Fluoxetine is used in the treatment of major depressive disorder, obsessive-compulsive disorder, premenstrual dysphoric disorder, bulimia nervosa, and panic disorder with or without agoraphobia. In addition, fluoxetine has been used for the treatment of depression associated with bipolar disorder; obesity; anorexia nervosa; myoclonus; cataplexy; alcohol dependence; and premature ejaculation.
Major Depressive Disorder
Fluoxetine is used in the acute and maintenance treatment of major depressive disorder in adults and pediatric patients 8 years of age and older. If fluoxetine is used for extended periods, the need for continued therapy should be reassessed periodically.
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks). According to DSM-IV criteria, a major depressive episode includes at least 5 of the following 9 symptoms (with at least one of the symptoms being either depressed mood or loss of interest or pleasure): depressed mood most of the day as indicated by subjective report (e.g., feels sad or empty) or observation made by others; markedly diminished interest or pleasure in all, or almost all, activities most of the day; significant weight loss (when not dieting) or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite; insomnia or hypersomnia; psychomotor agitation or retardation (observable by others, not merely subjective feelings of restlessness or being slowed down); fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt (not merely self-reproach or guilt about being sick); diminished ability to think or concentrate or indecisiveness (either by subjective account or as observed by others); and recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide.
Treatment of major depressive disorder generally consists of an acute phase (to induce remission), a continuation phase (to preserve remission), and a maintenance phase (to prevent recurrence). Various interventions (e.g., psychotherapy, antidepressant drug therapy, electroconvulsive therapy [ECT]) are used alone or in combination to treat major depressive episodes. Treatment should be individualized and the most appropriate strategy for a particular patient is determined by clinical factors such as severity of depression (e.g., mild, moderate, severe), presence or absence of certain psychiatric features (e.g., suicide risk, catatonia, psychotic or atypical features, alcohol or substance abuse or dependence, panic or other anxiety disorder, cognitive dysfunction, dysthymia, personality disorder, seasonal affective disorder), and concurrent illness (e.g., asthma, cardiac disease, dementia, seizure disorder, glaucoma, hypertension). Demographic and psychosocial factors as well as patient preference also are used to determine the most effective treatment strategy.
While use of psychotherapy alone may be considered as an initial treatment strategy for patients with mild to moderate major depressive disorder (based on patient preference and presence of clinical features such as psychosocial stressors), combined use of antidepressant drug therapy and psychotherapy may be useful for initial treatment of patients with moderate to severe major depressive disorder with psychosocial issues, interpersonal problems, or a comorbid axis II disorder. In addition, combined use of antidepressant drug therapy and psychotherapy may be beneficial in patients who have a history of poor compliance or only partial response to adequate trials of either antidepressant drug therapy or psychotherapy alone.
Antidepressant drug therapy can be used alone for initial treatment of patients with mild major depressive disorder (if preferred by the patient) and usually is indicated alone or in combination with psychotherapy for initial treatment of patients with moderate to severe major depressive disorder (unless ECT is planned). ECT is not generally used for initial treatment of uncomplicated major depression, but is recommended as first-line treatment for severe major depressive disorder when it is coupled with psychotic features, catatonic stupor, severe suicidality, food refusal leading to nutritional compromise, or other situations when a rapid antidepressant response is required. ECT also is recommended for patients who have previously shown a positive response or a preference for this treatment modality and can be considered for patients with moderate or severe depression who have not responded to or cannot receive antidepressant drug therapy. In certain situations involving depressed patients unresponsive to adequate trials of several individual antidepressant agents, adjunctive therapy with another agent (e.g., buspirone, lithium) or concomitant use of a second antidepressant agent (e.g., bupropion) has been used; however, such combination therapy is associated with an increased risk of adverse reactions, may require dosage adjustments, and (if not contraindicated) should be undertaken only after careful consideration of the relative risks and benefits.
(See Drug Interactions: Serotonergic Drugs, see Drug Interactions: Tricyclic and Other Antidepressants, and see Drug Interactions: Lithium.)
Efficacy of fluoxetine for the management of major depression has been established principally in outpatient settings. Most patients evaluated in clinical studies with fluoxetine had major depressive episodes of at least moderate severity, had no evidence of bipolar disorder, and had experienced either single or recurrent episodes of depressive illness. Limited evidence suggests that mildly depressed patients may respond less well to fluoxetine than moderately depressed patients. There also is some evidence that patients with atypical depression (which usually is characterized by atypical signs and symptoms such as hypersomnia and hyperphagia), a history of poor response to prior antidepressant therapy, chronic depressive symptomatology with or without episodic worsening of depressive symptoms, a longer duration of depression in the current episode, and/or a younger age of onset of depression may be more likely to respond to fluoxetine than to tricyclic antidepressant therapy.
As with other antidepressants, the possibility that fluoxetine may precipitate hypomanic or manic attacks in patients with bipolar or other major affective disorder should be considered. Fluoxetine monotherapy is not approved for use in treating depressive episodes associated with bipolar disorder. However, fluoxetine is used in combination with olanzapine for the treatment of acute depressive episodes in patients with bipolar disorder.
(See Uses: Bipolar Disorder.)
Considerations in Choosing Antidepressants
A variety of antidepressant drugs are available for the treatment of major depressive disorder, including selective serotonin-reuptake inhibitors (SSRIs; e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs; e.g., desvenlafaxine, duloxetine, venlafaxine), tricyclic antidepressants (e.g., amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine), monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine), and other antidepressants (e.g., bupropion, maprotiline, nefazodone, trazodone, vilazodone). Most clinical studies have shown that the antidepressant effect of usual dosages of fluoxetine in patients with moderate to severe depression is greater than that of placebo and comparable to that of usual dosages of tricyclic antidepressants, maprotiline, other selective serotonin-reuptake inhibitors (e.g., paroxetine, sertraline), and other antidepressants (e.g., trazodone). Fluoxetine appears to be as effective as tricyclic antidepressants in reducing most of the signs and symptoms associated with major depressive disorder, including depression, anxiety, cognitive disturbances, and somatic symptoms. However, in some studies, the drug did not appear to be as effective as tricyclic antidepressants or trazodone in reducing sleep disturbances associated with depression. In geriatric patients with major depressive disorder, fluoxetine appears to be as effective as and to cause fewer overall adverse effects than doxepin. The onset of action of fluoxetine appears to be comparable to that of tricyclic antidepressants, although the onset of action has been variably reported to be somewhat faster or slower than that of tricyclic antidepressants in some studies.
