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Antidepressant drugs
EJ. Cowen
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Antidepressant drugs
GENERAL Sexual function Most classes of antidepressant drugs are associated with sexual dysfunction of various kinds, including reduced desire and arousal, erectile difficulties, and ejaculatory and orgasmic inhibition. A literature review has shown that rates of sexual dysfunction of all kinds were highest with selective serotonin re-uptake inhibitors (SSRIs) and venlafaxine and least with amfebutamone (bupropion) and the reversible inhibitor of monoamine oxidase type A, moclobemide (1R). Switching to amfebutamone or mirtazapine from SSRIs often enabled patients to obtain relief from sexual dysfunction. However, commonly recommended antidotes to SSRI-induced sexual dysfunction, such as Ginkgo biloba, serotonin (5-HTz) receptor antagonists, such as cyproheptadine, and amfebutamone augmentation were not supported by placebo-controlled trials. These data suggest that antidepressant-induced sexual dysfunction is more likely to be associated with agents that greatly potentiate 5-HT neurotransmission. This notion is supported by the results of a 6-week double-blind study of 24 men with premature ejaculation, in which paroxetine (20 mg/day) increased latency to ejaculation six-fold while mirtazapine (30 mg/day) had minimal effect (2c). In a randomized, 8-week, double-blind, placebocontrolled study in 450 patients with major depression, fluoxetine ( 2 0 4 0 mg/day) significantly impaired sexual function, while the noradrenaline re-uptake inhibitor reboxetine had no effect (3c). In a double-blind, placebo-controlled study in 90 patients with sexual dysfunction who were taking a variety of 5-HT re-uptake inhibitor antidepressants, sildenafil (50-100 mg)
9 2005 Elsevier B.V. All rights reserved, Side Effects of Drugs, Annual 28 J.K. Aronson, ed. 14
produced improvement in all aspects of the sexual response in 54% of antidepressant-treated patients compared with a placebo response rate of 4.4% (NNT = 2) (4c). This suggests that sildenafil is an effective treatment for antidepressant-induced sexual dysfunction. Tumorigenicity Studies in rats have suggested that both tricyclic antidepressants and selective serotonin re-uptake inhibitors (SSRIs) promote the growth of mammary tumors. Rates of antidepressant prescribing have increased over the last 20 years, and breast cancer remains a leading cause of mortality in women. Two recent non-systematic reviews (5 R, 6 M) have examined the question of whether antidepressant treatment might increase the risk of breast cancer. A variety of studies have been conducted, including hospital- and population-based casecontrol studies and prospective cohort studies. Overall the evidence for an association between any use of antidepressant medication and breast cancer is weak and inconclusive. However, it is possible that sustained use of certain drugs, for example, the SSRI paroxetine, might be associated with an increased risk. Problems with the studies reviewed include defining what kind of antidepressant treatment regimen represents significant exposure, and the unknown nature of the time-course of any effect of antidepressants on the development of breast cancer. The increasing use of SSRIs, which are known to be associated with breast enlargement (SEDA-22, 12), suggests that further prospective studies are needed.
Overdose with antidepressant drugs Suicidal ideation o f some kind almost invariably accompanies severe depression. Hence the relative toxicity o f antidepressants in overdose can be important in determining treatment
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choice. It is accepted that SSRIs are less dangerous in overdose than tricyclic antidepressants, but there are fewer data on the toxicity of other antidepressants. The presentation and likely toxicity in overdose of several newer antidepressant drugs have been reviewed (7R). Deaths in overdose have been most clearly associated with amfebutamone and venlafaxine. Amfebutamone overdose typically presents with neurological symptoms, including delirium, agitation, and seizures; however, cardiac dysrhythmias, with QT intelwal prolongation and cardiac arrest, have occurred (8 c, 9c). Ventafaxine overdose is also associated with seizures and cardiac dysrhythmias (4R). Venlafaxine is a potent 5-HT re-uptake inhibitor, and signs of 5-HT toxicity (agitation, my_ octonus, hyperthermia) are common. In a prospective cohort study of over 450 patients who had attempted suicide by antidepressant ingestion the risk of seizures after venlafaxine overdose (14%) was significantly greater than that of SSRIs (1.3%) and similar to that seen with dosulepin (11%) (lOC). Rates of 5-HT toxicity did not differ significantly between ventafo_xine and SSRIs (29% versus 19%) but were greater than with tricyclic antidepressants (1.2%). Unlike SSRIs, venlafaxine was associated with significant prolongation of the QT interval; tricyclic antidepressants had a similar effect. Data on the consequences of overdose of other new antidepressant agents are limited, but current evidence suggests that reboxetine and mirtazapine have low toxicity in overdose (7R ). Reboxetine, as would be expected, presents with signs of noradrenergic overactivity, such as sweating, tachycardia, hypertension, and anxiety. The characteristic feature of mirtuzapine overdose is sedation (7R ). Overdose of moclobemide by itself rarely appears to give rise to serious problems. This is in contrast to overdose with conventional monoamine oxidase inhibitors, which can cause fatal 5-HT toxicity. However, if patients take moclobemide together with serotonergic antidepressants, such as SSRIs or clomipramine, 5HT toxicity is common. 5-HT toxicity occurred in 11 of 21 patients who took overdoses of moclobemide and serotonergic agents but in only one of 33 patients who took moclobemide alone (11c). Consistent with this, four patients died, presumably of 5-HT toxicity, after co-ingesting
15 3, 4-methytenedioxymethamphetamine (M DMA, ecstasy) and moclobemide (12c). Overall the current data suggest that the safety advantage in overdose relative to tricyclic antidepressants enjoyed by SSRIs may extend to reboxetine and mirtazapine. Amfebutamone and venlafaxine are more toxic than SSRIs in overdose, but they are still likely to be safer than tricyclic antidepressants.
TRICYCLIC ANTIDEPRESSANTS (SED-14, 44; SEDA-25, 13; SEDA-26, 11; SEDA-27, 11) Museuloskeletal Elderly people are at increased risk of fractures, and a case-control study of patients admitted to hospital suggested that both tricyclic antidepressants and SSRIs increased the probability of hip fracture about 2.5 times (SEDA-22, t t). In a prospective study of 8127 women aged 65 years and older who were followed for 4.8 years, the risk of a first hip fracture was 4% and the risk in women taking antidepressants was increased 1.7 times (95% CI = 1.05, 2.07) (13c). The relative risk among women taking tricyclic antidepressants (RR = 1.83; CI = 1.08, 3.09) was slightly higher than that for SSRIs, which had wider confidence intervals (RR -= 1.54; CI = 0.62, 3.08). Depression as an independent variable did not increase the risk of hip fracture. This study has confirmed that women taking antidepressants are at increased risk of hip fracture and has suggested that the effects of SSRIs and tricyclic antidepressants are similar.
SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs) (SED-14, 67; SEDA-25, 14; SEDA-26, 11; SEDA-27, 12) Nervous syslem SSRIs are often associated with sleep disturbances, particularly reduced sleep efficiency and altered sleep architecture. Paroxetine has been associated with sleepwalking (somnambulism) (14c).
