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Recent evidence from randomized, placebo controlled trials (1979 to 2016) has shown that, in about 15% of patients with depression, antidepressant treatment is robustly superior to placebo—contrary to the often-repeated claim that 

 are “not much better than a sugar pill.”

 It is not yet clear what clinical or biological features make this subgroup so antidepressant-responsive, although differences between drug and placebo increased significantly (P<0.001) with greater baseline severity of depression.

Perhaps if we had a better understanding of antidepressants’ mechanisms of action—and how these mechanisms interact with this drug-responsive subgroup—we would be better able to predict which patients are likely to do well on antidepressants. Unfortunately, the matter is further complicated by the marked heterogeneity of 

 (MDD), which almost certainly contains several biological subtypes.

Critics of antidepressant treatment sometimes argue that antidepressants work—to the extent that critics acknowledge they work—by “numbing” or “blunting” emotions. Thus, Moncrieff has hypothesized that “Antidepressant-induced emotional numbness may directly reduce the intensity of people’s feelings of depression.”

 Similarly, Moncrieff and Horowitz have argued that

“…antidepressants appear to have a generalized emotion-numbing effect which may influence people’s moods, although we do not know how this effect is produced or much about it…[but] if antidepressants exert their effects as placebos, or by numbing emotions, then it is not clear that they do more good than harm.”

A recent review provided a much more nuanced picture, concluding that

“Emotional blunting has been reported by many patients diagnosed with MDD, but its neuropsychological basis remains indefinite. Most patients specifically attribute this symptom to their antidepressant medication; however, some psychologists believe that emotional blunting is also a residual symptom of depression due to incomplete treatment.”

In this article, we examine 3 independent studies of antidepressant treatment in major depression and its effects on emotional numbing or blunting. The key difference between 2 of these studies and much of the critical writing about antidepressants is their use of the 

Oxford Questionnaire on the Emotional Side-effects of Antidepressants

 (OQESA or OQuESA)—arguably the “gold standard” of assessment in this area.

 (This scale is now called the Oxford Depression Questionnaire, or ODQ.)

We shall see that none of the studies support the claim that antidepressants act to reduce depression through a process of emotional blunting or “numbing.” This is not to deny the clinical importance of assessing emotional blunting in the course of antidepressant treatment, nor is it to discount in any way the patient’s felt experience during treatment.

A Randomized-Controlled Study from France

Corruble and colleagues carried out a randomized, controlled, double-blind study comparing agomelatine (25-50 mg/d, n=164) and the SSRI, escitalopram (10-20 mg/d, n=160).

 Agomelatine is an atypical antidepressant that acts as an agonist to the melatonin receptors MT1 and MT2 and an antagonist of the serotonin receptors 5HT2B and 5HT2C. It is not approved for use in the United States. [

https://www.psychiatryadvisor.com/home/depression-advisor/unique-attributes-of-agomelatine-might-renew-interest/]

The trial involved 12 weeks of active treatment, then a 12-week double-blind extension. The effects of these drugs on emotional experiences were compared in patients who completed the OQESA (agomelatine: n= 25; escitalopram: n= 20). Agomelatine and escitalopram similarly improved depressive symptoms, but emotional blunting was reported by 60% of patients taking escitalopram, versus 28% of those taking agomelatine.

At baseline before antidepressant treatment, the emotional experiences probed were extremely common and the same in both treatment groups. Of 20 OQESA items, 8 were more common in the escitalopram group and 12 in the agomelatine group. The occurrence of blunting items was associated with the depressed state measured by the Hamilton Depression Scale (HAMD) and Clinical Global Impression (CGI). Emotional blunting was significantly less prominent after 2 weeks, 12 weeks, and 24 weeks of treatment. At 24 weeks, emotional blunting was endorsed more frequently in the escitalopram group than in the agomelatine group, despite similar depression ratings in the 2 groups.

The authors concluded that “emotional blunting is prominent among patients with MDD at baseline” and hypothesized that emotional blunting “…behaves overall like a correlate of depressive symptoms.”

“The simplest explanation for our present findings is that emotional blunting is a symptom of depression not measured in conventional scales, which is incompletely treated with SSRIs as compared with agomelatine.” 

In short, the study findings provide no support for the claim that antidepressants act by a generalized emotion-numbing effect.

Two More Studies Reach Similar Conclusions

In a 16-week study of 98 patients diagnosed with MDD, Aşçibaşi et al analyzed the effects of antidepressant treatment (SSRI, n = 41; SNRI, n=40, other, n=13) on Montgomery-Åsberg Depression Rating Scale (MADRS) and OQESA scores.

 The OQESA scale was used at the 8- and 16-week visits. In brief, the study found that 

as the rate of remitted patients is increased, OQESA scores get decreased; 

and furthermore, the OQESA score of the remitted group was statistically low when compared with that of the nonremitted group at the 8- and 16-week visits. OQESA and MADRS scores were significantly correlated in all assessments. The authors opined that “…during the treatment of depression, depression-related emotional blunting symptoms and antidepressant-related emotional adverse effects may coexist”; however, “…as the severity of [the] depressive syndrome decreases, the severity of emotional adverse effects due to the antidepressants also decreases.”

These findings are not consistent with the claim that 

 reduce depressive symptoms via an emotion-numbing effect.

