Depression Symptoms Treatment

Precautions

Because of their epileptogenic effect SSRIs should be used with caution in patients with epilepsy or a history of such disorders (and should be avoided if the epilepsy is poorly controlled). Treatment should be stopped if seizures develop or when there is an increase in seizure frequency. Care is advised in patients receiving ECT as prolonged seizures have occurred rarely. SSRIs should also be used with caution in patients with cardiac disease or a history of bleeding disorders. Although SSRIs are preferred to tricyclics for the treatment of depression in patients with diabetes, they may alter glycaemic control and therefore caution is also warranted in diabetic subjects. SSRIs should be used with caution in patients with angle-closure glaucoma. Fluoxetine should be stopped in patients who develop a rash since systemic effects, possibly related to vasculitis, have occurred in such patients. Fluoxetine undergoes hepatic metabolism and should be used with caution and in reduced doses in patients with impaired hepatic function.

Patients should be closely monitored during early therapy until significant improvement in depression is observed because suicide is an inherent risk in depressed patients. For further details, see under Depression. For a discussion of the concern that SSRIs may

increase suicidal ideation, and concerns about their use for depression in children and adolescents, see Effects on Mental State in Adverse Effects, above. Suicidal thoughts and behaviour may also develop during early treatment with antidepressants for other disorders the same precautions observed when treating patients with depression should therefore be observed when treating patients with other disorders. If SSRIs are given for the depressive component of bipolar disorder, mania may be precipitated. Symptoms may also worsen during the initial treatment of panic disorder with SSRIs. SSRIs may impair performance of skilled tasks and, if affected, patients should not drive or operate machinery.

Some licensed product information recommends reduced or less frequent dosage of SSRIs for elderly patients.

SSRIs should generally be withdrawn gradually to reduce the risk of withdrawal symptoms although this may be unnecessary for fluoxetine because of its long half-life.

Abuse. There have been occasional reports of individuals abusing fluoxetine.

Blood disorders. For a reference recommending cautious use of SSRIs in patients with a history of bleeding disorders, see Effects on the Blood in Adverse Effects, above.

Breast feeding. The American Academy of Pediatrics considers that all antidepressants, including SSRIs (fluoxetine, fluvoxamine, paroxetine, and sertraline) are drugs whose effect on nursing infants is unknown but may be of concern. In addition, most licensed drug information advises that SSRIs should be avoided by the mother during breast feeding.

• Citalopram and its metabolites have been detected in breast milk however, in one study, the plasma concentrations in exposed infants were either very low or undetectable and no adverse effects were reported. In another study, 3 out of 31 breast-fed infants whose mothers were taking citalopram had adverse effects, specifically one case each of colic, decreased feeding, and irritability. However, there was no significant increase in the risk of adverse events in this group of infants when compared with either infants of depressed mothers not taking citalopram, or infants of healthy controls.

• Symptoms of colic were reported in a 6-week-old infant whose mother was taking fluoxetine 20 mg daily. The concentrations of fluoxetine and its active metabolite norfluoxetine were 69 nanograms/mL and 90 nanograms/mL respectively in breast milk, and 340 nanograms/mL and 208 nanograms/mL respectively in the infant’s plasma. The infant’s symptoms resolved when he was formula fed. Postnatal weight gain has been reduced in infants exposed to fluoxetine during breast feeding, although in all cases the reduction was less than 2 standard deviations below the norm. In another report, several seizure-like episodes occurred in a breast-fed infant whose mother was taking fluoxetine in addition to carbamazepine and buspirone however, plasma drug concentrations in the infant were significant only for fluoxetine and norfluoxetine. In a study of 10 women taking fluoxetine while breast feeding 11 infants, breast milk concentrations of fluoxetine ranged from 17.4 to 293 nanograms/mL and of norfluoxetine from 23.4 to 379.1 nanograms/mL. No adverse effects were noted in the infants. Similar levels have occurred in other breast-fed infants without any apparent drug-induced adverse effects. Fluoxetine and norfluoxetine were detected in the milk of 14 nursing women. Blood samples were taken from 9 of the infants in the study, and of these, fluoxetine was detected in the plasma of 5 and norfluoxetine in 7. Although it was felt that many infants would tolerate the mean combined dose of fluoxetine and norfluoxetine transmitted via breast milk in this study, there was considerable interpatient variability in estimated infant dose and caution should be exercised neonates in particular exhibited higher concentrations of norfluoxetine than older infants. Moreover, since both fluoxetine and norfluoxetine have long half-lives, neonates already exposed in utero may have an additional risk of adverse effects during breast feeding.

