Case Report

Isoniazid- and ethambutol-induced

psychosis
Prasad R., Rajiv Garg, Sanjay Kumar Verma

Department of Abstract:
Pulmonary Medicine, Most cases of antituberculous agent–associated psychoses were caused by isoniazid (INH), with ethambutol
CSM Medical (EMB)-induced psychosis being rare. The concomitant occurrence of INH- and EMB- induced psychosis and
University, UP, in a single individual is extremely uncommon. We report a case of 28-year-old male who developed psychotic
Lucknow - 226 003, symptoms on start of EMB initially and later on INH also. He was prescribed rifampicin, pyrazinamide, and
India ofloxacin and had no further psychotic symptoms.
Key words:
Ethambutol, isoniazid, psychosis

I soniazid (INH) is included in all drug regimens

used for the treatment of tuberculosis because
of its potency, safety and low cost. The most
and pyrazinamide followed by 4 months of
rifampicin and isoniazid. The first 3 days of
treatment with this four-drug regimen was
common adverse reactions observed with uneventful. On the fourth day, however, the
INH are peripheral neuropathy and hepatitis. patient suddenly became restless, irritable,
In our review of the literature, we found that and agitated, with aimless, incongruous acts,
most cases of antituberculous agent–associated and irrelevant talking; he also started having
psychoses were caused by INH, with ethambutol visual hallucinations. He had no past history of
(EMB)-induced psychosis being rare. The any mental illness. There was no neurological
concomitant occurrence of INH- and EMB- deficit and fundus examination was normal
induced psychosis and in a single individual, (as per the neurology evaluation). An initial
an extremely uncommon event, prompted us to diagnosis of drug-induced psychosis was made
report this case. after a psychiatric consultation, with isoniazid
being identified as the likely culprit. The
Case Report patient’s symptoms responded to an injection of
diazepam. All the antituberculous drugs were
A 28-year-old male, a nonsmoker, was admitted to withdrawn. The patient became free of psychotic
our department with the complaints of recurrent symptoms over the next 2 days. Antituberculous
hemoptysis and loss of appetite for 1 month. His therapy was now restarted, with ethambutol,
past history was not significant. His resting pulse
rifampicin, and pyrazinamide being added
rate was 102/min and blood pressure was 112/74
one by one, starting with a low ‘test’ dose of
mm Hg and his respiratory rate was 26/min.
each [Table 1]. We avoided isoniazid initially
His general examination revealed no significant
since we were fairly certain that it was the
abnormality. His respiratory system examination
revealed bilateral coarse crepitations. He was offending agent. As can be seen from the table,
given symptomatic treatment for the hemoptysis psychotic symptoms were seen 5 days after
and a chest x-ray was taken, which showed ethambutol was started, disappeared after the
infiltrative lesions confined to the upper zones drug was stopped, and recurred when it was
Correspondence to: of both lungs. restarted. Similarly, we were able to show that
Dr. Prasad R., isoniazid could also independently bring on the
Department of Pulmonary His blood examination revealed a total leucocyte symptoms and that withdrawal of the drug led
Medicine, count of 10,200/cmm; the differential count to remission of symptoms.
C.S.M. Medical University, showed 66% polymorphs and 34% lymphocytes.
Lucknow - 226 003, UP, Thus, both isoniazid and ethambutol proved to
His PPD showed 30 mm induration. Sputum tested
India. E-mail: rprasad2@
on three consecutive days was positive for AFB. be responsible for his psychotic behavior and
sancharnet.in
He was prescribed short-course antituberculous had to be stopped. He was, instead, prescribed
Submission: 03-04-08 treatment as per WHO guidelines, with an initial rifampicin, pyrazinamide, and ofloxacin and had
Accepted: 16-05-08 2 months of rifampicin, isoniazid, ethambutol, no further psychotic symptoms.

