anorexia nervosa - PRESENTAZIONE DELLA...

04/12/13 massimo cuzzolaro 1

a n o r e x i a n e r v o s a

AN and drugs open and placebo-controlled studies • a

primo autore farmaco n durata (settimane) dose risultati

Dally, 1958 cloropromazina open open Crisp, 1965 cloropromazina

Vigersky, 1977 ciproeptadina 24 8 s. 12 mg/d ns

Goldberg, 1979 ciproeptadina 81 variabile variabile ns

Lacey, 1980 clomipramina 16 8 s. 50 mg/d ns

Gross, 1981 litio 16 4 s. variabile ns

Vandereycken, 1982 pimozide 18 3 s. 4-6 mg/d ns

Gross, 1983 tetraidrocannabinolo 11 4 s. 30mg ns

Vandereycken, 1984 sulpiride 18 3 s. 300-400 mg/d ns

Biederman, 1985 amitriptilina 25 5 s. m = 160 mg/d ns

Halmi, 1986 amitriptilina 72 4 s. m = 175 mg/d f > p


AN and drugs open and placebo-controlled studies • b


Halmi, 1986 ciproeptadina 72 4 s. 32mg/d f > p Casper, 1987 clonidina 4 8 s. 0,5-0,7 mg/d ns

Stacher, 1993 cisapride 12 12 s. 30 mg/d ns

Kaye, 1998 fluoxetina 7 52 s. variabile f > p

Attia, 1998 fluoxetina 31 7 s. m = 56 mg/d ns

Kaye, 2001 Walsh, 2006

fluoxetina fluoxetina

35 93

48 s. 48 s.

variabile variabile

f > p ns

Brambilla, 2007 olanzapina 30 12 s. 2-5 mg/d f > p


•  Citalopram

•  Venlafaxina •  Olanzapina

•  Risperidone

•  Sali di zinco

•  …



SSRIs!!

Do not appear to confer advantage regarding

weight gain in malnourished patients who are concurrently receiving an inpatient organized treatment!

(I)!

SSRIs!!

May be considered in weight-restored patients

(weight close to 80% of the standard) with persistent:!

-  depressive!-  anxiety!

-  obsessive-compulsive!-  bulimic symptoms!

(II)!


Clinicians however should attend to the black box warnings.!

(I)!bupropion!

Increased seizure risk in ED !(FDA, black box warning)!

!mirtazapine!

associated with neutropenia!

Antidepressants and other psychotropic

drugs!!

May be used in weight-restored patients to treat specific ongoing symptoms!

(I)!


TCAs & MAOIs!!

Should be avoided in malnourished individuals because adverse reactions are

more pronounced!

(I)!

!Fluoxetine!

!After weight restoration, in dosages of up to 60 mg/day

may help prevent relapse!!

(II)!

Fluoxetina e AN-R: durata del trattamento (Kaye W et a l . , 1991; Strober M et a l , 1997; Kaye W et a l . , 2001)

Per quanto riguarda la fluoxetina nell’anoressia nervosa restrittiva,!la somministrazione ininterrotta durante il ricovero e dopo la dimissione,

per un paio d’anni,!è sembrata in grado di favorire la conservazione nel tempo!

dell’aumento ponderale ottenuto durante la fase acuta del trattamento!

e, quindi,!

di prevenire le ricadute.!


Fluoxetina e AN-R: durata del trattamento (Walsh et a l . 2006) • a

Walsh BT, Kaplan AS, Attia E, Olmsted M, Parides M, Carter JC, et al.""Fluoxetine after weight restoration in anorexia nervosa: a randomized controlled trial."!

Jama 2006; 295(22): 2605-12"


Fluoxetina e AN-R: durata del trattamento (Walsh et a l . 2006) • b


JAMA, The Journal of the American Medical Association!Researchers from Columbia and the University of Toronto !

•  93 women (ages 16 to 45) who, after receiving intensive psychotherapy, gained enough weight to fall into the normal range.!

•  Half the group then received daily doses of Prozac, and the other half took dummy pills. All of them continued in weekly psychotherapy, where they practiced techniques to examine and diffuse irrational assumptions about weight and body image.!

Fluoxetina e AN-R: durata del trattamento (Walsh et a l . 2006) • c


JAMA, The Journal of the American Medical Association!Researchers from Columbia and the University of Toronto !

