Apuntes del Curso de PSICOFARMACOLOGIA APLICADA - 2009

Unidades Docentes de Psiquiatra del Instituto Psiquitrico Jos Germain de Legans

y del Hospital Universitario 12 de Octubre (Madrid)










TRATAMIENTO FARMACOLOGICO
DE LA ESQUIZOFRENIA.
FARMACOS DE MANTENIMIENTO



Dr. Javier Sanz Fuentenebro



Mdico psiquiatra
Unidad de Hospitalizacin Breve
Hospital Universitario 12 de Octubre (Madrid)




1
ANTIPSICTICOS
F.JAVIER SANZ FUENTENEBRO
2
antipsicticos
Bloqueo D
2
y 5-HT
2
Modulacin del receptor D
2
EIicacia sintomas (), (-), cognitivos
y aIectivos
Bajo perIil SEP
Bajo riesgo de discinesia tardia
Ausencia de hiperprolactinemia
Bloqueo receptor D
2
EIicacia sintomas ()
EIectos secundarios de tipo
extrapiramidal (SEP)
Riesgo de discinesia tardia
Hiperprolactinemia
Nuevos (attpicos) Clisicos
3
Farmacocintica
Absorcin va oral 2 a 6 horas; va I.M. 0.5 - 1 hora
cafena, anticidos, tabaco y alimentos alteran la
biodisponibilidad de la va oral. (SALVO
ZIPRA.)
Atraviesan bien b. hematoenceflica
Metabolizados en hgado (SALVO
AMISULPIRIDE...)y eliminados por orina. Muchos
metabolitos son activos.
Los niveles plasmticos .identificar no
respondedores., no cumplidores. .y"ventana
teraputica"
4
niveles plasmticos
Clozapina: menores en jovenes, varones y
Iumadores, mayores en asiaticos; rango 350-500
microgr/l (proIilaxis valproato por encima?)
Risperidona (OH Ris): 20-60 microgr/l (~ 65
ocup receptores). Con 25 mg de Consta solo se
logran niveles de 4.4-22.7, .dosis mayores o
suIiciente si es consta?
Olanzapina: 20-40 microgr/l (12h tras dosis).
poco claro.
5
Farmacocintica
t.mx. 30 min. a 1 hora (I.M.) y 2-6 horas (V.O.);
equilibrio a los 3-5 das .
Vida media promedio 10-35 horas
La U.A.P. elevada en la mayora (exc. Quetiapina
83).
Olanzapina, Haloperidol, Aripiprazol pueden
administrarse una sola vez al da,
Tiapride, Loxapina, Tioridazina, Perfenazina,
Clorpromazina, Risperidone, Clozapina y
Quetiapina deben administrarse en dosis
divididas
..OTRA COSA ES LA REALIDAD.
6
Farmacodinamia
.La dopamina.(y ms)
Bloquean competitivamente los receptores
dopaminrgicos D2 en un 65 - 85, en el
sistema limbico y corteza:
efectos antipsicoticos y efectos aaversos como
la hiperprolactinemia y extrapiramiaalismo
7
La ocupacion de receptores D
2
predice la respuesta clinica
Kapur y cols. Am J Psychiatry 2000
0
10
20
30
+0
S0
60
70
80
90
100
< 6S > 6S
Porcentaje de ocupacin de receptores D2
p = 0,07 en
sintomas (+)
del PANNS
P
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)
Respuesta Ausencia de respuesta
8
Afinidad (binding) de los
antipsicticos por el receptor D
2
100
10
1
0,1
Quetiapina
Clozapina
Olanzapina
Ziprasidona
Amisulpride
Risperidona
Clorpromazina
Haloperidol
Dopamina K
(1,S nN)
9
Disociacin del receptor D
2
Quetiapina
Clozapina
Remoxipride
Amisulpride
Olanzapina Haloperidol
$QWLSVLFyWLFRV DWtSLFRV $QWLSVLFyWLFRV FOiVLFRV
RAP!DA NED!A LENTA
Sertindol Raclopride Clorpromazina
0 1 2 + 6 8 10 20 30
Ninutos para la liberacin del S0 del antipsictico del D
2
10
10
Afinidad a subtipos Afinidad a subtipos receptoriales receptoriales
Constantes de aIinidad para receptores de los sistemas de Constantes de aIinidad para receptores de los sistemas de
neurotransmisi neurotransmisio on cl n cla asicos sicos. . ( (COMBINACIONES COMBINACIONES. .) )
~10.000 ~10.000
