Heikki Rytsälä

Major depressive disorder and white matter abnormalities: A diffusion tensor imaging study with tract-based spatial statistics

BACKGROUND A few diffusion tensor imaging (DTI) studies have shown abnormalities in areas of white matter tracts involved in mood regulation in geriatric depressive patients, using a region-of-interest technique. A voxel-based morphometry DTI study of young depressive patients reported similar results. In this study, we explored the structure of the white matter of the whole brain with DTI in middle-aged major depressive disorder (MDD) patients, using novel tract-based spatial statistics. METHODS Sixteen MDD patients and 20 controls underwent DTI. An automated tract-based spatial method (TBSS) was used to analyze the scans. RESULTS Compared with controls, the MDD patients showed a trend for lower values of fractional anisotropy (FA) in the left sagittal stratum, and suggestive decreased FA in the right cingulate cortex and posterior body of corpus callosum. Regressing out the duration and severity of disorder in the model did not change the finding in the sagittal stratum, but dissipated the decrease of FA in latter regions. LIMITATIONS Possibly by reason of a relatively small study sample for a TBSS, the results are suggestive, and should be replicated in further studies. CONCLUSIONS A novel observer-independent DTI method showed decreased FA in the middle-aged MDD patients in white matter regions that have previously connected to the emotional regulation. Lower FA might imply underlying structural abnormalities that contribute to the dysfunction detected in the limbic-cortical network of depressive patients.

Breakdown of Long-Range Temporal Correlations in Theta Oscillations in Patients with Major Depressive Disorder

Neuroimaging has revealed robust large-scale patterns of high neuronal activity in the human brain in the classical eyes-closed wakeful rest condition, pointing to the presence of a baseline of sustained endogenous processing in the absence of stimulus-driven neuronal activity. This baseline state has been shown to differ in major depressive disorder. More recently, several studies have documented that despite having a complex temporal structure, baseline oscillatory activity is characterized by persistent autocorrelations for tens of seconds that are highly replicable within and across subjects. The functional significance of these long-range temporal correlations has remained unknown. We recorded neuromagnetic activity in patients with a major depressive disorder and in healthy control subjects during eyes-closed wakeful rest and quantified the long-range temporal correlations in the amplitude fluctuations of different frequency bands. We found that temporal correlations in the theta-frequency band (3-7 Hz) were almost absent in the 5-100 s time range in the patients but prominent in the control subjects. The magnitude of temporal correlations over the left temporocentral region predicted the severity of depression in the patients. These data indicate that long-range temporal correlations in theta oscillations are a salient characteristic of the healthy human brain and may have diagnostic potential in psychiatric disorders. We propose a link between the abnormal temporal structure of theta oscillations in the depressive patients and the systems-level impairments of limbic-cortical networks that have been identified in recent anatomical and functional studies of patients with major depressive disorder.

Impaired Functional Connectivity at EEG Alpha and Theta Frequency Bands in Major Depression

Recent reports on functional brain imaging in major depression have lead to an assumption that observed psychopathology might be related to an altered brain functional connectivity. Our hypothesis was that an increase in brain functional connectivity occurs in major depression. As a measure of functional connectivity, the electroencephalogram (EEG) structural synchrony approach was used in 12 medication‐free depressive outpatients and 10 control subjects. Differences in the number and strength of structurally synchronized EEG patterns were compared between groups. In depressive patients the number and strength of short cortex functional connections were significantly larger for the left than for the right hemisphere, while the number and strength of long functional connections were significantly larger for the right than for the left hemisphere. Some of the functional connections were positively correlated with the severity of depression, thus being predictive. These were short‐range anterior, posterior, and left hemisphere functional connections for the alpha frequency band and short‐range anterior functional connections for the theta frequency band. The topology of the most representative functional connections among all patients with major depression indicated that the right anterior and left posterior brain parts may discriminate depressive patients from healthy controls. The obtained data support our hypothesis that there is an increase in brain functional connectivity in major depression. This finding was interpreted within the semantic framework, where different specialization of left (monosemantic context) and right (polysemantic context) hemispheres is functionally insufficient in patients with depression. Hum Brain Mapp, 2007.

