Thinking About Medications Differently #1

Will an SSRI Help Me? (Or: Let's Not Call Them Antidepressants)

By Jose Mantilla-Rivas, MD

Part of an ongoing series on thinking about medications differently.

This series is about taking a step back to think about medications differently. In medicine, we often use. or prescribe, a medication, to cure, or to 'fix' something. Although this applies to all medicine (antibiotics, statins or BP meds), I will focus on psychiatric medications for now. Just know that some antibiotics have been used (with low efficacy) to prevent alcohol use, statins seem to improve overall wellbeing besides their lowering of cardiovascular risk, and certain blood pressure medications can help to treat ADHD or PTSD. The point that I will argue about is not whether medications are "good", "bad" or "useful", nor arguing about whether they address whatever is considered a "root cause" or not. The point of this series is to actually complicate things a bit more to bring nuance to the discussion. At the end of the day, each person, each story and patient/physician relationship has a determined set of goals, and whether a medication fits (and how) in this complicated matrix is what I am writing about.

So, without further ado, let's take a look at these studies:

1. Effect of chronic escitalopram versus placebo on personality traits in healthy first-degree relatives of patients with depression: a randomized trial (10.1371/journal.pone.0031980)

2. Personality change after Internet-delivered cognitive behavior therapy for depression (10.7717/peerj.39)

3. Association between SSRI use and cardiovascular outcomes in patients with coronary artery disease and generalized anxiety disorder: A real-world cohort study (10.1016/j.atherosclerosis.2025.120390)

4. Off-label Uses of Selective Serotonin Reuptake Inhibitors (SSRIs) (10.2174/1570159X19666210517150418)

5. Personality change during depression treatment: a placebo-controlled trial (10.1001/archgenpsychiatry.2009.166)

6. Personality change in a trial of psilocybin therapy v. escitalopram treatment for depression (10.1017/S0033291723001514)

7. Neuroticism and Individual Differences in Neural Function in Unmedicated Major Depression: Findings from the EMBARC Study (10.1016/j.bpsc.2016.11.008)

Let's focus on the following question as we go over each paper:

Will (sertraline/fluoxetine/escitalopram-(you name an SSRI) help me?

Part of answering this question involves exploring what help me means

When taken together, papers 1), 5), 6), 7) and 2) seem to suggest that:

1. Depression itself is associated with changes in personality: It appears that people who meet criteria for a depressive episode according to diagnostic manuals have a change in personality during the depressive episode. I don't think this comes as a surprise to anyone.

2. Different domains of personality often change during the treatment of depression, be it with an SSRI, psychotherapy, or psychedelic medications. Some of these changes can last for months. Again, not a surprise. As the episode improves, people often engage in more frequent social activities, or in treatment they realize how holding back, or lack of sleep, or any number of social stressors, are prolonging a depressive episode. These things have an impact in our personality, or at least how it is perceived. Both the treatment and the condition that led to treatment have a potential to change how the construct of our personality is perceived.

3. These changes don't happen in genetically-related people who do not have depression (at least with medication). So here's the kicker, if a person doesn't meet criteria for a depressive episode, the personality changes that were described above don't seem to occur. And if they do, the magnitude of change appears to be much smaller. In other words, the personality changes mentioned in some of the papers above don't appear to happen in people who don't meet criteria for a clinical diagnosis of depression.

Now, let’s go for more nuance!

The state effect describes an appearance of personality changes because of behavior changes that occur in a depressed state. Although the concept of depression is broad and encompasses a diverse clinical entity with different causes, prognosis & treatments, this is not the topic today.

But back to our story. Here is where some of the papers conflict. I’m looking at you, Paper # 5. In this trial, people on an SSRI changed more in neuroticism and extraversion than patients who were taking placebo, even if both of them had improvement in their depression. Roughly 6.8 times as much change in neuroticism. This does appear to point out that SSRIs independently improve depression.

