How Antidepressants Work

A neuropsychological story featuring emotional processing shifts, cognitive flexibility, neuroticism, and emotional blunting

It has been recognized for decades by the scientific community that there is no straightforward deficit of serotonin or other monoamines (dopamine, norepinephrine) in depressive and anxiety disorders that is being corrected by antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRIs), which do otherwise increase the levels of monoamines in the synapses between neurons. Nonetheless, the notion that antidepressant medications “correct a chemical imbalance” became a widely accepted explanation among the public and was frequently echoed by physicians. On the other hand, a wealth of actual neuroscientific literature on how antidepressants produce their therapeutic effects has not yet penetrated into public consciousness, perhaps even in the medical community, and skepticism around chemical imbalance explanations has led some people to the other problematic explanations, such as the idea that antidepressants are merely placebos with side effects or that they simply suppress normal and healthy emotions.

The current scientific thinking around how antidepressants work—as illustrated in a recent paper by Page at al. (2024) in Molecular Psychiatry—tends to coalesce around the neuroplasticity hypothesis (antidepressants promote neuroplasticity in the brain) and the cognitive neuropsychological hypothesis (antidepressants decrease the negative bias in the processing of emotionally salient information), with these two mechanisms working in coordination. Brought up less commonly, but otherwise a respectable explanation, is the hypothesis that a reduction in neuroticism mediates clinical improvement with antidepressants. [Peter Kramer’s discussion of the role of neuroticism in antidepressant effect in his books Ordinarily Well (2016) and Listening to Prozac, 30th anniversary edition (1993/2023) is excellent in this regard; for a scientific review, see Soskin et al. 2012.] And in my opinion, emotional blunting continues to be a relevant mechanism as well, although not the primary explanation as some think it is.

In this post I will share a summary of this literature, with a focus on neuropsychological effects of antidepressants (without going into details of receptor actions or changes in activity of brain circuits), and I will discuss how I make sense of these explanations in light of my clinical experience as a practicing psychiatrist. A bibliography of relevant academic sources is at the end of the post for further reading.

An important qualificatory note for general readers: the medications known as “antidepressants” are clinically useful not just in the treatment of depression but in a wide range of conditions, such as anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, anorexia, etc. Any adequate explanation of how antidepressants work should also address why they are helpful in such a broad spectrum of psychopathological states.

Newsweek, 1990. Good ol’ days.

---

Individuals in states of depression and anxiety often show a negativity bias in processing emotionally significant information, and they can be “stuck” in a negative cognitive and emotional state such that their usual mental flexibility is lost. People with depression and anxiety are more likely to interpret neutral or ambiguous facial expressions as negative, such as assuming someone looks sad. They also tend to focus more on negative information and remember it more easily. Additionally, they don’t respond as positively to rewards, have less motivation to seek them out, and are more sensitive to punishment. Individuals not only view the world and themselves negatively but also find it difficult to benefit from positive experiences around them. Depressed people often struggle with cognitive and emotional flexibility and are limited in their ability to switch between emotions and experience a range of emotions.

Shifts in Emotional Information Processing

The cognitive neuropsychological hypothesis suggests that antidepressants lead to early positive changes in emotional processing that predict later clinical improvements. Studies on healthy volunteers who take antidepressants show a shift in emotional processing tasks, such as recognizing emotions in facial expressions, within days, sometimes even after a single dose. Similar effects have subsequently been reproduced in individuals with depression and are also supported by animal studies. SSRIs seem to primarily affect the processing of negative emotions, while norepinephrine reuptake inhibitors have a better impact on how participants respond to positive or rewarding stimuli. 

An important aspect of this hypothesis is that while a positive shift in emotional processing is crucial, it is not necessarily sufficient on its own. The interaction between changes in emotional processing and the environment is vital to improvement. Social interactions allowing individuals to relearn positive emotional associations play a key role. Patients in more positive environments and with stronger social supports are more likely to benefit from these early emotional changes.

