TCPR: When it comes to medication trials, how do you know when enough is enough?
Dr. Goldberg: I don’t think I would ever say “enough is enough,” but there is a point at which the probability of medicines having a big effect becomes very, very low. In depression, that point is pretty black-and-white in my mind: 5 trials. In a study from Massachusetts General Hospital, the chance of remission after 5 medication trials was a stark zero (Petersen T et al, J Clin Psychopharmacol 2005;25(4):336–341). This doesn’t mean I would refuse a patient a sixth or seventh trial, but it does mean that we need to adopt a different mindset of what help looks like at that point.

TCPR: But we have therapies that work in treatment-resistant depression.
Dr. Goldberg: Yes, but most of those studies enrolled patients who failed 2–5 trials in the current episode. That’s how the esketamine, TMS, and olanzapine-fluoxetine trials were done. Pramipexole is an exception. There is a case series of 42 patients with bipolar or unipolar depression who had failed at least 4 medication trials (average of 6 failed trials; 20% had failed ECT). They went a little higher on the dose, averaging 2.5 mg/day instead of the usual 1.5 mg/day. Half the patients remitted, and another third responded (Fawcett J et al, Am J Psychiatry 2016;173(2):107–111). I’ve also seen it work well in these cases.

TCPR: Are there any other meds you would try in highly resistant cases?
Dr. Goldberg: ECT, ketamine, and heroic MAOI trials have some evidence to work. But even there the odds are slim. The success rate of ECT goes down with the number of past trials as well as the length of the current episode (Goldberg JF, J Clin Psychiatry 2018;80(1):18ac12276).

TCPR: What are “heroic MAOI trials”?
Dr. Goldberg: That means high doses, like tranylcypromine over 90 mg per day, or using them in combination with other psychotropics. There’s a risk of hypertensive crisis and serotonin syndrome with those combinations, but that risk is pretty low if patients avoid tyramine-containing foods and stay away from vasopressors and serotonergics like the SSRIs and clomipramine. People have combined MAOIs with dopaminergics (stimulants, modafinil, and pramipexole), buproprion, amitriptyline, trimipramine, doxepin, and trazodone without significant problems, but such approaches must be undertaken with caution and should only be done by clinicians who are very familiar with and comfortable using MAOIs (Adli M et al, Pharmacopsychiatry 2009;42(1):39; Stewart JW et al, Affect Disord 2014;167:148–152). The main impediment with high doses is orthostasis, which I treat with glucocortisone and abdominal binders (ie, elastic waistbands).

TCPR: What else can we do?
Dr. Goldberg: To start with, you need to assess these patients carefully. Have they had hypomania? How is their adherence to meds? Maybe there are comorbidities that haven’t been addressed. Look for factors in their life history that might moderate their response. Maybe their antidepressant worked better when they were exercising or in a relationship. Bring the family in. You may learn that the patient did respond to an antidepressant in the past but they’ve forgotten that hope in the cloud of the current episode.

TCPR: You wrote that further medication trials are “futile” once we’ve exhausted these options. That’s not a word I see too often in psychiatry.
Dr. Goldberg: The word “futile” comes up in nearly every other field of medicine, but psychiatry somehow imagines itself different. Many of the illnesses we treat are chronic, persistent, and progressive, and it’s a bit of hubris to think we can always treat them to resolution. There is good reason behind this ideal, because if you don’t intervene early, the patient can progress to treatment resistance. The problem is that our treatments are not that great. Most of our medications have effect sizes in the small to medium range. Buspirone for anxiety: 0.17. SSRIs in depression: 0.3 (Hidalgo RB et al, J Psychopharmacol 2007;21(8):864–872; Turner H et al, N Engl J Med 2008;358:252–260). A few have large effect sizes, like ketamine for depression or amphetamines in ADHD (Editor’s note: The large effect size was for ketamine, not esketamine).

TCPR: Where’s the hope here?
Dr. Goldberg: We shouldn’t equate pharmacologic futility with hopelessness about the ability to manage chronic disorders. We have to maintain some sense with the patient of “we’ll get you through this,” though it may not be with pills. We need to be honest with the patient and set realistic expectations. The goals should shift away from disease transformation and toward disease management. “Whatever we do in terms of medication, we need to talk about how you’re coping with it.”

TCPR: Is psychotherapy the answer?
Dr. Goldberg: Psychotherapy may not be able to bring highly intractable cases to remission, but it can certainly improve patients’ ability to cope with a chronic disorder and accept difficult circumstances.

Pharmacologic Futility: The Conversation

TCPR: How do you open up this conversation with a patient?
Dr. Goldberg: I’ll say, “I hope we’re going to find something that’s transformative, but this depression has been going on a long time and the chance that it’s going to resolve in the near future is low. So let’s talk about how you are living with it.”

TCPR: Do they need to accept the depression first?
Dr. Goldberg: Yes, that’s part of it. They need to accept the reality of their current situation and shed magical thinking that “the right med” will provide a miraculous solution. But I’m also trying to build resilience, to help them pull on their inner resources and overcome adversity. There’s no shortage of opportunities to overcome adversity during depression, whether it’s job loss, family conflicts, the side effects of our meds, or the illness itself. So we’re moving the conversation away from “I’ve got a thorn in my side and I need you to take it out” to “You’ve got a thorn in your side that’s not moving, so how are you going to go to work with that thorn in your side?”