16 9 A 61-year-oldwomantakingparoxetine 10mg/day for depression had difficulty falling asleep, but there was no personal or family history of parasomnia. After 2 weeks the paroxetine was increased to 20 mg/day and l week later she was noted by her husband to be sleep-walking and trying at times to leave the house. When wakened she was confused and had no memory of the event. The paroxetine was withdrawn; the sleep-walking stopped and did not recur. Other classes of antidepressant dmgs can sometimes cause somnambulism, and it seems likely that paroxetine provoked this rare adverse effect. Sleep-walking is thought to be initiated during slow-wave sleep, after which partial arousals activate motor behaviors in the absence of full consciousness. The disrupting effects of antidepressants on sleep architecture might lead to somnambulism in pre-disposed individuals. Psychiatric Over the last decade there has been a debate as to whether SSRIs might increase the risk of suicide in certain individuals. Some patients can respond to SSRIs by becoming agitated and restless and developing symptoms that resemble akathisia. Case reports have suggested that adverse effects of this type could underlie an increased risk of selfharm and aggression. However, results from the placebo-controlled randomized trials carried out for regulatory purposes have not supported the proposal that SSRIs increase the risk of suicide of suicidal behavior. A review of the database of the Food and Drug Administration showed 77 suicides among 48 277 patients who had participated in placebocontrolled trials of antidepressants (15M). The rate of suicide with SSRIs (0.59%; CI = 0.31, 0.87) was similar to that of other antidepressants (0.76%; CI = 0.49, 1.03) and placebo (0.45%; CI = 0.01, 0.89). While these data are reassuring, patients considered clinically at high risk of suicide were excluded from the trials and the patients received a greater degree of supervision than would occur in routine practice. In a re-analysis of antidepressant trial data there was an odds ratio for a suicidal act while taking SSRIs relative to placebo of 2.0 (CI = 1.2, 3.3), while the risk for completed suicide on SSRIs, although raised, had wide confidence intervals (RR = 3.1; CI = 0.4, 23.1) (16R). One of the author's arguments was that in previous analyses suicidal behaviors occurring during placebo wash-out have been misclassified
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as happening during placebo treatment. Separation of these two classes of event allows a pro-suicidal effect of SSRIs to be revealed. Overall the randomized studies suggest that the risk of suicide and suicidal behavior in patients taking placebo is numerically less than in patients taking active antidepressants. Since on clinical rating scales, antidepressant drugs usually reduce suicidal ideation more than placebo, this is a paradoxical observation. It might, however, reflect the old adage that the risk of suicide is greatest during the early stages of antidepressant treatment, when motor retardation has remitted but depressed mood and suicidal thinking persist. Such an effect might be exaggerated with modem antidepressants, which are more activating than tricyclic antidepressants. The need for caution in both clinical practice and trial evaluation is underlined by a warning from the Committee of Safety of Medicines that paroxetine is no more effective than placebo in the treatment of depression in adolescence, and may also be associated with a greater risk of self-harm and suicidal behavior (17s). Gastrointestinal A previous case-control study linked SSRI treatment with gastrointestinal bleeding (SEDA-24, 15), and this has been confirmed in a cohort study in 26005 antidepressant users (18c). The risk of being hospitalized for upper gastrointestinal bleeding within 90 days of antidepressant prescription was increased in people taking SSRIs (OR = 3.6; CI = 2.7, 4.7). Combined use of SSRIs and aspirin increased the risk 5.2 times (CI = 3.2, 8.0), while combined use with an NSAID increased the risk 12 times (CI = 7.1, 20). There was a lower risk of gastrointestinal bleeding (OR = 2.3; CI = 1.5, 3.4) with antidepressants with less potency to inhibit 5-HT re-uptake (amitriptyline, dosulepin, imipramine), while non-serotonergic antidepressants (desipramine, nortriptyline, mianserin) did not increase the risk. These findings suggest that SSRIs should be used with caution in patients taking aspirin or NSAIDs. The risk of upper gastrointestinal bleeding with SSRIs used by themselves appears to be of the same order as that with aspirin. This observation is of interest, in view of a case-control study suggesting a lower risk of first myocardial infarction in patients taking SSRIs (OR = 0.59; CI -----0.39, 0.91) (19c). This effect was not seen with non-SSRI antidepressants.
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L i v e r Hepatitis has been reported in association with paroxetine and fluoxetine (SEDA-21, 12; SEDA-24, 15) and a case has now been associated with sertraline (20c). 9 A 23-year-old woman taking sertraline (dose and length of time not stated) developed a mild pyrexia, fight-sided abdominal pain, nausea, vomiting, and chills. She had a raised serum alanine transaminase activity but no other abnormality of liver function tests. A liver biopsy showed changes consistent with either a drug-induced reaction or autoimmune disease. Sertraline was withdrawn and prednisone 20 mg/day started. Four weeks later her alanine transaminase activity had fallen significantly, but she then restarted sertraline because of increasing depression. The alanine transaminase activity rose again, despite continuing prednisone, and only fell when sertraline was withdrawn. While there have been other cases of hepatitis in association with sertraline this is the first case to have been confirmed by re-challenge. R e p r o d u c t i v e system SSRIs can be associated with breast enlargement in w o m e n and gynecomastia has been reported in men. 9 Gynecomastia occurred in a 30-year-old man who had taken paroxetine 40 mg/day for 5 years (21c). Over this time gynecomastia of the left breast became increasingly marked. There was no evidence of metabolic or hormonal abnormalities and plasma prolactin was within the reference range. Biopsy showed no evidence of malignancy. The gynecomastia was reduced by surgery and paroxetine was replaced with mirtazapine. At 2-year follow-up there was no evidence of recurrence. 9 A similar but more acute case of gynecomastia in association with fluoxetine has been reported in a 21 year old man (22c). The gynecomastia resolved after fluoxetine withdrawal. Fetotoxicity An increasing number of w o m e n take SSRIs during pregnancy and in the postnatal period. Some studies have suggested that SSRI treatment in pregnancy is not associated with an increased risk of malformations (SEDA-24, 15). However, neonates born to woman taking SSRIs can have a variety of symptoms, including jitteriness, hypoglycemia, hypothermia, and respiratory distress. 9 A boy (3.4 kg) was born by cesarean section, because of fetal distress, to a mother who had taken paroxetine (40 mg/day) and olanzapine (10 mg/day) until 48 hours before delivery (23c). After delivery, the baby had increased tone and was hypoglycemic. The next day he was increasingly jittery, with profuse salivation. At 44 hours
17 there was no detectable paroxetine or olanzapine in the neonatal plasma and CSF concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were normal. The baby's condition improved over the next few days, and 1 week after birth the only abnormality was slight jitteriness. At 6 months the baby was considered normal. This infant's symptoms were similar to those described in other neonates whose mothers took SSRIs shortly before delivery, although in this case a contributory effect from olanzapine was also possible. The authors made the point that it can be difficult to decide from the clinical presentation whether neonatal problems, such as those described above, represent SSRI withdrawal (5-HT deficiency) or SSRI toxicity (5H T excess). The fact that no paroxetine was detected in the infant's plasma led them to conclude that SSRI withdrawal was responsible for the symptoms in this case. In a follow-up study in 20 infants born to mothers who had taken either fluoxetine ( 2 0 40 rag/day) or citalopram (21)--40 mg/day), the children of mothers who had taken SSRIs had raised scores in the first 4 days of life on scales rating symptoms of 5-HT excess, including tremor, rigidity, and restlessness (24c). Children who had been exposed to SSRIs had lower concentrations of 5 - H I A A in cord blood (consistent with persistent 5-HT reuptake blockade) and there was a significant negative correlation between the 5-HT symptom score and cord blood 5-HIAA. At 4 days citalopram and fluoxetine were detectable in plasma samples from the infants. By 2 weeks there was no significant difference in 5-HT symptom scores between exposed infants and controls. Weight gain over this time was similar in the two groups. These findings support the view that the neonatal syndrome associated with SSRI treatment of mothers around the time of delivery can sometimes be due to 5-HT toxicity rather than SSRI withdrawal. L a c t a t i o n Mothers taking antidepressants often want to breast feed their babies. Generally SSRI treatment of nursing mothers is without an obvious acute effect on the infant (SEDA26, 14), although adverse effects in infants are occasionally reported (SEDA-25, 15). When blood and milk were sampled in 22 nursing women taking sertraline (25-200 mg/day), sertraline and its metabolite, desmethylsertraline,
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18 were found in all the milk samples (25c). The maximum concentration of sertraline and desmethylsertraline in the milk occurred 8 9 hours after maternal ingestion of the daily dose of sertraline. Eleven infants had detectable desmethylsertraline; of these, four also had detectable sertraline. No adverse effects were noted in any of the children. The authors calculated that the infants had received on average about 0.5% of the maternal sertraline dose. These data confirm that the infants of nursing mothers taking SSRIs are likely to be exposed to low doses of antidepressants. While this rarely causes overt effects, the possibility of subtle long-term behavioral consequences cannot be excluded. In the case of sertraline it would be wise to discard breast milk accumulated 8-9 hours after dosing as this will reduce the daily dose that the infant receives.
