March 3, 2008


Photograph: The Irish Times

Research casting doubt on the effectiveness of anti-depressants also raises questions about doctors prescribing drugs to people with mild depression who can't access other treatments.

Research carried out at Hull University and released this week questions the effectiveness of anti-depressant medication, focusing on a number of drugs from the selective serotonin reuptake inhibitor (SSRI) group of anti-depressants. They include fluoxetine (Prozac), venlafaxine (Efexor) and paroxetine (Seroxat).

SSRIs are the newest family of anti-depressant drugs. They work by increasing the availability of the neurotransmitter serotonin in the brain. As well as raising serotonin, venlafaxine also raises the level of the neurotransmitter, noradrenaline. Prozac was the first of the class to hit the market in 1988.

One of the main drivers of SSRI development was the unpleasant side effect profile of the existing tricyclic group of anti-depressants and the search for a drug that would be safer in overdose.

But any hopes of a miracle cure were soon dashed: up to one-third of patients do not respond to SSRIs.

The new drugs were increasingly prescribed for the treatment of mild depression. In the US, they became fashionable as lifestyle drugs, with a reported ability to make people in a normal mood happier and more productive.

Now well-established in the marketplace, prescriptions for anti-depressants grew by 50 per cent in the three years up to 2004. Excluding prescriptions paid for privately, Prozac cost the State over €5 millionin 2006.

Low levels of serotonin, noradrenaline and dopamine in the brain have been implicated in depression. The mood department and cable systems in the brain are stimulated by SSRIs, leading to an increase in positive thinking, self-esteem and memory and a reduction in suicidal impulses and anxiety. Modern neuroimaging techniques seem to confirm these changes.

But this week's study has raised serious doubts about the effectiveness of SSRIs.

It did not involve a new group of patients being tested with the drugs and a placebo; rather it was a meta-analysis of other trials submitted to the US Food and Drugs Administration (FDA).

A meta-analysis is essentially a statistical method for combining the results of many studies on the basis that the pooled information will offer a better opportunity to assess a drug's effectiveness. Nevertheless, it has caused more than a ripple among healthcare professionals and in the pharmaceutical industry.

BY CONCLUDING THAT the difference in improvement between patients taking placebo and those taking antidepressants is not very great, Prof Irving Kirsch and his psychologist colleagues in Canada and the US, who co-authored the Hull University study, are saying that people with depression can improve without chemical treatments.

But like many sweeping statements in medicine, it does not accurately reflect the nuances of looking after the individual. There is also a societal aspect to the dilemma – a major change in what depression means in the modern world – which has influenced decision-making in the consultation.

When doctors classify depression, they talk of mild, moderate and severe versions of the disease.

But the dividing line between mild clinical depression and someone feeling fleetingly depressed has become blurred. The lexicon has changed: where before we spoke of "feeling down" or "being in a bad mood", now people more readily say: "I am depressed."

It seems that much of the overprescribing of anti-depressants can be linked to this change and to the readiness of doctors to reach for the prescription pad.

In turn, this ready prescribing is influenced by the severe lack of psychologists, especially those trained in cognitive behavioural therapy (CBT), who provide the recommended first-line treatment for mild depression.

It can take many weeks to access CBT as a private patient; it is almost impossible to obtain if you are dependent on public outpatient services. Should we now ask doctors to shrug their shoulders and say: "There is nothing I can do for you?"

It would take years – and a great deal of money – to train enough therapists to provide community access to CBT for everyone with mild and more severe forms of depression. This has lead to trials of computerised CBT, in which patients are taken through a guided self-help programme. The initial results of this approach are promising.

In addition, general practitioners must be given the time and training to offer support to people going through relationship breakdowns and other transient life events.

Unfortunately, the current emphasis on "tick box" medicine and increased patient turnover means that health authorities are unlikely to make these much-needed changes.

For the patient with moderate clinical depression, UK health body the National Institute of Clinical Excellence's guidelines recommend combined treatment with exercise, CBT or other psychological intervention and anti-depressants.

Clinical Evidence , an authoritative resource to evidence-based treatment, published by the British Medical Journal Group, advises a combination of drugs and talking therapy.

The authors of this week's research rather grudgingly say: "There is little reason to prescribe new-generation anti-depressant medication to any but the most severely depressed patients."

Try telling that to a person with severe depression, who has endured months of disabling physical and psychological symptoms until a course of antidepressants slowly returned them to something resembling their former self.

Severe weight loss, social withdrawal and marked suicidal thoughts are just some of the life-threatening symptoms that will envelop the person without effective pharmacological intervention. No caring health professional could deny them the opportunity for recovery offered by antidepressants as part of a multi-faceted approach to their illness.

For those with moderate depression, who are on treatment they feel is working, the clear advice is: don't stop taking the tablets on foot of this week's research.

And for people experiencing symptoms of mild depression, go to your GP for an initial assessment. It may just be the blues, in which case a supportive discussion may do the trick.

But if the doctor says you have mild clinical depression, then the ideal course of treatment is referral to a psychologist specialising in CBT.


Achieving a medical cure can be explained in a number of ways. The treatment, in this case the anti-depressant, has worked. Many illnesses are self-limiting over time and so the improvement may be due to the healing power of nature, or the improvement may be due to the placebo effect.

The word placebo literally means "I will please". Traditionally defined as "an inert substance given for its psychological effect to satisfy the patient", it first appeared in a medical sense in the 19th century.

It was once accepted practice to use placebos in the form of water injections or a bread pill covered in sugar (pillula panis).

But for it to work, the patient must believe it contains an active ingredient. In a world governed by modern medical ethics, such decepti
on i
s clea
rly unacceptable and so the use of placebo as an active treatment no longer occurs.

However, placebos are central to many clinical trials. In the classic randomised, double-blind trial, one-half of the participants randomly receive a placebo, while the remainder get the active treatment. Neither the doctor nor the patient know who is getting what.

It is common for patients to report a benefit from the dummy pill. In pain research, a placebo response has been recorded in 50 per cent of recipients.

In the anti-depressant trial reported this week, an especially large placebo response of 80 per cent was recorded.

This led the researchers to conclude, perhaps speculatively, that "the relationship between initial [depression] severity and anti-depressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication".

Allied to the placebo effect is the concept of "the doctor as drug". Depending on how enthusiastically and persuasively a doctor prescribes a treatment, he may invoke a positive response in the patient that adds to the effect of the medication itself. This and other factors, raise questions about the direct applicability of academic research to the everyday reality of front-line medical practice. – Dr Muiris Houston


Doctors diagnose major depression in someone with a depressed mood for more than two weeks, combined with at least four of these symptoms:

Low mood; Fatigue; Sleep difficulties; Anxiety; Weight loss / gain; Loss of self-esteem; Loss of drive; Negative thinking; Poor memory; Reduced concentration; Lack of joy or pleasure; Suicidal thoughts.