In a recent study (Colwell et al., 2024) in which serotonin was directly increased in brain synapses without using SSRIs, people became less sensitive to negative outcomes with more serotonin, and their self-control improved during decision-making. That is, an increase in synaptic serotonin decreases reinforcement sensitivity to loss outcomes and enhances behavioral inhibition and impulse control.¹

Cognitive Flexibility and Neuroplasticity

Shine et al. (2022) hypothesize the role of serotonin as allowing for a switch between modes of “cognitive automaticity” and “cognitive flux.” If a person becomes overly reliant on recurrent, well-established behavioral patterns—behaviors that are increasingly stereotyped and inflexible (such as depressive ruminations and compulsive behaviors)—this could be conceptualized as a state of “cognitive constipation.” Increasing serotonergic activity in such a situation allows for a switch to more flexible modes of cognitive processing. [A patient of mine once described his improvement on an antidepressant as, “It is as if I mentally feel more malleable, better able to identify and move away from unhelpful thinking patterns.”]

Mechanisms of this cognitive flexibility appear to be related to both serotonergic enhancement as well as neuroplasticity. Antidepressants appear to facilitate two key processes: rapid changes in emotional processing along with molecular cascades that promote long-term neuroplasticity.² There is a decent body of literature supporting the idea that antidepressants promote neurotropic signaling, particularly by increasing brain-derived neurotrophic factor (BDNF) and activating the receptor TrkB, which enhances synapse formation and maintenance. The outcome can resemble the flexible state seen in early brain development. Studies in rodents show that environmental interventions alone don’t induce functional changes, but when combined with antidepressants, they can reverse maladaptive behaviors like aggression. Similarly, in humans, antidepressants seem to create a “window of plasticity” that allows environmental factors, such as positive experiences or psychotherapy, to reshape neural activity.³

Effects on Neuroticism

SSRIs appear to reduce neuroticism, a personality trait characterized by emotional instability, negative emotions, and a heightened sensitivity to stress. Neuroticism is closely linked to vulnerability to depression and anxiety, and a reduction in neuroticism appears to be a mediator of antidepressant response.

The effects of neuroticism are well illustrated in a 2009 placebo-controlled trial (n=240) that investigated the effects of an SSRI (paroxetine) on personality traits in patients with major depression. The study compared patients receiving paroxetine, a placebo, or cognitive therapy to examine whether SSRIs specifically influence these personality traits beyond simply improving depressive symptoms.

Patients who took paroxetine experienced significantly greater changes in neuroticism and extraversion compared to those who received a placebo. These personality changes were observed even after accounting for improvements in depression. Patients taking paroxetine showed much larger reductions in neuroticism (6.8 times greater) and increases in extraversion (3.5 times greater) than those on placebo, even when matched for similar depression improvements. While placebo patients experienced substantial reductions in depression, they showed minimal changes in neuroticism and extraversion. Cognitive therapy also led to notable changes in personality traits, particularly neuroticism, though the effect was less distinct once depression improvement was controlled for. In addition, a reduction in neuroticism during SSRI treatment was linked to lower relapse rates among those who responded to paroxetine, but this was not observed among those who responded to cognitive therapy.

This suggests that SSRIs have a specific pharmacological effect on neuroticism, and the effect on neuroticism contributes directly to acute and prophylactic therapeutic effects in treating depression.⁴

Antidepressant effects on neuroticism may be linked to findings from animal models that antidepressants confer “resilience” against stress. In animal models, for example, chronic antidepressant administration can protect against the cognitive and emotional disturbances that result from chronic, unpredictable stress.

Emotional blunting and indifference

It is commonly acknowledged that antidepressants can produce emotional blunting or emotional numbing in a subset of people treated with them. That part is not quite controversial. What is more controversial is the idea that this is not simply an unwanted adverse effect but it is the primary mechanism by which antidepressants produce clinical improvement in mood. Part of the confusion is determining what “emotional blunting” in this context actually refers to. As a subjectively experienced phenomenon, it refers to a restriction in the usual range of emotions. Patient can feel numb, “like a zombie,” emotionally indifferent, or they may lose the ability to cry or feel joy. In a mechanistic sense, however, emotional blunting can also be used to refer to any generalized attenuation of emotional processing regardless of whether the person subjectively feels “numb” or not. In this second sense, we can consider studies such as Langley et al. (2023) in which healthy participants taking escitalopram exhibited lower reinforcement sensitivity, i.e., they were less likely to use the positive and negative feedback to guide their learning of the task versus folks on placebo.

Emotional blunting is commonly reported in many surveys of depressed individuals on antidepressants. Only some people attribute it to their antidepressants. In one survey of 752 patients, 56% thought that their emotional blunting was due to depression, and 45% thought it was because of antidepressants. 39% were considering stopping or had already stopped their antidepressant because of it. Another study reveals that patients are often divided on whether emotional blunting is a good or bad thing: “Among the patients with emotional blunting, 37% had a negative perception of their condition and 38% positive.”