• The excretion of fluvoxamine into breast milk was studied in a woman who had been receiving fluvoxamine maleate 100 mg twice daily for 2 weeks. The concentration of fluvoxamine base 4.75 hours after a dose was 310 nanograms/mL in maternal plasma and 90 nanograms/mL in breast milk. It was estimated that an infant would ingest only 0.5% of the daily maternal intake. It was considered that these data supported the notion that the use of fluvoxamine by nursing mothers posed little risk to the infant. A subsequent study found no detectable drug levels in the plasma of breast-fed infants exposed to fluvoxamine the authors suggested that fluvoxam-ine was a reasonable choice for nursing mothers requiring treatment for depression.

• Although paroxetine was detected in measurable concentrations in the breast milk of a group of 10 nursing mothers receiving paroxetine no adverse effects were reported in any of their breast-fed infants. Paroxetine could not be detected in the plasma of 7 of the 8 infants from whom samples were obtained and in the other infant, concentrations were not quantifiable. Another study involving 7 women suggested that the dose of paroxetine to suckling infants would be 0.7 to 2.9% of the weight-adjusted maternal dose. A later study also found no detectable drug levels in the plasma of breast-fed infants exposed to paroxetine the authors suggested that paroxetine was a reasonable choice for nursing mothers requiring treatment for depression. In a prospective cohort study, weight gain at 6 and 12 months of age in infants whose mothers took paroxetine during breast feeding was not adversely affected when compared with the infants of mothers who either did not breast feed or breast fed without taking any drugs during lactation in addition, there was no difference in reaching the usual developmental milestones between the infants of the 3 groups.

• Plasma concentrations of sertraline were undetectable in a breast-fed infant despite the presence of concentrations in the mother’s breast milk ranging from 8.8 to 43 nanograms/mL over a 24-hour period. However, the authors pointed out that metabolite levels were not measured and that sertraline may have been present in the infant at a concentration below the level of sensitivity of the assay. Other studies have detected desmethylsertraline in breast milk, which was also detected in the plasma of some of the infants in a number of the studies but not all. The authors of at least one study suggested that sertraline was a reasonable choice for nursing mothers requiring treatment for depression. In addition, some authors recommend expressing and discarding breast milk 8 to 9 hours after a maternal dose, when levels of desmethylsertraline and sertraline are maximal, in order to significantly reduce infant exposure to sertraline.

Children. SSRIs are associated with an increased risk of potentially suicidal behaviour when used for the treatment of depression in children and adolescents under 18 years old for further details, see under Effects on Mental State, above.

Diabetes m el I it us. A patient with type 1 diabetes mellitus experienced a loss of hypoglycaemic awareness following the start of treatment with fluoxetine. Awareness returned on tapered withdrawal of fluoxetine. Changes in blood sugar concentrations may occur in patients with diabetes treated for depression with SSRIs (see also Effects on the Endocrine System, above) however, these may represent an improvement in glycaemic control.

Driving. While affective disorders probably adversely affect driving skill, treatment with antidepressants can also be hazardous, although patients may be safer drivers with medication than without. Impairment of performance is largely related to sedative and antimuscarinic effects. These are more pronounced with older antidepressants such as the tricyclic antidepressants than with the SSRIs, but a comparative study of fluoxetine (an SSRI) and dosulepin (a tricyclic) in healthy subjects showed a similar but apparently small potential for impairing psychomotor and driving performance. A later epidemiological study was unable to confirm any increased risk of road-traffic accidents in those drivers receiving tricyclic antidepressants or SSRIs. In the UK, the Driver and Vehicle Ticensing Authority considers that drugs such as SSRIs may have fewer adverse effects on drivers than antidepressants with pronounced antimuscarinic or antihistaminic adverse effects, such as tricyclic antidepressants. However, all drugs acting on the CNS can impair alertness, concentration, and driving performance, particularly at the start of treatment or when the dose is increased driving must cease if patients are adversely affected. Patients with severe depressive illnesses complicated by significant memory or concentration problems, agitation, behavioural disturbances, or suicidal thoughts should also cease driving pending the outcome of medical enquiry.

