Fluoxetine

Systematic reviews

In a meta-analysis based on 9087 patients in 87 different randomized clinical trials fluoxetine was more effective than placebo from the first week of therapy [ ]. In bulimia nervosa, fluoxetine was as effective as other agents. It was as effective as clomipramine in the treatment of obsessive–compulsive disorder.

An updated meta-analysis conducted by Lilly, the manufacturers of fluoxetine, assessed suicidality in a database that brought together results from 18 double-blind, placebo-controlled, fluoxetine trials in adults (fluoxetine, n = 2200; placebo, n = 1551) [ ]. Fluoxetine treatment led to greater improvement and faster resolution of suicidal ideation than placebo. Of course, this result does not exclude the possibility that there may be individual patients in whom the opposite occurs, i.e. the result is still compatible with there being adults in whom fluoxetine leads to increased suicidal ideation.

Cardiovascular

Fluoxetine appears not to have the cardiovascular effects associated with tricyclic compounds, but 10 patients did discontinue treatment because of tachycardia, palpitation, and dyspnea [ ]. Two older women each had a myocardial infarction and subsequently died, although these events may not have been drug-related.

In general, SSRIs are assumed to be safe in patients with cardiovascular disease, although there have been few systematic investigations in these patients. In a prospective study of 27 depressed patients with established cardiac disease, fluoxetine (up to 60 mg/day for 7 weeks) produced a statistically significant reduction in heart rate (6%) and an increase in supine systolic blood pressure (2%) [ ]. One patient had worsening of a pre-existing dysrhythmia and this persisted after fluoxetine withdrawal. These findings suggest that, relative to tricyclic antidepressants, fluoxetine may have a relatively benign profile in patients with cardiovascular disease. However, the authors cautioned that in view of the small number of patients studied, these findings cannot be widely generalized.

The effects of fluoxetine (20 mg/day for 12 weeks) on sitting and standing blood pressures have been reported [ ]. Fluoxetine modestly but significantly lowered sitting and standing systolic and diastolic blood pressures by about 2 mmHg. Patients with pre-existing cardiovascular disease showed no change. This study confirms that fluoxetine has little effect on blood pressure in physically healthy depressed patients and in those with moderate cardiovascular disease.

Fluoxetine-induced remission of Raynaud’s phenomenon has been reported [ ].

Nervous system

Several cases in which fluoxetine worsened parkinsonian disability have been described, and the problem of exacerbation of Parkinson’s disease by fluoxetine has been reviewed [ ].

Five patients taking fluoxetine developed akathisia, perhaps due to enhanced serotonergic inhibition of dopamine neurons [ ]. A causal link between fluoxetine-induced akathisia and suicidal behavior has been suggested [ , ], and akathisia has also been associated with “indifference” [ ].

Neuroleptic malignant syndrome has been described with fluoxetine [ ].

Tics after long-term fluoxetine therapy have been described; the symptoms subsided several months after withdrawal [ ].

Migraine associated with fluoxetine has been reported, with no further attacks when the drug was withdrawn [ ].

Stuttering has been reported with fluoxetine [ ].

Two patients who had been maintained successfully on fluoxetine (20 mg/day) for 6 and 10 years respectively began to have agitation, tension, and sleep disturbance [ ]. There had been no recent changes in medications or life events to explain these symptoms, which closely resembled the kind of adverse reactions that can occur shortly after the start of SSRI treatment. Both patients improved after downward titration of the dose of fluoxetine. Blood concentrations of fluoxetine were not reported, so it is possible that for some reason (for example a change in diet or activity) plasma fluoxetine concentrations had recently increased in these subjects. However, the development of characteristic adverse reactions after such a long trouble-free period suggests that patients taking maintenance medication need long-term follow-up, or at least ready access to specialist advice.

Sensory systems

Tricyclic antidepressants can precipitate acute glaucoma through their anticholinergic effects. There are also reports that SSRIs can cause acute glaucoma, presumably by pupillary dilatation (see the monograph on Paroxetine).

In a placebo-controlled study in depressed patients a single dose of fluoxetine (20 mg) increased intraocular pressure by 4 mmHg [ ]. This increase is within the normal diurnal range, but could be of clinical consequence in individuals predisposed to glaucoma. However, post-marketing surveillance has not suggested an association between the use of fluoxetine and glaucoma [ ].

Blurred vision has occasionally required withdrawal of fluoxetine [ ].

Psychological

Cognitive function can be impaired by fluoxetine; a negative effect on learning and memory has been described [ ].

Psychiatric

An analysis of severe adverse reactions that caused drug withdrawal showed that psychotic reactions occurred in nine of 1378 patients; in four cases this appeared to be a stimulant psychosis and in three a conversion to mania [ ].

Reports of acute mania and manic-like behavior after treatment with fluoxetine or fluvoxamine have appeared [ ], but there are not enough data to estimate the incidence.

Suicidal ideation has been described after 2–7 weeks of fluoxetine [ ] and other case reports have appeared [ ], although the association has been debated [ ]. A causal link was initially questioned [ ], and in one controlled trial there was no increase [ ]. Furthermore, a meta-analysis of controlled trials did not point to a greater risk of suicide attempts or suicidal ideation with fluoxetine than with tricyclic antidepressants [ ].

In a meta-analysis based on 9087 patients in 87 different randomized clinical trials with fluoxetine there was no increased risk of suicide [ ].

In an analysis of data from the National Institute of Mental Health Collaborative Depression Study in 643 patients with affective disorders who were followed up after fluoxetine was approved by the FDA in December 1987 for the treatment of depression, nearly 30% (n = 185) took fluoxetine at some point [ ]. There was an increased rate of suicide attempts before fluoxetine treatment in those who subsequently took fluoxetine. Relative to no treatment, fluoxetine and other antidepressants were associated with non-significant reductions in the likelihood of suicide attempts or completions. Severity of psychopathology was strongly associated with increased risk, and each suicide attempt after admission to the study was associated with a marginally significant increase in the risk of suicidal behavior. The authors concluded that the results did not support the speculation that fluoxetine increases the risk of suicide.

Endocrine

Fluoxetine causes weight loss, in contrast to tricyclic antidepressants [ ]. In one study there was a mean fall in weight of 1.76 kg over 6 weeks compared with a gain of 2.09 kg with amitriptyline [ ].

Serotonin pathways are involved in the regulation of prolactin secretion. Amenorrhea, galactorrhea, and hyperprolactinemia have been reported in a patient taking SSRIs.

• A 71-year-old woman who had taken fluoxetine (dose unspecified) for a number of weeks noted unilateral galactorrhea and had a raised prolactin of 37 ng/ml (reference range 1.2–24 ng/ml) [ ]. She was also taking estrogen hormonal replacement therapy, benazapril, and occasional alprazolam. Withdrawal of the fluoxetine led to normalization of the prolactin concentration and resolution of the galactorrhea.

Estrogens also facilitate prolactin release, and so hormone replacement therapy may have played a part in this case.