Understanding fluoxetine

Understanding fluoxetine

Barbara Bihm

A considerable body of evidence has emerged in recent years to support the premise that most affective disorders have a biochemical basis. Many studies suggest that common mood disorders, such as depression, result from malfunctioning of neuronal pathways in the limbic regions of the brain. Neurons, which release or are stimulated by norepinephrine and 5-hydroxytryptamine (5-HT, also called serotonin), are considered the most likely biochemical causes of mood disorders. According to the monoamine theory of depression, for example, symptoms of affective disorders arise as a consequence of a defect in the availability of 5-HT and/or norepinephrine in the central nervous system. Alternatively, the receptor sensitivity hypothesis of depression postulates an abnormality in neurotransmitter receptor function as the cause of depression.

In the brain there are several neurotransmitters affected by various psychotropic drugs. An important group of neurotransmitters, chemically classified as monoamines, include in addition to serotonin and norepinephrine, dopamine, and histamine. Individual neurons contain one of the transmitters in vesicles located at the end of the neuron just before the synapse. The presynaptic terminal, as this end of the neuron is called, is stimulated by a nerve impulse to release its neurotransmitter into the synaptic space. The neurotransmitter diffuses across the synaptic space, also called the synaptic cleft, and contacts the end of the next neuron in the sequence. The end of this neuron, referred to as the postsynaptic terminal, is covered with receptors to which neurotransmitter molecules attach.

When neurotransmitter concentration is high in the synaptic cleft, a large proportion of the postsynaptic receptors are bound to neurotransmitter molecules, and when the concentration falls, the neurotransmitter diffuses away from the receptors. The binding of the neurotransmitter to the receptors produces an action potential which activates the neurons. Neurotransmitters exert their effect on neurons until they are removed from the synaptic cleft. Serotonin, for example, is removed by active transport back into the presynaptic terminal by the serotonin uptake pump. Following this process of reuptake, serotonin is either enzymatically inactivated by monoamine oxidase (MAO) or returned to the presynaptic terminal storage vesicles.

The class of drugs referred to as selective serotonin uptake inhibitors (SSUIs) or selective serotonin reuptake inhibitors (SSRIs) exert their pharmacologic effect by blocking the uptake pump in the presynaptic terminal. The blockage results in an increased concentration of serotonin in the synaptic cleft with resulting increased stimulation of serotonin receptors. Inhibition of serotonin reuptake results in numerous functional changes associated with enhanced serotonin-mediated neurotransmission. The mechanism of antidepressant action of SSRI agents may involve inhibition of reuptake of serotonin at the presynaptic neuronal membrane. However, as has been noted above, it has also been suggested that postsynaptic serotonin receptor modification is mainly responsible for the antidepressant action observed during long-term administration of antidepressant agents. According to this latter hypothesis, SSRI drugs exert their mood altering effects by correcting some abnormality in neurotransmitter receptor function.

Among the SSRI drugs, the most well known is fluoxetine (Prozac[R]). However, there are three other drugs in this class: fluvoxamine (Luvox[R]), paroxetine (Paxil[R]), and sertraline ((Zoloft[R]). Fluoxetine is the most widely used of the SSRIs and is currently commonly prescribed for treating major depression, bipolar disorder, obsessive compulsive disorder, obesity, anorexia, bulimia, panic attacks, myoclonus, and alcohol dependence.

The pharmacology of all SSRIs is in some ways similar to that of other antidepressants, such as the tricyclic antidepressant compounds (TCAs), which block the reuptake of various neurotransmitters. However, as the name implies, SSRI drugs are highly selective reuptake inhibitors and have little effect on other neurotransmitters, such as norepinephrine or dopamine. Moreover, drugs such as fluoxetine are associated with a lower incidence of anticholinergic effects, antihistamine effects, and alpha-adrenergic blocking actions than other types of antidepressants. The lower incidence of adverse effects of SSRIs is one of the main reasons for the popularity of these drugs in treating mood disorders. Since the drugs have fewer significant side effects, they are most often better tolerated than other drug classes leading to better adherence of patients to the prescribed drug regimen.

Fluoxetine is well absorbed after oral administration and food does not affect the extent of drug absorption. Therefore, the drug may be administered with or without food. The oral capsules and the solution of fluoxetine are reportedly bioequivalent; therefore, no dosage adjustment is needed when changing from one form of the drug to the other. Following absorption through the GI track, fluoxetine is thought to be highly protein bound. In vitro studies indicate 94.5% binding to serum proteins. This characteristic of fluoxetine creates a potential for drug interactions with other highly protein-bound drugs, such as warfarin, digoxin, and hypoglycemic agents. Hypoglycemia has occurred with concurrent administration of fluoxetine and sulfonylureas probably through partial displacement of hypoglycemic agents from their protein-binding sites. Drugs that are bound to serum proteins are inactive, thus displacement of sulfonylureas from serum protein-binding sites converts them from an inactive to active state.

