John J. Miller, MD

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 (

 Mechanisms of Action of Serotonergic Receptor-Specific Drugs

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 (

 The Various Elements of the Serotonin System

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 

A Simplistic Rendering of Several Different Sites that Antidepressant Drugs and Nutraceuticals Can Target to Affect the Serotonergic Monamine System

 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

Articles

"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

 A Simplistic Rendering of Several Different Sites that Antidepressant Drugs and Nutraceuticals Can Target to Affect the Serotonergic Monoamine System

These are the extra figures for John J. Miller, MD's article, "Serotonin: A Biography" from the 2022 September issue. 

Figures for Serotonin: A Biography

John J. Miller, MD, shares why it is important to differentiate between CBD and THC when discussing cannabis 

2022 Annual Psychiatric Times™ World CME Conference

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

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I was attending a lecture on movement disorders approximately 4 years ago when the speaker, a neurologist, described how, in neurology, the term 

 (EPS) is an example of a “4-letter word.” Yes, one of those irreverent and foul 4-letter words that have most of their letters replaced by “*”s. The neurologist went on to say that a psychiatric referral to a neurologist requesting evaluation for EPS is like a neurologist referring us a patient for evaluation for a psychiatric disorder. 

It was refreshing to hear this, as I have always viewed the adverse event term EPS, which includes many potential movement disorder adverse effects from antipsychotics, to be far too vague and nondescript. 

 lists the numerous movement disorders that are defined as an EPS adverse event during clinical trials submitted to the US Food and Drug Administration (FDA).

Movement Disorders Included Under "EPS" as an Adverse Event in FDA Trials of Antipsychotic Medication

Additionally, since the FDA approval of 2 vesicular monoamine transporter type 2 (VMAT2) inhibitors (deutetrabenazine and valbenazine) in 2017 for the treatment of tardive dyskinesia (TD), the new standard is to describe the various medications that can cause TD and other types of EPS by the mechanism by which these movement disorders are putatively caused: dopamine-2 receptor blocking agents (D2RBAs). 

Although all antipsychotics do block the dopamine-2 (D-2) receptor, drugs in other classes also block this same receptor and have the same risks of causing EPS. A few common examples include metoclopramide, which is used for the treatment of gastroesophageal reflux disorder and diabetic gastroparesis, and prochlorperazine, which is commonly prescribed to treat nausea and vomiting.

The first description of EPS in medicine occurred in 1952 when drug-induced parkinsonism was seen in patients treated with our very first antipsychotic medication, chlorpromazine.

 Five years later, the first case report of TD was published, which occurred in a patient who was also being treated with chlorpromazine. As the antipsychotic mechanism of chlorpromazine was ultimately believed to be related to its ability to block the D-2 receptor, 2 additional types of EPS were added to the list: acute dystonic reactions and akathisia. 

These 4 movement disorders are common adverse events from all D2RBAs, and as we have increased our understanding of the neuropathophysiology of these 4 movement disorders, we now understand them as distinct from each other both in terms of etiology and treatment. 

 provides a simple overview of the different properties of these 4 types of movement disorders as well as the different treatments for them.

Four Most Common Types of EPS From Antipsychotics

Significantly, the presentation and treatment of these movement disorders are quite heterogenous. Acute dystonias and drug-induced parkinsonism are believed to result from a dopamine-acetylcholine imbalance that results from the blockade of the D-2 receptors. This results in a disequilibrium, creating a relative excess of acetylcholine activity due to the relative decrease in dopamine activity resulting from the D-2 receptor blockade. 

An acute dystonia, such as an oculogyric crisis or torticollis, can be quite frightening to the patient, as the dystonia occurs rapidly and can be painful. Fortunately, the treatment is simple and results in immediate relief. Administering the patient an anticholinergic drug (including diphenhydramine, benztropine, or trihexyphenidyl) appears to restore the dopamine-acetylcholine balance. Treatment is usually only required for a few days or a week at most.

Drug-induced parkinsonism follows a different clinical path, although it is quite variable in both time of onset and duration. The same 3 anticholinergic drugs are used to treat drug-induced parkinsonism; however, the treatment is longer and can last for weeks to months. The ultimate goal is to taper off the anticholinergic medication as soon as possible to minimize the many burdensome adverse events of anticholinergic medications (eg, blurred vision, dry mouth, tachycardia, urinary retention, constipation, cognitive impairment, effects on thermoregulation). Alternatively, amantadine can be used, which has a different—albeit not fully understood—mechanism of action.

Akathisia sits in a category by itself, as there are many etiologies to it in addition to D-2 receptor blockade. One common example is selective serotonin reuptake inhibitor–induced akathisia. Not surprisingly, anticholinergics often do not improve akathisia. Like drug-induced parkinsonism, there is also a large range of variability in both time of onset and duration. 

The first step, if possible, is to lower the dose of the D2RBA or change to a different one. Beta-blockers have proved to be the most effective pharmacological treatment, with most of the published literature supporting propranolol. Second-line treatment, in the appropriate patient, is clonazepam. Some evidence suggests that mirtazapine may also be of benefit.

Tardive dyskinesia emerges over time, often not appearing for years or even decades. If the D2RBA dose is decreased, TD will initially look worse due to withdrawal dyskinesia, which will last from 4 to 8 weeks after lowering the D2RBAs dose. For approximately 80% of patients, some degree of TD will be irreversible. It is well established that anticholinergic medications increase the risk of TD and should be avoided in patients with TD. 

The 2 VMAT2 inhibitors described earlier are both quite effective, and the evidence to date suggests that discontinuation of the VMAT2 inhibitors results in recurrence of the TD symptoms. The recently updated American Psychiatric Association guidelines for the treatment of schizophrenia serve as an excellent reference for the diagnosis and treatment of these 4 movement disorders.

We have come a long way in understanding the relationship between D2RBAs and movement disorders. In addition to the 4 movement disorders reviewed here, Table 1 puts in perspective the immense diversity of potential movement disorders that can emerge from the use of D2RBAs. The diagnosis and treatment for each of these can vary significantly, and treating one can worsen another. So to continue to improve our diagnosis and treatment of the numerous movement disorders that can occur with the use of D2RBA, I would like to ask that 

Extrapyramidal side effects: a historical perspective

2. Pringsheim T, Gardner D, Addington D, et al. 

The assessment and treatment of antipsychotic-induced akathisia

The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia, Third Edition

. American Psychiatric Association; 2021. ❒

Is the term, "extrapyramidal symptoms," an example of a “4-letter word”?