1,9 1,9 + + 0,2 0,2
1,9 1,9 + + 0,2 0,2
~ 3.000 ~ 3.000
~ 3.000 ~ 3.000
1.475 1.475
148 148
5 5 + + 0,7 0,7
5 5 + + 0,7 0,7
0,6 0,6 + + 0,4 0,4
~ 10.000 ~ 10.000
23 23 + + 3 3
23 23 + + 3 3
60 60
~ 10.000 ~ 10.000
30 30
7 7 + + 0,3 0,3
7 7 + + 0,3 0,3
155 155 + + 35 35
~ 10.000 ~ 10.000
3.630 3.630
270 270
228 228 + +
40 40
8 8 + + 3 3
3 3 + + 0,7 0,7
2.904 2.904
360 360+ +98 98
90 90
19 19 + + 1 1
7 7 + + 4 4
2 2 + + 0,1 0,1
27.870 27.870
46 46 + + 6 6
89 89
3,2 3,2
2,3 2,3
329 329
11 11 + + 2 2
126 126 + + 20 20
3 3 + + 0,1 0,1
274 274 + + 179 179
2,8 2,8
1 1 + + 0,04 0,04
1.243 1.243
31 31 + + 0,7 0,7
85 85 + + 0,7 0,7
75 75 + + 8 8
~ 10.000 ~ 10.000
~ 1.000 ~ 1.000
25 25 + + 7 7
Quetiapina Quetiapina
Olanzapina Olanzapina
Clozapina Clozapina
Risperidona Risperidona
Remoxeprid Remoxeprid
Amisulpride Amisulpride
Haloperidol Haloperidol
M M
1 1
5 5- -HT HT
2 2
5 5- -HT HT
2 2
1C 1C H H
1 1

2 2

1 1
D D
3 3
D D
2 2
D D
1 1
F F rmaco rmaco
Noorey y cols., 1993; Schoemaker y cols., 1996
11
Efectos secundarios
Aunque se sigue relacionando potencia con
bloqueo dopaminrgico, sabemos que es
mas complejo.
No selectivos ningunos, NA, serotonina,
acetilcolina, histamina.
ESTAMOS DANDO UN TOXICO
NEUROLOGICO (ALVAREZ)!!;
12
Efectos secundarios
EFECTOS EXTRAPIRAMIDALES
Distonias
10 tipicos, inicio tto mas pero tambin en
abstinencia, adherencia.
Parkinsonismo
20 tipicos,
NO anticolinrgicos proIilacticos (no inocuos en si y
posible aumento riesgo DT)
13
Efectos secundarios
Akatisia
.inIravalorada y conIundida MUCHAS veces, papel en
incumpliiento y violencia/suicidio; 25 tipicos,
Bajar dosis, / akineton/ ppl 30-80/ antiserotoninrgicos
ciproheptadina / mianserina/ benzos (?) / clonidina 0,2 0,8
Discinesia Tarda
.hipersensibilidad por denervacion., mas complejo, papel del
GABA
(Ojo, 15 riesgo esquizoIrenia sin antipsicoticos, tal vez
prevalencia en psicoticos ancianos igual con que sin.)
Mayor riesgo T AIectivos (que tambin mas riesgo de Distonia
tardia), mujeres, R Mental, diabetes y ancianos; peor los que
sIrieron EPS,
...pasar a cloza /quetia, tetrabenacina, benzos, vitam E,
melatonina...
14
15
La discinesia oroIacial no siempre es consecuencia del uso
de APs. Los pacientes con esquizofrenia pueden
presentar tasas de DT de aparicin espontnea cercanas
al 15 (Fenton et al., Br J Psychiatry. 1997; 171:265-268).
16
Las tasas de DT son mayores en pacientes con
trastornos del aIecto tratados con AP que en
aquellos con esquizoIrenia (Yassa et al.
Psychosomatics 1984;25:135-138).
17
Efectos secundarios
Cardiovascular:
Hipotension ortostatica, Bloqueo alIa1, peor
Ienotiacinas en ancianos, pero todos a altas dosis; cloza,
ris, quetia. subir despacia de entrada.
Alteraciones ECG,: Aumento del intervalo QT,,
Fibrilacion ventricular
18
Efectos secundarios
Endocrino:
HIPERPROLACTINEMIA
.galactorrea, amenorrea, ginecomastia, hipogonadismo, alts
sexuales y osteoporosis..CA de mama, 'niveles del pobre
De los nuevos poco :
sertindol, quetiapina, ziprasidona, aripiprazol y clozapina;
olanzapina bajo,
risperidona y amisulpiride igual que tipicos.
AUMENTO DE PESO
EsquizoIrenicos mas riesgo de obesidad y asociados (HTA,
diabetes, dislipemia y altscardiovasculares). Peor varones 40 aos
no blancos en los primeros meses de tto;
peor Cloza y olanza. ris, quetia...Ienotiacinas...
