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6 Reasons to Use Tricyclics

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Tricyclics are much better tolerated than their reputation suggests, and countdown 6 reasons to use them, from melancholic depression to irritable bowel syndrome.

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Published On: 05/23/2022

Duration: 14 minutes, 16 seconds

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


65 years ago the first tricyclic was launched in America: Imipramine. Today, we countdown 6 good reasons to use this time-honored class of medications. 

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.

CHRIS AIKEN: In the 1990’s, Joe Goldberg was working on a placebo controlled trial of desipramine in depression and, well, let’s let him tell the story

Joe Goldberg: [story of patient on placebo who recovered and then developed multiple tricyclic side effects without ever taking the drug]

KELLIE NEWSOME: When Joe told us that story in 2020, we were struck with how remarkable the patient recovered with only a placebo. And as we prepared for today’s episode on the tricyclics something else stood out. This patient developed classic tricyclic side effects – urinary retention, constipation, sexual dysfunction, without ever taking the tricyclic he thought he was on. 

CHRIS AIKEN: That raises a question. Could our own biases about these drugs influence the side effects that patients develop on them? In 2009 Winfried Rief conducted an unusual study that gives a very clear answer. They pulled together 143 placebo controlled trials of tricyclics and SSRIs, but they weren’t interested in the medication response. Instead they compared the placebo response between the two drugs – specifically, the side effects that were induced by the placebo. They hypothesized that the patients who were taking a placebo would experience more side effects if they thought they were taking a tricyclic than if they thought they were taking an SSRI. 

KELLIE NEWSOME: Here’s what they found.  Compared to the SSRI placebo, the tricyclic placebo was 4 times more likely to cause dry mouth; 3 times more likely to cause drowsiness or constipation; and twice as likely to cause sexual dysfunction. Maybe the patients had an unconscious bias, or maybe the investigators had a bias that they passed on to the patients. Makes me wonder how much we muck up the picture when we prescribe – say, lithium, clozapine, MAOIs or tricyclics and inadvertently convey that these are serious, dangerous drugs. 

CHRIS AIKEN: I have to admit I was pretty afraid to start those meds you just mentioned when I first started practice. But I was kind of forced into them, because my patients just weren’t getting better on the usual stuff. You see – where I was working – in Western North Carolina – there was a shortage of psychiatrists so, and this is true for most places in the country – most patients went to their PCP for psych meds, and at the PCP’s office they are given SSRIs. So anyone who made it to my door had already failed those drugs. Once I spoke with a psychiatrist in New York City and mentioned that I rarely see much improvement with SSRIs – “What do you mean” he said “All my patients get better on them.” Well, what you see in practice has a lot to do with the demographics that funnel there. Oh, and here’s a related tip – if you live in a town where doctors rarely use – say – buspirone because they think it won’t work, or lithium because they think it’s intolerable – those meds may be worth trying – because every town has its share of buspirone and lithium responders, and they are much easier to find if no one is prescribing them.

KELLIE NEWSOME: Most of us live in places where tricyclics are underprescribed, and if you start using them I think you’re going to find they are a lot more tolerable than their reputation suggests. In fact, it wasn’t because of tolerability that the SSRIs replaced the tricyclics – it was safety, and of course a supersized advertising budget. Here’s Nassir Ghaemi recalling the transition:

Nassir Ghaemi: [recalls how it was fear of overdose that lead people away from tricyclics]

KELLIE NEWSOME: In our May issue we cover reasons to avoid tricyclics – and active suicidality is certainly one of them – but we also found 6 reasons why you might consider starting a tricyclic in your practice. And, if you do go that route, the issue has a detailed dosing guide and a handy table on how to manage side effects that arise like Constipation, dry mouth, orthostasis, and urinary retention. Pretty much everything that Joe Goldberg’s patient went through on the placebo. Well, except sexual dysfunction. Some of the tricyclics cause less sexual dysfunction than the SSRIs – particularly the ones that have more noradrenergic and less serotonergic action – nortriptyline, protriptyline, and desipramine (Werneke U et al, Acta Psychiatr Scand 2006 Dec;114:384-97). 

CHRIS AIKEN: This is not to say that the tricyclics are well tolerated – overall, patients are about twice as likely to stop a tricyclic because of tolerability issues than they are on an SSRI – 19% change vs. 10% chance. But the tricyclics vary a lot in their adverse effects – as well as their benefits, and those drop out rates go down significantly when we look at the newer tricyclics – the secondary amines. 