Because response rates in patients with major depression are similar for most currently available antidepressants, the choice of antidepressant agent for a given patient depends principally on other factors such as potential adverse effects, safety or tolerability of these adverse effects in the individual patient, psychiatric and medical history, patient or family history of response to specific therapies, patient preference, quantity and quality of available clinical data, cost, and relative acute overdose safety. No single antidepressant can be recommended as optimal for all patients because of substantial heterogeneity in individual responses and in the nature, likelihood, and severity of adverse effects. In addition, patients vary in the degree to which certain adverse effects and other inconveniences of drug therapy (e.g., cost, dietary restrictions) affect their preferences.
In the large-scale Sequenced Treatment Alternatives to Relieve Depression (STAR*D) effectiveness trial, patients with major depressive disorder who did not respond to or could not tolerate therapy with one SSRI (citalopram) were randomized to switch to extended-release (''sustained-release'') bupropion, sertraline, or extended-release venlafaxine as a second step of treatment (level 2). Remission rates as assessed by the 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Quick Inventory of Depressive Symptomatology--Self Report (QIDS-SR-16) were approximately 21 and 26% for extended-release bupropion, 18 and 27% for sertraline, and 25 and 25% for extended-release venlafaxine therapy, respectively; response rates as assessed by the QIDS-SR-16 were 26, 27, and 28% for extended-release bupropion, sertraline, and extended-release venlafaxine therapy, respectively. These results suggest that after unsuccessful initial treatment of depressed patients with an SSRI, approximately 25% of patients will achieve remission after therapy is switched to another antidepressant, and either another SSRI (e.g., sertraline) or an agent from another class (e.g., bupropion, venlafaxine) may be reasonable alternative antidepressants in patients not responding to initial SSRI therapy.
Patient Tolerance Considerations
Because of differences in the adverse effect profile between selective serotonin-reuptake inhibitors and tricyclic antidepressants, particularly less frequent anticholinergic effects, cardiovascular effects, and weight gain with selective serotonin-reuptake inhibitors, these drugs may be preferred in patients in whom such effects are not tolerated or are of potential concern. The decreased incidence of anticholinergic effects associated with fluoxetine and other selective serotonin-reuptake inhibitors compared with tricyclic antidepressants is a potential advantage, since such effects may result in discontinuance of the drug early during therapy in unusually sensitive patients. In addition, some anticholinergic effects may become troublesome during long-term tricyclic antidepressant therapy (e.g., persistent dry mouth may result in tooth decay). Although selective serotonin-reuptake inhibitors share the same overall tolerability profile, certain patients may tolerate one drug in this class better than another. In an open study, most patients who had discontinued fluoxetine therapy because of adverse effects subsequently tolerated sertraline therapy. Antidepressants other than selective serotonin-reuptake inhibitors may be preferred in patients in whom certain adverse GI effects (e.g., nausea, anorexia) or nervous system effects (e.g., anxiety, nervousness, insomnia, weight loss) are not tolerated or are of concern, since such effects appear to occur more frequently with fluoxetine and other drugs in this class.
The clinical presentation of depression in children and adolescents can differ from that in adults and generally varies with the age and developmental stages of the child. Younger children may exhibit behavioral problems such as social withdrawal, aggressive behavior, apathy, sleep disruption, and weight loss; adolescents may present with somatic complaints, self esteem problems, rebelliousness, poor performance in school, or a pattern of engaging in risky or aggressive behavior.
Data from controlled clinical studies evaluating various antidepressant agents in children and adolescents are less extensive than with adults, and many of these studies have methodologic limitations (e.g., nonrandomized or uncontrolled, small sample size, short duration, nonspecific inclusion criteria). However, there is some evidence that the response to antidepressants in pediatric patients may differ from that seen in adults, and caution should be used in extrapolating data from adult studies when making treatment decisions for pediatric patients. Results of several studies evaluating tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline) in preadolescent and adolescent patients with major depression indicate a lack of overall efficacy in this age group.
Based on the lack of efficacy data regarding use of tricyclic antidepressants and MAO inhibitors in pediatric patients and because of the potential for life-threatening adverse effects associated with the use of these drugs, many experts consider selective serotonin-reuptake inhibitors, including fluoxetine, the drugs of choice when antidepressant therapy is indicated for the treatment of major depressive disorder in children and adolescents. However, the US Food and Drug Administration (FDA) states that, while efficacy of fluoxetine has been established in pediatric patients, efficacy of other newer antidepressants (i.e., citalopram, desvenlafaxine, duloxetine, escitalopram, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine) was not conclusively established in clinical trials in pediatric patients with major depressive disorder. In addition, FDA now warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.
(See Cautions: Pediatric Precautions.)FDA currently states that anyone considering using an antidepressant in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need. (See Cautions: Precautions and Contraindications.)
The response to antidepressants in depressed geriatric patients without dementia is similar to that reported in younger adults, but depression in geriatric patients often is not recognized and is not treated. In geriatric patients with major depressive disorder, SSRIs appear to be as effective as tricyclic antidepressants (e.g., amitriptyline) but may cause fewer overall adverse effects than these other agents. Geriatric patients appear to be especially sensitive to anticholinergic (e.g., dry mouth, constipation, vision disturbance), cardiovascular, orthostatic hypotensive, and sedative effects of tricyclic antidepressants. The low incidence of anticholinergic effects associated with fluoxetine and other SSRIs compared with tricyclic antidepressants is a potential advantage in geriatric patients, since such effects (e.g., constipation, dry mouth, confusion, memory impairment) may be particularly troublesome in these patients. However, SSRI therapy may be associated with other troublesome adverse effects (e.g., nausea and vomiting, agitation and akathisia, parkinsonian adverse effects, sexual dysfunction, weight loss, hyponatremia). Some clinicians state that SSRIs including fluoxetine may be preferred for treating depression in geriatric patients in whom the orthostatic hypotension associated with many antidepressants (e.g., tricyclics) potentially may result in injuries (such as severe falls). However, despite the fewer cardiovascular and anticholinergic effects associated with SSRIs, these drugs did not show any advantage over tricyclic antidepressants with regard to hip fracture in a case-control study. In addition, there was little difference in the rates of falls between nursing home residents receiving SSRIs and those receiving tricyclic antidepressants in a retrospective study. Therefore, all geriatric individuals receiving either type of antidepressant should be considered at increased risk of falls and appropriate measures should be taken. In addition, clinicians prescribing SSRIs in geriatric patients should be aware of the many possible drug interactions associated with these drugs, including those involving metabolism of the drugs through the cytochrome P-450 system.
