, to trust this person in a way that you normally wouldn't trust a person.
Dr. Cummings:
There's also the element of educating your children about what is and is not appropriate interaction about touching. I would encourage parents to, fairly early on, teach their children the correct names of things related to their genitals so that they can come and accurately report. And if there is a violation, and it goes to court, they make much better witnesses. If they know, they can accurately describe what happened.
Restless Leg Syndrome (RLS)
Dr. Puder: 25:40
Someone asked, “I want to ask if there are any clinical pearls for differentiating between restless leg syndrome and akathisia?”
Dr. Cummings:
Yes, there are. Restless leg syndrome [RLS], of course, is a syndrome which occurs typically when the person lies down and is attempting to go to sleep. They have an uncomfortable feeling in the lower extremities. It is relieved when they're getting up and walking around. But then tends to return when they get back in bed and try to go to sleep. In contrast with that, akathisia tends to be present throughout the day. It's not specifically associated with bedtime or attempting to go to sleep. It is a more generalized restlessness and may be much more associated with subjective feelings of anxiety, as well. Whereas, restless leg syndrome is more purely a physical sensation. An important feature of restless leg syndrome is iron levels. Check the person's iron status because iron deficiency is a frequently overlooked cause of restless leg syndrome. Also, restless leg syndrome usually responds exceedingly well to either a low dose benzodiazepine or to a small dose of dopamine agonist at bedtime—things like amantadine, for example.
When to Check a Lithium Level
Dr. Puder: 28:33
Another person asked, “When do you check a lithium level if you're giving once a night bedtime dosing?” They're confused about checking it after 4 or 12 hours.
Dr. Cummings:
The standard, and what all of the labs are using as their standard for lithium is a 12-hour trough. When you get back the lab report and it says the lithium level is this, and this is the usual range, that usual range is based on a 12-hour trough. For example, if the person takes their lithium at 8 p.m., then they need to get their blood drawn reasonably close to 8 a.m. Or, if they take it at 10 p.m., then aim for around 10 a.m.
Although the question is about lithium, there is a difference for valproic acid extended release. As you know, the most common forms are valproic acid, depakene, divalproex DR, where the delay is only a few minutes to get it to the distal stomach, and then there's the extended release, which has a very slow release for the extended release. Unlike 12 hours for the other two, you need to either measure that at 24 hours, or if you have a 12-hour measurement, you can estimate the 24-hour trough by dividing it by 1.3.
Behavioral Disturbances in Dementia
Dr. Puder: 30:00
That's good. I like that. “What's your best advice for treating dementia patients with behavioral disturbances in the long-term care setting?”
Dr. Cumming:
For the dementia patient with behavioral disturbance, the medications that have data to support their effectiveness include memantine, in combination with the acetylcholinesterase inhibitors, the SSRIs, and trazodone when given in small doses multiple times per day. Trazodone 12.5 to 25 milligrams two or three times a day can help decrease psychomotor agitation. The antipsychotics do work for people who are demented and suffer from psychotic signs and symptoms. However, antipsychotics increase mortality rates in the elderly demented. Coming back to the Veterans Administration, the Maust study was the largest study done in this area. They calculated the number needed to harm, calculating harm as death and extra death, over six months. Haloperidol, for example, had a number needed to harm of eight. So if you treat eight patients, you'll kill one of them. The mood stabilizers also had problems. I think valproic acid had a number needed to harm of 26 and risperidone was in the low 20s, around 22. The best of the dopamine antagonists was quetiapine, with number needed to harm of 31. In contrast to that, the number needed to harm with the SSRIs was right around 150, which is actually close to the non medicated mortality rate in people of similar age.
