Antidepressants versus placebo in major depression: an overview (Khan & Brown) Flashcards

1
Q

Although the early antidepressant trials which included severely ill and hospitalized patients showed substantial drug-placebo differences,
these robust differences have not held up in the trials of the past couple of decades, whether sponsored by pharmaceutical companies or
non-profit agencies.

A

oke

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

wat voor redenen werden gegeven voor dat er minder drug-placebo differences werden gevonden

A
  • DSM-III aanpassingen, bredere diagnose criteria voor MDD (dus inclusie mild/moderate patients into antidepressant trials) -> deze patienten gevoelig voor placebo-effect
  • drug development regulators hebben een grote rol, wilden geen vals positieven en daardoor slechte, lastige trials gemaakt. en nu vinden ze geen goede resultaten meer
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

wat geloofden we 20 jaar geleden over antidepressants and placebo

A

Twenty years ago we believed that antidepressants worked in 70% of depressed patients and placebo in 30% of them

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

A considerable body of research subsequently
exploredwhich depressed patients
responded to select antidepressants
such as …. compared to ….

A

imipramine and phenelzine compared to electroconvulsive therapy (ECT)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what did Klerman and Cole find regarding the trials evaluating the effectiveness of imipramine

A

they reported that hospitalized depressed patients with a melancholic pattern of symptoms were most likely to respond to the drug

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Much of the wisdom about the magnitude of antidepressant and placebo response was based on these early clinical trials of tricyclic antidepressants, and these data carried well into the early 1990s (6).

A

oke

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

wat was de belangrijkste psychiatrische verandering in de 1970s en 1980s

A

the advent of DSM 3

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

waarom had de advent van de dsm 3 zo’n grote impact op de antidepressant industry

A

Using an atheoretical approach, this diagnostic system minimized differences between subtypes of depression and conceptualized a broad syndrome called major depressive disorder, characterized by a single or recurrent bouts named major depressive episodes. Such a “uniform” diagnosis now included millions of patients and became an attractive target for the pharmaceutical industry. Thus, the American PsychiatricAssociation, sponsor of the DSM-III, unintentionally expanded the market for antidepressants.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

wat gebeurde er na de advent van de dsm met clinical trials

A

die includeerden allerlei soorten patienten, vaak gewoon met generalised mdd, soms met subtypes zoals melancholic maar lang niet altijd.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

wat was toen de symptom reduction van deze antidepressants (na dsm3)

A

40% antidepressants, 30% placebo

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

wat vonden walsh et al

A

the magnitude of symptom reduction with placebo had been increasing in the past three decades

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

the effectiveness of modern antidepressants was not only questioned by placebo controlled trials…

A

but also by trials based on non placebo trials

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

wat liet het STAR*D project zien

A

dat alleen 4 uit 10 depressed outpatients een therapeutic response kregen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

wat is nog meer een kritiekpunt op de antidepressiva

A

dat het heel duidelijk een commerciele venture is. vooral kritiek op integriteit van de data, die gegenereerd wordt door de industrie zelf

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

wat was een belangrijke beviding over placebos in dit onderzoek

A

the magnitude of reduction due to placebo pills was larger in non-industry trials than FDA depression trials (dus het placebo effect is groter in non-industry dan FDA depression trial data)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

wat laten de gestreepte bars zien en de zwarte

A

striped: the magnitude of depressive syptom reduction in trials where the investigators and their staff were aware of the design and expectations of the study

black: the magnitude of symptom reduction when the investigators and raters were blinded to the design and execution of the study

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

dus wat laat het verschil in deze bars zien

A

expectation bias!

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

wat is te zien aan de gestreepte bars, wat voor trend

A

je ziet echt dat de verwachtingen van de onderzoekers dit representateren: de combinatie therapie, antidepressants en psychotherapie scoorden het hoogste. treatment as usual scoorde heel laag (terwijl dit eigenlijk wel goed werkte toen de researchers geblindeerd waren)

19
Q

wat was het patroon van de zwarte bars

A

de symptom reduction was ongeveer gelijk voor alle soorten treatments, en ook vergelijkbaar met placebo!!!!

so if the level of blinding is high, the differences between these treatments, controls and placebo become quite small

20
Q

wat zag je bij de treatments die lastig te blinderen waren en welke waren dit

A

psychotherapie (lastig om clinician te blinderen) en waiting list (lastig om patient te blinderen)

-> psychotherapy superior to placebo, and waiting list inferior to placebo

-> both clinicians and depressed patients continued to fulfill expectations of each treatment based on prior assumptions

21
Q

wat vond Sinyor et al

A

Sinyor et al (14) reported that, if there was no placebo control in an antidepressant trial comparing two antidepressants, the magnitude of symptom reduction was 65.7%. If the trial included two antidepressant treatments and one placebo arm (33% placebo exposure risk), the magnitude of symptom reduction with the antidepressants was 57.7%, while that with placebo was 44.6%. If the antidepressant trial included one antidepressant arm and one placebo arm (50% placebo exposure risk), the magnitude of symptom reduction with antidepressant was 51.7% and that with placebowas 34.3%

dus the therapeutic effect of antidepressants is related to the risk of expxosure to placebo,. if you lower the risk of exposure to placebo, then the apparent therapeutic effect with the antidepressants and placeo is greater.

