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How to Use Nortriptyline

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Nortriptyline + lithium is one of the top combos for keeping patients well after ECT, and in this episode we walk you through how to prescribe it, including side effects, dosing, drug levels, and drug interactions. Then, the word of the day: Antisocial personality disorder.

Published On: 8/30/2021

Duration: 28 minutes, 49 seconds

Article Referenced: ECT Worked: Now What?“, The Carlat Psychiatry Report, August 2021


It’s not the easiest drug to prescribe. It can cause GI problems, sexual dysfunction, weight gain, possibly falls and bone demineralization, and rare but dangerous reactions like cardiac arrhythmias that are made even riskier by common drug interactions. But the medication we just described is citalopram – Celexa. And yes, we could say similar things about nortriptyline, but today we’re going to ask you to drop any preconceived notions you have about new vs. old antidepressants, because there are times when you need to use this tricyclic, and it’s a lot better tolerated than commonly thought. 

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: Electroconvulsive therapy – ECT – is one of the most effective treatments for depression we have, but it is not very good at keeping patients well. 80% of patients will go right back into the depression within 6 months of stopping it. We can improve on those disappointing odds with treatment, but which treatment does the best job of preventing depression after ECT?

Michael Posternak tackles that question in this month’s Carlat report, and he distills the literature down to three treatments that can keep your patient well after a successful course of ECT. One of those is the combination of lithium and an antidepressant – particularly nortriptyline. 

Dr. Aiken: That recommendation is based on a trial by Harold Sackeim and colleagues from 2001. The study randomized patients to 3 treatments after ECT: nortriptyline, nortriptyline plus lithium, and placebo. 6 months later, here’s how things looked. For those on placebo, 84% relapsed into depression – which is what we’d expect from other studies. We do a little better with nortriptyline –  60% relapsed. But the winner was nortriptyline-lithium combination with a 39% relapse rate. 

Nortriptyline is not at the top of everyone’s prescription pad these days, so in this podcast we’re going to teach you how to use this tricyclic antidepressant. 

But first, a little about lithium. Something in Dr. Sackeim’s study stood out to me. Nearly all of the relapses on lithium occurred in the first 5 weeks of stopping ECT – all but one in fact. And that wasn’t the case for the other treaments, where the relapses were spread out evenly throughout the study. 

Kellie Newsome: What do you make of that Dr. Aiken?

Dr. Aiken: There are two camps on lithium. Some think it’s a powerful treatment for depression, and others see it as fairly weak and best reserved for bipolar disorder. And depending on which studies you look at, you could reasonably come out on either side. In short term studies, lithium augmentation comes up average or below average for its antidepressant effects. But it’s in long-term studies that lithium really shines, which it did in this ECT study. If your patient

Lithium is not a fast acting medication, but its long-term effects are pretty robust. We see some evidence of of this in the Sackeim study. If your patient made it past the first 5 weeks after ECT without getting depressed on lithium and nortriptyline, they had a 95% chance of staying well throughout the study. In long term studies, lithium lowers the suicide risk and prevents rehospitalization for depression.

Kellie Newsome: Here’s some shocking results from a 2017 Finnish study that illustrates that point. They looked at 120,000 patients who had been hospitalized for depression to see which medications helped them stay out of the hospital. This study was long-term – with an average follow up of 9 years. And the medication that helped them stay out of the hospital the most: Lithium. Patients on lithium were twice as likely to stay out of the hospital. The antidepressants and antipsychotics, however, offered no protection. And that is a surprise, because these were unipolar depressed patients – not bipolar. 

