This is the first study investigating the presence of anxiety, depression and general distress using the HADS tool in a large series of CMT patients (n = 252). Even if the mean scores for CMT were similar to those of the control group and the normal Italian population , there was a significantly higher rate of CMT patients with depression and general distress as compared to controls.
Although the HADS scale has been previously used in other neuromuscular disorders, such as amyotrophic lateral sclerosis and Duchenne muscular dystrophy, showing the same prevalence of depression than other neuromuscular disorders and the general population [7, 8], it has never been used in large enough samples of CMT subjects. Indeed, only a few studies investigated the presence of depression in CMT, the majority using the BDI, and yield conflicting results [9,10,11,12, 20,21,22]. In a series of 73 CMT patients, the mean BDI score was normal (6.1, normal values 5–9) and the prevalence of current neuropsychiatric disorders (assessed with the Structured Clinical Interview for DSM-IV) was 11%, similar to patients with Duchenne muscular dystrophy and facioscapulohumeral dystrophy . In other studies, researchers administered the BDI to CMT patients in the context of larger analysis [10, 11] focussing on quality of life and found no relationship with clinical examination, but for a slight direct association between depression and referred paresthesias and hypoesthesia . The Minnesota Multiphasic Personality Inventory (MMPI) was within the normal range in a series of 23 CMT patients . Vinci and colleagues evaluated anxiety and depression with the Kellner’ symptoms questionnaire (KSQ) Italian validated version and found no difference between 53 CMT subjects and 53 controls . On the other hand, Ivanovic and colleagues observed that 29% of a series of 45 CMT1A patients had symptoms of depression according to the BDI, which were a cause of worse quality of life . Depression negatively affects quality of life in patients with hereditary neuropathies also according to Bjelica et al. .
Our results may partly explain these conflicting results. If we analyse the mean scores of the whole population we do not see any significant difference either with controls or with a national reference population (Table 1) . However, the percentage of patients with scores above the threshold for depression and general distress was significantly higher in the CMT group as compared to healthy controls collected among friends and unaffected relatives.
We then analysed factors correlating with neuropsychiatric disturbances and found that disease severity, as indicated by the CMTES, correlated with the presence of depression and general distress. Positive sensory symptoms were more frequent in anxious and distressed subjects. Overall, these data suggest that disease severity negatively affects mood and neuropsychiatric status. On the other hand, it is likely that anxious and distressed patients are more liable to perceive sensory disturbances including pain. Our results confirm the previous study by Padua and colleagues  in which a significant association between mood disorders and sensory symptoms was found. While in neurodegenerative disorders like Parkinson disease and Huntington’s chorea depression and general distress are symptoms of the disease itself, in CMT they are likely to be secondary to the consequences of the disease burden on patients’ life, which includes also limitations in mobility and employment. We observed no correlation with age and disease duration, suggesting that disease progression per se does not significantly affect the rate of depression and distress. It is possible that longitudinal studies may better detect a correlation with disease course, but we already know the remarkable adaptation to disability of many CMT patients as confirmed for instance by the absence of significant worsening in quality of life scales (e.g., Short-Form 36, SF36) over time [10, 26].
It is notable that a high percentage of CMT patients takes anxiolytics and/or antidepressant drugs, which again indicates that the neuropsychiatric disturbances lead many CMT patients to medical attention and to treatment. On the other hand, it is worrying that about one half of patients with depression and general distress receive no specific drug treatment at all, although we did not investigate whether psychological support was provided to them. In any case, this is a relevant finding and underlines the importance of assessing neuropsychiatric conditions in CMT patients and offering adequate treatment when needed.
Another impressive result of this study is the high percentage (70%) of patients making use of analgesic/anti-inflammatory drugs, with consumption at least twice a week in 17%. Indeed, pain is a frequent symptom in CMT, being reported by 23–85% of the patients  and may be skeletal-muscular or neuropathic in nature, or both. The effect of pain on mood in CMT is poorly investigated, but it is interesting to note that depressed and distressed patients reported more frequently positive sensory symptoms including pain and that consumption of analgesic/anti-inflammatory drugs was significantly higher in patients reporting such symptoms.
This study has some limitations. First, patients joining the registry and filling out the questionnaires may not fully represent the whole CMT population but those more liable to participate in investigations and followed at some of the tertiary centres. Second, we could not directly evaluate the patients with respect to neuropsychiatric disorders and we know that the HADS is insufficient to diagnose depression or anxiety disorders. However, we used higher cut-off values, those with the best sensibility/specificity ratio and positive predictive values, to rule out false positives . It is worth noting that the present study was conducted before the COVID-19 pandemic and was not affected by the psychological impact of the pandemic, which led to an increase in anxiety, depression, and feelings of distress in the entire population. A third issue is the limited number of healthy controls, recruited in seven of the nine centres in a 17–37% ratio with respect to patients; while we could compare the mean HADS values of CMT patients with the general Italian population, we could rely only on our control sample for comparing percentages of subjects with scores above threshold, as this information was not available for the Italian population . Further studies are needed to confirm our observation of higher rates of depressed and distressed subjects among CMT, but in any case, it is important to identify depressed/distressed patients and treat them appropriately.
In conclusion, our findings confirm that, although neuropsychiatric disorders in CMT have a frequency lower than other chronic neurological disorders such as Parkinson’s disease and multiple sclerosis, they are nonetheless an important issue that requires proper attention. CMT severity appears to be one of the determinants of depression and distress. Although depressed/distressed patients took drugs acting on anxiety and mood more frequently than controls, still one half of them is not treated. Taking care of psychological status must become part of the general assessment of CMT patients and, when needed, proper treatment administration may alleviate their disease burden.