"After a year:"

•  26% of those on Prozac"

•  31% of those taking placebo pills"

remained in a healthy weight range.""The differences between the two groups, in weight and on measures of beliefs about"

–  food "–  weight gain"

were not large enough to be significant."

Up to now the rationale for the administration of antipsychotics has been more associated with:

•  psychomotor hyperactivity control

•  induction of weight gain •  reward system regulation.

The potential impact on

delusional fear of weight gain or on body image disturbance

has often been disregarded.


Hypothesis:

can haloperidol - potent D2 receptor

antagonist – act on delusional body

image distortion regardless of

sedation or weight gain?

Minimal doses (0.5-3.£ mg/die)

to lower cardiovascular risk and extra-

pyramidal effects

9 AN patients

age: 25.8 ± 11.3 years (18-51)

BMI: 12.2 ± 0.5 kg/m2

illness duration: 7.6 ± 11.2

hospitalization: from 30 to 125 days

No psychotherapies were performed.

Eight of the nine patients had enteral feeding.


Haloperidol was well tolerated.

The delusional body image disturbance and the drive for thinness were

subjectively perceived as less intense.

BMI increased from the initial 12.2 ± 0.5 to 16.0 ± 1.5 kg/m2 .


A systematic review and meta-analyses

to estimate the influence of

atypical antipsychotics on

BMI, eating disorder, and psychiatric symptoms

in individuals with AN.

Outcomes for the ITT (intention-to-treat) group from randomized clinical trials.

In an ITT analysis, everyone who begins the treatment is considered to be part of the

trial, whether he or she finishes it or not. (Since it started in the 1960s, the principle of ITT has become widely accepted for the analysis of controlled

clinical trials)


Atypical antipsychotics were

associated with:

•  a nonsignificant increase in BMI

•  a nonsignificant effect on

Ø  drive for thinness

Ø  body dissatisfaction.

•  an increase in anxiety

•  an increase in overall ED

symptoms

•  a significant reduction on level of

depression


Biological Therapies for Eating Disorders • AN (Mitchel l J et a l , 2013)

The treatment literature in AN consists of relatively

few controlled pharmacotherapy studies in comparison

to BN and BED.

Overall,

pharmacological treatment of AN

has been disappointing.

The antidepressants and antipsychotics

appeared promising in early clinical trials,

and

larger trials have since shown a lack of

efficacy for both classes of medications.


Anoressia Nervosa: tre suggerimenti generali

•  Non iniziare un trattamento farmacologico prima di aver affrontato le complicanze mediche più gravi e aver ottenuto un certo recupero del peso

•  Se dopo il recupero persistono sintomi depressivi o ossessivi, utilizzare antidepressivi, in particolare serotoninergici

•  Gli antipsicotici, tipici e atipici, possono trovare impiego soprattutto in casi di tenace rifiuto delle cure.



b u l i m i a n e r v o s a

BN and drugs placebo-controlled studies • a


Wermuth, 1977 fenitoina 19 12 s. variabile incerti Pope, 1983 imipramina 36 8 s. 200 mg/d f > p

Sabine, 1983 mianserina 19 8 s. 60 mg/d ns

Mitchell, 1984 amitriptilina 32 8 s. 150 mg/d ns

Hughes, 1986 desipramina 22 6 s. 200 mg/d f > p

Agras, 1987 imipramina 22 16 s. m = 167 mg/d f > p

Igoin, 1987 naltrexone 10 120 mg/d ns

Russell, 1988 d-fenfluramina 42 12 s. 30 mg/d ns

Horne, 1988 bupropione 81 8 s. ≤ 450 mg/d f > p

Barlow, 1988 desipramina 24 6 s. 150 mg/d ns

Blouin, 1988 desipramina 10 6 s. 150 mg/d f > p

Kennedy, 1988 isocarbossazide 18 13 s. 60 mg/d f > p


BN and drugs placebo-controlled studies • b


Walsh, 1988 fenelzina 50 12 s. 60-90 mg/d f > p Mitchell, 1989 naltrexone 16 6 s. 50 mg/d ns

