The Case for Antidepressants

Antidepressants are NOT Placebos
 

Hey team,

I recently revisited Peter Kramer’s book "Ordinarily Well," in which he makes a compelling argument that antidepressants are significantly more than mere placebos, they indeed have tangible effects that can alter the course of depression for the better. This case arises amidst significant pushback against antidepressants, particularly the claim that they're nothing more than "placebos with side effects," a position I once explored but no longer find convincing.

While antidepressants aren't correcting a "chemical imbalance"—a concept I've previously gone over—they undeniably have tangible effects on mental processes. Notably, antidepressants influence unconscious mechanisms related to emotional processing in ways that placebos simply don't replicate. This is in addition to unique effects on personality again not seen with placebos. Additionally, standard clinical trials are rife with limitations that serve as poor proxies for the true effect of medication. To better illustrate these distinct effects beyond placebo, let's explore how antidepressants specifically influence emotional processing.
 

Effect on Biases and the Brain

 
Antidepressants rapidly influence emotional processing, shifting bias toward positive stimuli well before clinical mood improvement is detectable. It has been demonstrated, and repeated, that selective serotonin reuptake inhibitors (SSRIs) induce early alterations in emotional perception and memory within hours to days post-administration, independently of subjective mood improvement.1 This looks like being better able to recognize happy faces, even in the face of ambiguity. It is also important to emphasize that this is not unique to the drug that is often used (citalopram) or the SSRI class either, this is indeed an widespread antidepressants phenomena regardless of specific mechanism, as acute effects are seen with norepinephrine reuptake inhibitors (NRI), and atypical agents like mirtazapine and bupropion.2,3, 4

These early changes in emotional processing offer insight into the often-misunderstood delay in antidepressant efficacy. While traditional theories state downstream neuroadaptive mechanisms—such as a buildup of neurotransmitters, receptor desensitization and neurogenesis—as explanations for the lag in symptom relief, a more nuanced perspective suggests that antidepressants do not act as direct mood enhancers. Instead, they gradually reshape cognitive and emotional biases, allowing individuals to process information in a less negatively skewed manner, a trope of depression that keeps individuals stuck in their suffering.5 This shift occurs relatively quickly but requires time to translate into conscious improvements in mood and behavior. As individuals begin to engage more positively with their environment—interpreting social cues with less negativity and reinforcing rewarding experiences—the cumulative effect fosters a more sustained mood improvement. The delay in symptom response is not due to a lack of immediate drug action but rather the time it takes for these cognitive and emotional recalibrations to manifest in everyday life.

Further distinguishing antidepressants from placebos, meta-analysis highlights their unique modulation of amygdala activity, reducing hyper-responsiveness to negative emotional stimuli—effects not replicated by placebo administration.6 These neurobiological changes underscore the pharmacological distinctiveness of antidepressants, reinforcing that their effects extend beyond subjective mood alterations to fundamental shifts in emotional reactivity.
 

Effect on Personality

In line with my belief about the root of familial depression or one's tendency to become depressed—specifically, trait neuroticism—research indeed shows that antidepressants modulate this trait, as well as others such as extraversion and openness.7 This makes sense due to the protective aspects of social participation and cognitive flexibility, traits that help individuals adopt new perspectives and behaviors. What I find confusing though, but would like to point out, is that these personality changes appear distinct from the direct antidepressant effects on mood. However after accounting for improvements in depressive symptoms, reductions in neuroticism strongly predict lower relapse rates. This aligns closely with what psychiatrists like Peter Kramer and patients alike have observed: individuals often feel fundamentally different—not just less depressed, but less emotionally reactive, more resilient, and better socially connected. Such findings challenge the idea that antidepressants merely alleviate symptoms, instead suggesting they reshape deeper emotional and cognitive patterns, ultimately encouraging a more resilient personality.

The Problem with Placebos and Clinical Drug Testing

The frequently high placebo response observed in antidepressant clinical trials often reflects methodological rather than pharmacological equivalence. As Rutherford and Roose (2013) highlight, methodological choices in trials—such as intensive therapeutic interactions, recruitment of individuals experiencing socioeconomic hardships, and suboptimal dosing aimed at retention—can significantly amplify placebo responses.8 These factors mask the true efficacy of antidepressants. The drug approval process and drug testing process it's quite elaborate, and is somewhat of an industry itself designed to get a drug to market, not necessarily demonstrate efficacy to its fullest extent. The assumption that antidepressant efficacy can simply be measured by subtracting placebo responses overlooks the complex interactions between medication effects and placebo responses, emphasizing why traditional clinical trials may be inadequate for fully appreciating the true therapeutic potential of antidepressants. The assumption that an antidepressant’s effect is simply the sum of the placebo response plus an additional drug-specific effect is likely flawed, undermining a key premise of traditional clinical trials. For example, if you give patients a tonic drink (placebo that they can’t tell apart from the real thing), tell them, it's a vodka tonic, they will behave drunk. Give another group vodka tonics (active drug) , tell them it's vodka tonic and they will also behave drunk. If you subtract the tonic group that was told it was vodka tonic from the vodka tonic group that was told they were receiving vodka tonic you get a relatively small difference. Does that mean that the majority of the effect of vodka can be explained by expectancy? No, that's ridiculous and I believe there's something similar going on with antidepressants.


