In this paper, I would like to discuss Prozac and some of the issues that surround it, including a brief look at the role of serotonin in depression, how Prozac is different from the drugs that came before it, and what Prozac means to society. The purpose of this paper is not to bring up new issues, but to clarify and review what we know about Prozac and the biological basis of depression.
What is Depression?
Depression, as it is dealt with in this paper, is an affective disorder, or mood disorder,
characterized by a sad or depressed mood which is more severe or lengthy than what we
would consider normal. There are four categories of characteristics of depressive
symptoms: emotional pain, or a sad or blue mood; difficulties in cognition, for example
difficulty concentrating; changes in behavior associated with depression, such as crying,
social withdrawal, and attempting suicide; and somatic changes, such as sleep
disturbances, loss of appetite, or a decreased libido.(Jefferson 467) Depression
influences the patient's social activity and disturbs his/her regular work patterns and motivation.
Figure 1 shows a decision tree for diagnosis of major depression, which is the primary illness studied with respect to Prozac treatment. Figure 2 shows the DSM-IV criteria for a major depressive episode. Major depressive disorder is either recurrent, consisting of multiple episodes, or nonrecurrent, consisting of a single episode.
Affective disorders seem to run in families. According to one study, people with close relatives who were diagnosed with affective disorders were 23 times as likely to be diagnosed with an affective disorder (Jefferson 472)
Figure 1: Decision Tree for Diagnosis of Major Depression (Nemeroff, 4)
Figure 2: DSM-IV Criteria for a Major Depressive Episode. (Kaplan, 523)
Depression is startlingly common; "more common than hypertension in primary care medicine," according to one article. (Manolis 21) The lifetime risk for a major depressive disorder is 7 to 12 percent for men and 20 to 25 percent for women. (21)
Another characteristic of depression is its stubborn persistence:
In a later section of this paper, we'll discuss some of the societal effects of depression.
What is Prozac?
Prozac is the commercial name for fluoxetine, the first selective serotonin reuptake inhibitor (SSRI). It was invented at Eli Lilly Pharmaceuticals, and was originally referred to as Lilly 110140, or p-trifluoro-phenoxyphenylo N-methyl-propylamine. (Wong 82) Prozac evolved from a family of chemical compounds called the phenoxyphenylpropylamine series which were discovered to inhibit serotonin reuptake. (Wong 417) The phenoxyphenylpropylamine series schematic and the fluoxetine molecule schematic are illustrated in figures 3 and 4.
Prozac has four effective enantiomers: S-fluoxetine, its primary metabolite S-norfluoxetine, and their chemical "mirror images," R-fluoxetine and R-norfluoxetine. The entaniomers of Prozac are pictured in figure 5. The S-entaniomers are more potent than their corresponding R- entaniomers: about 1.5 times more potent for fluoxetine, and 20 times more potent for norfluoxetine.(Gram 1354) It is believed that the differences in metabolism of these entaniomers is what makes it difficult to get consistent dose-effect studies of fluoxetine.(1355) More than half the metabolic end products of fluoxetine are unknown. (1354)
Figure 3: The Phenoxyphenylpropylamine series: fluoxetine's chemical family. |
Numerous compounds were substituted at the "R." (Group of chemical compounds found to inhibit 5-HT reuptake. Wong 417)
Figure 4: Chemical Structure of Fluoxetine (Kaplan, 977)
Figure 5: Entantiomers of fluoxetine and norfluoxetine(Wong, 84)
Compared to antidepressant drugs that came before it, most notably the TCAs and MAOIs (described later in this paper,) Prozac is nearly as effective with fewer side effects. The lack of side effects is attributed to Prozac's affinity specifically for the serotonin receptor, whereas previous drugs interfered with other neurotransmitter systems in the brain.(Klieser 14) Because it is, according to one psychiatrist, "less toxic than salt," there is little threat of overdose. (Nightline) This may be a bit of an exaggeration, but so far, there has only been one reported fatality due to a Prozac overdose. (Kaplan 978)
Prozac has the longest half life of all the SSRIs, one to three days. Its primary metabolite, norfluoxetine, has a half life of 4 to 16 days. In comparison, the SSRI setraline has a half life or 26 hours, and its major metabolite, desmethylsertraline has a half life of 62 to 104 hours. Paroxetine, another SSRI, has a half life of only 21 hours. (Nemeroff 9) One of the advantages of Prozac's long half life is that it keeps the blood plasma level of the drug fairly regular, even if a day is missed, and the blood level lowers gradually when medication is stopped, so that withdrawal is slow and steady without having to calculate a gradual dose reduction.
