In a frequently cited study (Kirsch, et al., 2008)1, researchers found that "drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively
small even for severely depressed patients". In patients who initially have moderate or even very severe depression, new-generation antidepressants do not produce clinically significant improvements
over those achieved with placebo, and they show significant effects only in the most severely depressed patients, among whom the apparent efficacy correlates with decreased responsiveness to placebo rather
than with increased responsiveness to the medication.2
Though it has received some criticism and has certain limitations3,4 a recent patient-level meta-analysis (Fournier, et al., 2010)5 shows similar results and
calls into question the validity of prescribing antidepressants for patients with low to moderate symptoms, given the fact that such patients are often excluded from registration trials. As MedPage Today Senior Editor John Gever reports:
"The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or
moderate symptoms," Fournier and colleagues wrote.
This important feature of the evidence base is not reflected in the implicit messages present in the marketing of these medications to clinicians and the public," they added. "There is little mention of the fact that efficacy data often come from studies that
exclude precisely those [depression] patients who derive little specific pharmacological benefit from taking medications.
Evidence-based evaluation of any antidepressant requires access to the full range of studies conducted on the drug's efficacy, including those studies which show negative outcomes.
There is no shortage of double-blind, placebo-controlled antidepressant trials — they number well over a thousand, depending upon the eligibility criteria; but published reports
are largely "positive", almost ubiquitously claiming significant results, with "negative" trials either left unpublished or distorted to present "positive" results (Ioannidis, 2008).6
The marketing7 of antidepressants and the readiness of many physicians to prescribe them in circumstances where symptoms are mild to moderate and other treatments, including
cognitive and behavioral approaches, may prove more effective ought to raise serious concerns in our increasingly medicalized society. Patient demand is clearly influenced
by television and print promotions of such medications, despite the sometimes chilling litany of adverse effects spoken sotto voce or shown in smaller font.8 In 2004 and 2006, responding
to alarming reports of suicide ideation and behaviors in children and adolescents on antidepressant medications, the FDA proposed that makers of all antidepressant medications update
the existing black box warning on their products' labeling to include warnings about suicidality in young adults ages 18 to 24 during initial treatment (generally the first one to
two months).9 All antidepressants now carry such warnings.
Suicidality10 is not the only problem, however; idiosyncratic response and withdrawal are equally important concerns. In this context, Darcy Baston's
Paxil Withdrawal Guide (2005) is a very interesting read. David Healy (Let Them Eat Prozac, 2004)11 writes the following
in Dependence on Antidepressants & Halting SSRIs: Protocol for the Withdrawal of SSRI Antidepressants:
Following the benzodiazepine crisis of the 1980s, psychiatrists and general practitioners turned with relief to the antidepressants, which the Royal Colleges of Psychiatrists & General
Practitioners assured us and our patients did not cause dependence and were not addictive. I shared this belief. And indeed antidepressants are not addictive in the sense that they
lead to altered motivational hierarchies such that an individual would mortgage their livelihoods and all they hold dear for further supplies of the drug. But patients are worried about
being "hooked" on antidepressants and antidepressants can hook in the sense of making you physically dependent.
In the 1960s the concept of therapeutic drug dependence on antipsychotics and antidepressants emerged and it became clear that some individuals might never be able to halt these
drugs. Withdrawal from antipsychotics for instance could lead to tardive dyskinesia, which it was later recognised could emerge in the course of treatment(Healy, 2001). The fact that "withdrawal"
could emerge while still on treatment with drugs that were not euphoriants and did not disrupt motivational hierarchies was completely incompatible with theories of addiction then and
now. This, allied to the need to contain the use of opiates, LSD and amphetamines in 1960s, led to an eclipse of the concept of therapeutic drug dependence. Since the 1960s we have had
a demonisation of some drugs and glorification of others. The bad drugs are supposedly characterised by dependence even though LSD and other bad drugs do not cause physical dependence.
The good drugs are supposed to be free of this problem.
Against this background, therapeutic drug dependence on benzodiazepines provoked a crisis. Patients resented being hooked and resented not being warned about the risks of getting hooked
and further resented being blamed as authors of their own misfortune. The emergence of the SSRI antidepressants offered the possibility of an almost "political" compromise.
