NSAID induced hypomania in stable bipolar disorder.

Sir,

Some case reports have proposed the antidepressant role of the non-steroidal anti- inflammatory drugs. These effects might reflect the activation syndrome[1] induced by these agents.

We describe three patients of bipolar mood disorder currently in remission as per the DSM-IV criterion who were on treatment with mood stabilizers (lithium carbonate/sodium valproate). Patients experienced pain due to neuromuscular conditions and were advised treatment with NSAIDs (nimesulide/etoricoxib/celecoxib). While on treatment, they developed symptoms of hypomania. The symptoms were seen within 3 days of the administration of the agent and remitted when the NSAIDs were stopped. Symptoms reappeared with the drug rechallenge and disappeared within 2 days of drug discontinuation. All patients stabilized after that and did not restart the NSAID. Can NSAIDs induce transient reproducible hypomanic symptoms in certain vulnerable patients with history of mood disorders?

Another possible explanation for the phenomenon could be the effect of NSAIDs on substance P (SP), which has a proven role in anxiety and nociception and acts through the activation of NK1R[2] (neurokinin 1 receptor).

SP and NK1R might play an important role in the modulation of stress-related, affective and/or anxious behavior as they are expressed in brain regions that are involved in stress, fear, and affective responses. The SP content in these areas is affected by stressful stimuli and can thus alter these states.[2]

Monoaminergic neurons of the locus coeruleus receive SP innervations and possess NK1R and are in close apposition to NK(1)-containing cells in the dorsal raphe nucleus. The action of NK1R antagonists may result from the modulation of such brain function.[3] Antagonism or the genetic inactivation of the NK1R causes alterations in serotonin and norepinephrine neuronal transmission.[2] The systemic administration of NK1R antagonists enhances the firing rate of dopaminergic, noradrenergic, and serotonergic neurons, thereby suggesting a predominating inhibitory role of SP upon monoaminergic neurons.[3] NSAIDs and Cox-2 inhibitors are known to decrease the levels of SP and thus modulate the monoaminergic system indirectly, thereby causing an increase in monoamine levels and disinhibition. Another effect of SP could be mediated through abnormalities in the signal transduction pathways and CREB (cyclic adenosine monophosphate (cAMP) response element binding proteins). These changes have been identified in patients with mood disorders.[4]

Systematic clinical studies are needed to explain the clinical manifestations of SP and NK1 Rantagonists in the mediation of mood symptoms.