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3.7 Benefits of long-term use

Risk and severity of dependence on psychotropics tend to increase with higher doses and long-term use. But because "dependence is not a problem with antidepressants" (Priest et al., 1996), long-term treatment is recommended on the grounds that it helps to prevent either relapse (re-emergence of an underlying condition) and/or recurrence (the onset of a new one).

Probably the most important single source of recommendations for long-term SSRI use is the psychiatry department at St Mary’s Hospital, London. Chairman of the department is Dr. Robert Priest, prime mover of the Consensus Statement and Treatment Guidelines and Chairman of the Defeat Depression Campaign. Another key figure is Dr. Stuart Montgomery, who has developed research methodology on the prophylactic use of SSRIs and been involved in probably more long-term trials than anyone.

Both men have published prolifically and are widely quoted, and Montgomery’s impact has been further enhanced through numerous international conference engagements, many of which he has chaired and/or later edited the published proceedings. Montgomery is also editor of a learned journal, International Clinical Psychopharmacology, itself a major source of information on prophylactic antidepressant use. The journal carries no drug advertisements, though many papers are by research staff from pharmaceutical companies and no doubt many reprints are purchased.

Some indication of the significance of Montgomery’s work is also evident from the declarations of interests he made as a member of the Committee on Safety of Medicines (1987-1992). Personal interests included payments for "Lectures/Advice" from ten different companies, including four manufacturers of SSRIs: Lilly (Prozac) SmithKline Beecham (Seroxat/Paxil), Duphar (Faverin/Luvox) and Wyeth (Effexor/Efexor). Non-personal interests, involving "contributions to support research and staff costs" were declared for 11 companies, including Lundbeck (Cipramil).

By way of illustrating the kinds of studies on which long-term use recommendations have been based, consider the report by Montgomery and Dunbar (of SmithKline Beecham Pharmaceuticals) entitled: "Paroxetine is better than placebo in relapse prevention and the prophylaxis of recurrent depression". This was published in International Clinical Psychopharmacology in 1993.

In outline, the need to examine the possible benefits of long-term use was explained as follows: "Major depression is a serious illness ... Depression is a common illness with a prevalence rate of 16.4% ... The recurrent nature of the illness has tended to be underestimated ... more thorough studies have found that ... 78% of depressions were recurrent". Given also the high rate of relapse from "stopping the treatment too early after apparent response", the need for effective long-term treatments was clear.

The main measure of outcome in the study "was the withdrawal of the patient from the study ... because of the reappearance of depression ...". The report did not mention withdrawal symptoms; the possibility of mistaking withdrawal symptoms for relapse did not therefore arise.

The design of the study led to the recruitment and screening of patients in a way which ensured that everyone on the main trial responded well to paroxetine, and this was accomplished so successfully that withdrawals for side effects were similar for active drug and placebo. The authors permitted themselves to conclude that their research "confirms the reports from acute studies that the side effects of paroxetine diminish with time until they become indistinguishable from placebo".

The screening began when 171 prospective entrants were given 2 months on paroxetine, to eliminate mainly those with side effect or lack of efficacy problems; they included one suicide by hanging. The 135 patients who went on the main trial were then either continued on paroxetine or switched to placebo, effectively randomised in double blind conditions.Apparently no attempt was made in the placebo group to achieve gradual withdrawal, consistent with the view that no problems would be encountered on discontinuing the drug.

In the one-year, double-blind segment of the trial, patients were first seen two weeks after they had been put on drug or placebo. The published study says nothing about the observations made at that time, just when one would expect the main flurry of withdrawal problems. Apparently there were none. The first observations reported in the paper were those made after four months: six times as many on placebo were reported to have had a relapse as those who stayed on their accustomed drug.

There is a hint that unblinding problems were encountered, since the most sensitive single criterion for deciding to withdraw a patient from the trial "was the clinical judgement that the patient needed to be withdrawn from the placebo-controlled study and needed an antidepressant". At the end of the one-year phase of the study, the reappearance of depression had been noted in 16% of patients on paroxetine (11/68) and 43% of patients on placebo (29/67). Five different criteria were relied on to assess whether or not or depression had reappeared, and any one of these was considered enough to support the diagnosis. If all five criteria for reappearance of depression were applied, the apparent benefit of placebo was increased (the proportions reducing to 12% and 28% respectively).

The conclusions were that: "the low side effect and good safety profile of paroxetine seen in this study is reassuring and confirms its suitability for long-term treatment ... Paroxetine is associated with clear-cut efficacy compared with placebo in the long-term treatment of depression over a one-year period .... This study confirms the benefit of the long-term treatment of depression with an effective and well tolerated antidepressant ... These results confirm the benefit of long-term pharmacotherapy for treating depressive illness"


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