In the summary of product characteristics of infliximab (IFX), psychiatric side effects are reported to be rare, and in literature only limited data exist. This report presents a case of a patient with ulcerative colitis who developed a depression with psychotic symptoms during IFX therapy and made a suicide attempt 4 months after the initiation of therapy. Although the time between start of IFX therapy and onset of symptoms could suggest a correlation, this, of course, does not prove that IFX was the causative factor for his depression and suicide attempt.
Infliximab (IFX) is a chimeric monoclonal antibody directed against the proinflammatory cytokine TNF-alpha. It has been shown to be highly effective in the treatment of autoimmune disorders such as rheumatoid arthritis and inflammatory bowel disorders (IBD). 1 –3 Since 2006 IFX has been approved in Europe for the treatment of moderate-to-severe Ulcerative Colitis (UC) in patients who have an inadequate response to conventional therapy. 4
The discussion about the general safety profile of IFX is mainly focused on opportunistic infections, (haematological) malignancies and immunogenicity to the drug. 5 –7 In addition, publications exist on safety of surgery in patients undergoing proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis in the setting of prior IFX therapy. 8
Psychiatric side effects while under IFX treatment are reported to be rare. In the summary of product characteristics of IFX, undesirable psychiatric effects in clinical studies and post-marketing observations are reported as ‘uncommon’ (> 1/1000–<1/100) and include: depression, amnesia, agitation, confusion, insomnia, somnolence, nervousness and apathy. 9 Psychosis and suicide are not reported in the summary of product characteristics.
We present a case of a patient who developed a depression with psychotic symptoms during IFX therapy and made a suicide attempt 4 months after the initiation of therapy.
A 43 year old male with steroid refractory UC was treated with IFX since 4 months. In this period a total of 4 infusions were administered according to the remission induction scheme, followed by one maintenance infusion. His UC symptoms responded well to this therapy. In this same period, the patient experienced some minor work-related stress caused by the worldwide recession. He developed negative thoughts and sleeping problems during these months. There was no past psychiatric history.
In the week before his suicide attempt, which was 4 weeks after his last infusion, the negative thoughts increased. He developed insomnia, psychomotor agitation and feelings of insufficiency. Five days prior to his attempt he visited his general practitioner, who concluded that he was suffering from a burnout. He was referred to a psychologist. He was told there was a waiting-list of several weeks to months, leading to more rumination. Two days later, the patient was collected by the police after an emergency call from his wife, who had received a confused phone call from the patient. Psychiatric examination led to the diagnosis depressive disorder for which olanzapine (Zyprexa) 5 mg and venlafaxine XR (Efexor XR) 75 mg were started. After one day he refused to take his medication. One day later he was found in the bathroom with multiple stab wounds in his abdomen and neck.
Emergency surgery was performed in which two small bowel perforations, a cut sternocleidomastoid muscle and a transected trachea were treated. Following surgery the patient was admitted to the intensive care ward. After 2 days of sedation and intubation the patient wakened in the presence of psychiatric support. In the following days the patient explained, during psychiatric consultations, to feel useless and hear voices who told him to stop his life. He had ambivalent thoughts about his suicide attempt; on the one hand he regretted his attempt not to be successful, but on the other hand he did not understand why he had tried to kill himself as he does want to live. As he was suffering from persistent guilt- and nihilistic delusions, he was diagnosed with a severe psychotic depression and the dose of olanzapine was increased up to 20 mg. Venlafaxine XR had to be stopped for a period of 2 days because of a paralytic ileus. Four days later the patient had regained his confidence and he was motivated to get therapy. The suicidal ideations, delusions, acoustic hallucinations and rumination had disappeared and he slept well.
The patient was discharged from the intensive care unit to the department of surgery after 4 days and was subsequently transferred to an open ward in a psychiatric clinic after 8 days. In this clinic he was admitted for 11 days, after which he was discharged to an ambulatory treatment setting.
The IFX treatment was stopped, and further maintenance therapy for UC was restarted, consisting of azathioprine (Imuran) 100 mg, 5-aminosalicylic acid (Asacol) 2400 mg and enemas containing 1 g 5-aminosalicylic acid and 6 mg beclomethasone.
Although the time between start of IFX therapy and onset of symptoms could suggest a correlation, it is not certain that the IFX therapy was the causative factor for this depressive disorder. Conversations with the patient, his wife and his gastroenterologist, who had been treating him for over 10 years, revealed that the patient was an otherwise stable person and not easily out of balance. On the other hand, the patient did experience a stressful period at work. The psychiatrist concluded that the patient had a depression with psychotic symptoms. Although there is no scientific base from previous publications, IFX was mentioned as possible triggering factor. As possible alternative trigger the work-related stress was mentioned. The patient himself blamed IFX as a causative factor.
A known factor that may induce psychiatric symptoms is the use of glucocorticosteroids. 10 A sudden stressor, like the work-related stress, might in this context have been a provocative factor. Our patient however had his last course of steroids in 2001. He did use daily enemas containing 6 mg beclomethasone, but it has been a stable dose since 2002. Therefore it is unlikely that the sudden psychiatric disorder was caused by this locally applied therapy.
In literature, one case of suicide attempt after IFX therapy has been reported. 11 A patient with Crohn's disease had 5 IFX infusions over a 2 year period, and experienced panic attacks 2 h after each perfusion, which lasted 2–48 h. After the 5th infusion the panic attack was so strong that she took an overdose of paroxetine, without any consequence. In this case the correlation between IFX infusion and onset of panic attack was more obvious than in the presented case.
Contact with the manufacturer learned that suicidal depression, suicidal ideation and suicide attempt are reported as ‘very uncommon’ (< 1/10,000 patients) in the pharmacovigilance data in the periodically safety update report. But as this database is dependent of spontaneous reporting, it might be underreported.
In conclusion, although other factors possibly have contributed to the depression and suicide attempt, we strongly suspect that the IFX therapy has been the causative factor, but we have no proof of it. The exact risks of suicidal depression, suicidal ideation and suicide attempt in patients treated with IFX could not be clear due to underreporting and, in addition, the low incidence. Therefore it is important that cases like these are reported.
We thank the patient who consented to report the case.