A generational leap for a less studied antidepressant …

Despite the availability of newer drugs, fluoxetine remains extremely popular

There have been many books written about what may be called the Prozac Revolution. For example: Listening to Prozac: The Landmark Book About Antidepressants and the Remaking of the Self; Prozac Nation; Prozac Backlash: Overcoming the Dangers of Prozac, Zoloft, Paxil—Prozac: Panacea or Pandora?; Prozac Diary; Prozac Attack: Laugh, Don’t Cry; Why I love My Prozac; Pros of Prozac: A Faith-Based Memoir of Overcoming the Stigma, and on and on.

One can readily gather from the titles above that along with high praise for “remaking the self,” Prozac has also been condemned for “opening Pandora’s box.” Revolutions do not take place without dissent.

The Successes and Failures of Fluoxetine

Fluoxetine (the generic name for the trade name Prozac, Sarafem, and Fontex, among others) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. SSRIs work by preventing the reuptake of the inhibitory neurotransmitter serotonin from the synapses—the structures between neurons that permit a nerve cell to pass an electrical or chemical signal to another cell—where serotonin functions.

One can readily gather from 
the titles above that 
along with high praise for “remaking 
the self,” Prozac has also been 
condemned for “opening Pandora’s 
box.” Revolutions do not take place 
without dissent.

Biochemically derived from tryptophan or 5-HTP, serotonin is primarily found in the GI tract and the central nervous system of animals and humans, where it is thought to be an important contributor to feelings of well-being and happiness.

Serotonin operates as a kind of natural braking system in the brain. If there is more available serotonin, to continue the metaphor, you are able to steer your mind more safely, empowering you to stay on the road. This in turn prevents your vehicle of consciousness from going over the cliff. And into depression.

First shown to be effective in 1974 by Eli Lilly scientists,1 fluoxetine received final approval for marketing in 1987, and went off patent in the summer of 2001. All told, the FDA approved it for the treatment of major depression (including pediatric depression), obsessive-compulsive disorder (in both adult and pediatric populations), bulimia nervosa, panic disorder and premenstrual dysphoric disorder.2 Dysphoria is a state of feeling unwell or unhappy.

The Third Historical Generation of Antidepressants

Despite the availability of newer drugs—for example, the multiple reuptake inhibitors—fluoxetine remains extremely popular. In 2010, over 24.4 million prescriptions for generic formulations of fluoxetine were filled in the United States alone, making it the third most prescribed antidepressant after two other SSRIs, sertraline and citalopram. There are good reasons for fluoxetine’s success, and for the success of all SSRIs, the third historical generation of antidepressants. But there are also reasons for its failure: its many side effects, and some which are very bad.

Fluoxetine may cause nausea, headaches, anxiety, insomnia, drowsiness, and loss of appetite. Some patients may experience withdrawal reactions such as nausea, nervousness, and insomnia upon stopping it. Then there are severe reactions in some:3severe blistering, peeling, and red skin rash, very stiff (rigid) muscles, high fever, sweating, fast or uneven heartbeats, tremors, overactive reflexes, vomiting, diarrhea, loss of appetite, feeling unsteady, loss of coordination, trouble concentrating, memory problems, weakness, confusion, hallucinations, fainting, seizures, shallow breathing or breathing that stops. Not to be dismissed are fluoxetine’s sexual side effects, including difficulty becoming aroused, erectile dysfunction, lack of interest in sex, and the inability to achieve orgasm. And some effects that can last for months, years, or permanently after the drug has been completely withdrawn.

Generation Two: Monoamine Oxidase Inhibitors

SSRIs were preceded by the second generation of antidepressants, monoamine oxidase inhibitors (MAOIs), and the first generation, tricyclics. MAOIs are chemicals that inhibit the activity of the monoamine oxidase enzyme family. These enzymes break down (deaminate) the powerful monoamine neurotransmitters such as serotonin. When these enzymes are inhibited, antidepressant benefits are gained.

Fundamentally, there are two forms of monoamine oxidase: MAO-A and MAO-B. The A-type preferentially breaks down serotonin (along with melatonin, epinephrine, and noradrenaline) and the B-type preferentially breaks down phenylethylamine and trace amines. Dopamine is broken down by both types of MAO.

MAOIs have a long history of use as medications prescribed for the treatment of depression. But they also have potentially lethal dietary and drug interactions. Consequently, today they are only used as a last resort for those who are resistant to tricyclic antidepressant therapy.

Generation One: Isoniazid, Iproniazid, and Tricyclics

In 1951, clinical trials on two new anti-tuberculosis agents developed by Hoffman-LaRoche, isoniazid and iproniazid, showed that the drugs improved the vigor of TB patients with poor outcomes.4 In 1952, learning of the stimulating side effects of isoniazid, the Cincinnati psychiatrist Max Lurie tried it on his patients. In the following year, he and psychiatrist Harry Salzer reported that isoniazid improved depression in two thirds of their patients. They coined the term antidepressant to describe the action of isoniazid. Also in 1952, similar results were reported in Paris, where Jean Delay, head of psychiatry at Sainte-Anne Hospital, heard of this effect from his pulmonology colleagues at Cochin Hospital.

Psychiatrists Max Lurie and Harry 
Salzer coined the term antidepressant 
to describe the actions of diamine 
oxidase inhibitors.

Isoniazid as an antidepressant was soon overshadowed by the more toxic iproniazid, although it remains a mainstay of tuberculosis treatment. It is thought that the action of isoniazid is due to the inhibition of diamine oxidase, coupled with a weak inhibition of MAO-A.