Drug interactions Alprazolam
SSRIs and the benzodiazepine alprazolam are often used to treat panic disorder. Pharmacokinetic reactions between them could therefore be important. AIprazolam is metabolized by CYP3A4, which fluvoxamine inhibits (SEDA-22, 13). In 23 outpatients (11 men, 12 women, mean age 39 years) who took alprazolam both as monotherapy (mean dose 1.0 mg/day) and in combination with fluvoxamine (mean dose 34 mg/day), fluvoxamine increased plasma alprazolam concentrations by 58% (26c). This was not associated with increased sleepiness, measured by a subjective rating scale, but objective measures of psychomotor function were not carried out and these could have been impaired by raised alprazolam concentrations. The effects of SSRIs on alprazolam pharmacokinetics have been studied in 21 healthy volunteers (age and sex not given) who were pre-treated with either fluoxetine or citalopram (20 mg/day for 21 days) (27c). Fluoxetine increased the AUC of a single 1.0 mg dose of alprazolam by 32%; citalopram had no effect. These findings are consistent with previous reports that fluoxetine and its active metabolite, norfluoxetine, produce moderate inhibition of CYP3A4 while citalopram does not.
Grapefruit juice Grapefruit juice is also a modest inhibitor of CYP3A4. Grapefruit juice (250 ml tds) for 5 days produced a 1.6-fold increase in the AUC of a single dose of fluvoxamine 75 mg in 10 healthy men (aged 19-30
PJ. Cowen
years) (28c). Fluvoxamine is metabolized by CYP2D6 and CYP1A2, but this study suggests that there may also be a modest contribution from CYP3A4.
Pethidine
Pethidine plus an SSRI may have caused a 5-HT syndrome (29c). A 43-year-old man was premedicated for endoscopy with intravenous midazolam 2 mg and pethidine 50 mg). He immediately became agitated and restless. His blood pressure rose to 180/100 mmHg, he sweated, had widely dilated pupils, and had diarrhea. Over the next 90 minutes his condition remitted without specific treatment. He then reported that he had been taking fluoxetine (20 mg every other day), which he had stopped taken about 2 weeks before.
The symptoms described here resemble the 5-HT toxicity syndrome (SEDA-25, 16) and suggest that pethidine can provoke this reaction when combined with SSRIs, as it can with monoamine oxidase inhibitors. The report is also a useful reminder that the active metabolite of fluoxetine, norfluoxetine, has a half-life of about 1 week and would still have been present at the time of endoscopy, even though fiuoxetine had been stopped 14 days before.
OTHER ANTIDEPRESSANTS Amfebutamone (bupropion) (SED-14, 60; SEDA-25, 17; SEDA-26, 15; SEDA-27, 14) Nervous system
Somnambulism has been re-
ported with amfebutamone (30c). A 35-year-old man took amfebutamone 150 mg bd as part of a smoking cessation program. After 14 days he stopped smoking, after which he noted some increase in mood and appetite. Three days later a friend reported that the patient had telephoned him at 1.00 am, about 2 hours after he had gone to sleep, but the patient had no memory of this. Over the next week he discovered evidence of several episodes of nocturnal eating but again had no recall of getting up at night to obtain food. He stopped taking amfebutamone and the sleepwalking episodes disappeared and did not recur. Amfebutamone promotes slow wave sleep, the sleep stage during which somnambulism is
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initiated. However, this case was complex, because of the possible interaction with nicotine withdrawal. Nicotine withdrawal is associated with increased appetite and weight gain, and sleep walking can be associated with nocturnal eating (31c). Amfebutamone has been associated with extrapyramidal movement disorders (SEDA-27, 15) and ballismus has been reported (3 l C). 9 A 42-year-old woman developed ballismus 4 days after increasing her dose of amfebutamone to 150 mg bd. She had an involuntary urge to move, gross flexion movements of the torso, and slapping movements of her arms. She had no previous history of movement disorders and was taking only occasional sumatriptan for migraine. Amfebutamone was withdrawn and she was given haloperidol and oxazepam. The movements abated. It seems likely from this that the dopaminergic effects of amfebutamone can provoke movement disorders in therapeutic doses in some individuals. Immunologic Amfebutamone has been associated with a variety of hypersensitivity reactions, including urticaria and serum sickness (SEDA-25, 17). Further reactions in association with amfebutamone have been reported. 9 A 24-year-old man developed a fever and a generalized maculopapular rash after taking amfebutamone 150 mg bd for 3 weeks (32c). Amfebutamone was withdrawn but he went on to develop angioedema, eosinophilia, and a systemic syndrome with hepatitis, myositis, and obstructive lung disease. His symptoms resolved over several weeks with a glucocorticoid.
Mirtazapine
(SED-14, 63; SEDA-27, 16)
Nervous system Mirtazapine is a potent histamine H1 receptor antagonist and is perceived by patients as being sedative. While this may improve disturbed sleep, it also has implications for daytime psychomotor performance. The effect of mirtazapine (15 mg at night for 2 days, then 30 mg at night for 2 days) and paroxetine (20 mg in the morning for 5 days) has been studied in a placebo-controlled, crossover design in 12 healthy volunteers (10 women, 2 men, median age 26 years) (33c). On the fifth
19 day the subjects undertook a battery of psychomotor tests. Mirtazapine significantly impaired several aspects of psychomotor performance and increased daytime sleepiness, while paroxetine did not. These results suggest that patients who take mirtazapine should be warned about its deleterious effects on psychomotor performance, particularly driving. It is likely that tolerance to this effect will occur, but the time course of adaptation is uncertain. Also uncertain is how far these results in healthy subjects can be extrapolated to depressed patients, many of whom will have performance deficits due to poor sleep, which could conceivably be helped by mirtazapine.