22
Q

patients with mild to moderate depression are prone to nonspecific therapeutic effects

A

oke

23
Q

The comments made by Brown (15) regarding the experience of patients assigned to placebo are pertinent. He states: “The capsule they receive is pharmacologically inert, but hardly inert with respect to its symbolic value and its power as a conditioned stimulus. In addition, placebo-treated patients receive all the components of the treatment situation common to any treatment, i.e., a thorough evaluation; an explanation for distress; an expert healer: a plausible treatment; a healer’s commitment, enthusiasm, and positive regard; an opportunity to verbalize their distress”

Since antidepressant clinical trials involve extensive evaluations, long visits, many experts and new and exotic treatments, it is not suprising that the differences between active and inactive treatments (zoals acupuncture and placebo) are at best small.

A

oke

24
Q

is het placebo effect alleen te zien bij mdd

A

nee, illnesses that are chronic, have a fluctuating course and are associated with subjective distress are prone to placebo response.

25
Q

het placebo effect was ook te zien bij non pill treatments zoals ect, vns pacemakers etc

A

oke

26
Q

wat is de course van placebo

A

early onset, fluctuating course, remain well for a considerable period of time

27
Q

wat zagen mayberg et al

A

Mayberg et al (27) noted that clinical improvement with either fluoxetine or placebo was associated with cerebral glucose metabolism increases in depressed patients. Such a potential biological basis for placebo response is further supported by similar studies in pain and Parkinson’s disease (28).

28
Q

In summary, depressed patients are prone to non-specific treatment effects, in particular when receiving placebo. Expectations by both patients and clinicians play a significant role in the magnitude of treatment effects in depression clinical trials. Once set, placebo
response tends to persist and there are sufficient data to suggest that this is associated to changes in brain
glucose metabolism.

A

oke

29
Q

wat is het belangrijkste aan de trials

A

dat zij bewijzen dat hun drug beter is dan placebo

30
Q

de FDA en EMA hebben heeeel veel invloed op de trials, door de keuzes die ze maken!

A

oke

31
Q

wat vinden zij een valid response, en wat niet

A

niet: therapeutic response (counting the number of depressed patients who responded vs who did not)

wel: maximumscores op de scales

32
Q

waarom vinden zij de therapeutic response niet goed

A

omdat het dan kan zijn dat de drug focust op factoren die niet gerelateerd zijn aan de specifieke disorder.
een drug kan dan wel therapeutic voelen en iemand beter laten voelen, maar dat betekent niet dat het ook echt aanslaat op de ziekte zelf

-> they require a syndromal improvement rather than a global feeling of well being

33
Q

waardoor wordt de variability die gevonden wordt in clinical trials beinvloedt? en wat beinvloedt dit weer?

A

door de grote range aan scores die je kan hebben op de vragenlijsten

dat je kleinere verschillen ziet tussen drug en placebo.

34
Q

wat voor measurement data analyse zorgen ook voor een minder groot verschil tussen drug en placebo

A

de last observation carried forward (LOCF)

-> want placebo onset is vroeger dan die van antidepressants, dus hierdoor lijkt het alsof antidepressiva minder effectief zijn

mixed-effect model repeated measure (MMRM)

-> heel confusing en niet favorable voor antidepressants

35
Q

wat is lastig aan EMA en FDA verschillen

A

zijn niet complementair aan elkaar en daardoor kan het niet goed samen gebruikt worden. ook is dit niet echt bekend bij de media & wetenschappers zelf

36
Q

what is the best way to show antidepressant-placebo differences

A
  • reduce number of investigation sites (10-12)
  • two treatment option w/ placebo risk of 50%
  • compare to a known effective dose of the AD
  • minimum of 120 depressed patients at each arm
37
Q

waarom hebben veel trials meer dan 2 armen

A

weer door keuzes van de FDA: requires that trials attempt to show a dose-response relationship (en dus moet er altijd doses gebruikt worden die misschien helemaal niet effectief zijn, zodat de minimale dosis bepaald kan worden)

38
Q

wat was de hele boodschap van dit artikel

A

Thus, several studies are conducted in
futility that simply make the results of
antidepressant trials look worse than
they are

39
Q

wat is er mis met assay sensitivity/the use of an active control group

A
  • likely to increase the magnitude of placebo response (want placebo exposure risk gaat naar beneden)
  • many trials showing that the active comparator is not superior to placebo (which adds more confusion)
40
Q

het is nog steeds zo dat mensen met ernstigere klachten beter reageren op AD. wat deden ze met deze info?

A

probeerden meer mensen met ernstige klachten toe te voegen aan de sample. maar… simply lead to a higher placebo response. dus forcing a higher pre-randomization severity may simply not work.

41
Q

using the longer version of HAMD results in…

A

een grotere antidepressant-placebo difference
misschien door meer variation in mood, paranoia and sense of hopelessness antwoorden, that may be more sensitive to antidepressant effects bij mensen met meer severe depression?

42
Q

wat is een alternatieve verklaring voor dat mensen met meer severe mdd

A

dat de staff de mensen raten als meer depressed dan ze eigenlijk zijn voor commercial gain. maar dit blijkt niet zo te zijn, omdat anderen die er los van staan juist ook minder antidepressant-placebo differences aantoonden…

43
Q
A