I have often wondered why fluoxetine (Dista Products, Prozac) was introduced at a standard dosage of 20mg/day, given the evidence that some patients respond well to much less. This was one of the reasons why the Swedish and Norwegian authorities initially refused to license it [SCRIP, 1991]. I do not know why they changed their minds, but Eli Lilly and the regulators have been near here before.

Never mind the liquid formulations - they sell much less - why make fluoxetine available only in a 20mg capsule? What use is an average dose, in a global market - considering all we know and don't know about the very different ways people react to the same doses of drugs? There are huge variations in individual response to fluoxetine and the evidence is clear that some people do better on half the average dose or less (Louie et al., 1993, Wernicke et al., 1988). In a global market, millions would find a low dose of Prozac efficacious, and be less exposed to adverse effects.

With a single, global dose, there have to be casualties: with a potent and highly unspecific drug like fluoxetine, there will always be the small minority who find the average dose is more like an overdose for them. And response to fluoxetine is highly unpredictable too: "The broad spectrum of (its) unwanted effects is worrying, with some people becoming badly agitated and hyped up, and others brought right down; in extreme cases, manic psychoses and suicide have been mentioned as real risks" (Medawar, 1994). At the back of my mind was the thought that, if Prozac can make a small minority feel absolutely marvellous (Kramer, 1993), might it not also make another small minority feel completely wretched instead?

Now, the question of dose arises again: [a] because, Eli Lilly has just introduced a 10mg tablet version of Prozac - scored, to be easily divisible into two 5mg halves; and [b] because the company decided that this low-dose Prozac tablet "will not be available outside the USA". The rest of the world will have to go on using the capsule formulation, i.e. an indivisible 20mg dose:

"Because the new tablet version of Prozac can be split in half, it will provide greater dosing convenience for physicians. Therapy for most depressed patients using Prozac includes one 20mg capsule daily. Some patients - particularly older patients - occasionally are prescribed dosages of less than 20 milligrams. The new tablet will provide physicians with the ability to customise dosages to the needs of their patients." (Company press release, 18 May 1999)

But what does this really mean? Why would Lilly now be responding to this tiny, "occasional" demand? And if there is real need, why has it taken the company and regulators a decade to respond? If this were simply to do with Prozac soon coming out of patent, and Lilly wanting to raise the stakes for the generic competition, why confine the change only to the USA? I imagine the main reason is to do with product liability, but perhaps FDA requirements come into it too. But beware of that word, "occasionally": clearly not many doctors are going to be prescribing half-strength fluoxetine if armed only with a 20mg capsule, the 'usual dose'.

I suspect all this has something to do with one particularly nasty adverse effect of fluoxetine (and probably other SSRIs) - namely, "akathisia". More usually associated with anti-psychotic drugs, this is a disorder characterised by "extreme restlessness and agitation". Akathisia is increasingly mentioned in discussion about a possible link between Prozac, suicide and violence (Teicher et al., 1993; Healy, 1998a, 1998b, 1999).

The gist of Dr David Healy's paper "A failure to warn" (1999) has just been prominently reported in The Guardian, but the evidence has not yet been published - though it has now been circulated in draft to the MCA/CSM among several other authorities and experts. It suggests real cause for concern - enough to prompt Healy to write to all coroners in England and Wales, as well.

Usually soon after starting fluoxetine, a small but uncertain percentage of patients develop symptoms of akathisia - the severity of symptoms depending, not least, on dosage and individual disposition. Some other risk factors are suspected, but very little is known about the prevalence of the condition (Campomori et al, 1999). This is partly for lack of research but surely also because of confusion over definition and meaning.

Healy's paper (1999) makes the point that "akathisia is in principle not codable" using current adverse drug reaction reporting systems: "As a result, the most authoritative compendium on psychotropics (Ayd, 1996b) can state that 'fluoxetine's propensity to cause akathisia is widely recognised' yet Lilly's published database of 42 side effects of Prozac does not mention akathisia" (Plewes et al., 1997).

The thing is that many different terms may credibly (or not) describe what happens to patients, without using the word "akathisia" at all. The situation is also complicated because the more traditional and obvious signs of akathisia (the characteristic inability to sit down) may mask the more subtle (psychic) ones - and sometimes vice versa. The potential for deep confusion comes across vividly in an interview between Healy (1996) and one of the pioneers of psychotropic drug evaluation, Dr. Jonathon Cole:

Healy: "What about a group of patients who may get worse on it (fluoxetine)?

Cole: Yes. I'm one of the authors of the suicide paper … I didn't realize it would be quite that famous. I don't know whether Teicher (1993) or I would have published it, if we'd known, although I guess we would have done. Yes, I have seen people, at least a handful, that clearly got more agitated and got weird thoughts and suicidal drive. Tony Rothschild, who has taken over my depression programme in McLean, found three people who had jumped off something while on fluoxetine, who didn't kill themselves, and agreed to take it again. He re-created the same desperate driven quality with fluoxetine.