KELLIE NEWSOME: But to apply all this to your patient you have to think about what side effect they’re causing, not just the overall rate. I mean, last time I checked my biology textbook sex is pretty important to most adults, and the difference in sexual side effects alone may be worth considering. So it’s worth thinking about a tricyclic, even though in practice we’d recommend a switch to bupropion, vortioxetine, and possibly trazodone, mirtazapine, or even SAMe if sexual dysfunction is the issue.

CHRIS AIKEN: Reminds me of my first week of medical school.


CHRIS AIKEN: The attending asked us all to call out what was important to patients. “Family, job, health, sleep, friendships, religion….” We were hitting all the right buttons and at the end he had a chalkboard full of them. But then he looked at us and said “What’s missing?” Not a single med student had mentioned “sex.”

KELLIE NEWSOME: There are all kinds of biases in medicine. So let’s start by cleaning up our own biases about meds – which is how Alan Schatzberg opens up his chapter on tricyclics in his thick textbook on psychopharmacology.  It’s worth reading:

“One very important issue is attitude. Early on, some psychiatrists commonly had rather negative views about [tricyclics], which were communicated indirectly or overtly to the patient…. In our experience, such attitudes can be troubling to the patient, who must rely on the physician’s belief in the importance of medication trials and in being able to deal with the side effects.”

And with that new attitude, let’s look at the 6 reasons to consider a tricyclic, but first a preview of the CME quiz for this episode

Which tricyclics are the best tolerated overall?

A. Secondary amines

B. Tertiary Amines

C. Clomipramine and amitriptyline

D. Clomipramine and imipramine

Now for the 6 reasons…

  1. Melancholic depression. These patients wake up early in the morning, often with a nameless sense of dread – their mood is usually worse in the morning. And their mood is very different from ordinary sadness – they have a profound despondency, despair, or moroseness or may just feel “empty”. Their mood is unreactive. Their appetite is low and they ruminate with guilt, but one thing that you’ll notice is their physical appearance. They are slowed down with no expression – pale skin, lifeless, or sometimes agitated with muscle tension. Patients with melancholic depression respond better to tricyclics than to SSRIs (Undurraga J, et al, J Psychopharm 2020;34:1355–1341).
  2. Antidepressant augmentation. Imagine this – before the 1980’s it was taboo to combine different antidepressants. Think about it – the only antidepressants at the time were the MAOIs and the tricyclics, and if you mixed them your patient could end up with a serious case of serotonin syndrome. That started to change in 1981, when the first antidepressant with a novel mechanism came out – trazodone – followed soon after by buproprion, fluoxetine and the full flock of SSRIs. But is two really better than one? (Taylor D, Br J Psychiatry 1995;167:575–580). Marginally – the latest meta-analysis of treatment resistant depression – it came out a month ago – found that tricyclic augmentation improved response rates but not remission rates, and that’s similar to what we see with most reviews of the subject – there’s definitely a signal there, though probably not strong enough to pass for FDA approval. In theory, the combination of an SSRI and a tricyclic targets both serotonin and norepinephrine, and if you try it in practice the tricyclic with the best evidence is nortriptyline – which is one of the more noradrenergic ones.
    One risk to look out for – start low and go slow with these – because most antidepressants raise tricyclic levels (Palaniyappan L et al, Advances in Psych Treatment 2009;15:90–99).  The exceptions are citalopram, escitalopram, desvenlafaxine, mirtazapine, trazodone, vilazodone, and vortioxetine.
  3. Preventing depression after ECT. You’ll see a lot of patients get their life back with ECT, and you’ll see almost as many fall apart again within a few months of stopping it. So here’s a pearl worth remembering: One of the best studied strategies for preventing depression after ECT is the combination of nortriptyline and lithium (unless they have bipolar disorder, in which case I’d just stick with the lithium (Sacheim HA et al, JAMA 2001;285:1299–1307).
  4. Depression with chronic pain. Tricyclics relieve neuropathic pain – and this analgesic effect is independent of their antidepressant effects. In some analyses, amitriptyline has the strongest anti-pain effects of any antidepressant.
  5. Depression with irritable bowel syndrome. Tricycilcs, particularly amitriptyline and imipramine, are more effective than SSRIs in irritable bowel syndrome (Xie C et al, PLoS One 2015, 10:e0127815).
  6. OCD. Clomipramine is the only tricyclic with good evidence in OCD, and it may be slightly more effective than the SSRIs (Sanchez-Meca J et al, Journal of Anx Dos 2014;28(1):31–44). But this pearl is just for the highly serotonergic clomipramine – nortriptyline, amitriptyline and imipramine have all been studied in OCD and do not work.

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