« Antipsicóticos »

"Show me a sane man and I will cure him for you." - Carl Jung

Psychopharmacologicals 237

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Chlorpromazine

Butyrophenone type:Haloperidol

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Autonomic disturbancedue to atropine-likeaction

Movement disordersdue to dopamineantagonism

Antiemetic effect

A. Effects of neuroleptics in schizophrenia

Phenothiazine type:

Neuroleptics

Lüllmann, Color Atlas of Pharmacology © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.

Psychopharmacologicals 239

40%

40%

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strongly

Dopamine- ≈ ACh effect

Triflupromazine30 – 150 mg/d

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FlupentixolTrifluoperazine

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Long-actingor“depot”neuroleptics i.m. 50–150 mg every 2 weeks i.m. 50–150 mg every 4 weeks

R =O

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Dopamine- < ACh effect extrapyramidal disturbancesDopamine

A. Neuroleptics: Antipsychotic potency, sedative, and extrapyramidal motor effects

R

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Relative potency

Lüllmann, Color Atlas of Pharmacology © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.

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Una breve historia…

Desertion and shell shock

Medicine Under Hitler. Bull N Y Acad Med - 1949.

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“DSM-5: un instrumento de poder corporativo sin credibilidad científica que va contra la ética y el sentido común” —

NoGracias

DSM 0

¿El mito del antipsicótico?

« Story of antipsychotics is one of myth and misrepresentation »

« Henri Laborit, the French surgeon proclaimed as a hero for introducing it to psychiatrist colleagues, was using it in a highly dangerous procedure he devised called “artificial hibernation” or “sedation without narcosis”. But the procedure killed off most of the dogs it was demonstrated on during Laborit’s tour of the US. »

« As Richard Bentall, an expert on psychosis and a volunteer into a study of Droperidol, described it:

For the first hour I didn’t feel too bad. I thought maybe this is okay. I can get away with this. I felt a bit light-headed … [After being asked to fill in a form] I couldn’t have filled it in to save my life. It would have been easier to climb Mt Everest … It was accompanied by a feeling that I couldn’t do anything, which is really distressing. I felt profoundly depressed. They tried to persuade me to do these cognitive tests on the computer and I just started crying. »

Antipsychotics gained a reputation as “chemical straight-jackets”

Serotonin and depressionThe marketing of a myth

David Healy professor of psychiatryHergest Unit, Bangor LL57 2PW, UK

The serotonin reuptake inhibiting (SSRI) group of drugs came

on stream in the late 1980s, nearly two decades after first being

mooted. The delay centred on finding an indication. They did

not have hoped for lucrative antihypertensive or antiobesity

profiles. A 1960s idea that serotonin concentrations might be

lowered in depression1had been rejected,

2and in clinical trials

the SSRIs lost out to the older tricyclic antidepressants as a

treatment for severe depression (melancholia).3-5

When concerns emerged about tranquilliser dependence in the

early 1980s, an attempt was made to supplant benzodiazepines

with a serotonergic drug, buspirone, marketed as a

non-dependence producing anxiolytic. This flopped.6The lessons

seemed to be that patients expected tranquillisers to have an

immediate effect and doctors expected them to produce

dependence. It was not possible to detoxify the tranquilliser

brand.

Instead, drug companies marketed SSRIs for depression, even

though they were weaker than older tricyclic antidepressants,

and sold the idea that depression was the deeper illness behind

the superficial manifestations of anxiety. The approach was an

astonishing success, central to which was the notion that SSRIs

restored serotonin levels to normal, a notion that later transmuted

into the idea that they remedied a chemical imbalance. The

tricyclics did not have a comparable narrative.

Serotonin myth

In the 1990s, no academic could sell a message about lowered

serotonin. There was no correlation between serotonin reuptake

inhibiting potency and antidepressant efficacy. No one knew if

SSRIs raised or lowered serotonin levels; they still don’t know.

There was no evidence that treatment corrected anything.7

The role of persuading people to restore their serotonin levels

to “normal” fell to the newly obligatory patient representatives

and patient groups. The lowered serotonin story took root in the

public domain rather than in psychopharmacology. This public

serotonin was like Freud’s notion of libido—vague, amorphous,

and incapable of exploration—a piece of biobabble.8If

researchers used this language it was in the form of a symbol

referring to some physiological abnormality that most still

presume will be found to underpin melancholia—although not

necessarily primary care “depression.”

The myth co-opted the complementary health market. Materials

from this source routinely encourage people to eat foods or

engage in activities that will enhance their serotonin levels and

in so doing they confirm the validity of using an antidepressant.9

The myth co-opts psychologists and others, who for instance

attempt to explain the evolutionary importance of depression

in terms of the function of the serotonin system.10Journals and

publishers take books and articles expounding such theories

because of a misconception that lowered serotonin levels in

depression are an established fact, and in so doing they sell

antidepressants.

Above all the myth co-opted doctors and patients. For doctors

it provided an easy short hand for communication with patients.

For patients, the idea of correcting an abnormality has a moral

force that can be expected to overcome the scruples somemight

have had about taking a tranquilliser, especially when packaged

in the appealing form that distress is not a weakness.

Costly distraction

Meanwhile more effective and less costly treatments were

marginalised. The success of the SSRIs pushed older tricyclic

antidepressants out of the market. This is a problem because

SSRIs have never been shown to work for the depressions

associated with a greatly increased risk of suicide (melancholia).