Dr. Aiken: So if lithium can keep severely depressed patients out of the hospital, it makes sense that it could help people who recently recovered with ECT from relapsing. Dr. Sackeim’s study is not the only one to show protective effects with lithium after ECT. This year a meta-analysis looked at 14 studies that followed some 10,000 patients after ECT, and concluded that lithium was effective at preventing post-ECT relapse. The target serum level for lithium in depression is 0.6-0.8, which is generally the range used in these studies. Most of them paired lithium with an antidepressant, and it wasn’t always a tricyclic. One successful study paired lithium with venlafaxine/Effexor after ECT. But the gold standard is nortriptyline, as that is the antidepressant with the best evidence. So let’s look at how to use nortriptyline in depression.

Kellie Newsome: First, you need to adjust your attitude. If you don’t use tricyclics very much, you may be thinking these are heavy-duty meds that are difficult to tolerate, but in reality they are a lot better tolerated than medications we prescribe routinely now-days like aripiprazole (Abilify). 

Dr. Aiken: In the 1960’s and 70’s many psychiatrists had a negative attitude toward medication, not just because of their side effects, but because they were seen as a crutch – a way of avoiding and covering up the real problems that should be worked through in psychotherapy. Alan Schatzberg recalls that time and draws from it some advice that can help us today. Kellie can you read from his Manual of Clinical Psychopharmacology:

[Schatzberg p132 on attitude]

Kellie Newsome: So let’s take a look at those side effects. To make them easier to remember we’ll divide them into 3 categories: Anticholinergic, cardiovascular, and the usual.

Nortriptyline has the usual side effects that bother patients on most medications. I call them the “big 3”: Sedation, weight gain, and sexual dysfunction. Nortriptyline is a little more favorable than most tricyclics in those areas, but if sedation is an issue, the least sedating tricyclic is… desipramine.  

There’s actually a fourth one on the big 3 list – cognitive problems – but nortriptyline is pretty favorable there, in fact it, like a lot of noradrenergic mediations, it treats ADHD. Rarely, though, people can get delirium and mental status changes on nortriptyline and other tricyclics, and you may see this in the elderly or medically ill, due to their anticholinergic properties. Fortunately nortriptyline is low on anticholinergic burden – that infamy goes to amitriptyline, the tricyclic with the most potent anticholinergic properties.

Dr. Aiken: And that’s unfortunate as amitriptyline is also one of the most commonly prescribed tricyclics. Physicians from all specialties are very comfortable using it because it’s often used off label for migraines, pain, and insomnia. Here’s a pearl about amitriptyline – if you’ve every prescribed amitriptyline you’ve also prescribed nortriptyline, because amitriptyline breaks down into nortriptyline, its main metabolite.

Kellie Newsome: Back to side effects. We have the usual “big 3”, and the second category is anticholinergic, the ones that dry you up and prevent you from getting rid of urine and stool. So we’re talking about constipation, dry mouth, and urinary retention. These are all more likely in the elderly, and they can all have serious consequences. Dry mouth puts people at risk for dental problems, gum inflammation and tooth decay; constipation can cause bowel obstruction with potentially fatal paralytic ileus and sepsis; and urinary retention can lead to urinary tract infections and renal or bladder damage. Another anticholinergic effect is blurry vision and difficulty accommodating – or reading – at close range.

Finally we get to the cardiac side effects, and there are two big ones to know: orthostasis and arrhythmias. Nortritpyline is actually the least likely of the tricyclics to cause orthostasis and falls, which is why it’s often preferred in the elderly. Cardiac arrhythmias, like conduction delays where the heart slows to a dead stop, are what makes tricyclics lethal. A weeks supply of the medication is often enough to create a fatal dose.  

To recap: The usual big 3 (sexual, weight gain, and sedation); anticholinergic (constipation, urine retention, dry mouth, blurry vision); and cardiac (orthostatic falls and arrhythmias). 