Gastrointestinal disorders. For the opinion that the SSRIs may produce a clinically important increase in the risk of upper gastrointestinal bleeding in patients with a high risk of such bleeding, see under Effects on the Gastrointestinal Tract, above.

Glaucoma. For reference to SSRIs precipitating or exacerbating symptoms of glaucoma, see Effects on the Eyes, above.

Mania. Hypomania or mania have been reported with the SSRIs consequently, UK licensed drug information recommends that SSRIs should be withdrawn in any patient entering a manic phase.

Fluvoxamine was associated with manic behaviour in 8 patients who were being treated for major depression 3 also had obsessive-compulsive disorder. Daily doses of fluvoxamine ranged from 75 to 300 mg and duration of therapy to development of manic behaviour from 2 to 6 weeks. The authors were unable to determine whether fluvoxamine had induced mania or unmasked latent bipolar disorder in these patients. However, they recommended that fluvoxamine-treated patients should be monitored for manic behaviour.

Symptoms of manic behaviour also developed in a 7-year-old girl after taking sertraline for about 2 weeks for the treatment of major depression. She recovered within a few weeks of stopping sertraline.

Pregnancy. In an early prospective study comparing 128 pregnant women exposed to a mean daily dose of about 26 mg of fluoxetine during their first trimester with control groups receiving tricyclic antidepressants or non-teratogens, the incidence of neonatal malformations was similar in all groups and did not exceed that in the general population. However, there was a tendency to a higher incidence of miscarriages in the groups receiving fluoxetine or tricyclics. A more recent prospective study comparing 228 pregnant women taking fluoxetine with a control group taking non-teratogens also failed to find a significant increased incidence in major fetal abnormalities in the fluoxetine group it also did not reveal an increased risk of miscarriage. There was an increase in the incidence of minor fetal abnormalities in infants exposed to fluoxetine during the first trimester. Also, infants exposed to fluoxetine during the third trimester experienced more perinatal complications such as prematurity, low full-term birth-weight and length, and poor neonatal adaptation compared with infants exposed only during the first and second trimesters. However, the design of this study was criticised because of several methodological problems such as unmatched controls and a higher maternal age in the fluoxetine group, which may partly explain the excess of poor perinatal outcomes.

The manufacturer evaluated the outcome of 796 pregnancies in which the mother received fluoxetine during the first trimester and considered that it was unlikely that fluoxetine increased the risk of miscarriage or fetal malformation A prospective controlled study on pregnancy outcome in women exposed to fluvoxamine, paroxetine, or sertraline also found that, when used in recommended doses, there appeared to be no increase in the risk of major congenital malformations, miscarriages, or still-births when compared with women exposed to non-teratogens. Nonetheless, the results from a more recent meta-analysis which included some of the above studies have suggested that maternal exposure to antidepressant treatment (specifically SSRIs, tricyclics, nefazodone, trazodone, or venlafaxine) may significantly increase the risk of miscarriage in comparison to women not exposed to antidepressants. However, the authors acknowledged that the underlying depression itself might be a contributing factor to the increased risk.

There is some evidence that paroxetine may be more teratogenic than other antidepressants. The manufacturer GlaxoSmithKline has reported that overall the data from a retrospective US epidemiological study and a study using the Swedish national birth registry have indicated that there was a twofold increase in cardiovascular malformations, particularly ventricular septal defects, in infants born to mothers who had taken paroxetine during pregnancy compared with the general population. However, whereas the US study also showed an overall risk of major congenital malformations (inclusive of the cardiovascular defects), the Swedish study found no such increase.

