Development of mild to major tics  -  mild or major muscle spasms  -  severe agitation and restlessness
parkinsonism  -  fatigue and apathy  -  possible silent brain damage  -  pronounced withdrawal effects
loss of libido  -  male and female sexual dsyfunction  -  preoccupation with suicide  -  violent outbursts
increased vulnerability to relapse...  

These are some of the major side-effects now emerging from the users of the modern SSRI anti-depressants.  This article comes from the mental health journal Human Givens: Radical Psychology Today, and was written by the editor, Denise Winn.  

Prozac - Paxil - Seroxat - It is starting to hit the fan...
The major drugs manufacturer GlaxoSmithKline has been forced to admit that its best-selling drug, the antidepressant paroxetine, a selective serotonin re-uptake inhibitor, can cause severe withdrawal symptoms when stopped, despite a spokesman's claim only a year previously that withdrawal effects occurred in only two out of every thousand patients. Respected Harvard psychiatrist Dr Joseph Glenmullen has blown the whistle on the hidden dangers of all the serotonin-boosting medications in his shocking book, Prozac Backlash. And a report in the British publication Health Which? questioning the efficacy and safety of antidepressants, particularly SSRIs, has led the Royal College of Psychiatrists to qualify its recommendations in its guidelines for patients.
Antidepressants came onto the psychiatric scene in the 1950s, followed in the 1980s by selective serotonin re-uptake inhibitors, a new class of anti-depressants, which quickly became better known by the initials SSRIs. Promoted as more effective and less likely to cause side effects than older versions, despite being far more expensive, the SSRIs have gradually become the treatment of choice given by psychiatrists and GPs, on both sides of the Atlantic, for mild, moderate and severe depression. Even the public started clamouring for the drugs after American psychiatrist Peter Kramer published his eulogy; Listening to Prozac, in 1993, a book in which he claimed that the drugs could also treat quirks of personality or tendencies such as shyness, sensitivity, lack of confidence, fastidious-ness, low self esteem and jealousy.
Around the same time, in Britain, the Defeat Depression Campaign, organised by the Royal College of Psychiatrists and the Royal College of General Practitioners, and sponsored in no small part by drug companies, was seeking the help of the media to de-stigmatise depression and urge people to go to their doctors for treatment. In a book published with "the kind support of Boots Pharmaceuticals" for the campaign, the author claimed, "Counselling alone will not do for more severe depression, and a great deal needs to be taught to the public about the safety and effectiveness of antidepressants. ... It needs, apparently, to be shouted again and again from the housetops: ANTIDEPRESSANTS ARE NOT ADDICTIVE!
"They are not at all the same as tranquillisers, any more than antibiotics are the same as analges-ics. They do not usually work for three weeks, but after that time they generally do, and can then be continued for months without any risk of depend-ency. Yet Dr John Henry from Guy's Hospital has calculated that only one depressed person in 20 in Britain at present benefits from antidepressant treatment. This is mainly because the drugs are never prescribed, but also because they are not taken - at all or for long enough - or because the dose is inadequate."
Just under 10 years on, despite confident claims by the Royal College of Psychiatrists that six or seven of every 10 people will get better on antide-pressants within six to eight weeks, the safety and efficacy of SSRIs and the rarity of withdrawal symptoms are all being strongly questioned. Several researchers are now saying that many of the statistics supporting SSRIs have been skewed, by the way that trials were carried out or reported.