From 1960 to 1990, the antidepressants were generally prescribed only to severely depressed patients, and in these patients evidence of relapse on discontinuation could often reasonably
be seen as evidence of relapse of an illness. This position became harder to maintain in patients who had formerly been cases of Valium but who now became cases of Prozac, Seroxat,
Lustral and Effexor. These patients did not have the severe conditions that might have been expected to lead to early relapse on discontinuation. Reports of withdrawal streamed in to regulators. [...]
|
Features of Withdrawal/Withdrawal Symptoms |
The common symptoms on withdrawal from SSRIs break down into two groups(Rosenbaum, et al., 1998). The first group may be unlike anything you have had before and include:
- Dizziness
- Headache
- Muscle Spasms
- Tremor
- Electric Shock-like Sensations
- Other Strange Tingling or Painful Sensations
- Nausea,
Diarrhoea, Flatulence
- Dreams, including Vivid Dreams
- Agitation
|
The second group overlaps with general nervousness and may lead to you or your physician to think that all you have are features of your
original problem. These symptoms include:
- Depression
- Lability of Mood
- Irritability
- Agitation
- Confusion
- Fatigue/Malaise
- Flu-like Feelings
- Insomnia or Drowsiness
- Mood Swings
- Sweating
- Feelings of Unreality
- Feelings of being Hot or Cold
|
|
These symptoms appear in anything between 20% to 50% of patients taking SSRIs, sometimes within hours of the last dose. Paroxetine and
Venlafaxine appear the most problematic agents at the moment but similar symptoms are liable to occur with all SSRIs and to a lesser extent with
tricyclic antidepressants. In milder cases problems may clear up after a week or two, but in others symptoms may continue weeks or months after the last dose and
for some patients it may not be possible to stop treatment. Specialist help may benefit some patients in this latter group, if only to provide suggestions on
antidotes to continuing drug induced problems such as loss of libido. [...] |
Is This Withdrawal?
There are three ways to distinguish withdrawal from SSRIs from the nervous problems that the SSRI might have been used to treat in the first instance.
First if the problem begins immediately on reducing or halting a dose or begins within hours or days or perhaps even weeks of so doing then it is more likely to be a
withdrawal problem. If the original problem has been treated and you are doing well, then on discontinuing treatment no new problems should show up for several months.
Second if the nervousness or other odd feelings that appear on reducing or halting the SSRI (sometimes after just missing a dose) clear up when you are put back on the SSRI
or the dose is put back up, then this also points towards a withdrawal problem rather than a return of the original illness. When original illnesses return, they take a
long time to respond to treatment. The relatively immediate response of symptoms on discontinuation to the reinstitution of treatment points towards a withdrawal problem.
Third the features of withdrawal may overlap with features of the nervous problem for which you were first treated - both may contain elements of anxiety and of depression. However
withdrawal will also often contain new features not in the original state such as pins and needles, tingling sensations, electric shock sensations, pain and a general flu-like feeling.
Before starting to withdraw, it should be noted that many people will have no problems. Some will have minimal problems, which may peak after a few days before diminishing. Symptoms can
remain for some weeks or months. Others will have greater problems but these can be helped by the management plan outlined below.
Finally however there will be a small group of people who are simply unable to stop. It is important to recognise this latter possibility in order to avoid punishing yourself. Specialist
help may make a difference for some people in this latter group, if only to provide possible antidotes to attenuate the problems of ongoing SSRIs such as loss of libido. [...] [Read More]
On Depression (what it is) and Drugs (evidence-based treatments?)
|
2.2 Aetiology
The enormous variation in the presentation, course and outcomes of depressive illnesses is reflected in the breadth of theoretical explanations for their aetiology, including genetic
(Kendler & Prescott, 1999), biochemical, endocrine and neurophysiological (Goodwin, 2000; Malhi et al., 2005), psychological (Freud, 1917), and social (Brown & Harris, 1978) processes
and/or factors. An emphasis upon physical, and especially endocrine, theories of causation has been encouraged by the observation that some physical illnesses do increase the risk of
depression, including diabetes, cardiac disease, hyperthyroidism, hypothyroidism, Cushing's syndrome, Addison's disease and hyperprolactinaemic amenorrhea (Cassano & Fava, 2002). Advances
in neuroimaging have reinforced the idea of depression as a disorder of brain structure and function (Drevets et al., 2008) and psychological findings emphasise the importance of cognitive
and emotional processes (Beck, 2008).