Fluoxetine is partially metabolized to an active metabolite, norfluoxetine. Both fluoxetine and norfluoxetine are slowly eliminated from the body. The half-life of fluoxetine and its metabolite varies considerably from one individual to the next. Following a single dose, the half-life of fluoxetine ranges from 1 to 9 days and for norfluoxetine 3 to 15 days. With chronic administration, the clearance of fluoxetine is slower and the half-life longer, resulting in a prolonged elimination half-life of approximately 27 days for fluoxetine and its metabolite. Therefore, complete removal of the drug from the body may take several weeks. A major advantage of the very long half-life of fluoxetine is that several missed consecutive doses are of little consequence. The effect of age on the elimination of fluoxetine has not been fully determined. The elimination half-lives of fluoxetine and norfluoxetine may be prolonged in patients with hepatic impairment since these drugs are extensively metabolized by the liver. Therefore, the drug should be used with caution in persons with liver disease and reduction in dose by half seems to be warranted.

Fluoxetine is specifically containdicated in combination with MAO inhibitors. Very serious, sometimes fatal, reactions have been reported in patients receiving MAO inhibitors in combination with fluoxetine. The reaction produced by this particular drug interaction is characterized by hyperthermia, rigidity, autonomic instability, and mental status changes progressing to delirium and coma. Therefore, particular caution must be exercised when MAO inhibitors are used either before beginning or after discontinuing therapy with fluoxetine. Fluoxetine should not be used within 14 days of discontinuing therapy with a MAO inhibitor. However, because of the prolonged elimination half-life of fluoxetine and norfluoxetine, at least 5 weeks should be allowed between stopping fluoxetine and starting an MAO inhibitor.

Fluoxetine is metabolized primarily by the cytochrome P450 system in the liver. This cytochrome system is responsible for metabolism of a wide variety of drugs. Since fluoxetine inhibits the activity of this system, other drugs metabolized by cytochrome P450 should be started at a lower dose if given concurrently or within 5 weeks of discontinuation of fluoxetine. When fluoxetine therapy is initiated in a person already taking drugs metabolized by cytochrome P450, doses of these drugs should be decreased. Among the drugs of particular importance in this regard are those with a narrow therapeutic index including flecainide, encainide, vinblastine, carbamazepine, and TCAs.

Adverse Reactions

In the treatment of depression, adherence to the prescribed regime is critical. Prior to the introduction of selective serotonin uptake inhibitors, patients being treated with other antidepressants (such as TCAs and MAO inhibitors) often experience side effects which detract from the quality of their lives despite improvement in depression. SSRIs have fewer and milder side effects when compared with TCAs and MAO inhibitors.

As has been noted, fluoxetine and other SSRIs cause serotonin uptake blockade with little or no effect on other neurotransmitters or their receptor sites. Serotonin uptake blockade is the mechanism of therapeutic action of SSRIs as well as the primary source of adverse effects. Serotonin blockade is associated with gastrointestinal disturbances, specifically nausea, dyspepsia, and diarrhea, insomnia, sedation, anxiety, jitteriness, headache, and sexual dysfunction.

In contrast to the high selectivity for serotonin uptake of SSRIs, TCAs and MAO inhibitors interfere with other neurotransmitters and receptors producing the potential for a wide array of clinical consequences. Antagonism of these other neurotransmitters and receptors is associated with side effects such as dry mouth, blurred vision, urinary retention, constipation, memory impairment, and vaginal dryness. Additional side effects common to other antidepressants include potentiation of CNS depressant drugs, sedation, dizziness, postur al hypotension and reflex tachycardia, sinus tachycardia, and weight gain. Patients taking SSRIs may present with some side effects similar to the foregoing; however, these side effects are usually less severe than those associated with TCAs and MAO inhibitors.

Fluoxetine offers the advantage of a relatively mild side-effect profile that contributes to improved compliance and fewer disruptions in therapy. In clinical trials, 45% fewer fluoxetine users discontinued therapy because of side effects when compared with patients receiving TCAs. Adverse effects affecting the GI system (nausea) and the nervous system (anxiety, nervousness, and insomnia) occur more frequently with fluoxetine than with TCAs.

Nausea is the most frequently reported adverse effect (in about 21% of patients); however, most cases are mild, tend to occur early in the course of treatment, and subside after a few weeks. Discontinuation of fluoxetine due to nausea occurs in approximately 3% of patients, suggesting that the nausea is tolerable. Other adverse GI effects include diarrhea (12%) anorexia (9%), and dyspepsia (6%). Occurring in less than 5% of patients are side effects such as vomiting, abdominal pain, and flatulence.

Fluoxetine may induce or worsen tension, vascular, and/for migraine headaches possibly through enhanced serotonin neurotransmission. Data reveal that the incidence of fluoxetine-related headache occurs in approximately 20% of patients. Significantly, only about 2% of patients discontinue fluoxetine due to headaches.