Healy: Is it a form of akathisia?

Cole: I think it probably is but whether you get the neuromuscular form or whether it's purely psychic I don't know. One patient I followed through it was so distressed by thoughts telling her to kill herself over and over again, that I never got around to asking her whether her muscles felt funny. The psychic end is so predominant that you forget to ask about the muscle end. I told her to take some Ativan and go to sleep and she did and within 36 hours it had passed. At the end of it she said 'gee, I've been depressed for 21 years, and suicidal a lot but that was ridiculous'. She thought it was clearly different than anything she had ever experienced before which is why I put her case and my name on the paper. Lilly doesn't believe it."

The urgency and complexity of the task now facing the MCA/CSM and the medical establishment is further underlined by the following report, not cited in the Healy (1999) paper. It dates from not long after the days when Lilly was still wondering whether they had a drug at all:

"In fact, in the 1970s, Eli Lilly had a conference about a drug they had called fluoxetine which they didn't know what to do with. So they had a conference at their base in Surrey and they asked me to make a contribution. Of course I was enthusiastic about 5HT (serotonin) and the possibilities in mood disorders. I always remember the Vice-President of Research saying, 'I thank Dr Coppen for his contribution, but I can tell you we won't be developing fluoxetine as an antidepressant'." (Coppen, in Healy, 1996).

The study in question (Shopsin et al., 1981) gives some glimpse of what might happen to people who were unusually sensitive to fluoxetine, if prescribed something like two to three times the appropriate dose. The study was uncontrolled and involved only twelve outpatients with depression, with most taking fluoxetine 60mg/day - scientifically very thin, but still enough to show that the presumptive starting dose should be hugely reduced: 

"Since pharmacokinetic studies in man show that blood levels after initial doses of 60 mg/day continue to rise with decreasing dosage thereafter (apparently the drug accumulates in tissue and is reluctant to exit) we designed our study to conform with that dosage regimen. However, this leads to anxiety, agitation, and restlessness, which can become intolerable. We have found that this behavioural toxicity can apparently be avoided by using lower starting doses of 20mg/day with dosage progressively increased during the first week."

Of the 12 patients in this study, four showed definite improvement. Note that they experienced much more than alleviation of depression; They evidently became quite high:

"In the 4 patients who showed a clinical response, a stimulant-energizing like effect was documented. Although, not readily recognizable to the patient, it was clinically apparent and confirmed by the family. Assertive behavior, loquaciousness, increased energy, and general stimulant-like symptoms, rather than euphoria, were characteristic. In the 4 patients who improved, a sudden onset of action occurred between days 10 and 17; the onset was not insidious. Dosage was 40 mg/day in 2 patients and 60 mg/day in the other 2 patients."

At the same time, four other patients deteriorated. The term "akathisia" is not used, but this description is as vivid as they come:

"The 4 patients who showed symptom worsening all had increased anxiety, agitation, severe motor restlessness, racing thoughts, pressured speech, and assertiveness. There was a dreadful feeling of apprehension. The symptoms became unbearable in the 3 patients at different stages in treatment, 2 of whom (both females in their 50s) required hospitalization."

What comes across in this brief description is that the connection between fluoxetine and the kind of mental distress that could provoke suicidal or violent thoughts or behaviour may be nothing like as tenuous as Lilly has insisted so far (Beasley et al., 1991, Nakielny, 1994, Beasley, 1998). Different patients clearly react very differently to identical doses of fluoxetine, and individuals who are unusually sensitive may sometimes respond in quite frightening ways.

Akathisia seems more and more likely to be a serious problem, needing urgently to be addressed. It must be time to start writing to the MCA/CSM again.


Note Twenty years ago, Eli Lilly (Dista Products) had a drug on the market called benoxaprofen. It was marketed as Opren (UK) and Oraflex (USA) and by other brand names elsewhere. Benoxaprofen (BNX) was an NSAID - a non-steroidal anti-inflammatory drug, used to treat the symptoms of arthritis. It was hugely over-hyped: experts were trundled out to hint that this was the greatest discovery since aspirin, perhaps capable of "arresting the disease process" in rheumatoid arthritis. The hype proved to be one of several factors in its downfall. Another factor was the dose. Extraordinary as it now might seem, BNX was licensed with a recommended dose that was identical to the recommended maximum dose - i.e. there was no "therapeutic margin". This led to problems, in particular, for some very elderly patients: the drug tended to accumulate in the body and to cause sometimes fatal liver toxicity. If BNX had been properly tested in elderly populations (those most likely to use it), the problem could have been anticipated and perhaps the drug would be on the market today. As it was, the recommendation to reduce the dosage in elderly patients came too late, and benoxaprofen was withdrawn worldwide in 1983.

Charles Medawar, November 1999

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