(See Drug Interactions.)
Patients with dementia of the Alzheimer's type (Alzheimer's disease, presenile or senile dementia) often present with depressive symptoms, such as depressed mood, appetite loss, insomnia, fatigue, irritability, and agitation. Most experts recommend that patients with dementia of the Alzheimer's type who present with clinically important and persistent depressive symptoms be considered as candidates for pharmacotherapy even if they fail to meet the criteria for a major depressive syndrome. The goals of such therapy are to improve mood, functional status (e.g., cognition), and quality of life. Treatment of depression also may reduce other neuropsychiatric symptoms associated with depression in patients with dementia, including aggression, anxiety, apathy, and psychosis. Although patients may present with depressed mood alone, the possibility of more extensive depressive symptomatology should be considered. Therefore, patients should be evaluated and monitored carefully for indices of major depression, suicidal ideation, and neurovegetative signs since safety measures (e.g., hospitalization for suicidality) and more vigorous and aggressive therapy (e.g., relatively high dosages, multiple drug trials) may be needed in some patients.
Although placebo-controlled trials of antidepressants in depressed patients with concurrent dementia have shown mixed results, the available evidence and experience with the use of antidepressants in patients with dementia of the Alzheimer's type and associated depressive manifestations indicate that depressive symptoms (including depressed mood alone and with neurovegetative changes) in such patients are responsive to antidepressant therapy. In some patients, cognitive deficits may partially or fully resolve during antidepressant therapy, but the extent of response will be limited to the degree of cognitive impairment that is directly related to depression. SSRIs such as fluoxetine, citalopram, escitalopram, paroxetine, or sertraline are generally considered as first-line agents in the treatment of depressed patients with dementia since they are usually better tolerated than some other antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors). Some possible alternative agents to SSRIs include bupropion, mirtazapine, and venlafaxine. Some geriatric patients with dementia and depression may be unable to tolerate the antidepressant dosages needed to achieve full remission. When a rapid antidepressant response is not critical, some experts therefore recommend a very gradual dosage increase to increase the likelihood that a therapeutic dosage of the SSRI or other antidepressant will be reached and tolerated. In a randomized, double-blind study comparing fluoxetine and amitriptyline in a limited number of patients with major depression complicating Alzheimer's disease, fluoxetine and amitriptyline were found to be equally effective; however, fluoxetine was better tolerated.
The relatively low incidence of adverse cardiovascular effects, including orthostatic hypotension and conduction disturbances, associated with fluoxetine and most other selective serotonin-reuptake inhibitors may be advantageous in patients in whom cardiovascular effects associated with tricyclic antidepressants may be hazardous. However, most clinical studies of fluoxetine for the management of depression did not include individuals with cardiovascular disease (e.g., those with a recent history of myocardial infarction or unstable heart disease), and further experience in such patients is necessary to confirm the reported relative lack of cardiotoxicity with the drug.
(See Cautions: Precautions and Contraindications.)
Because fluoxetine and other SSRIs generally are less sedating than some other antidepressants (e.g., tricyclics), some clinicians state that these drugs may be preferable in patients who do not require the sedative effects associated with many antidepressant agents; however, an antidepressant with more prominent sedative effects (e.g., trazodone) may be preferable in some patients (e.g., those with insomnia).
Suicidal Risk Considerations
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidal thinking and behavior (suicidality) in certain patients during the early phases of treatment. FDA states that antidepressants increased the risk of suicidality in short-term studies in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.
(See Cautions: Pediatric Precautions.)An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older. It currently is unknown whether the suicidality risk extends to longer-term antidepressant use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression. Because the risk of suicidality in depressed patients may persist until substantial remission of depression occurs, appropriate monitoring and close observation of patients of all ages who are receiving antidepressant therapy are recommended. (See Cautions: Precautions and Contraindications.)
Dosing Interval Considerations
Fluoxetine can be administered once weekly as delayed-release capsules for continuing management of major depressive disorder. Whether the weekly regimen is equivalent to daily therapy with conventional preparations for preventing relapse has not been established. In a double-blind study in adults who responded to daily fluoxetine therapy for major depressive disorder, the relapse rate for continuing therapy with fluoxetine 20-mg conventional capsules administered daily, fluoxetine 90-mg delayed-release capsules administered once weekly, or placebo was 26, 37, or 50%, respectively.
Fluoxetine has been effective for the treatment of depression in adults with human immunodeficiency virus (HIV) infection. In one randomized, placebo-controlled study, analysis of patients who completed the study showed a statistically significant benefit in patients receiving fluoxetine compared with those receiving placebo. However, results of intent-to-treat analysis did not show a statistically significant benefit in those receiving the antidepressant, possibly because of a high attrition rate and substantial placebo response. There was no evidence that the degree of immunosuppression affected the response to antidepressant therapy.
Fluoxetine has been effective when used in combination with lithium in a limited number of patients with refractory depression who had not responded to prior therapy (including tricyclic antidepressants and MAO inhibitors administered alone or in combination with lithium), suggesting that lithium may potentiate the antidepressant activity of fluoxetine.
(See Drug Interactions: Lithium.)In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) level 2 trial, patients with major depressive disorder who did not respond to or could not tolerate therapy with citalopram (another SSRI) were randomized to receive either extended-release (''sustained-release'') bupropion or buspirone therapy in addition to citalopram. Although both extended-release bupropion and buspirone were found to produce similar remission rates, extended-release bupropion produced a greater reduction in the number and severity of symptoms and a lower rate of drug discontinuance than buspirone in this large-scale, effectiveness trial. These results suggest that augmentation of SSRI therapy with extended-release bupropion may be useful in some patients with refractory depression.
