Antidepressants - Going Backwards: SOLUTIONS: How to Diagnose Depression and When to use MAOIs

Ethan: Ken, for the general listener or young professional, give us a brief commentary on when it is appropriate to use MAOIs, and how to identify biologic depression compared to neurotic or situational depression.

Ken: My view would be that anergia and anhedonia are absolutely the core symptoms that lie at the heart of depression and explain of themselves the genesis of most of the other symptoms. Lack of drive, motivation, and energy. You can't separate the mental from the physical entirely, but if you like to say it's a physical and a mental thing, people with biologic depression, their thinking is slower, less decisive, more hesitant, all of those things. And, of course, anhedonia is diminished ability to get what I call positive feedback, pleasure, enjoyment, satisfaction, fulfillment. Obviously you use different words depending on what sphere of activity you are talking about in life. So it will affect, work, social leisure, relationships of all sorts, and all the positive feelings you get back from those things are diminished. It's always struck me that people have said in the definition that it's an inability to get pleasure. Of course it isn't, it's not a switch, it's not an on-off thing. It's a progressive phenomenon. And people with less severe illnesses may well be able to smile and laugh, but if you inquire carefully, you can see clearly that their ability to enjoy things normally is clearly diminished from what it would normally be. That takes us back to Gordon Parker and, simply because he's the person who's done more formal scientific research work on that subject, Clinically, especially because I started off looking after extremely severe depressions who were tertiary referrals to our special unit back in London in those days; I got used to understanding those things because I dealt with an extraordinarily large number of very severely depressed patients right from the beginning, which a lot of people don't, you know? So they perhaps don't have the opportunity to learn quite so clearly what those symptoms are like, and how to elicit them, and that sort of thing.

But do you know, as an aside, when I was writing something about this several years ago about core symptoms and Parker's stuff and answering the question you've asked, I started to look at the DSM criteria as they've changed over the years. I've never taken any notice of the DSM. I've always thought it's nonsense. I used to call it the cookbook, and I was greatly amused when I heard one of the famous American doctors who'd been part of the committee or whatever that had produced it, who was being interviewed on the radio here in Australia, Nancy Andreason, and she called it the cookbook, and I thought, ‘How fascinating, that somebody who actually worked on it has the same opinion about it as I've always had.’ When I was looking at the criteria for serious depression, I nearly fell off my chair when I realized that anhedonia was not an essential symptom for the diagnosis of depression in DSM until, I think it was the middle of, or the end of, the 1990s. You could have knocked me off my chair with a feather. I thought if they don't understand that anhedonia is a core symptom, they're obviously not worth listening to. They don’t know what they're talking about.

Ethan: I have a clarification question in terms of that internal monologue that all of us are having at all times. In depression, is it a lack of willingness to speak things aloud though the internal milieu remains hyperactive?

Ken: Dopamine! Getting back to this business of melancholic depression and to what extent different neurotransmitters might be involved in it, hand-in-hand with this business of anhedonia not being an essential core symptom according to DSM. Until more recently, from a research point of view, dopamine has been almost ignored through most of my professional career. And this has always puzzled me because Herman Van Prague wrote about this back in the ‘70s, and I remember thinking, ‘Yes. That's clearly a reasonable line to follow.’ And I've thought like that ever since. But the amount of research on dopamine has been pathetic. Professor Nutt wrote an article about dopamine and depression in his journal, Journal of Psychopharmacology, in the UK, but if you look at the available research, especially animal research, the evidence that it plays a key part in, motivation and mentation and decision-making and reward behavior and all that kind of thing. It is huge. I'm not an expert in all of this kind of basic research, but I'm pretty sure also that extends to work that's been done in humans too, that show that dopamine's pretty important from that point of view.

It's always puzzled me that people haven't paid as much attention to dopamine as they might because of course, one of the things that struck me most powerfully from my early days of treating these very severe patients, that if you had a hierarchy, you'd go Amitriptyline, Clomipramine, Tranylcypromine, and of course, what you are doing there is going from a Noradrenalin Reuptake Inhibitor to a Serotonin and Noradrenalin Reuptake Inhibitor to a drug that increases Dopamine and Serotonin and Noradrenaline. And so it seemed to me that it was fairly clear as the illness got more severe and as people got older, boosting all those three neurotransmitters was clearly superior. And when you've seen many patients who've gotten better when you've changed them from an SNRI to an MAOI, and people often will report an improvement in an extremely short period of time, four or five days.