19
Tendencia en cuidados y
tratamiento de la esquizoIrenia
Inters creciente por la mortalidad y
morbilidad somatica
Necesidad de evaluaciones globales de los
pacientes esquizoIrnicos (Mayer y
Nasrallah, 2003)
20
Criterios diagnosticos para el
sindrome metabolico (NCEP)
_110 a _ 100 mg/dl o en
tratamiento
Glucosa
_130/85 mmHg o en tratamiento Presion arterial
50 mg/dl Mujer
40 mg/dl Hombre
HDL
_ 150 mg/dl Triglicridos
88 cm Mujer
102 cm Hombre
Obesidad abdominal
Medida definida Factor de riesgo
Derivados del NCEP (National Cholesterol Education Program), ATP !!!, 2001.
3 criterios para establecer el diagnstico
21
Riesgos de salud con antipsicoticos
American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of
Obesity. Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care 200+; 27: S96-601
De Nayer A, De Hert N, Scheer A, van Gaal L, Peuskens J. Belgian Consensus on metabolic problems associated with atypical antipsychotics. !nt J Psychiatr
Clin Pract 200S; 9: 130-137
- - /- Ziprasidona
- - /- Amisulprida
- - /- Aripiprazol
? ? Quetiapina
? ? Risperidona
Olanzapina
Clozapina
Empeoramiento
del perfil lipdico
Diabetes peso Antipsictico
22
23
Efectos secundarios
DESCENSO UMBRAL CONVULSIONES
Mas a mas dosis y menor potencia, Cloza mayor riesgo
Eleccion haloperidol y sulpiride, cuidado risperidona, olanza,
quetia y amisulpi, evitar clorpromacina, cloza y depots
EFECTOS ANTICOLINERGICOS (...)
Ojo a obstruccion con clozapina, ojo a glaucoma angulo cerrado,
haloperidol menor riesgo, en prostaticos igual.
HIPONATREMIA:
Por potomania psicotica, sed por anticolinerg,
SIADH (Ienotiacinas, hl, pimocide, ris, cloza, olanza quetia)
24
Efectos secundarios
NMS
0,5 de nuevos ttos, inIradiagnosticado!,
mortalidad del 20
Bloqueo rapido de DA en hipotalamo y
estriado que bloquea termorregulacion y
espasmo masivo musculoesqueletico.
hipertermia no disipada
Peor altas dosis alta potencia rapido
ascenso, TODOS los antipsicoticos,
tambin Litio y ISSR (y ADT, IMAOS.
y suspension de LDOPA)
25
1.Antipsicticos convencionales
26
Antipsicticos clsicos
Incisivos
Haloperidol
Zuclopentixol
Pimozida
Atipicos
Sulpiride
Sedativos
Clorpromazina
Levomepromazina
Clotiapina
Depot
FluIenazina
Zuclopentixol
27
Los antipsicticos al ser comparables en su efecto
teraputico sobre sntomas positivos, pueden ser
intercambiados entre s, teniendo en cuenta la potencia
comparativa con 100 mg de Clorpromazina
28
Clorpromacina
Patron de sedativos, Iotosensibilidad, ictericia
obstructiva, peso, umbral,
Haloperidol
(porqu sigue l?), menos de 20 mg, niveles 5-
12miclogr/l (ventana, probablemente por mas inquietud
por acatisia y mas SSNN por acinesia al subir dosis.)
Pimocide
D2, especiIicidades de indicacion con poca base
(delirios hipocndriacos.tradicion.), max 20, ojo
arritmias ventriculares
29
A.P. CONVENCIONALES
manejo clnico :
eIicaces en fases agudas , sint. positiva :
70 de los casos, esencialmente primeras 5
a 12 semanas
dosis que oscilan entre los 300 y 750 mg de
clorpromacina o equivalente,
mantenerse tras la estabilizacin , dosis
entre 300 y 600 mg, si bien en torno al 50
de los pacientes se mantienen asintomaticos
con dosis en torno a los 300 mg
30
no mayor eIicacia en el mantenimiento con
dosis mayores de 600 mg; riesgo de recaida
se eleva por debajo de los 150 mg de
clorpromacina,
estrategias de mantenimiento no
continuado elevan el riesgo de recaida,
no evidencia de mayor eIicacia en el
mantenimiento con una sustancia
determinada .Iormulaciones depot
A.P. CONVENCIONALES
manejo clnico :
31
se ha consensuado (conferencia de Brujas,
kissling 1989, APA 97) un mantenimiento en
EsquizoIrenia:
ae 1-2 aos como minimo para pacientes con un primer
episoaio esqui:ofrenico,
ae 5 aos a inaefiniao para episoaios repetiaos.
...decision de suspender individualizar
rigurosamente...soporte, deteccion de prodromos,
antecedentes, ...descenso muy lento!