Prozac is a potent inhibitor of the liver cytochrome P-450 enzyme (CYP2D6) which breaks down tricyclic antidepressant drugs; as a result, it may produce unexpected drug interactions with TCAs. (Gram 1358) It is also recommended that an SSRI never be taken with an MAOI, because it could result in a fatal "serotonin syndrome-like illness characterized by anxiety, restlessness, confusion, chills, incoordination, and insomnia."(1359)
Prozac does have some mild side effects, including nausea, anorexia, loss of weight, nervousness, tremor, anxiety, insomnia, diarrhea, and sexual dysfunction, but most of these disappear in a week or two as the patient becomes accustomed to the drug. (1356) There is no evidence that Prozac causes birth defects, although it may slightly increase the risk of miscarriage. (1359) It has "minimal effects on blood pressure and cardiac function."(Kaplan 976) The FDA has found no link between Prozac and violent behavior or suicidal thoughts (Burton) In extremely rare incidences, Prozac may cause skin reactions, or possibly deterioration in Parkinson's disease. (1358)
The Role of Serotonin
What is serotonin, and what does it have to do with depression? Serotonin, known to chemists as 5-hydroxytryptamine, or 5-HT, is one of the biogenic amine neurotransmitters. This group of neurotransmitters, which includes norepinephrine and dopamine, makes up a relatively small percentage of neurotransmitter substance in the body's neurons. (Kaplan 130)
Serotonin is the neurotransmitter that triggers sleep. (Birkmeyer 43) Serotonin raises the threshold for pain, inhibits "arousal functions," lowers blood pressure, stimulates secretion of mucus in the lungs, and is associated with emotional calming.(17) Serotonin hyperactivity results in improved appetite, weight increase, an urge to sleep, dampened consciousness, slower thought processes, loss of drive, decreased muscle tone, slowing of the circulation, introversion, and poor sleep.(17)
"The major site of serotonergic cell bodies is in the upper pons and the midbrain-specifically, the median and dorsal raphe nuclei, the candal locus ceruleus, the area postrema, and the inter peduncular area. Those neurons project to the basal ganglia, the limbic system, and the cerebral cortex."(Kaplan 139) Since I was unfamiliar with several of these brain areas until researching this paper, I have included figure 6, which illustrates the dispersion of serotonin through the brain.
Serotonin is created from tryptophan, and oxidized by monoamine oxidase. The "life cycle" of serotonin is illustrated in figures 7 and 8. The availablity of serotonin does depend to some extent on tryptophan in the diet. Tryptophan competes with other amino acids to cross the blood brain barrier and be converted into serotonin. This is illustrated by an experiment in which patients who were treated with SSRIs for depression were given amino acid rich drinks that contained a negligible amount of tryptophan. A significant number of the patients relapsed into depression.(Wong 89)
There are four types of serotonin receptors (5-HT1, 5-HT2, 5-HT3, 5-HT4) and four subtypes of receptor type 5-HT1 (5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D.)(Kaplan 139) All of the serotonin receptors are G-protein linked to ion channels except for the 5-HT3 type, which is directly linked to an ion channel.(130)
We have come to take it for granted that neurotransmitters play a role in depression: "Biochemical hypotheses [of depression] evolved from clinical observations linking reserpine- depleter of norepinephrine, serotonin, and dopamine-with depressive symptoms in some patients. On the other hand, certain drugs that increased neuronal uptake and increased synaptic availability of these transmitters or that inhibited their metabolism were found to be effective treatments for depression." (Jefferson 472)
The explanation for serotonin's role in depression is evolving: it was once thought "simply that depression is associated with too little serotonin and that mania is associated with too much serotonin."(Kaplan 141) Now scientists favor a view that mood is determined by a balance or more complicated interaction of neurotransmitters. There is the "permissive hypothesis" that "postulates that low levels of serotonin permit abnormal levels of norepinephrine to cause depression or mania."(141) It is also possible that the neurotransmitters keep each other in a "dynamic multidimensional equilibrium" by using a chemical feedback mechanism. (Birkmeyer 22-23)
