Abstract
Dear Sir A 30-year-old man presented for a previously diagnosed migraine without aura. During the last few weeks symptoms of migraine attacks had worsened and the patient also reported mood swings with depressive symptoms occurring during the daytime and accompanied by worsening of social anxiety. In fact, he suffered from cyclothymic disorder with social phobia diagnosed 3 years before and symptoms had partially benefited from valproate, venlafaxine and lorazepam. No other significant physical or mental disorder was present.
The migraine attacks occurred about four times a month with very severe intensity, prolonged for 1–2 days and accompained by autonomic symptoms. The only proposed treatment was symptomatic therapy with 5-HT1B/D receptor agonist (almotriptan).
Three months later the patient showed an excellent response to the almotriptan therapy, with pain relief within 30 min and disappearance of the autonomic symptoms. Morover, he reported that, if the drug was administered when depressive symptoms or signs of social anxiety occurred, after about 40 min mood impairment disappeared and symptoms such as embarrassment, blushing and fear of being observed or judged also improved, to the point of mild euphoria. This effect was observed most of the times he took the drug and lasted about 8 h, suggesting a relationship with its administration. We stress the highly anecdotal nature of this case.
In fact, 5-HT1B/1D receptor agonists represent a major advance in the treatment of migraine attacks by inhibition of the peripheral trigeminal nerve (5-HT1D) and constriction of intracranial extracerebral blood vessels (5-HT1B) (1). Morover, serotonin has been implicated in several mental disorders, including depression and anxiety disorders, although it is not yet clear which of the 14 5-HT receptor subtypes identified in the brain are involved in regulation of emotional states (2). Is this also true for 5HT1B/1D receptors? A high density of these receptors is found in substantia nigra, globus pallidus, striatum, cortex and other regions of the brain (2). Some studies have shown that 5-HT1B agonist administration leads to an increase of anxious behaviour in rats (3). Furthermore, these receptors may be supersensitive in depression, anxiety and obsessive compulsive disorders (4). However, it has also been documented in animal models that selective 5HT1B agonist receptors produce effects similar to those of anxiolytics and that they also act as antidepressive drugs (5). Some studies have conducted pharmacological challenges utilizing serotonin agents (sumatriptan) in patients with obsessive compulsive disorder and conflicting results were found, because symptoms worsened in sumatriptan-treated patients if the drug was administrated for few days (6) and improved in chronic administration (7). No data are available concerning social anxiety.
Studies of the serotonergenic system have suggested a genetic susceptibility to mood disorders, anxiety, aggression and tendencies towards drug abuse (8) and the 5HT-1B/D receptor system appears to be involved in this (9).
It is interesting to observe that some antidepressive drugs, such as lithium, have been hypothesized to acts as 5HT1D receptor partial agonists or as modulating these receptors (10). Besides, 5HT1D receptors may show reduced function in major depression (2). Therefore, may activation of these receptors improve depression and anxiety symptoms?
A mediator of sterile inflammation such as substance P has also been related to the source of migraine pain, but clinical and experimental evidence supports the view that neurokinin-1 (NK1) receptor antagonists may have no significant antimigraine properties (11). A role for substance P and NK1 receptor in anxiety and depression is also hypothesized (12), but clinical studies have shown controversial results (13).
Taking all these considerations into account, the relief of mood and anxiety symptoms observed in our patient after 5HT1B/D agonist administration might be related to direct stimulation of serotoninergic neurons in the central nervous system, other than re-uptake inhibition. However, the effects of 5HT1B/D agonists on mood and anxiety remain controversial and require clarification. Multifactorial aspects may be involved in this topic and other explanations may be possible to explain our observation.