Fluoxetine

Brand Names: Prozac

Clinical Names: Fluoxetine

Summary

generic name: Fluoxetine

trade name: Prozac®

type of drug: Selective serotonin reuptake inhibitor (SSRI).

used to treat: Depression, bulimia, obsessive-compulsive disorder.

overview of interactions:
• nutrient affecting drug performance: Folate (Folic Acid)

• nutrient affecting drug toxicity: Tryptophan

• nutrient affecting drug toxicity: 5-Hydroxytryptophan (5-HTP)

• herb affecting drug toxicity: Ginkgo biloba (Ginkgo)

• herb affecting drug toxicity: Hypericum perforatum (St. John’s Wort)

• substance affecting drug toxicity: Alcohol



Interactions

nutrient affecting drug performance: Folate (Folic Acid)

• research: Fava M et al investigated folate, vitamin B12, and homocysteine status in 213 outpatients with major depressive disorder taking 20 mg per day of fluoxetine for 8 weeks. They found that subjects with low folate levels were more likely to have melancholic depression and were significantly less likely to respond to fluoxetine. They also found that homocysteine and B12 levels were not associated with depressive subtype or treatment response.
(Fava M, et al. Am J Psychiatry 1997 Mar;154(3):426-428.)

• nutritional support: Individuals suffering from depression who do not respond adequately to pharmaceutical antidepressants, specifically fluoxetine, might benefit from supplementation with folate levels. Individuals taking fluoxetine should consult with their prescribing physician and/or a nutritionally trained healthcare professional before initiating supplementation with folate. Folic aid supplementation at levels of 400-800 mcg per day may serve to enhance the action of fluoxetine with no attendant risk. Folic acid is also plays a key role in the production of S-adenosyl methionine (SAM) which can also influence emotional state.

nutrient affecting drug toxicity: Tryptophan

• reports: Reports have suggested that when taken in the form of a supplement, L-tryptophan can interact adversely with fluoxetine. Typical symptoms include nausea and vomiting, agitation, anxiety and restlessness, headache, dizziness and increased perspiration.
(Barr LC, et al. Biol Psychiatry. 1997 May 1;41(9):949-954; Threlkeld DS, ed. Apr 1997.)

• nutritional concerns: Individuals taking fluoxetine should avoid the use of L-tryptophan supplements without consulting the prescribing physician and/or a nutritionally trained healthcare professional. Apparently this response has never been elicited when fluoxetine has been combined with a protein-rich diet containing significant levels of L-tryptophan.

nutrient affecting drug performance and toxicity: 5-Hydroxytryptophan (5-HTP)

• mechanism: While fluoxetine works to increase the functional level of serotonin by inhibiting its reuptake, 5-HTP is converted into serotonin in the brain. Simultaneously taking fluoxetine and 5-HTP could result in excessive levels of serotonin. Such a combination could produce an adverse reaction in the form of serotonin syndrome; it could also alter the levels of other related hormones.

• research: Meltzer et al have found that fluoxetine potentiates the 5-hydroxytryptophan-mediated increase in plasma cortisol and prolactin secretion in subjects with major depression or with obsessive compulsive disorder.
(Meltzer H, et al.  Neuropsychopharmacology. 1997 Jul;17(1):1-11.)

• nutritional concerns: Even though a potentially valuable synergy might conceivably develop from the careful combining of fluoxetine and 5-hydroxytryptophan, such experimentation would be premature until more thorough research has been conducted. Individuals taking fluoxetine should avoid using 5-HTP as a supplement if they are taking fluoxetine or any other SSRI drug.

herb affecting drug toxicity: Ginkgo biloba (Ginkgo)

• research: Sexual dysfunction, decreased sex drive, delayed ejaculation and difficulty achieving orgasm are common side effects associated with taking fluoxetine and other SSRI drugs. In small studies involving both men and women using SSRI drugs, Dr. Alan Cohen, University of California at San Francisco, has found that an extract of Ginkgo biloba (240 mg per day) could effectively reverse many of these adverse side effects. Ellison and DeLuca have also reported success in using Ginkgo to counter adverse effects of fluoxetine upon genital sensation. Meanwhile, in related research, Sohn and Sikora have explored the efficacy of Ginkgo in the treatment of impotence.
(Cohen AJ. Psychiatry On-Line; Sohn M, Sikora R. J Sex Educ Ther 1991;17:53-61; Ellison JM, DeLuca P. J Clin Psychiatry. 1998 Apr;59(4):199-200.)