“Compared with antidepressant users, mortality risk ranged from 12.3% (95% CI, 8.6%–16.0%; P < .01) with an NNH of 8 (95% CI, 6–12) for haloperidol users to 3.2% (95% CI, 1.6%–4.9%; P < .01) with an NNH of 31 (95% CI, 21–62) for quetiapine users.” (Maust, et al 2015)
Dr. Puder:
I was looking at a study of antipsychotic drugs and risk of stroke and myocardial infarction, a systematic review and meta analysis as published in 2019 (Zivkovic et al., 2019). In this study, they were looking at 7008 articles and what they found was that in patients with dementia, the risk of issues was much lower. So in the cohort, general population, without dementia and without psychiatric illness, the risk increased twofold for stroke–hazard ratio at 2.3. However, the risk among patients with dementia was much lower at 1.16; and they also found no clear association among studies of psychiatric populations (hazard ratio 1.44) and the confidence interval crossed one. Any thoughts on treating different populations? It seems like there's a lower risk of treating people in the psychiatric population in the dementia population with antipsychotics.
Dr. Cummings:
There does seem to be. It's not very clear why this group is different, although a number of researchers have found very similar numbers. It may be that having a long-term psychotic illness may in some way be protective, perhaps by long-term exposure to antipsychotic medications. Frankly, we don't know that very well. However, it's certainly clear, for example, in people with schizophrenia spectrum disorders they actually have a lesser risk of things like tardive dyskinesia than, say, people with an anxiety or a mood disorder who are exposed to a dopamine antagonist antipsychotic. Why are they at lower risk? I don't think anyone knows the answer to that.
Co-prescribing of Benzodiazepines And Stimulants
Dr. Puder: 35:02
What are your thoughts on co-prescribing benzodiazepines and stimulants? How problematic is this? I can remember one time I got probably the most upset at any resident moonlighting that I'd ever been upset at. And, if you're listening to this, I'm not going to give away your identity to anyone, so don't worry. But this resident was moonlighting and treating someone with Xanax 2mg TID and Concerta. No, I think it was Adderall. Like, 60 milligrams a day. I'm like, “What are you doing? You've never learned this from anyone here!”
Dr. Cummings:
In general, my comment would be that, pharmacologically, that makes very little sense because you're treating the person with medications that are directly opposing each other. You're giving the person the stimulant hoping to target, in particular, the cortical D1 receptors in the frontal lobe and you're also giving them a drug that increases GABAergic effects at GABAA receptors, which are also most plentiful in cortical regions in the frontal lobe. So, you're trying to turn up the activity of those neurons and turn it down at the same time, which makes very little sense. Now, I would admit there can be subtleties if someone, for example, is on a routine dose of stimulant and takes an occasional dose of benzodiazepine for acute anxiety, for example, because they might also suffer from social anxiety disorder, or something like that. Their stimulant will be less effective when they take the benzodiazepine, but if it's limited, that may not be entirely unreasonable given the clinical circumstances. But from a pharmacological standpoint, it makes no sense to give somebody a drug to increase neuronal activity and a drug to decrease neuronal activity at the same time.
Dr. Puder:
That kind of reminds me of patients who have a history of using methamphetamines and alcohol heavily at the same time.
Dr. Cummings:
Yes. And the reason they do that is because indeed the alcohol does take the edge off of the methamphetamine, but compared to reasonable levels of treatment with say, methylphenidate, or mixed amphetamine salts, like Adderall, at clinical doses, people who abuse methamphetamine are typically using gigantic doses of methamphetamine. That's why the high can take on a very harsh edge or characteristic in terms of paranoia, jitteriness, anxiety, and then, indeed, people will attempt to soften that by co-administering alcohol or other sedative hypnotics.
Kratom
Dr. Puder: 38:23
This is from a patient who says, “The knowledge I've gained from Dr. Cummings in these episodes has greatly shaped the way I practice and educate patients. I'm so grateful for every episode he does with you. Thank you.” This person goes on to say, “I'm seeing many patients in practice who are taking kratom capsules and drinking kratom tea, daily. Attempts to decrease or cease use result in severe withdrawal symptoms. I was wondering if you had any guidance on the use of suboxone to taper or any pearls regarding management of these patients?”