Another hypothesis focuses not on blunting per se but rather on a particular state of cognitive and emotional indifference, manifesting as an attitude of “who cares?” This is how Simon Sobo, a psychiatrist, has described the hypothesis:

“The most frequent description of the effects of SSRIs that I have heard from my patients are “It doesn’t matter.” or “Don’t sweat the small stuff.” or “What’s the big deal?” It is this “Don’t sweat the small stuff” perspective that I believe is SSRIs unique blessing and curse. It means relief from worry, relief from the feeling that something is missing, something needs to be done, something needs to be fixed, “my makeup isn’t right, the sky is falling, I won’t be able to pay my bills, I’m not smart enough, I won’t be able to tolerate the loneliness if I leave my lover” (even if he/she is abusive).

SSRIs supply, if not always happiness, a nice contented feeling that all is well and will be well. They can allow parents to be able to play with their children more, fret less over the details, appreciate what is, actually want to do the proverbial modern mantra, stop and smell the roses. They are the answer to existential angst…

On the other side of the equation, I have a psychiatrist colleague who took Prozac to relax and enjoy his vacation. It worked very well. He told me that he tried it at home when he returned. He quickly stopped it when he found himself thinking, “Who cares?” when his patients described their problems.

According to this theory it is the “well whatever” feeling, emotional blunting, that is so useful in the great variety of different syndromes.”

Another psychiatrist on Substack (@

AffectiveMedicine

) has recently made the case that serotonin as an emotional inhibitor is a parsimonious way of explaining various clinical and research findings. The focus of the explanation is not necessarily on “blunting” or “numbing” per se in the phenomenological sense, but in the mechanistic sense.

“Here are specific ways I can imagine serotonin affecting an emotion circuit:

1. Raise the threshold for activation (wider deadband)

2. Add lag or delay

3. Lower the gain of the response

4. Dampen the whole system

5. Reduce noisy input via a low-pass filter effect

I see arguments for all of these. I like the idea of serotonin reducing noise, because this fits the apparent use of SSRIs in reducing worry (noise from the future), rumination (noise from the past), and hypervigilance (noise from the present). On the other hand, a wider deadband fits really well with the unique efficacy of serotonergic meds for OCD, a disorder of repetitive thoughts and behavior that resembles a thermostat hunting its setpoint in repeated activation-deactivation cycles. But surely there are different effects at different receptors, and this is all complicated.”

“We view this as a side-effect, rather than the therapeutic effect, only because it’s undesirable. They are inseparable, though, like a beta-blocker medication to lower heart rate that also makes it harder to exercise. One follows from the other.”

Our friend also astutely observes:

“I suspect researchers and psychiatrists are reluctant to make the argument since “SSRIs actually do numb emotions” is unappealing, and the handful of researchers with this position are viewed as distasteful.”

That SSRIs can help by generally attenuating emotions without a person subjectively feeling numb is similar to how benzodiazpines can be CNS depressants that can leave a person feeling calm without necessarily feeling sedated.

The challenge for the emotional blunting hypothesis is that—unlike the cognitive neuropsychological hypothesis or the neuroticism hypothesis—clinical studies that have examined this issue have not found any evidence that subjective report of emotional blunting actually mediates or predicts clinical improvement with antidepressants. For a review of these studies, see Dawson and Pies (2022) in Psychiatric Times.

Nonetheless, it remains plausible—given available neuropsychological evidence of reduced reinforcement sensitivity and the fact that some people perceive their emotional blunting to be beneficial—that for some people, a generalized attenuation of emotional reactivity that is not severe enough to be subjectively distressing or unpleasant can be a mechanism of clinical improvement, by itself or in coordination with other mechanisms.

---

What to make of all this?

We have several contender processes within the cognitive-psychological-behavioral domain that potentially explain or account for the therapeutic effects of SSRIs across a range of clinical conditions. They are:

1. A positive shift in emotional processing (which allows individuals to relearn positive emotional associations in a suitable social environment)

2. An increase in emotional and cognitive flexibility—a behavioral correlate of neuroplasticity—that allows people to become “unstuck” from inflexible behavioral patterns.