Finally, Peters et al analyzed data from adult outpatients with acute MDD who participated in 3 8-week randomized controlled trials.

 Trials 1 and 2 were pooled (venlafaxine, n = 378; bupropion, n = 389; placebo, n = 383), and Trial 3 (escitalopram, n = 254; bupropion, n = 260) was analyzed separately. Emotional blunting was measured with the “inability to feel” item from the MADRS. The study found that emotional responsiveness 

, on average, in all treatment groups, and that fewer than 6% of participants experienced more emotional blunting after antidepressant treatment. The authors acknowledged that this was a short-term study that cannot speak to the long-term effects of antidepressant treatment. Nonetheless, they concluded that, “The study medications did not significantly decrease emotional responsiveness, and there was no evidence that emotional blunting mediated treatment response.” Rather—and consistent with the previous 2 studies—the authors hypothesized that “In acute treatment, emotional blunting may be better conceptualized as a residual symptom than as an adverse drug effect.”

Some Important Caveats and Study Limitations

 highlight the methodological advantages and limitations of the research discussed in this article. The Peters et al study has the highest-quality evidence, using completed controlled clinical trials, with a substantial number of research participants in each arm, including the placebo group.

 The study also uses the most neutral screen for emotional blunting, in that there is no suggestion of what might be the cause.

 both use the OQESA/ODQ, which was designed to measure more than emotional blunting and has a separate section to determine if the patient endorses emotional blunting to be caused by antidepressant treatment. The wording of the questions—and the fact that no other possible etiology for emotional blunting is suggested in the remainder of the questionnaire—is a potential source of bias. In this case, the participants are forced to choose antidepressants as an etiology. In effect, this is a “leading question,” and research participants may be able to guess that antidepressant induced emotional blunting is a focus of the research.

 In contrast, MADRS Item 8 captures emotional blunting but does not suggest a specific cause.

Emotional numbing or blunting is a fairly common complaint among patients taking serotonergic antidepressants and appears less common with noradrenergic/dopaminergic agents like 

 It is important to inform and educate patients about this problem and to inquire about it periodically, since emotional blunting is both distressing and associated with poor adherence to antidepressant treatment.

 However, it should not be assumed that the patient’s antidepressant is necessarily 

 of the patient’s complaint, since emotional blunting or numbing is frequently reported at baseline (prior to treatment).

Indeed, the studies reviewed here show that antidepressants did 

 significantly decrease emotional responsiveness, and that treatment response was 

 mediated by emotional blunting. More likely, emotional numbing, in most cases, is a residuum of the original depression.

How, then, do antidepressants work? Their precise mechanism of action is not fully understood, although recent studies point to the role of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which is now regarded as “… a key player in antidepressant action.”

 Antidepressants may also have anti-inflammatory effects—potentially important, since major depression is associated with elevated biomarkers of inflammation.

 During the past 4 years, 2 antidepressants modulating the glutamate system have been approved by the US Food and Drug Administration (FDA) for the treatment of major depression.

 Evidence supporting a role for stress, GABAergic dysfunction, altered neurosteroid signaling, and HPA axis dysregulation in 

 may suggest a role, in the near future, for neuroactive steroids in the treatment of depression.

In summary, there is no credible, scientific basis for telling patients that antidepressants are acting by means of generalized emotional numbing. On the contrary, our review shows that several antidepressants are actually associated with 

 of emotional numbing during the course of treatment. That said, if emotional blunting is convincingly related to use of a serotonergic antidepressant, changing to a noradrenergic/dopaminergic agent is a viable option for many patients.

 is recently retired from clinical practice and is a freelance writer and researcher on psychiatric topics. He writes the Real Psychiatry Blog. 

 is professor emeritus of psychiatry and a lecturer on bioethics and humanities at SUNY Upstate Medical University in Syracuse, New York; a clinical professor of psychiatry at Tufts University School of Medicine in Boston, Massachusetts; and editor in chief emeritus of 

(2007-2010). He is the author of several books. A collection of his works can be found on Amazon.

Dr Pies would like to thank Dr Marc Stone, Dr Randall Moore, and Prof Cathryn Lewis for their helpful email comments on aspects of this article. Thanks to Dr John J. Miller for suggestions re: mechanism of action. The views presented here are solely those of the authors. 

1. Stone MB, Yaseen ZS, Miller BJ, et al. 

Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis.

Unpacking major depressive disorder: from classification to treatment selection.

Against the stream: antidepressants are not antidepressants – an alternative approach to drug action and implications for the use of antidepressants.

4. Moncrieff J, Horowitz M. Depression is probably not caused by a chemical imbalance in the brain – new study. 

. July 20, 2022. Accessed September 22, 2022. 

https://theconversation.com/depression-is-probably-not-caused-by-a-chemical-imbalance-in-the-brain-new-study-186672

Emotional blunting in patients with major depressive disorder: a brief non-systematic review of current research.

The Oxford Questionnaire on the Emotional Side-effects of Antidepressants (OQuESA): development, validity, reliability and sensitivity to change.

7. Corruble E, de Bodinat C, Belaïdi C, Goodwin GM; agomelatine study group. 

Efficacy of agomelatine and escitalopram on depression, subjective sleep and emotional experiences in patients with major depressive disorder: a 24-wk randomized, controlled, double-blind trial.