The business of 'unblinding'
Dr Joanna Moncrieff, senior lecturer in psychiatry at University College London and honorary con-sultant psychiatrist in the North East London Mental Health Trust, has published a critical review of trials of antidepressants for the highly respected Cochrane Library. In March, she wrote an editorial on 'the antidepressant debate' in the British Journal o[Psychiatry. Her interest in the area was aroused because of her own puzzlement at the popularity of the drug treatment. "There are a lot of myths around in psychiatry," she said, "and I have never been convinced, in 10 years of clinical work, that I have definitely seen antidepressants work."
In a paper published in the Journal of Nervous and Mental Disease, she considers at length the problem of 'unblinding', which may make anti-depressants appear more efficacious than they are. Randomised controlled trials (RCTs), the accepted 'gold standard' for establishing efficacy of a treat-ment, are usually 'double blind', meaning that neither the experimenter nor the patient knows whether they are taking the active drug or a placebo. However, Moncrieff argnes, the detailed explanations of trial design and side effects, which are now obligatory in RCTs, may mean that both the experimenter and patient know whether the pill being taken is active or not. In such cases, the expectations associated with being on active treatment may itself exert a placebo effect, independent of any pharmacological therapeutic effect, and, conversely, disappointment at being on placebo may diminish any natural placebo effect. She cites research showing that participants can distinguish antidepress-ants, including SSRIs, from placebo better than would be predicted by chance.
Other factors which may tip the evidence in favour of antidepressants include a tendency for journals not to publish negative trials - those which don't find the drug under test superior to an older drug or placebo. The Health Which? report cited two studies which managed to circumvent this difficulty and which came up, as a result, with a rather less glossy picture of SSRI efficacy Use of the US freedom of information laws enabled researchers to look at the US Food and Drug Administration's database of published and unpublished trials. After reviewing trials involving nearly 20,000 people, they found that patients on antidepressants experienced a reduction in symptoms of 40 per cent while those on placebo reported a reduction of 30 per cent. In the second study reported by Health Which?, a doctor from the Food and Drug Administration itself used the same database to look at 50 trials. The findings showed that 54 per cent of patients experienced benefit greater than placebo from the drug, but that 46 per cent did not.
Then there is the impact of 'placebo washout' procedures, raised by David Antonnucio, professor of psychiatry and behavioural sciences at the University of Nevada School of Medicine. This is where all people entered into a randomised controlled trial start out on placebo. Those whose symptoms significantly improve are removed from the trial, leaving the rest to be given the active drug. This, it is argued, can bias the result of the trial, artificially enhancing the effectiveness of the drug.
Drug withdrawal effects may also confuse the true picture of drug and placebo effects. Moncrieff points out that studies of long term treatment with antidepressants rely on a discontinuation design. This means that patients who have responded to treatment with antidepressants are randomised either to continue on the active drug or to be given a placebo instead. The withdrawal syndrome (which has long been recognised by critics and is now at last being acknowledged by drug companies and medical bodies) may cause symptoms which are mistaken for relapse or worsening of the condition.

Intention to treat
A further complication in the attempt to make true sense of trial findings is that many trials fail to include in their results patients who were random-ised to the drug or placebo but who dropped out of the trial - most commonly because of insupportable side effects from the active drug. Trials which include all patients who started the trial, whether or not they completed the treatment (so-called 'intention to treat' trials) most commonly produce response rates to antidepressants of no greater than 40-50 per cent - a figure rather lower than the 60-70 per cent claimed by the Royal College of Psychiatrists.
Even leaving methodological concerns aside, many trials have simply failed to find in favour of antidepressants. Moncrieff cites a study of enhanced treatment programmes in primary care in America which led to increased prescribing and patient compliance but which failed to help those with mild depression and had short term but not long term positive effects on those with major depression. In the UK, educational initiatives with GPs that have improved recognition of depression and increased prescribing of antidepressants have not been found to improve the outcome for patients.

Dependence by any other name
The recent climb down by GlaxoSmithKline in admitting that paroxetine (marketed as Seroxat and Paxil), can cause severe withdrawal symptoms when stopped has turned the spotlight on all SSRIs. Paroxetine has what is termed a short half-life, meaning that the drug is eliminated from the body much more quickly than a drug like fluoxetine (Prozac), and therefore any withdrawal effects are apparent much sooner. However, concerns about withdrawal are not new.
Social Audit, the publishing arm of the registered charity Public Interest Research Centre, largely funded by the Joseph Rowntree Charitable Trust, has posted on its website a paper on antidepressants by indefatigable researcher Charles Medawar, which was first published in the International Journal of Risk and Safety in Medicine. A part of this concerns withdrawal problems with SSRIs. Medawar describes how, despite notorious under-reporting of drug side effects by doctors, nearly 1000 Yellow Card reports of suspected withdrawal problems relating to SSRIs had been received by 1997, compared with just 28 relating to benzodiaza-pines after 17 years of use. Even though paroxetine, with its much shorter half life, appears to be the greatest culprit, fluoxetine had attracted over twice as many Yellow Card reports as diazepam (Valium) in many fewer years.
Drug companies and doctors say that SSRIs are not addictive, in that they are not substances that lead people to want to increase the dose or are abused. However, that is very different from not causing withdrawal symptoms (which the drug in-dustry euphemistically refers to as dis-continuation symptoms). This confuses patients, who tend to think that only addictive substances, such as heroin, nicotine and benzodiazepines, can cause withdrawal symptoms. They are therefore unprepared for un-pleasant symptoms if they discontinue antidepressants and these may be misinterpreted, by doctors as well as themselves, as a sign of relapse and a need to return to the drug.
Alarmingly, this similarity to relapse has even confused researchers and may have been responsible for the questionable common medical advice to take SSRIs for at least six months. Dr Moncrieff says, "One not very large study concluded that, if people were taken off their drugs earlier than six months, they were more likely to relapse. But these were probably discontinuation symptoms, and all this study shows is how difficult it can be to take people off antidepressants, rather than that they need to be on them any specific length of time. So the evidence on which the six-months recommendation is based is not strong at all."