Most people now believe that all these factors influence an individual's vulnerability to depression, although it is likely that for different people living in different circumstances,
precisely how these factors interact and influence that vulnerability will vary between individuals (Harris, 2000). Nevertheless, the factors identified as likely to increase a person's
vulnerability to depression include gender, genetic and family factors, adverse childhood experiences, personality factors and social circumstances. In the stress-vulnerability model
(Nuechterlein & Dawson, 1984), vulnerability factors interact with social or physical triggers such as stressful life events or physical illness to result in a depressive episode (for
example, Harris, 2000).
A family history of depressive illness accounts for around 39% of the variance of depression in both sexes (Kendler et al., 2001), and early life experiences such as a poor parent–child
relationship, marital discord and divorce, neglect, physical abuse and sexual abuse almost certainly increase a person's vulnerability to depression in later life (Fava & Kendler, 2000).
Personality traits such as 'neuroticism' also increase the risk of depression when faced with stressful life events (Fava & Kendler, 2000). However, different personalities have different
expectancies of stressful life events, and some personalities have different rates of dependent life events, which are directly related to their personality – such as breaking up a relationship
(Hammen et al., 2000). The possession of a specific variation in particular genes has also been reported to make individuals more likely to experience depression when faced with life events
(for example, Caspi et al., 2003).
The role of current social circumstances in increasing the risk of depression, such as poverty, homelessness, unemployment and chronic physical or mental illness cannot be doubted even
from a brief examination of the epidemiology of depression (see above). In the UK, an influential study found that social vulnerability factors for depression in women in Camberwell,
South-East London, included: having three or more children under the age of 14 years living at home; not having a confiding relationship with another person; and having no paid employment
outside the home (Brown & Harris, 1978). Lack of a confiding relationship appears to be a strong risk factor for depression (Patten, 1991).
The neatness of this social model of depression, in which vulnerabilities interact with stressful life events, such as separation or loss of a loved one, triggering a depressive episode,
is not always supported by the 'facts': some episodes of depression occur in the absence of a stressful event, and conversely many such events are not followed by a depressive disorder in
those with vulnerabilities. Having said that, the presence of some factors protects against depression following a stressful life event, such as having a supportive confiding relationship
with another person (Brown & Harris, 1978), or befriending (Harris et al., 1999).
In addition to considering the aetiology of the onset of depressive episodes it is equally important to consider factors which maintain or perpetuate depression as these are potential targets
for intervention. Although many studies have reported on factors which predict outcome (including earlier age of onset, greater severity and chronicity, ongoing social stresses, comorbidity
with other psychiatric or physical disorders and certain types of personality disorder) we lack an understanding of what determines how long a depressive episode lasts, why is varies so much
between individuals and why for some it becomes persistent. It is also clinically apparent that depression, especially when it persists, may lead to secondary disability that compounds, and
is difficult to distinguish from, the depression itself. Features include loss of self-esteem and independence, feelings of helplessness and hopelessness (which increase the risk of suicide)
and loss of engagement in outside activities with social withdrawal. These are aspects that self-help interventions and organisations often target but about which we have little systematic
evidence. These are likely to relate to, and benefit from, the non-specific effects of interventions and the placebo effect [...]
In using guidelines, it is important to remember that the absence of empirical evidence for the effectiveness of a particular intervention is not the same as
evidence for ineffectiveness. |
BACKGROUND
Evidence-based medicine is valuable to the extent that the evidence base is complete and unbiased. Selective publication of clinical trials — and the outcomes within
those trials — can lead to unrealistic estimates of drug effectiveness and alter the apparent risk–benefit ratio.
METHODS
We obtained reviews from the Food and Drug Administration (FDA) for studies of 12 antidepressant agents involving 12,564 patients. We conducted a systematic literature
search to identify matching publications. For trials that were reported in the literature, we compared the published outcomes with the FDA outcomes. We also
compared the effect size derived from the published reports with the effect size derived from the entire FDA data set.