8. Aşçibaşi K, Çökmüş FP, Dikici DS, et al. 

Evaluation of emotional adverse effects of antidepressants: a follow-up study.

Emotional blunting with bupropion and serotonin reuptake inhibitors in three randomized controlled trials for acute major depressive disorder.

11. Goodwin GM, Price J, De Bodinat C, Laredo J. 

Emotional blunting with antidepressant treatments: a survey among depressed patients.

BDNF - a key transducer of antidepressant effects.

13. Tynan RJ, Weidenhofer J, Hinwood M, et al. 

A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia.

The effect of glutamatergic modulators on extracellular glutamate: how does this information contribute to the discovery of novel antidepressants?

The novel rapid-acting neurosteroid-based antidepressant generation.

A new depression scale designed to be sensitive to change.

As patients improve with antidepressant treatment, emotional numbing decreases.

Antidepressants Do Not Work by Numbing Emotions

Partial or inadequate response to antidepressants—whose mechanisms primarily involve monoamine pathways—are common.

 Multiple lines of evidence suggest that the glutamatergic system is also involved in the pathophysiology of 

. Dextromethorpahn is a N-methyl-D-aspartate receptor antagonist and a sigma-1 receptor agonist, both of which modulate glutamate neurotransmission. The clinical utility of dextromethorphan is limited by extensive CYP2D6 metabolism.

 AXS-05, an oral tablet that combines dextromethorphan and bupropion, is formulated to increase the bioavailability and half-life of dextromethorphan through inhibition of its metabolism by bupropion, and is under development for the treatment of 

 performed a phase 2, 6-week randomized double-blind active-controlled trial of AXS-05 in MDD at 4 sites in the US. They specifically used confirmation of disease severity through independent assessment and comprehensive blinding of trial sites to address factors that may contribute to poor signal detection in clinical trials.

 They included patients aged 18-65 with DSM-5 MDD and a current moderate or severe major depressive episode. Subjects had a score ≥ 25 on the Montgomery-Åsberg DepressionRating Scale (MADRS) and a score ≥ 4 on the ClinicalGlobal Impressions severity scale (CGI-S). Exclusion criteria were bipolar disorder, panic disorder, OCD, treatment-resistant depression (≥ 2 failed antidepressant trials in the current episode), substance use disorder in the past year, lifetime history of psychotic disorder, clinically significant suicide risk, and history of seizure disorder. Participants were randomized 1:1 to either dextromethorphan-bupropion (45 mg/105 mg) or bupropion (105 mg) once daily for 3 days then twice daily thereafter.

The primary efficacy variable was the change from baseline to week 6 in the MADRS total score. Secondary endpoints were clinical response (≥ 50% reduction in MADRS total score) or remission (MADRS total score ≤ 10), CGI-S and CGI-Improvement scores, scores in the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), and MADRS-6 score. Study patients also tracked their mood daily with a visual analogue mood scale. The study safety population included all patients who received at least 1 dose of study medication. The efficacy population included all patients with illness severity confirmed by the independent assessor who were randomized, received at least 1 dose of study medication, and had at least 1 postbaseline assessment. Efficacy variables assessing a change from baseline were analyzed using mixed models with repeated measures. Those efficacy variables related to percentages were analyzed by chi-square tests.

The authors randomized 97 patients, of whom the independent assessment failed to confirm diagnosis or severity for 17 patients, resulting in 80 patients. Seventy-four of the 80 patients completed the trial. Mean treatment adherence was > 90% in both groups based on tablet counts. There were nonsignificantly more women, Black or African American, and Hispanic or Latino patients in the bupropion group (p > 0.15 for each). Dextromethorphan-bupropion was associated with significantly greater reduction in MADRS scores versus bupropion (-13.7 versus -8.8 points, effect size = 1.2), with statistically significant differences beginning at week 2. Response (60.5% versus 40.5%) and remission (46.5% versus 15.2%) at week 6 was significantly more likely in the dextromethorphan-bupropion group. Dextromethorphan-bupropion was also associated with significantly greater improvement on the CGI-S scale (-1.6 versus -1.0). The prevalence of any adverse events was 73% in the dextromethorphan-bupropion group and 65% in the bupropion group. The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, dry mouth, decreased appetite, and 

. There were no serious adverse events in the trial. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, sexual dysfunction, increased suicidality, or significant changes in laboratory parameters and vital signs.

The authors concluded that AXS-05 showed rapid, substantial, and statistically significant antidepressant efficacy compared to the active comparator on multiple clinician- and patient-reported measures of depression severity. A primary strength was the use of bupropion (at an identical dose to AXS-05) as the active comparator. Study limitations include exclusion of patients with lower levels of symptom severity and other psychiatric or medical comorbidities. Thus, findings from efficacy trials may not be mirrored in general practice. Another limitation is the short duration of the trial (6 weeks).

This study demonstrates that dextromethorphan-bupropion significantly improves depressive symptoms compared to bupropion and was generally well tolerated. This combination represents a novel pharmacologic approach to the treatment of MDD.

is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

1. Machado-Vieira R, Henter ID, Zarate CA Jr. 

New targets for rapid antidepressant action.

Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers.

4. Tabuteau H, Jones A, Anderson A, et al. 

Effect of AXS-05 (Dextromethorphan-bupropion) in major depressive disorder: a randomized double-blind controlled trial.

