Invest Clin 65(4): 470 - 475, 2024 https://doi.org/10.54817/IC.v65n4a08

Corresponding author: Trino

Baptista. Departamento de Fisiología, Facultad de Medicina, Universidad de Los An-

des, Mérida, Venezuela. E-mail: trinobaptista@gmail.com

Severe necrotic colitis in an adolescent

with polypharmacy and high clozapine

doses according to his ancestry.

Trino Baptista

1,2,3

, José de Leon

4,5

, Antonio Guizar

2,6

and Laura Evia

Departamento de Fisiología, Facultad de Medicina, Universidad de Los Andes, Mérida,

Venezuela.

Clínica NeuroORIGEN, Queretaro, México.

Facultad de Medicina, Universidad Anahuac Queretaro, Queretaro, México.

Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA.

Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apostol

Hospital, University of the Basque Country, Vitoria, Spain.

Universidad Americana de Europa (UNADE), Spain.

Keywords: clozapine; constipation; colitis; ethnicity; polypharmacy.

Abstract. The antipsychotic drug Clozapine (CLZ) is approved for treat-

ment-resistant schizophrenia and reduction in the risk of recurrent suicidal

behavior in schizophrenia or schizoaffective disorder. However, it is increasingly

used in psychiatry and neurology worldwide in numerous off-label conditions.

Clozapine is associated with diverse side effects which require careful monitor-

ing in its use for prevention and treatment. The quality of CLZ use and pharma-

covigilance varies considerably among Latin American countries. CLZ-induced

gastrointestinal hypomotility (CIGH) is a relevant clinical problem, ranging

from innocuous constipation to lethal necrotic colitis. Thus, optimal preven-

tion, early detection, and treatment of CIGH deserves considerable attention.

We describe here the case of a 15-year-old Mexican boy diagnosed with Opposi-

tional Defiant- and Attention-Deficit/Hyperactivity Disorder who developed se-

vere necrotic colitis after nine months of CLZ treatment, leading to permanent

ileostomy. We ascribed this unfortunate outcome to careless polypharmacy that

did not consider drug-related antimuscarinic activity, deficient clinical moni-

toring, and lack of attention to ethnicity concerning drug dosing. This case is

of educational value for the mental health team in order to promote the proper

use of CLZ, which may be life-saving in patients with severe mental disorders.

Clozapine and necrotic colitis 471

Vol. 65(4): 470 - 475, 2024

Severa colitis necrotizante en un adolescente con polifarmacia

y dosis elevada de clozapina con relación a su origen étnico.

Invest Clin 2024; 65 (4): 470 – 475

Palabras clave: clozapina; colitis; constipación; etnicidad; polifarmacia.

Resumen. El antipsicótico Clozapina (CLZ) está aprobado en el tratamien-

to de la esquizofrenia resistente y para reducir el riesgo suicida en esta condi-

ción y en el trastorno esquizoafectivo. Sin embargo, su uso no aprobado en psi-

quiatría y neurología ha aumentado recientemente en todo el mundo. La CLZ

se asocia a diversos efectos indeseables, los cuales ameritan monitorización

cuidadosa para su prevención y tratamiento. La hipomotilidad gastrointestinal

(HMGI) asociada al uso de Clozapina (CLZ), es un problema clínico relevante

que se manifiesta desde un nivel de constipación inocua hasta colitis necroti-

zante letal. En consecuencia, la prevención óptima, detección temprana y el

tratamiento de la HMGI amerita atención considerable. Presentamos el caso de

un adolescente mexicano de 15 años con los diagnósticos de Trastornos Opo-

sicionista-Desafiante y Déficit de Atención con Hiperactividad, que desarrolló

colitis necrotizante severa que condujo a ileostomía permanente luego de 9 me-

ses de tratamiento con CLZ. Atribuimos este cuadro clínico al uso inadecuado

de polifarmacia en donde no se valoró adecuadamente al efecto antimuscaríni-

co de los medicamentos, y al desconocimiento del impacto de grupo étnico en

la dosificación de la CLZ. Este caso clínico es de valor educativo para el equipo

de salud mental, con el fin de promover el uso adecuado de la CLZ, que puede

ser una medida vital en pacientes con enfermedades mentales severas.