Trazodone
(SED-14, 64)
Teratogenieity The use of antidepressants in pregnancy is a difficult area, because the teratogenic effects of many antidepressants are not known. While tricyclic antidepressants and SSRIs are believed to present a low risk of fetal abnormality (SEDA-24, 15), the teratogenic potential of trazodone has been unclear. In 147 women who took either trazodone or nefazodone during the first trimester of pregnancy, the rate of major malformations in the trazodone/nefazodone group (1.6%) did not differ statistically from that in a control group (3.0%) (34c). Similarly, there were no statistically significant differences in rates of spontaneous abortion or stillbirth or in birth weight in the babies of women who took trazodone or nefazodone. These findings are reassuring. However, as the authors pointed out, the study, while prospective, was not randomized. In addition they did not examine the effects of trazodone and nefazodone separately, and did not state how many women were taking each drug. While trazodone and nefazodone are pharmacologically similar, they are not identical, and nefazodone has recently been withdrawn in the UK because of a rare association with severe liver disease (SEDA-26, 16).
Venlafaxine
(SED-14, 66; SEDA-25, 18; SEDA-26, 16; SEDA-27, 16) R e s p i r a t o r y There has been a previous report linking venlafaxine to pneumonia associated
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20 with eosinophilic infiltration, and SSRIs have been associated with drug-induced infiltrative lung disease. 9 A 21-year-old woman developed progressive dyspnea, a non-productive cough, weight loss, and syncope (35c). She had been taking venlafaxine for depression for 2 months (75 mg/day for 1 month, then 37.5 mg/day). A chest X-ray showed diffuse reticulonodular opacities throughout both lung fields, and a CT scan showed numerous diffuse, ill-defined pulmonary nodules. Lung function tests showed a restrictive ventilatory defect, depression of gas transfer, and resting hypoxia. Histological examination showed a lymphocytic interstitial infiltrate. Venlafaxine was withdrawn and glucocorticoid treatment started. Her clinical condition improved rapidly over the next 2 weeks after which the ghicocorticoid treatment was stopped. At 3 years she remained well. It is difficult to be sure how far venlafaxine contributed to this presentation, but no other cause could be established and the patient improved quickly when venlafaxine was withdrawn. Venlafaxine is a potent 5-HT re-uptake inhibitor and 5-HT has been implicated in fibrotic reactions in a variety of tissues. Nervous system The 5-HT toxicity syndrome usually results from the combination of two drugs with potentiating effects on 5-HT neurotransmission. However, it can occasionally result from therapeutic doses of a conventional 5-HT re-uptake inhibitor antidepressant. 9 A 29-year-old woman developed anxiety, restlessness, shivering, diarrhea, nausea, and vomiting after taking venlafaxine 37.5 mg/day for 3 days (36c). She also had ataxia and myoclonus. Her symptoms resolved after a few hours and treatment with prochlorperazine and lorazepam. Two weeks later she took fluoxetine 20 rag/day without adverse effects. This case shows how sensitive some patients can be to even low doses of 5-HT potentiating drugs and also the rather puzzling fact that another drug, equally potent at facilitating 5-HT neurotransmission, can then be taken without apparent adverse consequences. Psychiatric Delusions of love (erotomania or De C16rambault's syndrome) is a rare but striking disorder. 9 A 39-year-old woman with a history of treatmentresistant depression developed delusions that her
P.J. Cowen
medical attendants were in love with her on two separate occasions when taking venlafaxine in doses of 225 mg mad more (37c). There was no evidence of mania and no other psychotic symptoms. On both occasions the delusional beliefs subsided when venlafaxine was withdrawn. She was subsequently treated with another antidepressant and made a good recovery. The absence of a history of psychosis and the re-emergence of delusional thinking when venlafaxine was prescribed again suggest that venlafaxine played a role in producing this psychotic state. At high doses venlafaxine potentiates dopamine activity, which could lead to psychotic reactions in predisposed individuals. E n d o c r i n e SSRIs can facilitate prolactin release and have been associated with galactorrhea (SEDA-26, 13). A similar effect would be expected with venlafaxine. 9 A 38-year-old woman developed galactorrhea on two separate occasions while taking venlafaxine 225 mg/day and 75 mg/day (38c). On the first occasion prolactin concentxations were modestly raised but on the second they were not. This report confirms that, like SSRIs, venlafaxine can cause galactorrhea and also suggests, as has been observed with other drugs, that the symptom of lactation is not necessarily closely linked to plasma prolactin concentrations. This suggests that other mechanisms could be involved in the production of druginduced galactorrhea. D r u g abuse usual.
Misuse of antidepressants is un-
9 A 38-year-old man without a previous history of substance misuse took up to 3600 mg of venlafaxine daily (about 10 times the maximum therapeutic dose) because it caused a subjective "high" (39c). He maintained his high doses by obtaining illicit supplies of venlafaxine until a dose of 4050 mg produced acute central chest pain. He was then admitted to be treated for depression and substance misuse. This patient developed features of drug dependence. Such reactions are unusual but might be related to the ability of venlafaxine to potentiate dopamine function at high doses. This pharmacological property characterizes many drugs that are misused for their euphoriant properties.
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sants and placebo: analysis of FDA reports. Am J Psychiatry 2003; 160: 790-2. 16. Healy D. Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors. Psychother Psychosom 2003; 72: 71-9. 17. Committee on Safety of Medicines 2003. Paroxetine (Seroxat). Safety in children and adolescents. SSRI and venlafaxine use in children. 2003 September; 29: 4. 18. Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen I-IT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinai tract bleeding: a population-based cohort study. Arch Intern Med 2003; 163: 59-64. 19. Sauer WH, Berlin JA, Kimmel SE. Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation 2003; 108: 32. 20. Persky S, Reinus JE Sertraline hepatotoxicity. A case report and review of the literature on selective serotonin reuptake inhibitor hepatotoxicity. Dig Dis Sci 2003; 48: 939-44. 21. Damsa C, Sterck R, Schulz P. Case of gynecomastia during paroxetine therapy. J Clin Psychiatry 2003; 64: 971. 22. Boulenger A, Viseux V, Plantin-Eon I, Commegeille P, Plantin P. Gynaecomastia following treatment by fluoxetine. J Eur Acad Dermatol Venereol 2003; 17:97-116. 23. Jaiswal S, Coombs RC, Isbister GK. Paroxetine withdrawal in a neonate with historical and laboratory confirmation. Eur J Pediatr 2003; 162: 723-4. 24. Laine Kari, Heikkinen T, Ekblad U, Kero P. Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry 2003; 60: 720-6. 25. Stowe, ZN, Hostetter AL, Owens M J, Ritchie JC, Sternberg K, Cohen LS, Nemeroff CB. The pharmacokinetics of sertraline excretion into human breast milk: determinants of infant serum concentrations. J Clin Psychiatry 2003; 64: 73-80. 26. Suzuki Y, Shioiri T, Muratake T, Kawashima Y, Sato S, Hagiwara M, Inoue Y, Shimoda K, Someya T. Effects of concomitant fluvoxamine on the metabolism of alprazolam in Japanese psychiatric patients: interaction with CYP2C19 mutated alleles. Eur J Clin Pharmacol 2003; 58: 829-33. 27. Hall J, Naranjo CA, Sproule BA, Herrmann N. Pharmacokinetic and pharmacodynamic evaluation of the inhibition of alprazolam by citalopram and fluoxetine. J Clin Psychopharmacol 2003; 23: 34957. 28. Hori H, Yoshimura R, Yeda N, Eto S, Shinkai K, Sakata S, Ohmori O, Terao T, Nakamura J. Grapefruit juice-fluvoxamine interaction. Is it risky or not? J Clin Psychopharmacol 2003; 23: 422-4. 29. Tissot TA. Probable meperidine-induced serotonin syndrome in a patient with a history of fluoxetine use. Anesthesiol (Phil) 2003; 98:1511-12.
