Serotonin

Serotonin

CHEMICAL COMPOSITION AND ACTION

TYPES OF SEROTONIN MEDICATIONS

MEDICATION SIDE EFFECTS

BIBLIOGRAPHY

Serotonin, like dopamine and norepinephrine, is a brain neurotransmitter. When the brain produces serotonin, tension is eased and the subject feels less stressed and more focused and relaxed. In contrast, when it produces dopamine or norepinephrine there is alertness in thinking and acting. Serotonin is called the “calming chemical.” It can be obtained naturally by eating sugar or other carbohydrates, which raise the insulin level in the blood, triggering a greater ratio of a chemical (actually, an enzyme) called tryptophan. This in turn rushes to the brain, where it produces serotonin. Vitamin C is required for the conversion of tryptophan into serotonin. Tryptophan is found in foods such as bananas, plums, turkey, and milk. A diet poor in omega-3 fatty acids may lower brain level serotonin and cause depression.

CHEMICAL COMPOSITION AND ACTION

Serotonin was isolated and named by Maurice M. Rapport, Arda Green, and Irvine Page in 1948. First, Rapport identified it as a vasoconstrictor substance in the blood serum, and because it is a serum agent that affected vascular tone he called it serotonin. Later, in 1950, Rapport identified serotonin chemically and gave it the chemical name 5-hydroxytryptamine. The chemical name of serotonin is 3-(2-aminoethyl)-1 H -indol-5-ol, and in pharmacological terminology 5-HT.

The chemical formula of serotonin is N₂OC₁₀H₁₂. Its molecular mass is 176.2182 g/mol, its monoisotopic mass is 176.0950 g/mol, and its composition is as follows: N (15.8970 percent), O (9.0793 percent), C (68.1598 percent), and H (6.8638 percent).

Specifically, serotonin is a monoamine neurotransmitter that is synthesized in the central nervous system by the serotonergic neurons and in the gastrointestinal tract by the enterochromaffin cells. Serotonin is formed by the hydroxylation and decarboxylation of tryptophan. The greatest concentration of serotonin is found in the enterochromaffin cells of the gastrointestinal tract (90 percent), and the rest is found in platelets and in the central nervous system. The effects of serotonin are mostly felt in the cardiovascular system, with additional effects in the respiratory system and the intestines.

The function of serotonin is exerted upon its interaction with specific receptors. Several serotonin receptors have been cloned, such as 5HT1, 5HT2, 5HT3, 5HT4, 5HT5, 5HT6 and 5HT7. Within each group there are subtypes that affect various aspects of bodily functions.

More specifically, serotonin can be found in the human gastrointestinal tract and in the bloodstream. In the human body, serotonin can be synthesized from the amino acid tryptophan by a short metabolic pathway that consists of two enzymes: tryptophan hydroxy lase and amino acid decarboxylase. The first enzyme, tryptophan hydroxylase, has two forms, one that is present in several tissues and the other one in a brain-specific isoform. In contrast, in the central nervous system serotonin can also be synthesized by the neurons of the Raphe nuclei that are distributed along the length of the brainstem in nine pairs. Specifically, there are swellings, called varicosities, along the axon that release serotonin into the extraneuronal space. From there, serotonin can be diffused to activate special receptors that exist on the dendrites, the cell bodies, and the presynaptic terminals of the adjacent neurons.

Serotonin plays an important role in the regulation of mood, sleep, appetite, vomiting, sexuality, memory and learning, temperature regulation, cardiovascular function, and endocrine regulation. Low levels of serotonin have been associated with migraines, bipolar disorders, apathy, fear, feelings of worthlessness, insomnia, fatigue, anxiety, and depression (www.chm.bris.ac.uk/motm/serotonin/depression.htm). Autopsies on suicide cases have revealed very low levels of serotonin in the brain. In turn, low levels of serotonin can be caused by an anxiety disorder because serotonin is required for the metabolism of stress hormones. The most concrete evidence for the connection between serotonin and depression is the decreased concentrations of serotonin in the cerebrospinal fluid and brain tissues of people suffering from depression. Extremely high levels of serotonin in the body cause toxic effects, and are even fatal in some cases; this is termed “serotonin syndrome.”