The developers of Prozac were led to serotonin by the empirical evidence that linked it to depression. Studies show that "concentrations of 5-HT [serotonin] and its metabolite, 5- hydroxyindole acetic acid (5-HIAA) were found to be lower in the hindbrains of depressed victims of suicide than in hindbrains [of patients] killed in sudden deaths, coronary occlusion, or schizophrenic patients. The concentration of 5-HIAA in cerebrospinal fluid was lower in depressed patients, particularly among those who made attempts of suicides."(Wang 79) Studies show that suicide victims have increased 5-HT2 receptor density. (Jefferson 472) The release of corticotrophin releasing factor (CRF) from the hypothalamus is partially regulated by serotonin and other neurotransmitters; an over abundance of CRF has been linked to depression. (473)
Whether or not we know the exact relationship between serotonin and mood, to date, "every effective antidepressant treatment, from ECT[electroconvulsive therapy] to MAOIs to TCAs to SSRIs, increases the efficacy of serotonergic neurotransmission." (Nemeroff 9) We know this from studies of single cell neuronal firing, and we it appears that they consistently "facilitate 5-HT [serotonin] but not norepinephrine neurotransmission."(Jefferson 473)
How effective is Prozac?
About two-thirds of people who take Prozac, or "any of the currently available antidepressants"
for six to eight weeks will respond very favorably. (Nemeroff 4) Prozac may appear to be more
effective than traditional antidepressants from a statistical standpoint because the side effects are
insignificant enough that patients continue to take it enough long enough for it to become
effective. Figure 9 and figure 10, which illustrate the results of three dose/effect studies of
Prozac, show that response to Prozac levels off at about 20 mg per day. Figure 11 which
illustrates drop out rates from Prozac treatment and the reasons cited, illustrate that at 40 to 60
mg/day or more, the side effects compel many people to stop treatment, but they are manageable
at 20 mg/day or less.
|Figure 9: Relationship between dose and change in score on 21-item Hamilton Depression Scale. (Gram, 1355)||Figure 10: Relationship between dose and response (50% or greater decrease in Hamilton score after at least three weeks of treatment with fluoxetine.) (Gram, 1355)|
Figure 11: Dropout Rates in Dose-Effect Studies of Fluoxetine in Patients with Depression. (Gram, 1336)
Comparing Prozac with Other Drugs
There are four groups of antidepressants: the tricyclic or tetracyclic antidepressants (TCAs,) the selective serotonin reuptake inhibitors (SSRIs,) the monoamine oxidase inhibitors (MAOIs,) and other miscellaneous antidepressants, like bupropion, trazodone, vehlafaxine, and hefazodone.(Nemeroff 4)
TCAs work by inhibiting serotonin and norepinephrine reuptake into the synaptic cleft.(Manolis 20) This group includes among its members the tricyclics imipramine, nortriptyline, and clomipramine, and the tetracyclics maprotiline and amoxapine. (Kaplan 991) Unlike SSRIs, TCAs do not selectively inhibit only the reuptake of serotonin. It is the inhibition of norepinephrine reuptake that is believed to cause TCAs side effects, which include sedation, manic episodes, profuse sweating, palpitations, increased blood pressure, tachycardia, twitches and tremors of the tongue or upper extremities, and weight gain. (Nemeroff 5, Kaplan 994) Compared with SSRIs, "TCAs have very significant side effects, some virtually life threatening, and others merely difficult for patients to tolerate." (Nemeroff 5)
Although SSRIs are not more effective, and may actually be slightly less effective than some TCAs, TCAs are less attractive because they are more toxic than SSRIs and pose a greater threat of overdose. A TCA overdose results in central nervous system and cardiovascular toxicity (Gram 1358) making the relative risk of death by overdose with a TCA 2.5 to 8.5 times that with Prozac.(Nemeroff 5) However, in reality, less than 5 percent of suicides are carried out with TCAs. The greater danger is that side effects will persuade the patient not to continue treatment (which may or may not result in some form of suicide.) (Gram 1358) Studies indicate that patients taking a classical antidepressant (TCA or MAOI) are three times as likely to drop out of treatment due to side effects as patients taking Prozac. (Kleiser 14)
Monoamine oxidase is what degrades the biogenic amine neurotransmitters: dopamine, serotonin, and norepinephrine. MAOIs work by inhibiting monoamine oxidase, and preventing the breakdown of these neurotransmitters. (Birkemeyer 29) They also block serotonin reuptake, increasing serotonin concentration in the synaptic cleft. (Kaplan 139) MAOIs are historically the first antidepressants. (Nemeroff 5) Their side effect profile includes "orthostatic hypotension, weight gain, edema, sexual dysfunction, and insomnia." (Kaplan 974) Combining MAOIs with any common tyramine-rich food (including Wisconsin staples beer, wine, aged cheese, and beef) can result in a fatal hypertensive crisis accompanied by the warning signs: headache, sweating, nausea, and vomiting.