22 30. Khazaal Y, Krenz S, Zullino DE Bupropioninduced somnambulism. Addict Biol 2003; 8: 35962. 31. De Graaf L, Admiraal P, Van Puijenbroek EP. Bailism associated with bupropion use. Ann Pharmacother 2003; 37: 302-3. 32. Bagshaw SM, Cload B, Gilmour J, Leung ST, Bowen TJ. Drug-induced rash with eosinophilia and systemic symptoms syndrome with bupropion administration. Ann Allergy Asthma Inununol 2003; 90: 572-5. 33. Ridout F, Meadows R, Johnsen S, Hindmarch I. A placebo controlled investigation in to the effects of paroxetine and mirtazapine on measures related to a car driving performance. Human Psychopharmacol 2003; 18: 261-9. 34. Einarson A, Bonari L, Voyer-Lavigne S, Addis A, Matsui D, Johnson Y, Koren G. A multicentre prospective controlled study to determine the safety
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of trazodone and nefazodone use during pregnancy. Can J Psychiatry 2003; 48: 106-10. 35. Drent M, Singh S, Gorgeis APM, Hansell DM, Bekers O, Nicholson AG, Van Suylen RJ, Du Bois RM. Drug-induced pneumonitis and heart failure simultaneously associated with venlafaxine. Am J Resp Crit Care 2003; 167: 958~51. 36. Pan JJ, Shen WW. Serotonin syndrome induced by low-dose venlafaxine. Ann Pharmacother 2003; 37:209-11. 37. Adamou M, Hale AS. Erotomania induced by venlafaxine: a case study. Acta Psychiatr Scand 2003; 107: 314-17. 38. Sternbach H. Venlafaxine-induced galactorrhea. J Clin Psychopharmacol 2003; 23:109. 39. Sattar SP, Grant KM, Bhatia SC. A case of venlafaxine abuse. New Engl J Med 2003; 248: 764-5.
2
Antidepressant drugs
GENERAL Sexual function Most classes of antidepressant drugs are associated with sexual dysfunction of various kinds, including reduced desire and arousal, erectile difficulties, and ejaculatory and orgasmic inhibition. A literature review has shown that rates of sexual dysfunction of all kinds were highest with selective serotonin re-uptake inhibitors (SSRIs) and venlafaxine and least with amfebutamone (bupropion) and the reversible inhibitor of monoamine oxidase type A, moclobemide (1R). Switching to amfebutamone or mirtazapine from SSRIs often enabled patients to obtain relief from sexual dysfunction. However, commonly recommended antidotes to SSRI-induced sexual dysfunction, such as Ginkgo biloba, serotonin (5-HTz) receptor antagonists, such as cyproheptadine, and amfebutamone augmentation were not supported by placebo-controlled trials. These data suggest that antidepressant-induced sexual dysfunction is more likely to be associated with agents that greatly potentiate 5-HT neurotransmission. This notion is supported by the results of a 6-week double-blind study of 24 men with premature ejaculation, in which paroxetine (20 mg/day) increased latency to ejaculation six-fold while mirtazapine (30 mg/day) had minimal effect (2c). In a randomized, 8-week, double-blind, placebocontrolled study in 450 patients with major depression, fluoxetine ( 2 0 4 0 mg/day) significantly impaired sexual function, while the noradrenaline re-uptake inhibitor reboxetine had no effect (3c). In a double-blind, placebo-controlled study in 90 patients with sexual dysfunction who were taking a variety of 5-HT re-uptake inhibitor antidepressants, sildenafil (50-100 mg)
9 2005 Elsevier B.V. All rights reserved, Side Effects of Drugs, Annual 28 J.K. Aronson, ed. 14
produced improvement in all aspects of the sexual response in 54% of antidepressant-treated patients compared with a placebo response rate of 4.4% (NNT = 2) (4c). This suggests that sildenafil is an effective treatment for antidepressant-induced sexual dysfunction. Tumorigenicity Studies in rats have suggested that both tricyclic antidepressants and selective serotonin re-uptake inhibitors (SSRIs) promote the growth of mammary tumors. Rates of antidepressant prescribing have increased over the last 20 years, and breast cancer remains a leading cause of mortality in women. Two recent non-systematic reviews (5 R, 6 M) have examined the question of whether antidepressant treatment might increase the risk of breast cancer. A variety of studies have been conducted, including hospital- and population-based casecontrol studies and prospective cohort studies. Overall the evidence for an association between any use of antidepressant medication and breast cancer is weak and inconclusive. However, it is possible that sustained use of certain drugs, for example, the SSRI paroxetine, might be associated with an increased risk. Problems with the studies reviewed include defining what kind of antidepressant treatment regimen represents significant exposure, and the unknown nature of the time-course of any effect of antidepressants on the development of breast cancer. The increasing use of SSRIs, which are known to be associated with breast enlargement (SEDA-22, 12), suggests that further prospective studies are needed.
Overdose with antidepressant drugs Suicidal ideation o f some kind almost invariably accompanies severe depression. Hence the relative toxicity o f antidepressants in overdose can be important in determining treatment
Antidepressant drugs
Chapter 2
choice. It is accepted that SSRIs are less dangerous in overdose than tricyclic antidepressants, but there are fewer data on the toxicity of other antidepressants. The presentation and likely toxicity in overdose of several newer antidepressant drugs have been reviewed (7R). Deaths in overdose have been most clearly associated with amfebutamone and venlafaxine. Amfebutamone overdose typically presents with neurological symptoms, including delirium, agitation, and seizures; however, cardiac dysrhythmias, with QT intelwal prolongation and cardiac arrest, have occurred (8 c, 9c). Ventafaxine overdose is also associated with seizures and cardiac dysrhythmias (4R). Venlafaxine is a potent 5-HT re-uptake inhibitor, and signs of 5-HT toxicity (agitation, my_ octonus, hyperthermia) are common. In a prospective cohort study of over 450 patients who had attempted suicide by antidepressant ingestion the risk of seizures after venlafaxine overdose (14%) was significantly greater than that of SSRIs (1.3%) and similar to that seen with dosulepin (11%) (lOC). Rates of 5-HT toxicity did not differ significantly between ventafo_xine and SSRIs (29% versus 19%) but were greater than with tricyclic antidepressants (1.2%). Unlike SSRIs, venlafaxine was associated with significant prolongation of the QT interval; tricyclic antidepressants had a similar effect. Data on the consequences of overdose of other new antidepressant agents are limited, but current evidence suggests that reboxetine and mirtazapine have low toxicity in overdose (7R ). Reboxetine, as would be expected, presents with signs of noradrenergic overactivity, such as sweating, tachycardia, hypertension, and anxiety. The characteristic feature of mirtuzapine overdose is sedation (7R ). Overdose of moclobemide by itself rarely appears to give rise to serious problems. This is in contrast to overdose with conventional monoamine oxidase inhibitors, which can cause fatal 5-HT toxicity. However, if patients take moclobemide together with serotonergic antidepressants, such as SSRIs or clomipramine, 5HT toxicity is common. 5-HT toxicity occurred in 11 of 21 patients who took overdoses of moclobemide and serotonergic agents but in only one of 33 patients who took moclobemide alone (11c). Consistent with this, four patients died, presumably of 5-HT toxicity, after co-ingesting
15 3, 4-methytenedioxymethamphetamine (M DMA, ecstasy) and moclobemide (12c). Overall the current data suggest that the safety advantage in overdose relative to tricyclic antidepressants enjoyed by SSRIs may extend to reboxetine and mirtazapine. Amfebutamone and venlafaxine are more toxic than SSRIs in overdose, but they are still likely to be safer than tricyclic antidepressants.