Pope, 1989 trazodone 42 4 s. ≤ 400 mg/d f > p

Mitchell, 1990 imipramina 85 10 s. 300 mg/d f > p

Alger, 1991 imipramina 55 8 s. 200 mg/d ns

Hsu, 1991 litio 91 8 s. variabile ns

Fichter, 1991 fluoxetina 40 5 s. 60 mg/d f > p

Walsh, 1991 desipramina 78 6 s. 300 mg/d ns

FBNC, 1992 fluoxetina 387 12 s. 20, 60 mg/d f > p

Fahy, 1993 d-fenfluramina 43 8 s. 45 mg/d ns

Kennedy, 1993 brofaromina 36 8 s. ≤ 200 mg/d f > p Goldstein, 1995 fluoxetina 398 16 s. 60 mg/d f > p


BN and drugs placebo-controlled studies • c


Faris, 2000 ondansetrone 26 6 s. 24 mg/d f > p Carruba 2001 moclobemide 52 6 s. 600mg/d ns

Romano, 2002 fluoxetina 150 52 s. 60 mg/d f > p

Hedges, 2003 topiramate 69 10 s. 25-400 mg/d f > p

Milano, 2004 sertraline 20 12 s. 100 mg/d f > p

Nickel, 2005 topiramate 30 6 s. 25-250 mg/d f > p

Sundblad, 2005 flutamide 56 12 s. 500 mg/d f > p


* risultati positivi se gli attacchi bulimici diminuiscono a < 50%

Bulimia Nervosa: gli effetti dei farmaci (a (Mi tchel l J , 2001; Nakash-Eis ikov i ts O, 2002)

•  I farmaci hanno un effetto tra piccolo e moderato

•  La percentuale dei casi in cui, grazie alla terapia farmacologica, la frequenza dei sintomi nucleari (abbuffate compulsive e pratiche di compenso) si riduce a zero (astinenza) è molto bassa: in media, circa uno su quattro dei partecipanti ai vari trial (25%)

•  La maggior parte dei pazienti, alla fine dei trial, soddisfa ancora i criteri diagnostici DSM-IV (e, quindi, DSM-5) per la bulimia nervosa


Bulimia Nervosa: gli effetti dei farmaci (b (Mi tchel l J , 2001; Nakash-Eis ikov i ts O, 2002)

•  Più della metà delle pazienti con BN mostra un rischio lifetime di Disturbo Depressivo Maggiore.

•  L’efficacia nell BN non differisce sostanzialmente tra le differenti classi di AD (TCA, SSRI, IMAO e altri agenti AD)

(Bacaltchuk e Hay, 2005)


Bulimia Nervosa: gli effetti dei farmaci (c (Mi tchel l J , 2001; Nakash-Eis ikov i ts O, 2002)

L’efficacia degli AD nella BN è attribuibile a due effetti:"a)  riduzione dei sintomi nucleari (binge eating e vomito autoindotto)"b)  miglioramento dei disturbi dell’umore e dei disturbi d’ansia associati ai disturbi

alimentari"Mitchell et al 2001"

"L’efficacia dei farmaci AD appare però indipendente dal fatto che le

pazienti siano state affette o meno da una depressione pre-esistente"Goldstein et al 1999!Walsh e Devlin 2000 !



Clinicians should attend to the black box

warnings!!

And discuss with patients and families potential benefits and

risks!(I)!

!

Antidepressants!!

Are effective as one component of an initial treatment program for most patients with bulimia

nervosa!(I)!


TCAs and MAOIs!!

Have been rarely used with bulimic patients and are not

recommended as initial treatments!

(I)!

SSRIs!Have the most evidence for

efficacy and the fewest difficulties with side effects!

(I)!!

Several different antidepressants may have to be tried

sequentially to identify the specific medication with the

optimum effect!(I)!


FLUOXETINE!!

To date fluoxetine (60 mg/day) is the best studied of these and the only FDA-approved medication for bulimia nervosa!

(I)!!

A small open trial suggests that fluoxetine may be useful for adolescents with bulimia!

(II)!


FLUOXETINE!!

Substantial rates of relapse occur even with treatment!

(II)!

FLUOXETINE!!

Limited evidence supports the use of fluoxetine (60 mg/day) for

relapse prevention!(II)!

Most clinicians recommend continuing antidepressant therapy for a minimum of 9 months and probably for a

year!(II)!