Now, let’s look at papers 3) and 4). SSRIs can decrease mortality in people with cardiovascular disease. Is this because of the treatment? Is this because targeting anxiety and learning to listen to it with attentive and actionable ears can lead to better treatment? Or maybe that the people who had anxiety at baseline are more conscious of their condition and have better results?

so here’s where I think we are: 1) SSRI’s are associated with increased extraversion and decreased neuroticism, and 2) some people can have mortality benefits, could be a direct effect of the medication, an effect of addressing potentially impairing behaviors secondary to anxiety or depression, or the changes in neuroticism and extraversion improve social contact, which can have mortality benefits.

Now, these are studies that look at big numbers, and use averages of scales and numbers to produce a complicated, yet (hopefully) as helpful as complicated picture. And averages hide people. Paper 7) is a good reminder. Neuroticism in unmedicated depression maps onto specific differences in brain function, in the right anterior insula. And personality is one of the few things that actually predicts who responds to which treatment (10.1016/j.bpsc.2016.11.008). So the question isn't only "do these work?" It's "for whom, and how would I know?"

Take a step back now, and think outside of this reductionistic biomedical model and turn it back to you.

How would (or could) a medication be helpful to you? would being more open to expereinces be helpful to you? how about agreeable? what if these don't change and you feel better? Outside of a subjective feeling of sadness or depressed mood, what has this diagnosis meant (or not) to you? do you have other medical problems where an SSRI may be of benefit to you?

What if these changes happen to you without needing to take a medication? or, what story are you telling yourself about the medication you take? what would it take for you to let go of the medication once you feel better?

That question about the story you tell yourself isn't just philosophical. Paper 6) compared psilocybin therapy to escitalopram. Both shifted personality in these short term trials. But here's the detail that sticks with me. The changes on escitalopram were predicted by how much people expected it to work. The psilocybin changes weren't (10.1017/S0033291723001514). So the story you tell yourself about the pill may be part of how the pill works. The molecule is hard to separate from the meaning we give it.

One more from paper 5), and I'll pick it up in the de-prescribing posts. Among the people who responded to the SSRI, those whose neuroticism dropped the most were less likely to relapse (10.1001/archgenpsychiatry.2009.166). So the personality shift may not be a side curiosity. It may be part of what drives what is considered the therapeutic effect of the medication.

A quick word before you go. None of this is a reason to start, stop, or change a medication on your own. If you're already taking something and these questions are stirring, bring them to whoever prescribes it. Ideally before you change anything. Some medications shouldn't be stopped abruptly-maybe the desire to stop them is a question that should be explored together in a meaningful treatment, and stopping a medication without a conversation could be a symptom of a more complicated conversation.

More on this on upcoming diagnoses, therapy and tapering / de-prescribing posts.

Questions? Concerns? Message me on the contact page.

Q&A

Do you always prescribe a medication? Should a medication always be prescribed for depression?

A: Research suggests that for some people with depression, psychotherapy and lifestyle modifications may be at least as effective treatments compared to medication. That said, SSRIs and some other medications, when thoughtfully used, and then later deprescribed if appropriate, can be a helpful solution for the right person. In short, no I don't always prescribe medication, nor an effective treatment for depression has to include medications, though they can be helpful for some people.

Wait so does this mean that the medication changes who I am?

Not really! One could argue the opposite. The effects of ongoing and untreated depression often include behavior changes that can translate into changes in brain networks and functioning. Any treatment that is effective is likely to affect your behaviors, But here's the thing, for most people, treatment of depression involves change. Be it an effect of medication, or therapy, it is common that in a good treatment, the decision of changing comes up. Nope, this doesn't mean getting a motorcycle or bangs, but actually, meaningful change in how we relate to ourselves, to our lives, and to other people. I included paper 2) above to show that therapy also changes our personality, even when delivered online.

This probably also means that social media affects our personality more than we'd like to admit - and talking about change, what parts of it would you be willing to change?

So do antidepressants work?

Let's not call these medications antidepressants. If anything, some of the papers above that for some people they can be sugar pills, for some people they can be life-prolonging agents, anti-menopausal agents, or even extraversion pills. But yeah, for some people with certain specific personality, genetic and clinical features, medications can be, at different degrees, helpful