A.P. CONVENCIONALES
manejo clnico :
32
2.Nuevos antipsicticos (atpicos)
Bloqueo D
2
-5-H1
2
Clozapina
Olanzapina
Quetiapina
Risperidona
Ziprasidona
0RGXODFLyQ GRSDPLQpUJLFD
Amisulpride
Aripiprazol
'HSRW
Risperidona
33
CLOZAPINA
34
1. Recordar la especiIicidad de
clozapina
clozapina es el patrn de atpico desde los 80, inicialmente por su
perfil de efectos secundarios no EPS, luego por perfil receptorial
tan diferente . modelo a imitar.
baja afinidad por D2 y elevada afinidad por receptores 5-H12, 5-H13,
5-H1 y 5-H17 . alta afinidad por alfa1 y 2 y muscarnicos, pero
tambin acta en circuitos gabargicos y sobre el glutamato.
Cual de esas actuaciones es la responsable de su eficacia sigue
siendo objeto de controversia.
Resulta llamativa esta modestia frente a la alegra con que se relacionan
mecanismos con respuestas clnicas al estudiar antipsicticos ms
recientes.
35
2 .sus riesgos son asumibles.
a. eIectos frecuentes de bajo riesgo:
hipotension, hipertension
sedacion, inicial
Fiebre inicial.
taquicardia benigna, inicial
estreimiento
sialorrea., . Muy importante efecto, frecuente y perturbaaor,
Sockalingam2007
enuresis nocturna.
aumento de peso .Mas primer ao, profilaxis.
convulsiones
36
2 .sus riesgos son asumibles.
b. eIectos infrecuentes y de riesgo, menos
conocidos
Miocarditis y cardiomiopata, (primeras semanas).
Riesgo no aefiniao (1/12000-67000), similar a otros
antipsicoticos (Tomasen 2000, Hagg 2002, Coulter 2001)
Tromboembolismo pulmonar riesgo1/4500, similar otros
AP atipicos (Liperoti 2005)
37
2 .sus riesgos son asumibles.
c. Neutropenia y agranulocitosis
agranulocitosis ( 500 / mm3), baja incidencia ( 0,73 ), y (neutropenia
( 2000) , (2,7), eIectos generalmente diIerentes, Iactores de riesgo
independientes (Kerwin 2007)
especialmente durante las semanas 6-18 de tratamiento ( 75 - 80 )
(Kerwin 2007), La incidencia de leucopenia disminuye
exponencialmente con el tiempo, en el segundo semestre baja a 0.70/1000
paciente-ao, tras el primer ao a 0.39/1000. (Schulte 2006)
...mas en aIricanos o aIro-caribeos (en los que ademas es Irecuente la
neutropenia tnica.), asiaticos y tal vez mujeres, contradictorio edad., mas
con ciIras basales bajas, NO dosis dependiente
asumible riesgo de reintroduccin?, no claro, cautela, el riesgo sube del
2.7 al 38 , sobre todo 10 semanas (Dunk 2006); probablemente si en
neutropenia, cautela en agranulocitosis (Barrons 96 Whiskey 2007)
38
39
.PERO:
Riesgo global de muerte menor de 1/10.000 pacientes
expuestos (Thuillier 2006) ; 0,016 (Kerwin 2007)
Despus del periodo de riesgo, este se iguala al de
butirofenonas y fenotiacinas (Atkin 96), tras el primer
semestre el riesgo de mortalidad al suspender los
controles es el mismo que tomando mianserina o el de
sufrir un accidente de trfico o laboral. (Schulte 2006)
EL RIESCO DE MUER1E POR ESQUIZOFREAIA ES
MUY SUPERIOR AL DE MUER1E POR CLOZAPIAA
(Walter 97, Munro 99, 1AYLOR 27)
40
Interacciones:
evitar depresores medula (cbz,, captopril...),
Fluvoxamine can cause large increases in clozapine serum
levels and should be avoided.
Some other serotonin reuptake inhibitors (SSRIs) and
neIazodone may also cause clinically signiIicant increases
in clozapine serum levels and should be used careIully in
clozapine treated patients.
Clozapine serum levels should be monitored aIter adding one oI
the above ntidepressants to clozapine.
Because bupropion itselI hasan inherent risk oI seizures, a
pharmacodynamic interaction exists with
clozapine.ThereIore, the combination oI clozapine and
bupropion should be avoided.
41
dosis
empezar con 12,5, subir hasta
300, max 900, (mas varones
Iumadores, menos mujeres y
ancianos...)
Niveles 350-500 microg/l (250-
550 mg/dia)
SEGUID EL PROTOCOLO, A
MANO TABLA DE CIFRAS!!!!
42
3 . sus ventajas son notables:
a.En EsquizoIrenia resistente por supuesto:
National Institute Ior Clinical Excellence
2009
11.4.6.1 For people with schizophrenia whose illness has not responded adequately to
pharmacological or psychological treatment:
review the aiagnosis
establish that there has been aaherence to antipsychotic meaication, prescribea at an aaequate aose ana for the
correct auration
review engagement with ana use of psychological treatments ana ensure that these have been offerea accoraing to
this guiaeline. If family intervention has been unaertaken suggest CBT, if CBT has been unaertaken suggest family
intervention for people in close contact with their families
consiaer other causes of non-response, such as comorbia substance misuse (incluaing alcohol), the concurrent use of
other prescribea meaication or physical illness.