Maternal use of SSRIs has been associated with neonatal complications. CNS toxicity and an increased heart rate were reported in a neonate whose mother had received 20 mg of fluoxetine daily throughout most of her pregnancy. The neonate’s symptoms resolved 96 hours after delivery. In another neonate whose mother took up to 30 mg daily of fluoxetine throughout the third trimester cardiac arrhythmias were noted. In a matched-control study the rate of complications after delivery in 55 infants exposed to paroxetine during the third trimester was higher than in a control group who had been exposed to paroxetine or non-ter-atogenic agents during the first or second timesters. Complications that occurred in the infants exposed in the third trimester included respiratory distress (9), hypoglycaemia (2), bradycardia (1), jaundice (1), and suckling problems (1). More recently, another matched-control study has suggested that exposure to SSRIs (in this case fluoxetine, paroxetine, and sertraline) after the 20th week of gestation may increase the risk of persistent pulmonary hypertension of the newborn (PPHN). Of 377 infants with a confirmed diagnosis of PPHN, the mothers of 14 (3.7%) had taken an SSRI after the 20th week of gestation, compared with only 6 out of 836 infants (0.7%) in the matched-control group. Although these figures represent about a sixfold increase in the risk of PPHN in infants exposed to SSRIs in utero, the absolute risk remains relatively low (about 6 to 12 per 1000 women).

A number of reports have described symptoms such as jitteriness, irritability, sleep disturbances, and altered muscle tone in neonates who had been exposed to SSRIs in utero, especially during the third trimester in the majority of cases the symptoms are mild and self-limiting. Although withdrawal symptoms have been reported with most SSRIs, they have been more commonly reported in those neonates exposed to paroxetine. More recently, some authors have used the term neonatal behavioural syndrome to refer to such symptoms. It is unclear whether the symptoms represent a withdrawal syndrome or direct serotonin toxicity however, it has been suggested by some that in utero exposure to SSRIs with a short half-life such as paroxetine may lead to a neonatal withdrawal syndrome whereas exposure to an SSRI with a long half-life, particularly fluoxetine, may manifest as neonatal serotonin toxicity. There have been case reports of intraventricular haemorrhage in neonates whose mothers took SSRIs during late pregnancy but there is currently not enough data to determine whether the frequency of such bleeds in infants exposed to SSRIs is higher than normal.

The effects of fluoxetine on fetal neurodevelopment were studied in 55 pregnant women by later assessing global IQ of the children no differences were seen in those exposed to fluoxetine in utero during the first trimester compared with those exposed to tricyclic antidepressants or adverse developmental influences. A subsequent study indicated that exposure to fluoxetine or tricyclic antidepressants throughout gestation did not appear to affect cognition adversely. In another follow-up study, subtle differences in motor development and control, in particular tremulousness and inappropriate fine motor movements, were noted in the infants and children of depressed mothers who had taken S SRIs during pregnancy when compared with the infants of depressed mothers who had not taken any medication. However, in other measures of mental development there were no observed differences between the two groups.

Surgery. In patients undergoing orthopaedic surgery, the risk of perioperative blood loss was significantly increased in those taking serotonergic antidepressants (specifically clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine) when compared with those on non-serotonergic antidepressants. In addition, there was a significant increase in the need for blood transfusion during surgery in those on serotonergic antidepressants compared with those not receiving antidepressant medication.

Withdrawal. Withdrawal reactions have been reported for all SSRIs and the related antidepressants mirtazapine and venlafaxine on dosage reduction or stopping treatment, although the frequency of such reactions may vary. Paroxetine and venlafaxine have been associated with withdrawal reactions more often than other serotonergic antidepressants in the case of paroxetine this may be due, in part, to its short half-life. Fluvoxamine also has a short half-life and has been shown in some studies to have a high risk of withdrawal reactions. The apparent lower risk of withdrawal reactions with fluoxetine may be due to its long half-life. Other factors that increase the risk of withdrawal reactions include abrupt withdrawal, the use of high doses, and prolonged therapy.