Dr. Cummings:
Like most addictions, it can be difficult to get the person off of the thing that they have become addicted to. Drugs like buprenorphine have been used, usually in a time-limited fashion, although time-limited in this context usually means a year or two, while the person is gradually tapered off the kratom. It's not a very common addiction, but it does seem to be one of the more stubborn addictions.
Deprescribing Benzodiazepines
Dr. Puder: 39:51
Here's the next person: “I inherited several patients from another provider who are on high doses of daily benzodiazepines, especially alprazolam. What are your thoughts on management and tapering these individuals? Do you feel as though the pendulum has swung too far in the direction of demonizing benzodiazepines?”
Dr. Cummings:
I think benzodiazepines have reasonable uses. Albeit, they're fairly limited. Certainly if you have somebody who is acutely agitated or is in need of an acute muscle relaxant, for example, or who needs to have a seizure stopped, those are perfectly appropriate uses of benzodiazepines. Interestingly, most of the studies looking at longer-term efficacy have found that (and I know there are exceptions, everyone has one or two patients who swear by their benzodiazepine), for the most part, efficacy of benzodiazepines over the long haul is very low. Do I believe that means that they're demonic drugs? Well, no. But I think we should indeed encourage people not to use them, except as essentially brief rescue medications, because they create more problems than they fix for most individuals. Now in terms of tapering somebody who has been on a benzodiazepine for a long time, be prepared for it to be a very long and slow process. The problem most clinicians have is they want to go too fast. When I've had patients who've been on a benzodiazepine for decades, the taper and withdrawal often takes one to two years.
“Any patient who has taken a benzodiazepine for longer than 3-4 weeks is likely to have withdrawal symptoms if the drug is ceased abruptly. The risk of inducing dependence can be reduced by issuing prescriptions limited to 1–2 weeks supply” (Brett & Murnion, 2025, p. 152-155).
Dr. Puder:
Another person asked, “How do you taper?” Let's say someone is on one milligram of Klonopin [clonazepam] per day. How would you just decrease it by 0.25 every couple of months or would you work with a compounding pharmacist? What are your thoughts?
Dr. Cummings:
Most of the people I've seen who are truly having problems with, for example, clonazepam, are typically taking a dose much higher than 1 milligram a day. It is a very slow process. I typically don't taper people from clonazepam, for example, faster than 0.25-0.5 milligram per month and I work with the patient to find the rate that is comfortable for them. The exception to that is people who've only been on a benzodiazepine for a very short time. It takes about 30 days for somebody to become tolerant of a benzodiazepine. So if the person is only on it for a short period of time, taper becomes much less of an issue because they have not become tolerant of the benzodiazepine.
There are no standard tapering regimens and the rate of tapering depends on the starting dose, duration of therapy, risk of relapse and how well tapering is tolerated by the patient. In general, at higher doses (e.g. greater than 10 mg diazepam equivalents per day) the dose may be tapered more rapidly. Once the patient achieves 10 mg, the dose should be tapered more slowly (e.g. 5 mg twice daily for two weeks, then once daily for two weeks, and then 2 mg daily for two weeks and then cease).
A meta-analysis of treatment for benzodiazepine discontinuation found that gradual dose reduction combined with psychological treatment was superior to gradual dose reduction alone (Brett & Murnion, 2015, p. 152-155).
Clozapine
Dr. Puder: 43:16
Dr. Pearson asks: “For a patient who benefited from clozapine, but cannot continue due to inability to follow up with regular labs, for whom single antipsychotics are ineffective, what is the best combination of antipsychotics you would recommend?”
Dr. Cummings:
Probably the very next best would be a combination of olanzapine and a potent D2 antagonist. Although, having said that, the response numbers for somebody who has truly treatment-resistant schizophrenia (via the HOWARD study data, which are based on the older Kane criteria) to all of the antipsychotics, other than olanzapine, is 0% to 5%—not very impressive. So as monotherapy, those drugs have a 95% failure rate. Olanzapine at concentrations of 120-250 nanograms per milliliter, where you get a little bit of glutamate modulation, has a success rate of 7%. I haven't seen very good numbers on the combination, but my guess would be you get some additive effects or you may be looking at a response rate of more in the 9 to 12% range—still not very impressive. I wouldn't want to go to my doctor and say, “Well, you're proposing treating me with something that has a 88-91% probability of failure.” But sometimes, that's the best we can do.