5. Freeman MP, Pooley J, Flynn MJ, et al. 

Guarding the gate: remote structured assessments to enhance enrollment precision in depression trials.

A new—cough, cough—combination treatment for depression. Researchers performed an RCT of dextromethorphan-bupropion in major depressive disorder.

Dextromethorphan-Bupropion in Depression

Serotonin is a ubiquitous neurotransmitter that has earned its reputation as a highly significant molecule in humans that lies at the center of a diverse range of functions. When Vittorio Erspamer first discovered serotonin—which he initially named enteramine—in 1935, he demonstrated that it was produced by enterochromaffin cells, which are endocrine cells adjacent to the lining of the gastrointestinal tract. When released, enteramine increased motility and secretions of the intestines.

At Cleveland Clinic in 1948, 3 researchers discovered a molecule released by platelets in the blood that facilitated vasoconstriction, helping facilitate blood clotting and decrease blood loss. They named this molecule serotonin, which is Latin for 

. Finally, in 1952, it was confirmed that enteramine and serotonin were the same molecule.

Although it is often referred to as serotonin today, its official chemical name is 5-hydroxytryptamine (5-HT). Serotonin is one of several molecules collectively called monoamines, which also include norepinephrine, dopamine, and histamine.

Serotonin is localized in 3 primary systems in the human body, with 90% of it in the enterochromaffin cells in the gastrointestinal tract, 8% in platelets, and the remaining 2% in the central nervous system. Serotonin’s presence in these 3 diverse body systems tells a powerful story about how this single molecule ultimately integrates disparate systems to increase survival of the organism. If you were to eat a toxic substance, the enterochromaffin cells in your gastrointestinal tract would secrete serotonin, which would then agonize the numerous 5HT-4 receptors throughout the gut, which results in increased gastrointestinal motility and secretions. The wisdom of the body wants to get that toxic substance out as quickly as possible.

The increased serotonin diffuses into the vasculature where platelets—which cannot synthesize the vasoconstricting serotonin on their own—use serotonin transport pumps to fill their serotonin vesicles and remove this excess serotonin from the blood at the same time. However, if that toxic substance raises a red alert, the platelets’ serotonin transport pumps get saturated with serotonin, and the blood serotonin levels rise to an abnormal level. As this blood perfuses the brain, the increased serotonin will agonize the 5HT-3 ionotropic receptors in the chemoreceptor trigger zone, which induces vomiting. The serotonin thus facilitates expulsion of the toxin from both ends of the gastrointestinal tract, increasing the likelihood of surviving the ingestion of this toxin.

This example is a microcosm of the massive macrocosms of circuitry that serotonin orchestrates. Serotonin’s activity in the gastrointestinal tract and platelets is straightforward and well established. When we attempt to understand serotonin’s detailed functioning in the brain, the mountains of information that exist give us a few clues here and there. Ultimately, we are not yet smart enough to map out the system, and all the interfaces serotonergic pathways share with the other neuronal circuits and neurotransmitters.

The brain directs its serotonergic pathways starting at the raphe nuclei in the brain stem. Serotonin has been shown to have some involvement in complex processes, including mood, anxiety, sleep, circadian cycles, cognition, thermoregulation, sexual drive, and appetite.

Often in science, as we peel away the layers of the knowledge onion, we simply discover new layers. During the 1930s and ‘40s, the serotonin story began by simply identifying the molecule and discovering a few of its simple properties—increasing intestinal motility/secretions and being released by platelets trying to stop a bleed by helping out with vasoconstriction. The next step was to figure out how serotonin fit into these physiologies, and good basic science discovered the serotonin transport pump on the surface membrane of the platelets and a serotonin receptor in the gastrointestinal tract.

Over the next 4 decades, the receptor part of serotonin’s story exploded, ultimately discovering 7 different families of serotonin receptors, with many families having subfamilies, allowing for heterogeneity of function. The 5HT-7 family was discovered in 1993, and the full sequencing of the human genome in 2003 increased our confidence that we had a basic understanding of the divergent serotonin receptors.

Intensive pharmaceutical research has developed serotonergic receptor-specific drugs with mechanisms of action that fit with what we currently know about this complex system (

Ondansetron, a 5HT-3 receptor antagonist, is an effective antiemetic. Tegaserod, a 5HT-4 agonist, effectively treats constipation (although it has recently been withdrawn from the US market). The many triptans for the treatment of migraine headaches agonize the 5HT-1 B and D receptors, putatively treating the headache through vasoconstriction. The hallucinogens psilocybin, LSD, and mescaline induce a dramatic effect on one’s perception of reality by agonizing the 5HT-2A receptor. The 5HT-2C agonist lorcaserin is associated with weight loss. And the 5HT-2B agonists fenfluramine and pergolide cause cardiac valve fibrosis. Additional discoveries helping us understand the complexity of serotonin’s biography continue to emerge (

Serendipity has been a good friend to science, and such was the case in our early research into treating major depressive episodes. In 1952, at Sea View Hospital on Staten Island, New York, Hoffman-LaRoche were studying 2 novel antituberculosis drugs—isoniazid and iproniazid—to treat infected patients. In addition to effectively treating the tuberculosis, the physicians observed significant improvements in the patients’ mood, appetite, and sense of well-being. Iproniazid was subsequently shown to be a potent inhibitor of the enzyme mono-amine oxidase, which results in increased levels of serotonin, norepinephrine, and dopamine in the pre-synaptic neurons, and was approved by the US Food and Drug Administration (FDA) as the first antidepressant in 1958. In 1959, imipramine, derived from an antihistamine, was the second FDA-approved antidepressant.

