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Fluoxetine: pharmacologic observations
BACKGROUND: Randomized, controlled medication trials have shown fluoxetine to
effectively treat the symptoms of DSM dysthymia.1,2 When taken at a therapeutic dose,
fluoxetine, a selective serotonin reuptake inhibitor, fully treats the symptoms of
serotonin-neuron-communication dysfunction (SNCD) (i.e., pervasive dysphoria).
MECHANISM OF ACTION: Fluoxetine facilitates serotonin neurotransmission by
competing with serotonin for reuptake of the neurotransmitter into the pre-synaptic
neuron and effectively increasing the concentration of serotonin in the synaptic space
thus driving its chemical reaction with the post-synaptic neuron.
PATIENT EDUCATION: Men taking the medicine need to know they will have a lasting
erection; specifically, ejaculation (but, rather, sexual pleasure) no longer determines the
length of intercourse. Women need to know that clitoral stimulation may no longer be
attractive and to trust they will feel something new and lovely during intercourse. Also,
patients need to know they will feel fatigue when their body needs rest -- and to trust the
feeling of fatigue.
TOXICITY AND DOSING: Hyperserotonism (an internal “racy feeling
specifically due to exaggeration of serotonin neurotransmission) represents fluoxetine
toxicity3, is dose-related, and is most noticeable 2 hours after the medication is ingested
(likely the transit time from ingestion to crossing the blood brain barrier). Patients
recognize the feeling and need to look for it – both in assessing a test-dose and in
determining their specific therapeutic dose.
Patients whose symptoms do not represent SNCD experience hyperserotonism
two hours after ingestion of a 10-mg test dose. The reaction is brief but clearly
observable. Similarly, patients with SNCD dependably experience mild hyperserotonism
two hours after ingesting a dose of fluoxetine 10 mg higher than their therapeutic dose.
Dropping the dose by 10mg typically allows full therapeutic effect without side effects
(although a few patients need to alternate higher and lower doses on a qod basis for full
therapeutic effect without mild toxicity).
Patients notice full effect the day of taking the therapeutic dose. Reducing the
dose even 10 mg eliminates its therapeutic value. This observation strongly suggests liver
metabolism (via the portal circulation) to determine the therapeutic dose (with only a
minute amount required at the synaptic level). The hypothesis is supported by the
observation that patients with a liver “powerful” enough to metabolize “a quart of Jack
Daniels at one sitting” consistently require 100mg of fluoxetine qd for therapeutic effect.
Similarly, patients with histories of heavy exercise (and, presumably, liver metabolism of
muscle break-down products) also require 100mg qd. No patient was observed to tolerate
a dose higher than 100mg qd without hyperserotonism toxicity.
Titration can be rapid: a 48-hour interval between dosage increases is more than
the 4 half-lives suggested by the plateau period of pharmacokinetics.4 Knowledge of
hyperserotonism toxicity allows patients to be active participants in determining their
therapeutic dose.
Beyond the toxicity of hyperserotonism, the only side effect associated with
fluoxetine is a dyspepsia commonly experienced when the medication is taken without
food.
It is my experience that patients need to know that they can stop and restart the
medication at will without danger, so can “work” with the medication – deciding whether
it is “right” for them or not. That said, patients do need to know that guilty ruminative
symptoms will reappear and that, should they decide to stop the medicine, they let their
health practitioner know. If not, they may “be lost to treatment” if, after stopping the
medicine, guilt or shame prevent follow up with care.
ALTERNATIVE THEAPIES: While other medications are marketed as SSRI’s (e.g.
sertraline and paroxetine), fluoxetine is the only medication is designed to only react with
the serotonin reuptake receptor. Sertraline also reacts with dopamine receptors and is
therefore complicated by akathisia; paroxetine reacts with GABA receptors and is
complicated by tachyphylaxis and withdrawl symptoms. General therapies such as
improved diet, exercise, hobbies, writing, talking therapy are all temporarily helpful but,
not addressing the underlying neurobiology, are eventually found ineffective.
1
Hellerstein DJ, et al. (1993) A randomized double-blind study of fluoxetine versus
placebo in the treatment of dysthymia. Am J Psychiatry;150:1169-1175.
2
Akiskal H (1993) Dysthymic disorder and its treatment. Encephal; 2:375-8.
3
Rothchild AJ, Locke CA (1991): Re-exposure to fluoxetine after serious suicide
attempts by three patients: the role of akathisia. J Clin Psychiatry 52:491-493.
4
Fingl E, Woodbury DM. General Principles. In Goodman LS, Gilman A, eds (1975).
Pharmacological Basis of Therapeutics. New York: Macmillan Publishing Co.