Fluoxetine has been used safely for the management of depression in at least one patient with established susceptibility to malignant hyperthermia, suggesting that the drug may be useful in depressed patients susceptible to malignant hyperthermia and in whom tricyclics and MAO inhibitors are potentially hazardous; however, additional experience is necessary to confirm this preliminary finding.
Because fluoxetine possesses anorectic and weight-reducing properties, some clinicians state that the drug may be preferred in obese patients and/or patients in whom the increase in appetite, carbohydrate craving, and weight gain associated with tricyclic antidepressant therapy may be undesirable (e.g., potentially hazardous to the patient's health; result in possible discontinuance of or noncompliance with therapy). However, the possibility that some patients with concurrent eating disorders or those who may desire to lose weight may misuse fluoxetine for its anorectic and weight-reducing effects should be considered.
(See Uses: Eating Disordersand also see Chronic Toxicity.)
Fluoxetine is used in the acute and maintenance treatment of obsessive-compulsive disorder in adults and pediatric patients 7 years of age and older when the obsessions or compulsions cause marked distress, are time consuming, or interfere substantially with social or occupational functioning. Obsessions are recurrent and persistent ideas, thoughts, impulses, or images that, at some time during the disturbance, are experienced as intrusive and inappropriate (i.e., ''ego dystonic'') and that cause marked anxiety or distress but that are not simply excessive worries about real-life problems. Compulsions are repetitive, intentional behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) performed in response to an obsession or according to rules that must be applied rigidly (e.g., in a stereotyped fashion). Although the behaviors or acts are aimed at preventing or reducing distress or preventing some dreaded event or situation, they either are not connected in a realistic manner with what they are designed to neutralize or prevent or are clearly excessive. At some time during the course of the disturbance, the patient, if an adult, recognizes that the obsessions or compulsions are excessive or unreasonable; children may not make such a recognition.
The efficacy of fluoxetine for the management of obsessive-compulsive disorder has been established in several multicenter, placebo-controlled studies, including 2 studies of 13 weeks' duration in adults and one study of 13 weeks' duration in children and adolescents 7-17 years of age. Patients in these studies had moderate to severe obsessive-compulsive disorder with average baseline total scores on the Yale-Brown Obsessive-Compulsive Scale (YBOCS) of 22-26 in adults and 25-26 in children and adolescents (measured on the Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]).
In 2 fixed-dose studies of 13 weeks' duration, adults receiving fluoxetine dosages of 20, 40 and 60 mg daily experienced substantially greater reductions in the YBOCS total score than those receiving placebo. Mean reductions in total scores on the YBOCS in fluoxetine-treated patients were approximately 4-6 units in one study and 4-9 units in the other study compared with a 1-unit reduction in patients receiving placebo. In these 2 studies, a positive clinical response (much or very much improved on the Clinical Global Impressions improvement scale) occurred in 36-47 or 11% of patients receiving fluoxetine or placebo, respectively. While there was no indication of a dose-response relationship for effectiveness in one study, a dose-response relationship was observed in the other study, with numerically better responses in patients receiving 40 or 60 mg of fluoxetine daily compared with those receiving 20 mg of the drug daily. No age- or gender-related differences in outcome were noted in either of these studies.
In another randomized, placebo-controlled study of 13 weeks' duration, children and adolescents 7-17 years of age with obsessive-compulsive disorder who received mean fluoxetine dosages of approximately 25 mg daily (range: 10-60 mg daily) demonstrated substantially greater reductions in the CY-BOCS total score than those receiving placebo. In this study, a positive clinical response (much or very much improved on the Clinical Global Impressions improvement scale) occurred in approximately 55-58 or 9-19% of patients receiving fluoxetine or placebo, respectively. In addition, 49% of patients who received fluoxetine were classified as responders (i.e., patients with a 40% or greater reduction in their CY-BOCS total score from baseline) compared with 25% of those who received placebo. Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender.
Results from comparative studies to date suggest fluoxetine and other selective serotonin-reuptake inhibitors (SSRIs; e.g., fluvoxamine, paroxetine, sertraline) are as effective or somewhat less effective than clomipramine in the management of obsessive-compulsive disorder. In a pooled analysis of separate short-term (10-13 weeks) studies comparing clomipramine, fluoxetine, fluvoxamine, or sertraline with placebo, clomipramine was calculated as being more effective (as determined by measures on the YBOC scale) than SSRIs, although all drugs were superior to placebo.
Many clinicians consider an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) or clomipramine to be the drugs of choice for the pharmacologic treatment of obsessive-compulsive disorder. The decision whether to initiate therapy with an SSRI or clomipramine often is made based on the adverse effect profile of these drugs. For example, some clinicians prefer clomipramine in patients who may not tolerate the adverse effect profile of SSRIs (e.g., nausea, headache, overstimulation, sleep disturbances) while SSRIs may be useful alternatives in patients unable to tolerate the adverse effects associated with clomipramine therapy (e.g., anticholinergic effects, cardiovascular effects, sedation). Consideration of individual patient characteristics (age, concurrent medical conditions), pharmacokinetics of the drug, potential drug interactions, and cost of therapy may also influence decisions regarding use of SSRIs or clomipramine as first-line therapy in patients with obsessive-compulsive disorder. Although not clearly established, it has been suggested that the mechanism of action of fluoxetine and other drugs (e.g., clomipramine) used in the management of obsessive-compulsive disorder may be related to their serotonergic activity.
Other Disorders with an Obsessive-Compulsive Component
Experience in a limited number of patients suggests that fluoxetine also reduces obsessive-compulsive symptoms associated with Tourette's disorder (Gilles de la Tourette's syndrome); however, the drug did not appear to be effective in suppressing motor and vocal tics associated with the condition.
