TCPR: You were one of the first to document changes in temperamental traits on selective serotonin reuptake inhibitor (SSRI) antidepressants. Tell us what you found.

Dr. Kramer: I was treating patients with psychotherapy in the late 1980s when fluoxetine (Prozac) came out, followed soon after by sertraline (Zoloft). These meds were having the kind of effects I tried to get in psychotherapy. Some patients had dramatic responses and felt better than they did before the depression. They were more confident, more comfortable socially, and free for the first time from anxious or obsessive personality traits (Kramer PD, Lancet Psychiatry 2016;3(1):e2–e3).

TCPR: Sounds like the kinds of traits people seek out.

Dr. Kramer: Yes. I thought there was an eerie consonance between what fluoxetine did and what the culture demanded. In particular, women were more assertive and men were quicker decision makers on the job. And I ­worried about whether there would be some implicit coercion. If these medication effects were reliable, I could see a boss saying to their employee, “If we’re going to keep you on this job, we’re going to expect you to take that medicine.”

TCPR: What have we learned in the 30 years since your book came out?

Dr. Kramer: One theory is that antidepressants change emotional biases. They make it easier for people to think good things about themselves or see the good in the events that happen to them. The patients become more flexible, less stuck in negative emotions, and better able to learn and adapt to reality.

TCPR: How do they help learning?

Dr. Kramer: For example, when a young child has an eye disorder or has to wear a patch at a critical moment for brain development, that child’s brain may favor the unpatched eye for the rest of their life, to the point that they have trouble with binocular vision (this is called amblyopia). In studies of rodents, similarly patched in infancy, researchers were able to create a new critical learning period by administering fluoxetine later in life. They patch the dominant eye while the rodent is on the SSRI, and the nondominant eye starts learning again so that later the two eyes work in concert. This result may be related to fluoxetine’s effects on neuroplasticity and neurogenesis, but it’s not yet clear that this technique works in humans with amblyopia (Huttunen HJ et al, Sci Rep 2018;8(1):12830).

TCPR: How does that translate to therapy?

Dr. Kramer: A lot of what we do in treatment is to open up new periods of learning, whether through psychotherapy, medication, or possibly in the future with psychedelics. People just get less stuck. They go around in circles less. When we see that window open, we say, “Maybe this would be a good time to see if you could restart that friendship or reapproach the problems in your marriage.”

TCPR: It’s learning new paradigms, new ways to approach problems.

Dr. Kramer: Yes, and experiencing new feelings. I had anhedonic patients whom I wrote about in Listening to Prozac who didn’t believe anyone was happy. They thought people were faking it. They had chronic, low-level depression and had never experienced happiness before taking the SSRI.

TCPR: How do you talk to a patient about the temperamental changes they might expect on an SSRI?

Dr. Kramer: I don’t set up expectations. What I do is look for those windows of change. As the patient tells a story from their life, I might pick up that they are more assertive, less sensitive to rejection, or more able to experience pleasure. I’d point out new capacities and say, “This used to be very hard for you. Maybe facing disappointment will be easier now and you can take a chance on entering relationships.”

TCPR: Do these temperamental effects differ among the antidepressant classes?

Dr. Kramer: Nobody knows the answer, but my sense is that the SSRIs have more of an effect on assertiveness—something like alpha status, hierarchy status, or dominance hierarchy effects. My sense is that those newer drugs did more of that. On the other hand, bupropion seems less likely to cause emotional numbing or apathy.

TCPR: Last year, we covered a study that compared outcomes for depression with mirtazapine vs an SSRI. Those with neurotic traits responded better to the SSRI (Naito M et al, J Affect Disord 2022;314:27–33).

Dr. Kramer: Yes, I would agree with that. Neuroticism is a technical term that describes people who are easily overwhelmed by stress and prone to negative emotions like anxiety, sadness, anger, and jealousy. Other studies have found that the response to SSRIs in depression is largely attributable to changes in this vulnerability. Also, the loss of neuroticism added extra protection against depression—the benefits of SSRIs lasted longer in these patients (Tang TZ et al, Arch Gen Psychiatry 2009;66(12):1322–1330; Quilty LC et al, J Affect Disord 2008;111(1):67–73).

TCPR: Your book was controversial. Some psychiatrists worried it would lead people to take antidepressants cosmetically, to improve their personality.