11.4.6.2 Offer clozapine to people with schizophrenia whose illness has
not responded adequately to treatment despite the sequential use of
adequate doses of at least two different antipsychotic drugs. At least one oI
the drugs should be a non-clozapine second-generation antipsychotic.
11.4..3 For people with schi:ophrenia whose illness has not responaea aaequately to clo:apine at an optimisea aose,
healthcare professionals shoula consiaer recommenaation 11.4.6.1 (incluaing measuring therapeutic arug levels)
before aaaing a secona antipsychotic to augment treatment with clo:apine. An aaequate trial of such an augmentation
may neea to be up to 810 weeks. Choose a arug that aoes not compouna the common siae effects of clo:apine.
43
National Institute Ior Clinical
Excellence 2009
6.5.11 Clinical evidence summary
In 18 RCTs including 2,554 participants whose illness had not responded
adequately to treatment, clozapine had the most consistent evidence
for efficacy over the FGAs included in the trials.
Further evidence is required to establish equivalence between clozapine and
any other SGA, and to establish whether there are diIIerences between any oI
the other antipsychotic drugs. Side eIIects were consistent with those reported
in the SPC Ior each drug.
In 10 RCTs including 1,200 participants with persistent negative symptoms,
there was no evidence oI clinically signiIicant diIIerences in eIIicacy between
any oI the antipsychotic drugs examined. CareIul clinical assessment to
determine whether such persistent Ieatures are primary or secondary is
warranted, and may identiIy relevant treatment targets such as drug-induced
parkinsonism, depressive Ieatures or certain positive symptoms.
In six RCTs including 252 participants with schizophrenia whose illness has
not responded adequately to clozapine treatment, there is some evidence that
clozapine augmentation with a second antipsychotic may improve both total
and negative symptoms iI administered Ior an adequate duration
44
3 . sus ventajas son notables:
a.En EsquizoIrenia resistente por supuesto:
2004 American Psychiatric Association
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45
3 . sus ventajas son notables:
c. Estos datos que podran justificar un uso ms temprano
en la evolucin de la Esquizofrenia?, incluso en primeros
episodios psicticos? (II)
,usar clozapina de entrada?, muchas iniciatias, muy pocos trabajos.
.,Green plantea a mediados de los 90` clozapina al inicio buscando eitar
la toxicidad` de la psicosis
Woerner en 2003 en primeros brotes no encuentra dierencias entre
clozapina y luenacina en 13 semanas. (O WUDEDMR HV PHWRGROyJLFDPHQWH PX\
FXHVWLRQDEOH
2003 Lieberman publica su conocido trabajo en primeros brotes
comparando con clorpromacina , clozapina UHPLVLyQ PiV WHPSUDQD \ PD\RU D
FRUWR SOD]R PiV DGKHUHQFLD \ PHQRV HIHFWRV VHFXQGDULRV.
46
3 . sus ventajas son notables:
c. Estos datos que podran justificar un uso ms temprano
en la evolucin de la Esquizofrenia?, incluso en primeros
episodios psicticos? (III)
NUESTRO GRUPO LLEJA bastantes aos trabafanao
esencialmente en neuroimagen en esqui:ofrenia, los primeros
estuaios ae evolucion nos llevaron al aeterioro y la
resistencia, y esto logicamente a la clo:apina.
47
.y cuando se resisten a
CLOZAPINA?
.considerad criterios de resistencia.
TEC.
48
National Institute for Clinical Excellence 2009
For people with schizophrenia whose illness has not responded
adequately to pharmacological or psychological treatment:
11.4.6.1
review the diagnosis
establish that there has been adherence to antipsychotic medication,
prescribed at an adequate dose and Ior the correct duration
review engagement with and use oI psychological treatments and ensure
that these have been oIIered according to this guideline. II Iamily
intervention has been undertaken suggest CBT; iI CBT has been
undertaken suggest Iamily intervention Ior people in close contact with
their Iamilies
consider other causes oI non-response, such as comorbid substance
misuse (including alcohol), the concurrent use oI other prescribed
medication or physical illness.
49
National Institute for Clinical Excellence 2009
For people with schizophrenia whose illness has not responded
adequately to pharmacological or psychological treatment:
11.4.6.2 OIIer clozapine to people with schizophrenia whose illness
has not responded adequately to treatment despite the sequential use oI
adequate doses oI at least two diIIerent antipsychotic drugs. At least
one oI the drugs should be a non-clozapine second-generation
antipsychotic.
11.4.6.3 For people with schizophrenia whose illness has not
responded adequately to clozapine at an optimised dose, healthcare
proIessionals should consider recommendation 11.4.6.1 (including
measuring therapeutic drug levels) beIore adding a second
antipsychotic to augment treatment with clozapine.