Imipramine, along with other properties, inhibits the presynaptic transport pumps in neurons that recycle serotonin and norepinephrine from synapses back into the pre-synaptic neuron, resulting in a global increase of these neurotransmitters in their corresponding synapses. Although through different mechanisms, iproniazid and imipramine shared the properties of increasing brain levels of both serotonin and norepinephrine (and dopamine with iproniazid).

 drug development research that followed in subsequent decades resulted in an armamentarium of drugs that by different mechanisms altered some part of the complex pathways of serotonin, norepinephrine, or dopamine. However, throughout these decades, research tirelessly pursued other potential drug candidates as well, realizing that 

 is a complex syndrome with countless synergizing factors, including all dimensions of the biopsychosocial elements of human life.

 is a partial list of the wide range of treatments that have been shown to improve depression, either alone or in various combinations.

In the field of psychopharmacology, current research has focused on the role of the glutamate system in contributing to this complex puzzle. Synaptogenesis and neuroplasticity—2 properties critical to brain health, adaptation, and learning—can be enhanced by most of the items listed in Table 3, and by much more.

Through clinical observations, drugs that specifically blocked serotonin transport pumps showed a signal that in some cases this mechanism could improve anxiety. The FDA approved clomipramine in 1989 as the first drug for the treatment of obsessive-compulsive disorder (OCD). Clomipramine was synthesized by adding a chlorine atom to imipramine, which had the effect of increasing the binding at the serotonin transport pump relative to the norepinephrine transport pump in comparison to the other tricyclic antidepressants. The only other drugs that are FDA approved for OCD are the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline, paroxetine, and fluvoxamine.

Significantly, the most effective treatment for OCD is a cognitive behavioral treatment called exposure/response prevention. However, early in treatment, or for patients who are not interested in psychotherapy to improve their OCD symptoms, SSRIs remain the first-line medications. SSRIs have also demonstrated efficacy for other anxiety disorders including panic disorder, social anxiety disorder, and posttraumatic stress disorder, with at least 1 SSRI having FDA approval for these anxiety disorders. However, psychotherapy ideally should also be part of the treatment plan.

Not surprisingly, despite the initial excitement in psychiatry during the SSRI explosion in the 1990s, it became clear that raising synaptic serotonin levels could only help some of our patients some of the time, and with a wide range of symptom improvement. Pharmacologically, the SSRIs are blocking all serotonin transport pumps (AKA reuptake pumps) throughout the entire human body, resulting in ubiquitous elevation of serotonin levels everywhere. With the serotonin transport pump being a simple and basic component of the complex serotonin system, increased serotonin levels result in agonism of all 7 families (as well as the many subfamilies) of serotonin receptors.

Our understanding of the impact of this is rudimentary and mostly derived by patient-reported effects. Many of the common adverse events from SSRIs are likely due to the collateral effects on serotonin receptors, in which increased agonism would ideally be avoided. Additionally, blocking the serotonin transport pumps on platelets depletes platelet serotonin, decreasing the platelets’ ability to use serotonin for vasoconstriction at a bleed, hence increasing the body’s bleeding time—a well-established result of SSRI use. To come full circle with the discovery of serotonin, SSRIs result in agonism of the 5HT-3 and 5HT-4 receptors, increasing the adverse events of nausea/vomiting and gastrointestinal cramping/diarrhea, respectively, and decreasing the vasoconstriction component of how platelets stop a bleed.

In addition to the serotonin transport pump and the numerous and diverse serotonin receptors, there are many other targets that have been studied in an attempt to develop drugs to treat various psychiatric disorders targeting the serotonin system. These include precursors and enzymes involved in serotonin’s metabolic pathway, storage in presynaptic vesicles, and metabolic breakdown. Without a doubt, science, medicine, and psychiatry have learned a great deal about the serotonin system since its discovery in 1935. (A gross simplification of 2 serotonin neurons with a synapse between them is available in the 

 in the brain remains a mystery. For that matter, the etiology to most disorders of the brain in psychiatry and neurology await continued discoveries. However, it really should be no surprise. In my medical school training in the 1980s, we called the brain a black box. We were taught that the brain is fully wired at birth. We did not believe neuronal stem cells existed. Neuroplasticity and synaptogenesis were not yet part of our basic curriculum. Epigenetic, and even genetic, contributors were shrouded in darkness. The biopsychosocial model of psychiatric disorders was well established, but still in its infancy. All in all, it seems to me we are right where we should be: We know a little bit, but we do not know a lot.

The human brain has 80 billion neurons on average. Each neuron has a synaptic connection to roughly 10,000 other neurons. Hence, our brains have roughly 800 trillion synaptic connections. Wrap your brain around that number. It would be naïve to believe that targeting a single neurotransmitter, receptor, or circuit in the brain will cure any psychiatric or neurological disorder. However, we would be remiss if we did not try.