• herbal support: Cohen recommends an initial dose of 60 mg Ginkgo, twice daily, gradually increasing up to 240 mg, twice daily. He noted that some patients have safely taken more than 500 mg in combination with their antidepressant treatments. Individuals taking fluoxetine should avoid the use of Ginkgo without consulting the prescribing physician and/or a healthcare professional trained in botanical medicine.

herb affecting drug toxicity: Hypericum perforatum (St. John’s Wort)

• reports: Since the emergence of Hypericum as a popular herbal supplement in recent years many have been concerned about the risk of serotonin syndrome due to excessive dosing and the combination of the herb with SSRI drugs. Demott has reported one case where a patient taking another SSRI drug, trazadone, may have experienced a serotonin syndrome reaction upon taking Hypericum with their drug. In that instance, the patient reported symptoms consistent with a serotonin syndrome such as confusion, flushing, perspiration, muscle twitching, and ataxia. Gordon reported on another case where a patient took one dose of paroxetine (Paxil) after using Hypericum for ten days and experienced nausea, lethargy, fatigue and weakness,
(Demott K. Clinical Psychiatry News 1998;26:28; Gordon JB. Am Fam Physician 1998;57:950.)

• herbal concerns: Even though a potentially valuable synergy might conceivably develop from the careful combining of fluoxetine and Hypericum, such experimentation would be premature until more thorough research has been conducted. Individuals taking fluoxetine should avoid using Hypericum unless they have consulted with and are being monitored by their prescribing physician and/or a healthcare provided trained in medical herbalism.

substance affecting drug toxicity: Alcohol

• mechanism: Dizziness and drowsiness are side effects commonly associated with fluoxetine, and other SSRI drugs.

• research: Naranjo and Bremner, along with fellow researchers, have published several studies which found that fluoxetine could decrease the desire to consume alcohol and assist in the reduction of alcohol intake in alcoholics .
(Naranjo CA, et al. Int Clin Psychopharmacol 1994 Sep;9(3):163-172; Naranjo CA, Bremner KE. EXS. 1994;71:209-219; Naranjo CA, Bremner KE. Alcohol Alcohol Suppl. 1993;2:221-229; Naranjo CA, et al. Clin Pharmacol Ther. 1990 Apr;47(4):490-498; Cornelius JR, et al Arch Gen Psychiatry 1997 Aug;54(8):700-705; Lejoyeux M. Alcohol Alcohol Suppl. 1996 Mar;1:69-75.)

• dietary concerns: Given the tendency of both fluoxetine and alcohol to cause disorientation and diminished motor control the combined use of these two substances represents serious risk to the user and those around them. Individuals taking fluoxetine should avoid consumption of alcohol during the course of treatment.

Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.


References

Barr LC, Heninger GR, Goodman W, Charney DS, Price LH. Effects of fluoxetine administration on mood response to tryptophan depletion in healthy subjects. Biol Psychiatry. 1997 May 1;41(9):949-954.
Abstract: Short-term reduction in plasma tryptophan (tryptophan depletion) produces a relapse of depressive symptoms in 60% of previously depressed patients recently recovered with serotonin reuptake inhibitor treatment. Tryptophan depletion does not consistently increase depressive symptoms in unmedicated depressed patients or in depressed patients whose symptoms are remitted with a norepinephrine reuptake inhibitor. These data suggest that serotonin reuptake inhibitor treatment itself may confer vulnerability to the development of depressive symptoms during tryptophan depletion. In order to further investigate this possibility, six healthy individuals underwent double-blind placebo-controlled tryptophan depletion before and following six weeks of treatment with fluoxetine 20 mg/day. No increased vulnerability to the mood-lowering effects of tryptophan depletion occurred as a result of fluoxetine treatment. Additionally, fluoxetine treatment itself was not associated with changes in mood or quality of life in these healthy volunteers. These data indicate that serotonin reuptake inhibitor treatment alone does not produce the depressive effects of tryptophan depletion that are observed in serotonin reuptake inhibitor-treated depressed and obsessive compulsive disorder patients.