RESULTS
Among 74 FDA-registered studies, 31%, accounting for 3449 study participants, were not published. Whether and how the studies were published were associated with
the study outcome. A total of 37 studies viewed by the FDA as having positive results were published; 1 study viewed as positive was not published. Studies viewed by the
FDA as having negative or questionable results were, with 3 exceptions, either not published (22 studies) or published in a way that, in our opinion, conveyed a positive
outcome (11 studies). According to the published literature, it appeared that 94% of the trials conducted were positive. By contrast, the FDA analysis showed that
51% were positive. Separate meta-analyses of the FDA and journal data sets showed that the increase in effect size ranged from 11 to 69% for individual drugs and was
32% overall.
CONCLUSIONS
We cannot determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors
and reviewers not to publish, or both. Selective reporting of clinical trial results may have adverse consequences for researchers, study participants, health care professionals,
and patients. [...]
We wish to clarify that nonsignificance in a single trial does not necessarily indicate lack of efficacy. Each drug, when subjected to meta-analysis, was shown to be superior to placebo. On the
other hand, the true magnitude of each drug's superiority to placebo was less than a diligent literature review would indicate.
We do not mean to imply that the primary methods agreed on between sponsors and the FDA are necessarily preferable to alternative methods. Nevertheless, when multiple analyses are conducted,
the principle of prespecification controls the rate of false positive findings (type I error), and it prevents HARKing,36 or hypothesizing after the results are known.
It might be argued that some trials did not merit publication because of methodologic flaws, including problems beyond the control of the investigator.
However, since the protocols were written according to international guidelines for efficacy studies37 and were carried out by companies
with ample financial and human resources, to be fair to the people who put themselves at risk to
participate, a cogent public reason should be given for failure to publish.
Selective reporting deprives researchers of the accurate data they need to estimate effect size realistically.
Inflated effect sizes lead to underestimates of the sample size required to achieve statistical
significance. Underpowered studies — and selectively reported studies in general — waste
resources and the contributions of investigators and study participants, and they hinder the advancement
of medical knowledge. By altering the apparent risk–benefit ratio of drugs, selective publication
can lead doctors to make inappropriate prescribing decisions that may not be in the best interest of their patients and, thus, the public health. |
|
In their conclusion, the authors address the issue of failed placebo-controlled trials and suggest that, since placebo-controlled trials are becoming
increasingly difficult to do, notwithstanding their importance for ethical and safety reasons, such trials instead should be conducted with an antidepressant
as standard comparator. While this may indeed result in the accelerated development of "new treatments", it seems both scientifically and ethically unsound.
[...] Placebo-controlled trials are required to adequately assess the efficacy of novel antidepressant drugs. In
both the USA and Europe, regulatory authorities require placebo-controlled studies for marketing authorisation.
The selective publication of placebo-controlled antidepressant trials and its effect on apparent efficacy is
well recognised and there is currently controversy on this topic. Placebo-controlled trials are mainly designed
for regulatory approval purposes; to meet both ethical and safety requirements, they tend to recruit patients
with a mild form of disease. Although placebo-controlled trials can be efficient because they need smaller sample
sizes than non-placebo-controlled trials, difficulties in carrying out these trials when effective treatments are
known to exist can introduce artifacts into clinical trials.
Response to placebo across antidepressant trials has been shown to vary and has clearly increased in the past
two decades, with a similar increase occurring in the fraction of patients responding to active medication as
well. The issue of changes in trial outcomes over time is still under debate; however, the change in placebo
response does not seem to be directly explained by changes in study characteristics. Inflation of baseline severity, for
example, is likely to be a cause for the temporal rise in placebo response rates, which increases the proportion of
failed trials. As placebo-controlled trials of antidepressants become increasingly difficult to do, it is perhaps time to
reconsider the standard requirements. Our analysis suggests that sertraline is better than other new-generation
drugs in terms of efficacy and acceptability, and could be used as a standard comparator in phase III and also in
pragmatic (or effectiveness) trials to increase the real-world applicability of the results. Although the sample-size
requirements might be larger than in the ideal placebo-controlled trial, the increased real-world
applicability of the results would, in our opinion, off set this disadvantage. Furthermore, the need of new
treatments to show either greater efficacy or acceptability than an existing standard therapy would serve as a
disincentive to the development of me-too agents that offer little to patients other than increased costs. |
Antidepressants and the Risk of Suicide...