50
National Institute for Clinical Excellence 2009
Clozapine augmentation
For people with treatment-resistant schizophrenia whose illness has shown only a
partial response to clozapine, is augmentation oI clozapine monotherapy with an
appropriate second antipsychotic clinically and cost eIIective?
Why is this important?: Clinicians commonly use a second antipsychotic to augment
clozapine when the response has been unsatisIactory, but the Iindings Irom clinical trials
so Iar are inconclusive.
There is some indication that an adequate trial oI such a strategy may be longer than the
68 weeks usually considered adequate Ior a treatment study oI an acute psychotic
episode.
The pharmacological rationale Ior the choice oI a second antipsychotic should be tested,
that is:
potent dopamine D2 receptor blockade, as a hypothesised mechanism oI pharmacodynamic
synergy, and
a low liability Ior compounding the characteristic side eIIects oI clozapine.
51
LA ESQUIZOFRENIA 'RESISTENTE AL
TRATAMIENTO...
Pero...de qu estamos hablando ?
Como bien apunta mi admirado Colodron, el concepto de EsquizoIrenia Resistente
que se he ido imponiendo en los ultimos aos puede resultar aceptable como
convencin grosera para la practica general y, especialmente, de cara a la
investigacion, pero no supera una crtica seria.
En primer lugar, y cito textualmente, '...solo cabe este consenso entre quienes
reconocen la curabiliaaa sin aefecto (o este sea aespreciable) ae algunas
esqui:ofrenias , no entre quienes entienaen la enfermeaaa como una forma ae
existir patologico que aestruye progresivamente las relaciones ael sufeto con el
munao.` ...Es decir Qu se nos resiste, a qu concepto de esquizoIrenia nos
reIerimos ?.
Pero por otra parte...Quien se nos resiste ?.Qu Iorma clinica, con qu sexo ,qu
edad de inicio, carga gentica, historia de uso de toxicos, ajuste premorbido,
personalidad de base, cumplimiento del tratamiento...etc,etc,etc... ?
...Y lo que no es menos interesante : a qu / a quin se resiste ? Desae
luego,...qu consideramos mejoria / curacion ?,... pero tambien, como Iue
diagnosticado, qu Iarmacos recibio, en qu medio los recibe, qu ambiente
Iamiliar y social le rodea, se interviene en todo ello... ?
52
Los conceptos de EsquizoIrenia Resistente al uso
desprecian olmpicamente las dos primeras preguntas y
se centran en los puntos ms simples de la tercera : los
tratamientos farmacologicos que se han empleado y la
sintomatologia que persiste durante largo tiempo. .Seria
pues mas correcto hablar, y volvemos a Colodron, de
"Formas clnicas con sntomas positivos resistentes a los
neurolpticos".
53
Prevalence oI Treatment Resistance
Nasrallah 2007
Because the deIinition oI treatment resistance is not standardized, the
precise prevalence oI treatment resistance is not known.
Comprehensive estimates, however, predict that at least 25 oI
chronic patients are resistant and that resistance is less common in
patients early in the course oI illness when positive symptoms are
usually more responsive to antipsychotic medication.
However, the disorganized subtype oI schizophrenia, also known as
hebephrenia, may have a poor treatment response early in its course
and a worse long-term prognosis than other types.|11|
54
Neurobiology oI Treatment
Resistance
Some neuroimaging studies have Iound that treatment-resistant
patients more oIten have cortical atrophy than do other patients with
schizophrenia
Patients with a history oI perinatal complications have poorer
responses to treatment. An hypothesis meriting Iurther investigation is
that prenatal and perinatal insults associated with the loss oI cerebral
volume contribute to poor treatment responsiveness.
A pharmacologic hypothesis is that treatment resistance in
schizophrenia represents a Iorm oI neurochemical adaptation to
antipsychotic medication, related to the phenomenon called
"supersensitivity psychosis."|17| This could result Irom heightened
dopamine activity in the mesocortical and mesolimbic dopamine
pathways in response to chronic DRD2 blockade,
55
Neurobiology oI Treatment
Resistance
In a small study oI Finnish patients with schizophrenia, those who had
an inadequate response to Iirst-generation antipsychotics were
signiIicantly more likely to have low activities oI monoamine oxidase
A (MAO-A) and catechol-O-methyltransIerase (COMT).The
investigators speculate that a lower ability to metabolize dopamine and
norepinephrine, associated with COMT and MAO-A, may either
impair medication response or may be associated with a more severe
kind oI schizophrenia.
The role oI other neurotransmitters is less certain. Faber|24| has
hypothesized a model oI psychosis that involves the hypoIunctioning
oI the NMDA-glutamate receptor with a resulting decrease in GABA-
mediated inhibition oI excitatory cortical projections. Antagonists oI
NMDA receptors, such as phencyclidine, cause psychotic thought,
perceptions, and behavior that do not Iully respond to D2 antagonists.