Dr. Puder:
Is there any ability, with this type of patient, to get approval due to the risk factor of them not being compliant with labs, bypassing clozapine REMS [risk evaluation and mitigation strategy] or writing them a letter saying, “I have a patient who will die if they don't continue this. They're not going to monitor, but they really need to be on this and they've been safe on it for years. So the risk of developing side effects is pretty low.”
Dr. Cummings:
Presently, there's no way around the clozapine REMS program. However, there may be in the near future. A number of people in psychopharmacology, including myself, have been lobbying the FDA to drop the monitoring requirement at some point. The most aggressive recommendation has been 18 weeks. Meaning, stopping monitoring after 18 weeks, because that's when you start to see a very large fall off in the rate of severe neutropenia, all the way out to, most conservatively, about two years and then not monitoring beyond that. Probably the strongest data in this area has come from the Europeans. For a number of decades now, the Europeans have not required ANC [absolute neutrophil count] monitoring beyond 12 months. Their mortality rate from severe neutropenia does not differ from ours. It's about one per 10,000 cases. Arguing that all the additional monitoring we're doing is not moving the needle and, therefore, has no reason to exist. We'll see what the FDA does. The FDA is actually contemplating scrapping the REMS program altogether, which I don't think would be such a bad thing. The other thing about labs these days is that we have gotten to the point where there is technology available where you can obtain an ANC count by fingerstick rather than by venipuncture. It is not quite as accurate as venipuncture, but it's typically within 5% of the venous puncture value, which is adequate for monitoring purposes; and that, for a lot of patients, removes the barrier because you can actually set up one of the fingerstick machines in a clinic. I know in San Bernardino County the county clinic is working toward having a couple of their clinics actually have the monitoring device in the clinic. It's basically a finger stick. The person puts a drop of blood on a strip. You put the strip into the machine and about two minutes later you get an ANC value.
Dr. Puder:
I'm going to look into that. I have a couple patients that have been hesitant and although the family would like to do it, the patients are completely unwilling.
Dr. Cummings:
I think there is more than one device on the market now. The very first machine that came out was made by Athelas, Inc. [Athelas One (A1)] for $1,000 and the test strips are around $35.
Trichotillomania
Dr. Puder: 49:13
I'm gonna look into that. So trichotillomania—how do you treat patients with trichotillomania?
Dr. Cummings:
Trichotillomania, in terms of theory, fits into what has become known as sort of an extended version of obsessive compulsive disorder, leaving people to try SSRIs and other serotonergic agents to decrease it. Frankly, with somewhat mixed results, a number of studies indicate a decrease. There has also been some evidence to support use of naltrexone for trichotillomania, as well as for things like drinking and kleptomania. Trichotillomania fits into a category of compulsive behaviors, essentially being driven by the dorsal striatum, the same area that gives rise to obsessive-compulsive disorder. So people are looking for ways to target that area.
TMS vs. ECT
Dr. Puder: 50:34
From a clinical psychiatrist who has listened to Dr. Cummings many times, asks, “What is your opinion of the research efficacy of TMS [transcranial magnetic stimulation] versus ECT [electroconvulsive therapy]? Any update on the availability of TMS in the general population?”
Dr. Cummings:
Basically, ECT remains our most effective treatment if you're talking about treating major depressive disorder, psychotic disorders, catatonia, and bipolar illness. TMS has more modest efficacy. However, it can be quite effective as either a primary or adjunctive treatment in major depressive disorder. It has also shown efficacy in suppressing auditory hallucinations. Probably, the main thing that makes it attractive is that it is easier to administer than ECT.
Dr. Puder:
Any thoughts on the SAINT TMS protocol? This is, for those of you who don't know, a lot of TMS.
