Reply: Parkinson's disease, DBS and suicide: a role for serotonin?

We would like to thank Temel et al. for their communication highlighting the potential role of serotonin and suicidal behaviours, which are intriguing and potentially of relevance. Temel et al. have previously shown that subthalamic nucleus (STN) HFS in a rat study inhibits serotonergic dorsal raphe firing rate and elicits depressive-like behaviour which can be prevented with pre-treatment with a serotonin reuptake inhibitor (Temel et al., 2007). Post-mortem and biological challenge studies suggest serotonergic hyporesponsivity particularly in suicide attempts of high lethality and lower prefrontal serotonin receptor density with a compensatory increase in midbrain serotonin neuron density and function (Mann et al., 1996; Oquendo et al., 2003; Boldrini et al., 2008). Temel et al. point to a potential mechanistic link between serotonin and post-surgical suicidal behaviours mediated via depression and impulsivity, which is less clear and very complex. In our paper, we identified an association between suicide attempts and post-STN HFS depression (Voon et al., 2008). However, the link between STN HFS and depression is poorly understood in human studies and there are likely several different mechanisms leading to a similar depressive phenomenology. Post-surgical depression can be conceptualized as being mechanistically related to STN HFS itself, dopaminergic medication changes, psychosocial factors, Parkinson's disease-related depression or premorbid vulnerability to depression (Voon et al., 2006). Temel et al. implicate STN HFS-related depression secondary to serotonergic inhibition, which may be one possible mechanism. The majority of STN HFS studies report an improvement of post-surgical depressive symptoms as measured using rating scales. Systematic assessments of STN HFS have been associated with acute mood changes (Okun et al., 2003) and case studies have reported depressive mood states (Tommasi et al., 2008), but not with long-term depressive symptoms. In contrast, there is also clear association with STN HFS and hypomania (Mallet et al., 2007). Post-STN HFS depression based on case ascertainment has been reported in single centre uncontrolled studies as the authors indicate; however, well-designed randomized controlled trial studies comparing STN HFS and medical treatment or unilateral STN HFS and unilateral HFS targeting the globus pallidus interna did not demonstrate any differences in mood changes (Witt et al., 2008; Okun et al., 2009). Similarly, STN HFS for obsessive compulsive disorder did not affect depressive symptoms; rather, the predominant side-effect appeared to be hypomania rather than depression (Mallet et al., 2008). This suggests that factors other than STN HFS itself may be associated with post-surgical depression. Depressive and apathy symptoms have been well-established to arise from dopaminergic medication withdrawal which responds to an increase in dopaminergic medications (Funkiewiez et al., 2006; Czernecki et al., 2008). Furthermore, if postoperative depression is related to Parkinson's disease depression, this appears to be more likely to be related to pre-synaptic noradrenergic and dopaminergic activity (Remy et al., 2005) with better response to tricyclic antidepressants rather than SSRIs demonstrated in a well-designed randomized controlled trial study (Menza et al., 2009). An individual premorbid risk towards depression may also heighten the risk for postoperative depression, which may be related to various neurotransmitters. Multiple psychological changes including motivation for surgery, and changes in identity and relationships may also impact on mood and respond preferentially to psychotherapy.

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