Dr. Aiken: Now for how to dose nortriptyline. There is no secret formula other than to start low and raise slowly, every 4-7 days (the PDR doesn’t even have a titration schedule). How slow and how low you go will depend on your patient – go easier on the elderly, the medically ill, and the anxious and somato-sensitive. However you raise it, the target dose is 50-150 mg/day, and here are some sample schedules to get you there:

Kellie Newsome: For the average patient, Dr. Aiken starts at 25 mg and raises by 25 mg a week until he gets to 75mg and then reassesses and personalizes from there. He gives it all at night, which the PDR says is OK to do, unless the patient is at risk for orthostasis, then he gives some in the morning. For more sensitive patients, he will start with a 10mg dose to test things out and then raise it a little faster if possible.

Dr. David Osser raises it a little faster. He recommends to start nortriptyline at 10 or 25mg at night, increase by 10-25 every 2 days until 50-150 per day in divided doses and then check level.

Dr. Alan Schatzberg starts higher, at 50 mg/day for 1 week and then 100 mg/day, but in the elderly he recommends starting at 25 mg/day and increasing after 3-4 days to 50 mg/day.

Dr. Aiken: You often see that recommendation to titrate a drug every 3-4 days, and I think that has to do with half-lives. Remember that serum levels are going to rise a little higher each day as you approach steady state, which is 5 half-lives. Nortritpyline’s half-life is 24 hours, so that’s 5 days, but most of the increase is in the first 3-4 days. What that means in practice is that if a patient tolerates 25 mg on day 1, it doesn’t mean they will tolerate that dose on day 2, because the serum level is going to be higher on day 2, and higher still on day 3. I tend to raise meds like this every week because it’s easier for patients to remember, and it gives me a little buffer of a few days for them to get used to the higher, steady-state level of each dose. If you raise a med too quickly, they may call complaining of side effects on the 50 mg dose, when it’s really the build up toward steady state on the 25 mg dose that they are complaining about.

Kellie Newsome: We’ve covered side effects, dosing, and now for the fun part, serum levels. Nortriptyline is one of tricyclics with a clearly defined therapeutic serum level – the others are imipramine and possibly desipramine. Now, if you really delve into the literature you’ll find that “clearly defined” is not as clear as we’d like to think – there were some flaws in the studies that established these serum levels. So follow your patient’s response and don’t be too rigid about the serum level.

Dr. Aiken: And nortriptyline’s serum level is unique because it forms a U shaped curve, meaning it has cut-off’s on both sides. Imipramine and desipramine have only a lower threshold you need to pass, but nortriptyline has a sweet spot, and that spot is between 50 and 150 ng/ml.

Kellie Newsome: And that’s easy to remember, because the therapeutic dose is 50-150 and the therapeutic level is 50-150, just the units are different.

Dr. Aiken: Both of those cut-off’s matter, because depression tends to get worse when you go below the 50 ng/ml level or when you go above the 150 mark.

Kellie Newsome: The blood level should be checked 8-12 hours after the last dose, and – as with all psych meds – wait at least 5 half-lives, which is 5 days for nortriptyline, before checking the level.

Dr. Aiken: You know, it’s interesting that serum levels matter with the tricyclics but are almost never checked for other antidepressants. And while it may be that the tricyclics have very specific effects on the brain that need a more precise level to enact, there’s another explanation that has a clinical pearl buried within it. Tricyclics are rather sensitive to drug interactions and genetic differences in the CYP metabolic enzymes – particularly the 2D6 enzyme. Even when you dose a tricyclic by weight – giving the same mg/kg dose – the blood levels can vary up to 30 fold in different patients. In today’s world, patients are asking us to check their pharmacogenetic panel, but for 50 years psychiatrists have been essentially doing just that, only in a more direct way, by checking the blood levels of tricyclics, because those CYP enzymes are the most important part of the pharmacogenetic panel. 

Kellie Newsome: And with tricyclics it’s not just efficacy we worry about but safety, because high levels can cause cardiac arrhythmias. And that brings us to the 4th and final step in our how to guide – drug interactions. We’ll keep that simple – check them when your patient is taking a tricyclic. Each one is a little different, but nortriptyline is relatively simple. It exits the body through one primary route: CYP 2D6. Anything that slows this enzyme down – and that includes bupropion (Wellbutrin), duloxetine (Cymbalta), and most SSRIs except citalopram and escitalopram – is going to raise the tricyclic levels. So start the tricyclic 50% lower and aim for 50% lower when one of these 2D6 inhibitors is on board. And you don’t have to worry about drug interactions with lithium which we hope you’ll consider prescribing along with nortriptyline when your patient returns after a successful course of ECT.