In general, withdrawal reactions tend to occur within 3 days of stopping an SSRI or related antidepressant, although a delay of up to 2 weeks may be noted with fluoxetine. Common symptoms include dizziness, numbness and tingling, gastrointestinal disturbances (particularly nausea and vomiting), headache, sweating, anxiety, and sleep disorders. In some cases withdrawal symptoms may be severe and disabling. There has also been a report of 2 patients without a history of major psychiatric disorder who developed severe behavioural symptoms when paroxetine was withdrawn. Withdrawal was abrupt in one patient and more gradual, over a 12-day period, in the other. Symptoms were mainly hypomanic over the first few days, followed by a period of escalated ego-dystonic aggression, behavioural dyscontrol, and suicidal ideation.

Antidepressant dose tapering appears to reduce the frequency and severity of withdrawal reactions. The BNF recommends that any antidepressant, including an SSRI, that has been taken regularly for 8 weeks or more should be stopped gradually over a period of about 4 weeks, or as much as 6 months in patients who have been receiving long-term maintenance therapy. The withdrawal syndrome of the SSRIs is not considered to be a consequence of dependence.’

See also Extrapyramidal Effects under Adverse Effects, above. For debate about whether a withdrawal syndrome exists in neonates whose mothers have received SSRIs see Pregnancy, above.

Interactions

SSRIs interact with other drugs mainly as a result of their inhibitory activity on hepatic cytochrome P450 isoenzymes. Individual SSRIs do not all exhibit the same degree of inhibition nor do they react with the same isoenzymes. The drugs inhibited by specific SSRIs depends on the isoenzyme affected. As SSRIs have occasionally been associated with bleeding disorders and other effects on the blood, caution is advised when they are given with drugs known to affect platelet function.

Although different antidepressants have been used together under expert supervision in refractory cases of depression, severe adverse reactions including the serotonin syndrome may occur. Sequential prescribing of different types of antidepressant may also produce adverse reactions, and an appropriate drug-free interval should elapse between stopping one type of antidepressant and starting another. SSRIs should not generally be given to patients receiving MAOIs or for at least 2 weeks after their use. No treatment-free period is necessary after stopping a reversible inhibitor of monoamine oxidase type A (RIMA) and starting an SSRI. At least one week should elapse between withdrawing an SSRI and starting any drug liable to provoke a serious reaction (e.g. phenelzine) in the case of the SSRI sertraline the drug-free interval is extended to 2 weeks, and for fluoxetine 5 weeks, because of their longer half-lives. (For fluoxetine, the interval may need to be further extended if therapy has been prolonged or if high doses have been given.) Adverse effects such as the serotonin syndrome may also occur when the SSRIs are given with other drugs known to act on the same neurotransmitter, a consequence of synergistic interaction.

Further details concerning some of these interactions, and others, are given below.

Antibacterials. Rapid development of delirium was reported in a patient when clarithromycin was added to his existing regimen of fluoxetine and nitrazepam It was suggested that his delirium was a result of increased plasma-fluoxetine concentrations produced by the inhibition of cytochrome P450 enzymes by clarithromycin. Serotonin syndrome developed in a patient given erythromycin in addition to sertraline this was attributed to inhibition of CYP3A4 by the antibacterial, resulting in accumulation of the SSRI. There have also been reports of serotonin syndrome when linezolid was given with fluoxetine, sertraline, paroxetine, and citalopram in the latter case the patient developed complications including metabolic acidosis and ultimately fatal cardiac arrest. Reviews of serotonin syndrome associated with the use of linezolid suggest that SSRIs are the interacting drug most often implicated. However, it has been suggested that if warranted, linezolid may be given to patients receiving SSRIs provided the patient is carefully monitored for signs and symptoms of serotonin syndrome.

Anticoagulants. SSRIs may increase the anticoagulant activity of some anticoagulants including acenocoumarol and warfarin.

Antidepressants. Combination therapy with differing classes of antidepressants has been used successfully in the treatment of drug-resistant depression. It should be emphasised, however, that such combinations may result in enhanced adverse reactions or interactions, and should be used only under expert supervision. This practice is considered unsuitable or controversial by some authorities. For further details of the interactions between different antidepressants when given together, see Phenelzine. For details of the serotonin syndrome that can arise when two serotonergic drugs with different mechanisms of action are given, see under Adverse Effects of Phenelzine.