Dr. Cummings:
I haven't seen much data to suggest that it is qualitatively better than other forms of TMS. People have tried very frequent frontal and frequent bilateral TMS and there are some indications of improved efficacy when you do that, but it's not a day and night difference between it and the more standard TMS protocols.
Dr. Puder:
The initial studies to me look very positive. So are you seeing something that I'm not seeing?
Dr. Cummings:
I'm seeing that it can be effective, but it's not like oh, this is now going to cure mood disorders across the board.
Dr. Puder:
They're expensive. The centers that I know about, over a week of TMS, giving the TMS throughout the day, eight hours a day. It could be $20,000 for a week's treatment. The private pay TMS centers are very expensive.
So you're not as excited about the SAINT protocol?
Dr. Cummings:
No. There's often at the initial outset of something like the SAINT TMS, or ketamine, is another example, a lot of very positive excitement and there's also often, at the beginning, a very huge placebo effect.
Ketamine vs. Esketamine
Dr. Puder: 53:39
There is a question about ketamine versus esketamine. The person says, “I have numerous ECT referrals for young clients being prescribed and failed esketamine. I can't find evidence to support this kind of esketamine use, and I'm wondering if there's research information I missed?”
Dr. Cummings:
No, basically esketamine is a viable treatment for some people with depression, but it is not, in most patients, as effective as infusion of ketamine. But even an infusion of ketamine is limited. It's very rapid in effect, but its effect is fairly short-lived and the more you give it, the shorter its antidepressant benefits become. My own view of ketamine is that it can be an excellent treatment for somebody with severe depression who's had suicide risk and you're needing to get them to a euthymic state quickly, but then transitioning them to a lot more long-term treatment. I don't think either ketamine infusion or esketamine is very viable as an ongoing treatment for mood disorder. There are some other uses people have been putting it to people who've been indeed looking at a number of psychedelics, including ketamine, to see if it would enhance some forms of psychotherapy. Early indications are fairly positive. But indeed, they're just that—they're early indications.
Dr. Puder:
When I look at the effect size even for those studies, they're not larger than partial [partial hospitalization program (PHP)]. Partial, for me, for a depressed patient is effect size of two to three, which is what Loma Linda partials are getting. We monitor patients on a regular basis. So when I think about if someone's not being treated effectively in the outpatient, I think partial first. If they get to partial and they’re in partial for a couple of months and they're still not doing well, sometimes we think about ECT.
ECT and Ketamine For Borderline Personality Disorder
Dr. Puder: What's your thought on borderline personality disorder and the effectiveness of ketamine and ECT?
Dr. Cummings: 56:18
I'm not sure I've seen much solid data to support ECT for either of those indications. Certainly, someone who develops a concurrent major depressive episode might be an ECT candidate or ketamine candidate, but I don't see it for borderline personality disorder, as it doesn't have a primary pharmacological treatment really.
Dr. Puder:
Even a really good ketamine outpatient provider I know tends to stay away from treating patients with borderline personality disorder with ketamine.
Dr. Cummings:
These are people who are already more prone than the average person to dissociative states. And of course, ketamine is a dissociative anesthetic, so I would have some trepidation for that reason.
The other thing is, I haven't seen very good outcome data suggesting that any medication is, if you will, greatly effective for treating borderline personality disorder. Medications in that context seem to be mostly useful at targeting specific symptoms so that the person can manage their life better and make progress in something like dialectical behavioral therapy [DBT].