Dr. Aiken: Many psychiatrists prefer nortriptyline as their go-to tricyclic for severe depression, even when ECT is not part of the picture, although desipramine is probably tied for popularity. The reason is that both of these are relatively well tolerated, and both have well-described blood levels to guide their prescribing. We’ll close now with a case that drives this all home. The patient arrived for her first visit profoundly depressed – not eating, barely moving and almost mute because her thinking was so slow. But 6 months early she was doing great – she had recovered fully on ECT. After recovery she was treated with nortriptyline, lithium, and an antipsychotic, but she developed a pretty bad tremor so the psychiatrist stopped the lithium. That’s when she arrived at my office – free of tremor, but fully depressed. The changes were slow and subtle, so no one thought that coming off lithium had anything to do with her current depression. But – based on this research – I restarted it – and she recovered 100%.

Kellie Newsome: What about the tremor?

Dr. Aiken: Well, remember she was on nortriptyline, lithium, and an antipsychotic – but she did not have psychotic features. There’s a drug interaction you’ll often see reported for lithium and antipsychotics – neurotoxicity – which sounds like some kind brain damage but really just means that both drugs can make people tremulous, stiff, and possibly confused. In fact, most evidence suggests these are just additive side effects rather than a drug interaction – but there it stands in all the PDRs causing unnecessary alarm for many patients and pharmacists. So if lithium and antipsychotics both raise the risk of tremor, and lithium is the only one of those two meds that’s likely to keep someone well after ECT – it makes more sense to come off the antipsychotic, which is eventually what we did. The patient had been scared by this tremor and was reluctant to restart lithium, but I assured her that we could treat the tremor and – if she recovered – get her off the antipsychotic – and that with these changes she’d likely feel a lot better and not have any tremor.

Kellie Newsome: That was an elderly patient, and we shouldn’t shy away from lithium and nortriptyline in the elderly after ECT, even though they are more vulnerable to side effects. In a recent meta-analysis, lithium’s post-ECT protective effects were even stronger in the elderly. But lithium is not the only way to keep people well after ECT. Check out Dr. Posternak’s review online for a full review of the options. I think at least one of them will surprise you.

And now for the word of the day…. Antisocial

Antisocial personality disorder is an adult disorder characterized by a long-term pattern of disregard for, or violation of, the rights of others. The term first appeared in DSM-II in 1968, where it replaced the earlier incarnation, “sociopathic personality disturbance,” which was pretty much the same idea. And if you’re using ICD-10 for billing, you’ll find it under dissocial personality disorder, again, pretty much the same thing. But it’s not the same as conduct disorder, which is the childhood equivalent of antisocial and is characterized by repeated antisocial acts that are not age-appropriate. And that distinction is important, because only 24-40% of youth with conduct disorder go on to have full antisocial personality disorder as adults, so we don’t want to take away hope by diagnosing the personality disorder too early. A lot of times, a change of environment is all the child needs.

Joel Paris is a specialist in personality disorders, and he believes that only two of the 9 personality disorders in DSM have a strong scientific foundation: Antisocial and borderline. He also believes that psychiatrists are overdiagnosing a lot of conditions at the expense of others. Find out why when we interview him next Monday.

We’d like to give a special thanks to our anonymous listener who downloaded the one millionth episode of the Carlat Podcast. We don’t know who you are, and you may not even know yourself, but you brought us over a pretty big threshold when you downloaded that episode on How to Use a Lightbox last month. Each of you helped us pave the way since our first episode launched in May 2019. Thank you.

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