As a multimodal antidepressant, VOR acts not only on 5-HT transporter but also on multiple 5-HT receptors, including agonism at the 5-HT1A receptor, antagonism at the 5-HT3 and 5-HT7 receptors, and partial agonism (functional antagonism) at the 5-HT1B/1D receptors. VOR is thought to contribute to antidepressant and anxiolytic effects by inhibiting local negative feedback in the dorsal raphe nucleus (4), disinhibiting pyramidal neurons by suppressing GABAergic interneurons in the prefrontal cortex and hippocampus (5), and promoting presynaptic release of arousal-promoting neurotransmitters such as norepinephrine, dopamine (DA), acetylcholine, and histamine (6). While these mechanisms suggest potential broad antidepressant and anxiolytic effects, clinical evidence supporting its anxiolytic efficacy is limited. Some small-sample studies and case reports have reported effectiveness in treating patients with major depressive disorder patients with comorbid social anxiety disorder (10) or with a history of trauma (11), as well as preventing panic attacks in patients with panic disorder (12). However, a meta-analysis has shown no significant efficacy in treating generalized anxiety disorder (13, 14). This evidence indicates that the efficacy of VOR for anxiety is not strong. This discrepancy between receptor profiles and clinical outcomes suggests that the mechanisms of action may not fully translate into consistent clinical benefits for anxiety.

Meanwhile, the heterogeneous nature of anxiety and stress-related disorders is increasingly recognized. Specifically, OCD and its spectrum disorders are distinct from other anxiety disorders. OCD was categorized under anxiety disorders in DSM-IV-TR (15), but this heterogeneity led to the creation of a new category of “obsessive-compulsive and related disorders (OCRD)” separated from anxiety disorders in DSM-5 (8, 16). This new category is often referred to as OCSD, reflecting the broader range of related conditions (17, 18).

Additionally, some indirect evidence suggests a potential connection between SSD and OCSD. Hypochondriasis (HC) is often considered part of the OCSD due to its preoccupation with illness resembling obsessive thoughts, and HC shows a high rate of comorbidity and familial occurrence in OCD patients (19–21). Similarly, SSD involves an excessive focus on health concerns (22, 23), which is similar to HC. Given the relationship between HC, SSD, and OCD, HC is classified as obsessive-compulsive or related disorders in the ICD-11 (24), while it is mostly categorized as SSD in the DSM-5 (8, 22). One cognitive mechanism that further links SSD and OCSD is somatosensory amplification, where normal bodily sensations are perceived as intense and distressing (25). This heightened perception of somatic sensations is a hallmark of SSD (26) and is closely tied to emotional factors, particularly catastrophizing, which involves rumination, magnification, and feelings of helplessness, are thought to play a critical role in this process (26–28). Notably, rumination, characterized by persistent focus on distressing thoughts or sensations, has been shown to correlate with the severity of OCD symptoms (29), further suggesting shared cognitive pathways between SSD and OCSD.

Neurobiologically, regions such as the amygdala, insular cortex, and anterior cingulate cortex are broadly implicated in anxiety disorders (30, 31), whereas areas including the orbitofrontal cortex (OFC) and ventromedial prefrontal cortex—which are adjacent and partially overlapping (32)—have been suggested as more specifically involved in OCD (33, 34) and stress-related somatic symptoms (35). However, it should be noted that the stress-related somatic symptoms include not only SSD, but also fibromyalgia, psychosomatic disorders, and subthreshold states. Furthermore, although current evidence is limited to case reports, the observed augmenting effects of antipsychotics on SRIs in treating SSD (36–39) suggest that the neuropathology of SSD may overlap with that of OCD. These findings point to potential shared neural circuits, supporting the hypothesis that SSD may be considered part of the OCSD. Further studies, including randomized controlled trials, are necessary to confirm this relationship and clarify the underlying mechanisms.