Trichotillomania (an urge to pull out one's hair) has some features in common with those of obsessive-compulsive disorder and some studies have suggested that antiobsessional agents such as SSRIs and clomipramine may be useful in treating this condition. Successful treatment with fluoxetine has been reported in some patients with trichotillomania, including in 2 short-term, open studies in which dosages of up to 80 mg daily were given. However, fluoxetine's efficacy in the management of this disorder was not demonstrated in 2 double-blind, placebo-controlled, crossover studies. In addition, behavioral therapy was found to be more effective than fluoxetine in treating trichotillomania in a short-term, controlled study. Further studies are needed to more clearly determine the role of fluoxetine and other serotonin-reuptake blockers in the management of this condition.
Premenstrual Dysphoric Disorder
Fluoxetine is used in the treatment of premenstrual dysphoric disorder (previously late luteal phase dysphoric disorder). DSM-IV criteria for premenstrual dysphoric disorder (PMDD) require that in most menstrual cycles of the previous year at least 5 of the following 11 symptoms must have been present for most of the time during the last week of the luteal phase (with at least one of the symptoms being the first 4 listed): marked depressed mood, feelings of hopelessness, or self-deprecating thoughts; marked anxiety, tension, feelings of being ''keyed up'' or on ''edge''; marked affective lability (e.g., feeling suddenly sad or tearful or increased sensitivity to rejection); persistent and marked anger or irritability or increased interpersonal conflicts; decreased interest in usual activities (e.g., work, school, friends, hobbies); a subjective sense of difficulty in concentrating; lethargy, easy fatigability, or marked lack of energy; marked change in appetite, overeating, or specific food cravings; hypersomnia or insomnia; a subjective sense of being overwhelmed or out of control; and other physical symptoms, such as breast tenderness or swelling, headaches, joint or muscle pain, or a sensation of ''bloating'' or weight gain. Such symptoms should begin to remit within a few days of the onset of menses (follicular phase) and are always absent in the week following menses. The presence of this cyclical pattern of symptoms must be confirmed by at least 2 consecutive months of prospective daily symptom ratings. PMDD should be distinguished from the more common premenstrual syndrome (PMS) by prospective daily ratings and the strict criteria listed above.
There is some evidence that serotonergic agents (e.g., fluoxetine, paroxetine) have greater efficacy compared with non-serotonergic agents (e.g., bupropion, maprotiline) in relieving the physical and/or emotional symptoms of PMDD. In published studies, the response rates to fluoxetine therapy in women with PMDD appear to be similar to those described in patients with depression, panic disorder, and obsessive-compulsive disorder. However, unlike the onset of action of fluoxetine in other psychiatric conditions (6-8 weeks), some clinicians have observed a rapid onset of response to fluoxetine (approximately 2-4 weeks) in women with PMDD, suggesting that the mechanism of action of these agents in PMDD is not mediated by the drug's antidepressant or anti-obsessive effects. In addition, use of fluoxetine in the treatment of PMDD does not appear to produce the sustained remission typically seen in the treatment of major depressive disorder. PMDD symptoms recur soon after discontinuance of fluoxetine therapy (e.g., within 2 menstrual cycles), even in women who have received the drug for more than 1 year. It has been suggested that a past history of major depression may be associated with a partial or absent response to lower dosages of fluoxetine therapy. Because patients on oral contraceptives were excluded from most clinical studies to date, efficacy of fluoxetine used in conjunction with oral contraceptives for the treatment of PMDD has not been determined.
The efficacy of fluoxetine for the management of PMDD has been established in 3 randomized, placebo-controlled (1 intermittent- and 2 continuous-dosing) studies of 3 or 6 months' duration in adult women who met DSM-III-R or DSM-IV criteria for PMDD. One study involved over 300 women (20-40 years of age) who were randomized to receive either fluoxetine (at fixed dosages of 20 or 60 mg daily) or placebo continuously throughout the full menstrual cycle, beginning on the first day of their cycle. In this study, fixed doses of fluoxetine were shown to be substantially more effective than placebo in decreasing the mean total of 3 visual analog scale scores (tension, irritability, dysphoria); total scores decreased by 36-39% on 20 or 60 mg of fluoxetine and 7% on placebo. However, marked (greater than 50% reduction from baseline) improvement in total luteal phase visual analog scale scores occurred only in 18% of patients receiving 60 mg of fluoxetine and in 6 or 4% of those receiving 20 mg of fluoxetine or placebo, respectively. Fluoxetine therapy appeared to be well tolerated in patients receiving dosages of 20 mg daily, but approximately 33% of women receiving 60 mg daily discontinued the drug because of adverse reactions and 86% of those receiving this dosage who remained in the study reported one or more adverse effects attributable to the drug.
In a second double-blind, placebo-controlled, crossover study, women with PMDD who received flexible doses of fluoxetine (20-60 mg daily; mean dosage of 27 mg daily) throughout the menstrual cycle for a total of 3 cycles had an average visual analog scale total score (follicular to luteal phase increase) that was 3.8 times lower than that of patients receiving placebo. However, results of another double-blind, parallel study indicated that the response rate in women receiving fluoxetine 20 mg daily or bupropion 300 mg daily continuously for 2 cycles was not substantially superior to placebo on the Clinical Global Impressions scale.
The efficacy of intermittent dosing (defined as initiation of daily dosage 14 days prior to the anticipated onset of menstruation and continuing through the first full day of menses) was established in a double-blind, parallel group study of 3 months' duration. In this study, women receiving intermittent dosing of 20 mg daily dosages of fluoxetine had substantially greater improvements on the Daily Record of Severity of Problems, a patient-rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, than those receiving placebo. Further studies are needed to evaluate the comparative efficacy of continuous and intermittent dosing regimens.
Fluoxetine is used in the acute and maintenance treatment of bulimia nervosa in adults; the drug also has been used in a limited number of patients with other eating disorders (e.g., anorexia nervosa).
Although DSM-IV criteria provide guidelines for establishing a diagnosis of a specific eating disorder, the symptoms frequently occur along a continuum between those of anorexia nervosa and bulimia nervosa. The primary features in both anorexia nervosa and bulimia nervosa are weight preoccupation and excessive self-evaluation (i.e., disturbed perception) of body weight and shape, and many patients exhibit a mixture of both anorexic and bulimic behaviors.