Ethan: To go back to that question, if you have a completely apathetic person, they don't have any motivation to commit suicide because they're completely apathetic. They don't have any motivation to do so. They don't care. Is there an internal realization or recognition that, ‘Other people have it better than I do,’ or, ‘I see that things in my life could be different, but they're not.’ And that internal commentary is hyperactive.

Ken: I don't know, I don't think I'd claim to have an answer to that question, Ethan. As another historical thing for our younger listeners, it's been recognized right from the beginning of treatment with MAOIs in the late 1950s and the other antidepressants as they came in subsequently, that, for a proportion of people, an increased period of risk as they began to get better. And that's perfectly understandable. When I used to treat people with Parnate, I used to routinely say to people, ‘Look, it's perfectly logical and understandable that anxiety symptoms are gonna get worse before you really start to get better,’ because if the central symptoms are anergia and anhedonia and you are treating those symptoms rather than giving an anxiolytic just to reduce the anxiety, many anxiety symptoms are secondary, if you like, to anergia and anhedonia. The less you do and the less positive you feel about the result, the less confident you feel because confidence is Practice-makes-Perfect. Therefore, your threshold for experiencing anxiety is lower, therefore you experience more anxiety. And in my view, that explains a great percentage of the anxiety symptoms that occur in people with serious depression. Obviously, as you get better and your drive and motivation improves, your confidence and anxiety is gonna lag behind because you can't get more confident until you've done more. Practice makes perfect. So I used to routinely say to people, ‘You need to realize that initially you might have a little bit more drive and motivation to do things, but when you try and do things, it'll create anxiety because you're not used to doing it, you're out of practice. If that's a problem, you need to discipline yourself and just do a little bit at a time until your confidence builds up. Don't try and tackle some big task just because you feel so much better in terms of having more energy.’ And I think that explains why there's an increased risk of suicide for some people. I wouldn't say everybody. And of course, don't forget that some people who are very psychomotor retarded and all the rest of it will commit suicide because, if the nurse leaves them out on the balcony unattended for 5 minutes, they might have enough energy just to topple over the balcony. It's not a black and white thing, but yes, I think there is a tendency.

Ethan: And Charlie brought up the Default Mode Network. I would love to talk about that. It's fascinating to me, but they have to have the thought to topple over the balcony.

Ken: I don't think I portend to understand what the Default Mode Network exactly is.

Ethan: I always call it the gateway between your more internal, animalistic brain, the older evolutionary parts of your brain, and your higher cortex. It's a gateway that they found in severely depressed people, and this is what kind of led to my question, they found a Default Mode Network, that, when you're not doing anything, when you are consciously disengaged, Default Mode Network is very active. And especially in severely depressed persons, that internal milieu is rapid firing, even though they may not have the drive to express themselves externally. If you're not familiar with Relational Frame Theory, you need to check that out as well, because I think it ties very closely into the Default Mode Network, in my own understanding of how the brain functions as a whole, and has given me a lot of insight into how to treat not just biologic depression, but also neurotic depression.

Are you familiar with Nassir Ghaemi’s work, or Ghaemi? The way that he describes what we now call bipolar illness, but much more appropriately, I think, is manic-depressive spectrum illness, in my understanding of how he understands depression, that, everybody is on the manic-depressive spectrum. There's just a large proportion of people that don't ever get over to the manic side, but there's almost a manic-type quality in severely depressed individuals internally that is very self-defeating, a very negative self commentary that may lead them to have that thought or have the idea, ‘Hey, you could jump off the balcony,’ and there is not the frontal lobe capacity to inhibit that behavior.

Ken: Yes. I've certainly read and respected his work. I don't claim to be able to remember it well enough right now to speak in any erudite fashion about it, but I understand what you're saying and I essentially agree with that. And what you made me think of as you were describing that, Jules Angst, Switzerland, Zurich, he's still alive. When I say still alive, what I mean is, academically alive. He's published some fabulous long-term studies on the symptom patterns of depression over decades. His group, perhaps, has published the greatest number of long-term studies on this sort of thing than any group in the world. And what fascinates me about his work and what I think is a really important observation for many people to be aware of, is this business of unipolar and bipolar. And how he showed that the longer you follow up patients who are diagnosed as unipolar depression, the more likely they are to exhibit an episode of elevated mood. And I think that probably fits with what your fellow Ghaemi was saying. We must apologize if we are mispronouncing his name, but that'll have to do for the moment. That means that you have to take a lot of research with a pinch of salt because if the research has substantial numbers of patients in their 30s, 40s, and 50s and people are making pronouncements about what the best drug to treat unipolar depression is, the differences are so relatively small probably that if you hypothesize that group is probably contaminated with 10, 15% of people who will in fact turn out to be bipolar, it makes a nonsense of all the results.