Over the years, decades, and ultimately centuries, our mission is to continue to expand our knowledge of the brain and utilize the tools that we do have at any point in time. As with all good medicine, we will continue to weigh and discuss the risks and benefits with each of our patients, allowing them to make informed decisions as to their preferred treatment plans.

The future of psychiatry is exciting. I am awed by the biography of serotonin that has been written since its discovery in 1935. Yet serotonin is but one letter in the encyclopedia of how the brain works—making a presence on page 1, but humbled by all that is still to be discovered.

is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, 

; Staff Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Exeter Hospital, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

Antidepressants, part 2: kinetics, dynamics, mechanisms of action, and the future

Antidepressants, part 1: 100 years and counting

"It would be naïve to believe that targeting a single neurotransmitter, receptor, or circuit in the brain will cure any psychiatric or neurological disorder. However, we would be remiss if we did not try."

Serotonin: A Biography

“Mrs Norbert” is a 32-year-old Hispanic female with a history of recurrent major depressive disorder, with illness onset in her teens. She failed previous trials, with adequate dose and duration, of citalopram and sertraline (“felt worse”). She experienced some benefit with bupropion extended-released, titrated to 450 mg/day, although she has significant residual symptoms of depression. Subsequently, she failed a trial of adjunctive lithium due to tolerability concerns (nausea, diarrhea, and increased thirst). Her psychiatrist started adjunctive oral aripiprazole 10 mg daily. She reported improvements in depressed mood, irritability, energy, suicidal ideation, and overvalued ideas that people are generally against her in the first 2 weeks of treatment. The improvement was maintained after 4 weeks, and she requested to transition from oral to long-acting injectable aripiprazole.

Antidepressant non-response is common in major depressive disorder (MDD).

 Augmentation with atypical antipsychotics represents a viable strategy for treatment-refractory MDD.

 Among atypical antipsychotics, aripiprazole is an approved treatment in the United States, the United Kingdom, and Japan, with evidence of efficacy.

 However, the recommended dose of adjunctive aripiprazole in treatment guidelines varies widely (2 to 15 mg/day), which could impact on efficacy and tolerability.

 aimed to use dose-effect meta-analysis to inform on the optimal dose of adjunctive aripiprazole in patients with MDD and inadequate response to antidepressants. They included all assessor-masked trials of 2 or more doses of aripiprazole augmentation (versus continuation of antidepressant treatment) in adults with a primary diagnosis of non-psychotic MDD and inadequate response to at least 1 antidepressant trial. 

Psychotherapy was permitted, but electroconvulsive therapy was exclusionary. They excluded trials with active comparators; quasi- and non-randomized trials; studies with a high risk of bias; trials with ≥20% of patients treated with tricyclic antidepressants; studies in patients with significant physical illness, alcohol, or substance use comorbidity; and trials in postpartum depression.

The authors systematically searched Cochrane, CENTRAL, PubMed, ClinicalTrials.gov, and the WHO’s International Clinical Trials Registry Platform for trials. They also hand-searched drug approval agencies in the United States, the European Union, the United Kingdom, Australia, and Japan. Lastly, they contacted the developer of aripiprazole, Otsuka Pharmaceutical Co, Ltd. The primary outcomes were efficacy (responder—defined as ≥50% reduction in depressive symptoms), tolerability (dropouts due to adverse effects), and acceptability (all-cause dropouts), measured as odds ratios. 

Dose-effects relationships were analyzed using random effects models with restricted cubic splines with 3 knots, set at 3 mg (lowest expected effective dose), 1.5 mg, and 6 mg. Dose-effect curves of the primary analyses were used to estimate the 50% (ED50) and 95% (ED95) effective doses. The variance partition coefficient and funnel plots were used to evaluate heterogeneity and publication bias, respectively.

The authors identified 2678 records via databases and registries, and 14 through contact with Otsuka. Ten studies (7 published and 3 unpublished), comprising 2625 outpatient subjects, were identified for inclusion. These studies included 2 fixed-dose arms, 9 flexible-dose arms, and 10 placebo arms. The 3 unpublished studies were terminated early and only provided data for tolerability. The mean participant age was 42, and 55% were female. Median treatment duration was 6 weeks. The mean baseline Montgomery-Asberg Depression Rating Scale score was 26. There was no evidence of significant between-study heterogeneity.

The dose-efficacy curves showed an increase up to doses between 2 and 5 mg, then a non-increasing trend through doses up to 20 mg. The ED50 was 1.7 mg (OR=1.39, 95% CI 1.13-1.72), and the ED95 was 4.0 mg (OR=1.88, 95% CI 1.29-2.73). Tolerability also increased up to 5 mg, after which there was a non-increased trend. There was no significant difference in acceptability between aripiprazole and placebo at any dose. In the placebo arms, the average response rate was 23% and the all-cause dropout rate was 9%. Adjunctive aripiprazole at 4.0 mg had an estimate response rate of 36% and an all-cause dropout rate of 10%.

The authors performed the first dose-effect meta-analysis of aripiprazole augmentation in MDD. They concluded that aripiprazole may achieve most of its efficacy at the lower end of the dose range in patients with inadequate response to antidepressants, with limited evidence for efficacy above 10 mg. Study strengths included the identification of unpublished studies, modeling dose as a continuous variable, and consideration of efficacy, tolerability, and acceptability as outcomes. Limitations included the relatively small number of trials, especially in the lower end of the dose range, and risk of bias in the included trials.