Received: 02-09-2024 Accepted: 07-11-2024

INTRODUCTION

The atypical antipsychotic drug Clozap-

ine (CLZ) was synthesized in 1958. Howev-

er, it was not until the years 1990-92 that

the Food and Drug Administration (FDA)

approved its use in the United States (US)

for treatment-resistant schizophrenia (TRS)

and the extension of the label for the reduc-

tion in the risk of recurrent suicidal behavior

in schizophrenia or schizoaffective disorder.

These are the only label indications for CLZ

use in the whole field of psychiatry

However, CLZ use in psychiatry and neu-

rology has significantly increased in the last

twenty years for off-label indications such

as dementia-related behavioral disorders, bi-

polar disorders, anxiety, autism spectrum,

suicidality, drug use in psychosis, borderline

personality, and neurological patients with

movement disorders and/or psychosis

. While

there are now available treatments more spe-

cific for these neurological disorders, they

are not readily accessible in Latin American

countries, and numerous neurologists still

use off-label CLZ at low doses as adjunctive

therapy, in general benefiting from CLZ-alle-

viating effects on anxiety and insomnia.

This trend is also due to the increas-

ing understanding of CLZ pharmacokinet-

ics, drug interactions, the role of ethnicity,

genes, and adverse drug reactions (ADRs)

2,3

CLZ has numerous ADRs, such as pneu-

monia, agranulocytosis, metabolic syndrome,

472 Baptista et al.

Investigación Clínica 65(4): 2024

orthostatic hypotension, bradycardia, synco-

pe, seizures, myocarditis, cardiomyopathy,

mitral valve incompetence, hepatotoxicity,

pancreatitis, sialorrhea, cancer, and gastro-

intestinal hypomotility (CIGH)

. The proper

use of CLZ, thus, request for an ad hoc men-

tal health team training, ideally including

drug-serum monitoring, since many of those

ADRs correlate with the drug blood levels.

Latin American countries considerably differ

in CLZ-ADR monitoring, pharmacovigilance,

and related research quality. In Venezuela,

there was even a recent CLZ shortage, and

it is now provided without any mandatory

regular blood monitoring, as suggested by

experts

4,5

The CIGH disorders range from mild

constipation to severe and often lethal gut

obstruction and necrosis, such as we de-

scribe in the following case.

CASE PRESENTATION

The mother’s patient signed an in-

formed consent for publishing this case. On

Day 1, T.B., examined a 15-year-old Mexican

non-smoking boy with severe restlessness,

insomnia, and verbal and physical violence

towards his mother and pets. He was of In-

digenous American ethnicity with limited

economic resources. At 12 years of age, he

was diagnosed with severe Oppositional De-

fiant Disorder and Attention-Deficit/Hyper-

activity Disorder and required a one-month

hospitalization in a public institution. He

was prescribed lithium carbonate (900 mg/

day), methylphenidate (18 mg/day) and ris-

peridone (up to 8 mg/day), this last agent

being the only antipsychotic drug recom-

mended for those disorders

. His irregular

outcome led to poor school adaptation.

In the first interview, he exhibited an

intelligence in the lower limit of normality,

irritability, extreme restlessness (running in

and out of the office) and a quarrelsome at-

titude toward his mother, who had Type II

Bipolar Disorder with good insight.

Clozapine, 6.25 mg at bedtime, was

started off-label (day 1). Therapeutic drug

monitoring was unavailable. The slow titra-

tion was based on standard clinical tolerance

and weekly serum C-reactive protein (CRP).

The dose was slowly increased to 100 mg in

three weeks, resulting in only a minimal im-

provement in sleep.

