White matter abnormalities: Insights into the pathophysiology of major affective disorders

Table 1 Salient publications of our research group about white matter hyperintensities in affective disorders

Ref.	Sample characteristics	Study type	Location of WMHs	Main findings	Limitations of the study	Conclusion
Serafini et al[5]	148 patients (77 men, 71 women) with BD-I having a mean age of 47.9 yr	Research article	Centrum semiovale (24.4%) and corona radiata (20.2%) regions, cortical and subcortical deep frontal (17.6%), parietal (15.1%), and temporal (8.4%) areas	A total of 73 subjects (49.3%) reported PWMHs and 59 (39.9%) had DWMHs. Overall, 41 (27.7%) subjects had both PWMHs and DWMHs. Patients with BD-I and lower insight for mania had significantly more PWMHs (54.6% vs 22.2%; P < 0.05), significantly higher scores on the HDRS17 (27.05 ± 6.54 vs 23.67 ± 8.64; t146 = -1.98; P < 0.05), and more frequent BHS score ≥ 9 (66.2% vs 38.9%; P < 0.05) when compared to those with higher insight for mania	All participants were inpatients (a potential confounder). The present study did not include a formal measure of insight. The effects of psychoactive medications on insight ratings and image processing were not analyzed	Patients with PWMHs were more likely to have impaired insight than those without. Different insight levels reflected different MRI findings
Serafini et al[19]	85 adult outpatients (16 men and 69 women) with CH and having a mean age of 50.1	Research article	Not specified	Above 40% of patients had PWMHs and almost 98% had DWMHs. Patients with PWMHs differed from those without periventricular lesions on depression severity (t 77.76 = 2.30; P < 0.05). Patients with PWMHs had lower CES-D scores (13.79 ± 7.51 vs 18.19 ± 9.68) than patients without PWMHs. Patients with more severe DWMHs were older (53.89 ± 13.26 vs 47.40 ± 11.91) and reported lower scores on the drive dimension (9.97 ± 2.86 vs 11.14 ± 2.52) than patients with mild lesions or without any deep lesion	Different mechanisms may be considered in the emergence of WMHs and it is possible that WMHs may represent only the ‘tip of the iceberg’ in terms of structural white matter lesions	Patients with PWMHs were 1.06 times more likely to have lower CES-D scores (P < 0.05) than patients without PWMHs. Patients with more severe DWMHs were 1.04 times more likely to be older (P < 0.05) than patients with mild or without any DWMHs
Serafini et al[16]	247 patients (118 men, 129 women) with major affective disorders, specifically 143 BD-I, 42 BD-II, and 62 with MDD	Research article	Centrum semiovale (24.4%) and corona radiata (20.2%) regions, cortical and subcortical deep frontal (17.6%), parietal (15.1%), and temporal (8.4%) areas	48% of patients had PWMHs (more than 15% had PWMHs of 2 or higher on the Fazekas modified scale), and 39% had DWMHs (more than 7% had DWMHs of 2 or higher on the Fazekas modified scale). Patients in the high dysthymic, cyclothymic, irritability, and anxiety group were more likely to have higher BHS ≥ 9 = 77% vs 52%; P > 0.001), more DWMHs (46% vs 29%; χ2n =3 = 9.90; P < 0.05), higher MINI suicidal risk (54% vs 42%; P < 0.05), and more recent suicide attempts (24% vs 14%; P < 0.05), than patients in the hyperthymia group	The small sample size did not allow to generalize findings. The association between the lethality or number of suicide attempts and the presence, severity, or number of hyperintensities was not assessed. The study lacks of accounting for the cognitive effects of medications	Differences among temperament groups as measured by the TEMPS-A are supported by differences at the MRI indicating that different temperament profiles are associated with differences in subcortical brain structures
Serafini et al[20]	A 76-year-old woman with BD hospitalized for a mixed state	Case report with a 2-yr follow-up	Not specified	Patient had severe WMHs, she took lithium and haloperidol during the hospitalization. She was euthymic at discharge as well as after two-years of follow-up. Her nutrition had a high concentration of Vitamin-D	A second MRI was not performed	Although WM lesions were persistent, the patient improved in both mood and quality of life. Lithium and Vitamin-D may have exerted possible protective effects