Low-dose (2 to 5 mg) aripiprazole may maximize efficacy and tolerability in patients with inadequate response to antidepressants. However, dosing should be tailored to the individual patient.

is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

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Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report

2. MacQueen G, Santaguida P, Keshavarz H, et al. 

Systematic review of clinical practice guidelines for failed antidepressant treatment response in major depressive disorder, dysthymia, and subthreshold depression in adults

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Pharmacological augmentation in unipolar depression: a guide to the guidelines

Efficacy, acceptability, and safety of adjunctive aripiprazole in treatment-resistant depression: a meta-analysis of randomized controlled trials

5. Furukawa Y, Hamza T, Cipriani A, et al. 

Optimal dose of aripiprazole for augmentation therapy of antidepressant-refractory depression: preliminary findings based on a systematic review and dose-effect meta-analysis

What is the optimal dose of aripiprazole as augmentation for treatment-refractory depression? Researchers performed a systematic review and dose-effect meta-analysis.

Dosing Adjunctive Aripiprazole for Treatment-Refractory Depression

The US Food and Drug Administration (FDA) has approved Auvelity (dextromethorphan HBr -bupropion HCl) extended-release tablets for the treatment of major depressive disorder (MDD) in adults, the first and only oral N-methyl D-aspartate (NMDA) receptor antagonist approved for the treatment of MDD. It is also the first and only rapid-acting oral medicine approved for the treatment of MDD with labeling of statistically significant antidepressant efficacy compared to placebo starting at 1 week.

“The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile. Auvelity, which was granted Breakthrough Therapy designation by the FDA, represents the first new oral nonmonoamine-based mechanism of action approved to treat major depressive disorder in over 60 years,” said Maurizio Fava, MD, psychiatrist-in-chief in the department of psychiatry at Massachusetts General Hospital; executive director at the Clinical Trials Network & Institute; associate dean for Clinical & Translational Research; and Slater Family Professor of Psychiatry at Harvard Medical School. “Nearly two thirds of patients treated with currently available antidepressants do not adequately respond, and those that do may not achieve clinically meaningful responses for up to 6 to 8 weeks. Given the debilitating nature of depression, the efficacy of Auvelity observed at 1 week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition.”

Auvelity works on the NMDA receptor and on the sigma-1 receptor in the brain via its dextromethorphan component. The bupropion component is an aminoketone, increasing blood levels of dextromethorphan by competitively inhibiting cytochrome P450 2D6 (CYP2D6), which catalyzes a major biotransformation pathway for dextromethorphan.

In a comprehensive clinical program that included more than 1100 participants with depression, Auvelity’s efficacy was demonstrated in the GEMINI placebo-controlled study, and the ASCEND study comparing Auvelity to bupropion sustained-release tablets. In the GEMENI study, Auvelity was statistically and significantly superior to placebo in improvement of depressive symptoms as measured by the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at the study’s primary endpoint, week 6. The difference between AUVELITY and placebo in change from baseline in MADRS total score was statistically significant at week 1 and week 2.

In the ASCEND study, Auvelity was statistically and significantly superior to bupropion sustained-release tablets 105 mg twice daily on the primary outcome measure. The most common adverse reactions were dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis.

“Auvelity’s oral NMDA receptor antagonist and sigma-1 receptor agonist activity, which targets glutamatergic neurotransmission, provides clinicians a long sought after new mechanistic approach which may benefit the millions of patients living with this serious condition,” said Dan V. Iosifescu, MD, professor of psychiatry at the New York University School of Medicine, and Director of the Clinical Research Division at the Nathan Kline Institute for Psychiatric Research.

In March 2019, the FDA granted Breakthrough Therapy designation for Auvelity for the treatment of MDD. The Auvelity New Drug Application (NDA) was evaluated by the FDA under Priority Review.

Michael Pollock, chief executive officer of the Depression and Bipolar Support Alliance (DBSA), said, “The mental health crisis in the United States is one of the most pressing health issues facing our country today. Over 20 million American adults experienced major depressive disorder each year prior to the COVID-19 pandemic. These numbers increased dramatically during the pandemic with approximately 30% of adults in the US or more than 80 million Americans experiencing elevated symptoms of depression. The need for new treatment options, particularly those with new mechanisms of action, could not be clearer and more urgent for those living with, or impacted by, major depressive disorder.”

1. Axsome Therapeutics announces FDA approval of AUVELITY™, the first and only oral NMDA receptor antagonist for the treatment of major depressive disorder in adults. Global Newswire. August 19, 2022. 

https://www.globenewswire.com/news-release/2022/08/19/2501453/33090/en/Axsome-Therapeutics-Announces-FDA-Approval-of-AUVELITY-the-First-and-Only-Oral-NMDA-Receptor-Antagonist-for-the-Treatment-of-Major-Depressive-Disorder-in-Adults.html

Dextromethorphan HBr -bupropion HCl extended-release tablets for the treatment of major depressive disorder just became FDA approved. 