After no significant improvement, the

family placed the patient in a short-term psy-

chiatric inpatient unit for three weeks, with

no participation of the previous treating psy-

chiatrists (days 31 to days 52). He was pre-

scribed six psychiatric drugs: CLZ 300 mg/

day (100 mg three times a day), olanzapine

20 mg/day (10 mg twice a day), quetiapine

200 mg/day (100 mg twice a day), sodium

valproate 1500 mg/day (500 mg three times

a day), lamotrigine 50 mg/day (25 mg twice

a day), and diazepam 20 mg/day (10 mg

twice a day). Propranolol was added for sus-

pected akathisia 40 mg/day (20 mg twice

a day). The white blood cell (WBC) count

remained normal, but no other laboratory

tests were completed. Worried by the combi-

nation of three antipsychotics with antimus-

carinic activity, TB constantly insisted, by

phone, on monitoring for constipation but

was told that disrupting behavior interfered

with that. He prescribed preventive daily

lactulose at bedtime.

After three weeks of minimal improve-

ment (day 53), the patient was transferred

to an outpatient facility without continu-

ous medical or nursing monitoring. Ap-

proximately six months on CLZ (day 180),

the patient started to complain of abdomi-

nal discomfort, and after two weeks, he was

transferred to a hospital (day 194), where

he was diagnosed with sepsis, renal failure,

and severe gastrointestinal obstruction. The

emergency surgery revealed massive dry fe-

cal content and necrotic colon and led to

a colon removal except for a small sigmoid

portion with permanent ileostomy. After sur-

gery, zuclopentixol, 20 mg every 3 weeks,

levetiracetam 1000 mg/day (500 mg twice

Clozapine and necrotic colitis 473

Vol. 65(4): 470 - 475, 2024

a day), and oral clonazepam 2 mg/day at

bedtime were prescribed. On the phone, the

family informed TB they wanted to restart

CLZ administration, but contact was lost af-

terwards.

DISCUSSION

The term CLZ-associated CIGH has

been used to describe an extensive set of

possible complications in the digestive

system

7,8

. The World Health Organization

(WHO) pharmacovigilance database receives

reports on adverse drug reactions (ADRs).

On July 19, 2019, CIGH was the fifth cause

of fatal outcomes in CLZ patients, with 326

fatal outcomes associated with 2814 cases

of constipation, toxic megacolon, and/or

paralytic ileus

2,3

. CIGH develops

7,8

gradually

during CLZ treatment, but up to 50% of pa-

tients may be unaware while gastrointestinal

motility is objectively decreased

9,10

Preventive laxatives and careful use of

agents with antimuscarinic properties are rec-

ommended at the start of CLZ treatment

7,8

This is a case of severe, almost lethal

colonic necrosis in a young man. CLZ and its

metabolite norclozapine have high antimus-

carinic activity, which reduces gastrointesti-

nal motility

During the first month of treatment

under T.B. control, a carefully slow CLZ ti-

tration, including CRP monitoring, was

conducted since he had Indigenous Ameri-

can ethnicity following a recent guideline

Later, the complications probably happened

by a combination of at least three significant

factors:

1. Lack of proper bowel monitoring. First,

at home, it happened due to the cons-

tant hostility between the patient and

his relatives. In the unsupervised outpa-

tient facility, medical assessment hap-

pened only after two weeks of severe

constipation and abdominal pain.