Antiepileptics. Antidepressants may antagonise the activity of antiepileptics by lowering the convulsive threshold. There has been a report of the serotonin syndrome developing in a patient 14 days after fluoxetine had been added to carbamazepine therapy.

Phenobarbital has been reported to reduce serum concentrations of paroxetine. Steady-state serum concentrations of paroxetine were found to be lower in patients taking phenytoin than in those taking carbamazepine or valproate.

Low serum concentrations of citalopram have been reported in 2 patients also taking carbamazepine. Serum concentrations increased when carbamazepine was changed to oxcarbazepine. Some SSRIs have been reported to increase plasma concentrations of carbamazepine and phenytoin. For conflicting reports of the effect of fluoxetine on serum-valproate concentrations.

Antihistamines. Cyproheptadine given to male and female patients as treatment for sexual dysfunction induced by fluoxetine or paroxetine has produced re-emergence of previously controlled depressive symptoms or bulimia nervosa in some patients. Citalopram, fluoxetine, and fluvoxamine may increase plasma concentrations ofastemizole or terfenadine by inhibition of their hepatic cytochrome P450 metabolism, increasing the risk of ventricular arrhythmias use together should be avoided.

Antimalarials. For mention of the effect of the SSRI fluvoxamine on the metabolism of proguanil.

Antimigraine drugs. There have been rare reports of serotonin syndrome associated with the use of SSRIs with serotonin (5-HT1) agonists such as sumatriptan. Fluvoxamine may inhibit the metabolism of frovatriptan and zolmitriptan. Fortheeffectswhensome SSRIs are used with dihydroergotamine.

Antimuscarinics. For the effect of SSRIs on benzatropine. For the effect of paroxetine on procyclidine.

Antineoplastics. Paroxetine may inhibit the metabolism of tamoxifen for further details.

Antipsychotics. For reports of adverse effects in patients treated with SSRIs and antipsychotics, see under Chlorpromazine. Interactions between SSRIs and atypical antipsychotics are also mentioned under clozapine, olanzapine, risperidone, sertindole, and zotepine.

Antivirals. Plasma concentrations of fluoxetine and other SSRIs are possibly increased by HIV-protease inhibitors, such as ritonavir, which may inhibit metabolism of the SSRI. Unexpectedly, however, total exposure to paroxetine was approximately halved by a ritonavir-boosted fosamprenavir combination in a study in healthy subjects. Although the free fraction of paroxetine in plasma was increased, suggesting that it had been displaced from protein binding, the maximum concentration of free paroxetine was reduced.

The serotonin syndrome has been described in a few patients given regimens that included fluoxetine and antiretroviral-dose ritonavir. The reaction also occurred in another patient given fluoxetine and efavirenz.

Anxiolytics. Fluoxetine and fluvoxamine increase plasma concentrations of some benzodiazepines (see under Diazepam). There is a report of hyponatraemia and serotonin syndrome developing in a patient who received high doses of citalo-pram and buspirone.

Beta blockers. For the effect of fluoxetine and fluvoxamine on beta blockers.

Ciclosporin. For the effect of fluoxetine and fluvoxamine on ciclosporin.

Cough suppressants. For the effects when using fluoxetine or paroxetine with dextromethorphan.

Dopaminergics. Selegiline is an irreversible selective inhibitor of monoamine oxidase type B. Serious adverse effects have been reported when selegiline and S SRIs have been used together. In some instances, these reactions resemble the potentially fatal serotonin syndromes reported when SSRIs are given with non-selective MAOIs.

SSRIs should not generally be given to patients receiving selegiline, or for at least 2 weeks after it has been stopped. Similarly, at least one week should elapse between withdrawing an SSRI and starting selegiline this interval should be increased to 2 weeks for sertraline, and to 5 weeks for fluoxetine because of their longer half-lives.

Gastrointestinal drugs. Acute dystonia has been noted in a patient given fluvoxamine and metoclopramide. Similar reports have been published for other SSRIs (fluoxetine or sertraline) and metoclopramide. Involuntary twitching, tremor, and stiffness of the jaw and tongue occurred on both occasions after the use of intravenous metoclopramide in a patient also taking sertraline. The authors considered the adverse effects to be features of the serotonin syndrome.

