Psychiatry and Clinical Neurosciences (2002), 56, 647–648

Letter to the Editor

Case of mania induced by withdrawalof interferon-a in a patient affected bybipolar disorder

Interferon (IFN)-a is one of the most importantcytokines that are known to demonstrate antiviraland immunomodulatory effects. Interferon-a is theonly proven treatment for chronic hepatitis C. Inter-feron-a’s psychiatric adverse effects are clinically relevant because they are the most common reasonsfor discontinuing this therapy; psychiatric manifesta-tions include psychotic symptoms (i.e. delusions and/or hallucinations), delirium and manic symptoms.1

The present report describes a case of mania sub-sequent to the withdrawal of treatment with IFN-a ina patient suffering from bipolar I disorder who was previously stabilized with clozapine and lithium.

A 59-year-old man who had been suffering from asevere bipolar I disorder for many years, reachedmood stability with lithium (900 mg a day) and cloza-pine (200 mg a day) treatment. In May 1999 he wasdiagnosed with post-infective hepatitis C by his hepa-tologist, in the absence of illicit drug use. In Septem-ber 1999 he began taking 3 million units of IFN-asubcutaneously three times a week for 1 month,and then 6 million units of IFN-a subcutaneouslythree times a week. In June 2000, due to blood nega-tivity of HCV-RNA, the IFN-a treatment was with-drawn. During the first month, gradually, he becameeuphoric, hyperactive and exhibited tension, insom-nia, talkativeness, and sexual disinhibition despite psychopharmacotherapy.

During hospitalization he did not improve after theclozapine dose regimen was increased to 400 mg. Onthe contrary, the patient became confused with tem-poral–spatial disorientation, ataxia, and motor incoor-dination. This symptomatology was similar to that ofhis previous manic episodes, which were also charac-terized by long duration (approx. 6 months) and poorresponse to drug treatment. We hypothesize that thismanic episode was not a natural evolution of bipolardisorder but was caused by the abrupt withdrawal ofIFN-a (i.e. tertiary mania). We decided upon a drugregimen reduction of 50% with the addition of clon-azepam (10 mg/day). The clozapine was decreasedbecause of its anticholinergic properties that couldfurther worsen the ‘cognitive’ symptoms of the

patient. The lithium was reduced to avoid organiccomplication due to possible dehydration caused byagitation. The clonazepam was added because of itswide use in agitated patients. Within 2 weeks he expe-rienced mild relief, then we gradually recommencedthe lithium and clozapine therapy. Four weeks latermania regressed completely and he continued lithiumand clozapine (50 mg a day).

COMMENT

The mechanism of action responsible for maniainduced by IFN-a is as yet unknown.

While short-term treatment with IFN-a appears toact as a dopaminergic agonist, long-term administra-tion may cause depression that provokes a decreasein central dopaminergic activity through binding toopiate receptors that seem to modulate presynapticdopamine release. The mania in the present patientcould be the consequence of dopaminergic hyperac-tivity following the abrupt discontinuation of IFN-atreatment not balanced by neuroleptic therapy aselsewhere reported.2 This hypothesis seems to be con-sistent with evidence of dopaminergic system hyper-activity obtained through the use of an animal modelof mania-like conditions.3 In contrast, mania could becaused by an influence of IFN-a on N-methyl-D-aspartate (NMDA) responses through opiod recep-tors4 or by other indirect mediators such as cytokines(interleukin-1, tumor necrosis factor) for which thelevels, higher in bipolar patients, are normalized withlithium therapy.5

We suggest that patients with bipolar disorders areat greater risk of becoming manic if IFN-a treatmentis withdrawn abruptly.6

REFERENCES

1. Hosoda S, Takimura H, Shibayama M, Kanamura H,Ikeda K, Kumada H. Psychiatric symptoms related tointerferon therapy for chronic hepatitis C: Clinicalfeature and prognosis. Psychiatry Clin. Neurosci. 2000;54: 565–572.

2. Carpiniello B, Orrù MG, Baita A, Pariante C, Farci G.Mania induced by withdrawal of treatment with inter-feron alfa. Arch. Gen. Psychiatry 1998; 55: 88–89.

3. Gessa GL, Pani L, Fadda P, Fratta W. Sleep deprivationin the rat: An animal model of mania. Eur. Neuropsy-chopharmacol. 1995; 5 (Suppl.): 89–94.

4. Katafuchi T, Take S, Hori T. Roles of cytokines in the neural immune interactions: Modulation of NMDA-responses by IFN-alpha. Neurobiology 1995; 3: 319–327.

5. Rapaport MH, Guylai L, Whybrow P. Immune para-meters in rapid cycling bipolar patients before and

648 A. Rossi et al.

after lithium treatment. J. Psychiatr. Res. 1999; 33:335–340.

6. Kingsley D. Interferon-alpha ‘tertiary mania’. Hosp. Med.1999; 60: 381–382.

ALESSANDRO ROSSI, md,1,2

DANIELA RENZETTI, md,2

LUIGI D’ALBENZIO, md,2

DANIELA GIANFELICE, md,1

ARTEMIS KALYVOKA, md,1

OSVALDO RINALDI, md1

1University of L’Aquila and 2Clinical Psychology Unit at Villa Serena Medical Center, Città S.Angelo,

Pescara, Italy

Correspondence address: Alessandro Rossi, University of L’Aquila,Clinical Psychology Unit at Villa Serena Medical Center, Città S.Angelo, Pescara, Italy. Email: rossi.aq@tin.it

Received 19 April 2002; revised 3 June 2002; accepted 10 June2002.