Expectancy and the Placebo Response

 
Placebo responses are largely driven by expectations, but does this hold true for antidepressants as well? Leuchter et al. demonstrated that higher patient expectations at the start of a clinical trial strongly predicted better outcomes among placebo responders—but notably, not among patients receiving antidepressants.9 This suggests placebo efficacy is primarily driven by psychological expectations established before treatment begins, rather than by pharmacological effects. Further distinguishing antidepressants from placebo, the study revealed distinct neurobiological changes: medication responders exhibited decreased prefrontal EEG activity, while placebo responders showed increased activity in the same region, clearly indicating non-overlapping mechanisms. Thus, antidepressants exert therapeutic effects independent of patient expectancy, highlighting fundamental differences between how antidepressants and placebos work.
 

A Tale of Two Trajectories 

The notion that antidepressants and placebo responses follow separate trajectories is vividly illustrated by Gueorguieva et al. Through sophisticated trajectory modeling of clinical trials comparing duloxetine, SSRIs, and placebo, researchers discovered distinct patterns of patient responses. Notably, antidepressant-treated patients consistently separated into two distinct groups—trajectory responders and nonresponders—while placebo-treated patients showed a uniform, gradual improvement without clearly differentiated response groups. These findings reinforce the idea that antidepressants' efficacy can't be understood merely as placebo responses enhanced by patient expectation; rather, antidepressants initiate distinct pharmacologically driven response patterns. Interestingly, the study also demonstrated that while most antidepressant-treated patients improved more rapidly and sustainably than placebo recipients, a subgroup on antidepressants fared worse than those receiving placebo. This highlights the complexity in antidepressant responses and underscores the necessity for careful, ongoing monitoring of individual responses rather than relying solely on aggregate data from traditional clinical trials​
 

Trade-Offs not Solutions

Throughout this discussion, I have aimed to show that antidepressants are far more than placebos; they have tangible and even acute effects, contrary to common misconceptions, that progressively alter the trajectory of depression, influencing not only symptom severity but fundamental aspects of personality. Indeed, early psychiatrists rightly celebrated antidepressants enthusiastically, considering them revolutionary compared to previously ineffective or harsh treatments. Peter Kramer famously coined the phrase “cosmetic psychopharmacology” to describe antidepressants' potential to enhance an individual's functioning above baseline, even in the absence of clear psychiatric illness.10

However, beyond the small minority of patients who experience transformative results with minimal side effects, antidepressants entail significant and often lasting trade-offs. These medications commonly induce substantial side effects, such as sexual dysfunction (loss of desire, loss of sensation/ numbing, and anorgasmia)—affecting up to 70% of patients depending on the drug—and emotional blunting ("numb", less sadness, but also less joy, love, or excitement), with prevalence rates around 50%.11,12 Even more concerning are withdrawal effects: research indicates approximately 56% of patients experience withdrawal symptoms upon stopping antidepressants, nearly half describing these symptoms as severe and enduring for weeks, months, or sometimes years.13

When evaluating antidepressants, we must clearly acknowledge them as powerful substances capable of profoundly altering brain chemistry, leading to enduring physiological adaptations that do not quickly revert upon discontinuation. While tolerance and physiological dependence are inherent, it is crucial to distinguish this from addiction. Despite their drawbacks, antidepressants remain among the most effective tools we have for alleviating profound suffering and improving long-term mental health and wellbeing..

Looking forward, I am optimistic about the promising avenues in psychiatric research, particularly psychedelic-assisted therapies, which have shown impressive potential to rapidly and persistently alleviate suffering without the significant caveats of current antidepressant treatments.14 Although regulatory and societal obstacles presently limit progress in this domain, growing scientific evidence and public support give reason for cautious optimism. Just as early psychiatrists once touted antidepressants as revolutionary, we may be standing at the shores of another transformation in mental health care, one that moves beyond symptom suppression toward genuine psychological healing. Until we have a broader spectrum of truly transformative therapeutic options, our existing antidepressants remain necessary compromises rather than comprehensive solutions.
 

References
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2. Harmer CJ, O'Sullivan U, Favaron E, et al. Effect of acute antidepressant administration on negative affective bias in depressed patients. Am J Psychiatry. 2009;166(10):1178-1184. doi:10.1176/appi.ajp.2009.09020149
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8. Rutherford BR, Roose SP. A model of placebo response in antidepressant clinical trials. Am J Psychiatry. 2013;170(7):723-733. doi:10.1176/appi.ajp.2012.12040474
9. Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams M. Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry. 2002;159(1):122-129. doi:10.1176/appi.ajp.159.1.122
10. Kramer PD. Listening to Prozac: A Psychiatrist Explores Antidepressant Drugs and the Remaking of the Self. New York, NY: Viking; 1993.
11. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry. 2001;62 Suppl 3:10-21.
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14. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of Psilocybin versus Escitalopram for Depression. New England Journal of Medicine. 2021;384(15):1402-1411. doi:https://doi.org/10.1056/nejmoa2032994