Therapeutic efficacy
There is a large amount of research evaluating the potential therapeutic
effects of antidepressants, whether through efficacy studies under experimental
conditions (including randomized clinical trials) or through studies of "real
world" effectiveness. A sufficient response to a drug is often defined as
at least a 50% reduction in self-reported or observed symptoms, with a
partial response often defined as at least a 25% reduction. The term
remission indicates a virtual elimination of depression symptoms, albeit
with the risk of a recurrence of symptoms or complete relapse.
Full remission or recovery signifies a full sustained return to a
"normal" psychological state with full functioning.
Recent clinical reviews include:
- A comparison of the relative efficacy of different classes of
antidepressants
in different settings
and in regard to different kinds of depression
- An assessment of antidepressants compared with an "active placebo"
- An assessment of the newer types of the MAOI class
- A meta-analysis of randomized trials of St John's Wort
- A review of the use of antidepressants for
childhood depression
- A review of all antidepressant trials submitted to the US
FDA from 1987 to 2004 has shown that around half of the trials failed to
show any benefit over placebo. All but one of the successful trial results
were published in scientific journals, while nearly all the unsuccessful
trials were either not published or were presented in a misleadingly
positive light (compared to the FDA's own evaluation of the data). This
arose because whilst studies are required for medical approval, studies
showing adverse findings are not necessarily required to be published or (if
published) given similar prominence. As a result, while it appeared in the
research literature that 94 percent of trials had positive outcomes, in the
actual data submitted to the Food and Drug Administration, only 51 percent
did. This
publication bias inflated the apparent statistical effect of every
antidepressant studied, by between 11% and 69%.
- Meta-analysis published in 2008 assessed linear and quadratic effects of
initial severity on improvement scores for drug and placebo groups and on
drug-placebo difference scores. Drug-placebo differences increased as a
function of initial severity, rising from virtually no difference at
moderate levels of initial depression to a relatively small difference for
patients with very severe depression, reaching conventional criteria for
clinical significance only for patients at the upper end of the very
severely depressed category.
Clinical guidelines The
American Psychiatric Association 2000 Practice Guideline for the Treatment
of Patients with Major Depressive Disorder
[15] indicates that, if preferred by the patient, antidepressant medications
may be provided as an initial primary treatment for mild major depressive
disorder; antidepressant medications should be provided for moderate to severe
major depressive disorder unless
electroconvulsive therapy is planned; and a combination of antipsychotic and
antidepressant medications or electroconvulsive therapy should be used for
psychotic depression. It states that efficacy is generally comparable between
classes and within classes and that the initial selection will largely be based
on the anticipated side effects for an individual patient, patient preference,
quantity and quality of clinical trial data regarding the medication, and its
cost.
The UK
National Institute for Clinical Excellence (NICE) 2004 guidelines indicate
that antidepressants should not be used for the initial treatment of mild
depression, because the risk-benefit ratio is poor; that for moderate or severe
depression an SSRI is more likely to be tolerated than a tricyclic; and that
antidepressants for severe depression should be combined with a psychological
treatment such as
Cognitive Behavioural Therapy.
Efficacy limitations and strategies Between 30% and 50% of individuals treated with a given antidepressant do not
show a response.
Even where there has been a robust response, significant continuing depression
and dysfunction is common, with relapse rates 3 to 6 times higher in such cases.
In addition, antidepressant drugs tend to lose efficacy over the course of
treatment
A number of strategies are used in clinical practice to try to overcome these
limits and variations.
"Trial and error" switching
The
American Psychiatric Association 2000 Practice Guideline advises that where
no response is achieved following six to eight weeks of treatment with an
antidepressant, to switch to an antidepressant in the same class, then to a
different class of antidepressant.
A recent meta-analysis review found wide variation in the findings of prior
studies; for patients who had failed to respond to an SSRI antidepressant,
between 12% and 86% showed a response to a new drug, with between 5% and 39%
ending treatment due to adverse effects. The more antidepressants an individual
had already tried, the less likely they were to benefit from a new
antidepressant trial.
Augmentation and combination
For a partial response, the American Psychiatric Association guidelines
advise adding a different kind of pharmaceutical agent to the antidepressant.
Studies suggest that most patients fail to achieve remission on a given
antidepressant, and augmentation strategies used in clinical practice include
the use of
lithium and
thyroid augmentation, but there is not a good evidence base for these
practices or for more novel strategies such as the use of selective
dopamine agonists,
sex steroids,
NRI's,
glucocorticoid-specific agents, or the newer
anticonvulsants
A combination strategy involves adding one or more additional
antidepressants, usually from different classes so as to have a diverse
neurochemical effect. Although this may be used in clinical practice, there is
little evidence for the relative efficacy or adverse effects of this strategy.
Long-term use
The therapeutic effects of antidepressants typically do not continue once the
course of medication ends, resulting in a high rate of relapse. A recent
meta-analysis of 31 placebo-controlled antidepressant trials, mostly limited to
studies covering a period of one year, found that 18% of patients who had
responded to an antidepressant relapsed while still taking it, compared to 41%
whose antidepressant was switched for a placebo.
The American Psychiatric Association guidelines advise four to five months of
continuation treatment on an antidepressant following the resolution of
symptoms. For patients with a history of depressive episodes, the British
Association for Psychopharmacology's 2000 Guidelines for Treating Depressive
Disorders with Antidepressants advise remaining on an antidepressant for at
least six months and as long as five years or indefinitely.
Whether or not someone relapses after stopping an antidepressant does not
appear to be related to the duration of prior treatment, however, and gradual
loss of therapeutic benefit during the course also occurs. A strategy involving
the use of pharmacotherapy in the treatment of the acute episode, followed by
psychotherapy in its residual phase, has been suggested by some studies.
Medication failure Approximately 30% of patients have remission of depression with medications.
For patients with inadequate response, either adding sustained-release
upropion
(initially 200 mg per day then
increase by 100 mg up to total of
400 mg per day) or
uspirone
(up to 60 mg per day) for augmentation
as a second drug can cause remission in approximately 30% of patients,
while switching medications can achieve remission in about 25% of patients.
By pregnancy
There is uncertainty whether pregnancy contributes to medication failure,
because the only report so far has drawn much controversy on itself:
In 2006, a widely reported study published in the
Journal of the American Medical Association (JAMA) challenged the
common assumption that hormonal changes during pregnancy protected expectant
mothers against depression, finding that discontinuing anti-depressive
medication during pregnancy led to more frequent relapse.
The JAMA article did not disclose that several authors had financial ties
to pharmaceutical companies making antidepressants. The JAMA later
published a correction noting the ties
and the authors maintain that the ties have no bearing on their research work.
Obstetrician and perinatologist Adam Urato told the
Wall Street Journal that patients and medical professionals need advice
free of industry influence.
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