2. High doses of CLZ and polypharma-

cy. After one month on CLZ with poor

response, another consultant psychia-

trist tried to manage the challenging

behavior in the hospital by increasing

CLZ to 300 mg/day, and adding val-

proate (1.500 mg/day), quetiapine

(200 mg/day) and olanzapine (20 mg/

day). In retrospect, this was an unwise

decision due to a lack of drug serum

levels and clinical monitoring. The

CLZ dose (300 mg/day) was higher

than the 225 mg/day recommended

for male non-smokers among patients

of Indigenous American ancestry

In this regard, our research group has

defined six personalized schedules for

inpatients: 1) ancestry from Asia or

the original people from the Americas

with lower metabolism (obesity or val-

proate) needing minimum therapeutic

dosages of 75–150 mg/day, 2) ancestry

from Asia or the original people from

the Americas with average metabo-

lism needing 175–300 mg/day, 3) Eu-

ropean/Western Asian ancestry with

lower metabolism (obesity or valpro-

ate) needing 100–200 mg/day, 4) Euro-

pean/Western Asian ancestry with aver-

age metabolism needing 250–400 mg/

day, 5) in the U.S. with ancestries other

than from Asia or the original people

from the Americas with lower clozap-

ine metabolism (obesity or valproate)

needing 150–300 mg/day, and 6) in the

U.S. with ancestries other than from

Asia or the original people from the

Americas with average clozapine me-

tabolism needing 300–600 mg/day.2.

Moreover, olanzapine is also mainly me-

tabolized by the cytochrome P450 1A2

(CYP1A2) like CLZ

2,3

, and due to the

patient’s ancestry, he was expected also

to have higher plasma olanzapine con-

centration. As CIGH is a dose-depen-

dent adverse reaction, which is more

appropriately defined as concentration-

dependent, the patient probably dis-

474 Baptista et al.

Investigación Clínica 65(4): 2024

played very high serum antimuscarinic

activity by high plasma concentrations

of CLZ and norclozapine and from the

additions from the plasma concentra-

tions of olanzapine and quetiapine

Valproate can inhibit CLZ and olanza-

pine, particularly in early treatment

CIGH complications such as ileum and

necrosis result from a complex set of an-

timuscarinic-induced hypomotility and

inflammation. The associated inflam-

mation probably inhibited CYP1A2 and

caused significant increases in CLZ and

olanzapine concentrations and possi-

bly milder quetiapine concentrations

These pharmacokinetic issues request

for blood level CLZ and norclozapine

monitoring. Unfortunately, Chile is the

only Latin American country where pu-

blic mental health facilities provide such

monitoring in sections of Psychiatric

Institutions designed as ‘CLZ clinics’

3. Whereas the indication of CLZ in chil-

dren and adolescents with schizophre-

nia is well established

, that is not

the case for CLZ off-label indications,

such as the present case. Among other

potential factors, CLZ might display a

heterogeneous and unexpected side

effect profile, which are not necessarily

explained by ancestry or its pharmaco-

logical properties

CONCLUSIONS

The use of CLZ in psychiatry and neu-

rology is rapidly increasing, mostly as off-la-

bel indications. Thus, the proper monitoring

and treatment of diverse, potentially lethal

CLZ-related ADRs, besides neutropenia, is

mandatory. This case shows how CIGH may

lead to almost lethal consequences, and it

could have been prevented by taking into

account the complex pharmacokinetic and

pharmacodynamic properties of CLZ and

the other drugs used in this case, ethnicity,

monitoring constipation’s severity and prop-

er use of laxatives

2,7,8,10

Psychiatric educators play a crucial role in

training all mental health members on these

issues in a CLZ-treated patient. This is particu-

larly important in Venezuela, where there are

no current mandatory guidelines for CLZ use

in psychiatry and neurology. Hence, we rec-

ommend improving the knowledge about CLZ

pharmacokinetics and drug interactions and

using it as monotherapy when possible.

ACKNOWLEDGEMENTS

The authors thank the patient’s family

for authorizing this publication.

Funding

None

Conflict of interest

None

Authors’ ORCID number

• Trino Baptista (TB):

0000-0001-6839-4614

• Jose de Leon (JDL):

0000-0002-7756-2314

• Antonio Guizar (AG):

0009-0005-0661-0576

• Laura Evia (LE):

0000-0009-2527-698X

Author contribution

TB and JDL wrote the manuscript. TB

was the former treating physician. AG and

LE assisted TB in treating the patient and

revised the manuscript.

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