Dr. Kramer: When I coined the term, I wasn’t recommending cosmetic psychopharmacology, which is using medication to move from one normal state to another that is more socially rewarded or desirable. The question I raise is: If we had a medication that could reliably change normal people from—say—shy to bold, should we use it for that purpose? At the time, I thought that lots of medications like this were on the horizon, but after 40 years, the serotonergic antidepressants are still the best example of the potential for cosmetic effects along these lines.

TCPR: Another criticism is that you weren’t doing anything cosmetic but were simply treating undiagnosed dysthymic disorder with an SSRI (now called persistent depressive disorder).

Dr. Kramer: Perhaps that’s true in part. Some of the patients I wrote about had dysthymic disorder, and we didn’t appreciate back then how broad the personality effects of dysthymic disorder were. On the other hand, you do see these effects in studies of people who are squeaky clean—no depression. For example, studies find that healthy adults have better leadership traits and are more collaborative in gaming scenarios after taking an SSRI. They are better able to recognize happy faces and less reactive to fearful or angry ones (Knorr U et al, Exp Clin Psychopharmacol 2019;27(5):413–432).

TCPR: The changes you saw in psychiatric patients are pretty similar to what researchers have found in healthy adults.

Dr. Kramer: Yes, and they are consistent with animal studies. If you give fluoxetine to a ­nondominant monkey and take the dominant monkey away, you can artificially create a new leader for the monkey troop. Now that we have, sadly, SSRIs in the water supply, there are crayfish that are being too bold in water that has a lot of these antidepressants in it. They come out of their underground holes more often than they should (Reisinger AJ et al, Ecosphere 2021;12(6):e03527).

TCPR: One more criticism. I’ve heard people say you were just causing hypomania.

Dr. Kramer: (laughs) Yes, I did hear that. None of these patients had hypomanic signs or went on to develop mania or mood cycling. That was not their fate.

TCPR: Any other traits you’ve seen change with SSRIs?

Dr. Kramer: I saw someone who was obsessive about collecting things. He spent a lot of time going to auctions, and after taking fluoxetine, he no longer felt the need to do that. This wasn’t OCD, but more an obsessional personality trait. I also saw a woman who was less obsessional about taking care of her ailing mother.

TCPR: Did that raise some ethical questions?

Dr. Kramer: Indeed! But since then, studies have looked at whether SSRIs make people more or less charitable, and on the whole it’s more. They are more empathic, less self-centered, and more outward looking (Crockett MJ et al, Curr Biol 2015;25(14):1852–1859).

TCPR: One thing that has stood in the way of “cosmetic psychopharmacology” is that we have a greater awareness of the risks with SSRIs, such as sexual dysfunction, withdrawal problems, decreased bone mineral density, and—in younger patients—rare suicidality.

Dr. Kramer: Yes, and the effects on temperament are not always positive. Patients can feel bland, apathetic, or emotionally numb on SSRIs. I think of an angry, rebellious undergraduate who didn’t like the way fluoxetine took his rough edges off, saying, “This isn’t me.”

TCPR: But even if we reject that cosmetic use, I imagine your findings have a lot of relevance for patients who had a good response and then came off SSRIs.

Dr. Kramer: Yes, that can be a problem for people who experienced those positive temperamental changes. They come back saying, “I was really a better parent on that medicine,” or, “I have a job interview coming up and I know I would have a better chance if you put me back on that medicine.” This is a challenge. As psychiatrists, we are used to addressing those needs through psychotherapy, not medication. So people stay on them longer, which has created another problem. As they stay on them longer, we see more problems with SSRI withdrawal.

TCPR: How do you stop SSRIs?

Dr. Kramer: Very slowly. My sense is that the brain gets acclimated to the medication, and as we come off, I don’t want the brain to notice what is going on. If patients were on an antidepressant with a short half-life like paroxetine, I might switch to or add fluoxetine, which in most cases has a long half-life. Typically I would lower the dose by 20% at a time over the course of a year, trying not to end in February in New England when seasonal depression might peak. Better to aim for May.

TCPR: What was it like being Donald Trump’s psychiatrist?

Dr. Kramer: (laughs) My latest book, Death of the Great Man, is a novel about a psychiatrist who is dragooned into the treatment of a narcissistic, buffoonish, autocratic national leader in his corrupt and disastrous second term. It made me think about what a person such as Donald Trump would be like close up, and what it’s like to work with extremely dislikeable patients. The doctor in the novel is very dedicated. He tries to see the best in his patient, as I did with difficult patients in my own practice. Perhaps, in imagination, I was overly empathetic. I wrote the book before the events of January 6, 2021. What happened that day surprised me. I underestimated how bad things could get.

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