For the effect of fluvoxamine on alosetron, and a recommendation that the combination be avoided. For the effect of fluvoxamine on proton pump inhibitors, including omeprazole.

General anaesthetics. For a report of a generalised tonicclonic seizure in a patient receiving paroxetine and methohexital sodium.

Hypnotics. For reference to visual hallucinations in patients receiving an SSRI concomitantly with zolpidem.

Levothyroxine. For mention of a decreased effect of levothy-roxine in patients given sertraline concomitantly.

Local anaesthetics. For the effect of fluvoxamine on ropivacaine.

Muscle relaxants. For a report of QT prolongation in a patient taking fluoxetine and cyclobenzaprine. For the effect of fluvoxamine on tizanidine.

NSAIDs. For reference to an increased risk of upper gastrointestinal bleeding in patients taking SSRIs and NSAIDs together, see under Effects on the Gastrointestinal Tract, above.

Opioid analgesics. A possible case of serotonin syndrome has been reported with tramadol and sertraline, and another when sertraline was given with high doses of oxycodone There have also been occasional reports of the syndrome in patients given tramadol with citalopram, fluoxetine, or paroxetine. Other reports of serotonin syndrome were associated with use of oxycodone and fluvoxamine, pethidine and fluoxetine, and citalopram with fentanyl or pethidine. For reference to SSRIs enhancing the effects and toxicity of methadone.

Parasympathomimetics. For the effect of fluvoxamine on tacrine. For the effect of some SSRIs on galantamine.

Sibutramine. There is a risk of CNS toxicity due to synergistic serotonergic actions when an SSRI is given with sibutramine.

Smoking. Serum concentrations of fluvoxamine were lower in smokers than non-smokers in a single-dose study. It was proposed that the polycychc hydrocarbons present in cigarette smoke stimulated hepatic metabolism of fluvoxamine by cytochrome P450 isoenzymes.

Stimulants. For the effect of paroxetine on the metabolism of atomoxetine.

Theophylline. For the effect of fluvoxamine on theophylline.

Pharmacokinetics

Fluoxetine is readily absorbed from the gastrointestinal tract with peak plasma concentrations appearing about 6 to 8 hours after oral doses. Systemic bioavailability does not appear to be affected by food. Fluoxetine is extensively metabolised, by demethylation, in the liver to its primary active metabolite norfluoxetine. Excretion is mainly via the urine. Protein binding is reported to be about 95%.

Fluoxetine used clinically is a racemic mixture consisting of R- and S-enantiomers in equal amounts. Both enantiomers are active according to animal studies, but S-fluoxetine is eliminated more slowly. Metabolism is believed to be mediated by cytochrome P450 isoen-zyme CYP2D6 (but see below), and leads to R- and S-enantiomers of norfluoxetine, with the S-enantiomer being considered as active as the parent drug the R-enantiomer is considered to be much less active. This metabolism is subject to genetic polymorphism. While the small proportion of the population known as slow metabolisers do show a different spectrum of parent drug and metabolite, the overall activity does not appear to be altered.

Fluoxetine is widely distributed throughout the body. Fluoxetine has a relatively long elimination half-life of about 1 to 3 days after acute use and 4 to 6 days after long-term use that of its metabolite, norfluoxetine, is even longer, being about 4 to 16 days. These long half-lives have clinical implications. Steady-state plasma concentrations will only be attained after several weeks. Additionally, fluoxetine and its metabolites may persist for a considerable time after treatment, and this has led to precautions concerning the subsequent use of other serotonergic drugs (see Interactions, above).

Fluoxetine and norfluoxetine are distributed into breast milk (see Breast Feeding under Precautions, above).

Metabolism. Although fluoxetine is stated by the manufacturers to be metabolised by the cytochrome P450 isoenzyme CYP2D6, which is supported by studies indicating that its disposition is altered in poor metabolisers of debrisoquine (a substrate for this enzyme), others have suggested that CYP2C19, and perhaps CYP2C9, play an important role.