3. Reduced neuroticism, which correlates with clinical improvement and predicts subsequent relapse prevention (depression also improves with placebo but without the reduced neuroticism).

4. A generalized inhibition of emotional responses across the board, or a reduced sensitivity to reinforcements, generating a state that can be described as emotional blunting, emotional indifference, or emotional thick skin. Depending on the severity, the context, and the nature of the problem, this may be described either as therapeutic effect or as a side-effect.

I believe that all of these capture a piece of the puzzle of what is happening clinically.

One of the most fascinating and frustrating things to observe in the clinic is the remarkably diversity of ways in which different people respond to different antidepressant medications.⁵

It is clinically very obvious that a subgroup of depressed and anxious patients demonstrates a substantial and sustained response to antidepressants. This group appears to be the one in which positive effects on emotional processing, cognitive flexibility, and neuroticism are all experienced, and they are experienced in a mutually-enhancing manner. Because emotional processing changes happen quickly within days, these patients often start noticing signs of improvement in their emotional outlook within days.

Patients whose depression is characterized by greater psychomotor and cognitive symptoms and low baseline neuroticism rarely demonstrate a quick response to antidepressants in my clinical experience. Response to antidepressants is often painfully slow, perhaps because neuroplastic changes have to slowly produce therapeutic effects without a synergistic boost from emotional processing shifts or improvements in neuroticism. Greater cognitive flexibility seems more relevant as a mechanism of improvement in conditions such as OCD, hypochondriasis, and anorexia as well, where improvement takes time. Serotonergic antidepressants are described as having more of an effect on emotional processing of negative emotions but have less of an effect on reward processing (which may require actions on norepinephrine and dopamine), and certain depressive states may be characterized more by impairments in reward processing.

Patients who experience a notable reduction in neuroticism also seem to be the ones that show the most clear benefit with on-going antidepressant treatment beyond the acute phase. Treating high neuroticism is in some ways like treating chronic pain; it is not “episodic.” Baseline neurotic traits resurface as soon as patients go off antidepressants, and patients are often unwilling to tolerate their neurotic selves once they have had a reprieve on medication.

I suspect that at a certain ‘threshold’ serotonin loses whatever specificity it possess in terms of emotional processing and begins to inhibit emotions in an indiscriminate manner. This indiscriminate inhibition can nonetheless be therapeutic for some people. In patients with high emotional reactivity, a generalized attenuation of emotions can be quite helpful and welcome. In other patients, emotional inhibition is experienced not as “blunting” or “numbing,” but as psychological “indifference.” These patients would not say that they feel blunted or numbed, but rather they seem to care less about things and are not bothered easily. This sort of effect can be helpful in the short term but is generally unwanted in the long run (a patient once told me, “Looking back, I think I got divorced because I was on Lexapro; I just stopped caring.”). It is common for me to see highly anxious and distressed patients respond well to antidepressants and then for them to realize several weeks later that they have been numb or indifferent in ways they had not previously recognized. People who experience benefit from antidepressants due to emotional inhibition generally do not stay on antidepressants very long, or if they do, they find the experience to be a mixed blessing.

The clinical challenge here is that we do not know in advance what effect any particular patient will get from an antidepressant. They could experience cognitive flexibility, reduced neuroticism, emotional indifference, or nothing at all. To make matters complicated, patients often experience paradoxical reactions⁶ in the form of worsening of anxiety, dysphoria, depression, agitation, and even suicidality. The systems regulated by monoamines apparently can easily swing in the other direction when perturbed.⁷ The experience also varies from medication to medication. I am often surprised by how a person may get dysphoric on, say, Lexapro, only for them to do remarkably well on Zoloft (or vice versa), or a person may experience emotional blunting on Prozac but experience reduced neuroticism on Cymbalta.

These broad effects also help explain why “antidepressants” are not just “antidepressants” and why they are clinically useful in a wide range of problems. The therapeutic value of shifts in emotional processing, cognitive flexibility, reduced neuroticism, reduced impulsivity, and emotional indifference cuts across diagnostic boundaries. We have clinical rationales for broad applications of these medications, but the practical reality is that they don’t help everyone. In the clinic, this often means an attitude of “let us try and see what happens,” which requires tremendous clinical humility and caution. In a psychiatric setting, prescribing an antidepressant is rarely straightforward and the boundary between therapeutic benefit and iatrogenic harm is razor-thin.

