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Keywords:

  • delusions;
  • hallucinations;
  • interferon-β-1b;
  • multiple sclerosis;
  • psychosis

Abstract

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. ACKNOWLEDGMENTS
  6. REFERENCES

Interferon-β is used in patients with multiple sclerosis to reduce autoimmunity; although other psychiatric side-effects are common, in contrast to interferon-alpha, psychosis has been reported only once. A patient with multiple sclerosis developed auditory hallucinations, paranoid delusions, and increased aggressiveness after 16 months of treatment with interferon-β-1b, 250 µg every other day. He responded after about one month to antipsychotic treatment, but tended to relapse upon dose reduction, and after 2 years still needs antipsychotics to control his symptoms. Because there was no change in his magnetic resonance imaging between pre- and post-treatment with interferon, we concluded that psychosis was more related to interferon treatment than to the underlying disease.

INTERFERON (IFN)-β IS used to reduce self-directed immunity in multiple sclerosis (MS). It is less likely to be associated with other psychiatric symptoms than IFN-α and is extremely rarely associated with psychosis. The reason for differences in psychiatric symptoms and psychosis-inducing potential between IFN-α and IFN-β is unclear.1

MS is very commonly associated with depression2,3 and much less with psychosis; however, life-time prevalence of psychosis in the MS population is three- to fourfold higher than in the general population.4

Psychosis in MS during IFN-β is extremely rare.5 To date, only one case has been reported with IFN-β-1a in a patient with MS.6 Another, unpublished case occurred in the French National Pharmacovigilance System database.6 Psychotic symptoms in MS appear to relate to temporal lobe white matter demyelinization, and its progression corresponds to clinical worsening.7 It is unknown whether IFN-β may act on clinically silent demyelinized tissue and trigger psychosis or whether it is able to induce psychosis in the absence of psychosis-specific demyelinizing alterations in MS.

IFN-induced psychotic symptoms tend to resolve after IFN discontinuation. Persistent IFN-induced psychotic symptoms were reported after IFN discontinuation only with IFN-α.8–12 In the only case of IFN-β-1a-induced psychosis, psychotic symptoms resolved upon discontinuation.6 Psychosis persisted after discontinuation and the patient needs continuing psychiatric care.

Here we describe a case of secondary progressive MS in which the patient developed psychosis while on IFN-β-1b.

CASE REPORT

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. ACKNOWLEDGMENTS
  6. REFERENCES

A 38-year-old man presented with suspiciousness, mistrust, poor insight, insomnia, and restlessness. He was delusional, self-referential and suspecting that someone was trying to poison him. These symptoms developed after one-and-a-half years of subcutaneous administration of 250 µg IFN-β-1b every other day for secondary progressive MS, which started in April 2006 and was prematurely suspended in September 2007.

In the last three months the patient perceived increased environmental hostility, manifesting suspiciousness, self-reference ideas, nihilism, and auditory hallucinations. Symptoms increased surreptitiously, becoming pervasive and occupying most of his time. He was severely anxious, and became physically and verbally aggressive towards others. He scored 25 on the positive scale of the Positive and Negative Syndrome Scale (PANSS-P), 18 on the negative scale (PANSS-N), and 91 on the general psychopathology scale (PANSS-GP); he also scored 20 on the Young Mania Rating Scale (YMRS), and 13 on the Hamilton Depression Rating Scale (HAMD).

His psychiatric and family histories were negative. His T2-weighted magnetic resonance imaging (MRI) showed both diffuse and circumscribed, punctiform areas of white matter hyperintensity bilaterally at the corona radiata, around the ventricles, and at the semi-oval centers, while altered intensity patches were also found in the cerebellar peduncles, bilaterally, and in the right part of the pons. This picture was not different from pre-IFN-β-1b MRI. Daily oral olanzapine at a dose of 20 mg was prescribed to him. One month later he was quiet, confident and smiling, with improved sleep and insight and no evidence of thought disorder, delusions or hallucinations.

The patient discontinued medication and missed follow-up visits. He was compulsorily hospitalized 4 months later for psychomotor agitation, aggression, and delusional thinking. He scored 38 on the PANSS-P, 18 on the PANSS-N, 55 on the PANSS-GP, 29 on the YMRS, and 14 on the HAMD. He was given 20 mg/day olanzapine, 6 mg haloperidol, and 7.5 mg lorazepam. Twenty days later he was discharged with a diagnosis of drug-induced psychotic disorder, with symptom improvement, but with core psychosis persisting.