Annals of Thoracic Medicine - Vol 3, Issue 4, October-December 2008 149

 Prasad, et al.: Antituberculous drugs and psychosis

Table 1: The reintroduction schedule of antituberculous drugs in present case report

Days Drug given Appearance of psychotic symptoms
Day 1 Ethambutol 300 mg No
Day 2 Ethambutol 600 mg No
Day 3 Ethambutol 800 mg No
Day 4 Rifampicin 150 mg + ethambutol 800 mg No
Day 5 Rifampicin 300 mg + ethambutol 800 mg Appearance of psychotic symptoms
Day 6 All drugs stopped Psychotic symptoms persisted
Day 7 All drugs stopped Psychotic symptoms resolved
Day 8 Ethambutol 300 mg No
Day 9 Ethambutol 600 mg
Thus, the ethambutol could be proved to be the responsible for the Appearance of psychotic symptoms
causation of the psychotic symptoms and could not be reintroduced.
Day 10 All drugs stopped till the resolutions of psychotic symptoms. Psychotic symptoms persisted
Day 11 No ATT given Psychotic symptoms resolved
Day 12 Rifampicin 150 mg No
Day 13 Rifampicin 300 mg No
Day 14 Rifampicin 450 mg No
Day 15 Rifampicin 450 mg+ pyrazinamide 250mg No
Day 16 Rifampicin 450 mg+ pyrazinamide 500mg No
Day 17 Rifampicin 450 mg+ pyrazinamide 1500mg No
Day 18 Day 16 regimen + isoniazid 50 mg No
Day 19 Day 16 regimen + isoniazid 300 mg
Thus, isoniazid was also proved to be responsible for the causation Appearance of psychotic symptoms again
of the psychotic symptoms and could not be reintroduced.
Day 20 Day 16 regimen Psychotic symptoms persisted
Day 21 Day 16 regimen continued Psychotic symptoms resolved

Discussion pyridoxine), which leads to a decrease in brain gamma-

aminobutyric acid and other synaptic transmitters, resulting
Psychiatric disorders have traditionally been considered in neurologic ill effect.[6] Other predisposing factors for the
to be mental rather than physical illnesses. This is because occurrence of psychotic illness are diabetes mellitus, hepatic
they manifest with disordered functioning in the areas of insufficiency, old age, alcoholism, and family and personal
emotions, perceptions, thinking, and memory, and/or have no history of mental illness. Incidentally, no such risk factors were
established biological basis. Psychiatric disorders are diagnosed seen in our patient.
primarily by recognizing the pattern of symptoms. The term
psychosis is used to described illness in which the patient has There is great variability in the clinical features of isoniazid-
altered perception of reality as evidenced by delusions and or induced psychosis in the various reported cases. Jackson, in
hallucination 1957, reported five cases of isoniazid-induced psychosis that
presented with excessive argumentation, mental depression,
Our review of literature showed that most cases of euphoria, grandiose ideas, and complex delusions; none
antituberculous drug–associated psychoses were due to of these patients had any previous history of mental
isoniazid; ethambutol-induced psychosis is rare and the illness.[7] Agarwala, in 1974, reported symptoms of restlessness,
concomitant occurrence in an individual of both isoniazid- and irritability, emotional instability, agitation, apprehension,
ethambutol-induced psychosis, as seen in the present case, is and fluctuation in behavior after isoniazid therapy[8] (as was
extremely rare. seen in our patient). Bedi, in 1994, reported a case of isoniazid
psychosis in a 74-year-old, who developed restlessness,
Isoniazid-related psychiatric disorders reported in the literature irritability, aimless activity, and incongruous actions 10 days
include psychosis, obsessive-compulsive neurosis, and after starting isoniazid therapy.[9] In 1996, Tiwari reported
mania.[1] Loss of memory and death following ingestion of a case of isoniazid-induced psychosis with disturbed sleep,
isoniazid has also been reported.[2–3] restlessness, and abnormal behavior[10] (as in the present case).
The durations of psychotic symptoms in these case reports
The first description of psychotic symptoms due to isoniazid varied widely: i.e., 7–45 days,[7] 7 days,[8] 10 days,[9] and 120
was by Mandel et al., who reported three such cases in days.[10]
1956.[4]
Ethambutol is one of the most commonly used drugs in
The mechanism of production of isoniazid-related psychiatric the treatment of tuberculosis. The principle side effect is
disorders is not clearly known, but isoniazid is known to retrobulbar neuritis. Central nervous system toxicity is not
interfere with several metabolic processes essential for widely reported and psychosis secondary to it is very rare.[11]
the normal functioning of the neuron.[5] Isoniazid causes The exact mechanism of ethambutol-induced psychosis is not
deficiency of vitamin B6 by causing excessive excretion of clear. The symptomatology of ethambutol-induced psychosis
the vitamin, which in turn leads to a disturbance of normal is almost same as that of isoniazid. Hsu in 1999 reported a case
tryptophan metabolism. Isoniazid also inhibits the activity of ethambutol-related psychosis where there were symptoms
of brain pyridoxal-5-phosphate (produced in the body from like dizziness, disorientation, and auditory and visual