More worrying consequences
Dr Joseph Glenmullen, author of Prozac Backlash, questions the accepted 'wisdom' that SSRIs do not lead users to abuse them. He tells of one of his patients, Joanna, who found herself turning to extra doses of Zoloft to get her through the day - an extra 50 mg on top of her daily 100 mg, and discusses the issue of sensitisation of brain cells by psychiatric drugs. An Italian psychiatrist, Dr Giovanni Fava of the University of Bologna, first raised the possibility that psychotropic drugs could in some cases worsen the conditions they were intended to treat, citing a long term study carried out at the University of Pittsburgh which found that patients on antidepressants for more than three years did poorly if taken off them. In the Journal of Clinical Psychopharmacology, October 1995, he said that withdrawal effects of SSRIs raised concern about "sensitisation of serotonergic systems... leading to increased vulnerability to depressive relapse in the long run". This has since been supported.
Glenmullen's book is based on extensive experi-ence treating patients in private practice and at the Harvard University Health Services and a thorough review of research published in psychiatric journals. It makes sobering reading. He describes how, after seeing a patient who developed a pronounced tic while on an SSRI, he spent whole weekends ploughing through esoteric psychiatric journals in Harvard Medical School's library, and found reports amounting to thousands of cases of neurological side effects occurring with SSRIs. These were tics (e.g. eye and lip twitching, tongue darting and pelvic rocking); agitation, ranging from leg tapping to overwhelming restlessness to sheer panic; muscle spasms, ranging from tension in the neck, shoulder and jaw, to body parts becoming locked in bizarre position; and Parkinsonism.
One woman prescribed Zoloft for nail-biting came to see Dr Glenmullen when she started to be con-cerned about sudden serious memory loss and blanking out. She was the first of a number of patients he observed whose memories appeared to have been affected by SSRIs, yet another worrying neurological side effect.
His final serious concern, in this regard, is silent brain damage. He draws the comparison with major tranquillisers which, it was discovered, can cause tics, muscle spasm, agitation and Parkinsonism even in healthy young patients. Major tranquillisers have also long been suspected of impairing intel-lectual functioning.
"We still do not fully understand how tics reflect-ing permanent brain damage develop with major tranquillisers," he says. "But when one looks at the symptoms, the best model to explain them is that the appearance of noticeable tics is merely the final stage in a process of slow, progressive damage. Even in patients who do not develop tics, significant dam-age may have occurred. One sees this dramatically in patients restarted on a drug who quickly develop tics or other side effects not present during the previous course of the medication. Prior exposure left them with significant injury, which then pre-disposes them to rapid development of the side effect with just a little additional damage from the re--exposure.
In the light of the neurological effects, Glenmullen fiercely questions the prescribing of SSRIs to children. "When major tranquillisers were in vogue, they were readily prescribed to children with mild anxiety, insomnia or hyperactivity. The drugs are no longer used in this way on children because they cause tics. Current estimates are that serotonin boosters are being prescribed to over half a million children in this country and the USA, with paediatric use of the drugs one of the fastest-growing 'markets'." He also documents common findings of sexual dysfunction in people taking SSRIs.