Since then we have followed him up as an outpatient. Two months later, his neurologists treated him intravenously with the immunosuppressor mitoxantrone, 8 mg/m2 monthly. We progressively tapered-off haloperidol and lorazepam, leaving only olanzapine at the same dose. After a further 2 months, the patient was well, with no delusions and adequate insight into his experience. He was euthymic, but somnolent and overweight. Half a year later, his olanzapine was reduced to 10 mg/day, but one month later his symptoms returned; he was persecutory, verbally aggressive, and suspicious; his mood was stable. Olanzapine was brought back to 20 mg/day, and 3 mg/day haloperidol was added. He improved again within one month, and haloperidol was again discontinued. At his last visit, while on 15 mg/day olanzapine, PANSS scores had dropped to 8 on PANSS-P, 10 on PANSS-N, and 24 on PANSS-GP, while his current YMRS and HAMD scores were 0 and 4, respectively.

DISCUSSION

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. ACKNOWLEDGMENTS
  6. REFERENCES

We describe a 38-year-old man with secondary progressive MS who, after being subjected to IFN-β-1b treatment, developed persistent psychosis, characterized by paranoid and depressive delusions and hallucinations, which were controlled only with antipsychotic treatment and IFN-β-1b discontinuation. To our knowledge, this is the third case of psychosis associated with IFN-β treatment and the first with IFN-β-1b, as well as the first to persist after IFN-β suspension and one of the few with IFN, in general. We attributed the psychosis to IFN based on a score of 6 obtained on the Naranjo Adverse Drug Reaction (ADR) Probability Scale.13

Our patient's MRI showed palisade-like and point-like supratentorial bilateral white matter periventricular hyperintensities, as well as at the corona radiata and centrum semiovale, and subtentorial at the cerebellar peduncles, bilaterally, and in the right part of the pons. Similar distributions of white matter hyperintensity have been described also in other MS cases with psychosis; periventricular and deep white matter hyperintensities were found in a woman with MS presenting with delusional depression, but she had a prominent reduction in parietal white matter,14 which were spared in our patient. Our case showed some MRI features that could explain some symptoms he manifested after IFN-β-1b treatment. However, we consider it more likely that the syndrome was induced by IFN-β-1b because the MRI picture did not change from the pre-IFN-β-1b period.

The only published case of psychosis after IFN-β treatment regards a man with MS who developed a delusional, mood-congruent, major depressive episode with persecution and delirium, about 8 months after 22 µg IFN-β-1a, three times a week.6 Psychosis gradually subsided over five days after IFN-β-1a withdrawal and introduction of antipsychotics. This patient had presented with major depression 1 year before diagnosis of MS and was treated with the serotonin-noradrenaline reuptake inhibitor, venlafaxine, at a dose at which effects on the serotonin transporter predominate. He further differed from our patient in that he received IFN-β-1a, as opposed to IFN-β-1b in our patient, in the time needed to develop the psychotic episode (8 vs 16 months), and in the reversibility of the clinical picture.

Persistent psychosis after IFN has been observed only with IFN-α, but not IFN-β. It is difficult to distinguish whether the psychosis was related to IFN treatment, to the underlying disease, or to an independent event. All cases were male, except one 21-year-old healthy volunteer with positive family history for both bipolar and schizophrenic psychoses who participated in a clinical trial of pegylated IFNα-2a.12 All other cases of persistent psychosis following IFN-α were men, three had hepatitis C virus,8,9,11 and one had hepatitis B virus infection.10 Only partial response to IFN suspension and antipsychotic drug introduction has been observed in two of these cases,10,11 with some psychotic symptoms persisting, as in our case. We may conclude that IFN-α and IFN-β induce variable and different forms of psychosis.

We considered pre-existing psychosis as a remote possibility, considering age at onset and absence of significant risk factors. We also considered it unlikely that mitoxantrone had influenced the course of psychosis, as the psychological effects of this drug are extremely rare and the only ones reported include confusion, lethargy, anxiety,15 insomnia, and, remarkably, improved cognitive function.16

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. ACKNOWLEDGMENTS
  6. REFERENCES

This paper received no support from any agency.

REFERENCES

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. ACKNOWLEDGMENTS
  6. REFERENCES