In light of the relationship between SSD and OCSD discussed above, we now turn to the consideration of pharmacological treatments for SSD. SRIs are effective in both OCD and other anxiety disorders, but what distinguishes OCD is the involvement of the mesolimbic DA pathway and the effectiveness of D2 antagonists (20, 40). While D2 antagonism are beneficial in treating OCD patients (41), they carry risks of side effects such as extrapyramidal symptoms, hyperprolactinemia, and neuroleptic malignant syndrome. Recently, the 5-HT3 receptor has emerged as another promising target. Meta-analyses have shown that 5-HT3 antagonists are effective for treating OCD, both as monotherapy (42) and as augmentations to SRIs (42, 43). By selectively inhibiting phasic DA release in the mesolimbic pathway, 5-HT3 antagonists may help reduce the side effects often associated with D2 antagonists (3). Additionally, animal and clinical studies also suggest that presynaptic 5-HT1B/1D antagonism promotes 5-HT release in the OFC, potentially contributing to symptom improvement (34). Consistent with these mechanisms, VOR, a 5-HT3 and 5-HT1B/1D antagonist that does not act on D2 receptor, has been shown to be effective in treating OCD patients (44–47).

In the present cases, although neither patient exhibited the obsessive thoughts or compulsive behaviors required for an OCD diagnosis, Case 1’s preoccupation with the unpleasant throat sensation, accompanied by repetitive coughing, aimed at relieving this sensation, and Case 2’s preoccupation with pain, along with overly detailed complaints in the internal medicine setting suggested some OCD-like features and somatosensory amplification. The treatment with VOR led to an improvement in the somatic symptoms of these cases, together with the alleviation of their preoccupation with them. The efficacy of VOR in treating SSD may be attributed to its augmenting effects via 5-HT3 and 5-HT1B/1D receptor antagonism, in addition to 5-HT reuptake inhibition, supporting the hypothesis that SSD may share several neuropathological features with OCD/OCSD.

Additionally, somatic symptoms could also be influenced by the involvement of hypothalamic–pituitary–adrenal (HPA) axis and inflammatory pathways. Numerous studies have shown the association of HPA axis and inflammation with fibromyalgia (48, 49), psychosomatic disorders (50, 51), and conversion disorder/functional neurological symptom disorder (52, 53), all of which should be differentiated from SSD. Whether inflammation is elevated in SSD remains a topic of debate, but recent reports from two groups suggest the involvement of inflammatory pathways in SSD (54) and somatic symptom and related disorders (SSRD) (55). It is important to note, however, that neither group was able to fully explain the mechanism by which inflammation leads to the development of SSD or SSRD, and the causal relationship between physical symptoms and the inflammatory process remains unclear, so it is possible that inflammation was a stress response caused by SSD or SSRD.

Given the suspected role of inflammation in SSD, it is relevant to examine the anti-inflammatory properties of antidepressants, particularly VOR. Antidepressants are known to affect the HPA axis and inflammatory pathways. For instance, SSRIs have been shown to prevent increases in inflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and interferon-γ (56), as well as reduce quinolinic acid synthesis (57). Some SSRIs have also been shown to exert effects on the HPA axis (58), they have been shown to exert effects on this system. Furthermore, VOR has been found to promote anti-inflammation effects in macrophages (59), increase the anti-inflammatory cytokine IL-4 (56), and inhibit cyclooxygenase-1/2 (60), suggesting a stronger anti-inflammatory effect than SSRIs. Moreover, as a treatment for post-COVID-19 condition, VOR has shown significant cognitive improvement in patients with elevated CRP levels (61), which further supports VOR’s anti-inflammatory effects. These findings suggest that VOR’s anti-inflammatory properties might have contributed to the improvement observed in both cases.

In addition to its anti-inflammatory effects, VOR’s analgesic potential also warrants attention, especially considering the primary symptom in Case 2 was pain. Pain at the spinal level is generally suppressed through the descending inhibitory pathway. 5-HT3 antagonism acts on spinal-level analgesia, while 5-HT7 antagonism promotes pain. Additionally, VOR has a higher receptor affinity for 5-HT3 than for 5-HT7, suggesting that VOR may reduce “true” pain. There have also been reports of VOR’s effectiveness for various types of pain, including chronic pain (62) and neuropathic pain (63) associated with depression, and burning mouth syndrome (64). However, a previous study suggests that spinal 5-HT3 receptor expression increases under sub-chronic stress, leading to heightened physical pain, and that 5-HT3 antagonists can alleviate this “true” pain. Furthermore, as discussed in Section 4.1, psychological factors such as catastrophizing (26) and rumination, which is linked to OCD (29), are involved in somatosensory amplification (25, 27, 28). Serotonergic dysfunction has also been suggested to play a role in this amplification (65). These observations suggest that the boundary between psychological and “true” physical pain might be more ambiguous than expected, and 5-HT3 antagonism might be broadly effective for both psychological and “true” physical pain.