Serafini et al[18]	54 patients (30 men and 24 women) with LOBD (≥ 60 yr old) having a mean age of 68 yr. 76% had a diagnosis of BD-I, and 24% had a diagnosis of BD-II	Letter to the Editor including research data	Centrum semiovale (22%), corona radiata (15%), paratrigonal regions (6%), cortical, subcortical deep frontal (46%), parietal (24%) areas	Confluence of DWMH lesions were found in 17% of the patients (modified Fazekas scale ≥ 2) whereas in 28% PWMH confluent lesions (modified Fazekas scale ≥ 2) were reported. No significant association resulted between diagnosis and PWMHs or DWMHs. BD-II with DWMHs had a poorer quality of life than BD-I subjects	The link between clinical features of bipolar disorders and deep brain lesions on MRI remains quite unknown	MRI findings of DWMHs could be a useful biological predictor of severity in patients with BD-II
Pompili et al[17]	47 LOBD patients (55.3% men and 44.7% women)	Review article including research data	Frontal (26.1) and centrum semiovale areas (26.1%), corona radiata (17.4%), parietal (17.4%), and paratrigonal regions (8.7%)	55.3% of these patients had periventricular WMHs, 46.4% had WMHs of mild severity, 50% WMHs of moderate severity, and only 3.6 WMHs of high severity. 34% of LOBD patients had both deep and periventricular WMHs. A significant relationship between older age with LOBD and WMHs was reported	Vascular-related mechanisms cannot be the only factors implicated in the pathophysiology of the WMHs in LOBD subjects. The study did not assess how cerebro-vascular risk factors are related to the type /intensity of medications, and the progression of WMHs	MRI findings of WMHs could be a useful biological predictor of severity in patients with LOBD
Pompili et al[15]	99 patients having a mean age of 46.5 yr. 40.4% were diagnosed as BD-I, 21.2% as BD-II, and 38.4% as unipolar MDD	Research article	Corona radiate (n = 10), centrum semiovale (n = 6), and frontal subcortical white matter (n = 18)	It has been suggested that 27.3% of patients showed evidence of PWMHs and 36.4% of DWMHs whereas 14.1% of patients had hyperintensities in both locations. The presence of PWMHs was the only variable significantly associated with attempted suicide even after controlling for age. Subjects with PWMHs were 8 times more likely to have attempted suicide than individuals without PWMHs [OR = 8.08 (95%CI: 2.67-24.51)]	The small sample size may affect the generalization of results. PWMHs were able to explain only a small part of the variability of suicide attempt risk, indicating that one single variable is not sufficient to predict suicidality	Patients with affective disorders and PWMHs are more likely to have a history of suicide attempts even after controlling for potential confounding variables such as cardiovascular risk factors and age
Pompili et al[12]	65 subjects, 29 (44.6%) with a history of at least one suicide attempt, and 36 (65.4%) without. Subjects had a mean age of 44.61 yr	Research article	Not specified	After logistic regression analyses, the prevalence of WMHs was significantly higher in subjects with past suicide attempts (P = 0.01) and other clinical indicators of elevated suicide risk	The association between WMHs and suicidality holds true for both unipolar and bipolar depressed patients	WMHs in patients with major affective disorders might be useful biological markers of suicidality

AD: Affective disorders; BD-I: Bipolar disorder type I; BD-II: Bipolar disorder type II; BHS: Beck Hopelessness Scale; CES-D: Center for Epidemiologic Studies Depression Scale; CH: Chronic headache; DWMHs: Deep WMHs; LO: Late-onset; LOBD: Late-onset bipolar disorder; Mini: Mini International Neuropsychiatric Interview; MDD: Major depressive disorder; MRI: Magnetic resonance imaging; PWMHs: Periventricular WMHs; SA: Suicide attempts; WMHs: White matter hyperintensities; TEMPS-A: Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire. WMHs that usually appear as hyperintense signals on T2-weighted MRI, are characterized by ependymal loss and differing degrees of myelination and can be related to several clinical conditions such as major depressive disorders (BDI, BDII, MDD), and CH. The mentioned Table reported the most relevant publications of our research group about WMHs and their significance in major affective disorders.