---

See also:

The Case for Antidepressants in 2022

30 Years of Listening to Prozac: A Discussion with Peter Kramer

Serotonin strikes back

---

Bibliography

• Page, C. E., Epperson, C. N., Novick, A. M., Duffy, K. A., & Thompson, S. M. (2024). Beyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder. Molecular Psychiatry, 1-12.

• Godlewska, B. R., & Harmer, C. J. (2021). Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment. Psychopharmacology, 238(5), 1265-1278.

• Colwell, M. J., Tagomori, H., Shang, F., Cheng, H. I., Wigg, C. E., Browning, M., ... & Harmer, C. J. (2024). Direct serotonin release in humans shapes aversive learning and inhibition. Nature Communications, 15(1), 6617.

• Soskin, D. P., Carl, J. R., Alpert, J., & Fava, M. (2012). Antidepressant effects on emotional temperament: toward a biobehavioral research paradigm for major depressive disorder. CNS Neuroscience & Therapeutics, 18(6), 441-451.

• Langley, C., Armand, S., Luo, Q., Savulich, G., Segerberg, T., Søndergaard, A., ... & Sahakian, B. J. (2023). Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomised study. Neuropsychopharmacology, 48(4), 664-670.

• Shine, J. M., O’Callaghan, C., Walpola, I. C., Wainstein, G., Taylor, N., Aru, J., ... & John, Y. J. (2022). Understanding the effects of serotonin in the brain through its role in the gastrointestinal tract. Brain, 145(9), 2967-2981.

• Tang, T. Z., DeRubeis, R. J., Hollon, S. D., Amsterdam, J., Shelton, R., & Schalet, B. (2009). Personality change during depression treatment: a placebo-controlled trial. Archives of general psychiatry, 66(12), 1322-1330.

• Goodwin, G. M., Price, J., De Bodinat, C., & Laredo, J. (2017). Emotional blunting with antidepressant treatments: a survey among depressed patients. Journal of affective disorders, 221, 31-35.

• Sobo, S. A Reevaluation of the Relationship between Psychiatric Diagnosis and Chemical Imbalances.

• Dawson, G., & Pies, R. W. (2022). Antidepressants Do Not Work by Numbing Emotions. Psychiatric Times.

---

1. I am not going into further discussion of this, but enhanced behavioral inhibition and impulse control are another mechanism of clinical improvement. They are often hard to distinguish amidst other improvements in mood and anxiety, but they become evident in situations such as impulse control disorders, borderline personality disorder, substance use disorders, and dementias. Overall, based on my clinical guess, I would rate this mechanism of antidepressant action as weaker and infrequent compared to effects on emotional processing and cognitive flexibility.

2. It is unclear to what extent neuroplasticity changes depend on monoamine actions. Some researchers argue that neuroplasticity effects are independent. As Peter Kramer notes, it is rather implausible that diverse agents selected on the basis of their serotonergic action also just happen to independently promote neuroplasticity. “It is strange that drug developers should have gotten so lucky. They aimed to influence one active factor in the brain, and they influenced two. Better yet, the two work synergistically.” (Listening to Prozac, 30th anniversary edition, page 322)

3. It remains unclear what happens when antidepressants enhance neuroplasticity in negative environments, especially environments that may promote maladaptive learning!

4. Improvements in neuroticism could be one possible reason why so many real-world patients with bipolar disorder find antidepressants to be helpful for their mood, even though RCTs struggle to show superiority of antidepressants to placebo in bipolar depression.

5. This may partly be because their social learning environments are so different (see footnote #3)

6. For example, SSRIs tend to reduce amygdala reactivity to fearful faces, but in one study, in patients with high neuroticism, they increased amygdala reactivity, which may possibly related to increased anxiety and agitation as side-effects early in treatment.

7. This perhaps manifests as inconsistent results across different studies. From Colwell et al, 2024: “For example, several studies report seemingly contradictory effects of SSRIs on tasks of aversive and reward processing (reinforcement learning); specifically, different reports show that SSRIs increase reward sensitivity, increase loss sensitivity and decrease reward sensitivity, and decrease sensitivity to both reinforcement valences. Inconsistent behavioural effects of SSRIs are also observed across other domains, including behavioural inhibition and memory processing; in some cases, these behavioural changes align with those seen after tryptophan depletion (e.g., reduced cognitive flexibility) despite the expectation that they would have opposing effects on net synaptic 5-HT.”