In 2005 scientific evidence emerged that genetic polymorphisms in the enzyme tryptophan hydroxylase in both its forms can affect susceptibility to depression and anxiety (Nash et al. 2005; Zhang et al. 2005). Furthermore, a study in 2006 showed that ovarian hormones can affect the expression of tryptophan hydroxylase, triggering postnatal depression and premenstrual stress syndrome (Hiroi et al. 2006). Also, where infants have abnormal serotonergic neurons—those neurons on the brain stem that synthesize serotonin—there is a high possibility of sudden infant death syndrome (SIDS) (Weese-Mayer, et al. 2003). Based on recent research, by Lesurtel et al. (2006), serotonin mediates liver regeneration and induces cell division throughout the body.

The pharmacology of serotonin is very complex because there is a large and diverse range of serotonin receptors in the human body. At least seven types of such receptors have been identified in different places of the body, and they all have different effects. Serotonin receptors can be stimulated by psychoactive drugs such as ecstasy (MDMA), LSD, DMT, and psilocybin (a substance found in psychedelic mushrooms). A small dose of ecstasy, for example, stimulates a big release of serotonin in the body, causing feelings of well-being, comfort, and tactile sensitivity. High doses of such substances can produce feelings of emotional empathy, or entactogenesis.

The 5-HT3 receptor is an antiemetic agent used mainly in cases of postoperative nausea and nausea caused by anticancer chemotherapy using cytotoxic drugs. It is also used to treat depression and other mental and psychological conditions. The 5-HT 1B/D receptor is an agent to treat migraines. The role of 5-HT receptors is a topic of intense research, so more therapeutic applications may be discovered in the future.

If depression is severe as a result of serotonin deficiency, antidepressants—that is, pharmaceutical agents that increase the level of serotonin in the brain—may be used. If depression is mild, it can be cured without medications because levels of serotonin can be increased with rigorous exercise. Studies have shown that the amount of serotonin in the brain is increased with increased activity, and the production of serotonin is raised for some days after exercise.

TYPES OF SEROTONIN MEDICATIONS

There are certain psychiatric medications that modulate the levels of serotonin in the human body. These have been classified into four general categories: (1) monoamine oxidase inhibitors, (2) tricyclic antidepressants, (3) atypical antipsychotics, and (4) selective serotonin reuptake inhibitors.

Monoamine oxidase inhibitors (MAIOs) are used to prevent the breakdown of monoamine neurotransmitters (one of which is serotonin). Hence, they increase the concentrations of serotonin in the brain. They are used for patients suffering from depression, but they may have serious side effects, including adverse drug interactions such as hypertensive crisis. Trycyclic antidepressants (TCAs) inhibit the reuptake of both serotonin and norepinephrine. Selective serotonin reuptake inhibitors (SSRIs) are also used in the treatment of depression. They are newer drugs and inhibit only serotonin’s reuptake, hence they are safer, having fewer side effects and fewer adverse drug interactions. One of their side effects is anorgasmia, or a delay of sexual climax.

SSRIs available in the United States (with trade names given in parentheses) include:

Citalopram (Celexa, Cipramil, Emocal, Sepram, Seropram);

Escitalopram oxalate (Lexapro, Cipralex, Esertia);

Fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem);

Fluvoxamine maleate (Luvox, Faverin);

Paroxetine (Paxil, Seroxat, Aropax, Deroxat, Paroxat);

Sertraline (Zoloft, Lustral, Serlain);

Dapoxetine (no known trade name).

SSRIs are prescribed for treatment of major depression, anxiety disorders, panic disorders, obsessive-compulsive disorders (OCD), social phobia, eating disorders, irritable bowel syndrome (IBS), and premature ejaculation (which affects up to 60 percent of men).

Briefly, the mechanism of brain cells is as follows: The messages in the brain are passed between two nerve cells through a synapse, which is a small gap between the cells. The sender (presynaptic) cell releases neurotransmitters such as serotonin, dopamine, and norepinephrine into that gap. These neurotransmitters are recognized by special receptors on the surface of the receiver cell (postsynaptic), which, upon this stimulation, relays the signal. During this process, approximately 10 percent of the neurotransmitters are lost; the remaining 90 percent are released from the receptors to be taken back by monoamine transporters into the sender cell (presynaptic). This process is called “reuptake.” When there is a problem in this operation, some type of disorder appears in the person’s behavior.