However, evidence supporting the relationship between inflammation and SSD is currently limited, and given the shifting location of pain, Case 2 is more likely associated with psychiatric symptoms than with ‘true’ physical pain. Further research is needed to explore the impact of inflammation and pain mechanisms in SSD.

We used the Japanese version of PHQ-15 (9) to assess the somatic symptoms of the cases, because no other suitable scale is available in Japan. Although the PHQ-15 scores were relatively low (2 points for Case 1 and 8 points for Case 2), the patients experienced significant distress. This may be because the PHQ-15, commonly used to assess SSD, quantifies the number of somatic symptoms and their severity on a scale of 0 to 2, making the score more sensitive to the number of somatic symptoms rather than their intensity. These cases highlight the need for the development of a Japanese version of tools like the SSD-12 (66), an SSD scale based on DSM-5 criteria B, which can evaluate the psychological symptoms of SSD (i.e. abnormal cognitive, affective, and behavioral state), irrespective of the number of somatic symptoms. Additionally, we did not administer psychological scales for anxiety and depression. Although the levels of anxiety and depression did not meet the DSM-5 diagnostic threshold, not using these scales prevented us from observing subclinical fluctuations in anxiety or depression. While we primarily focused on SSD core symptoms, especially obsessive-compulsive preoccupation and rumination, which are related to somatosensory amplification, it is possible that the observed improvement was mediated by effects on anxiety or depression. Future research should compare the temporal changes in psychological scales for anxiety and depression with those for core symptoms of SSD.

Additionally, in Case 2, VOR was chosen over SSRIs due to the patient’s concern about nausea, a common side effect of SSRIs, with the expectation that the antiemetic effect of the 5-HT3 antagonism (67) in VOR would alleviate this concern. However, no clinical evidence currently supports the notion that VOR induces less nausea compared to SSRIs (68, 69). In fact, the patient’s nausea worsened as a side effect of VOR. Therefore, in line with clinical evidence, no advantage of VOR in terms of reducing nausea as a side effect was observed in this case. Furthermore, the lack of direct comparison between VOR and SSRIs in Case 2 limits our ability to assess the superiority or specific benefits of VOR’s effects on 5-HT receptors over other treatments.

Moreover, this study has limitations inherent to the study design of case reports, along with specific factors related to the presented cases. First, the small sample size of only two cases limits the generalizability of our findings. For example, Case 1 involved an elderly patient whose main symptom was throat discomfort, whereas Case 2 involved a young adult whose main symptom was pain due to workplace stress. Additionally, in both cases, the types of physical symptoms were relatively limited. These factors may not represent the full spectrum of individuals with SSD. Second, potential biases such as selection bias, reporting bias, and observer bias may have influenced the results. The cases were not randomly selected, and both patients and clinicians might have had expectations that affected symptom reporting and assessment. Third, the absence of a control group and lack of randomization prevent us from establishing causality between VOR treatment and symptom improvement; without a control group receiving placebo or standard treatment, we cannot rule out the influence of placebo effects, natural fluctuations in symptom severity, or spontaneous remission. Although SSD is a chronic disorder, the follow-up period in our study was relatively short—4 months in Case 1 and 6 months in Case 2—which increases the possibility of confounding factors affecting the results. Given these limitations, future robust studies are needed, including randomized controlled trials with larger and more diverse sample sizes, appropriate control groups using placebo or SSRIs, and extended follow-up periods. Such studies would help address potential biases, account for placebo effects, and consider the influence of psychosocial factors, thereby providing more definitive conclusions about the role of VOR in managing SSD.