Reflective Function
Dr. Puder: 58:07
I'm releasing an episode today, as in May 17 when Dr. Cummings and I are recording this episode, on reflective function, which is probably one of the coolest assessment tools I've seen on attachment and also on the capacity to really understand borderline personality disorder. So essentially, the reflective function scale uses a tool called Adult Attachment Interview (AAI) to gauge, by looking at certain questions, your internal reflectiveness of yourself and other people as you complete the Adult Attachment Interview. And they gauge this on an 11 point scale, -1 to 9. Nine being the highest. Most patients with borderline personality disorder score around a three. One good study by Levy et al. found that reflective function increased from three to four. Five is average. So, three to four is a big jump. With a year of transference-focused therapy. Interestingly, in this specific study, dialectical behavioral therapy showed no increase and supportive psychotherapy showed no increase. Transference-focused therapy is very much based on the relationship with the patient and the therapist. It's thought that this could potentially help your understanding of your early life attachments and that's maybe why your reflectiveness would increase. I would say that is kind of a new pinnacle of understanding because when you measure a therapist's reflective function, you're going to find this really interesting. We think about common factors, right? Like what makes one therapist better than another therapist? Common factors have been kind of the buzzwords like “empathy, therapeutic alliance.” Everyone will say that kind of stuff. There was a new study that I stumbled upon that showed if you look at the difference between the best therapists and the worst therapists, 70.5% of it could be made sense of by the reflective function score of the therapist. So the therapist is talking about their childhood, aged zero to 12. You're gauging their ability to reflect deeply and meaningfully. That actually predicted the best versus the worst therapist and the outcome at 70.5%. I was like blown away. So that's what I think about when I think of borderline personality disorder and I think of the effective treatments that may be coming on the horizon. What we need to do, is we need high reflective function therapists working with these types of clients, whether that's DBT, mentalization-based therapy, or transference-focused therapy. There needs to be some emphasis on the interpersonal relationship with the therapist. Any thoughts on that?
Dr. Cummings:
Yeah, I think that's a very promising area. And, again, the psychotherapies that have shown good outcomes with borderline personality disorder are much more effective than medications in treating the underlying disorder. Medications are largely useful for helping the patient manage some of the more intense symptoms. But that's about it. Its medications are much more symptomatic treatment in this context, rather than addressing the underlying disorder. I think that a lot of people have an unrealistically negative view of borderline personality disorder. I've always been impressed by the fact that studies have shown that if you wait long enough, meaning till the borderline person has reached middle age, half of those people who once met the diagnostic criteria no longer do.
Dr. Puder:
Yeah, and I would say in the mentalization-based study, which I know probably the best for if they meet the criteria anymore, the vast majority of them, after treatment, were followed for five years afterwards and did not meet the criteria. I think 85% did not meet the criteria. So when we think about personality disorder, it's a bit of a misnomer [that it lasts forever] because personality never changing. And we've talked about this before, Dr. Cummings, that it is primarily affect dysregulation and maybe there are better names for it.
Dr. Cummings:
Indeed. I know there has to be a better name out there because borderline is a complete misnomer in the sense that these people are not bordering on anything. They are what they are. And what they are, are people who have a difficult time modulating their mood state–their affective state.
Dr. Cummings’ Story
Dr. Puder: 1:04:02
Well, we are at about an hour. Anything that's still on your mind that you wanted to teach the audience here—the next generation of providers? Maybe we could go to a fun question, a Dr. Cummings question. Someone was interested, “What is your story, Dr. Cummings? Can you tell us about your training pathway and how you ended up where you are?”
Dr. Cummings:
I can and briefly. I was actually, as an undergraduate, a history major and physics minor—an odd combination to begin with. I went to grad school in physics and in the process of doing that, I worked as a teacher's assistant and was in charge of a couple of classes for premed students and pre nursing students who needed to get their non heavy duty calculus/physics prerequisite. So I spent a lot of time teaching them and became interested in medicine. And from that, went from grad school and physics to medicine. I was actually originally intending to pursue a career in neurosurgery, but became blind and, because I was so very interested in the brain, switched to psychiatry and went to Loma Linda University for psychiatry residency. Then I went to an NIMH extramural program located at UC San Diego. At that time, it was termed a fellowship in psychobiology and psychopharmacology, which got me into research and interested in medications. Then, I worked for the VA for seven years, and then migrated from the VA to the California Department of State Hospitals—a roundabout way of saying I don't think I've ever been quite able to make up my mind what I want to do when I grow up.