(Reuters Health) - People have about the same risk of having suicidal thoughts or attempting suicide when starting out on antidepressants no matter what type of pill they're prescribed,
new research shows.
"There is no meaningful difference between these agents," Dr. Sebastian Schneeweiss of Brigham and Women's Hospital and Harvard Medical School in Boston, one of the study's authors,
told Reuters Health. This means that psychiatrists prescribing antidepressants can base their choice on what works best for the patient, rather than what's safest, he explained.
But the findings don't mean that the drugs are risk-free, Schneeweiss added. "You always have to worry about the safety of these medications, the increased (suicide risk) is still there," he said.
The US Food and Drug Administration issued a warning in 2004 that children and adolescents taking antidepressants might have an increased risk of suicidal
thoughts and behaviors. In 2006, it extended the warning to include young adults up to age 25. All antidepressant labels must now carry a "black box" warning stating that they can increase a person's likelihood of suicidal
thoughts and behaviors. [See Historical Information on Antidepressant Use in Children, Adolescents, and Adults.]
But it has been difficult to pin down whether a certain antidepressant drug or class of medications might be more dangerous -- or safer -- than others, Schneeweiss noted. To investigate, he
and his colleagues looked at data on nearly 300,000 adults in British Columbia, Canada, who had been prescribed antidepressants between 1997 and 2005. They evaluated whether specific medications
would increase the risk that a person would attempt or complete suicide during their first year of taking that drug.
Among the 287,543 men and women in the study, there were 751 suicide attempts and 104 suicides.
Schneeweiss and his team found no difference in risk between different classes of medications, such as selective serotonin reuptake inhibitors (SSRIs for short, which include Prozac,
Zoloft and other widely used medications) or older antidepressants called tricyclic antidepressants. Risks also were similar for individual SSRIs.
In April, Schneeweiss and his colleagues published a similar study in the journal Pediatrics of 20,000 10- to 18-year-olds that found no difference in suicide risk among antidepressants.
It's still unclear why antidepressants could increase suicide risk, Schneeweiss noted in an interview. "You cannot really tease that apart in non-randomized studies," he added. But for now,
he and his colleagues conclude, "clinicians should be vigilant in monitoring after initiating therapy with any antidepressant agent."
|
Context A US Food and Drug Administration advisory has warned that antidepressants may be associated with an increased risk of suicidal thoughts and behaviors
in adolescents. This prompted a meta-analysis of trials in adults that found no overall increase in risk, but individual agents could not be studied.
Objective To assess the risk of suicide and suicide attempts associated with individual antidepressant agents.
Design Cohort study of incident users of antidepressant agents.
Setting Population-based health care utilization data of all residents of British Columbia, Canada, aged 18 years and older between January 1, 1997, and December 31, 2005.
Patients British Columbia residents who had antidepressant therapy initiated and had a recorded diagnosis of depression.
Intervention Initiation of various antidepressant medications.
Main Outcome Measures Combined suicide death or hospitalization due to self-harm.
Results In a population of 287 543 adults aged 18 years and older with antidepressant therapy initiated, we observed outcome rates ranging from 4.41/1000 person-years
to 9.09/1000 person-years. Most events occurred in the first 6 months after treatment initiation. After extensive propensity score adjustment, we found no clinically meaningful
variation in the risk of suicide and suicide attempt between antidepressant agents compared with fluoxetine hydrochloride initiation: citalopram hydrobromide, hazard ratio = 1.00
(95% confidence interval, 0.63-1.57); fluvoxamine maleate, hazard ratio = 0.98 (95% confidence interval, 0.63-1.51); paroxetine hydrochloride, hazard ratio = 1.02 (95% confidence
interval, 0.77-1.35); and sertraline hydrochloride, hazard ratio = 0.75 (95% confidence interval, 0.53-1.05). Compared with selective serotonin reuptake inhibitors as a drug class,
other classes including serotonin-norepinephrine reuptake inhibitors, tricyclic agents, and other newer and atypical agents had a similar risk. Restriction to patients with no
antidepressant use in the past 3 years further reduced apparent differences between groups.