The influence of adversity and perceived social support on the outcome of major depressive disorder in subjects with different levels of depressive symptoms.

BACKGROUND Adverse life events and social support may influence the outcome of major depressive disorder (MDD). We hypothesized that outcome would depend on the level of depressive symptoms present at the outset, with those in partial remission being particularly vulnerable. METHOD In the Vantaa Depression Study (VDS), patients with DSM-IV MDD were interviewed at baseline, and at 6 and 18 months. Life events were investigated with the Interview for Recent Life Events (IRLE) and social support with the Interview Measure of Social Relationships (IMSR) and the Perceived Social Support Scale - Revised (PSSS-R). The patients were divided into three subgroups at 6 months, those in full remission (n = 68), partial remission (n = 75) or major depressive episode (MDE) (n = 50). The influence of social support and negative life events during the next 12 months on the level of depressive symptoms, measured by the Hamilton Rating Scale for Depression (HAMD), was investigated at endpoint. RESULTS The severity of life events and perceived social support influenced the outcome of depression overall, even after adjusting for baseline level of depression and neuroticism. In the full remission subgroup, both severity of life events and subjective social support significantly predicted outcome. However, in the partial remission group, only the severity of events, and in the MDE group, the level of social support were significant predictors. CONCLUSIONS Adverse life events and/or poor perceived social support influence the medium-term outcome of all psychiatric patients with MDD. These factors appear to have the strongest predictive value in the subgroup of patients currently in full remission.

Functional and work disability in major depressive disorder

We examined factors related to social and occupational disability, social adjustment, and work disability among patients with major depressive disorder (MDD), the dominant mental disorder causing functional and work disability. The Vantaa Depression Study comprises a cohort of 269 psychiatric inpatients and outpatients with MDD in the city of Vantaa, Finland. Axis I and II diagnoses were assessed via semistructured WHO Schedules for Clinical Assessment in Neuropsychiatry Version 2.0 and Structured Clinical Interview for DSM-III-R personality disorders interviews. Global disability, social and work adjustment, and being at work or on sick leave were assessed. The most important factors associated with level of social, functional, and work disability were severity and recurrence of depression, but older age and current Axis I and II comorbidity also significantly contributed. Of those employed, almost half (43%) were on sick leave. The most pervasive factors explaining level of functional and work disability among patients with MDD were severity and recurrence of depression. However, older age and comorbidity also contributed.

Composition of brain oscillations in ongoing EEG during major depression disorder.

In the present study, we examined the composition of electroencephalographic (EEG) brain oscillations in 12 unmedicated major depressive outpatients and 10 healthy subjects during resting conditions (closed eyes). The exact composition of brain oscillations was assessed by the probability-classification analysis of short-term EEG spectral patterns. In contrast to previous studies of depression, the current study found that major depression affects brain activity in nearly the whole cortex and manifests itself in considerable reorganization of the composition of brain oscillations in a broad frequency range: 0.5-30 Hz. At the same time, the magnitude of the effect of depression was maximal in the posterior cortex of the brain. Interhemisphere asymmetry during major depression was also observed in the whole cortex with right hyperactivity in frontal, parietal and occipital brain areas. It is suggested that depressive brain is manifested in the superposition of distributed multiple oscillations. Our findings provide new insight on the relationship between major depressive disorder and cortical oscillatory activity.