Dr. Puder:
Well, I'm very curious, if you don't mind telling the story of how you lost your sight.
Dr. Cummings:
Yeah, I was serving in the U.S. Navy and I came down with a viral infection, which was a fairly ordinary upper respiratory infection, except that it caused a lot of oral and nasal ulceration. The infection died down after about 10 days, but subsequent to that, I developed chorioretinitis, which basically resulted in the death and rupture of retinal blood vessels.
Dr. Puder:
Awful. I'm in awe that you have been able to gain the level of knowledge that you have despite that setback. You just kept going. Psychologically, what was that like?
Dr. Cummings:
It was difficult, of course, because I had frankly intended to make a career of the Navy, perhaps aiming for aerospace medicine. Of course, I got discharged from the Navy and then had to figure out a new career path. Luckily, I had good relationships with a couple of the people in the department of psychiatry at Loma Linda, and they were open to the idea of my pursuing psychiatry residency, which I did with some technical aids along the way. I've gained a lot of information education by using computers and screen readers. I have to say the screen readers, fortunately, have improved. The very early one sounded a lot like a Norwegian with a very bad head cold. And they actually now have fairly pleasant, relatively human sounding voices which are much easier to listen to when you're reading something.
Dr. Puder:
What advice would you give to your younger self? Let's say the younger self that was just starting, or somewhere in their psychiatry residency?
Dr. Cummings:
I think the best piece of advice I could give people is to always read—be curious and read. I think the best piece of advice I could give people is to always read—be curious and read. Osler, at the beginning of the 20th century/end of the 19th century made the comment that it's amazing how many physicians practice without reading. Of course, it's also amazing how badly they practice. Physicians and psychiatrists need to remain curious. We need to be educating ourselves. There's an awful lot we still don't know. And frankly, we owe it to our patients to educate ourselves as much as we can and then to attempt to apply that to helping our patients.
Dr. Puder:
Okay, so someone's hearing this like, “Yes, I would like to read.” We have, of course, a lot of free content on our website. You can download PDFs, and any of Dr. Cummings’ episodes, and in those episodes, we hyperlink a ton of articles that Dr. Cummings has recommended over the years. So that's one place you can start. Are there any other books that you like? Maybe the top three pharmacotherapy books that you recommend?
Dr. Cummings:
Yeah, certainly. I am somewhat biased answering this because I work quite a bit with Stephen Stahl. I would say his Essentials of Psychopharmacology is an excellent beginning for most people. It's readable, it's of sufficiently short length—not quite the tome that the Comprehensive Textbook of Psychiatry is. It's even a little shorter than the synopsis of that book. Although that also is an excellent, general background reference for psychiatry. I think probably the most important thing about reading is to develop the habit of spending 30 minutes a day reading whatever you're interested in, but reading. Pick your favorite journals. A typical journal article is about 2500 to 3500 words. If you're a fairly fast reader, you can easily read that in 30 minutes. And the main trap I see most people fall into is they see things they want to read, but they're busy, and they say, “I’ll get to it later.” Unfortunately, often “later” never comes. If you can basically rigidly set aside some quiet period of around 30 minutes every day—have a cup of tea, a cup of coffee, read an article—that's 365 articles a year.
Dr. Puder:
Well, I think that's excellent advice. And I would say if you're trying to get through one of those big textbooks, what I used to do is, I would just say, “Okay, I'm gonna try to read 15 pages a day or 10 pages a day,” depending on what rotation I was in, and then just click through them. If you commit to that, you'll get through 100 pages in 10 days. It's a good way to get through a big book.
Thank you, Dr. Cummings. I really appreciate you coming on. I wasn't able to read all these questions. We'll get to some more. If you're part of the email list, if you go on the website and look at our resources, you will be on our list automatically. And we'll do this again. I think this could be like a 20 part series…200 part series, the endless questions. Take care.
Dr. Cummings:
Okay, thanks.