Other SSRIs include fluvoxamine, paroxetine (Paxil), and sertaline (Zoloft.)(Jefferson 473) Since these drugs have not been on the market as long as Prozac, there is less information available about them. There are early indications that these drugs are just as effective as Prozac and may have even fewer side effects.
The Impact of Prozac on our Society
Depression has an immense impact on the mental, physical, and fiscal health of the United States. The eighth leading cause of death is suicide in the US, ranking just ahead of HIV. Somewhere between 45 and 70 percent of those who commit suicide have an affective disorder. It is also estimated that 15 percent of patients with affective disorders will end their own lives. (Jefferson 467, Nemeroff, 3-4) "According to the Medical Outcome Study, depression had a greater adverse impact on individuals than did other chronic conditions such as hypertension, diabetes, arthritis, and lung disease, as measured across the dimensions of physical functioning, role functioning, social functioning, number of days in bed due to poor health, perceived current health, and bodily pain." (Jefferson 468) It is estimated that in 1980, depression cost the United States 16.3 billion dollars. (467) According to an estimate published in 1993, depression swallowed 43.7 billion dollars in direct costs, mortality costs, and loss of productivity the previous year. (467)
Prozac was first approved by the Federal Drug Administration as an effective tool against depression, on December 29, 1987, and as of 1995, over 10 million Americans have tried it. (Manolis 19) In 1994 it became FDA approved for use against obsessive-compulsive disorder and bulimia.(Wong 412) Financially, insurance companies prefer the relatively low cost and statistical success rate of Prozac to psychotherapy.(Frontline) Possibly as a result, about 60 percent of all Prozac prescriptions come from non-psychiatrists. (Manolis 21) Representatives of Eli Lilly, the manufacturer of Prozac, claim that the acceptance and popularity of their product and other SSRIs have "helped to inform the public about the biological nature of depression and have heightened awareness about the underdiagnosis of the illness." (Wong 412) Critics, including author of Listening to Prozac Peter Kramer, worry that Prozac has been made so attractive to the public that patients are being overmedicated. People who may not need the drug are using it as an emotional cosmetic to make them excessively happy and easier to get along with.(Frontline)
Some other critics, most notably the Church of Scientology, are opposed to any drug used for psychiatric purposes, and are incensed at Prozac's popularity and reputation for harmlessness. The Church of Scientology started a "Prozac Survivor's Group" for people who claim to be victims of violent behavior triggered by Prozac, (Frontline) and tried to block FDA approval of the drug.(Burton) Psychiatrist Peter Bergen spoke out against the use of medications to ease the pain of depression: "This is the human condition-to struggle-find meaning... to call it a medical disorder is to trivialize it and destroy the very fabric of what life is about." (Frontline)
Prozac's successes carry implications about the nature of the mind that may frighten or intrigue: "Its [Prozac's] truly astonishing effects on deep-seated and prolonged depressions have revolutionized our ideas about emotions and thought. If a person can begin to feel better about himself or herself as a result of a chemical that modifies the action of a brain neurotransmitter, even in situations when no outward changed has taken place in that person's day-to-day existence, what does that mean about the biological foundation for our inner life? At the very least it supports what neuroscientists have been suggesting over the past theree decades: All things mental are embedded within the chemistry and neuronal circuitry of the brain." (Restak 56)
In the course of researching this paper, I was able to answer many of the questions I had about Prozac and to gain some perspective on what the development of Prozac has meant to the scientific community. I have already seen what Prozac has meant in the lives of quite a few of my close friends and relatives, and I had hoped to resolve some of the mystery of how such a small thing could make such a profound change in their lives.