Finally, on the basis oI an evolving understanding oI the neurobiology
oI schizophrenia, treatment resistance may represent a subset oI early-
onset schizophrenia with more severe neurodevelopmental and
neurodegenerative impairments that Iail to respond to antipsychotic
pharmacotherapy.
56
"Pseudo-resistance" in
Schizophrenia Treatment
Antipsychotic Dosing
Adequate Treatment Trial Duration
Adherence to Treatment
Psychiatric Comorbidity
57
Antipsychotic Dosing
In some circumstances, the antipsychotic dose may need upward
adjustment because oI pharmacokinetic interactions with other
prescription or recreational drugs the patient is receiving. According to
a recent worldwide review, the point prevalence oI tobacco smoking
among patients with schizophrenia is 71 in males and 44 in
Iemales. Other agents that induce CYP1A2 activity are omeprazole,
riIampin, ritonavir, carbamazepine, and phenytoin.
RiIampin, carbamazepine, and phenytoin also induce CYP3A, which
metabolizes quetiapine.
This enzyme also metabolizes risperidone and aripiprazole, which may
need a 2-Iold dosage increase, and, to a lesser extent, ziprasidone,
which may require a 50 dosage increase.|30| Fewer data are
available on the anticonvulsants oxcarbazepine and topiramate, which
may also induce CYP1A2 and CYP3A.|30| Chronic use oI St. John's
wort, however, does signiIicantly induce CYP3A.|31|
58
Antipsychotic Dosing
Many drugs, including serotonin reuptake inhibitors and bupropion,
inhibit cytochrome P450 enzymes, requiring a lower dose oI the
coadministered antipsychotic
Another consideration is superimposed iatrogenic delirium, or
psychosis, which can conIound treatment oI the underlying
schizophrenia and may be misinterpreted as treatment resistance.
A less common pharmacokinetic consideration in an apparently
treatment-resistant patient is a predisposition Ior rapid metabolism that
occurs in individuals with certain alleles oI CYP2D6.|33| This enzyme
is important in the elimination oI haloperidol, zuclopenthixol,
risperidone, thioridazine, and perphenazine. The causative allelic
variants occur more oIten in certain ethnic groups: 3 oI white
northern Europeans may have a duplication oI the CYP2D6 gene, as
may as many as 10 oI white southern Europeans, 16 oI Saudi
Arabians, and 29 oI Ethiopians.|33,34|
59
Adequate Treatment Trial Duration
As measured by standard instruments such as the Positive
and Negative Symptoms Scale (PANSS) and the BrieI
Psychiatric Rating Scale (BPRS), more improvements
occurred during the Iirst 2 weeks oI treatment than during
the second 2 weeks.|37| Furthermore, 70 oI the total
improvement obtained at 1 year may be obtained by the
end oI the Iirst 4 weeks oI treatment.
Nonetheless, a "Iull response" may require several months
in many patients. Although the precise time course oI an
individual's response cannot be predicted, lack oI any
response whatsoever within 2 weeks, given evidence oI
adequate serum levels, would suggest the need Ior
diIIerent medication. Some response by that time indicates
continuing treatment Ior at least 4-6 weeks, which is the
standard recommendation Ior an adequate trial.|39|
60
Adherence to Treatment
The rate oI nonadherence in patients with psychotic
disorders has been estimated to be as high as 80, 42
discontinued medication within 2 years.
Iactors associated with poor adherence to antipsychotic
medication include poor insight, negative attitude toward
medication, substance abuse, shorter illness duration,
cognitive dysIunction, amotivation, and poor therapeutic
alliances.|44|
Studies strongly implicate intolerable side eIIects in
nonadherence, the rate oI poor adherence among patients
on second-generation agents was 41.5, slightly more
than the 37.8 oI patients on Iirst-generation agents
61
Psychiatric Comorbidity
Most oIten it involves substance use disorders (SUD), which occur in
approximately halI oI patients with schizophrenia, and depressive
symptoms, which pose a liIetime risk that may aIIect up to 81 oI
patients with schizophrenia
Some studies have Iound that caIIeine intake in patients with
schizophrenia may be as high as 500 mg per day compared with a
mean oI 210 mg per day in the general population.|55| CaIIeine acts
on adenosine receptors in the central nervous system to enhance
dopamine neurotransmission.
Some studies have Iound a higher prevalence oI obsessive-compulsive
symptoms in schizophrenia, up to 25.|58| Treatment oI this
comorbidity may be complicated by the Iact that, according to a series
oI case reports, atypical antipsychotics in monotherapy may be
associated with the ae novo appearance oI, or the aggravation oI,
preexisting obsessive-compulsive symptoms in a small proportion oI
patients with schizophrenia.|59|
Finally, certain medical illnesses may present with schizophrenia-like
psychoses. These include Wilson's disease, metachromatic
leukodystrophy, basal ganglia calciIication, and systemic lupus
erythematosus. 62
Managing Treatment-Resistant
Schizophrenia
Address Possible "Pseudo-resistance"
1. Optimize the dose oI antipsychotic medication, which includes upward
titration, and check serum levels iI there are concerns about
pharmacokinetic interactions.