Cappiello A, McDougle CJ, Malison RT, Heninger GR, Price LH. Yohimbine augmentation of fluvoxamine in refractory depression: a single-blind study. Biol Psychiatry 1995 Dec 1;38(11):765-767.

Cohen AJ. Long term safety and efficacy of Ginkgo biloba extract in the treatment of anti-depressant-induced sexual dysfunction. Psychiatry On-Line http://www.priory.com/ginkgo.html.

Cornelius JR, Salloum IM, Ehler JG, Jarrett PJ, Cornelius MD, Perel JM, Thase ME, Black A. Fluoxetine in depressed alcoholics. A double-blind, placebo-controlled trial. Arch Gen Psychiatry 1997 Aug;54(8):700-705.
Abstract: BACKGROUND: The selective serotonergic medication fluoxetine has demonstrated efficacy in the treatment of major depression and has suggested efficacy in the treatment of alcoholism. However, no completed trials with any selective serotonergic medication have been reported in patients who display both major depression and alcoholism, despite previous observations that both depression and alcoholism are associated with low serotonergic functioning. METHODS: Fifty-one patients diagnosed as having comorbid major depressive disorder and alcohol dependence were randomized to receive fluoxetine (n = 25) or placebo (n = 26) in a 12-week, double-blind, parallel-group trial. Weekly ratings of depression and alcohol consumption were obtained throughout the 12-week course of the study. RESULTS: The improvement in depressive symptoms during the medication trial was significantly greater in the fluoxetine group than in the placebo group. Total alcohol consumption during the trial was significantly lower in the fluoxetine group than in the placebo group. CONCLUSIONS: Fluoxetine is effective in reducing the depressive symptoms and the alcohol consumption of patients with comorbid major depressive disorder and alcohol dependence. It is unknown whether these results generalize to the treatment of less depressed and less suicidal alcoholics.

Demott K. St. John’s wort tied to serotonin syndrome. Clinical Psychiatry News 1998;26:28.

Ellison JM, DeLuca P. Fluoxetine-induced genital anesthesia relieved by Ginkgo biloba extract. J Clin Psychiatry. 1998 Apr;59(4):199-200. (Letter)

Fava M, Borus JS, Alpert JE, Nierenberg AA, Rosenbaum JF, Bottiglieri T. Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry 1997 Mar;154(3):426-428.
Abstract: OBJECTIVE: The authors examined the relationships between levels of three metabolites (folate, vitamin B12, and homocysteine) and both depressive subtype and response to fluoxetine treatment in depressed patients. METHOD: Fluoxetine, 20 mg/day for 8 weeks, was given to 213 outpatients with major depressive disorder. At baseline, depressive subtypes were assessed, and a blood sample was collected from each patient. Serum metabolite levels were assayed. Response to treatment was determined by percentage change in score on the 17-item Hamilton Depression Rating Scale. RESULTS: Subjects with low folate levels were more likely to have melancholic depression and were significantly less likely to respond to fluoxetine. Homocysteine and B12 levels were not associated with depressive subtype or treatment response. CONCLUSIONS: Overall, the results are consistent with findings linking low folate levels to poorer response to antidepressant treatment. Folate levels might be considered in the evaluation of depressed patients who do not respond to antidepressant treatment.

Gordon JB. SSRIs and St. John’s wort: possible toxicity? Am Fam Physician 1998;57:950.

Lejoyeux M. Use of serotonin (5-hydroxytryptamine) reuptake inhibitors in the treatment of alcoholism. Alcohol Alcohol Suppl. 1996 Mar;1:69-75. (Review)
Abstract: Animal studies have shown that alcohol consumption is reduced when serotonin (5-hydroxytryptamine, 5-HT) levels are increased in the central nervous system. Similarly, studies of alcohol-dependent human subjects have shown that treatment with 5-HT reuptake inhibitors (i.e. zimeldine, citalopram, fluoxetine, and fluvoxamine) decreases the desire to drink alcohol and improves symptoms of alcohol-related anxiety and depression in patients who have undergone detoxification. However, not all studies have shown them to be an effective treatment to help maintain recovery in alcohol dependence. The exact mechanisms of action of the 5-HT reuptake inhibitors are not yet fully understood and additional studies are needed. However, at this time, the 5-HT reuptake inhibitors may be effective pharmacotherapies for alcohol-related depression.

