Cyclical suicidal ideation following natalizumab infusion for multiple sclerosis

To the Editor

Immune modulating agents have been associated with depression and suicidality (Mumoli et al., 2013). Natalizumab is a monoclonal antibody that slows the progression of relapsing remitting multiple sclerosis (RRMS). Natalizumab blocks the migration of T cells across the blood brain barrier (BBB) preventing further demyelination and plaque formation (McCormack, 2013). We present an intriguing scenario wherein natalizumab infusion for RRMS worsened depressive symptoms in a cyclical pattern.

Ms H is a 51-year-old woman with an 8-year history of depression managed with antidepressants and psychotherapy. Ms H was diagnosed with RRMS in 2012 and despite treatment with fingolimod her neurological symptoms progressively worsened. Therefore, 4-weekly (300 mg IV) natalizumab infusions were commenced.

Following natalizumab infusions, Ms H noted a cyclical worsening of her depression associated with intense suicidal ideation. Worsening of symptoms began on day 3 post infusion, reaching maximum intensity on days 5–6, and resolving to baseline by day 10. This pattern was consistently observed after each natalizumab infusion. Beck Depression Inventory (BDI-II) scores were performed post sixth and seventh natalizumab infusions (Table 1).

Table 1.

Beck Depression Inventory (BDI-II) scores following infusions 6 and 7.

	Infusion cycle
Day post infusion	Sixth	Seventh
0	31	31
5	41	42
10	35	33
15	30	29

The rate of depression withnatalizumab infusions (19%) was not significant when compared to placebo (McCormack, 2013). However a recent report by Mumoli et al. (2013) suggests a causative link between natalizumab and an attempted suicide. Our patient’s cyclical symptom profile, if observed in others, could inform specific high-risk periods necessitating close monitoring of mental state.

In addition to its primary action, natalizumab induces peripheral cell-mediated inflammation and secretion of cytokines, particularly TNF-α (McCormack, 2013). An association between peripheral inflammation and depression has been reported (Postal and Appenzeller, 2015). While peripheral cytokines do not normally cross the BBB, primary afferent nerves, the choroid plexus and specific transporter proteins facilitate cytokine movement from peripheral inflammatory sites to the central nervous system (CNS) (Postal and Appenzeller, 2014). It is possible that transmission of cytokines and other peripheral inflammatory signals to the CNS could be the basis for worsening depressive symptoms and suicidal ideation following natalizumab infusions. Quantification of peripheral cytokine levels and temporal correlation with severity of depression/suicidal ideation following natalizumab infusions may provide some theoretical basis for the cyclical symptoms demonstrated by our patient. Such correlation, if it exists, also affirms the increasingly recognised role of the immune system in the pathogenesis of depression.