In serotonin syndrome

The major clinical applications of cyproheptadine are in the treatment of the smooth muscle manifestations of carcinoid tumor and in cold-induced urticaria. The usual dosage in adults is 12-16 mg/d in three or four divided doses. It is of some value in serotonin syndrome, but because it is available only in tablet form, cyproheptadine must be crushed and administered by stomach tube in unconscious patients. 

B. lit addition, severe rigidity and hyperthermia may occur when patients receiving MAO inhibitors use therapeutic doses of meperidine (Demeroi), dextromethorphan, fluoxetine (Prozac), paroxetine (Paxii), sertraiine (Zoloft), ven-lafaxine (Effexor), or tryptophan the mechanism is unknown but may be related to inhibition of serotonin metabolism in the CNS, resulting in serotonin syndrome (see p 22). 

Citalopram Citalopram is a substrate of CYP2C19, and inhibition of its metabolism by fluconazole can result in serotonin syndrome, as occurred in two patients, who developed prolonged delirium without tremor, myoclonus, rigidity, or autonomic instability [30 ]. Serotonin toxicity in patients with cancers may not present with the classic constellation of signs and symptoms and delirium may be the only presenting feature. 

MDMA overdose as well as the concomitant consumption of selective serotonin reuptake inhibitors (SSRI) with other dmgs that exert serotoninergic effects (such as inhibitors of monoamine oxidase) can rapidly lead to the serotonin syndrome. Its symptoms, which are reversible upon cessation, of the drug include confusion, muscle rigidity in the lower limbs, and hyperthermia suggesting an acute reaction to serotonin overflow in the CNS. Blocking the function of SERT outside the brain causes side effects (e.g., nausea), which may be due to elevated 5HT however , impairment of transporter function is not equivalent to direct activation of 5HT recqrtors in causing adverse effects such as fibrosis and pulmonary hypertension. 

Although many patients believe that dietary supplements will not interact with medications, recent literature suggests otherwise. Recently, many St. John s wort-drug interactions have been reported in the literature. Cases of patients developing symptoms of serotonin syndrome have been reported with St. John s wort alone and in concomitant therapy with other antidepressants such as monoamine oxidase inhibitors, serotonin reuptake inhibitors, and venlafaxine. St. John s wort may exacerbate the sedative effects of benzodiazepines, alcohol, narcotics, and other sedatives. St. John s wort may decrease the levels of protease inhibitors, cyclosporine, digoxin, and theophylline. 

The risk of potentially serious side effects should be enough to preclude the prescription of antidepressants for their placebo benefit, but this is not the only hazard associated with these medications. On 19 July 2006 the FDA issued a public-health advisory warning that, when taken in conjunction with other drugs that can affect serotonin levels, antidepressants can induce a life-threatening disorder called the serotonin syndrome .5 The serotonin syndrome is caused by an excess of serotonin in a person s body. 

FDA, Combined Use of 5-Hydroxytryptamine Receptor Agonists (Triptans), Selective Serotonin Reuptake Inhibitors (SSRIs) or Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) May Result in Life-Threatening Serotonin Syndrome , FDA Public Health Advisory (2006) http //www.fda.gov/Cder/Drug/advisory/ S SRI S S200607.htm... 

Spanos, L.J. and Yamamoto, B.K., Acute and subchronic effects of methylenedioxymethamphetamine [(+/-)MDMA] on locomotion and serotonin syndrome behavior in the rat, Pharmacol. Biochem. Behav. 32(4), 835-840, 1989. 

In addition to this serious diet-drug interaction, irreversible MAOIs also potentiate the effects of sympathomimetic drugs like ephedrine found in over-the-counter cold remedies and recreational stimulants like amphetamine. The MAOIs also interact with drugs that increase synaptic concentrations of 5-HT, such as the tricyclic antidepressant clomipramine and the herbal SSRI antidepressant St John s wort (Hypericum spp.). The resulting serotonin syndrome is characterised by hyperthermia and muscle rigidity. While devoid of these side effects the reversible MAO-A inhibitor moclobemide has yet to establish itself as a first-line alternative to the SSRIs. 