Conclusions Our finding of equal event rates across antidepressant agents supports the US Food and Drug Administration's decision to treat all antidepressants alike in
their advisory. Treatment decisions should be based on efficacy, and clinicians should be vigilant in monitoring after initiating therapy with any antidepressant agent. |
The U.S. Food and Drug Administration (FDA) today [5/2/2007] proposed that makers of all antidepressant medications update the existing black box warning
on their products' labeling to include warnings about increased risks of suicidal thinking and behavior, known as suicidality, in young adults ages 18 to
24 during initial treatment (generally the first one to two months).
Current Information
List of Antidepressant Drugs
with Medication Guides
Anafranil (clomipramine)
Asendin (amoxapine)
Aventyl (nortriptyline)
Celexa (citalopram hydrobromide)
Cymbalta (duloxetine)
Desyrel (trazodone HCl)
Elavil (amitriptyline)
Effexor (venlafaxine HCl)
Emsam (selegiline)
Etrafon (perphenazine/amitriptyline)
fluvoxamine maleate
Lexapro (escitalopram oxalate)
Limbitrol (chlordiazepoxide/amitriptyline)
Ludiomil (maprotiline)
Marplan (isocarboxazid)
Nardil (phenelzine sulfate)
nefazodone HCl
Norpramin (desipramine HCl)
Pamelor (nortriptyline)
Parnate (tranylcypromine sulfate)
Paxil (paroxetine HCl)
Pexeva (paroxetine mesylate)
Prozac (fluoxetine HCl)
Remeron (mirtazapine)
Sarafem (fluoxetine HCl)
Seroquel (quetiapine)
Sinequan (doxepin)
Surmontil (trimipramine)
Symbyax (olanzapine/fluoxetine)
Tofranil (imipramine)
Tofranil-PM (imipramine pamoate)
Triavil (perphenazine/amitriptyline)
Vivactil (protriptyline)
Wellbutrin (bupropion HCl)
Zoloft (sertraline HCl)
Zyban (bupropion HCl)
For more information on some of these drugs, please see the
Index to Drug-Specific Information.
| |
Antidepressants & Placebos...
|
Everyone feels miserable occasionally. But for some people — those with depression — these sad feelings last for months or years and interfere with daily life.
Depression is a serious medical illness caused by imbalances in the brain chemicals that regulate mood. It affects one in six people at some time during their life, making
them feel hopeless, worthless, unmotivated, even suicidal. Doctors measure the severity of depression using the "Hamilton Rating Scale of Depression" (HRSD), a 17–21 item
questionnaire. The answers to each question are given a score and a total score for the questionnaire of more than 18 indicates severe depression. Mild depression is often
treated with psychotherapy or talk therapy (for example, cognitive–behavioral therapy helps people to change negative ways of thinking and behaving). For more severe
depression, current treatment is usually a combination of psychotherapy and an antidepressant drug, which is hypothesized to normalize the brain chemicals that affect mood.
Antidepressants include "tricyclics," "monoamine oxidases," and "selective serotonin reuptake inhibitors" (SSRIs). SSRIs are the newest antidepressants and include fluoxetine,
venlafaxine, nefazodone, and paroxetine. [...]
The researchers obtained data on all the clinical trials submitted to the FDA for the licensing of fluoxetine, venlafaxine, nefazodone, and paroxetine. They then
used meta-analytic techniques to investigate whether the initial severity of depression affected the HRSD improvement scores for the drug and placebo groups in
these trials. They confirmed first that the overall effect of these new generation of antidepressants was below the recommended criteria for clinical significance.
Then they showed that there was virtually no difference in the improvement scores for drug and placebo in patients with moderate depression and only a small and
clinically insignificant difference among patients with very severe depression. The difference in improvement between the antidepressant and placebo reached clinical
significance, however, in patients with initial HRSD scores of more than 28 — that is, in the most severely depressed patients. Additional analyses indicated that the
apparent clinical effectiveness of the antidepressants among these most severely depressed patients reflected a decreased responsiveness to placebo rather than
an increased responsiveness to antidepressants. [...] |
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5.05.10)