TCPR: Do you focus more on functioning and less on symptoms in these cases?
Dr. Goldberg: I try to do both. I’ll say, “When I see you next week I’m going to ask about two things: how you’re feeling and what you’re doing.” If they come back and their mood is better but they’re still in bed all day, I’ll say, “Why is that?!” I’ll try to mobilize the patient against the illness, and I may appeal to their narcissism there. “You’re better than this. The illness is the enemy, and it’s getting in the way of your ability to tap into your inner reserves and solve problems. You could be a great father if it wasn’t for this depression!”

TCPR: How do you work with the so-called “help-rejecting complainers,” the patients who fight any help that’s offered?
Dr. Goldberg: That comes up a lot in chronic depression, and it can leave the clinician feeling de-skilled. The patient may scoff at our efforts to help, which makes it harder for us to want to help, and eventually we feel defeated and demoralized. What’s going on is that they need something to defeat, so we have to be careful to keep ourselves and the treatment out of that firing range. What I do instead is put forth the idea that perhaps their condition is not going to go away, at least any time soon, and let them defeat that idea. It’s a paradoxical technique.

TCPR: How does that dialogue look?
Dr. Goldberg: I’ll say, “You have a tough depression. I feel really bad for what you’re going through. I’m not sure I have anything that can work, and there’s a good chance that you’ll have a lot of side effects if we start something new.” At that point the patient usually starts to push back. They want to try something. They want to prove me wrong. So we start a medication, and the moment they come in and say, “I think I’m feeling a little better,” I’ll counter them: “Well, it’s a little too soon for the medication to be working, and I didn’t expect you to feel better yet, so I have to warn you that it may not last.” They’ll say, “No, I’m optimistic. I think we’re on to something.” And I’ll say, “Yeah, but I bet you’re having a lot of side effects.” “No, I don’t have any side effects!”

TCPR: It sounds like you’re trying to bring out the fighter in the patient.
Dr. Goldberg: I think you have to. Depression doesn’t have many emotions to draw on if you’re trying to mobilize a patient. Anhedonia, anxiety, despair… those aren’t going to work. But when people are in a bad predicament like depression, they’re usually angry. If the anger is directed inward, you have to give them something to get angry at. It’s not going to help if they get angry at you. It has to be an anger that mobilizes them, like “I’m not going to let this depression keep me from going to that job interview! I’m not going to fall victim to this. I’m going to fight it tooth and nail.”

TCPR: How do you use empathy with these patients?
Dr. Goldberg: It can be difficult, but it’s essential. Two common countertransference reactions to a chronically depressed patient are withdrawal and attack. These can be subtle. Withdrawal may take the form of daydreaming during the session, and attack might look like challenging the patient too much or assigning unrealistic homework. A sure sign that one of these is going on is that you’re dreading the appointment. A better approach is to align with the patient and all the injustices that have rained upon them. “Nobody should have to go through what you’ve been through. It’s not fair. You didn’t cause it. You didn’t ask for it. But you have to manage it.”

TCPR: Therapists advise families of patients with chronic depression, “Don’t do anything for your relative that they can reasonably do themselves.” In your work, when you’re mobilizing patients, how do you know when they can “reasonably” do it?
Dr. Goldberg: You need to know the patient well. These are not quick fixes. It takes tending and an ongoing therapeutic relationship. You don’t want to push the patient because that can be a setup for failure. Instead, I’ll make observations like “That’s too bad that you weren’t able to go to that job interview. I can understand that you feel so bad after missing an opportunity like that.” I’m hoping to mobilize their fight here, but you have to leave it up to them to pick up the ball and run with it.

TCPR: Do these techniques ever backfire?
Dr. Goldberg: I’ve learned that change is very difficult when the patient’s illness is a stable part of their family dynamics. If you march in and try to shake up that kind of long-standing, ingrained pattern, it can have bad consequences. Also, I wouldn’t go so far as to forecast a dire outcome, as in “Yeah, you probably are going to kill yourself someday.” This is always leveraged with hope. The message is, “You can work with this. People with chronic illness—whether spinal cord injuries or depression—have a way of mobilizing their resilience. I don’t know how that’s going to look for you, but I know that you are capable of it.”

Building a Better Placebo

TCPR: You talked earlier about how ineffective many of our medications are. But that’s after you remove the placebo effect, which is 30%–40% of their potency. Are you trying to enhance the placebo effect with this work?
Dr. Goldberg: Yes, but that doesn’t mean adding in a sugar pill or raising false hopes. “Placebo” is not the same as “no treatment.” In fact, it’s a very active treatment. John Kelley and colleagues from Massachusetts General Hospital published open-label trials of placebo as an active treatment in depression, and it worked: 80% got better (Kelley JM et al, Psychother Psychosom 2012;81(5):312–314). The patients were told they were getting placebo. They even had to sign consent for it.

TCPR: What did the consent form say?
Dr. Goldberg: It said something like “We’re going to give you a substance that has no active medicine in it but that some people have found helpful.” Now, there’s a ritual to this. They have to take the sugar pill every day and come in for regular assessments and rating scales. The placebo is a powerful treatment, but like all things, you have to know how to use it.

TCPR: Thank you for your time, Dr. Goldberg.