Serotonin syndrome SSRIs

Serotonin syndrome SSRIs, second generation antidepressants, MAOIs, linezolid, tramadol, meperidine, fentanyl, ondansetron, sumatriptan, MDMA, LSD, St. John s wort, ginseng Hypertension, hyperreflexia, tremor, clonus, hyperthermia, hyperactive bowel sounds, diarrhea, mydriasis, agitation, coma onset within hours Sedation (benzodiazepines), paralysis, intubation and ventilation consider 5-HT2 block with cyproheptadine or chlorpromazine... 

Selective serotonin reuptake inhibitors (SSRIs) [P] Fatalities have occurred due to serotonin syndrome SSRIs are contraindicated in patients taking MAOIs. 

Trazodone Concurrent use may cause serotonin syndrome. SSRIs may inhibit the metabolism of trazadone resulting in increased toxicity. 

The manufacturers siay that two weeks should elapse between taking an MAOI and mirtazapine. Mirtazapine combined with other serotonergic antidepressants may possibly increase the risk of bleeding and/or the serotonin syndrome. SSRIs may increase plasma levels of mirtazapine and there is a report of hypomania associated with combined use. The concurrent use of mirtazapine with amitriptyline may have a minor effect on the levels of both drugs. 

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. 

Synergy of therapeutic pharmacological effects St. John s Wort will induce serotonin syndrome when co-administered with SSRIs. 

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... 

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 combination of an SSRI with another 5-HT augmenting agent can lead to the serotonin syndrome, which is characterized by symptoms such as clonus, hyperthermia, and mental status changes. 

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

Add tryptophan to a standard antidepressant (usually an SSRI). There is a danger that the serotonin syndrome may occur however and occasionally the eosinophilia myalgia syndrome. The symptoms that occur with increasing severity are restlessness, diaphoresis, tremor, shivering, myoclonus, confusion, convulsions, death. 

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... 

A life-threatening condition, when selective serotonin reuptake inhibitors (SSRIs) and 5-hydroxytryptamine receptor agonists (triptans) are used together. However, many other drugs have been implicated (see below). Signs and symptoms of serotonin syndrome include the following ... 

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... 

Dmg-induced serotonin syndrome is generally mild and resolves when the offending drugs are stopped. However, it can be severe and deaths have occurred. A large number of drugs have been implicated including tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs), pethidine, lithium, and dextromethorphan. The most severe type of reaction has occurred with the combination of selective serotonin re-uptake inhibitors and monoamine oxidase inhibitors. Both non-selective MAOIs such as phenelzine and selective MAOIs such as moclobemide and selegiline have been implicated. 

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... 

SSRIs should not be taken with St. John s wort because of the risk of the onset of a serotonin syndrome characterized by nausea, tremor, and weakness. Alcohol also should be avoided. St. John s wort can increase opioid-induced sleep. 

A more common approach in difficult to treat cases would be the combination of clomipramine with a SSRI several reports lend support to this practice (Simeon and Thatte, 1990 Figueroa et al., 1998). In this situation, careful attention to the potential pharmacokinetic interactions discussed above are recommended. Sertraline and citalopram are least likely to elevate tricyclic levels due to less potential GYP interactions. By expert consensus, second- (venlafaxine) and third-line (nefazadone and gabapentin) agents may be used when clinical response is inadequate despite a lack of controlled data. Venlafaxine may be substituted for a more typical SSRI while nefazadone or gabapentin may be added to either clomipramine or a SSRI. The combination of venlafaxine with other SSRIs is not generally recommended as it may increase the risk of a serotonin syndrome. The addition of nefazadone to SSRIs presents a lesser risk. 

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 SSRIs. The amount of serotonin that is present is further increased when breakdown by MAO is inhibited. The serotonin syndrome can be life threatening. 

When an SSRI agent is used with a MAO inhibitor, a dangerous pharmacodynamic interaction may occur. The combination of increased stores of monoamine together with reuptake inhibition leads to a phenomenon termed serotonin syndrome. This syndrome, which arises from a marked increase in synaptic serotonin, is clinically... 

The combination of an MAOl plus an SSRI, venlafaxine, or nefazodone should not be attempted because of the risk of a serotonin syndrome. 

This antidepressant can interact with other drugs via its two mechanisms of action serotonin and NE uptake inhibition. The former action means that the same pharmacodynamic interactions will occur with venlafaxine as with SSRIs, including the serotonin syndrome. At higher doses, venlafaxine is also prone to the same pharmacodynamic interactions as NSRIs such as secondary amine TCAs like desipramine and with newer NSRIs such reboxetine. Thus, the combination of high-dose venlafaxine plus an MAOl could produce a hypertensive crisis as well as the serotonin syndrome. 

MAOIs have the most serious pharmacodynamic interactions of any antidepressant class. As discussed earlier, they can cause a hypertensive crisis and the serotonin syndrome. They potentiate the hypertensive effects of most sympathomimetic amines, as well as tyramine, which is the reason for the avoidance of over-the-counter preparations containing such agents, in addition to the tyramine-free diet ( 508, 509). The serotonin syndrome occurs most often when MAOIs are used in combination with SSRIs and venlafaxine but it can also occur when MAOIs are used with tryptophan, 5-hydroxytryptophan, and some narcotic analgesics. In addition, MAOIs can also significantly potentiate the sedative and respiratory depressant effects of narcotic analgesics. 

HT2 receptors are present on skeletal muscle membranes, but their physiologic role is not understood. Serotonin syndrome is a condition associated with skeletal muscle contractions and precipitated when MAO inhibitors are given with serotonin agonists, especially antidepressants of the selective serotonin reuptake inhibitor class (SSRIs see Chapter 30). Although the hyperthermia of serotonin syndrome results from excessive muscle contraction, serotonin syndrome is probably caused by a central nervous system effect of these drugs (Table 16-4 and Serotonin Syndrome and Similar Syndromes). 

MAOIs, monoamine oxidase inhibitors MDMA, methylenedioxy-methamphetamine (ecstasy) SSRIs, selective serotonin reuptake inhibitors. Serotonin Syndrome and Similar Syndromes... 

The prototype SSRI, fluoxetine, differs from other SSRIs in some important respects (Table 30-1). Fluoxetine is metabolized to an active product, norfluoxetine, which may have plasma concentrations greater than those of fluoxetine. The elimination half-life of norfluoxetine is about three times longer than fluoxetine and contributes to the longest half-life of all the SSRIs. As a result, fluoxetine has to be discontinued 4 weeks or longer before an MAOI can be administered to mitigate the risk of serotonin syndrome. 

The most common interactions with SSRIs are pharmacokinetic interactions. For example, paroxetine and fluoxetine are potent CYP2D6 inhibitors (Table 30-4). Thus, administration with 2D6 substrates such as TCAs can lead to dramatic and sometimes unpredictable elevations in the tricyclic drug concentration. The result may be toxicity from the TCA. Similarly, fluvoxamine, a CYP3A4 inhibitor, may elevate the levels of concurrently administered substrates for this enzyme such as diltiazem and induce bradycardia or hypotension. Other SSRIs, such as citalopram and escitalopram, are relatively free of pharmacokinetic interactions. The most serious interaction with the SSRIs are pharmacodynamic interactions with MAOIs that produce a serotonin syndrome (see below). 

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