The answer is a. (Hardman, p 444) This patient has the serotonin syndrome Serotonin is already present in increased amounts in synapses because of blockade of its reuptake by the SSRls. The amount of serotonin that is present is further increased when breakdown by MAO is inhibited. The serotonin syndrome can be life threatening. 

Examples of common animal models that have been used over the last decade include the following (a) disruption of the conditioned avoidance response in rats (27), (b) mouse head twitch (43), (c) rabbit hyperthermia (1), (d) cat rage response (244) and cat limb flick (121), (e) mouse ear scratch (135,251), (f) flexor and stepping reflex in chronic spinal dog (140,143), (g) serotonin syndrome in rats (118), (h) tactile startle response in rats (68), and (i) two-lever drug discrimination in rats (84). 

Methoxy-N,N-dimethyltryptamine (O-methylbufotenine 59) is hallucinogenic in man at a parenteral dose of approximately 6 mg (204). Numerous animal studies have shown that 5-OMeDMT is behaviorally quite active (16,65-67,71,178,184). This compound also produced limb-flick behavior in cats (119) and the serotonin syndrome in rats (209). Glennon et al. (85) demonstrated that 5-OMeDMT serves as a discriminative stimulus in rats and have employed rats trained to discriminate 5-OMeDMT from saline to investigate the structure-activity relationships of various substituted N,N-dialkyltryptamine derivatives. The results of these studies have recently been reviewed (84). 

Lucki, I., and Frazer, A. (1982) Prevention of the serotonin syndrome in rats by repeated administration of monoamine oxidase inhibitors but not tricyclic antidepressants. Psychopharmacology, 77 205-211. 

Initially 10 mg qd, max 15 mg qd after4 wks. Contraindicated in hypertension, tachycardia, coronary artery disease, or stroke. Serotonin syndrome with SSRIs. 

Free tryptophan is transported into the brain and nerve terminal by an active transport system which it shares with tyrosine and a number of other essential amino acids. On entering the nerve terminal, tryptophan is hydroxylated by tryptophan hydroxylase, which is the rate-limiting step in the synthesis of 5-HT. Tryptophan hydroxylase is not bound in the nerve terminal and optimal activity of the enzyme is only achieved in the presence of molecular oxygen and a pteridine cofactor. Unlike tyrosine hydroxylase, tryptophan hydroxylase is not usually saturated by its substrate. This implies that if the brain concentration rises then the rate of 5-HT synthesis will also increase. Conversely, the rate of 5-HT synthesis will decrease following the administration of experimental drugs such as para-chlorophenylalanine, a synthetic amino acid which irreversibly inhibits the enzyme. Para-chloramphetamine also inhibits the activity of this enzyme, but this experimental drug also increases 5-HT release and delays its reuptake thereby leading to the appearance of the so-called "serotonin syndrome", which in animals is associated with abnormal movements, body posture and temperature. 

Serotonin syndrome Some TCAs inhibit neuronal reuptake of serotonin and can increase synaptic serotonin levels (eg, clomipramine, amitriptyline). Either therapeutic or excessive doses of these drugs, in combination with other drugs that also increase synaptic serotonin levels (such as MAOIs), can cause a serotonin syndrome consisting of tremor, agitation, delirium, rigidity, myoclonus, hyperthermia, and obtundation. 

Serotonin syndrome The serotonin syndrome is a rare complication of therapy with serotonergic drugs. When this problem occurs with SSRIs, it is most commonly in... 

Serious toxic reactions with delirium can arise when specific serotonin reuptake inhibitors (SSRIs) are taken with other drugs that increase central and peripheral serotonergic activity. Known as the serotonin syndrome , this reaction consists of excitation, restlessness, fluctuations in consciousness, with tremor, rigidity, myoclonus, sweating, flushing, pyrexia, cardiovascular changes, and rarely coma and death (Sternbach, 1991). The syndrome has occurred when SSRIs have been combined with irreversible monoamine oxidase... 

Serotonin syndrome is best prevented by not using serotonergic drugs in combination. Special care is needed when changing from an SSRI to an MAOI and vice versa. The SSRIs, particularly fluoxetine, have long half-lives and serotonin syndrome may occur if a sufficient wash-out period is not allowed before switching from one to the other. When changing... 

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