TRICYCLIC ANTIDEPRESSANTS (SED-14, 44; SEDA-25, 13; SEDA-26, 11; SEDA-27, 11) Museuloskeletal Elderly people are at increased risk of fractures, and a case-control study of patients admitted to hospital suggested that both tricyclic antidepressants and SSRIs increased the probability of hip fracture about 2.5 times (SEDA-22, t t). In a prospective study of 8127 women aged 65 years and older who were followed for 4.8 years, the risk of a first hip fracture was 4% and the risk in women taking antidepressants was increased 1.7 times (95% CI = 1.05, 2.07) (13c). The relative risk among women taking tricyclic antidepressants (RR = 1.83; CI = 1.08, 3.09) was slightly higher than that for SSRIs, which had wider confidence intervals (RR -= 1.54; CI = 0.62, 3.08). Depression as an independent variable did not increase the risk of hip fracture. This study has confirmed that women taking antidepressants are at increased risk of hip fracture and has suggested that the effects of SSRIs and tricyclic antidepressants are similar.
SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs) (SED-14, 67; SEDA-25, 14; SEDA-26, 11; SEDA-27, 12) Nervous syslem SSRIs are often associated with sleep disturbances, particularly reduced sleep efficiency and altered sleep architecture. Paroxetine has been associated with sleepwalking (somnambulism) (14c).
16 9 A 61-year-oldwomantakingparoxetine 10mg/day for depression had difficulty falling asleep, but there was no personal or family history of parasomnia. After 2 weeks the paroxetine was increased to 20 mg/day and l week later she was noted by her husband to be sleep-walking and trying at times to leave the house. When wakened she was confused and had no memory of the event. The paroxetine was withdrawn; the sleep-walking stopped and did not recur. Other classes of antidepressant dmgs can sometimes cause somnambulism, and it seems likely that paroxetine provoked this rare adverse effect. Sleep-walking is thought to be initiated during slow-wave sleep, after which partial arousals activate motor behaviors in the absence of full consciousness. The disrupting effects of antidepressants on sleep architecture might lead to somnambulism in pre-disposed individuals. Psychiatric Over the last decade there has been a debate as to whether SSRIs might increase the risk of suicide in certain individuals. Some patients can respond to SSRIs by becoming agitated and restless and developing symptoms that resemble akathisia. Case reports have suggested that adverse effects of this type could underlie an increased risk of selfharm and aggression. However, results from the placebo-controlled randomized trials carried out for regulatory purposes have not supported the proposal that SSRIs increase the risk of suicide of suicidal behavior. A review of the database of the Food and Drug Administration showed 77 suicides among 48 277 patients who had participated in placebocontrolled trials of antidepressants (15M). The rate of suicide with SSRIs (0.59%; CI = 0.31, 0.87) was similar to that of other antidepressants (0.76%; CI = 0.49, 1.03) and placebo (0.45%; CI = 0.01, 0.89). While these data are reassuring, patients considered clinically at high risk of suicide were excluded from the trials and the patients received a greater degree of supervision than would occur in routine practice. In a re-analysis of antidepressant trial data there was an odds ratio for a suicidal act while taking SSRIs relative to placebo of 2.0 (CI = 1.2, 3.3), while the risk for completed suicide on SSRIs, although raised, had wide confidence intervals (RR = 3.1; CI = 0.4, 23.1) (16R). One of the author's arguments was that in previous analyses suicidal behaviors occurring during placebo wash-out have been misclassified
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P.J. Cowen
as happening during placebo treatment. Separation of these two classes of event allows a pro-suicidal effect of SSRIs to be revealed. Overall the randomized studies suggest that the risk of suicide and suicidal behavior in patients taking placebo is numerically less than in patients taking active antidepressants. Since on clinical rating scales, antidepressant drugs usually reduce suicidal ideation more than placebo, this is a paradoxical observation. It might, however, reflect the old adage that the risk of suicide is greatest during the early stages of antidepressant treatment, when motor retardation has remitted but depressed mood and suicidal thinking persist. Such an effect might be exaggerated with modem antidepressants, which are more activating than tricyclic antidepressants. The need for caution in both clinical practice and trial evaluation is underlined by a warning from the Committee of Safety of Medicines that paroxetine is no more effective than placebo in the treatment of depression in adolescence, and may also be associated with a greater risk of self-harm and suicidal behavior (17s). Gastrointestinal A previous case-control study linked SSRI treatment with gastrointestinal bleeding (SEDA-24, 15), and this has been confirmed in a cohort study in 26005 antidepressant users (18c). The risk of being hospitalized for upper gastrointestinal bleeding within 90 days of antidepressant prescription was increased in people taking SSRIs (OR = 3.6; CI = 2.7, 4.7). Combined use of SSRIs and aspirin increased the risk 5.2 times (CI = 3.2, 8.0), while combined use with an NSAID increased the risk 12 times (CI = 7.1, 20). There was a lower risk of gastrointestinal bleeding (OR = 2.3; CI = 1.5, 3.4) with antidepressants with less potency to inhibit 5-HT re-uptake (amitriptyline, dosulepin, imipramine), while non-serotonergic antidepressants (desipramine, nortriptyline, mianserin) did not increase the risk. These findings suggest that SSRIs should be used with caution in patients taking aspirin or NSAIDs. The risk of upper gastrointestinal bleeding with SSRIs used by themselves appears to be of the same order as that with aspirin. This observation is of interest, in view of a case-control study suggesting a lower risk of first myocardial infarction in patients taking SSRIs (OR = 0.59; CI -----0.39, 0.91) (19c). This effect was not seen with non-SSRI antidepressants.