The nervous states that SSRIs do treat are not associated with

increased risk of suicide.11The focus on SSRIs also coincided

with the abandonment of the pursuit of research into established

biological disturbances linked to melancholia (raised cortisol);

the SSRIs are ineffective inmood disorders with raised cortisol.12

Over two decades later, the number of antidepressant

prescriptions a year is slightly more than the number of people

in the Western world. Most (nine out of 10) prescriptions are

for patients who faced difficulties on stopping, equating to about

a tenth of the population.13 14

These patients are often advised

to continue treatment because their difficulties indicate they

need ongoing treatment, just as a person with diabetes needs

insulin.

Meanwhile studies suggesting that ketamine, a drug acting on

glutamate systems, is a more effective antidepressant than SSRIs

david.healy54@googlemail.com

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BMJ 2015;350:h1771 doi: 10.1136/bmj.h1771 (Published 21 April 2015) Page 1 of 2

Editorials

EDITORIALS

MAUDSLEY DEBATE

Does long term use of psychiatric drugs cause moreharm than good?We could stop almost all psychotropic drug use without deleterious effect, says Peter C Gøtzsche,questioning trial designs that underplay harms and overplay benefits. Allan H Young and JohnCrace disagree, arguing that evidence supports long term use

Peter C Gøtzsche professor, Nordic Cochrane Centre, Rigshospitalet, DK-2100 Copenhagen,

Denmark, Allan H Young professor of mood disorders, Institute of Psychiatry, Psychology and

Neurosciences, King’s College London, UK, John Crace psychiatric patient and parliamentary sketch

writer, Guardian, London, UK

Yes—Peter C GøtzschePsychiatric drugs are responsible for the deaths of more thanhalf a million people aged 65 and older each year in theWesternworld, as I show below.1 Their benefits would need to becolossal to justify this, but they are minimal.1-6

Overstated benefits and understated deathsThe randomised trials that have been conducted do not properlyevaluate the drugs’ effects. Almost all of them are biasedbecause they included patients already taking another psychiatricdrug.1 7-10 Patients, who after a short wash-out period arerandomised to placebo, go “cold turkey” and often experiencewithdrawal symptoms. This design exaggerates the benefits oftreatment and increases the harms in the placebo group, and ithas driven patients taking placebo to suicide in trials inschizophrenia.8

Under-reporting of deaths in industry funded trials is anothermajor flaw. Based on some of the randomised trials that wereincluded in a meta-analysis of 100 000 patients by the US Foodand Drug Administration, I have estimated that there are likelyto have been 15 times more suicides among people takingantidepressants than reported by the FDA—for example, therewere 14 suicides in 9956 patients in trials with fluoxetine andparoxetine, whereas the FDA had only five suicides in 52 960patients, partly because the FDA only included events up to 24hours after patients stopped taking the drug.1

Estimate of total deathsFor antipsychotics, I used a meta-analysis of placebo controlledtrials in patients with dementia because they would be less likelyto have been receiving psychiatric drugs before randomisation.The absolute death rate was 1% higher in the treatment group.11

The Finnish cohort study of mortality in patients withschizophrenia12—and all other such studies that support the ideathat antipsychotics lowermortality—is unreliable. (Themortalityin patients who were not taking drugs was very high and didn’tconcur with other Finnish data, and 64% of the deaths were notaccounted for.13)A well conducted cohort study of patients of average age 55found that benzodiazepines and similar drugs doubled the deathrate; the excess death rate was about 1% a year.14

A cohort study of patients older than 65 who were their owncontrol found that all cause mortality was 3.6% higher whenpatients were taking the newer antidepressants for one year thanwhen they did not take antidepressants.15

I used Danish prescription statistics to estimate the number ofdeaths caused by these three classes of drugs. Because falls,which are muchmore common in older people, are an importantcause of death in people taking psychotropic drugs,1 I includedonly people at least 65 years of age and used conservative deathrates: 1% for antipsychotics, 1% for benzodiazepines and similardrugs, and only 2% for antidepressants. The total number ofdeaths a year in Denmark (3693) when scaled up correspondedto 539 000 in the United States and European Union combined.1

What about the benefits?The randomised trials are not only biased by the “cold turkey”design but also because they have not been adequately blinded.A Cochrane review of tricyclic antidepressants included onlytrials that had atropine in the placebo to prevent unblindingbecause of the conspicuous side effects of the drugs. This reviewdid not find any meaningful effect4; the effect corresponded toonly 1.3 points on the Hamilton scale,1 and the smallest effectthat can be perceived is 5-6 points.16

Correspondence to: P C Gøtzsche pcg@cochrane.dk, A H Young allan.young@kcl.ac.uk

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BMJ 2015;350:h2435 doi: 10.1136/bmj.h2435 (Published 12 May 2015) Page 1 of 3

Head to Head

HEAD TO HEAD

« Now that we have a drug, let’s create a disease. »

« If a marketing campaign is really successful, it goes beyond hype to insinuate itself into the language and thought of the population as a whole, essentially remaking the way people think of themselves. Concepts such as reflux disease, erectile dysfunction, and irritable bowel syndrome have had considerable success, but the most remarkable changes have come in the language of psychiatry with the emergence of neurobiological concepts such as social anxiety disorder, attention deficit hyperactivity disorder, and bipolar disorder. What is striking about this neurobiological language is the extent to which ordinary people have come to incorporate it into their identities. You may have erectile dysfunction or irritable bowel syndrome, but you are bipolar or ADHD. Your diagnosis is part of who you are. »