Promoted by Nathan Kline, the influential and flamboyant head of research at Rockland State Hospital, iproniazid was popularized in the medical and popular press as a “psychic energizer,” a term proposed by Kline to refer to the drug’s action.5 Following this, Roche put significant marketing efforts into iproniazid, promoting its off-label use for depression. While its sales grew, it was eventually recalled in 1961, due to reports of lethal hepatotoxicity.

Roland Kuhn first discovered the antidepressant effect of a tricyclic drug in 1957 at a Swiss psychiatric hospital. Tricyclics are named after their chemical structure, which contains three rings of atoms.

Kuhn had set out to improve the effectiveness of the schizophrenia drug chlorpromazine(marketed in the U.S. as Thorazine). In collaboration with the Geigy Pharmaceutical Company, he discovered a compound, later renamed imipramine (Tofranil) that had a beneficial effect in patients with depression who showed mental and motor retardation. Kuhn described his new compound as a “thymoleptic” meaning that which took hold of the emotions. The sales of imipramine took off in the 1970s and 1980s, but were ultimately replaced by the third generation antidepressants (the SSRIs) due to the huge side effects of the first two generations of antidepressants, largely the tricyclics and the MAOIs.

Finding Equality between 5-HTP and Fluoxetine

The role of 5-hydroxytryptophan (5-HTP), an amino acid and precursor of serotonin—while noted in some studies to be of robust value in depression—has been significantly less studied than SSRIs. In a new randomized double blind study, Indian researchers assessed the value of 5-HTP as an antidepressant compared to fluoxetine, the earliest and most celebrated SSRI.6 The study examined first depressive episode patients in the Indian population. People are most likely to suffer their first depressive episode between the ages of 30 and 40.

The researchers started with 70 patients of first depressive episode, between the ages of 20–50, all of whom were diagnosed with International Classification of Diseases criteria, but only 60 patients completed the study. Initially, all were randomly divided into two groups, receiving 5-HTP and fluoxetine, respectively, for a period of 8 weeks. All patients in the first group received 150 mg of 5-HTP in three divided dosages during the first 2 weeks, and then the dose was doubled to 300 mg per day after the second week. The dosages were increased again to 400 mg/day in three divided dosages after the fourth week. Thereafter, the same dosages were continued. In the second group, all patients were given fluoxetine in 20 mg capsules along with two placebo dosages (made to appear like the 5-HTP dosages) during the first 2 weeks and then increased to 30 mg along with placebo dosages after the second week. The dosages were increased to 40 mg along with placebo dosages after the fourth week. Thereafter, the same dosages were continued.

All patients were administered the Hamilton Rating Scale for Depression (HAM-D), a multiple item questionnaire used to provide an indication of depression, and as a guide to evaluate recovery. The researchers first assessed the severity of depression at baseline, then again at 2 weeks, 4 weeks and 8 weeks.

Fluoxetine may cause nausea, head-
aches, anxiety, insomnia, drowsiness, 
loss of appetite, and worse.

By comparing HAM-D scores obtained at these examinations with the baseline examination, the efficacy of treatment was assessed. Then, the final evaluation of both efficacy and tolerance was assessed using the Clinical Global Impression (CGI) scale at the end of study. CGI rating scales are commonly-used measures of symptom severity, treatment response, and the efficacy of treatments in treatment studies of patients with mental disorders. However, many researchers, while recognizing the validity of the scale, consider it to be subjective as it requires the user of the scale to compare the subjects to typical patients in the clinician’s experience.

The antidepressant effect of 5-HTP
took 2 weeks to start, which 
subsequently continued.

At the end of the study each of the two treatment groups showed significant and nearly equal reduction in HAM-D scores beginning at week two and continuing through week eight. Twenty-two patients (73.33%) in the 5-HTP group and 24 patients (80%) in the fluoxetine group showed positive response when the study was completed.

The therapeutic efficacy of 5-HTP
was considered equal to fluoxetine.

Minimum Effective Dose for 5-HTP

5-HTP showed strong antidepressant effects in patients with a first depressive episode. The antidepressant effect was seen within 2 weeks of treatment and was apparent in all degrees of depression. 5-HTP definitely plays an antidepressant role in depressed patients. The antidepressant effect is apparent in all degrees of depression, including those severely depressed. The minimal effective dose of 5-HTP to produce antidepressant effect was found to be 150 mg/day, while a significant number of patients required 300 mg of 5-HTP. The antidepressant effect of 5-HTP took 2 weeks to start, which subsequently continued. 5-HTP was well tolerated by patients, meaning that there were few, if any, side effects, and none of any significant consequence. The therapeutic efficacy of 5-HTP was considered as equal to that of fluoxetine. From drugs to nutrients in no more than four generations. That’s progress, especially for those caught in the grip of depression.


  1. Wong DT, Horng JS, Bymaster FP, Hauser KL, Molloy BB. A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine. Life Sci. 1974 Aug 1;15(3):471-9.
  2. Prozac Pharmacology, Pharmacokinetics, Studies, Metabolism. RxList.com. 2013. Retrieved August 15, 2013.
  3. Ogbru O. Prozac Side Effects Center. http://www.rxlist.com/prozac-side-effects-drug-center.htm. 2013. Retrieved August 18, 2013.
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  5. Loomer HP, Saunders IC, Kline NS. Iproniazid, an amine oxidase inhibitor, as an example of a psychic energizer. Congr Rec. 1957:1382–1390.
  6. Jangid P, Malik P, Singh P, Sharma M, Gulia AK. Comparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with first depressive episode. Asian J Psychiatr. 2013 Feb;6(1):29-34.