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Chapter2
L i v e r Hepatitis has been reported in association with paroxetine and fluoxetine (SEDA-21, 12; SEDA-24, 15) and a case has now been associated with sertraline (20c). 9 A 23-year-old woman taking sertraline (dose and length of time not stated) developed a mild pyrexia, fight-sided abdominal pain, nausea, vomiting, and chills. She had a raised serum alanine transaminase activity but no other abnormality of liver function tests. A liver biopsy showed changes consistent with either a drug-induced reaction or autoimmune disease. Sertraline was withdrawn and prednisone 20 mg/day started. Four weeks later her alanine transaminase activity had fallen significantly, but she then restarted sertraline because of increasing depression. The alanine transaminase activity rose again, despite continuing prednisone, and only fell when sertraline was withdrawn. While there have been other cases of hepatitis in association with sertraline this is the first case to have been confirmed by re-challenge. R e p r o d u c t i v e system SSRIs can be associated with breast enlargement in w o m e n and gynecomastia has been reported in men. 9 Gynecomastia occurred in a 30-year-old man who had taken paroxetine 40 mg/day for 5 years (21c). Over this time gynecomastia of the left breast became increasingly marked. There was no evidence of metabolic or hormonal abnormalities and plasma prolactin was within the reference range. Biopsy showed no evidence of malignancy. The gynecomastia was reduced by surgery and paroxetine was replaced with mirtazapine. At 2-year follow-up there was no evidence of recurrence. 9 A similar but more acute case of gynecomastia in association with fluoxetine has been reported in a 21 year old man (22c). The gynecomastia resolved after fluoxetine withdrawal. Fetotoxicity An increasing number of w o m e n take SSRIs during pregnancy and in the postnatal period. Some studies have suggested that SSRI treatment in pregnancy is not associated with an increased risk of malformations (SEDA-24, 15). However, neonates born to woman taking SSRIs can have a variety of symptoms, including jitteriness, hypoglycemia, hypothermia, and respiratory distress. 9 A boy (3.4 kg) was born by cesarean section, because of fetal distress, to a mother who had taken paroxetine (40 mg/day) and olanzapine (10 mg/day) until 48 hours before delivery (23c). After delivery, the baby had increased tone and was hypoglycemic. The next day he was increasingly jittery, with profuse salivation. At 44 hours
17 there was no detectable paroxetine or olanzapine in the neonatal plasma and CSF concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were normal. The baby's condition improved over the next few days, and 1 week after birth the only abnormality was slight jitteriness. At 6 months the baby was considered normal. This infant's symptoms were similar to those described in other neonates whose mothers took SSRIs shortly before delivery, although in this case a contributory effect from olanzapine was also possible. The authors made the point that it can be difficult to decide from the clinical presentation whether neonatal problems, such as those described above, represent SSRI withdrawal (5-HT deficiency) or SSRI toxicity (5H T excess). The fact that no paroxetine was detected in the infant's plasma led them to conclude that SSRI withdrawal was responsible for the symptoms in this case. In a follow-up study in 20 infants born to mothers who had taken either fluoxetine ( 2 0 40 rag/day) or citalopram (21)--40 mg/day), the children of mothers who had taken SSRIs had raised scores in the first 4 days of life on scales rating symptoms of 5-HT excess, including tremor, rigidity, and restlessness (24c). Children who had been exposed to SSRIs had lower concentrations of 5 - H I A A in cord blood (consistent with persistent 5-HT reuptake blockade) and there was a significant negative correlation between the 5-HT symptom score and cord blood 5-HIAA. At 4 days citalopram and fluoxetine were detectable in plasma samples from the infants. By 2 weeks there was no significant difference in 5-HT symptom scores between exposed infants and controls. Weight gain over this time was similar in the two groups. These findings support the view that the neonatal syndrome associated with SSRI treatment of mothers around the time of delivery can sometimes be due to 5-HT toxicity rather than SSRI withdrawal. L a c t a t i o n Mothers taking antidepressants often want to breast feed their babies. Generally SSRI treatment of nursing mothers is without an obvious acute effect on the infant (SEDA26, 14), although adverse effects in infants are occasionally reported (SEDA-25, 15). When blood and milk were sampled in 22 nursing women taking sertraline (25-200 mg/day), sertraline and its metabolite, desmethylsertraline,
Chapter 2
18 were found in all the milk samples (25c). The maximum concentration of sertraline and desmethylsertraline in the milk occurred 8 9 hours after maternal ingestion of the daily dose of sertraline. Eleven infants had detectable desmethylsertraline; of these, four also had detectable sertraline. No adverse effects were noted in any of the children. The authors calculated that the infants had received on average about 0.5% of the maternal sertraline dose. These data confirm that the infants of nursing mothers taking SSRIs are likely to be exposed to low doses of antidepressants. While this rarely causes overt effects, the possibility of subtle long-term behavioral consequences cannot be excluded. In the case of sertraline it would be wise to discard breast milk accumulated 8-9 hours after dosing as this will reduce the daily dose that the infant receives.
Drug interactions Alprazolam
SSRIs and the benzodiazepine alprazolam are often used to treat panic disorder. Pharmacokinetic reactions between them could therefore be important. AIprazolam is metabolized by CYP3A4, which fluvoxamine inhibits (SEDA-22, 13). In 23 outpatients (11 men, 12 women, mean age 39 years) who took alprazolam both as monotherapy (mean dose 1.0 mg/day) and in combination with fluvoxamine (mean dose 34 mg/day), fluvoxamine increased plasma alprazolam concentrations by 58% (26c). This was not associated with increased sleepiness, measured by a subjective rating scale, but objective measures of psychomotor function were not carried out and these could have been impaired by raised alprazolam concentrations. The effects of SSRIs on alprazolam pharmacokinetics have been studied in 21 healthy volunteers (age and sex not given) who were pre-treated with either fluoxetine or citalopram (20 mg/day for 21 days) (27c). Fluoxetine increased the AUC of a single 1.0 mg dose of alprazolam by 32%; citalopram had no effect. These findings are consistent with previous reports that fluoxetine and its active metabolite, norfluoxetine, produce moderate inhibition of CYP3A4 while citalopram does not.
Grapefruit juice Grapefruit juice is also a modest inhibitor of CYP3A4. Grapefruit juice (250 ml tds) for 5 days produced a 1.6-fold increase in the AUC of a single dose of fluvoxamine 75 mg in 10 healthy men (aged 19-30
PJ. Cowen
years) (28c). Fluvoxamine is metabolized by CYP2D6 and CYP1A2, but this study suggests that there may also be a modest contribution from CYP3A4.
Pethidine
Pethidine plus an SSRI may have caused a 5-HT syndrome (29c). A 43-year-old man was premedicated for endoscopy with intravenous midazolam 2 mg and pethidine 50 mg). He immediately became agitated and restless. His blood pressure rose to 180/100 mmHg, he sweated, had widely dilated pupils, and had diarrhea. Over the next 90 minutes his condition remitted without specific treatment. He then reported that he had been taking fluoxetine (20 mg every other day), which he had stopped taken about 2 weeks before.
The symptoms described here resemble the 5-HT toxicity syndrome (SEDA-25, 16) and suggest that pethidine can provoke this reaction when combined with SSRIs, as it can with monoamine oxidase inhibitors. The report is also a useful reminder that the active metabolite of fluoxetine, norfluoxetine, has a half-life of about 1 week and would still have been present at the time of endoscopy, even though fiuoxetine had been stopped 14 days before.