150 Annals of Thoracic Medicine - Vol 3, Issue 4, October-December 2008

 Prasad, et al.: Antituberculous drugs and psychosis

hallucinations after 7 days of ethambutol intake.[12] Conclusion

The diagnostic criteria for substance-induced psychosis, as per It is important to be aware that both isoniazid and ethambutol
as DSM IV classification, are given below: can induce psychosis concomitantly in an individual when
A. Prominent hallucinations or delusions antitubercular medications are prescribed.
B. There is evidence from the history, physical examination,
or laboratory findings of either (1) or (2): References
(1) The symptoms in criterion A develop during, or within a
month of, substance intoxication or withdrawal 1. Alao AO, Yolles JC. Isoniazid-induced psychosis. Ann
(2) Medication use is etiologically related to the disturbance Pharmacother 1998;9:889-91.
C. The symptoms precede the onset of the substance 2. Olsen PZ, Torning K. Isoniazid and loss of memory. Scand J Respir
use (or medication use); the symptoms persist for a Dis 1968;49:1-8.
substantial period of time (e.g., about a month) after the 3. Friedman SA. Death following massive ingestion of isoniazid.
cessation of acute withdrawal or severe intoxication, or are Am Rev Respir Dis 1969;100:859-62.
4. Cohn ML, Mandel W, Middlebrook G, Russell WF Jr. Serum
substantially in excess of what would be expected given
isoniazid levels and catalase activities of tubercle bacilli from
the type or amount of the substance used or the duration isoniazid-treated patients. Am J Med Sci 1957;233:66-8.
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episodes). Union Tub 1984;53:152.
7. Jackson SL. Psychosis due to isoniazid. Br Med J 1957;28:743-5.
With regard to management, it is known that acute psychosis 8. Agarwala MC, Kansal HM, Gupta RK, Gupta DK, Kumar S. Toxic
induced by isoniazid and ethambutol tends to subside psychosis due to isoniazid. Indian J Tuberculosis 1975;3:119-20.
once the precipitating stresses are over or their intensity is 9. Bedi RS. Isoniazid induced pyrexia and psychosis in a single
reduced. Thus, patients with isoniazid induced-psychosis individual. Indian J Tuberculosis 1994;41:269-70.
recover without specific treatment after the withdrawal of the 10. Tiwari VK, Verma SM. Homicide by a tuberculous prisoner
possibly having drug Induced acute delusional psychosis. Indian
offending drug. The administration of pyridoxine, which has J Tuberculosis 1997;44:95-6.
been advocated for the prevention and treatment of isoniazid- 11. Martin SJ, Bowden FJ. Ethambutol toxicity manifesting as acute
induced neurologic manifestations,[1] failed to achieve desired onset psychosis. Int J STD AIDS 2007;4:287-8.
results in isoniazid-induced psychosis. 12. Hsu CW, Chu KA, Lu T, Lai RS, Lu JY. Ethambutol-induced
psychosis: A case report. Zhonghua Yi Xue Za Zhi (Taipei)
In the present case, following discontinuation of all 1999;10:724-7.
antituberculous agents, the psychiatric symptoms subsided.
When the patient was challenged with isoniazid and
ethambutol, the same psychiatric symptoms recurred, but
Source of Support: Nil, Conflict of Interest: None declared.
resolved again after discontinuation of the drugs.

Annals of Thoracic Medicine - Vol 3, Issue 4, October-December 2008 151