Meltzer H, Bastani B, Jayathilake K, Maes M.  Fluoxetine, but not tricyclic antidepressants, potentiates the 5-hydroxytryptophan-mediated increase in plasma cortisol and prolactin secretion in subjects with major depression or with obsessive compulsive disorder. Neuropsychopharmacology. 1997 Jul;17(1):1-11.
Abstract: It has been suggested that the clinical efficacy of chronic treatment with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and perhaps all antidepressants is due to their ability to enhance serotonergic activity. The effects of chronic treatment with fluoxetine or tricyclic antidepressants on the L-5-hydroxytryptophan (200 mg, L-5-HTP; PO)-induced increases in plasma cortisol and prolactin (PRL) concentrations were studied in patients with major depression or obsessive compulsive disorder (OCD). Administration of L-5-HTP increased plasma cortisol and PRL levels in medicated and unmedicated patients with major depression or OCD. The L-5-HTP-induced cortisol and PRL responses were significantly higher in fluoxetine-treated than in tricyclic-treated or unmedicated major depressed patients. The latter two groups did not differ significantly in their cortisol or PRL responses to L-5-HTP. The L-5-HTP-induced increases in cortisol and PRL in fluoxetine-treated patients with major depression or OCD were not significantly different. The results suggest that fluoxetine, but not tricyclic antidepressants, potentiates 5-HT receptor-mediated stimulation of cortisol and PRL secretion in humans, consistent with available evidence that fluoxetine treatment, but not tricyclic antidepressants, increases central serotonergic activity in patients with MD or OCD by a presynaptic mechanism.

Messiha FS. Fluoxetine: adverse effects and drug-drug interactions. J Toxicol Clin Toxicol 1993;31(4):603-630.
Abstract: This overview summarizes the major and minor side effects and drug interactions of fluoxetine. The adverse reactions include the "serotonin syndrome", cardiovascular complications, extrapyramidal side effects such as akathisia, dyskinesias, and parkinsonian-like syndromes and an apparently increased risk of suicidality. Fluoxetine-induced mania and hypomania, seizures and sexual disorders are evaluated along with minor symptoms of allergic reactions, stuttering, hematological changes, psoriasis, and inappropriate secretion of the antidiuretic hormone. The major fluoxetine-drug interactions involve the amino acids L-dopa and L-tryptophan, anorexiants, anticonvulsants, antidepressants, anxiolytics, calcium channel blockers, cyproheptadine, lithium salts, and drugs of abuse. The underlying mechanism and the paradoxical effects of fluoxetine are addressed.

Naranjo CA, Pouos CX, Bremner KE, Lanctot KL. Fluoxetine attenuates alcohol intake and desire to drink. Int Clin Psychopharmacol 1994 Sep;9(3):163-172.
Abstract: Several serotonin uptake inhibitors, including the long-acting fluoxetine, have been found to decrease alcohol intake in moderately dependent alcoholics. While the mechanism of their effect is not fully elucidated, a previous study with citalopram indicated that decreased desire to drink may be an important factor. Therefore, we tested fluoxetine effects on alcohol intake and desire to drink in a placebo-controlled study. Subjects, recruited by advertisement, were mildly/moderately dependent alcoholics (12 male, four female, aged 19-59 years, healthy, non-depressed) who did not believe they had a drinking problem and were not requesting treatment. After a 1 week baseline they received, single-blind, 2 weeks placebo followed by 2 weeks fluoxetine 60 mg/day. As out-patients, subjects recorded daily standard drinks (13.6 g ethanol) and rated interest, desire, craving and liking for alcohol biweekly. Each out-patient period was immediately followed by a double-blind experimental drinking session. Out-patient daily drinks slightly decreased during fluoxetine to 6.6 +/- 0.9 (mean +/- S.E.M.) compared with during placebo (7.16 +/- 0.95, p = 0.07, N.S.) and baseline (7.18 +/- 1.0, p > 0.1, N.S.). Desire, interest and craving for alcohol decreased during fluoxetine vs placebo baseline (p < 0.05), but not vs placebo. Appetite loss and decrease in food intake (p < 0.01, fluoxetine vs placebo) correlated with each other (r = 0.91, p < 0.01) but neither correlated with decrease in alcohol intake (appetite: r = 0.26, N.S.; food intake: r = 0.22, N.S.). Weight loss occurred during fluoxetine (p < 0.05 vs placebo) but did not correlate with decrease in alcohol intake (r = 0.1, N.S.). In the experimental drinking sessions after placebo and fluoxetine treatments subjects rated their desire for each of 18 mini-drinks (each one-third of a standard drink) offered at 5 min intervals. Fluoxetine decreased desire to drink throughout the sessions; both mean and maximum desire ratings were lower after fluoxetine than after placebo (ANOVA, p < 0.05). Therefore, fluoxetine seems to have a robust effect on decreasing desire for alcohol. We propose that in the absence of intention by subjects to reduce drinking, their habitual drinking patterns mitigated against reduced consumption in the out-patient phase. However, fluoxetine could be a useful adjunct for patients in a treatment context who are motivated to reduce their drinking.