Biological Therapies for Eating Disorders • BN (Mitchel l J et a l , 2013)

The bulimia nervosa (BN) literature underscores

the utility of antidepressants, particularly SSRIs,

in improving

the symptoms of the disorder.



b i n g e e a t i n g d i s o r d e r

BED and drugs placebo-controlled studies • a


primo autore farmaco n durata (settimane) dose frequenza

BE perdita peso

McCann, 1990 Desipramina 23 12 ≤ 300 d > p ns

Marcus, 1990 Fluoxetina 21 52 60 ns d > p

Stunkard,1996 d-fenfluramina 28 8 30 d > p ns

Hudson,1998 Fluvoxamina 85 9 50-300 d > p d > p

Laederach-Hoffmann,1999 Imipramina 31 8 75 d > p d > p

McElroy,2000 Sertralina 34 6 50-200 d > p d > p

Arnold, 2002 Fluoxetina 60 6 20-80 d > p d > p

Pearlstein,2003 Fluvoxamina 25 12 239 ns ns

McElroy,2003 Citalopram 38 6 20-60 d > p d > p

Grilo, 2005 Fluoxetina 108 16 up to 60 ns ns

Devlin, 2005 Fluoxetina 116 20 up to 60 ns ns

BED and drugs placebo-controlled studies • b


primo autore farmaco n durata (settimane) dose frequenza

BE perdita peso

McElroy,2003 Topiramato 61 14 25-600 d > p d > p

McElroy, 2007 Topiramato 407 16 25-600 d > p d > p

McElroy, 2006 Zonisamide 60 16 100-600 d > p d > p

Golay, 2005 Orlistat 89 24 360 ns d > p

Grilo, 2005 Orlistat 50 12 360 ns d > p

Appolinario,2003 Sibutramina 60 12 15 d > p d > p

Bauer, 2006 Sibutramina 73 16 ns d > p

Milano, 2005 Sibutramina 20 12 10 d > p d > p

McElroy, 2007 Atomoxetina 40 10 40-120 d > p d > p


BINGE EATING DISORDER, BED!

!… but, in most cases, not with

substantial weight loss!(I)!

!


!Treatment with antidepressant

medications - particularly SSRIs at the highest dosage - is associated with a reduction

in binge eating behavior …!(I)!



!Treatment with sibutramine is

effective for binge suppression and is associated with significant weight loss …!

(II)!


!Adding orlistat to CBT may yeld

additional weight reduction …!(II)!

Pharmacotherapy for BED: a meta-analysis (Reas & Gr i lo , Obesi ty - S i lver Spr ing, 2008)

•  Pharmacological treatments have a clinically significant advantage over placebo for

–  achieving short-term remission from binge eating (48.7% vs. 28.5%)

–  and for weight loss, although weight losses are not substantial.

•  No data exist to allow evaluation of

longer-term effects of pharmacotherapy-only treatment for BED

Combining medications

with cognitive or behavioral treatments

is unlikely

to enhance binge outcomes,

but

specific medications (orlistat, topiramate)

may enhance weight losses,

albeit modestly.


Biological Therapies for Eating Disorders • BED (Mitchel l J et a l , 2013)

The literature on binge eating disorder

supports efficacy on reduction

in

binge eating frequency for

a variety of compounds.


Farmaci vs. psicoterapie


The current reports, however, are not yet sufficiently convincing to suggest that medications have a routine role in the treatment of anorexia, bulimia and binge eating disorder and it is clear, till now, that any weight lost with the aid of medication is promptly reversed when the medication is withdrawn.

Stunkard AJ, Foreword. In DJ Goldstein (Ed), The Management of Eating Disorders and Obesity,

Totowa, NJ, Humana Press, 1999

Psychological treatment is still the cornerstone of therapy.

Development of effective psychotherapeutic strategies for anorexia and bulimia has given essential contributions to the understanding and treatment of binge eating disorder and obesity.

Terapia farmacologica dei DA conclusioni • 1

Alcuni farmaci possono sicuramente influenzare, a breve termine,

comportamenti alimentari patologici



Non esiste finora nessun farmaco specifico

per l'anoressia nervosa, la bulimia e il binge eating disorder,

capace di modificare

profondamente e durevolmente il decorso della malattia

nella maggior parte dei casi



Il ricorso a interventi psicofarmacologici appare giustificato, attualmente,

soprattutto come strumento terapeutico a breve-medio termine,

inserito nel quadro

di una strategia a lungo termine multidimensionale


anorexia nervosa - PRESENTAZIONE DELLA...

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