Fingolimod exacerbated affective psychosis?

To the Editor

Fingolimod (FTY720) is a sphingosine-1-phosphate (S1P) receptor modulator indicated in the treatment of relapsing–remitting multiple sclerosis (MS). Acting as a receptor antagonist, it inhibits the release of potentially auto-reactive T and B cells from the thymus, preventing entry into the central nervous system (CNS). Clinical trials have shown equivalent rates of depression in treatment and control groups (Scott, 2011). No report has been made of mania or psychosis associated with fingolimod treatment.

A 38-year-old woman was admitted to a large teaching hospital five weeks after commencing fingolimod for an exacerbation of relapsing–remitting MS, with a three-week history of increasing manic and psychotic symptoms. This occurred on a background of previous major depressive episodes with mild paranoid features treated with sertraline. Prior to the commencement of fingolimod, MS was treated with interferon-beta. This was ceased due to exacerbation of depression and glatiramer acetate commenced. Glatiramer was then ceased as it was ineffective in treating MS. Subsequently, the commencement of fingolimod was associated with derealisation, prominent grandiose and religious delusions, delusional guilt and delusions of misidentification. These were associated with disturbing visual hallucinations and features of metamorphosia. There was associated lability and elevation in mood, decreased need to sleep, increased spending and grandiose ideas. These features are consistent with the emergence of a mixed affective psychosis. Neurological examination was unremarkable for executive dysfunction. MRI showed stable white matter lesions without enhancement by active disease. In the context of this presentation, fingolimod was ceased, sertraline tapered and quetiapine introduced with gradual resolution of the psychotic features.

Psychosis is a rare feature of MS (Sidoti and Lorusso, 2007) and has been associated with the use of interferon-beta (Goeb et al., 2006) and glatiramer acetate (Pjrek et al., 2005). It is prudent to also consider that the patient’s symptoms could have been exacerbated by the introduction of fingolimod. In addition to its effect on S1P receptors, fingolimod is an antagonist at cannabinoid type 1 (CB1) receptors (Paugh et al., 2006). Rimonabant, a CB1 receptor antagonist, was introduced as an appetite suppressant for the management of obesity, but was withdrawn in 2008 due to its significant psychiatric side effects, notably anxiety and depression (Kirilly et al., 2011). We propose that the CB1 receptor antagonist properties of fingolimod may trigger mood or psychotic symptoms in patients with a past history of psychiatric disturbance. Alternatively, this woman’s symptoms may be mediated through an as-yet-uncharacterised S1P receptor pathway.

Similar to fingolimod, interferon-beta and glatiramer acetate are also known to act via changes in T cell migration or function (Lim and Constantinescu, 2010). Recent evidence suggests that modification of T cell transmigration into the CNS may impact on neuroplastic processes, leading to psychiatric symptoms (Eyre and Baune, 2012). Regardless of mechanism, this case report highlights the need for careful monitoring of psychiatric symptoms when using fingolimod, particularly in those with previous mental health issues.