Naranjo CA, Bremner KE. Serotonin-altering medications and desire, consumption and effects of alcohol-treatment implications. EXS. 1994;71:209-219. (Review)
Abstract: The relationship between serotonin neurotransmission and alcohol consumption (AC) was first determined in preclinical studies. AC generally increases following treatments which decrease serotonin activity, and levels of 5-HT and metabolites are low in some brain regions of alcohol-preferring rats. Pharmacological treatments which enhance serotonergic neurotransmission (uptake inhibitors, releasers, agonists) consistently reduce AC in rats. Serotonin uptake inhibitors (SUI; e.g., citalopram, fluoxetine) have been studied extensively in humans. In several double-blind randomized, placebo-controlled trials, SUI consistently decreased short-term (2-4 weeks) AC by averages of 15% to 20% in nondepressed mildly/moderately dependent alcoholics who received no other treatment. Some subjects decreased AC by up to 60%. The effects of SUI on AC were dose-dependent and not related to side effects (few and mild) or changes in anxiety or depression (not observed). SUI decreased desire to drink and liking for alcohol, suggesting a mechanism of action, to be considered in the development of treatments to reduce AC and prevent relapse. However, while an adjunctive brief psychosocial intervention enhanced the short-term effect of a SUI, the long-term (12-week) effects of SUI and placebo were similar. Other drugs acting on the 5-HT system have been tested in humans, but results are inconclusive. For example, buspirone, a 5-HT1A receptor partial agonist, reduced anxiety and alcohol craving, but not AC; a 5-HT partial agonist, m-CPP, increased craving in abstinent alcoholics; modest reductions in AC were observed with a 5-HT3 antagonist, ondansetron (0.5 mg/day, but not 4 mg/day). Ritanserin, a 5-HT2 antagonist, reduced desire to drink and prevented relapse in a small (n = 5) study, and there was some indication that it reduced desire to drink and enhanced alcohol effects without reducing AC, in another study. The therapeutic potential of these medications is being studied. SUI and other serotonin-altering medications are promising new neuropharmacological treatments for AC.

Naranjo CA, Bremner KE. Clinical pharmacology of serotonin-altering medications for decreasing alcohol consumption. Alcohol Alcohol Suppl. 1993;2:221-229. (Review)

Naranjo CA, Kadlec KE, Sanhueza P, Woodley-Remus D, Sellers EM.  Fluoxetine differentially alters alcohol intake and other consummatory behaviors in problem drinkers. Clin Pharmacol Ther. 1990 Apr;47(4):490-498.

Smith KA, Fairburn CG, Cowen PJ. Symptomatic relapse in bulimia nervosa following acute tryptophan depletion. Arch Gen Psychiatry 1999 Feb;56(2):171-176.

Sohn M, Sikora R. Ginkgo biloba extract in the therapy of erectile dysfunction. J Sex Educ Ther 1991;17:53-61.

Threlkeld DS, ed. Central Nervous System Drugs, Antidepressants, Selective Serotonin Reuptake Inhibitors. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparison, Apr 1997.