The American Psychiatric Association (APA) states that psychiatric management forms the foundation of treatment for patients with eating disorders and should be instituted for all patients in combination with other specific treatment modalities (e.g., nutritional rehabilitation and pharmacotherapy). Because patients with eating disorders often exhibit comorbid conditions and/or associated psychiatric features that may compromise clinical outcome, treatment programs should identify and address all comorbid conditions before initiating therapy. Clinicians should recognize that patients with concurrent diabetes mellitus often underdose their insulin in order to lose weight, and that pregnant patients with disturbed eating behaviors (e.g., inadequate nutritional intake, binge eating, purging, abuse of teratogenic medications) may be at high risk for fetal or maternal complications. Results from several studies indicate that patients with associated psychiatric features such as substance abuse/dependence or personality disorder may require longer-term therapy than those without these comorbid conditions. Although the presence of depression at initial presentation has no predictive value for treatment outcome, many clinicians suggest that severe depression can impair the patient's involvement in and/or response to psychotherapy, and such patients should receive initial pharmacologic therapy to improve mood symptoms.
Fluoxetine is used in the acute and maintenance treatment of binge-eating and self-induced vomiting behaviors in patients with moderate to severe bulimia nervosa (e.g., at least 3 bulimic episodes per week for 6 months).
According to DSM-IV, bulimia nervosa is characterized by recurrent episodes of binge eating and recurrent inappropriate compensatory behaviors to prevent weight gain (e.g., self-induced vomiting; misuse of laxatives, diuretics, enemas, or other medications; fasting; excessive exercise) and binge eating and compensatory behaviors both occur at least twice a week for 3 months.
Treatment strategies for bulimia nervosa include psychosocial interventions, nutritional counseling and rehabilitation, and pharmacotherapy. The primary goals in treating bulimia nervosa are to reduce binge eating and purging. Although antidepressants initially were used only in bulimic patients who were clinically depressed, evidence from recent studies indicates that nondepressed patients also respond to these agents, and that the presence of depression is not predictive of therapeutic response. Therefore, antidepressants are included as one component of initial treatment regimens for patients with bulimia nervosa. Because selective serotonin-reuptake inhibitors have a more favorable adverse effects profile, these drugs usually are preferred and may be especially useful for patients with symptoms of depression, anxiety, obsessions, or certain impulse disorder symptoms or for those who previously failed to achieve optimal response to psychosocial therapy. Other antidepressants also may be used to reduce the symptoms of binge eating and purging and help prevent relapse. However, the APA cautions against the use of tricyclic antidepressants in patients who are suicidal and cautions against use of MAO inhibitors in those with chaotic binge eating and purging.
The APA states that in patients who fail to respond to initial antidepressant therapy, it may be necessary to assess whether the patient has taken the drug shortly before vomiting or to determine whether effective drug concentrations have been achieved. Although only limited data are available regarding use of antidepressants for maintenance therapy, there appears to be a high rate of relapse during the treatment phase and an even higher rate following discontinuance of therapy. However, limited data indicate that the rate of relapse appears to correlate with the time at which drug therapy is initiated. In one small, open-label study, patients who received drug treatment within 13 weeks of diagnosis were more likely to exhibit sustained recovery during the first year than those who did not receive pharmacotherapy. Furthermore, continuing cognitive behavior therapy following discontinuance of drug therapy appears to prevent relapse in patients with bulimia nervosa. Additional study is needed to determine the effects of sequential use of psychotherapy and pharmacotherapy in the treatment of bulimia nervosa.
The efficacy of fluoxetine for the management of bulimia nervosa has been established in several multicenter, placebo-controlled studies, including 2 studies of 8 weeks' duration (using fluoxetine dosages of 20 or 60 mg daily) and one study of 16 weeks' duration (using fluoxetine dosages of 60 mg once daily) in patients with moderate to severe bulimia nervosa with median binge eating and self-induced vomiting of 7-10 and 5-9 times a week, respectively. In these studies, fluoxetine given in dosages of 60 mg daily (but not in dosages of 20 mg daily) was substantially more effective than placebo in reducing the number of binge-eating and self-induced vomiting episodes weekly. The superiority of fluoxetine compared with placebo was evident as early as within 1 week of therapy and persisted throughout each study period. The drug-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. The beneficial effect of fluoxetine therapy (compared with placebo), as measured by median reductions in the frequency of bulimic behaviors at the end of therapy compared with baseline, ranged from 1-2 and 2-4 episodes per week for binge eating and self-induced vomiting, respectively. The magnitude of clinical effect was related to baseline frequency of bulimic behaviors since greater reductions in such behaviors were observed in patients with higher baseline frequencies. Although binge eating and purging resolved completely in some patients who received fluoxetine therapy, the majority of fluoxetine-treated patients only experienced a partial reduction in the frequency of bulimic behaviors.
In an uncontrolled study in patients with bulimia nervosa, fluoxetine substantially reduced the frequency of binge eating and self-induced vomiting but did not affect bodily dissatisfaction in patients receiving 60-80 mg of the drug for 4 weeks; in several patients, therapeutic effects of the drug appeared to be maintained during chronic therapy. In another uncontrolled study, fluoxetine reduced the frequency of binge eating and self-induced vomiting in several patients with bulimia nervosa who were unresponsive to previous therapy with imipramine. The drug also reportedly improved bulimic symptoms, expanded food preferences, and resulted in weight gain in one underweight patient with anorexia nervosa and bulimia who was unresponsive to or unable to tolerate previous therapy for her eating disorder (including tricyclic antidepressants, monoamine oxidase inhibitors, bupropion, nomifensine, or lithium). In addition, fluoxetine used in combination with lithium was effective in improving bulimic symptoms in a patient with major depression and bulimia who was unresponsive to prior therapy.
The efficacy of fluoxetine for long-term use in the treatment of bulimia nervosa has been established in a placebo-controlled study of up to 52 weeks' duration in patients who responded to an initial single-blind, 8-week acute treatment phase with fluoxetine 60 mg daily for bulimia nervosa. In this study, fluoxetine decreased the likelihood of relapse and improved the clinical outcome. However, symptoms of bulimia gradually worsened over time in patients in both the fluoxetine and placebo groups in this study, suggesting that fluoxetine alone may not be an adequate maintenance treatment after acute response in some patients with bulimia nervosa. Additional management strategies, such as psychotherapy, may be required to augment or to sustain initial improvement in this condition.