According to some theories, a lack of stimulation of the receiver cell (a postsynaptic neuron) at a synapse can cause depression. In order to stimulate this receiver cell, SSRIs, as their name implies, inhibit the reuptake of serotonin only from the three neurotransmitters. In contrast, TCAs inhibit the reuptake of both serotonin and norepinephrine. When medication is used, serotonin stays in the synaptic gap longer than it normally would so that it can be recognized again by the receptors of the postsynaptic cell and the process can be repeated, thus the postsynaptic cell can finally be stimulated fully, as it should have been originally.

MEDICATION SIDE EFFECTS

Adverse effects of SSRIs include general side effects, suicidality, sexual side effects, and “discontinuation syndrome.” Specifically, during the first four weeks of treatment with SSRIs symptoms may include nausea, drowsiness, headache, changes in weight and appetite, changes in sexual behavior, increased feelings of depression and anxiety, tremors, and increased sweating. These symptoms usually disappear after the adaptation period, but they are highly individual and drug-specific.

Regarding suicidality, there have been many accusations by patients and their families that SSRIs cause suicidal ideation and behavior. However, there is little scientific support for these claims, and manufacturers of SSRIs usually have vehemently denied them. But in early 2006 GlaxoSmithKline announced to the media that new meta-analysis of their clinical trial data revealed a statistically significant higher frequency of suicidality in patients treated with their SSRI, paroxetine (Paxil) (GlaxoSmithKline, May 2006, “Clinical Worsening and Suicide Risk,” Press release; (www.healthfoundation.healthspace.eu/health/antidepressants-paxil.php.)

Regarding the sexual side effects, SSRIs can cause various types of sexual dysfunctions such as anorgasmia, erectile dysfunction, and diminished libido (Landen et al. 2005; Hu Xh et al. 2004). It is believed that sexual dysfunction is caused by an SSRI-induced reduction in dopamine. If the postsynaptic receptors 5-HT2 and 5-HT3 are stimulated, they decrease dopamine release from the Substantia Nigra. Because of these problems, the SSRI fluoxetine (Prozac) was recently classified as a reproductive and developmental toxin by the Center for the Evolution of Risks to Human Reproduction (CERHR), which is an expert panel at the National Institute of Environmental Health Sciences and people were advised to avoid it.

Finally, regarding the discontinuation syndrome, SSRIs have not been found to be addictive. However, a sudden discontinuation of their use may cause both somatic and psychological withdrawal symptoms that collectively are called the “SSRI discontinuation syndrome.” These reactions are different from and usually less significant than the withdrawal symptoms of drugs such as opium, alcohol, or cocaine, but occasionally they have been extreme, and some patients can never withdraw completely from the SSRI drugs. In some cases, stopping the use of SSRIs can cause unpredictable and irregular acts and behaviors (e.g., violent rages, suicidal ideation), as well as an intensification of previous symptoms. In Europe, SSRI products cannot be advertised as “non-habit-forming,” as they are in the United States. According to the World Health Organization, SSRIs meet the definition of “addictive” (Tamam and Ozpoyraz 2002).

Serotonin toxicity, commonly referred to as “serotonin sydrome,” is a toxidrome (a form of poisoning) caused by medical treatment. Increased serotonin levels in the central nervous system can result from the use of archetypal serotonergic drugs, examples being the specific or selective serotonin reuptake inhibitors (SSRIs). The toxicity of SSRIs increases with greater dosages, but overdose of an SSRI alone is not fatal in healthy adults. The toxicity can be fatal, however, when drugs with different mechanisms are mixed together. The most common combination of therapeutic drugs likely to raise serotonin to a fatal level is the combination of MAOIs with SRIs or TCAs (Gillman 2004; Isbister et al. 2004). The duration of an episode of serotonin toxicity depends on the type of drugs that precipitated it. Many of them have durations of less than twenty-four hours, and side effects or toxicity will subside over this time, without specific treatment, if one or all of the offending drugs are reduced or ceased completely. As of the mid-2000s there was no evidence of permanent or long-term neurological effects or damage from serotonin toxicity (Whyte 2004).