Nothing selective
The name 'selective serotonin re-uptake inhibitor' may also be misleading. These drugs 'select' for serotonin; that is, they don't affect other neurotrans-mitters. But, for that to be a benefit in depression, the implication is that serotonin is localised in a depression centre in the brain. Glenmullen goes to great pains to show that that is not the case. In humans, he explains, only five per cent of serotonin is found in the brain, while the rest is distributed throughout the body. Serotonin plays a significant part in the regulation of the gastro-intestinal tract and the cardiovascular and reproductive systems, as well being involved in controlling a variety of hormones. "While pharmaceutical companies have marketed Prozac, Zoloft, Paxil and Luvox as 'selective' for serotonin, serotonin is anything but selective in its widespread effects," says Dr Glenmullen. "There is, in fact, no known depression centre in the brain. Rather, the drugs have global effects owing to serotonin's vast influence." It also appears, from current research which he cites, that, far from topping up low serotonin levels, SSRIs create abnormally high levels of serotonin for which the brain may try to compensate by causing a drop in dopamine levels. This, experts believe, may account for some of the severe side effects being noticed. 
Dr David Healy, reader in psychological medicine at the University ofWales and an honorary consultant psychiatrist, has recently questioned whether antidepressants even have an antidepressant effect or exert just non-specific pharmacological effects such as sedation. Dr Moncrieff also addresses this issue, citing evidence to show that many substances not conventionally classed as antidepressants have shown superior efficacy to inert placebos or equival-ent efficacy to antidepressants.7

Drug company involvement
She freely admits that the studies she looked at for her Cochrane review are old and relatively few in number She has been criticised for that. However, she believes her findings still have validity as she looked at the studies which were not funded by drug companies. "The industry has been involved in promoting wider use of antidepressant drug treat-ment, strengthening the hegemony of biological psychiatry at the expense of other ways of under-standing and responding to mental distress," she says. "Its influence on research findings was shown in a recent meta-analysis of comparative trials of antidepressants in which trial sponsor emerged as the strongest predictor of antidepressant efficacy. "
One would, of course, expect drug companies to be involved in the promotion of antidepressants. However, the connection is not always transparent. Recently, Canadian researchers reported in the American Medical Association's journal that most guidelines on clinical practice are written by experts with undisclosed links to the pharmaceutical industry They surveyed 192 authors of 44 clinical guidelines and, of just over half who responded, 87 per cent admitted to financial links with at least one drug company (on average 10). Over half had been paid to conduct research; a third had acted as a consultant or had been an employee and two thirds had been paid for giving talks. The researchers contacted non-respondents again, to no avail, and speculated that those who didn't reply may have had even stronger links with the industry. The guidelines, endorsed by professional societies in America and Europe, included one on depression.
Cover up of the dangers of antidepressants has also been laid at drug company doors. This emerged dramatically in the case of manufacturer Eli Lilly in trials arising from Prozac's alleged involvement in murders and suicides, and is fully documented in Prozac Backlash. (The suggestion that taking Prozac might induce suicidal and violent impulses was first made in early 1990 in the American Journal of Psychiatry and was soon followed up in a variety of other respected journals.) At the height of public concern, Dr Leigh Thompson, Lilly's chief scientific adviser, wrote in a memo, "what are our priorities? I'd suggest that priorities are: (1) protect Prozac..."
During one court case, according to a statement made by Dr David Healy, when the company found out that two Taiwanese doctors were planning to publish a study showing that patients prescribed Prozac were more likely to have suicidal thoughts and attempt suicide than patients on another drug already associated with a high rate of attempted suicides, efforts were made to suppress the study. After a rash of meetings and visits with company representatives, the doctors agreed not to publish, an outcome recorded in an internal Eli Lilly memo as "mission successful". Lilly promised to fund the doctors for a large study, but the results have never been published.

The medicalisation of misery
Dr Moncrieff believes that the rise in popularity of antidepressants not only coincided with the fall in prescriptions for benzodiazepines, once they were found to be addictive, but can also partly be account-ed for by psychiatry's wish to improve its status through a closer alliance with the rest of medicine. "The arrival of drugs helped the psychiatric prof-ession to assert itself as a specialty It got them away from asylums and allowed the setting up of out-patient facilities, where people could walk out with a prescription, just as they could in other areas of medicine. The notion of specific drug treatments for specific psychiatric disorders helped to bolster the case that psychiatry was no different from other medical specialties," she says.
Professor David Antonuccio has pointed out that genetic influences on depression have been shown to be weaker than environmental ones; that biochemical theories are as yet unproven; that biological markers for depression remain elusive; and that preliminary evidence suggests that pat-ients who improve with cognitive behavioural therapy show similar biological changes to those who respond to medication.
Since the publication of the Health Which? report, the Royal College of Psychiatrists has softened its own position. Its patient information leaflet on depression has been revised to indicate that the efficacy of antidepressants is "an area of controversy".
"Depression shouldn't be medicalised," says Dr Moncrieff.  "Before the 1950s no one ever thought a drug could cure depression. Personally, I find the whole idea totally illogical."