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be associated with a poor clinical course, increased Many years ago, Hopkinson [124] reported that the risk
disability, negative psychosocial impairment [117] and of depression in the first‑degree relatives of depressed
response to treatment as well as functional decline. [118‑121] subjects was greater (20%) in the EOD group compared
with the LOD group (8.3%) over 50 years of age. Similar
Recently, WM abnormalities detected using DTI have findings have been later reported by Schultz [125] and
also contributed to clarify the pathophysiological Post [126] supporting the hypothesis that genetic factors
mechanisms underlying suicidal behavior. Olvet may show greater effects in EOD compared to late‑onset
et al. [15] conducted a DTI study on 13 suicide attempters depression. More recently, these findings have been
with MDD, 39 unipolar depressed non‑attempters, replicated by Takahashi et al. [55] who suggested that
and 46 healthy participants and found that low FA early‑onset type may be more closely associated with
in the dorsomedial prefrontal cortex (DMPFC) was nonvascular factors such as genetic factors.
associated with a suicide attempt history. Similar
results have also been reported by Jollant et al. [122] in a Komaki et al. [127] also reported that WM lesions were
functional MRI study. They found reduced activation significantly correlated with age at initial onset
in the DMPFC of remitted MDD suicide attempters of depression (45.8 years) in 123 MDD subjects.
compared with subjects who did not attempt suicide. The authors also found that the rate of suicide in
those patients with lacunar infarction (17.9% of the
Lopez‑Larson et al. [16] reported that nineteen veterans total sample) was significantly higher than that in
with mild traumatic brain injury and a history of subjects with no abnormal findings or those with
suicidal behavior had greater FA measures in bilateral WMHs but no lacunar infarction, suggesting that the
thalamic radiations compared to forty veterans prognosis was worse in those with lacunar infarction
with mild traumatic brain injury without suicidal relative to the other two groups. Unfortunately, not
behavior and healthy controls. Among veterans with all studies found a relationship between subcortical
mild traumatic brain injury and a history of suicidal hyperintensities and age at onset in patients with
behavior, right thalamic volumes negatively correlated mood disorders. [128‑130]
with anxiety symptoms whereas total mean FA values
for the right anterior thalamic radiations positively There may be many possible causes underlying WM
correlated with impulsivity. lesions that can occur over time and may be quite
progressive or rather static. WM lesions may be also
Furthermore, a positive correlation between current detected in younger adults without typical cardio‑ and
suicidal ideation and FA was reported in the cingulate cerebro‑vascular risk factors and are occasionally
[17]
of 15 male veterans with traumatic brain injury and 17 associated with inflammatory/demyelinating
matched healthy controls. Interestingly, the authors diseases. [131] In this case, it has been suggested that
suggested the existence of a neurobiological vulnerability they are presumably genetically determined. Recently,
to suicidal risk related to WM microstructure. Sprooten et al. [132] suggested that WM integrity was
a reliable endophenotype for bipolar disorder with
Another DTI study [123] investigated the effect of important behavioral associations linked to the etiology
past suicide attempts in 63 patients with MDD (23 of this condition. Specifically, they reported widespread
with and 40 without a history of suicide attempts) WM integrity reductions in unaffected relatives of bipolar
and 46 healthy controls. The authors reported that patients and cyclothymic temperament. Although the
those with a history of suicide attempts had greater authors did not investigate patients with a history of
abnormalities in the left orbitofrontal cortex and suicide and they did not report implications related
thalamus when compared with those without suicide to suicide risk in the analyzed cohort, their study
attempts whereas reduced fiber projections through suggested that impaired WM integrity might be a
the ALIC to the left medial frontal cortex, orbitofrontal potential mechanism of genetic predisposition for bipolar
cortex and thalamus were found in both groups of disorder. Reduced fronto‑temporal and fronto‑thalamic
patients [Table 2]. WM integrity may represent a structural substrate of
mood instability in both healthy control subjects and
Further potential support (external validation) to the unaffected relatives at high genetic risk for bipolar
association between microstructural WM abnormalities disorder. Interestingly, cyclothymia resulted negatively
and suicidality in patients with MDD may be also associated with WM integrity of the internal capsules
provided by the earlier age at illness onset in some MDD bilaterally and left temporal lobe in both high‑risk subjects
patients with higher WM abnormalities as well as the and controls. The authors supported the assumption that
very well replicated finding of early‑onset suicidality WM abnormalities might have behavioral associations
in patients with mood disorders. [2] related to the symptomatology of the illness.

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