Novel Oral NMDA Receptor Antagonist Approved for Treatment of MDD

“Is there one state-of-the-art treatment for depression? No, that was the dilemma I faced in trying to prepare for this talk,” Sidney Zisook, MD, told attendees at the 

“There is no state-of-the-art treatment because 

 [MDD] is such a broad, diverse, heterogeneous group of symptoms,” explained Zisook, who is distinguished professor at the University of California, San Diego, and a previous recipient of the 

. “In fact, there are 227 possible combinations of symptoms that will allow a person to meet the DSM criteria for major depressive disorder. And, in addition to the symptomatic heterogeneity, there are a host of other issues that affect this: severity—mild symptoms versus very severe problems; clinical features—are there anxious features, atypical features, or melancholic features? All of these may lead us to different approaches that we may take with that patient.”

Because of this heterogeneity and the many combinations, there are a number of issues and features that should be assessed for each patient. Zisook discussed a recent review that revealed 14 key areas: symptom profile, clinical subtypes, severity, neurocognition, functioning and quality of life, clinical staging, personality traits, antecedent and concomitant psychiatric conditions, physical comorbidities, family history, early and recent environmental exposures, protective factors, resilience, and dysfunctional cognitive schema.

Thus, the best care practice—which is really what makes for state-of-the-art treatment for MDD—begins and continues with a thorough history, Zisook said. “A really thorough history begins with lab studies, physical exam, etc,” he said. “But the initial assessment isn't enough. We want to repeat the workup for patients who aren't doing well over time. I can't tell you how many times in my career, when I redid my initial assessment 6 months down the line and somebody wasn't having a good response, how different that history was and how I now—for the first time—learned about their drinking history and the cocktails they had every night. Or their early life trauma that was very much affecting their day-to-day life as an adult, etc. So not only do you do good assessment to begin with, repeat it intermittently as you have a better relationship with the patient to get a better, fuller picture of who they are.”

This includes checking for coocurring conditions and ensuring treatment for those conditions, too, Zisook said.

Similarly, he said it is important to use measurement-based care to inform decisions. “Several studies

 have found that if you measure symptoms, if you measure side effects, even with a global side effect measure along the way, share those with the patients, and develop a diary of symptoms and tolerance, you'll actually end up with better results,” Zisook reported.

Then, clinicians should dip into the wide variety of choices from what he called the “2022 Antidepressant Tool Kit.” In terms of medications, Zisook said all FDA-approved antidepressants (ie, tricyclics, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, serotonin modulators, and atypical antidepressants, and novel nonmonoamines) are equally effective with some differing adverse effects.

When discussing medication treatment personalization, the topic of 

 often comes up, said Zisook. “There was a lot of excitement about pharmacogenetic testing a few years ago, a lot of that excitement has died down, because it hasn't really proven to have a dramatic impact on our ability to personalize medications,” he told attendees.

However, testing can provide information on the genes involved in the metabolism of antidepressants (eg, CYP2D6, 2C19, 1A2, 2C9, 342, and 2B6), how the drug may be metabolized in patients, and whether the medications should be used as usual, with caution, or with extra caution and increased monitoring. “If they [patients] are a very poor metabolizer, they may end up with a very high dose of the medication that you're providing in their system, and they may be more prone to significant side effects adversity and tolerance, etc. You may need to go slower or lower or avoid certain medications,” he advised attendees.

Brain stimulation options (ie, bright light therapy, electroconvulsive therapy, transcranial magnetic stimulation, and vagus nerve stimulation) are also effective strategies in the tool kit, he noted.

Furthermore, Zisook reminded attendees not to overlook the 

. “A recent survey showed only about 20% of psychiatrists do psychotherapy in their offices, even though we all know that psychotherapy plus meds better than meds alone.”

Lifestyle aids, like exercise, are also important, he noted. “I tell all my patients, ‘When you're feeling more energetic, when you're up to it, start exercising. Get out of the house, take advantage the sunlight.’ They may not be able to do it initially. But I plant the seed early on and go back to it.”

The therapeutic alliance is key, Zisook said, and sometimes may be overlooked. He shared results from an NIMH study that found psychiatrists can “augment the effects” of both the medications as well as placebo.

“Those patients who had the best results even with placebo were the ones that maximized the nontherapeutic, nonspecific factors that are common to psychotherapy that's effective, like developing a therapeutic alliance: getting a trustful, empathetic, and collaborative relationship with a patient,” he said.

“Take advantage of those factors—and yourself,” Zisook advised. “This may mean spending more than 20 minutes with a patient. It may mean seeing their family. It may mean talking about their life independent of their depressive symptoms. But that relationship is critical in helping many of our patients get better.”

Zisook concluded by reminding attendees of their network of support, and the importance of engaging colleagues as needed. “Never worry alone,” he said. “It's always so nice when you're treating people with depression—especially difficult to treat depression—to have a colleague, other people that you can work with, you can consult with, to talk about patients. And I've always found that a critical part of my overall practice.”

The clinical characterization of the adult patient with depression aimed at personalization of management. 

Major Depressive Disorder

Antidepressants Do Not Work by Numbing Emotions

Dextromethorphan-Bupropion in Depression

Serotonin: A Biography

Dosing Adjunctive Aripiprazole for Treatment-Refractory Depression

Novel Oral NMDA Receptor Antagonist Approved for Treatment of MDD

What Is State of the Art Treatment for MDD?

Delineating Between Depression and Grief: Key to Treatment

$5.3 Million in Grants Awarded to Address Youth Mental Health Crisis

The Serotonin Fixation: Much Ado About Nothing New

8 Key Issues in the World of Major Depressive Disorder