P2RX7 gene is associated consistently with mood disorders and predicts clinical outcome in three clinical cohorts

We investigated the effect of nine candidate genes on risk for mood disorders, hypothesizing that predisposing gene variants not only elevate the risk for mood disorders but also result in clinically significant differences in the clinical course of mood disorders. We genotyped 178 DSM‐IV bipolar I and II and 272 major depressive disorder patients from three independent clinical cohorts carefully diagnosed with semistructured interviews and prospectively followed up with life charts for a median of 60 (range 6–83) months. Healthy control subjects (n = 1322) were obtained from the population‐based national Health 2000 Study. We analyzed 62 genotyped variants within the selected genes (BDNF, NTRK2, SLC6A4, TPH2, P2RX7, DAOA, COMT, DISC1, and MAOA) against the presence of mood disorder, and in post‐hoc analyses, specifically against bipolar disorder or major depressive disorder. Estimates for time ill were based on life charts. The P2RX7 gene variants rs208294 and rs2230912 significantly elevated the risk for a familial mood disorder (OR = 1.35, P = 0.0013, permuted P = 0.06, and OR = 1.44, P = 0.0031, permuted P = 0.17, respectively). The results were consistent in all three cohorts. The same risk alleles predicted more time ill in all cohorts (OR 1.3, 95% CI 1.1–1.6, P = 0.0069 and OR 1.7, 95% CI 1.3–2.3, P = 0.0002 with rs208294 and rs2230912, respectively), so that homozygous carriers spent 12 and 24% more time ill. P2RX7 and its risk alleles predisposed to mood disorders consistently in three independent clinical cohorts. The same risk alleles resulted in clinically significant differences in outcome of patients with major depressive and bipolar disorder.

Predictors of long‐term work disability in Major Depressive Disorder: a prospective study

Objective:  Major Depressive Disorder (MDD) is a major cause of long‐term work disability. However, factors predicting this are not well known.

Life events, social support, and onset of major depressive episode in Finnish patients

We investigated differences in life events and social support between subgroups of depressed patients and the distribution of life events in phases preceding or during depression. In the Vantaa Depression Study, 269 psychiatric patients with DSM-IV major depressive disorder were diagnosed with Schedule for Clinical Assessment in Neuropsychiatry, Version 2.0, and Structured Clinical Interview for DSM-III-R personality disorders (SCID-II). Life events during the 12 months preceding the interview were investigated with the Interview for Recent Life Events, and social support with the Interview Measure of Social Relationships and the Perceived Social Support Scale—Revised. Nearly all patients (91%) reported life events, on average 4.1 per preceding year. No major differences between sociodemographic or clinical subgroups were found; the frequency of events was somewhat greater among the younger subjects, whereas those with comorbid alcoholism or personality disorders perceived less social support. Although events were distributed evenly between the time preceding depression, the prodromal phase, and the index major depressive episode, two thirds of the patients attributed their depression to some event. Despite clinical and sociodemographic heterogeneity, patients with major depressive disorder are fairly homogeneous in terms of life events during the preceding year. Events do not cluster in any particular phase of the progression to an episode.

Co-morbidity and stability of melancholic features in DSM-IV major depressive disorder

BACKGROUND The descriptive validity of the melancholic features specifier of the DSM-IV major depressive disorder (MDD) is uncertain. Little is known about its relationship to psychiatric co-morbidity, stability across episodes, or strength in predicting course of illness. METHOD The Vantaa Depression Study (VDS) is a prospective, naturalistic cohort study of 269 patients with a new episode of DSM-IV MDD who were interviewed with SCAN and SCID-II between 1 February 1997 and 31 May 1998, and again at 6 and 18 months. Ninety-seven (36%) MDD patients met DSM-IV criteria for the melancholic features specifier, and were contrasted with 172 (64 %) subjects with a non-melancholic MDD. The duration of the index episode was examined using a life chart. RESULTS We found no difference in rates of any current co-morbid Axis I or II disorders between melancholic and non-melancholic depressed patients. Of those who had melancholic features at the index episode and subsequent episodes during the 18-month follow-up, only 22 % (5/23) presented melancholic features during the latter. The non-melancholic subtype switched to melancholic in 25 % (8/32) of cases. Differences in the course of melancholic and non-melancholic depression were very minor. CONCLUSIONS The descriptive validity of the DSM-IV melancholic features specifier may be questionable in MDD. There appear to be no major differences in current co-morbidity, or course of depression between melancholic and non-melancholic patients. The consistency of DSM-IV melancholic features across episodes appears weak.