Pending further accumulation of data, most clinicians recommend that antidepressant therapy, including fluoxetine, be continued for at least 6-12 months in patients with bulimia nervosa before attempting to discontinue therapy. If fluoxetine is used for extended periods, the need for continued therapy with the drug should be reassessed periodically.
Fluoxetine has been used in a limited number of patients with anorexia nervosa. According to DSM-IV, anorexia nervosa is characterized by refusal to maintain body weight at or above a minimally normal weight for age and height (e.g., weight loss leading to maintenance of body weight less than 85% of that expected or failure to make expected weight gain during periods of growth, leading to body weight less than 85% of that expected); intense fear of gaining weight or becoming fat (even though underweight); disturbance in the perception of body weight and shape, undue influence of body weight or shape on self-evaluation, or denial of the seriousness of the current low body weight; and amenorrhea in postmenarchal females (i.e., absence of at least 3 consecutive menstrual cycles). Patients with anorexia nervosa often exhibit depressive (e.g., depressed mood, social withdrawal, irritability, insomnia, and diminished interest in sex) and obsessive-compulsive symptoms that may be associated with or exacerbated by undernutrition.
The APA recommends that a program of nutritional rehabilitation, including vitamin (e.g., potassium and phosphorus) supplementation, be established for all patients who are significantly underweight. The APA states that pharmacologic measures (e.g., antidepressants) may be considered in patients with anorexia nervosa to maintain weight and normal eating behaviors; to treat psychiatric symptoms associated with the disorder (e.g., depression, anxiety, or obsessive-compulsive symptoms); and to prevent relapse. However, such therapy should not be used as the sole or primary treatment for anorexia nervosa. Because associated psychiatric symptoms of anorexia nervosa (e.g., depression) often improve with weight gain, the APA states that the decision to initiate antidepressant therapy should be deferred until weight gain has been restored, and that the choice of an antidepressant agent depends on the remaining symptoms. According to the APA, selective serotonin-reuptake inhibitors commonly are considered in patients with anorexia nervosa whose depressive, obsessive, or compulsive symptoms persist in spite of or in the absence of weight gain.
Although there are few well-controlled, clinical studies of antidepressants for the treatment of anorexia nervosa, data from one study indicate that weight-restored patients with anorexia nervosa who received fluoxetine (40 mg daily) after hospital discharge had less weight loss, depression, and fewer rehospitalizations for anorexia nervosa during the subsequent year than those who received placebo. However, it should be noted that fluoxetine has been misused for its anorectic and weight-reducing effects in a patient with a history of chronic depression, anorexia nervosa, and laxative abuse who was receiving the drug for the treatment of depression; therefore, the misuse potential of fluoxetine in depressed patients with concurrent eating disorders or in other patients who may desire to lose weight should be considered.
(See Chronic Toxicity.)
Fluoxetine is used in the acute treatment of panic disorder with or without agoraphobia in adults. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a clinically important change in behavior related to the attacks.
According to DSM-IV, panic disorder is characterized by recurrent unexpected panic attacks, which consist of a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: palpitations, pounding heart, or accelerated heart rate; sweating; trembling or shaking; sensations of shortness of breath or smothering; feeling of choking; chest pain or discomfort; nausea or abdominal distress; feeling dizzy, unsteady, lightheaded, or faint; derealization (feelings of unreality) or depersonalization (being detached from oneself); fear of losing control; fear of dying; paresthesias (numbness or tingling sensations); and chills or hot flushes.
The efficacy of fluoxetine for the management of panic disorder with or without agoraphobia has been established by 2 randomized, double-blind, placebo-controlled studies in adult outpatients who met DSM-IV criteria for panic disorder with or without agoraphobia. These studies were of 12 weeks' duration and used a flexible dosing schedule. Fluoxetine therapy in both studies was initiated in a dosage of 10 mg daily for the first week and then the dosage was escalated to 20-60 mg daily depending on clinical response and tolerability. In these studies, 42-62% of patients receiving fluoxetine were free from panic attacks at week 12 compared with 28-44% of those receiving placebo. The mean fluoxetine dosage in one of these studies was approximately 30 mg daily.
The optimum duration of fluoxetine therapy required to prevent recurrence of panic disorder has not been established to date. The manufacturer states that the efficacy of fluoxetine for long-term use (i.e., longer than 12 weeks) has not been demonstrated in controlled studies. However, in a 10-week, placebo-controlled, fixed-dose study, patients responding to fluoxetine 10 or 20 mg daily were randomized to receive continued therapy with their previous fluoxetine dosage or placebo during a 6-month continuation phase. The patients who received an additional 6 months of fluoxetine therapy in this study demonstrated continued clinical improvement.. The manufacturer and some clinicians state that panic disorder is a chronic condition and requires several months or longer of sustained therapy. Therefore, it is reasonable to continue therapy in responding patients. The manufacturer recommends, however, that patients be reassessed periodically to determine the need for continued therapy.
Panic disorder can be treated with cognitive and behavioral psychotherapy and/or pharmacologic therapy. There are several classes of drugs that appear to be effective in the pharmacologic management of panic disorder, including tricyclic antidepressants (e.g., imipramine, clomipramine), monoamine oxidase (MAO) inhibitors (e.g., phenelzine), selective serotonin-reuptake inhibitors (SSRIs), and benzodiazepines (e.g., alprazolam, clonazepam). When choosing among the available drugs, clinicians should consider their acceptance and tolerability by patients; their ability to reduce or eliminate panic attacks, reduce clinically important anxiety and disability secondary to phobic avoidance, and ameliorate other common comorbid conditions (such as depression); and their ability to prevent relapse during long-term therapy. Because of their better tolerability when compared with other agents (such as the tricyclic antidepressants and benzodiazepines), the lack of physical dependence problems commonly associated with benzodiazepines, and efficacy in panic disorder with comorbid conditions (e.g., depression, other anxiety disorders such as obsessive-compulsive disorder, alcoholism), many clinicians prefer SSRIs as first-line therapy in the management of panic disorder. If SSRI therapy is ineffective or is not tolerated, use of a tricyclic antidepressant or a benzodiazepine is recommended.