OTHER ANTIDEPRESSANTS Amfebutamone (bupropion) (SED-14, 60; SEDA-25, 17; SEDA-26, 15; SEDA-27, 14) Nervous system
Somnambulism has been re-
ported with amfebutamone (30c). A 35-year-old man took amfebutamone 150 mg bd as part of a smoking cessation program. After 14 days he stopped smoking, after which he noted some increase in mood and appetite. Three days later a friend reported that the patient had telephoned him at 1.00 am, about 2 hours after he had gone to sleep, but the patient had no memory of this. Over the next week he discovered evidence of several episodes of nocturnal eating but again had no recall of getting up at night to obtain food. He stopped taking amfebutamone and the sleepwalking episodes disappeared and did not recur. Amfebutamone promotes slow wave sleep, the sleep stage during which somnambulism is
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Chapter2
initiated. However, this case was complex, because of the possible interaction with nicotine withdrawal. Nicotine withdrawal is associated with increased appetite and weight gain, and sleep walking can be associated with nocturnal eating (31c). Amfebutamone has been associated with extrapyramidal movement disorders (SEDA-27, 15) and ballismus has been reported (3 l C). 9 A 42-year-old woman developed ballismus 4 days after increasing her dose of amfebutamone to 150 mg bd. She had an involuntary urge to move, gross flexion movements of the torso, and slapping movements of her arms. She had no previous history of movement disorders and was taking only occasional sumatriptan for migraine. Amfebutamone was withdrawn and she was given haloperidol and oxazepam. The movements abated. It seems likely from this that the dopaminergic effects of amfebutamone can provoke movement disorders in therapeutic doses in some individuals. Immunologic Amfebutamone has been associated with a variety of hypersensitivity reactions, including urticaria and serum sickness (SEDA-25, 17). Further reactions in association with amfebutamone have been reported. 9 A 24-year-old man developed a fever and a generalized maculopapular rash after taking amfebutamone 150 mg bd for 3 weeks (32c). Amfebutamone was withdrawn but he went on to develop angioedema, eosinophilia, and a systemic syndrome with hepatitis, myositis, and obstructive lung disease. His symptoms resolved over several weeks with a glucocorticoid.
Mirtazapine
(SED-14, 63; SEDA-27, 16)
Nervous system Mirtazapine is a potent histamine H1 receptor antagonist and is perceived by patients as being sedative. While this may improve disturbed sleep, it also has implications for daytime psychomotor performance. The effect of mirtazapine (15 mg at night for 2 days, then 30 mg at night for 2 days) and paroxetine (20 mg in the morning for 5 days) has been studied in a placebo-controlled, crossover design in 12 healthy volunteers (10 women, 2 men, median age 26 years) (33c). On the fifth
19 day the subjects undertook a battery of psychomotor tests. Mirtazapine significantly impaired several aspects of psychomotor performance and increased daytime sleepiness, while paroxetine did not. These results suggest that patients who take mirtazapine should be warned about its deleterious effects on psychomotor performance, particularly driving. It is likely that tolerance to this effect will occur, but the time course of adaptation is uncertain. Also uncertain is how far these results in healthy subjects can be extrapolated to depressed patients, many of whom will have performance deficits due to poor sleep, which could conceivably be helped by mirtazapine.
Trazodone
(SED-14, 64)
Teratogenieity The use of antidepressants in pregnancy is a difficult area, because the teratogenic effects of many antidepressants are not known. While tricyclic antidepressants and SSRIs are believed to present a low risk of fetal abnormality (SEDA-24, 15), the teratogenic potential of trazodone has been unclear. In 147 women who took either trazodone or nefazodone during the first trimester of pregnancy, the rate of major malformations in the trazodone/nefazodone group (1.6%) did not differ statistically from that in a control group (3.0%) (34c). Similarly, there were no statistically significant differences in rates of spontaneous abortion or stillbirth or in birth weight in the babies of women who took trazodone or nefazodone. These findings are reassuring. However, as the authors pointed out, the study, while prospective, was not randomized. In addition they did not examine the effects of trazodone and nefazodone separately, and did not state how many women were taking each drug. While trazodone and nefazodone are pharmacologically similar, they are not identical, and nefazodone has recently been withdrawn in the UK because of a rare association with severe liver disease (SEDA-26, 16).
Venlafaxine
(SED-14, 66; SEDA-25, 18; SEDA-26, 16; SEDA-27, 16) R e s p i r a t o r y There has been a previous report linking venlafaxine to pneumonia associated
Chapter 2
20 with eosinophilic infiltration, and SSRIs have been associated with drug-induced infiltrative lung disease. 9 A 21-year-old woman developed progressive dyspnea, a non-productive cough, weight loss, and syncope (35c). She had been taking venlafaxine for depression for 2 months (75 mg/day for 1 month, then 37.5 mg/day). A chest X-ray showed diffuse reticulonodular opacities throughout both lung fields, and a CT scan showed numerous diffuse, ill-defined pulmonary nodules. Lung function tests showed a restrictive ventilatory defect, depression of gas transfer, and resting hypoxia. Histological examination showed a lymphocytic interstitial infiltrate. Venlafaxine was withdrawn and glucocorticoid treatment started. Her clinical condition improved rapidly over the next 2 weeks after which the ghicocorticoid treatment was stopped. At 3 years she remained well. It is difficult to be sure how far venlafaxine contributed to this presentation, but no other cause could be established and the patient improved quickly when venlafaxine was withdrawn. Venlafaxine is a potent 5-HT re-uptake inhibitor and 5-HT has been implicated in fibrotic reactions in a variety of tissues. Nervous system The 5-HT toxicity syndrome usually results from the combination of two drugs with potentiating effects on 5-HT neurotransmission. However, it can occasionally result from therapeutic doses of a conventional 5-HT re-uptake inhibitor antidepressant. 9 A 29-year-old woman developed anxiety, restlessness, shivering, diarrhea, nausea, and vomiting after taking venlafaxine 37.5 mg/day for 3 days (36c). She also had ataxia and myoclonus. Her symptoms resolved after a few hours and treatment with prochlorperazine and lorazepam. Two weeks later she took fluoxetine 20 rag/day without adverse effects. This case shows how sensitive some patients can be to even low doses of 5-HT potentiating drugs and also the rather puzzling fact that another drug, equally potent at facilitating 5-HT neurotransmission, can then be taken without apparent adverse consequences. Psychiatric Delusions of love (erotomania or De C16rambault's syndrome) is a rare but striking disorder. 9 A 39-year-old woman with a history of treatmentresistant depression developed delusions that her
P.J. Cowen
medical attendants were in love with her on two separate occasions when taking venlafaxine in doses of 225 mg mad more (37c). There was no evidence of mania and no other psychotic symptoms. On both occasions the delusional beliefs subsided when venlafaxine was withdrawn. She was subsequently treated with another antidepressant and made a good recovery. The absence of a history of psychosis and the re-emergence of delusional thinking when venlafaxine was prescribed again suggest that venlafaxine played a role in producing this psychotic state. At high doses venlafaxine potentiates dopamine activity, which could lead to psychotic reactions in predisposed individuals. E n d o c r i n e SSRIs can facilitate prolactin release and have been associated with galactorrhea (SEDA-26, 13). A similar effect would be expected with venlafaxine. 9 A 38-year-old woman developed galactorrhea on two separate occasions while taking venlafaxine 225 mg/day and 75 mg/day (38c). On the first occasion prolactin concentxations were modestly raised but on the second they were not. This report confirms that, like SSRIs, venlafaxine can cause galactorrhea and also suggests, as has been observed with other drugs, that the symptom of lactation is not necessarily closely linked to plasma prolactin concentrations. This suggests that other mechanisms could be involved in the production of druginduced galactorrhea. D r u g abuse usual.
Misuse of antidepressants is un-
9 A 38-year-old man without a previous history of substance misuse took up to 3600 mg of venlafaxine daily (about 10 times the maximum therapeutic dose) because it caused a subjective "high" (39c). He maintained his high doses by obtaining illicit supplies of venlafaxine until a dose of 4050 mg produced acute central chest pain. He was then admitted to be treated for depression and substance misuse. This patient developed features of drug dependence. Such reactions are unusual but might be related to the ability of venlafaxine to potentiate dopamine function at high doses. This pharmacological property characterizes many drugs that are misused for their euphoriant properties.
Antidepressant drugs
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21
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