Brainstem surgery remains challenging but can be a useful treatment strategy for lesions such as brainstem gliomas. Aiding the surgical approach is intraoperative monitoring of auditory, motor, and somatosensory evoked potentials as well as cranial nerve mapping. These features aid in determining the safest entry area for surgery. For lesions in the tegmentum of the pons near the raphe nuclei, an infratentorial supracerebellar approach provides good access with minimal disruption to surrounding structures such as the raphe nuclei.[7]

In recent studies, electrical stimulation of the raphe magnus increased myelination and reduced symptoms in a multiple sclerosis model mouse. In the future, surgeons may implant deep brain stimulators in the raphe nuclei to treat disease states such as multiple sclerosis.[8]

Research shows that changes to the dorsal raphe nucleus carry implications in major depressive disorder (MDD) and suicidality. MDD ranks as the leading cause of disability in developed countries, according to the World Health Organization. Genetic polymorphisms affecting the availability of tryptophan, activity of tryptophan hydroxylase 2 monoamine oxidase which degrades serotonin, 5-HT1 autoreceptors, and serotonin transporters all confer risk for depression, particularly with the onset of symptoms early in life. In later life depression, volume loss of the dorsal raphe, as well as decreased connectivity to the posterior cingulate cortex, is more strongly implicated.[3] These changes can develop by myriad means, including age-related degeneration as well as infarction.

Based on this understanding, SSRIs are considered first-line treatment for MDD. The mechanism of action for this drug is to increase the synaptic concentration of serotonin by binding and inhibiting the presynaptic serotonin reuptake transporter and decreasing responsiveness of 5-HT autoreceptors. The thinking is that this increased serotonin concentration, specifically in limbic synapses, results in a more positive appraisal of emotional information. Over time this change gradually results in a clinical antidepressant effect as conscious cognitive processing becomes altered and previous emotional associations are modified. This clinical effect typically takes place over 4 to 6 weeks.[9] Other classes of antidepressants also increase serotonin transmission. Monoamine oxidase inhibitors diminish the degradation of serotonin. Tricyclic antidepressants (TCAs) decrease 5-HT1A as well as alpha-2 adrenoceptor responsiveness, producing increased serotonin transmission. 

The fact that other treatment modalities for depression target dopamine, norepinephrine, and catecholamine transmission implies that the serotonergic system is one of the multiple components in the pathogenesis of depression. For example, in patients who respond well to selective norepinephrine reuptake inhibitors, the depletion of catecholamines rather than serotonin is more closely linked to symptomatology. Furthermore, some patients experience improvement of symptoms when SSRI therapy is augmented with a second agent such as a dopamine agonist, highlighting a multifactorial etiology. Current research explores novel targets to alleviate MDD symptoms and to do so more rapidly.[10] Also, the investigation into the microbiota-gut-brain axis holds promise for future treatment modalities. While the raphe nuclei synthesize the majority of serotonin in the central nervous system, most of the serotonin in the entire body gets synthesized in the gastrointestinal tract. Research linking abnormal gut microbiota to depressive symptoms highlights environmental factors in the pathogenesis of MDD. Studies demonstrating that depressive symptoms are reversible with transplantation of normal microbiota holds promise for future therapeutic measures.[11]

Alterations in serotonin pathways are also implicated in chronic pain syndromes, given the known process of pain modulation at the dorsal horn level of the spinal cord due to descending projections from the raphe nuclei. For this reason, SSRIs and TCAs may be considered to treat fibromyalgia, chronic pelvic pain, diabetic neuropathy, and headache syndromes.[12]

Serotonin syndrome is a medical emergency that can be precipitated by interaction or overdose of serotonergic drugs, causing overactivity of 5HT-1A and 5HT-2A receptors. Patients present with altered mental status, tremors, hyperreflexia, muscle rigidity, fever, tachycardia, and hypertension as a result of the excess central nervous system and peripheral serotonergic activation. Treatment is supportive care and most importantly, discontinuation of all serotonergic medications, and the prognosis is favorable.[13] Neuroleptic malignant syndrome also shares some of the symptoms of serotonin syndrome-like hyperthermia, altered mental status, and autonomic instability. But neuroleptic malignant syndrome demonstrates bradyreflexia, lead pipe rigidity, and extrapyramidal features. So, it is imperative to identify these emergencies early to prevent mortality.