Fluoxetine monotherapy has been used for the short-term treatment of acute depressive episodes in a limited number of patients with bipolar depression (bipolar disorder, depressed). In one poorly controlled study, fluoxetine was more effective than imipramine, and each drug was more effective than placebo in the management of depression in patients with bipolar disorder; fluoxetine appeared to be particularly effective in reducing anxiety and somatic symptoms in these patients. However, because the drug has been reported to cause manic reactions in some patients, the possibility that hypomanic or manic attacks may be precipitated in patients with bipolar disorder must be considered. In addition, some experts have reported an association between use of antidepressants and the development of rapid cycling and mixed affective states in patients with bipolar disorder, suggesting that such use may worsen the overall course of bipolar disorder in these patients. Consequently, the American Psychiatric Association (APA) does not recommend use of antidepressant monotherapy in patients with bipolar disorder. Initiation or optimization of dosages of maintenance agents (i.e., lithium, lamotrigine) are considered first-line therapies for the management of acute episodes of depression in patients with bipolar disorder. While the addition of either lamotrigine, bupropion, or paroxetine currently is recommended as the next step for patients who fail to respond to optimum dosages of maintenance agents, the APA states that other SSRIs (e.g., fluoxetine) can be used as an alternative to these agents. For further information on the management of bipolar disorder,
Fluoxetine also is used in combination with olanzapine for the treatment of acute depressive episodes in patients with bipolar I disorder. In 2 randomized, double-blind studies of 8 weeks' duration comparing a fixed combination of fluoxetine and olanzapine with olanzapine monotherapy and placebo, the fixed combination (flexible daily dosages of 6 mg olanzapine and 25 or 50 mg of fluoxetine or of 12 mg of olanzapine and 50 mg of fluoxetine) was more effective than olanzapine monotherapy (5-20 mg daily) or placebo in improvement in depressive symptoms as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS). Although the manufacturer states that efficacy beyond 8 weeks' duration remains to be established, patients have received the fixed combination for up to 24 weeks in clinical trials. Clinicians who elect to extend therapy beyond 8 weeks should reevaluate the risks and benefits of continued therapy periodically.
Fluoxetine has been used in a limited number of patients for the short-term management of exogenous obesity. In a controlled study, obese (i.e., more than 20% overweight), nondepressed individuals receiving fluoxetine (average dosage: 64.9 mg daily), benzphetamine hydrochloride (average dosage: 97 mg daily), or placebo concurrently with reduced food intake and increased exercise for 8 weeks lost an average of about 4.8, 4, and 1.7 kg, respectively. Fluoxetine-treated patients who usually experienced carbohydrate cravings reportedly lost more weight during this study than those who did not experience such cravings.
(See Pharmacology: Effects on Appetite and Body Weight.)
In a study evaluating the safety of fluoxetine therapy in the management of exogenous obesity, the drug was generally well tolerated. The adverse effect profile of the drug in nondepressed obese patients appeared to differ somewhat from that in depressed patients receiving similar dosages of the drug; obese patients reportedly had a higher incidence of fatigue and a lower incidence of nausea, anxiety, and tremor. Unlike amphetamines, the potential for addiction to or abuse of fluoxetine appears to be minimal
(see Chronic Toxicity), and tolerance to the drug's anorectic and weight-reducing effects has not been reported to date following short-term administration. However, long-term studies are necessary to fully determine whether tolerance develops during chronic fluoxetine therapy and to fully establish the relative efficacy and safety of fluoxetine in the management of exogenous obesity.
Fluoxetine has been used for the symptomatic management of cataplexy in a limited number of patients with cataplexy and associated narcolepsy. In one study, the drug appeared to be as effective as clomipramine in reducing the number of cataplexy attacks in patients concurrently receiving CNS stimulants (e.g., dextroamphetamine) for the symptomatic management of associated narcolepsy.
Like some other selective serotonin-reuptake inhibitors (SSRIs; e.g., citalopram, zimeldine [not commercially available in the US]), fluoxetine has been used in the management of alcohol dependence. However, studies of SSRIs have generally shown modest effects on alcohol consumption. In a limited number of early-stage problem drinkers (who drank an average of about 8 drinks daily prior to therapy), alcohol consumption was reduced by an average of 17% in patients receiving 60 mg of fluoxetine daily; however, response showed considerable interindividual variability, and alcohol consumption was not altered substantially in problem drinkers receiving 40 mg of the drug daily. It has been suggested that the clinical effects of SSRIs in the management of alcohol dependence may only be transient. In patients with mild to moderate alcohol dependence, alcohol consumption is substantially decreased for only the first 1-4 weeks of fluoxetine therapy or first 12 weeks of citalopram therapy. Additional study is required to fully determine the safety and efficacy of fluoxetine in the management of alcohol dependence.
(See Pharmacology: Effects on Alcohol Intakeand also see Drug Interactions: Alcohol.)
Fluoxetine has been used for the management of intention myoclonus, including postanoxic action myoclonus and progressive action myoclonus, in a limited number of patients. Although fluoxetine alone was not effective in improving myoclonus, speech abnormalities, gait abnormalities, or overall performance on neurological examination in such patients, the drug did appear to potentiate the therapeutic effects of combined oxitriptan (l-5-hydroxytryptophan, l-5HTP) and carbidopa therapy in some patients. In addition, fluoxetine reportedly reduced the dosage requirement of oxitriptan and the incidence of adverse GI effects (e.g., diarrhea, abdominal cramps) associated with such therapy. Fluoxetine used in combination with oxitriptan also has exhibited antimyoclonic activity in animals.
(See Pharmacology: Other Effects.)However, because toxic effects have been reported in some patients concurrently receiving fluoxetine and tryptophan, a serotonergic agent that is structurally similar to oxitriptan (see Tryptophan and Other Serotonin Precursors under Drug Interactions: Serotonergic Drugs), further study and experience are needed to fully determine the safety and efficacy of combined therapy with fluoxetine and oxitriptan-carbidopa in the management of inte