Fluoxetine is associated with overstimulation and jitteriness especially during the initial stages of treatment. This is believed to be caused by enhanced serotonin activity resulting in nervousness (in 15% of patients), anxiety (9%), and/or insomnia (14%). Management of these adverse effects may include dosage reduction, waiting for tolerance to develop (which often occurs), and subsequent gradual increase in dosage based on the patient’s response and side effects.

Drowsiness was reported by 12% of patients treated with fluoxetine, yet only 1% of these patients discontinued the drug as a result. This indicates that the drowsiness was mild enough to be tolerable to most patients. Tremors, dizziness, and fatigue reportedly occur in 8%, 6%, and 4%, respectively, of patients receiving fluoxetine therapy. Finally, fluoxetine has been associated with reversible short-term memory and concentration deficits, as well as mild difficulty in selecting appropriate words during conversation. If trouble some, these adverse effects can be managed by dosage reduction.

Insomnia, which itself is a common symptom of major depression, may be induced or exacerbated by fluoxetine. When insomnia appears or worsens following initiation of therapy, fluoxetine-induced insomnia should be considered, especially if other depressive symptoms have improved. Management of fluoxetine-induced insomnia includes dosage reduction, administration of fluoxetine in the morning, or changing to a more sedating antidepressant. Conversely, fluoxetine has been shown to be effective in improving sleep quality for many patients, probably by normalizing sleep patterns through suppression of REM-sleep. It may be that the REM-suppressing action of fluoxetine contributes to its overall antidepressant effect.

In addition to the foregoing, fluoxetine may cause a variety of other adverse effects. For example, upper respiratory infection has been reported in about 8%, excess sweating (8%), rash and/or urticaria (4%), blurred vision (3%), and pruritus (2%). Occurring in 1% to 2% are palpitations with hot flashes, as well as back, joint, muscle, and limb pain. Painful menstruation, sexual dysfunction, frequent micturition, and urinary tract infection, while infrequent (1%-2%) are among the most troublesome of adverse effects; patients should be aware that these adverse effects are often associated with long-term therapy.

Unlike TCAs weight gain is not associated with fluoxetine. Rather, weight loss frequently occurs in normal-weight and overweight depressed patients receiving fluoxetine. An average weight loss of 2 to 4 pounds is commonly reported following 6 weeks of therapy. Weight loss exceeding 5% of body weight has also been reported in approximately 13% of patients. Fluoxetine-induced weight loss appears to be reversible with a gradual increase in weight following drug discontinuation. There is evidence indicating that the weight loss is independent of the antidepressant effects of the drug.

Nursing Implications

Patients should be informed that all antidepressants, including fluoxetine, have side effects. In spite of the relatively mild adverse effects of fluoxetine, these effects may discourage compliance in some patients and detract from their quality of life. Nurses must recognize that some fluoxetine adverse effects (such as anxiety and insomnia) are similar to symptoms of major depression, and patients should be informed that these and all other troublesome adverse reactions should be reported immediately.

Patients must understand the importance of adherence to fluoxetine therapy. There must be recognition of a delay in onset of therapeutic effects, usually of 1 to 3 weeks. Nurses and patients should also recognize that approximately 65% of depressed patients respond positively to any single antidepressant drug. If fluoxetine is not effective, other medications may be useful either alone or in combination with fluoxetine.

Finally, nurses and patients should understand that there is no evidence to indicate that fluoxetine alone induces suicidal ideation. Since suicide is possible in high-risk depressed patients, caution should be exercised with these patients during initial fluoxetine therapy until depression improves.

Additional Readings

American Hospital Formulary Service. (1994). Drug information ’95. Bethesda, MD: Author. Bennie, E.H., Mullin, J.M., & Martindale, J.J. (1995). A double-blind multicenter trial comparing setraline and fuoxetine in outpatients with major depression. Journal of Clinical Psychiatry, 56(6), 229-237. Dista Products, Eli Lilly. (1993). Prozac: Fluoxetine hydrochloride (Product Information). Indianapolis, IN: Author. Facts and Comparisons. (1995). Drug facts and comparisons. St. Louis: Author. Leonard, B.E. (1993). The comparative pharmacology of new antidepressants. Journal of Clinical Psychiatry, 54(8), 3-15. McElroy, S.L., Keck, P.E., & Friedman, L.M. (1995). Minimizing ad managing antidepressant side effects. Journal of Clinical Psychiatry, 56(Suppl. 2), 49-55. Preskorn, S.H. (1995). Comparison of the tolerability of bupropion, fluoxetine, imipramine, nefazodone, parosetine, sertraline, and venlafaxine. Journal of Clinical Psychiatry, 56(Suppl. 6), 12-21. Sussman, N. (1994). The potential benefits of serotoni receptor-specific agents. Journal of Clinical Psychiatry, 55(2) (Suppl.), 45-51. Wilson, B.A., Shannon, M.T., & Stang, C. (1996). Nurses drug guide 1996. Norwalk, CT. Appleton & Lange.

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