In approximate order of seriousness (from least to most serious), the symptoms of serotonin toxicity, according to Dunkley (2003), include:

1. neuromuscular hyperactivity: tremor, clonus, myoclonus, hyperreflexia, and (only in late or severe stage) rigidity, which may effect truncal muscles;
2. altered mental status: excitement, agitation, and (only in late or severe stage) confusion;
3. autonomic hyperactivity: diaphoresis (excessive sweating), fever, mydriasis (eye dilation), tachycardia (elevated heart rate), moderately elevated blood pressure, and tachypnoea (rapid breathing).

The usual clinical picture is of a hypervigilant or agitated patient with tremor and hyperreflexia. Clonus and myoclonus (involuntary muscle contractions) usually begin in lower limbs and may spread and become generalized. Pyramidal rigidity (a rigidity of certain muscles) is a late development (usually it happens when MAOIs have beed mixed with SRIs) and may impair respiration if it affects truncal muscles. Serious toxicity is indicated by high rigidity, a fever higher than 38.5 degrees Celsius, and an increasing PaCO2 (arterial carbon dioxide pressures).

SEE ALSO Anxiety; Depression, Psychological; Dopamine; Drugs of Abuse; Emotion; Neuroscience; Psychoneuroendocrinology; Psychopathology; Suicide

BIBLIOGRAPHY

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Dunkely, E. J. C., et al. 2003. Hunter Serotonin Toxicity Criteria: A Simple and Accurate Diagnostic Decision Rule for Serotonin Toxicity. Quarterly Journal of Medicine 96: 635-642.

Gillman, P. K. 2004. Moclobemide and the Risk of Serotonin Toxicity (or Serotonin Syndrome). Central Nervous System Drug Reviews 10: 83-85.

Hiroi, Ryoko, Ross A. McDevitt, and John F. Neumaier. 2006. Estrogen Selectively Increases Tryptophan Hydroxylase-2 mRNA Expression in Distinct Subregions of Rat Midbrain Raphe Nucleus: Association between Gene Expression and Anxiety Behavior in the Open Field. Biological Psychiatry 60: 288-295.

Hoyer, Daniel H., Jason P. Hannon, and Graeme R. Martin. 2002. Molecular, Pharmacological, and Functional Diversity of 5-HT Receptors. Pharmacologicy, Biochemistry, and Behavior 71 (4): 533-554.

Hu Xh, et al. 2004. Incidence and Duration of Side Effects and Those Rates as Bothersome with Selective Serotonin Reuptake Inhibitor Treatment for Depression: Patient Report versus Physician Estimate. Journal of Clinical Psychiatry 65: 959-965.

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Lesurtel, Mickael, Rolf Graf, Boris Aleil, et al. 2006. Platelet-Derived Serotonin Mediates Liver Regeneration. Science 312 (April 7): 104-107.

Nash, Matthew W., K. Sugden, P. Huezo-Diaz, R. Williamson, A. Sterne, S. Purcell, S. Sham, P. C. Sham, and I. W. Craig. 2005. Association Analysis of Monomine Genes with Measures of Depression and Anxiety in a Selected Community of Sample Siblings. American Journal Medical Genetics Part B: Neuropsychiatric Genetics 135: 33-37.

Rapport, Maurice, Arda A. Green, and Irvine H. Page. 1948. Serum Vasoconstrictor (Serotonin). IV. Isolation and Characterization. Journal of Biological Chemistry 176, no. 3: 1243-1251.

Tamam, L., and N. Ozpoyraz. 2002. Selective Serotonin Reuptake Inhibitor Discontinuation Syndrome: A Review. Advances in Therapy 19: 17-26.

Weese-Mayer, D. E., E. M. Berry-Kravis, B. S. Maher, J. M. Silvestri, M. E. Curran, and M. L. Marazita. 2003. Sudden Infant Death Syndrome: Association with a Promoter Polymorphism of the Serotonin Transporter Gene. American Journal of Medical Genetics 117, no. 3 (March 15): 268-274.

Whyte, I. M. 2004. Serotonin Uptake Inhibitors. In Medical Toxicology, ed. R. C. Dart, 843-851. Baltimore: Lippincott, Williams and Wilkins.

Zhang, Xiaodong, Raul R. Gainetdinov, Jean-Martin Beaulieu, et al. 2005. Loss-of-Function Mutation in Tryptophan Hydroxylase-2 Identified in Unipolar Major Depression. Neuron 45: 11-16.

Katerina Lyroudi