References:
Brett, J., and Murnion, B. (2015) Management of benzodiazepine misuse and dependence. Aust Prescr. 38(5):152-5. doi: 10.18773/austprescr.2015.055.
Elbe, D. (2010). Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, Third Edition. J Can Acad Child Adolesc Psychiatry. 19(3):230.
Katz, I. R., Rogers, M.P., Lew, R., Thwin, S., Doros, G., Ahearn, E., Ostacher, M. J., DeLisi, L. E., Smith, E. G., Ringer, R. J., Ferguson, R., Hoffman, B., Kaufman, J. S., Paik, J. M., Conrad, C. H., Holmberg, E. F., Boney, T. Y., Huang, G. D., Liang, M. H., and Li+ plus Investigators. (2022). Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 79(1):24–32. doi:10.1001/jamapsychiatry.2021.3170
Levy, K. N., Meehan, K.B., Kelly, K.M., Reynoso, J.S., Weber, M., Clarkin, J. F., Kernberg, O.F. (2006). Change in attachment patterns and reflective function in a randomized control trial of transference-focused psychotherapy for borderline personality disorder. J Consult Clin Psychol. 74(6):1027-1040. doi: 10.1037/0022-006X.74.6.1027.
Maust, D. T., Kim, H. M., Seyfried, L. S., Chiang, C., Kavanagh, J., Schneider, L. S., Kales, H. C. (2015). Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry. 72(5):438-45. doi: 10.1001/jamapsychiatry.2014.3018.
Orzechowski, R. F., Currie, D. S., and Valancius, C. A. (2005). Comparative anticholinergic activities of 10 histamine H1 receptor antagonists in two functional models. Eur J Pharmacol. 506(3):257-64. doi: 10.1016/j.ejphar.2004.11.006.
PRAC. (2024, January 12). Potential risk of neurodevelopmental disorders in children born to men treated with valproate medicines: PRAC recommends precautionary measures.European Medicines Agency. Retrieved from: https://www.ema.europa.eu/en/news/potential-risk-neurodevelopmental-disorders-children-born-men-treated-valproate-medicines-prac-recommends-precautionary-measures
Rogers, J.P., Oldham, M.A., Fricchione, G., Northoff, G., Wilson, J. E., Mann, S. C., Francis, A., Wieck, A., Wachtel, L. E., Lewis, G., Grover, S., Hirjak, D., Ahuja, N., Zandi, M. S., Young, A. H., Fone, K., Andrews, S., Kessler, D., Saifee, T., Gee, S., Baldwin, D. S., and David, A. S. (2023). Evidence-based consensus guidelines for the management of catatonia: Recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 37(4):327-369. doi: 10.1177/02698811231158232.
Song, J., Sjölander, A., Joas, E., Bergen, S. E., Runeson, B., Larsson, H., Landén, M., and Lichtenstein, P. (2017). Suicidal Behavior During Lithium and Valproate Treatment: A Within-Individual 8-Year Prospective Study of 50,000 Patients With Bipolar Disorder. Am J Psychiatry. 174(8):795-802. doi: 10.1176/appi.ajp.2017.16050542.
Yesavage, J. A., Fairchild, J. K., Mi, Z., Biswas, K., Davis-Karim, A., Phibbs, C. S., Forman, S. D., Thase, M., Williams, L. M., Etkin, A., O'Hara, R., Georgette, G., Beale, T., Huang, G. D., Noda, A., George, M. S., and the VA Cooperative Studies Program Study Team. (2018). Effect of Repetitive Transcranial Magnetic Stimulation on Treatment-Resistant Major Depression in US Veterans: A Randomized Clinical Trial. JAMA Psychiatry.75(9):884-893. doi: 10.1001/jamapsychiatry.2018.1483.
Zivkovic, S., Koh, C. H., Kaza, N., and Jackson, C. A. (2019). Antipsychotic drug use and risk of stroke and myocardial infarction: a systematic review and meta-analysis. BMC Psychiatry.19(1):189. DOI: 10.1186/s12888-019-2177-5