Although I have a better understanding of Prozac's scientific background, I somehow feel
I understand no more about happiness than I did when I began. I still have a lot of
thinking to do about what it means if happiness is "merely" a neurochemical state. However, it
is somewhat comforting that the rest of the world shares my confusion.
Barge-Schaapveld, Daniela Q.C.M. et al. "Changes in daily life experience associated with clinical improvement in depression." Journal of Affective Disorders. 34(1995): 139-154.
Birkmeyer, W. and P. Riederer. Understanding the Neurotransmitters: Key to the Workings of the Brain. Translated by Karl Blau. New York: Springer-Verlag Wien, 1989.
Burton, Thomas M. "Scientologists Fail to Persuade FDA on Prozac." Wall Street Journal. Friday, August 2, 1991.
Gram, Lars F. (Review Article) "Drug Therapy: Fluoxetine." New England Journal of Medicine. November 17, 1994: 1354-1361.
Hirschfield, Robert M.A. "Guidelines for the Long-Term Treatment of Depression." Journal of Clinical Psychiatry(supplement.) December 1994:61-69.
Jefferson, James W. and John H. Greist. "Mood Disorders." The American Psychiatric Press Textbook of Psychiatry. Ed. Robert E. Hales, Stuart C. Yudofsky, and John A. Talbot. Washington DC: American Psychiatric Press, Inc., 1994. 465-492.
Kaplan, Harold I., Benjamin J. Saddock, and Jack . Grebb. Kaplan and Saddock's Synposis of Psychiatry. Baltimore, Maryland: Williams & Wilkins, 1994.
Klieser, E., E. Lehmann, and K. Heinrich. "Fluoxetine in Patients with Major Depressive Disorder - A Responder Analysis." Pharmacopsychiatry. 28(1995): 14-19.
Manolis, Deane C. "The Perils of Prozac." Minnesota Medicine. January 1995: 19-23.
Nemeroff, Charles B. "Evolutionary Trends in the Pharmacotherapeutic Management of Depression." Journal of Clinical Psychiatry. December 1994: 3-15.
Nierenberg, Andrew A. et al. "Early Nonresponse to Fluoxetine as a Predictor of Poor 8-Week Outcome." American Journal of Psychiatry. October 1995: 1500-1503.
Nierenberg, Andrew A. et al. "Social adjustment does not predict depressive relapse during continuation fluoxetine therapy." Journal of Affective Disorders. 34(1995):73-77.
Restak, Richard M. Brainscapes. New York: Hyperion, 1995.
"Welcome to Happy Valley." Frontline. PBS, 6 June 1995. Produced and Directed by Paul Sadat for the BBC.
Wong, David T. and Frank P. Bymaster. "Development of Antidepressant Drugs: Fluoxetine(Prozac) and Other Selective Serotonin Uptake Inhibitors." Neurochemistry in Clinical Application. Ed. Lily Tang and Steven Tang. New York: Plenum Press, 1995.
Wong, David T., Frank P. Bymaster, and Eric A. Engleman. "Minireview-Prozac (Fluoxetine, Lilly 110140), the First Selective Serotonin Uptake Inhibitor and an Antidepressant Drug: Twenty Years Since its First Publication." Life Sciences. Volume 57, No. 5. 1995:411-441.
caitlin at cs dot wisc dot edu