2. Optimize the duration oI antipsychotic therapy, typically a 4- to 6-week
trial, given optimal dosing.
3. Monitor adverse eIIects oI psychiatric and other medications that may
mimic worsening positive (akathisia, delirium) or negative (hypokinesia)
symptoms.
4. Screen Ior comorbid conditions such as substance use disorders, excessive
caIIeine intake, depression, and OCD.
5. Rule out a general medical or neurologic condition that may be presenting
with psychotic symptoms by conducting a complete physical and
neurologic examination, laboratory workup, and specialist consultations, as
appropriate.
6. Assess medication compliance by using several techniques, such as asking
patient and relatives about compliance, pill counting, measuring serum
levels, and checking pharmacy reIill dates.
63
Resistentes a CLOZAPINA
AADIR:
Sulpiride 400
Lamotrigina 300
Risperidona 6
Omega3 2-3 g
Amisulpiride 400-800
Haloperidol 2
Aripiprazol 15-30
ALTERNATIVAS:
Aripiprazol
TEC
Olanzapina 30-60
Olanzaamisulpi/aripip
razol/glicina/lam/sulpir
ide
Quetiapina
Risperidona
Estimul M T
64
Resistentes a CLOZAPINA
(Villagran2007)
1. Monoterapia atipico 8-10 semanas
2. Monoterapia atipico 8-10 semanas
3. Monoterapia convencional 8-10 semanas
4. Clozapina 600-800 , 8-10 semanas
5. Clozapina atipico (ris, Amisulp, Arip)
6. Clozapina Anticonvulsivos (Val, Lam)
65
RISPERIDONA (RISPERDAL).
derivado del bencisoxazol
actividad sobre receptores d2 comparable
al haloperidol, y con elevada afinidad
sobre receptores serotoninrgicos 5ht2,
alIa adrenrgicos e histaminrgicos.
bien oral, primer paso hepatico importante
citp450, metabolito activo, tmed 24h (...una o
dos dosis vale)
66
RISPERIDONA (RISPERDAL).
eIecto superior a placebo y comparable al
haloperidol en sintomas positivos de la
esquizoIrenia.
las dosis menores de 8-10 mg resultan
eIicaces en buen numero de pacientes,
evitandose la presentacion de sintomas
extrapiramidales; si se requieren dosis por
encima stos eIectos no se diIerencian de
haloperidol.
67
RISPERIDONA (RISPERDAL).
no se recogen aatos firmes sobre eficacia ae
risperiaona en pacienter resistentes a
antipsicoticos convencionales, tampoco sobre
utiliaaa en mantenimiento a largo pla:o, ni en
sintomas negativos primarios.
.. esquizoaIectivo, bipolar, borderline, depre
psicotica, eps/dt, psicosis por dopa, sida,
toxicoas, tourette, huntington..
68
RISPERIDONA (RISPERDAL).
eIectos2s : eps, sedacion, nauseas, peso...dt
snm..hipotension sobre todo inicial. empezar
bajo, ekg, estreimiento, hiperprolactinemia, dis
sexual
con depresores snc riesgo convulsiones, sedacion
y ekg
dosis 1- 16, media 6 mg
presentacion de deposito .microesIeras hechas
de un polimero biodegradable
69
OLANZAPINA (ZYPREXA)
tienobenzodiacepina, Iamilia clozapina y
quetiapina
80 absorcion oral, 405 primer paso, pico
6h, tmedia 31 horas (monodosis), alta
union a proteinas.
alta aIinidad 5ht2, d123y4, alIa,
muscarinicos y h1.
70
OLANZAPINA (ZYPREXA)
eIicaz psicosis...positivos...
negativos ?...
resistentes no deIinido a pesar...
mania aguda o episodios mixtos
bajo eps
71
OLANZAPINA (ZYPREXA)
eIectos secundarios, sedacion, peso, glucemia,
hipotension, , transaminasas, antiach
(estreimiento, glaucoma...), poca
hiperprolactinemia y sex
con depresores snc riesgo convulsiones, sedacion
y ekg
Niveles no bien deIinidos, orientativo 20-40 mg/l
tras 12 h
5-20 mg...megadosis??
Olanzapina IM en pacientes agitados
72
QUETIAPINA (SEROQUEL)
BENZOTIACEPINA, ESTRUCTURA FAMILIA
CLOZA Y OLANZA
antagonista de los receptores:
dopaminrgicos d1 y d2, adrenrgicos 1 y
2, histaminrgicos h1, serotoninrgicos
5ht2.